V. Intravenous immunoglobulin as a preventive strategy against BK virus viremia and BKV-associated nephropathy in kidney transplant recipients—Results from a proof-of-concept study
Intravenous immunoglobulin (IVIg) administration has been empirically
proposed as a preemptive and supportive treatment against
BKV infections. However, the available studies in the field should be
interpreted cautiously because of major methodological limitations
– including small sample sizes, the lack of a control arm, and the concomitant use of other antiviral strategies and/or a parallel reduction
of immunosuppression.
This is a retrospectively review of the clinical records of adult patients
who underwent KT in the Strasbourg University Hospital between
July 2012 and December 2017. All cases with available neutralizing antibodies ( Nab) titers measured on day 0 were choosen.
Exclusion criteria : were patient or graft survival lower than 3 months . A 20 patients with NAb titers below 4 log10 IC50 against the donor’s strain (which was determined by measuring NAb titers in the donor’s sera) were considered at high-risk. When the donor’s specimen was unavailable, the replicating strain was considered as reference for patients showing an active BKV replication.
Based on NAb titers on day 0 and the prescription of IVIg infusion
The patients were divided into 3 risk categories for BKV replication:
(1) patients with low Nab titers (“high-risk patients”) who received IVIg treatment for secondary immunodeficiency (SID) or for prevention or treatment of antibody-mediated rejection (AMR) during the first 3 posttransplant months and before BKV replication .
(2) patients with low NAb titers (“high-risk patients”) who did not undergo IVIg treatment during the first year of KT .
(3) patients with high NAb titers (“low-risk patients”) who did not receive IVIg .
The patients received the following commercial IVIg preparations:
Privigen®, 100 mg/mL (CSL Behring GmbH, Marburg, Germany);
Octagam®, 100 mg/mL (Octapharma, Langenfeld, Germany); Clairyg®,
50 mg/mL (LFB-Biomédicaments, Courtaboeuf, France); and Kiovig®,
100 mg/mL (Baxter, Deerfield, IL). IVIg were infused either as a preventive or curative treatment of AMR or in patients diagnosed with
SID. Patients received 0.4 g/kg IVIg doses every 3 weeks – with a total
number of doses ranging from 1 to 3 – according to their IgG levels.
Patients with de novo DSA, preformed DSA, or biopsy-proven AMR
were treated with three 2 g/kg doses of IVIg every 3 weeks.
The results:
– First, IVIg were found to increase NAb titers against BKV genotype I (ie, the largely predominant genotype) over the protective threshold of 4 log10 IC50.
-Second, passive immunization with IVIg in the early posttransplant
phase was associated with a significantly lower incidence of both
BKV viremia and BKVAN in high-risk KTR.
Other uses of IVIg ; humeral rejection, plasmapheresis, TMA, some types of anemia
This article is concerning BK virus and IVIG being treated as a preventive therapy for the infection. BKV linked nephropathy in renal recipients has also been discussed, keeping iVIG in mind.
BKV is a polyomavirus that can recur in transplant recipients frequently, and that can often lead to a fatal outcome. Sepsis and death are possible outcomes if the infection is not detected early and then treated aggressively. The theme of this article is directed towards a preventive approach in order give a better outcome following solid organ transplantation.
Discussion
The authors of this article have tried to assess whether IVIG as a preventive approach can decrease BKV and BKVAN incidence, especially in high risk cases of organ transplant.
The patients involved in the study have been given induction with basiliximab. Other immunosuppressive drugs that have been administered to these patients include cyclosporine or tacrolimus, MMF and steroids. Some patients were given everolimus.
The NAb titres (BKV genotype) were assessed in these patients and were found to be increased in those who were administered IVIG. There was also a decreased incidence of BKV viremia and BKVAN int these patients.
Conclusion
BKV and BKVAN are extremely problematic since they can frequently recur in patients and cause fatal complications such as sepsis. Early detection and aggressive treatment is vital, including monitoring for recurrence. Since the infection also has an asymptomatic phase it can be difficult to find out when it infects the patient. Focussing on prevention is a good approach, and this article finds that administration of IVIG in the early posttransplant period has a good effect in decreasing the incidence of BKV and BKVAN in kidney transplant patients, especially high risk cases.
Other uses of IVIG in transplant
CMV prevention and treatment
Desensitization in high risk cases, patients appearing for retransplant, older recipient, infected donor
Summary: The study evaluated the clinical data of adult Strasbourg University Hospital renal transplanted patients from July 2012 to December 2017. All day 0 NAb titers were eligible. –BKV PCR at day 0, every month in the first 6 months, and every 3 months in the first year.
-The fact that BKV replication occurs early after renal transplantation, -IVIG was evaluated as a preventative measure in the first three months. -After 1 year the high-risk group treated with IVIG showed 6.8% BKV viremia, equal to the low-risk group (10.1%) and much lower than the untreated high-risk group.
-The study showed that BKV neutralizing antibodies decreases BKV replication.
INTRODUCTION BKV infections are still a major concern following kidney transplantation with BKV replication occurring in 30%-50% of all kidney transplant recipients. BKVAN can affect up to 10% of BKV-infected KTR, potentially leading to kidney dysfunction and graft loss. Aim of the Study: To investigate whether the preventive administration of IVIg may reduce the incidence of BKV viremia and BKVAN in high-risk KTR. Risk stratification was based on NAb titers against the donor’s BKV strain measured on day 0. PATIENTS AND METHODS: Study patients: retrospectively the clinical records of adult patients (N=174),who underwent KT in the Strasbourg University Hospital between July 2012 and December 2017. All cases with available NAb titers measured on day 0 were deemed eligible. patients with NAb titers below 4 log10 IC50 against the donor’s strain (which was determined by measuring NAb titers in the donor’s sera) were considered at high-risk. Patient divided into 3 risk categories for BKV replication: (1) patients with low NAb titers (“high-risk patients”) who received IVIg treatment for secondary immunodeficiency or for prevention or treatment of antibody-mediated rejection, during the first 3 post-transplant months and before BKV replication (n = 44), (2) Patients with low NAb titers (“high-risk patients”) who did not undergo IVIg treatment during the first year of KT (n = 41), (3) Patients with high NAb titers (“low-risk patients”) who did not receive IVIg (n = 89). immunosuppressive regimens induction therapy with basiliximab or thymoglobulin . maintenance phase: the patient received CNI (ciclosporin or tacrolimus) in association with mycophenolate mofetil (MMF) or a mammalian target of rapamycin (mTOR) inhibitor (everolimus) and steroids. Monitoring of BKV infections day 0, every month in the first 6 post transplant months, and every 3 months thereafter (until 1 year following KT). assay NAb titers were measured : at day 0; at the third, sixth, and 12th posttransplant months; and at the onset of viremia. Additional measurements at the first and second post transplant months were performed in patients who received IVIg infusions. A neutralization titer of 2.5 log10 IC50 was set as the threshold for quantification of antibody-mediated neutralization. IVIg therapy Patients received IVIg were infused either as a preventive or curative treatment of AMR or in patients diagnosed with SID. Patients received 0.4 g/kg IVIg doses every 3 weeks – with a total number of doses ranging from 1 to 3 – according to their IgG levels. Patients with de novo DSA, preformed DSA, or biopsy-proven AMR were treated with three 2 g/kg doses of IVIg every 3 week. RESULTS: Donor NAb titers at D0 did not differ significantly between the 3 patient groups. IVIg administration increases BKV NAb titers in KTR Among the 44 high-risk patients who were treated with IVIg, we identified 35 (79.5%), 7 (15.9%), and 2 (4.5%) cases in whom there was a high risk of replication for BKV genotype I, genotype II, and genotype IV, respectively. A total of 41 patients (93.2%) received IVIg infusion at a dose of 0.4 g/kg because of SID. Of them, 28 cases (63.6%) received 3 doses. The remaining 12 (27.3%) and 1 (2.3%) patients received 2 and 1 doses, respectively. Three (6.8%) patients received 3 IVIg infusions at a dose of 2 g/kg because of preventive or curative treatment of AMR, with IVIg being administered during the first 3 post transplant months. The temporal course of BKV NAb titers was studied only in patients who received IVIg in the absence of BKV viremia (n = 41). This approach allowed investigating the impact of IVIg when immune system stimulation was lacking (owing to the increased BKV NAb titers observed in KTR with BKV viremia). At day 0, the mean BKV NAb titer was 3.06 (0.56) log10 IC50. Before the first IVIg injection, BKV NAb titers remained below 4 log10 IC50 in all patients (mean: 3.07 [0.56] log10 IC50). At 1 post transplant month, when the majority of patients (93%) had already received the first IVIg injection, the mean NAb titers significantly increased to 3.82 (0.61) log10 IC50 and remained at these levels for the subsequent 2 months (P < .001). A decrease in NAb titers occurred afterwards, with a return to the initial levels between 6 and 12 post transplant months. IVIg administration decreases the incidence of both BKV viremia and BKVAN in KTR.
DISCUSSION There are 2 principal findings from this study. First, IVIg were found to increase NAb titers against BKV genotype I (ie, the largely predominant genotype) over the protective threshold of 4 log10 IC50. Second, passive immunization with IVIg in the early posttransplant phase was associated with a significantly lower incidence of both BKV viremia and BKVAN in high-risk KTR. The current study is the first to demonstrate that IVIg infusion may be a valuable strategy for preventing BKV replication in kt. Strength including an accurate risk stratification for BKV replication based on the quantification of NAb titers against the 3 most common BKV genotypes and a high availability of donors’ samples .limitation: Its retrospective design, the relatively small number of patients who received IVIg infusions, and the use of different IVIg doses and administration schedule.
What are the other uses of IVIG in transplantation?
Introduction:
BK Virus infection affects patients especially post kidney transplantation up to 30-50% with 10 % having nephropathy reported with possibility of graft dysfunction and loss.
We don’t have any specific treatment with exception of RIS and monitoring BKV PCR and graft function.
IV immunoglobulin is a possible additional treatment against BK Virus.
High levels of BK antibodies might be protective as low antibodies levels have been linked to increased BK infection and vice versa Patients and methods:
Retrospectively nonrandomized study of adult patients who underwent KT between 2012 and 2017. Exclusion criteria include:
A. patient or graft survival lower than 3 m
B. NAb titers below 10^4
C. IC50 against the donor’s strain
D. Low-risk patients who received IVIg during the first posttransplant year
Genotype I was taken as reference for patients with a negative BKV DNA load.
Patients were divided into 3 risk categories for BKV replication. Immunosuppressive regimens:
Immunosuppressive therapy after KT consisted of:
Induction therapy with basiliximab or thymoglobulin based on the recipient’s immunological risk. Patients with a panel reactive antibody (PRA) >20% and a history of ABO-incompatible kidney transplantation were treated by thymoglobulin.
Maintenance phase: calcineurin inhibitor (ciclosporin or tacrolimus) in association with mycophenolate mofetil (MMF) or a mammalian target of rapamycin (mTOR) inhibitor (everolimus) and steroids.
Monitoring of BKV infections:
BKV quantitative PCR was done at day 0, monthly for the first 6 months then 3-monthly until 1 year following kidney transplantation.
graft biopsy was performed in case of graft dysfunction, sustained BKV viremia (i.e., presence of 4 log 10 copies/mL in 2 subsequent blood specimens), detection of DSA. Neutralization assay:
NAb titers were measured at day 0; 3rd, 6th and 12th month posttransplant and at the onset of viremia.
Additional NAb titers were done at the 1st and 2nd months post-transplant for patients who had received IVIG infusions. IVIG therapy:
IVIG was infused as preventive or a curative treatment for ABMR or in patients with secondary immunodeficiency.
IVIG can increase NAb titers.
depending on the IgG levels, patients received 0.4g/kg IVI doses every 3 weeks with the total number of doses ranging from 1 to 3.
patients with DSAs (de novo or preformed) or biopsy-proven AMR were treated with three 2g/kg doses of IVIG every 3 weeks. Results:
At 12 posttransplant months:
The incidence of BKV viremia in the high-risk group treated with IVIg (6.8%, 3 of 44 patients) was similar to that observed in the low-risk group (10.1%, 9 of 88 patients), but significantly lower than the untreated high-risk group (36.6%; 15 of 41 patients; P < .001).
Similar figures were observed with regard to the incidence of BKVAN at 12 posttransplant months (4.5% [2 cases] in the high-risk group treated with IVIg, 2.2% [2 cases] in the low-risk group, and 19.5% [8 cases] in untreated high-risk patients; (P = .001). Discussion:
IVIg were found to increase NAb titers against BKV genotype I (ie, the largely predominant genotype) over the protective threshold of 4 log10.
Passive immunization with IVIg in the early posttransplant phase was associated with a significantly lower incidence of both BKV viremia and BKVAN in high-risk KTR. Strength of the study: Accurate risk stratification for BKV replication based on the quantification of NAb titers against the 3 most common BKV (I,II, and IV) genotypes and a high availability of donors’ samples. Limitations of the study:
Retrospective study, small sample size, and different immunosuppressive protocol, not specified. Conclusion:
IVIg administration is capable of preventing BKV viremia and BKVAN in KTR with low NAb titers.
Multicenter controlled randomized study is needed. What are the other uses of IVIG in transplantation?
1) Desensitization protocol.
2) Treatment of AMR.
3) Prevention and treatment of infections: CMV, BKV nephropathy, and parvovirus B19 infection
In this study author retrospectively reviewed the clinical records of adult patients who underwent KT in the Strasbourg University Hospital between July 2012 and December 2017. All cases with available NAb titers measured on day 0 were deemed eligible.Based on NAb titers on day 0 and the prescription of IVIg infusion, the study patients (n = 174) were divided into the following 3 risk categories for BKV replication: (1) patients with low NAb titers (“high-risk patients”) who received IVIg treatment for secondary immunodeficiency (SID) or for prevention or treatment of antibody-mediated rejection (AMR) during the first 3 posttransplant months and before BKV replication (n = 44), (2) patients with low NAb titers (“high-risk patients”) who did not undergo IVIg treatment during the first year of KT (n = 41), and (3) patients with high NAb titers (“low-risk patients”) who did not receive IVIg (n = 89). Secondary immunodeficiency was defined either as (1) IgG levels <400 mg/dL or (2) IgG levels between 400 and 800 mg/dL in the presence of a concurrent infection. Low-risk patients who received IVIg during the first posttransplant year were not included in the study (n = 65)
Monitoring of BKV infections–Blood samples for assessing BKV viremia were collected at the following time points: day 0, every month in the first 6 posttransplant months, and every 3 months thereafter (until 1 year following KT). Neutralization assay-NAb titers were measured at day 0; at the third, sixth, and 12th posttransplant months; and at the onset of viremia. IVIG– Patients received 0.4 g/kg IVIg doses every 3 weeks – with a total number of doses ranging from 1 to 3 – according to their IgG levels. Patients with de novo DSA, preformed DSA, or biopsy-proven AMR were treated with three 2 g/kg doses of IVIg every 3 weeks.
Results- IVIg administration increases BKV NAb titers in KTR.. At 12 posttransplant months, the incidence of BKV viremia in the high-risk group treated with IVIg (6.8%) was similar to that observed in the low-risk group (10.1%) and markedly lower than that of the untreated high-risk group (36.6%; P < .001). Similar results were observed with regard to BKVAN. IVIg may be a valuable strategy for preventing BKV replication
Other uses of IVIG in transplantation-
Desenitization protocol,
Treatment of AMR, severe hypogammaglobulinemia (ie, immunoglobulin G [IgG] <400 mg/dL).
IVIG as a preventive strategy against the BK virus Introduction; BKVAN can affect up to 10% of BKV-infected KTR. BKVAN is associated with a potential risk of graft dysfunction and loss. Till today the available strategy for BKV treatment includes; IS reduction, with a regular screening of BKV viremia and viruria. This strategy is associated with an increased risk of DSA and rejection. IVIG
IVIG was found to increase NAb titers against the BKV genotype.
Passive immunization with IVIg in the early post-transplantation was associated with a significantly lower incidence of both BKV viremia and BKVAN in high-risk KTR.
IVIg early post-transplantation protects against BKV replication.
IVIG AS POSSSIBLE METHOD FOR BKV INFECTION AND NEPHROPATHY IN KTR -RESULTS FROM A PROOF OF CONCEPT STUDY:
INTRODUCTION:
-BK Virus infection affects pts esp post kidney transplantation upt 30-50% with 10 % having nephropathy reported with possibility of graft dysfunction and loss.
-We don’t have any specific tx with exception of RIS and monitoring BKV PCR and graft function.
-IV immunoglobulin is a possible additional tx against BK Virus.
-High levels of BK antibodies might be protective as low antibodies levels have been linked to increased BK infection and vice versa.
METHODS:
STUDY PTS;
568 KTR,297 excluded due to deficiency of antibodies,4 not included due to graft loss in 1st 3/12 post transplant and 2 mortalities in 1st 3/12 post transplant.
Inclusion criteria – All cases with antibodies on day 0.
Exclusion criteria – Graft loss or mortality within 3/12.
Definition – High risk pts were those with antibodies <4 log 10 IC50 against donor type.271 pts with D & R antibody titers were included,113 were high risk while 154 were low risk.
2.IMMUNOSUPPRESION.
Induction -Basiliximab /thymoglobulin subject to pt’s risk status.
Maintenance – CNI +MMF /MTOR + Steroids.
3.BKV MONITORING.
BKV PCR ‘; day 0, monthly -6/12 then every 3/12 in the 1st year post transplant.
Graft biopsy indications -Graft dysfunction and persistent viremia.
4.NEUTRALIZING ASSAY.
.Antibody levels were measured on day 0,3/12.6/12 and 12/12 post transplant and at the start of detection of BK virus in blood.
Further antibody levels ; 1st and 2nd month post transplant in those who got IV immunoglobulin.
5.IV IMMUNOGLOBULIN THERAPY.
This was given to those with secondary immunodeficiencies to help boost antibody levels.
Those with DSA or AMR were tx with x3 2g/kg doses every 3/52.
RESULTS:
-Classes ;
Low antibody levels/hgh risk group – n-44 -Got IV immunoglobulin for 1st 3/12 post transplant.
Low antibody -n -41- not given immunoglobulin.
High antibody/low risk group -n-89-did not get IV immunoglobulin.
-IV immunoglobulin increases BKV antibody levels post transplant;
IV immunoglobulin boosted antibody levels and they remained elevated for 3/12 and then reverted to pre transplanted levels 6/12-12/12 after sx.
-IV immunoglobulin reduces BKV infection and nephropathy post transplant;
1yr post transplant ,BKV infection and nephropathy in high risk group given IV immunoglobulin was equal to that in low risk group.
DISCUSSION:
-Key conclusions ;
IV immunoglobulin increases antibodies post transplant.
Post KTR ,IV immunoglobulin was found to decrease rate of BK infection and nephropathy.
OTHER USES OF IV IMMUNOGLOBULIN IN TRANSPLANT:
Mgt of Antibody mediated rejection.
Mgt of Viral infections like CMV post transplant.
Has application in reducing sensitivity in ABO/HLA incompatible groups.
Patients with high titers of BKV-neutralizing antibodies (NAbs) are protected against BKV replication. Intravenous immunoglobulin (IVIg) infusion can increase NAb titers.
NAb titers against the donor’s BKV strain lower than 4 log10 IC50 at the time of transplantation (day 0) are associated with an increased risk of BKV replication following KT.
available studies on pre-emptive and supportive treatment against BKV infections can’t be validated because of limitations.
This study, investigate whether the preventive administration of IVIg reduce the incidence of BKV viremia and BKVAN in high-risk KTR, based on NAb titers against the donor’s BKV strain.
Patients and methods:
Retrospectively analysis of clinical records of adult KTR in Strasbourg University Hospital, France between July 2012 and December 2017.
Inclusion criteria – cases with available NAb titers on day 0
NAb titers <4 log10 IC50 against the donor’s strain were considered high-risk.
– If donor’s specimen was unavailable, the replicating strain was considered as reference
– Genotype I, being most common, was taken as reference for patients with a negative BKV DNA load
Based on NAb titers on day 0 and the prescription of IVIg infusion, the patients (n = 174) were divided into 3 risk categories for BKV replication
1. patients with low NAb titers (“high-risk patients”) who received IVIg treatment for secondary immunodeficiency (SID) or for prevention or treatment of AMR – during first 3 months post-transplant and before BKV replication (n = 44). (SID = IgG levels <400 mg/dL or (2) IgG levels between 400 and 800 mg/dL in the presence of a concurrent infection><400mg/dl or 400-800mg/dl with concurrent infection). 2. patients with low NAb titers (“high-risk patients”) who did not undergo IVIg treatment during the first year of KT (n = 41) 3. patients with high NAb titers “low-risk patients”) who did not receive IVIg (n = 89). Immuno-suppression: Induction with Basiliximab or Thymoglobulin Tripple drug maintenance regimen Monitoring BKV infection: Blood samples for assessing BKV viremia were collected on – day 0, monthly x first 6months, then 3 monthly until 1 year post KT. Neutralization assay:
– NAb titers measured at day 0; 1-2-3-6 and 12months post KT; at onset of viremia. Additional measurements at the first and second posttransplant months were performed in patients who received IVIg infusions.
– The neutralization titer was defined as the sample dilution that resulted in 50% inhibition of pseudovirion infectivity (IC50), expressed as log10 of IC50.
– A neutralization titer of 2.5 log10 IC50 was set as threshold for quantification of antibody-mediated neutralization.
IVIg were infused either as a preventive or curative treatment of AMR or in patients diagnosed with SID. Patients received 0.4 g/kg IVIg doses every 3 weeks – with a total number of doses ranging from 1 to 3 – according to their IgG levels.
Patients with de novo DSA, preformed DSA, or biopsy-proven AMR were treated with three 2 g/kg doses of IVIg every 3 weeks.
Results:
IVIg administration increases BKV NAb titers in KTR
IVIg administration significantly increased BKV NAb titers above protective threshold (4 log10 IC50) during the first 3 posttransplant months – mostly against genotype I
IVIg administration decreases the incidence of both BKV viremia and BKVAN in KTR
At 12 months, the incidence of BKV viremia in the high-risk group treated with IVIg (6.8%, 3 of 44 patients) was similar to that observed in the low-risk group (10.1%, 9 of 88 patients) and markedly lower than that of the untreated high-risk group (36.6%; 15 of 41 patients; P < .001)
Median peak viral load was significantly lower in the high-risk group treated with IVIg (4.16 log10 copies/mL) compared with the low-risk group (5.03 log10 copies/mL) and the untreated high-risk group (4.9log10 copies/ml).
The 3 high-risk patients treated with IVIg who had evidence of BKV viremia underwent longitudinal analyses of BKV DNA loads and BKV NAb titers.
The results revealed that 2 of them were unable to achieve the protective threshold of 4log10IC50 before the first viremia episode.
The median peak viral load was significantly lower in the high-risk group treated with IVIg (4.16log10 copies/mL) compared with the low-risk group.
BK viremia was independently associated with D0 Nab titers and patient group in multivariate analysis – 24-folds more in high-risk untreated group compared to low-risk group.
BKVAN at 12months – (4.5% [2 cases] in the high-risk group treated with IVIg, 2.2% [2 cases] in the low-risk group, and 19.5% [8 cases] in untreated high-risk patients; P = 0.001.
Discussion:
IVIg were found to increase NAb titers against BKV genotype I (most predominant) over the protective threshold of 4log10 IC50.
Passive immunization with IVIg in early posttransplant phasewas associated withsignificantly lower incidence of BKV viremia as well as BKVAN in high-risk KTR.
T cell immunity is preferentially involved in the control of active BKV replication.
BKV-neutralizing antibodies and B cell immunity also playing key role in the prevention of BKV replication, is being evident in the current study.
Utility of IVIg in the management of BKV replication is still debatable owing to the concomitant use of other antiviral strategies and/or immunosuppression tapering.
IVIg have been previously administered with curative intent or rescue treatment, but its effective role in prevention of BKV replication in KTR is first time demonstrated in this study.
Strength of the study
Accurate risk stratification for BKV replication based on NAb titers against the 3 most common BKV genotypes
Limitations of the study
– Retrospective study
– Smaller sample size
– Different IVIg doses and administration schedule 2. What are other uses of IVIG in kidney transplantation
Managementof Acute ABMR
Induction for ABO incompatible live-donor kidney transplant
Desensitization protocol for live-donor KT in sensitized recipients
The study tried to investigate whether the preventive administration of IVIg may reduce the incidence of BKV viremia and BKVAN in high-risk KTR.
Risk stratification was based on NAb titers against the donor’s BKV strain measured on day 0.
Material and methods:
Retrospective study
KT in the Strasbourg University Hospital
July 2012 and December 2017
Exclusion criteria were patient or graft survival lower than 3 months
Based on NAb titers on day 0 and the prescription of IVIg in fusion, the study patients (n = 174) were divided into the following 3 risk categories for BKV replication:
(1) patients with low Nab titers (“high-risk patients”) who received IVIg treatment for secondary immunodeficiency (SID) or for prevention or treatment of antibody-mediated rejection (AMR) during the first 3 posttransplant months and before BKV replication (n = 44),
(2) patients with low NAb titers (“high-risk patients”) who did not undergo IVIg treatment during the first year of KT (n = 41)
(3) patients with high NAb titers “low-risk patients”) who did not receive IVIg (n = 89).
Blood samples for assessing BKV viremia were collected at the following time points: day 0, every month in the first 6 posttransplant months, and every 3 months thereafter (until 1 year following KT).
IVIg were infused either as a preventive or curative treatment of AMR or in patients diagnosed with SID. Patients received 0.4 g/kg IVIg doses every 3 weeks – with a total number of doses ranging from 1 to 3 – according to their IgG levels.
Patients with de novo DSA, preformed DSA, or biopsy-proven AMR were treated with three 2 g/kg doses of IVIg every 3 weeks.
Results:
IVIg administration increases BKV NAb titers in KTR
IVIg administration decreases the incidence of both BKV viremia and BKVAN in KTR
At 12 posttransplant months, the incidence of BKV viremia in the high-risk group treated with IVIg (6.8%, 3 of 44 patients) was similar to that observed in the low-risk group (10.1%, 9 of 88 patients) and markedly lower than that of the untreated high-risk group (36.6%; 15 of 41 patients; P < .001)
The 3 high-risk patients treated with IVIg who had evidence of BKV viremia underwent longitudinal analyses of BKV DNA loads and BKV NAb titers.
The results revealed that 2 of them were unable to achieve the protective threshold of 4log10IC50 before the first viremia episode.
The median peak viral load was significantly lower in the high risk group treated with IVIg (4.16log10 copies/mL) compared with the low-risk group.
The occurrence of BK viremia was independently associated with D0 Nab titers and patient group in multivariate analysis.
Patients in the high-risk untreated group had a 24-fold increase in the risk of developing BK viremia compared with the low-risk group.
Discussion:
First, IVIg were found to increase NAb titers against BKV genotype I (ie, the largely pre dominant genotype) over the protective threshold of 4log10 IC50.
Second, passive immunization with IVIg in the early posttransplant phase was associated with a significantly lower incidence of both BKV viremia and BKVAN in high-risk KTR.
Strengths:
Accurate risk stratification for BKV replication based on the quantification of NAb titers against the 3 most common BKV genotypes and a high availability of donors’ samples.
Limitation:
Retrospective design
Smaller sample size
Different IVIg doses and administration schedule
Other uses of IVIG in kidney transplantation
Managementof Acute antibody mediated rejection
Induction for incompatible live-donor kidney transplant
Tedla, Fasika M.; Roche-Recinos, Andrea; Brar, Amarpali. Intravenous immunoglobulin in kidney transplantation. Current Opinion in Organ Transplantation 20(6):p 630-637, December 2015. | DOI: 10.1097/MOT.0000000000000250
IVIG AS POSSSIBLE METHOD FOR BKV INFECTION AND NEPHROPATHY IN KTR -RESULTS FROM A PROOF OF CONCEPT STUDY.
INTRODUCTION.
-BK Virus infection affects pts esp post kidney transplantation upt 30-50% with 10 % having nephropathy reported with possibility of graft dysfunction and loss.
-We don’t have any specific tx with exception of RIS and monitoring BKV PCR and graft function.
-IV immunoglobulin is a possible additional tx against BK Virus.
-High levels of BK antibodies might be protective as low antibodies levels have been linked to increased BK infection and vice versa.
METHODS.
STUDY PTS;
568 KTR,297 excluded due to deficiency of antibodies,4 not included due to graft loss in 1st 3/12 post transplant and 2 mortalities in 1st 3/12 post transplant.
Inclusion criteria – All cases with antibodies on day 0.
Exclusion criteria – Graft loss or mortality within 3/12.
Definition – High risk pts were those with antibodies <4 log 10 IC50 against donor type.271 pts with D & R antibody titers were included,113 were high risk while 154 were low risk.
2.IMMUNOSUPPRESION.
Induction -Basiliximab /thymoglobulin subject to pt’s risk status.
Maintenance – CNI +MMF /MTOR + Steroids.
3.BKV MONITORING.
BKV PCR ‘; day 0, monthly -6/12 then every 3/12 in the 1st year post transplant.
Graft biopsy indications -Graft dysfunction and persistent viremia.
4.NEUTRALIZING ASSAY.
.Antibody levels were measured on day 0,3/12.6/12 and 12/12 post transplant and at the start of detection of BK virus in blood.
Further antibody levels ; 1st and 2nd month post transplant in those who got IV immunoglobulin.
5.IV IMMUNOGLOBULIN THERAPY.
This was given to those with secondary immunodeficiencies to help boost antibody levels.
Those with DSA or AMR were tx with x3 2g/kg doses every 3/52.
RESULTS.
-Classes ;
Low antibody levels/hgh risk group – n-44 -Got IV immunoglobulin for 1st 3/12 post transplant.
Low antibody -n -41- not given immunoglobulin.
High antibody/low risk group -n-89-did not get IV immunoglobulin.
-IV immunoglobulin increases BKV antibody levels post transplant;
IV immunoglobulin boosted antibody levels and they remained elevated for 3/12 and then reverted to pre transplanted levels 6/12-12/12 after sx.
-IV immunoglobulin reduces BKV infection and nephropathy post transplant;
1yr post transplant ,BKV infection and nephropathy in high risk group given IV immunoglobulin was equal to that in low risk group.
DISCUSSION.
-Key conclusions ;
IV immunoglobulin increases antibodies post transplant.
Post KTR ,IV immunoglobulin was found to decrease rate of BK infection and nephropathy.
OTHER USES OF IV IMMUNOGLOBULIN IN TRANSPLANT.
Mgt of Antibody mediated rejection.
Mgt of Viral infections like CMV post transplant.
Has application in reducing sensitivity in ABO/HLA incompatible groups.
● BKV replication occurring in 30%-50% of
KTR
● BKVAN affect 10% of BKV-infected KTR leading to kidney dysfunction and graft loss
● Regular screening of BKV viremia or viruria accompanied by RIS remains the only viable strategy to control BKV replication and successful in 50%-80%
● BKV associated with an increased risk of developing DSA and AR .
● IVIg has been proposed as a preemptive and supportive treatment against BKV infections
● limitations of these studies are :
☆ Small sample sizes
☆ Lack of a control arm
☆ The concomitant use of other antiviral strategies and/or a parallel reduction of IS
● BKV-neutralizing antibodies (NAb) having a protective effect.
● This study investigates whether IVIg may reduce the incidence of BKV viremia and BKVAN in high-risk KTR.
PATIENTS AND METHODS
● Retrospectively nonrandomized study of adult patients who underwent KT between 2012 and 2017.
● Exclusion criteria were
☆ patient or graft survival lower than 3 m
☆ NAb titers below 10^4
☆ IC50 against the donor’s strain
☆ Low-risk patients who received IVIg during the first posttransplant year
● Genotype I was taken as reference for patients with a negative BKV DNA load.
● Patients were divided into 3 risk categories for BKV replication:
1. Low NAb titers “high-risk patients” who received IVIg treatment for secondary immunodeficiency (SID) or for prevention or treatment of antibody-mediated rejection (AMR) during the first 3 posttransplant months and before BKV replication
2. low NAb titers (“high-risk patients”) who did not undergo IVIg treatment during the first year of KT
3. patients with high NAb titers “low-risk patients” who did not receive IVIg
● Secondary immunodeficiency was defined either :
1. IgG levels <400 mg/dL
2. IgG levels between 400 and 800 mg/dL in the presence of a concurrent infection.
Immunosuppressive regimens
☆ An induction therapy with basiliximab or thymoglobulin for high risk recipient’s
☆ Thymoglobulin for patients with PRA >20% and a history of ABO-incompatible kidney transplantation
☆ Maintenance with CNi , MMF or mTORi , and steroids
Monitoring of BKV infections
● Blood BKV PCR assessment at :
* Day 0
* Every month in the first 6 months posttransplant
* Every 3 months thereafter until 1 year
● Allograft biopsies in case of graft dys-
function, detection of DSA, or sustained BKV viremia
Neutralization assay
● NAb titers were measured at day 0; at the third, sixth, and 12th posttransplant months; and at the onset of viremia.
● Additional measurements at the first and second posttransplant months in patients who received IVIg infusions.
IVIg therapy
● Patients received 0.4 g/kg IVIg doses every 3 weeks with a total number of doses ranging from 1 to 3
● Patients with de novo DSA, preformed DSA, or biopsy-proven AMR were treated with three 2 g/kg doses of IVIg every 3 weeks.
RESULTS
● IVIg increases NAb titers against BKV genotype I
● Passive immunization with IVIg in the early posttransplant was associated with a significantly lower incidence of both BKV viremia and BKVAN in high-risk KTR
● BKV viremia was an early event that occurred after a median of 64 days from KT
● BK genotype I in 85% and IV in 15 %
● The frequency of viremia was higher in presence of donor/recipient BKV genotype mismatch
● The median peak viral load was higher in patients with viremia who developed BKVAN compared with those who did not ● 6.8 % of high-risk group treated with IVIg
have BKV viremia comparsion to 10.1% in the low-risk group and 36.6% in untreated high-risk group
● The median peak viral load was significantly lower in the high-risk group treated with IVIg
● Patients in the high-risk untreated group had a 24-fold increase in the risk of developing BK viremia compared with the low-risk group
● The incidence of BKVAN was 4.5% in the high-risk group treated with IVIg and (2.2%)
in the low-risk group and (19.5%) in untreated high-risk patients
● IVIg may be more useful as a preventive rather than curative strategy.
● Utility of IVIg administration in the management of BKV replication is still debatable because :
* concomitant use of other antiviral strategies
* Immunosuppression tapering
◇ The strength points of study :
● An accurate risk stratification for BKV replication based on the quantification of
NAb titers against the 3 most common BKV genotypes and a high availability of donors’ samples
● This study adds evidence showing that BKV-neutralizing antibodies and B cell immunity play a key role in the prevention of BKV replication.
● Conversely, T cell immunity is preferentially involved in the control of active BKV replication.
● There were no major intergroup differences at baseline the only exception being the use of everolimus (which was more frequent for patients who received IVIg)
● This study is the first demonstrates that IVIg infusion may be a valuable for preventing BKV replication in KT
◇ Limitations of study :
● A retrospective nonrandomized study, .
● small number of patients who received IVIg infusions so no firm conclusions
● Use of different IVIg doses and administration schedule
Other uses of IVIG in transplantation :
☆ ABMR
☆ Desensitization protocols
☆ Protection and treatment of viral infections as CMV , EBV , PKpyV , …
☆ Recurrence of FSGS
V. Intravenous immunoglobulin as a preventive strategy against BK virus viremia and BKV-associated nephropathy in kidney transplant recipients – Results from a proof-of-concept study
Summarise this article
Introduction
– BKV infections are a major concern among kidney transplant recipients (KTRs)
– BKV replications occurs in 30-50% while BKVAN can affect 10% resulting in graft dysfunction and graft loss
– currently there is no specific antiviral treatment available against BKV infections/ replication
– the mainstay of management remains reduction in immunosuppression with regular monitoring of kidney function and BKV viremia
– this treatment approach is only 50-80% successful, it does not guarantee against evolution to BKVAN and is associated with increased risk of developing DSAs and acute rejection
– IVIG is being proposed as an adjunctive preemptive and supportive treatment against BKV infections
– humoral immunity plays a critical role in preventing BKV replication in KTRs
– high titers of BKV-neutralising antibodies (NAb) have been found to have a protective effect i.e., lower NAb titers against the donor’s BKV strain at the time of transplantation is associated with an increased risk of BKV replication after kidney transplantation
– patients with high titers of BKV Nabs are protected against BKV replication
– IVIG can exert neutralizing activity against common BKV genotypes
– IVIG infusion results in increased NAb titers among KTRs
Methods
Study patients
– 568 kidney transplant recipients (KTRs), 297 excluded due to lack of BKV NAb titers (BKV-neutralising antibodies), 4 were excluded (2 due to graft loss within the first 3 months of KT and 2 deaths during the first 3 months of KT)
– Inclusion criteria: – all cases with available NAb titers measured on day 0
– Exclusion criteria: – graft or patient survival less than 3 months
– high risk patients: – patients with NAb < 4 log 10 IC50 against the donor’s strain
– 271 patients with donor and recipient NAb titers were recruited; of these,
o 113 were at high risk of BKV replication (28 excluded leaving 41 high-risk untreated patients and 44 high-risk treated patients);
o 154 were at low risk of BKV replication (65 were excluded due to IVIG treatment during the 1st year of KT leaving 89 at low-risk untreated patients)
Immunosuppressive agents
– induction therapy with basiliximab or thymoglobulin depending on the recipient’s immunological risk
– thymoglobulin was given to patients with a PRA >20% and a history of ABO-incompatible kidney transplantation
– maintenance phase: – CNI (tacrolimus or cyclosporine) + MMF or mTORi + steroids
Monitoring BKV infections
– BKV quantitative PCR was done at day 0, monthly for the first 6 months then 3-monthly
until 1 year following kidney transplantation
– graft biopsy was performed in case of graft dysfunction, sustained BKV viremia (i.e., presence of 4 log 10 copies/mL in 2 subsequent blood specimens), detection of DSA
Neutralization assay
– NAb titers were measured at day 0; 3rd, 6th and 12th month posttransplant and at the onset of viremia
– additional NAb titers were done at the 1st and 2nd months post-transplant for patients who had received IVIG infusions
IVIG therapy
– IVIG was infused as preventive or a curative treatment for ABMR or in patients with secondary immunodeficiency
– IVIG can increase NAb titers
– depending on the IgG levels, patients received 0.4g/kg IVI doses every 3 weeks with the total number of doses ranging from 1 to 3
– patients with DSAs (de novo or preformed) or biopsy-proven AMR were treated with three 2g/kg doses of IVIG every 3 weeks
Results
Patient characteristics
– patients were divided into 3 categories for BKV replication based on the NAb titers on the day of transplantation i.e.,
o patients with low NAb titers (“high-risk”) who received IVIG for the first 3 months post-transplant (n=44)
o patients with low NAb titers (“high-risk”) who did not receive IVIG treatment (n=41)
o patients with high NAb titers (“low-risk”) who did not receive IVIG (n=89)
IVIG administration increases BKV NAb titers in KTR
– the temporal course of BKV NAb titers was studied among patients who received IVIG in the absence of viremia
– it was found that with IVIG infusion, the mean NAb titers increased significantly and remained at these levels for 3 months before returning to the initial levels in 6th to 12th month post-transplant
IVIG administration decreases the incidence of both BKV viremia and BKVAN in KTR
– at 12 months following kidney transplant, the incidence of BKV viremia in the high-risk group treated with IVIG (6.8%) was similar to that observed in the low-risk group (10.1%) and markedly lower than that observed in the untreated high-risk group (36.6%)
– similar trends were observed with regard to BKVAN
Discussion
– the two main findings in this study were: –
o IVIG was found to increase the NAb titers against BKV genotype I above the protective threshold of 4 log 10
o among high-risk KTRs, passive immunization with IVIG in the early post-transplant phase was associate with a significantly lower incidence of both BKV viremia and BKVAN
Study strengths
– risk categorization of patient’s BKV replication status based on the NAb titers
Study limitations
– retrospective
– small number of patients
– different IVIG dosing and administration schedules
What are the other uses of IVIG in transplantation? (1)
– in desensitization protocols in ABO and HLA incompatible transplant pairs
– prevention and treatment of ABMR
– treatment and prevention of post-transplant infections like CMV, parvovirus B19 and BKPyV
References
1. Jordan SC, Toyoda M, Kahwaji J, Vo AA. Clinical aspects of intravenous immunoglobulin use in solid organ transplant recipients. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2011 Feb;11(2):196-202. PubMed PMID: 21219579. Epub 2011/01/12. eng.
Please summarise this article.
-BK virus (BKV) infections are still a major concern following kidney
transplantation (KT) .
-BKV-associated nephropathy (BKVAN) can lead to kidney dysfunction and graft loss.
-No specific antiviral treatment is currently available against
BKV infections but regular screening of BKV viremia or viruria
accompanied by a reduction of immunosuppressive therapy remains
the only viable strategy to control BKV replication.
-Humoral immunity plays a crucial role for the prevention of BKV
replication in KTR, with high titers of BKV-neutralizing antibodies
(NAb) having a protective effect.
-It is retrospective study between July 2012 and December 2017 in the Strasbourg University Hospital. Number of patients 174 divided into:: (1) patients with low NAb titers (“high-risk”) who received IVIg for the first 3 posttransplant months (n = 44), (2) patients with low NAb titers (“high-risk”) who did not undergo IVIg treatment (n = 41), and (3) patients with high NAb titers (“low-risk”) who did not receive IVIg (n = 89).
-NAb titers against the donor’s strain measured before KT are clinically useful for risk stratification of BKV-related disease.
– At 12 posttransplant months, the incidence of BKV viremia in the high-risk group treated with IVIg (6.8%) was similar to that observed in the low-risk group and markedly lower than that of the untreated high-risk group .
-A high donor seroreactivity can act as a risk factor for BKV replication especially in recipients with low BKV NAb titers.
-The incidence of BKVAN was as low as 4.5% in the high-risk
group treated with IVIg.
-Conversely, T cell immunity is preferentially involved in the control of active BKV replication.
-Strengths of study :an accurate risk stratification for BKV replication based on the quantification ofNAb titers against the 3 most common BKV genotypes and a high availability of donors’ samples.
-Limitation of study : retrospective design, the relatively small number of patients who received IVIg infusions, and the use of different IVIg doses and administration schedule. What are the other uses of IVIG in transplantation?
1.An immunomodulatory agent for highly HLA sensitized patients awaiting kidney transplantation
2.Desensitization agent for heart and lung allograft recipients
3.Treatment of AMR
4. Treatment of secondary hypogammaglobulinemia and infectious complications in solid organ transplant recipients Reference:
S.C. Jordan et al.Clinical Aspects of Intravenous Immunoglobulin Use in Solid Organ Transplant Recipients. American Journal of Transplantation
Volume 11, Issue 2, February 2011, Pages 196-202
Introduction BKV replication occurring in 30%-50% of all kidney transplant recipients, and nephropathy affect 10% of BKV-infected recipients, contributing in renal dysfunction and graft loss. No approved antiviral therapy for BKVN.
Screening of BKV viremia and viruria with reduction of immunosuppressive therapy is successful in 50%-80%, but does not prevent BKVAN, and associated with increased the risk of developing DSA and acute rejection.
IVIg is considered as a preemptive and supportive treatment against BKV infections, but studies were of small ample size, lacking control arm, and whether IS reduction and concomitant use of anti-viral therapy were used. Hypothesis that Humoral immunity plays a crucial role for the prevention of BKV genotypes replication in KTR, with high titers of BKV-neutralizing antibodies (NAb) having a protective effect. Patients and methods A retrospective study, conducted during 2012-2017 (in Strasbourg University Hospital, France). BKV genotyping was performed in all BKV DNA-positive recipients, the most common viral genotype (genotype I) was taken as reference for patients with a negative BKV DNA load. Allograft biopsies were performed in case of graft dysfunction, detection of DSA, or sustained BKV viremia (defined by the presence of 4 log10 copies per mL in 2 subsequent blood specimens). The neutralization titer—which was defined as the sample dilution that resulted in a 50% inhibition of pseudovirion infectivity (IC50) – was expressed as log10 of IC50. Patients received 0.4 g/kg IVIg doses every 3 weeks – with a total number of doses ranging from 1 to 3 – according to their IgG levels.
BKV viremia: day 0, every month in the first 6 posttransplant months, and every 3 months thereafter (for 1 year following KT).
NAb titers: at day 0; at 3, 6, and 12th posttransplant months; and at the onset of viremia.
Study arms: (1) patients with low NAb titers (“high-risk”) who received IVIg for the first 3 posttransplant months (n = 44)- received IVIG. (2) patients with low NAb titers (“high-risk”) who did not undergo IVIg treatment (n = 41)- did not receive IVIG (3) patients with high NAb titers (“low-risk”) who did not receive IVIg (n = 89)- did not receive IVIG.
Inclusion criteria: all cases with available NAb titers measured on day 0, with titers<4 log10donor’s strain considered as high risk.
Exclusion criteria: patient or graft survival lower than 3 months.
Immunosuppressive regimens: Induction therapy with basiliximab or r-ATG based on the recipient’s immunological risk. MMF+CNI+ low dose steroid+/- m-TORi. Target trough levels of tacrolimus were: 10-12 ng/mL during the first 3 months, 8-10 ng/mL from month 4 to month 6, and 6-8 ng/ mL from month 6 to month 12. Target trough levels of ciclosporin were 150-200 ng/mL during the first 6 months and 125-150 ng/mL from month 6 to month 12. The target for the mycophenolic acid area under the concentration-time curve (AUC) from 0 to 12 hours at months 1 and 3 was 30-60 mg·h·L. Target trough levels of everolimus were 3-8 ng/mL. All patients received 2 steroid pulses at a dose of 250 mg followed by 1 mg/kg/day oral steroids that were progressively tapered during the first 4 posttransplant months. Steroid administration at a dose of 0.1 mg/kg/day was continued in patients at high immunological risk or in those with a history of acute rejection. Results At 12 posttransplant months:
The incidence of BKV viremia in the high-risk group treated with IVIg (6.8%, 3 of 44 patients) was similar to that observed in the low-risk group (10.1%, 9 of 88 patients), but significantly lower than the untreated high-risk group (36.6%; 15 of 41 patients; P < .001).
Similar figures were observed with regard to the incidence of BKVAN at 12 posttransplant months (4.5% [2 cases] in the high-risk group treated with IVIg, 2.2% [2 cases] in the low-risk group, and 19.5% [8 cases] in untreated high-risk patients; (P = .001).
Discussion: IVIg were found to increase NAb titers against BKV genotype I (ie, the largely predominant genotype) over the protective threshold of 4 log10. Passive immunization with IVIg in the early posttransplant phase was associated with a significantly lower incidence of both BKV viremia and BKVAN in high-risk KTR.
Strength: Accurate risk stratification for BKV replication based on the quantification of NAb titers against the 3 most common BKV (I,II, and IV) genotypes and a high availability of donors’ samples.
Limitations: Retrospective study, small sample size, and different immunosuppressive protocol, not specified.
Conclusions IVIg administration is capable of preventing BKV viremia and BKVAN in KTR with low NAb titers. Multicenter controlled randomized study are needed.
What are the other uses of IVIG in transplantation?
Desensitization protocol.
Treatment of AMR.
Prevention and treatment of infections: CMV, BKV nephropathy, and parvovirus B19 infection.
BKV-associated nephropathy (BKVAN) can affect up to 10% of BKV-infected KTR, potentially leading to kidney dysfunction and graft loss; there is no specific antiviral treatment currently available against BKV infections. Regular screening of BKV viremia or viruria accompanied by a reduction of immunosuppressive therapy remains the preventable form of BKVN , but this approach proves successful only in 50%-80% of cases, besides increase the risk of developing donor-specific antibodies (DSA) and acute rejection.
Intravenous immunoglobulin (IVIg) administration has been empirically proposed as a preemptive and supportive treatment against BKV infections.
*A clinically relevant neutralizing activity against the most common BKV genotypes, with IVIg infusion resulting in increased NAb titers among KTR. This study investigates whether the preventive administration of IVIg may reduce the incidence of BKV viremia and BKVAN in high-risk KTR.
PATIENTS AND METHODS ; – Clinical records of adult patients who underwent KT in the Strasbourg University Hospital between July 2012 and December 2017 Study patients were retrospectively reviewed. All cases with available NAb titers measured on day 0 were deemed eligible.
Exclusion criteria:
– Patient death or graft loss less than 3 months post kidney transplant . – Based on NAb titers on day 0 and the prescription of IVIg infusion, the study patients (n = 174) were divided into the following 3 risk categories for BKV replication: (1) High-risk patients with low NAb titers who received IVIg treatment for secondary immunodeficiency (SID) or for prevention or treatment of antibody-mediated rejection (AMR) during the first 3 posttransplant months and before BKV replication (n = 44), (2) High-risk patients patwith low NAb titers who did not undergo IVIg treatment during the first year of KT (n = 41), and (3) low-risk patients with high NAb titers who did not receive IVIg (n = 89). Ethical approval was granted from the local institutional review board , and all participants provided written informed consent.
Immunosuppressive regimens :
Immunosuppressive therapy after KT consisted of
Induction therapy with basiliximab or thymoglobulin based on the recipient’s immunological risk. Patients with a panel reactive antibody (PRA) >20% and a history of ABO-incompatible kidney transplantation were treated by thymoglobulin.
Maintenance phase : calcineurin inhibitor (ciclosporin or tacrolimus) in association with mycophenolate mofetil (MMF) or a mammalian target of rapamycin (mTOR) inhibitor (everolimus) and steroids.
Monitoring of BKV infections:
-BKV quantitative plasmaPCR was checked at day 0, every month in the first 6 posttransplant months, and every 3 months thereafter (until 1 year following KT.
-Allograft biopsies were performed in case of graft dysfunction, detection of DSA, or sustained BKV viremia and systematically during the third posttransplant month.
BKVAN was diagnosed and classified according to the severity of virus-induced cytopathic effects, inflammatory infiltrates, tubular atrophy, fibrosis, and through immunohistochemistry using antibodies that cross-reacted against the large T antigen of the related simian polyomavirus (SV40 antibody .BKV genotyping was performed in all BKV DNA-positive recipients as previously described.
Neutralization assay :
NAb titers were measured at day 0; at the third, sixth, and 12th posttransplant months; and at the onset of viremia. Additional measurements at the first and second posttransplant months were performed in patients who received IVIg infusions.
-The neutralization assays were conducted using a BKV pseudovirion system that expressed the capsid proteins of BKV genotypes I, II, or IV.
IVIg therapy :
Patients received received 0.4 g/kg IVIg doses every 3 weeks – with a total number of doses ranging from 1 to 3 – according to their IgG levels. Patients with de novo DSA, preformed DSA, or biopsy-proven AMR were treated with three 2 g/kg doses of IVIg every 3 weeks. Data analysis :
Continuous variables are presented as means (standard deviations [SDs]) or medians and interquartile ranges (25th–75th percentiles). Categorical variables are given as counts and percentages using the Kruskal-Wallis test. and analyzed with the chi-square test or the Fisher’s exact test, as appropriate. The Kaplan-Meier method was used to plot BKV viremia-free survival and BKVAN-free survival . A multivariable Cox regression analysis was performed to identify independent predictors of BKV viremia.
Results: Patient characteristics : we have 174 patients through the study. 133 cases have available donor BKV NAb titers or genotypes of replicating BKV . At day 0, 170 (97.7%) recipients and 120 (96.7%) donors were seropositive for at least 1 BKV genotype. BKV genotype I—alone or in combination with other genotypes—was detected in 138 (79.3%) recipients and 100 (83.3%) donors, respectively. Fifty-three (30.5%) recipients and 22 (18.3%) donors were seropositive for BKV genotype II, whereas 22 (12.6%) recipients and 9 (7.5%) donors were seropositive for BKV genotype IV . Donor NAb titers at D0 did not differ significantly between the 3 patient groups .
IVIg administration increases BKV NAb titers in KTR : At day 0 the mean BKV NAb titer was 3.06 (0.56) log10 IC50. Before the first IVIg injection, BKV NAb titers remained below 4 log10 IC50 in all patients (mean: 3.07 [0.56] log10 IC50). At 1 post transplant month, when the majority of patients (93%) had already received the first IVIg injection, the mean NAb titers significantly increased to 3.82 (0.61) log10 IC50 and remained at these levels for the subsequent 2 months (P < .001). Twenty-nine of the 32 patients (91%) at high risk for BKV genotype I replication were capable of reaching a BKV NAb titer above the threshold of 4 log10 IC50 in at least 1 occasion during the first 3 posttransplant months. . Only 2 and 1 patients among those with a high risk of replication for BKV genotype II and genotype IV, respectively, were capable of obtaining a BKV NAb titer above the threshold of 4 log10 IC50 .
IVIg administration decreases the incidence of both BKV viremia and BKVAN in KTR;
– BKV viremia was observed in 27 of the 174 study patients (total incidence at 1 posttransplant year: 15.5%). At 12 posttransplant months, the incidence of BKV viremia in the high-risk group treated with IVIg (6.8%, 3 of 44 patients) was similar to that observed in the low-risk group (10.1%, 9 of 88 patients) and markedly lower than that of the untreated high-risk group (36.6%; 15 of 41 patients; P < .001; .
– Incidence of BKVAN at 12 posttransplant months (4.5% [2 cases] in the high-risk group treated with IVIg, 2.2% [2 cases] in the low-risk group, and 19.5% [8 cases] in untreated high-risk patients; P = .001;
DISCUSSION; In this study IVIg were found to increase NAb titers against BKV genotype as well as passive immunization with IVIg in the early posttransplant phase was associated with a significantly lower incidence of both BKV viremia and BKVAN in high-risk KTR. The anti-BKV antibody-mediated neutralizing response in KTR plays a key role in the protection against BKV replication.
NAb titers against the donor’s strain measured before KT are clinically useful for risk stratification of BKV-related disease. BKV NAb titers against genotype I increased in a similar fashion after low or high IVIg doses despite a higher burden of immunosuppression. The role of IVIg was examined in the first 3 posttransplant months because BKV replication generally occurs early following KT.2,24,25 At 12 posttransplant months, the incidence of BKV viremia in the high-risk group treated with IVIg (6.8%) was similar to that observed in the low-risk group (10.1%) and markedly lower than that of the untreated high-risk group (36.6%). Incidence of BKVAN was as low as 4.5% in the high-risk group treated with IVIg. Such figures are similar to those observed in the low-risk group (2.2%) and markedly lower than those of untreated high-risk patients (19.5%).
Limitation of the study : -Being retrospective study . -Rather a small number of patients who are given IVIG , – The administration of different doses of IVIG.
Strength of the study:
-This study is the first to demonstrate that IVIg infusion may be a valuable strategy for preventing BKV replication in KTR.
What are the other uses of IVIG in transplantation?
IVIG is used in desensitization protocols in high immunological risk patients before kidney transplant .
Prevention and treatment of ABMR .
Reference: Curr Opin Organ Transplant. 2015 Dec;20(6):630-7.doi: 10.1097/MOT.0000000000000250.
IVIG as a preventive strategy against BK virus viremia and BKN in kidney transplant recipients
Summary
· The only available method to prevent BKV infection and BLN is to do screening by blood PCR for viremia and apply preemptive reduction of immunosuppression. Unfortunately, it is effective only in 50 % of cases and is accompanied with higher risk of rejection.
· IVIG prophylaxis lower the risk of BKV infection and BKN among high risk patients for BKV infection (who had lower titers of antibodies) and even they had similar risk to those with protective high titer of anti BKV antibodies (low risk for BKV infection).
· IVIG was given at dose of 400 mg/kg IVIg doses every 3 weeks – for 1 to 3 – according to their IgG levels.
· Patients with de novo DSA, preformed DSA, or biopsy-proven AMR were treated with three 2 g/kg doses of IVIg every 3 weeks.
· It seems that B cell and neutralizing antibodies have role in BKV prophylaxis, while T cell mediated immunity is crucial in treatment and control of BKV infection.
· Points of strength as risk stratification and measurement of antibody titers.
· Points of weakness as being retrospective, none standardized regimen of IVIG and small number of cases.
Uses of IVIG in transplantation
· Treatment of ABMR.
· Treatment of recurrent FSGS.
· Given as replacement therapy after course of plasmapheresis done as in recurrent FSGS and ABMR treatment
· Desensitization protocol in HLA and ABO incompatible transplantation.
· Adjuvant therapy in treatment of CMV and BKV infection (together with reduction of IS therapy)
Treatment of sepsis (none specific and immunomodulatory effect
# The aim of the study:
To investigate whether the preventive administration of IVIg may reduce the incidence of BKV viremia and BKVAN in high-risk KTR. Risk stratification was based on NAb titers against the donor’s BKV strain measured on day0.
# Introduction:
*BKV infections are remaining a big trouble in renal transplantation, occurring in 30%-50% of all KTR.
*BKVAN can affect up to 10% of BKV-infected KTR, leading to kidney dysfunction and graft loss.
*No specific antiviral treatment is currently available against BKV infections.
* Regular screening of BKV viremia or viruria accompanied by a reduction of immunosuppressive therapy remains the only viable strategy to control BKV replication
*Administration of IVIg has been empirically planned as a preemptive and supportive treatment against BKV infections.
*Patients with high titers of BKV-neutralizing antibodies (NAbs) are protected against BKV replication, and IVIg infusion can increase NAb titers.
# The method and result:
Retrospective study reviewed the clinical records of adult patients who underwent KT in the Strasbourg University Hospital between July 2012 and December 2017. All cases with available NAb titers measured on day 0 were deemed eligible.
# Exclusion criteria:
*Patient or graft survival lower than 3 months.
*The KTR (n = 174) were retrospectively divided into the following 3 risk categories for BKV replication:
(1) patients with low NAb titers (“high-risk”) who received IVIg for the first 3 posttransplant months (n = 44).
(2) patients with low NAb titers (“high-risk”) who did not undergo IVIg treatment (n = 41).
(3) patients with high NAb titers (“low-risk”) who did not receive IVIg (n = 89).
*At 12 posttransplant months, the incidence of BKV viremia in the high-risk group treated with IVIg (6.8%) was similar to that observed in the low-risk group (10.1%) and markedly lower than that of the untreated high-risk group (36.6%; P < .001).
*Similar results were observed with regard to BKVAN.
**They concluded that IVIg may be a valuable strategy for preventing BKV replication.
# The strengths:
An accurate risk stratification for BKV replication based on the quantification of
NAb titers against the 3 most common BKV genotypes and a high availability of donors’ samples.
# The limitation:
retrospective design, the relatively small number of patients who received IVIg infusions, and the use of different IVIg doses and administration schedule.
What are the other uses of IVIG in transplantation?
*In desensitization protocols.
*As anti-rejection therapies (ABMR)
* Protection against post transplant infection (CMV, parvovirus B19)
Making Kidney Transplants Possible for More Patients
Apr 02, 2017 Cedars-Sinai Staff.
Summary of the article Intravenous immunoglobulin as a preventive strategy against BK virus viremia and BKV-associated nephropathy in kidney transplant recipients—Results from a proof-of-concept study
This is a retrospective review of the clinical records of adult patients who underwent KT in the Strasbourg University Hospital between July 2012 and December 2017. The review investigated whether early IVIg administration prevents BKV replication in patients with low neutralizing antibodies(Nab) titers.
Results and Discussion
1. IVIg were found to increase NAb titers against BKV genotype I(ie, the largely pre- dominant genotype).
2. Passive immunization with IVIg in the early post-transplant phase was associated with a significantly lower incidence of both BKV viremia and BKVAN in high-risk KTR.
3. The incidence of BKVAN was as low as 4.5% in the high-risk group treated with IVIg.
4. The study’s results add to the growing amount of evidence showing that BKV-neutralizing antibodies and B cell immunity play a key role in the prevention of BKV replication. Strength of the study
a) An accurate risk stratification for BKV replication based on the quantification of NAb titers against the 3 most common BKV genotypes.
b) A high availability of donors’ samples. Limitations of the study
a) Retrospective design.
b) The relatively small number of patients who received IVIg infusions.
c) The use of different IVIg doses and administration schedule. What are the other uses of IVIG in transplantation?
1. Use of IVIG in desensitization protocols and for treatment of antibody-mediated rejection (AMR) are supportive for kidney transplant recipients.
· Immediate pre and/or post‐transplant where donor specific antibody(s) prevent transplantation or threaten transplantation.
· Ongoing de-sensitization of patients to improve the likelihood of transplantation.
· Initial treatment of acute antibody mediated transplant rejection.
· Treatment of ongoing active antibody mediated transplant rejection.
· Treatment or prevention of graft rejection where the use of conventional immunosuppressive therapies is contraindicated or poses a threat to the graft or patient.
2. IVIG is useful in the treatment and prevention of post-transplant infectious complications including cytomegalovirus, parvovirus B19 and polyoma BK virus(1).
References Jordan SC, Toyoda M, Kahwaji J, Vo AA. Clinical aspects of intravenous immunoglobulin use in solid organ transplant recipients. Am J Transplant. 2011 Feb;11(2):196-202. doi: 10.1111/j.1600-6143.2010.03400.x. Epub 2011 Jan 10. PMID: 21219579.
Please summarise this article. BK virus (BKV) replication occurs in kidney transplant recipients (KTR) leading to BKV-associated nephropathy (BKVAN) and graft loss. Patients with high titers of BKV-neutralizing antibodies (NAbs) are protected against BKV replication, and intravenous immunoglobulin (IVIg) infusion can increase NAb titres.
Purpose To investigate whether early IVIg administration prevents BKV replication in patients with low NAb titers
Methodology KTR followed in the Strasbourg University Hospital (n = 174) were studied retrospectively. Patients were divided into three groups 1- High risk patients with low NAb titers who received IVIg for the first 3 posttransplant months (n = 44) 2- Patients with low NAb titers (“high-risk”) who did not undergo IVIg treatment (n = 41) 3- Patients with high NAb titers (“low-risk”) who did not receive IVIg (n = 89) BK virus replication and its effects was assessed
IVIg administration increases BKV NAb titers in KTR At one month the patients who received IVIG had higher mean NAb titres and remained at higher levels in subsequent two months. In high risk patients without IVIG and no viremia, there was no difference in NAb titres on the day of transplant and at one year.
IVIg administration decreases the incidence of both BKV viremia and BKVAN in KTR At 12 posttransplant months, the incidence of BKV viremia in the high-risk group treated with IVIg (6.8%) was similar to that observed in the low-risk group (10.1%) and markedly lower than that of the untreated high-risk group (36.6%; P < .001).
Conclusion IVIG was found to increase NAb titres against BKV. Immunization with IVIG was associated with low risk BKV viremia and BKV nephropathy in high risk group.
Strengths Accurate risk stratification for BKV replication based on the quantification of NAb titers High availability of donors’ samples
Limitations Retrospective design Small number of patients who received IVIg infusions Use of different IVIg doses and administration schedule
What are the other uses of IVIG in transplantation? · In ABMR · In desensitization protocols · CMV, BKV infections
Introduction
Currently, BK virus (BKV) viremia occurs in 30-50% of all kidney transplant recipients and BKV-associated nephropathy (BKVAN) can affect up to 10% of BKV-infected kidney transplant recipients. It has the potential to lead to kidney dysfunction and graft loss. There is no specific treatment available for the treatment of BKV viremia. Screening for the infection is accompanied by reduction of immune suppression. Unfortunately, this is not always successful, and does not eliminate the evolution to BKVAN. And it is associated with increased risk of rejection. IVIg has been suggested as a treatment for BKV infection. However, there have been a few studies conducted and their results require careful interpretation. This study investigated whether the preventative use of IVIg may reduce the incidence of BKV viremia and BKVAN in kidney transplant recipients at high risk.
Patients and Methods Study patientsPatients who underwent kidney transplantation in Strasbourg University Hospital between July 2012 and December 2017. All cases with available NAb titers measured on day 0 were deemed eligible. Exclusion criteria included patient or graft survival of less than 3 months. Patients were considered at high risk if they had Nab titers of less than 4log10IC50 against the donor’s strain.
Patients were divided in to three groups:
Patients with low NAb titers (“high risk patients”) who received IVIg treatment for secondary immunodeficiency (SID) or for prevention or treatment of antibody-mediated rejection (AMR) during the first 3 months after transplantation and before BKV replication
Patients with low NAb titers (“high risk patients”) who did not undergo IVIg treatment during the first year of kidney transplantation
Patients with high NAb titers (“low risk patients”) who did not receive IVIg.
Immunosuppressive regimens Immunosuppressive therapy after kidney transplantation consisted of an induction therapy with basiliximab or thymoglobulin. Subsequent maintenance phase included a CNI with MMF or a mTOR inhibitor and steroids. Monitoring of BKV infectionsBlood samples for assessing BKV infection were collected at day 0 of everymonth in the first 6 months post transplantation, and every 3 months after that for 1 year post transplantation. BKV was quantitatively measured using PCR. If graft dysfunction was noted, then allograft biopsies were performed. BKV genotyping was performed in all BKV DNA-positive recipients. Neutralization assay NAb titers were measured on day 0 at the third, sixth and twelfth month after transplantation. A neutralization titer of 2.5 log10 IC50 was set as the threshold for quantification of antibody-mediated neutralization. IVIg therapyPatients receiving the IVIg received 0.4g/kg every 3 weeks – with a total number of doses ranging from 1-3 depending on their IgG levels. Patients with de novo DSA, preformed DSA, or biopsy-proven AMR were treated with three 2g/kg doses of IVIg every 3 weeks. Data analysisContinuous variables were presented as medians and interquartile ranges, analyzed using the Kruskal-Wallis test. Categorical variables were given as counts and percentages, and analyzed with the chi-square test or the Fisher’s exact test.
Results Patient characteristicsAt day 0, 97.7% of the recipients and 120 donors were seropositive for at least one genotype of BKV. Donor NAb titers at day 0 did not differ between the three groups. IVIg administration increases BKV NAb titers in KTR 44 high-risk patients were treated with IVIg, 35 patients were at a high risk of replication of BKV genotype I, 7 for genotype II and 2 for genotype IV. 41 patients received IVIg due to SID. The temporal course of BKV NAb titers was studied only in patients who received IVIg in the absence of BKV viremia. This approach allowed investigating the impact of IVIg when immune system stimulation was lacking, because of the increased BKV NAb titers observed in kidney transplant recipients with BKV viremia. At day 0, the mean BKV NAb titer was 3.06 (0.56) log 10 IC50. Before the first IVIg injection, BKV NAb titers remained below 4 log 10 IC50 in all patients. After the first month post-transplant, when the majority of patients (93%) had already received the first IVIg injection, the mean NAb titers significantly increased to 3.82 (0.61) log 10 IC50 and remained at these levels for the subsequent 2 months. A decrease in NAb titers occurred later, with a return to the initial levels between the sixth and twelfth month after transplantation. Among these 41 patients, there was a high risk of replication for BKV genotype I, genotype II, and genotype IV in 32, 7, and 2 cases, respectively. Twenty-nine of the 32 patients (91%) at high risk for BKV genotype I replication were capable of reaching a BKV NAb titer above the threshold of 4 log 10 IC50 in at least 1 occasion during the first 3 post-transplant months. The remaining 3 cases who were unable to achieve high NAb titers received 2 or 3 low-dose IVIg infusions. All of them showed markedly low titers before IVIg treatment. This increased after IVIg administration.
In the 26 high-risk patients without IVIg and no BKV viremia, there were no significant differences in BKV NAb titers measured on the day of transplantation and 1 year thereafter. IVIg administration decreases the incidence of both BKV viremia and BKVAN in KTRBKV viremia was observed in 27 of the 174 study patients. It was noted that BKV viremia was an early event that occurred after a median of 64 days from the transplant. BKV genotype I and IV were identified as the replicating strains in 23 (85%) and 4 (15%) patients, respectively, and no case showed genotype II replication. The frequency of viremia was higher in presence of donor/recipient BKV genotype mismatch, but it was not significant. Despite immunosuppressive reduction, 12 patients evolved to a biopsy-proven BKVAN.
After 12 months post-transplant, the incidence of BKV viremia in the high-risk group treated with IVIg was similar to that observed in the low-risk group and markedly lower than that of the untreated high-risk group.
Discussion
There were two main findings in this study:
IVIg was found to increase NAb titers against BKV genotype I
Passive immunization with IVIg in the early post-transplant phase was associated with a lower incidence of BKV viremia and BKVAN in high-risk kidney transplant recipients.
These results help us better understand the evidence of BKV-neutralizing antibodies and how B cell immunity is involved in the prevention of BKV replication. This study shows that in high risk patients, IVIg may be considered as a prophylaxis against BKV infection
The strengths include an accurate risk stratification for BKV replication based on the quantification of NAb titers against the 3 most common BKV genotypes and a high availability of donors samples.
The limitations include its retrospective design, the relatively small number of patients who receive IVIg infusions and the use of different IVIg doses and administration schedule.
Other uses of IVIg in Transplantation:
Its used in treatment of antibody mediated rejection
It can be used in CMV infection treatment
It can be used in the treatment of Parvo B virus infection
Other uses of IVIg in transplantation:
1- Desensitization protocol pre-transplant in patients with DSA
2- Post transplant viral infection
3- Treatment of AMR
Objectives: to investigate whether the preventive administration of IVIg may reduce the incidence of BKV viremia and BKVAN in high-risk KTR. Risk stratification was based on NAb titers against the donor’s BKV strain measured on day 0.
Patients and methods:
A retrospective study.
Included 174 with available NAb titers measured on day 0
Patients with NAb titers below 4 log10 IC50 against the donor’s strain (which was determined by measuring NAb titers in the donor’s sera) were considered at high-risk.
Patients were classified into 3 groups:
1- High risk (n=44): Patients with low NAb titer who received IVIg treatment for secondary immunodeficiency (SID) or for prevention or treatment of antibody-
mediated rejection (AMR) during the first 3 posttransplant months.
2- High risk untreated (n=41): with low NA tite
3- Low risk (n=89): high titre and did not receive IVIg
BKV viremia were assessed at: day 0, every month in the first 6 posttransplant months, and every 3 months thereafter till 12 months.
Allograft biopsies were performed in case of graft dysfunction,detection of DSA, or sustained BKV viremia
NAb Assay: NAb titers were measured at day 0; at the third, sixth, and 12th posttransplant months; and at the onset of viremia. Additional measurements at the first and second posttransplant months were performed in patients who received IVIg infusions.
Results:
IVIg administration increases BKV NAb titers in KTR:
– At 1 posttransplant month, when the majority of patients (93%) had already received the first IVIg injection, the mean NAb titers significantly increased tand remained at these levels for the subsequent 2 months. then decrease to initial level between 6-12 months.
-Twenty-nine of the 32 patients (91%) at high risk for BKV genotype I replication were capable of reaching a BKV NAb titer above the threshold. the remaining three patients received 2nd and 3rd dose of IVIg and the titer increased.
-Only 2 and 1 patients among those with a high risk of replication for BKV
genotype II and genotype IV, respectively, were capable of obtaining a
BKV NAb titer above the threshold.
IVIg administration decreases the incidence of both BKV viremia and BKVN:
BKV viremia was observed in 27 (15.5%) of the 174 study patients at 1-year.
The median (IQR) onset was 64 (47.5-128) days
BK genotype I and IV were identified as the replicating strains in 23 (85%) and 4 (15%) patients.
12 (6.9%) patients evolved to a biopsy-proven BKVN which developed at a median of 93 days.
The median peak viral load was higher in the subset of patients with viremia who developed BKVN.
At 12 posttransplant months:
The incidence of BKV viremia in the high-risk group treated with IVIg (6.8%, 3 /44 patients) was similar to that observed in the low-risk group (10.1%, 9 of 88 patients) and markedly lower than that of the untreated high-risk group(36.6%; 15 of 41 patients) [ P < .001].
The median peak viral load was significantly lower in the high risk group treated with IVIg compared with the low-risk group and the untreated high risk (P = .025)
in multivariate analysis: the D0 NAb titer and the treatment groups were the independent predictors of viremia.
The incidence of BKVN was(4.5% [2 cases] in the high-risk group treated with IVIg, 2.2% [2 cases] in the low-risk group, and 19.5% [8 cases] in untreated high-risk patients; (P = .001).
Conclusion:
The results provide proof-of-concept evidence that IVIg administration is capable of preventing BKV viremia and BKVN in KTR with low NAb titers.
INTRODUCTION
·BKV infections are a major concern following kidney transplantation, with BKV-associated nephropathy and graft loss.
·Regular screening and immunosuppressive therapy is the only viable strategy to control BKV replication, but it is associated with an increased risk of DSA and acute rejection.
·IVIg is proposed as a preventive and supportive treatment against BKV infections.
·Humoral immunity is essential for preventing BKV replication in KTR. PATIENTS AND METHODS
Patients retrospectively divided into the following 3 risk categories for BKV replication:
Patients with low NAb titers (“high-risk”) who received IVIg for the first 3 posttransplant months (n = 44),
Patients with low NAb titers (“high-risk”) who did not undergo IVIg treatment (n = 41), and
Patients with high NAb titers (“low-risk”) who did not receive IVIg (n = 89)
RESULTS
·At 12 posttransplant months, the incidence of BKV viremia in the high-risk group treated with IVIg (6.8%) was similar to that observed in the low-risk group (10.1%) and markedly lower than that of the untreated high-risk group (36.6%; P < .001).
·Similar results were observed with regard to BKVAN. DISCUSSION
·It was discovered that IVIg elevated NAb titers against BKV genotype I (i.e., the genotype that is mostly predominate) over the protective threshold.
·In high-risk KTR, passive vaccination with IVIg during the first posttransplant phase was linked to a considerably decreased incidence of BKV viremia and BKVAN.
·The KTR’s ability to neutralize BKV replication is greatly aided by the anti-BKV antibody-mediated reaction.
·For the clinical purpose of risk stratification of BKV-related illness, NAb titers against the donor’s strain assessed before KT are helpful.
·When recipients have low BKV NAb titers, high donor seroreactivity can increase the probability of BKV reproduction.
· BKVAN incidence in the high-risk group receiving IVIg was as low as 4.5%.
· B-cell immunity and B-cell-neutralizing antibodies are crucial in preventing BKV replication.
·The inhibition of active BKV replication is predominantly mediated by T-cell immunity.
·The potential effectiveness of IVIg administration in the treatment of BKV replication is still up for debate due to the concurrent use of other antiviral therapies and/or the tapering of immunosuppression.
·mTOR inhibitors may be protective against BKV replication.
·The current study is the first to show that IVIg infusion could be a useful tactic for stopping BKV proliferation in KTR.
========================================================= What are the other uses of IVIG in transplantation?
Viral Inections post transplantation.
Desensitization protocol and treatment of acute rejection.
Intravenous immunoglobulin as a preventive strategy against BK virus viremia and BKV-associated nephropathy in kidney transplant recipients—Results from a proof-of-concept study. Introduction:
BKV infection post kidney transplant is considered one of the most common viral infection and unfortunately no definitive therapy for it except reduction of immunosuppression drugs and serial screening, BKV replication occurring in 30%-50% of all kidney transplant recipients (KTR). BKV-associated nephropathy (BKVAN) can affect up to 10% of BKV-infected KTR, potentially leading to kidney dysfunction and graft loss. Aim of the work:
we sought to know whether the preventive administration of IVIg may reduce the incidence of BKV viremia and BKVAN in high-risk KTR. Risk stratification was based on NAb titers against the donor’s BKV strain measured on day 0. Patients and methods:
It is retrospective study which KTR followed in the Strasbourg University Hospital from July 2012 and December 2017 (n = 174) were retrospectively divided into the following 3 risk categories for BKV replication: (1) patients with low NAb titers (“high-risk”) who received IVIg for the first 3 post-transplant months (n = 44), (2) patients with low NAb titers (“high-risk”) who did not undergo IVIg treatment (n = 41), and (3) patients with high NAb titers (“low-risk”) who did not receive IVIg (n = 89), and IVIg were infused either as a preventive or curative treatment of AMR or in patients diagnosed with SID. Patients received 0.4 g/kg IVIg doses every 3 weeks – with a total number of doses ranging from 1 to 3. RESULTS. IVIg administration increases BKV NAb titers in KTR.
At 1 post-transplant month, when the majority of patients (93%) had already received the first IVIg injection, the mean NAb titers significantly increased to 3.82 (0.61) log10 IC50 and remained at these levels for the subsequent 2 months, in contrast In the 26 high-risk patients without IVIg and no BKV viremia, there were no significant differences in BKV NAb titers measured on the day of transplantation and 1 year thereafter. IVIg administration decreases the incidence of both BKV viremia and BKVAN in KTR.
At 12 post-transplant months, the incidence of BKV viremia in the high-risk group treated with IVIg was similar to that observed in the low-risk group and markedly lower than that of the untreated high-risk group, and the median peak viral load was significantly lower in the high risk group treated with IVIg (4.16 log10 copies/mL) compared with the low-risk group (5.03 log10 copies/mL) and the untreated high risk group . Conclusion:
IVIg were found to increase NAb titers against BKV genotype I over the protective threshold of 4 log10 IC50.Second, passive immunization with IVIg in the early post-transplant phase was associated with a significantly lower incidence of both BKV viremia and BKVAN in high-risk KTR. strengths :
an accurate risk stratification for BKV replication based on the quantification of NAb titers against the 3 most common BKV genotypes and a high availability of donors samples. Limitation:
Retrospective design.
The relatively small number of patients who received IVIg infusions.
The use of different IVIg doses and administration schedule. Other uses of IVIG in transplantation?
-Desensitization protocol in ABO and HLA incompatible transplantation.
-Antibody mediated rejections.
-Viral infection such as (Parvovirus, CMV and BKVN).
I agree with your analysis of strengths and limitations, and summary of this article.I agree with your analysis of the level of evidence this article provides.
Intravenous immunoglobulin as a preventive strategy against BK virus viremia and BKV-associated nephropathy in kidney transplant recipients—Results from a proof-of-concept study Introduction:
BKV infection is a major concern following kidney transplantation, potentially leading to kidney dysfunction and graft loss.
No specific antiviral treatment is available to control BKV replication, leading to increased risk of DSA and acute rejection.
IVIg administration is a potential treatment for BKV infections but should be interpreted cautiously due to methodological limitations.
Humoral immunity is essential for preventing BKV replication in KTR, with NAb titers lower than 4 log10 IC50 associated with increased risk.
IVIg can reduce the incidence of BKV viremia and BKVAN in high-risk KTR by increasing NAb titers.
The Aim of the Study:
A retrospective nonrandomized study on 174 kidney transplant patients To investigate whether the preventive administration of IVIg may reduce the incidence of BKV viremia and BKVAN in high-risk KTR.
Inclusion criteria:
All cases with available NAb titers measured on day 0 were deemed eligible.
Exclusion criteria:
patient or graft survival lower than 3 months. Patients with NAb titers below 4 log 10IC50 were considered high-risk. The most common viral genotype (genotype I) was used as reference for patients with negative BKV DNA load.
The study patients (n = 174) were divided into 3 risk categories for BKV replication:
A- High-risk patients who received IVIg treatment for 2ry immunodeficiency (SID) or AMR for the first 3 posttransplant months (n = 44) .
B- Low-risk patients with low NAb titers. who did not undergo IVIg treatment (n = 41).
C- High NAb titers (low-risk) who did not receive IVIg (n = 89).
Secondary immunity was defined as IgG levels <400 mg/dL or 800 mg/dL in the presence of concurrent infection.
Low-risk patients were excluded due to ethical approval from DC-2013-1990.
The study examined the preventive role of IVIg in the first 3 post- transplant months because BKV replication generally occurs early following KT.
Immunosuppressive regimens:
IS therapy after KT included basiliximab or thymoglobulin, calcineurin inhibitor, MMF, mTOR inhibitor, and steroids.
Target trough levels of tacrolimus, ciclosporin, everolimus, and mycophenolic acid were achieved with steroid pulses at 250 mg and 1 mg/kg/day oral steroids.
Steroid administration was continued in patients at high immunological risk or with acute rejection.
The result:
At 12 post-transplant months:
The incidence of BKV viremia in the high-risk group treated with IVIg was similar to that observed in the low-risk group and markedly lower than that of the untreated high-risk group .
Similar results were observed regarding BKVAN. The investigators found that, there was no difference in the rate of BKV replication between the high and low risk groups( 6.8% vs 10.1%). However, those who received IVIG had significant lower rate of BKV replication compared to those who didn’t given IVIG. Discussion:
IVIg can increase NAb titers against BKV genotype I which is the most common variant over the protective threshold of 4 log10 IC50. Administration of IVIg as passive immunization in the early posttransplant period lead to significant decrease of the incidence of BKV viremia and BKVAN in high-risk KTR .
The possible utility of IVIg administration in the management of BKV replication is controversial due to the concomitant use of other antiviral strategies and/or immunosuppression reduction. The strength of this study is the precise risk stratification for BKV replication due to the quantification of NAb titers against the 3 most common BKV genotypes and availability of donors’ samples. Limitations were being a retrospective study with small number of included patients who Took IVIg infusions, and the use of different IVIg doses and administration schedule.
The strengths of the study :
The accurate risk stratification for BKV replication based on the quantification of NAb titer against the 3 most common BKV genotypes and a high availability of donors’ samples.
The limitations of the study :
1-Retrospective design.
2-The relatively small number of patients who received IVIg infusions.
3- The use of different IVIg doses and ad- ministration schedule.
Conclusion:
The study results add to the growing amount of evidence showing that BKV-neutralizing antibodies and B cell immunity play a key role in the prevention of BKV replication. Conversely, T cell immunity is preferentially involved in the control of active BKV replication. IVIg may be a valuable strategy for preventing BKV replication. What are the other uses of IVIG in transplantation?
Desensitization protocols (in ABO or HLA incompatible transplantation)
Treatment of antibody-mediated rejection (AMR).
IVIG is useful in the treatment and prevention of post-transplant infectious complications including cytomegalovirus, parvovirus B19 and polyoma BK virus. GVHD treatment in HSCT
I note that reducing immunosuppression is the key step. I appreciate your steps when considering retransplantation. None of the drugs mentioned have any conclusive proof of their efficacy in BKV
Intravenous immunoglobulin as a preventive strategy against BK virus viremia and BKV-associated nephropathy in kidney transplant recipients—Results from a proof-of-concept study Introduction
The only available strategy to control BKV replication is regular screening of BKV viremia or viruria accompanied by a reduction of immunosuppressive therapy .
This approach is successful only in 50%-80% of cases and is associated with an increased risk of developing DSA and acute rejection.
IVIg can exert a neutralizing activity against the most common BKV gnotypes.
Aim of the study:
To investigate whether the preventive administration of IVIg may reduce the incidence of BKV viremia and BKVAN in high-risk KTR.
The risk stratification was based on NAb titers against the donor’s BKV strain measured on day 0.
PATIENTS AND METHODS This is a retrospective nonrandomized study Inclusion criteria: All cases with available NAb titers measured on day 0 posttransplant. Exclusion criteria:
Patient or graft survival lower than 3 months.
Patients with NAb titers below 4 log10 IC50 against the donor’s strain were considered at high-risk.
Patients were divided into 3 groups , 2 high risk groups depending on the Nab titer and whether received IVIG for treatment AR and one low risk group.
Group 1: patients with low NAb titers (“high-risk”) who received IVIg for the first 3 posttransplant months (n = 44), group 2 patients with low NAb titers (“high-risk”) who did not undergo IVIg treatment (n = 41), and group 3 patients with high NAb titers (“low-risk”) who did not receive IVIg (n = 89).
IS regimen and monitoring of BKV infection
· Were as per protocol of the center of the study. Neutralization assay
NAb titers (for the three most common BKV genotypes) were measured at day 0; at the third, sixth, and 12th posttransplant months; and at the onset of viremia.
Additional measurements at the first and second posttransplant months were performed in patients who received IVIg infusions for AR.
IVIg therapy
IVIg were infused either as a preventive or curative treatment of AMR or in patients diagnosed with secondary immunodeficiency (SID).
Patients received 0.4 g/kg IVIg doses every 3 weeks – with a total number of doses ranging from 1 to 3 – according to their IgG levels.
Patients with de novo DSA, preformed DSA, or biopsy-proven AMR were treated with three 2 g/kg doses of IVIg every 3 weeks.
Results:
The preventive role of IVIg in the first 3 and at 12 months posttransplant were examined.
IVIg administration increases BKV NAb titers over the protective threshold of 4 log10 IC50 in KTR
At 12 posttransplant months, the incidence of BKV viremia in the high-risk group treated with IVIg (6.8%) was similar to that observed in the low-risk group (10.1%) and markedly lower than that of the untreated high-risk group (36.6%).
Conclusion
· IVIg administration in the early posttransplant phase decreases the incidence of both BKV viremia and BKVAN in high-risk KTR.
The limitation of the study:
Retrospective study
The relatively small number of patients who received IVIg infusions and the use of different IVIg doses.
Strength of the study
In this study they stratify the risk for BKV replication based on the quantification of NAb titers against the 3 most common BKV genotypes.
This probably considered as accurate risk stratification.
I agree with your analysis of strengths and limitations, and summary of this article.I agree with your analysis of the level of evidence this article provides.
1-Please summarise this article. Introduction; –BK virus (BKV) replication occurs frequently in kidney transplant recipients (KTR), –Potentially leading to BKV-associated nephropathy (BKVAN) and graft loss. –Patients with high titers of BKV-neutralizing antibodies (NAbs) are protected against BKV replication, and intravenous immunoglobulin (IVIg) infusion can increase NAb titers. Aim; –In current study, they sought to investigate whether the preventive administration of IVIg may reduce the incidence of BKV viremia and BKVAN in high-risk KTR. –Risk stratification was based on NAb titers against the donor’s BKV strain measured on day 0 of transplantation. Methods; –Based on NAb titers on the day of transplantation (Day 0) , KTR followed in the Strasbourg University Hospital (between July 2012 and December 2017). – (174 Patients) were retrospectively divided into the following 3 risk categories for BKV replication:
1- ( 44 ) Patients with low NAb titers (“high-risk”) who received IVIg for the first 3 post transplant months,
2- ( 41 ) Patients with low NAb titers (“high-risk”) who did not undergo IVIg treatment,
3- ( 89 ) Patients with high NAb titers (“low-risk”) who did not receive IVIg. Results; –At 12 post transplant months, the incidence of BKV viremia in the high-risk group treated with IVIg (6.8%) was similar to that observed in the low-risk group (10.1%) and markedly lower than that of the untreated high-risk group (36.6%; P < .001). –Similar results were observed with regard to BKVAN. Conclusion; –IVIg may be more useful as a preventive – rather than curative – strategy. –As far as published clinical studies are concerned, the potential utility of IVIg administration in the management of BKV replication is still debatable owing to the concomitant use of other antiviral strategies and/or immunosuppression tapering. –In addition, IVIg have been previously administered with curative intent or even as a rescue treatment. Strength; –The current study is the first to demonstrate that IVIg infusion may be a valuable strategy for preventing BKV replication in KTR. –Including an accurate risk stratification for BKV replication based on the quantification of NAb titers against the 3 most common BKV genotypes and a high availability of donors’ samples. Limitation; –Its retrospective design, the relatively small number of patients who received IVIg infusions, and the use of different IVIg doses and administration schedule.
2-What are the other uses of IVIG in transplantation? –Desensitization protocols in (ABO or HLA incompatible transplantation). –ABMR treatment and prevention after solid organ transplantation. –Adjunctive therapy in post-transplant infectious complications:(CMV, parvovirus B19 , BKVAN). –GVHD treatment in adult bone marrow transplant patients. –De novo DSA without concurrent antibody-mediated rejection. –Post exposure prophylaxis;of (hepatitis A and B, tetanus, rabies, diphtheria, botulism, varicella-zoster, respiratory syncytial virus, and cytomegalovirus infections). –Autoimmune and Inflammatory disorders;(inflammatory diseases such as Kawasaki disease, Guillain-Barre syndrome, myasthenia gravis, dermatomyositis and demyelinating polyneuropathy). –Other conditions; include (toxic epidermal necrolysis and Stevens-Johnson syndrome, neonatal sepsis , Henoch-Schönlein purpura, and toxic shock syndrome). References; Up To Date: Overview of intravenous immune globulin (IVIG) therapy
I agree with your analysis of strengths and limitations, and summary of this article.I agree with your analysis of the level of evidence this article provides.
Introduction:
BK virus (BKV) infections is major complication and highly prevalent among all kidney transplant recipients (KTR). It can result in BKV-associated nephropathy, potentially leading to kidney dysfunction and graft loss.
There is no specific treatment for BKV, reduction of immunosuppression is the mainstay of treatment in these conditions. This approach has variable success and may increase risk of rejection.
Previous study showed low level of BKV-Neutralizing Antibodies (Nab) increase the risk of viral replication. IVIg has been proposed as supportive treatment against BKV as it has neutralizing activity against the most common BKV genotypes.
Aim of the Study:
To investigate the the preventive role of IVIG in reducing the incidence of BKV viremia and BKVAN in KTR.
Patient And Method: Study patients:
-Retrospectively study reviewed the clinical records of adult patients who underwent KT in the Strasbourg University Hospital between
July 2012 and December 2017. – Included; all cases with available NAb titers measured on day 0
–Excluded; patient or graft survival lower than 3 months, those without Nab, low risk group who receive IVIG during the first year.
– Recipient with BKV- NAb titers < below 4 log10 IC50 against the donor’s strain were considered at high-risk. – Patients divided into the following 3 risk categories for BKV replication:
(1) high-risk patients; those with low Nab titers, “who received IVIg in the first 3 months post KT for secondary immunodeficiency (SID) before BKV replication (n = 44).
(2 high-risk patients; patients with low NAb titers; who did not undergo IVIg treatment during the first year of KT (n = 41)
(3 low-risk patients; patients with high NAb titers ; who did not receive IVIg (n = 89).
-Secondary immunodeficiency (SID) was defined either as:
(1) IgG levels <400 mg/dL or
(2) IgG levels between 400 and 800 mg/dL in the presence of a concurrent infection. IVIg therapy As a preventive or curative treatment of AMR or in patients diagnosed with SID. Immunosuppressive regimens
-Induction with basiliximab or thymoglobulin based on the recipient’s immunological risk.
-Maintenance; a CNI (ciclosporin or tacrolimus) with (MMF) or a (mTORi)) and steroids.
Monitoring of BKV infections
– BKV plasma PCR monitored at ; day 0, monthly in the first 6, and every 3 months thereafter (until 1 year following KT).
– Allograft biopsies( including SV-40 stain) done in case of graft dysfunction, detection of DSA, or sustained BKV viremia.
– BKV genotyping was performed in all BKV DNA-positive recipients.
Neutralization assay
-NAb titers were measured at day 0; at the third, sixth, and 12th ; and at the onset of viremia. Additional measurements in patients who received IVIg infusions at the first and second posttransplant months were performed.
– Nab titer; defined as the sample dilution that resulted in a 50% inhibition of pseudovirion infectivity (IC50) – was expressed as log10 of IC50.
RESULTS
– Genotype 1 was the most prevalent among both donors ( 79%) and recipients (83%).
– High risk group who received IVIG in the absence of BKV viremia: BKV Nab titer was significantly low before IVIG and significantly increases after IVIG above the threshold of 4 log10.
-High-risk patients without IVIg and no BKV viremia, there were no significant differences in BKV NAb titers measured on the day of transplantation and 1 year thereafter.
-BKV viremia total incidence at 1 posttransplant year: 15.5%. –IVIg administration decreases the incidence of both BKV viremia and BKVAN in KTR – At 12 posttransplant months, the incidence of BKV viremia in the high-risk group treated with IVIg (6.8%) was similar to that observed in the low-risk group (10.1%) and markedly lower than that of the untreated high-risk group (36.6%).
– The median peak viral load was significantly lower in the high risk group treated with IVIg (4.16 log10 copies/mL) compared with
the low-risk group and the untreated high risk group.
-Multivariate analysis did not reveal significant associations between immunosuppressive therapies and the incidence of BKV viremia.
– The occurrence of BK viremia was independently associated with D0 Nab titers and patient group in multivariate analysis.
-Patients in the high-risk untreated group had a 24-fold increase in the risk of developing BK viremia compared with the low-risk group
– The incidence of BKVAN at 12 posttransplant months 4.5% in the high-risk group treated with IVIg, 2.2% in the low-risk group, and
19.5% in untreated high-risk patients.
Conclusion:
-IVIg were found to increase NAb titers against BKV genotype and significantly lower incidence of both BKV viremia and BKVAN in high-risk KTR.
Limitations:
– Retrospective nonrandomized study
– The use of everolimus was more frequent for patients who received IVIG (which may has protective against BKV replication)
– Small sample size.
– The use of different IVIg doses and administration schedule
Strength:
-The first study demonstrate role of IVIg for preventing BKV replication in KTR.
-Accurate risk stratification for BKV replication based on the quantification of NAb titers.
What are the other uses of IVIG in transplantation?
-Desensitization in ABO or HLA incompatible transplantation.
– ABMR treatment and prevention.
– Adjunctive therapy in treatment of infection: resistant CMV, parvovirus B19 ,BKVAN.
– Post exposure prophylaxis.
– GVHD treatment in HSCT
Reference;
Jordan SC, Toyoda M, Kahwaji J, Vo AA. Clinical aspects of intravenous immunoglobulin use in solid organ transplant recipients. Am J Transplant. 2011 Feb;11(2):196-202. doi: 10.1111/j.1600-6143.2010.03400.x. Epub 2011 Jan 10. PMID: 21219579.
I agree with your analysis of strengths and limitations, and summary of this article.I agree with your analysis of the level of evidence this article provides.
The Aim of the Study ;
———————————-
To investigate whether the preventive administration of IVIg may reduce the incidence of BKV viremia and BKVAN in high-risk KTR.
The type of the study ;
—————————–
a retrospective non randomized study.
The study area ;
—————————
Strasbourg University Hospital between July 2012 and December 2017.
Population ;
———————————
174 kidney transplant patients .
Inclusion criteria ;
———————————–
All cases with available NAb titers measured on day 0 were deemed eligible.
Exclusion criteria ;
——————————————
patient or graft survival lower than 3 months.
The method ;
————————
Based on NAb titers on the day of transplantation, KTR followed in the Strasbourg University Hospital (n = 174) were retrospectively divided into the following 3 risk categories for BKV replication:
(1) patients with low NAb titers (“high-risk”) who received IVIg for the first 3 posttransplant months (n = 44) .
(2) patients with low NAb titers (“high-risk”) who did not undergo IVIg treatment (n = 41).
(3) patients with high NAb titers (“low-risk”) who did not receive IVIg (n = 89).
The study examined the preventive role of IVIg in the first 3 post- transplant months because BKV replication generally occurs early following KT.
The result ;
—————————————–
At 12 post transplant months ;
1-The incidence of BKV viremia in the high-risk group treated with IVIg was similar to that observed in the low-risk group and markedly lower than that of the untreated high-risk group .
2-Similar results were observed with regard to BKVAN.
The strengths of the study ; –
—————————————-
1- an accurate risk stratification for BKV replication based on the quantification of
NAb titers against the 3 most common BKV genotypes and a high availability of donors’ samples.
The limitations of the study ;
——————————————–
1-Retrospective design .
2-The relatively small number of patients who received IVIg infusions .
3- The use of different IVIg doses and ad- ministration schedule.
Conclusion ;
——————–
1-The study results add to the growing amount of evidence showing that BKV-neutralizing antibodies and B cell immunity play a key role in the prevention of BKV replication. Conversely, T cell immunity is preferentially involved in the control of active BKV replication.
2- IVIg may be a valuable strategy for preventing BKV replication.
What are the other uses of IVIG in transplantation?
————————————————————————-
1- In desensitization protocols .
2- treatment of antibody-mediated rejection (AMR) .
3- IVIG is useful in the treatment and prevention of post transplant infectious complications including cytomegalovirus, parvovirus B19 and polyoma BK virus.
Introduction
BK virus infections are still a major concern following Kidney transplantation, with BKV replication occurring in 30%-50% of all kidney transplant recipients (KTR).
BK virus associated nephropathy (BKVAN) can affect up to 10% of BKV -infected KTR, potentially leading to kidney dysfunction and graft loss.
No specific antiviral treatmnent is currently available against BKV
BKV infections. 4-6 Regular screening of BKV viremia or viruria accompanied by a reduction of immunosuppressive therapy re – mains the only viable strategy to control BKV replication.
NAb titers against the donor’s BKV strain lower than 4 log IC50 at the time of transplantation are associated with an increased risk of BKV replication following kidney transplantation.
Based on NAb titers on day 0 and the prescription of IVIg infusion, the study patients (n = 174) were divided into the following 3 risk categories for BKV replication, patients with low NAb.
BENOTMANE ET Al. titers (“high-risk patients”) who received IVIg treatment for second – ary immunodeficiency (SID) or for prevention or treatment of antibody-mediated rejection (AMR) during the first 3 posttransplant months and before BKV replication (n = 44), patients with low NAb titers (“high-risk patients”) who did not undergo IVIg treatment during the first year of kidney transplantation (n = 41), and patients with high NAb titers (“low-risk patients”) who did not receive IVIg (n = 89).
Induction therapy
Donor NAb and/or replicative strain available, n (%) 29 (70.7) 39 (88.6) 65 (73.0) .08.
At 1 posttransplant month, when the majority of patients (93%) had already received the first IVIg injection, the mean NAb titers significantly increased to 3.82 (0.61) log IC50 and remained at these levels for the subsequent 2 months
A decrease in NAb titers occurred afterwards, with a return to the initial levels between 6 and 12 posttransplant months
Among these 41 patients, there was a high risk of replication for BKV genotype I, genotype II, and genotype IV in 32, 7, and 2 cases, respectively.
2 and 1 patients among those with a high risk of replication for BKV genotype II and genotype IV, respectively, were capable of obtaining a BKV NAb titer above the threshold of 4 log IC50. Genotype II
At 12 posttransplant months, the incidence of BKV viremia in the high-risk group treated with IVIg (6.8%, 3 of 44 patients) was similar to that observed in the low-risk group (10.1%, 9 of 88 patients) and markedly lower than that of the untreated high-risk group
The median peak viral load was significantly lower in the highrisk group treated with IVIg (4.16 log copies/mL) compared with the low-risk group (5.03 log copies/mL) and the untreated highrisk group
Similar figures were observed with regard to the incidence of BKVAN at 12 posttransplant months Discussion
There are 2 principal findings from this study. First, IVIg were found to increase NAb titers against BKV genotype I (ie, the largely predominant genotype) over the protective threshold of 4 log IC50.
Because IVIg preparations contain high levels of BKV NAbs, we sought to assess whether among these patients, those receiving IVIg for SID or AMR early after kidney transplantation may be protected against BKV replication.
In the high-risk treated group, only 3 cases received high dose IVIg. Because IVIg preparations contain high levels of BKV NAbs, we sought to assess whether among these patients, those receiving IVIg for SID or AMR early after kidney transplantation may be protected against BKV replication.
In the high-risk treated group, only 3 cases received highdose IVIg
These patients were not excluded from the analysis for the following reasons: we have previously shown than BKV NAb titers against genotype I increased in a similar fashion after low or high IVIg doses22 .despite a higher burden of immunosuppression. Days from transplantation
3 high-risk patients treated with IVIg who had evidence of BKV viremia were unable to achieve the protective threshold of 4 log IC50.
A high donor seroreactivity can act as a risk factor for BKV replication especially in recipients with low BKV NAb titers..
The donor’s serotype was unavailable for the third patient, the recipient had a NAb titer of 4.69 log IC50 at the date of first BKV viremia .
The unavailability of urine samples does not allow excluding that BKV replication may have occurred before IVIg infusion
Another important finding from our study is TA B L E 2 Characteristics of patients with BKV viremia and/or BKV -associated nephropathy according to NAb titers at the day of transplantation and the infusion of IVIg.
Findings
BKV -associated nephropathy (BKVAN) can affect up to 10% of BKV -infected KTR, potentially leading to kidney dysfunction and graft loss..
In the 26 high-risk patients without IVIg and no BKV viremia, there were no significant differences in BKV NAb titers measured on the day of transplantation and 1 year thereafter (3.1 log IC50 vs 3.2 log IC50, respectively, P = .20, Figure S2).
The median peak viral load was significantly lower in the highrisk group treated with IVIg (4.16 log copies/mL) compared with the low-risk group (5.03 log copies/mL) and the untreated highrisk group (4.97 log copies/mL, P = .025; Table 2). Recipient NAb levels
The inhibitory effect was more pronounced when immunoglobulins were coincubated with BKV virions before experimental cell infection compared with their use in the postinfection phase
These in vitro results suggested that IVIg may be more useful as a preventive – rather than curative – strategy.
Our study is limited by its retrospective design, the relatively small number of patients who received IVIg infusions, and the use of different IVIg doses and administration schedule.
These caveats notwithstanding, we provide proof-of-concept evidence that IVIg administration is capable of preventing BKV viremia and BKVAN in KTR with low NAb titers.
Other use of IVIg
Antibody mediated rejection.
Desensitization protocol
Post transplant infection and malignancies
Handbook of Kidney Transplantation
Gabriel M. Danovitch, MD
Intravenous immunoglobulin as a preventive strategy against BK virus viremia and BKV-associated nephropathy in kidney transplant recipients—Results from a proof-of-concept study.
_______________________________ ◇ Introduction ▪︎BK virus (BKV) infections are still a major concern following kidney transplantation, with BKV replication occurring in 30%-50% of all KTR.
▪︎BKV-associated nephropathy (BKVAN) can affect up to 10% of BKV-infected KTR, potentially leading to kidney dysfunction and graft loss.
▪︎No specific antiviral treatment is currently available against BKV infections.
▪︎Regular screening of BKV viremia or viruria accompanied by a reduction of IS therapy remains the only viable strategy to control BKV replication.
▪︎It is associated with an increased risk of developing DSA and acute rejection. ▪︎Intravenous immunoglobulin (IVIg) administration has been empirically proposed as a preemptive and supportive treatment against BKV infections.
▪︎Humoral immunity plays a crucial role for the prevention of BKV replication in KTR, with high titers of BKV-neutralizing antibodies (Nab) having a protective effect.
▪︎IVIg can exert a clinically relevant neutralizing activity against the most common BKV genotypes, with IVIg infusion resulting in increased NAb titers
among KTR.
◇ Methodology:
▪︎This study investigated whether early IVIg administration prevents BKV replication in patients with low NAb titers (<4 log10 against the BKV-specific genotype).
▪︎Based on NAb titers on the day of transplantation, KTR followed in the Strasbourg University Hospital (n = 174) were retrospectively divided into the following 3 risk categories for BKV replication:
(1) patients with low NAb titers (“high-risk”) who received IVIg for the first 3 post- transplant months (n = 44)
(2) patients with low NAb titers (“high-risk”) who did not undergo IVIg treatment (n = 41), (3) patients with high NAb titers (“low-risk”) who did not receive IVIg (n = 89).
◇ Results
▪︎At 12 posttransplant months, the incidence of BKV viremia in the high-risk group treated with IVIg (6.8%) was similar to that observed in the low-risk group (10.1%) and markedly lower than that of the untreated high-risk group (36.6%; P < .001). ▪︎Similar results were observed with regard to BKVAN.
◇ Strengths of the study:
1. An accurate risk stratification for BKV replication based on the quantification of NAb titers against the 3 most common BKV genotypes
2. High availability of donors’ samples.
◇ Limitations of the study:
1. A retrospective design.
2. The relatively small number of patients who received IVIg infusions.
3. The use of different IVIg doses and administration schedule.
◇ Conclusion:
▪︎This study investigated whether the preventive administration of IVIg may reduce the incidence of BKV viremia and BKVAN in high-risk KTR.
▪︎Risk stratification was based on NAb titers against the donor’s BKV strain measured on day.
▪︎This study concluded that IVIg may be a valuable strategy for preventing BKV replication.
☆ What are the other uses of IVIG in transplantation?
IVIG can be used (1):
▪︎In desensitization protocols.
▪︎For treatment of antibody-mediated rejection (AMR)IVIG3
Also, IVIG is useful in:
▪︎Treatment and prevention of posttransplant infectious complications including cytomegalovirus, parvovirus B19.
_______________________
▪︎Reference:
(1) S C Jordan et al. . Clinical aspects of intravenous immunoglobulin use in solid organ transplant recipients. Am J Transplant. 2011 Feb.
I agree with your analysis of strengths and limitations, and summary of this article.That is a well-structured reply. Typing the whole sentence in bold amounts to shouting, however.
The reactivation of dormant BKV infection following immune suppression or transmission to the recipient after a kidney transplant has been one of the major concerns because of the possible result of allograft loss. Unfortunately, there are no specific antiviral agents against BKV infection, hence leaving more room for concern in kidney transplantation. It has been observed that patients with high titers of BKV-neutralizing antibodies (NAbs) are protected against BKV replication, and intravenous immunoglobulin (IVIg) infusion can increase NAb titers.
Aim of the study
To investigate if the preventive administration of IVIg may reduce the incidence of BK viremia and BKVAN in high-risk KTP.
Patient and Method
it’s a retrospective study of adults who underwent kidney transplant surgery
NAb titers level were measured at day, 0, then the 3rd, 6th, and the 12th-month post-KTP
Inclusion criteria
All cases with available NAb titers measured on day 0 of the surgery
Exclusion criteria
patient or graft survival lower than 3 months
patients with NAb titers below 4 log10 IC50 against the donor’s strain
Classification of study group based on the NAb titre at day 0
Patients with low NAb titers (“high-risk patients”) who received IVIg treatment for secondary immunodeficiency – (no -44)
2) patients with low NAb titers (“high-risk patients”) who did not undergo IVIg treatment during the first year of KTP – (no- 41)
patients with high NAb titers (“low-risk patients”) who did not receive IVIg- (no- 89)
Results
At day 0, 170 (97.7%) recipients and 120 (96.7%) donors were seropositive for at least 1 BKV genotype
In the high-risk group that received treatment with IVIg, there were 35 (79.5%), 7 (15.9%), and 2 (4.5%) cases with a high risk of replication for BKV genotype I, genotype II, and genotype IV, respectively.
BK genotype I and IV were identified as the replicating strains in 23 (85%) and 4 (15%) patients, respectively.
The frequency of viremia was higher in presence of donor/recipient BKV genotype mismatch
At 12 posttransplant months, the incidence of BKV viremia in the high-risk group treated with IVIg was similar to that observed in the low-risk group and markedly lower than that of the untreated
The median peak viral load was significantly lower in the high-risk group treated with IVIg.
Discussion
IVIg treatment was found to increase NAb titers against BKV genotype 1
passive immunization with IVIg in the early stage of KTP was associated with a significantly lower incidence of both BKV viremia and BKVAN in high-risk KTR
The measurement of NAb titer level in donors before KTP is a good way to stratify the risk of BKV-related disease
Strength of the study
accurate risk stratification for BKV replication based on NAb titers
high availability of donor samples
Limitations of the study
the small sample size of those that received IVIg treatment
is a retrospective study
the lack of a standard dose for use of IVIg treatments
Other uses of IVIg in KTP
use in the treatment of antibody-medicated rejection
use in desensitization protocol
use in the treatment of viral infections like resistant CMV Parvovirus
BKVAN affects 10% of BKV-infected KTR, with potential kidney dysfunction & graft loss.
No specific antiviral treatment is currently available.
Regular monitoring of viremia or viruria in combination with a reduction in IS treatment is the only practical method for preventing BKV replication. This method, however, only functions in 50% to 80% of situations, does not stop the progression to BKVAN, and raises the chance of acquiring DSA and AR.
The use of IVIG has been suggested as a preventative and supportive measure. The published studies, however, have significant methodological flaws, including small sample sizes, the absence of a control group, the concurrent use of additional antiviral treatments, and/or a parallel decline in IS.
The study
Retrospectively reviewed whether the preventive IVIG may reduce the incidence of BKV viremia & BKVAN in high-risk KTR.
Risk stratification based on NAb titers against the donor’s BKV strain measured on day 0.
Based on NAb titers on day 0 & the prescription of IVIG infusion, the study patients (n = 174) were divided into 3 risk categories for BKV replication:
“high-risk patients”: low NAb titers; received IVIG treatment for SID or for prevention or treatment of AMR during the first 3 post-TX months & before BKV replication (n = 44)
“High-risk patients”: low NAb titers & did not undergo IVIG during the 1styear of KT (n = 41)
“Low-risk patients”: high NAb titers & did not receive IVIG (n = 89).
Main results:
IVIG increased NAb titers against BKV genotype I (the predominant genotype) over the protective threshold of 4 log10 IC50.
In high-risk KTR, passive IVIG immunization early after TX resulted in a considerably decreased incidence of BKV viremia & BKVAN.
At 12 months post-TX, the BKV viremia in the high-risk group receiving IVIG was 6.8%, comparable to the low-risk group’s 10.1%, and significantly lower than the BKV viremia in the high-risk group receiving no treatment (36.6%). The findings of this study contribute to the mounting evidence that B cell immunity & B-cell-neutralizing antibodies are crucial in preventing BKV replication.
On the other hand, T cell immunity plays a predominant role in regulating active BKV replication.
Strengths:
Accurate risk stratification for BKV replication based on the quantification of NAb titers against the 3 most common BKV genotypes (I, II, & IV)
A high availability of donors’ samples.
Limitations:
Retrospective design
Relatively small number of patients who received IVIG infusions.
Future
A multicenter controlled randomized study (NCT 04222023) will start shortly in France to confirm these findings.
============================== 2. What are the other uses of IVIG in transplantation?
Desensitization protocols & treatment of AMR
De novo DSA without concurrent antibody-mediated rejection
BK virus replication occurs in 30%–50% of kidney transplant recipients, posing a serious risk. Up to 10% of BKV-infected KTR may develop nephropathy, causing kidney failure and graft loss. No BKV antiviral therapy exists. Only regular BKV viremia or viruria screening and immunosuppressive therapy can reduce BKV replication. It also increases donor-specific antibodies and acute rejection risk. In this situation, novel BKV prevention methods are eagerly awaited. Intravenous immunoglobulin has been shown to prevent and treat BKV infections. Due to methodological issues such as small sample sizes, the lack of a control arm, and the use of additional antiviral treatments and/or immunosuppression, the field’s findings should be interpreted cautiously.
Methods
Study patients In this article, the authors retrospectively evaluated the clinical data of adult Strasbourg University Hospital KT patients from July 2012 to December 2017. All day 0 NAb titers were eligible. Patient or graft survival below 3 months is excluded. According to our prior methods, 20 individuals with NAb titers 4 log10 IC50 against the donor’s strain were high-risk.
Immunosuppressive regimens Based on immunological risk, basiliximab or thymoglobulin induction therapy was followed by KT. Thymoglobulin treated patients with panel reactive antibodies >20% and ABO-incompatible kidney transplantation. The patient got a calcineurin inhibitor, mycophenolate mofetil, or everolimus, and steroids in the maintenance phase.
Monitoring of BKV infections BKV viremia was measured at day 0, every month in the first 6 posttransplant months, and every 3 months afterward (until 1 year following KT). BKV quantitative real-time polymerase chain reaction measured.
Neutralization assay At day 0, the third, sixth, and 12th posttransplant months, and at viremia, NAb titers were assessed. IVIg-infused patients were measured at the first and second posttransplant months.
IVIg therapy According to their IgG levels, patients got one to three 0.4 g/kg IVIg doses every three weeks. De novo DSA, preformed DSA, and biopsy-proven AMR patients received three 2 g/kg IVIg doses every three weeks.
IVIg administration increases BKV NAb titers in KTR 35 (79.5%), 7 (15.9%), and 2 (4.5%) of 44 high-risk patients treated with IVIg had a significant BKV genotype I, II, or IV replication risk. 41 SID patients received 0.4 g/kg IVIg infusions. 28 (63.6%) received 3 doses. The remaining 12 (27.3%) and 1 (2.3%) patients received 2 and 1 doses. Three (6.8%) patients got three 2 g/kg IVIg infusions to prevent or cure AMR in the first three posttransplant months. In 32, 7, and 2 of these 41 patients, respectively, there was a high chance of replication for BKV genotype I, genotype II, and genotype IV. Ninety-one percent of the 32 patients at high risk for BKV genotype I replication were able to achieve a BKV NAb titer over the threshold of 4 log10 IC50 on at least one occasion during the first three posttransplant months.
IVIg administration decreases the incidence of both BKV viremia and BKVAN in KTR 27 of 174 study patients had BKV viremia at 1 year posttransplant (15.5%). BKV viremia usually developed 64 days after KT (25th-75th percentiles: 47.5-128.5 days). Median peak viral load was 4.91 log10 copies per mL (25th-75th percentiles: 4.68-5.27). Six (22.2%) had viremia less than 90 days. In 23 (85%) and 4 (15%) patients, BK genotype I and IV replicated, while genotype II did not. 41 BKV genotype mismatches were found in 120 donor/recipient couples. Donor/recipient BKV genotype mismatch increased viremia.
Discussion This study found two main things. First, IVIg raised BKV genotype I NAb titers above 4 log10 IC50. Second, early posttransplant passive IVIg vaccination reduced BKV viremia and BKVAN in high-risk KTR. 85 patients with NAb titers <4 log10 IC50 at day 0 were considered high-risk for BKV replication in this investigation. It isinvestigated whether patients getting IVIg for SID or AMR early after KT may be protected against BKV replication due to its high BKV NAb content. Only 3 high-risk cases received high-dose IVIg. Because BKV replication occurs early after KT,2,24,25 we evaluated IVIg’s preventative function in the first three posttransplant months. At 12 posttransplant months, the high-risk group treated with IVIg had 6.8% BKV viremia, equal to the low-risk group (10.1%) and significantly lower than the untreated high-risk group (36.6%). Two of three high-risk IVIg patients with BKV viremia failed to reach the protective threshold of 4 log10 IC50. Findings of this study strengthen the case that BKV-neutralizing antibodies and B cell immunity hinder BKV replication. T cell immunity primarily controls active BKV replication. Everolimus use was the only substantial baseline difference in this retrospective nonrandomized trial. mTOR treatments may protect against BKV replication, but our study’s small number of everolimus-treated patients prevents definitive findings.
Introduction
o BKVAN affect 10% of BKV-infected KTR leading to kidney dysfunction and graft loss
o Currently, no specific antiviral treatment
o Screening of BKV accompanied by a reduction of immunosuppressive therapy is successful in only 50%-80% and does prevent BKVAN with the risk of developing DSA and acute rejection
o IVIg administration is used as a preemptive treatment against BKV infections
o High titers of BKV-neutralizing antibodies (NAb) are protective
o IVIg have a neutralizing activity against the most common BKV genotypes and resulting in increased NAb titers
o Aim of the this retrospective study: investigate whether the preventive administration of IVIg may reduce the incidence of BKV viremia and BKVAN in high-risk KTR
Patients and methods
Conducted during 2012-2017 (Strasbourg University Hospital, France)
Inclusion criteria: All cases with available NAb titers measured on day 0
Exclusion criteria: patient or graft survival lower than 3 months
Patients with NAb titers < 4 log10 against the donor’s strain were considered at high-risk
The most common viral genotype (genotype I) was taken as reference for patients with a negative BKV DNA load
Divided into 3 risk categories for BKV replication:
1. Patients with low NAb titers (high-risk patients): received IVIg treatment (0.4 g/kg IVIg doses every 3 weeks, 1-3 according to their IgG levels), (n = 41)
2. patients with low NAb titers (high-risk patients): did not recieve IVIg treatment (n = 41)
3. Patients with high NAb titers (low-risk patients):did not receive IVIg (n = 89)
BKV viremia: day 0, every month in the first 6 posttransplant months, and every 3 months thereafter (until 1 year following KT)
NAb titers: at day 0; at 3, 6, and 12th posttransplant months; and at the onset of viremia
Results
At 12 posttransplant months:
1. the incidence of BKV viremia in the high-risk group treated with IVIg (6.8%, 3 of 44 patients) was similar to that observed in the low-risk group (10.1%, 9 of 88 patients) and markedly lower than that of the untreated high-risk group (36.6%; 15 of 41 patients; P < .001)
2. Similar results with the incidence of BKVAN
Discussion
Two important findings from this study:
1. IVIg were found to increase NAb titers against BKV genotype I (ie, the largely predominant genotype) over the protective threshold of 4 log10
2. Passive immunization with IVIg in the early posttransplant phase was associated with a significantly lower incidence of both BKV viremia and BKVAN in high-risk KTR
Strengths and limitations
Strength: Accurate risk stratification for BKV replication based on the quantification of NAb titers against the 3 most common BKV genotypes and a high availability of donors’ samples
Limitations:
1. Retrospective study
2. Relatively small size
3. Use of different IVIg doses and administration schedule
Conclusions
IVIg may be valiable in the prevention of BKV replication
Further multicenter controlled randomized study are needed
What are the other uses of IVIG in transplantation?
Desensitization protocol:
As animmunomodulatory agent for highly HLA sensitizedpatients awaiting kidney transplantation
The use of IVIG was associated with acceptableoutcomes in this high risk group and was recommendedfor use in highly HLA sensitized ESRD patients to improverates of transplantation (anadian Blood Ser-vice and Canada’s National Advisory Committee on Bloodand Blood Products)
Treatment of AMR:
High-dose IVIG in treating resistant AMR episodes
There is sufficient evidence to support the use of IVIG for treatment of ARM
Prevention and treatment of infectious complications:
1. Resistant CMV infections
2. Resistant BK nephropathy
3. Chronic parvovirus B19 infections (PVB19). This includes PVB19 induced pure redcell aplasia and collapsing glomerulopathy variant of focalglomerulosclerosis
References
1. S. C. Jordan, M. Toyoda,J.Kahwaji, A.A.Vo. Clinical Aspects of Intravenous ImmunoglobulinUse in Solid Organ Transplant Recipients. American Journal of Transplantation 2011; 11: 196–202
BKV infection is an important & serious post transplant complication.
BKV activation affect 10% of BKV-infected kidney transplant recipients & can progressed to graft dysfunction & graft loss.
The only available & effective treatment is reduction of immunosuppression, but its successful in only 50-80%of cases.Also reduction of immunosuppression associated with risk of DSA development & acute rejection.
IVIg used as pre-emptive & supportive treatment against BKV infection.
BKV-neutralizing antibodies (Nab) against donor BKV strain <4log10IC50 at time of transplantation (day0) associated with increase risk of BKV replication after transplantation.
IVIg infusion result in increase Nab titer among kidney transplant recipients.
Aim of the study:
Assessment of the effect of IVIg infusion as preventive measure that reduce incidence of BKV viremia & BKVAN in high risk kidney transplant recipients.
Patients & method:
Retrospective non randomized study.
174 transplant recipient included(July 2012 – Dec 2017).
All patient included have Nab titer at day 0.
For those who have graft survival <3 months excluded from the study.
Based on Nab titer at day 0, the patient classified into 3 risk groups:
High risk group with low Nab titer & receive IVIg for SID treatment or for AMR prevention or treatment during first 3 months post transplantation.
High risk patients with low Nab titer didn’t receive IVIg during first year post transplantation.
Low risk patients with high Nab titer & didn’t receive IVIg.
Induction therapy decided according immunological risk (basiliximab or ATG).
Maintenance immunosuppression based on CNI with MMF or mTOR-I & steroid for high immunological risk patients.
BKV viral load monitored every month in first 6 months then every 3 months for first year post transplant.
Nab titer measured at day 0, 3rd, 6th &12th post transplant months & at onset of viremia.
Graft biopsy done for graft dysfunction or sustained viremia.
Result & discussion:
2 important results:
IVIg increase Nab titer against BKV genotype1 >4log10 IC50.
Passive immunization in early post transplant associated with significant lower rate of BKV viremia & BKVAN in high risk patients.
Strength of the study: Accurate risk stratification for BKV replication (high availability of donor sample & measurement of Nab titer against most common genotypes).
Limitation of the study:
Retrospective design
Relative small number of patients receive IVIg.
Use different IVIg doses & administration schedule.
Uses of IVIg in transplantation:
Desensitization
Treatment of AMR.
secondary hypogammaglobulinemia & infectious complications in SOT recipients.
treatment of resistant CMV infection & BKV nephropathy.
Aim of sudy
We have previously shown that NAb titers against the donor’s BKV strain lower than 4 log10 IC50 at the time of transplantation (day 0) are associated with an increased risk of BKV replication following KT.20 Conversely, IVIg can exerta clinically relevant neutralizing activity against the most common BKV genotypes, with IVIg infusion resulting in increased NAb titers among KTR.21,22 In this study, we sought to investigate whether the preventive administration of IVIg may reduce the incidence of BKV viremia and BKVAN in high-risk KTR. Risk stratification was based on NAb titers against the donor’s BKV strain measured on day 0
PATIENTS AND METHODS
retrospective clinical records of adult patients who underwent KT in the Strasbourg University Hospital between July 2012 and December 2017
. All cases with available NAb titers measured on day 0 were deemed eligible.
Exclusion criteria were patient or graft survival lower than 3 months
20 patients with NAb titers below 4 log10 IC50 against the donor’s strain (which was determined by measuring NAb titers in the donor’s sera) were considered at high-risk. When the donor’s specimen was unavailable, the replicating strain was considered as reference for patients showing an active BKV replication.
The most common viral genotype (genotype I) was taken as reference for patients with a negative BKV DNA load
.the study patients (n = 174) were divided into the following
3 risk categories for BKV replication:
(1) patients with low NAbtiters (“high-risk patients”) who received IVIg treatment for secondary immunodeficiency (SID) or for prevention or treatment of antibody-mediated rejection (AMR) during the first 3 posttransplant months and before BKV replication (n = 44)
(2) patients with low NAb titers (“high-risk patients”) who did not undergo IVIg treatment during the first year of KT (n = 41),
(3) patients with high NAb titers (“low-risk patients”) who did not receive IVIg (n = 89).
Allograft biopsies were performed in case of graft dysfunction, detection of DSA, or sustained BKV viremia (defined by the presence of 4 log10 copies per mL in 2 subsequent blood specimens). As of January 1, 2013, biopsies were performed systematically during the third posttransplant month. BKVAN was diagnosed and
classified according to the severity of virus-induced cytopathic effects, inflammatory infiltrates, tubular atrophy, fibrosis, and through immunohistochemistry using antib
Among the 44 high-risk patients who were treated with IVIg, we identified 35 (79.5%), 7 (15.9%), and 2 (4.5%) cases in whom there was a high risk of replication for BKV genotype I, genotype II, and genotype IV, respectively. A total of 41 patients (93.2%) received IVIg infusion at a dose of 0.4 g/kg because of SID. Of them, 28 cases (63.6%) received 3 doses. The remaining 12 (27.3%) and 1 (2.3%) patients received 2 and 1 doses, respectively. Three (6.8%) patients received 3 IVIg infusions at a dose of 2 g/kg because of preventive or curative treatment of AMR, with IVIg being administered during the first 3 posttransplant monthsodies that cross-reacted against the large T antigen of the related simian polyomavirus
Results IVIg administration decreases the incidence of both BKV viremia and BKVAN in KTR
Among these 41 patients, there was a high risk of replication for BKV genotype I, genotype II, and genotype IV in 32, 7, and 2 cases, respectively. Twenty-nine of the 32 patients (91%) at high risk for BKV genotype I replication were capable of reaching a BKV NAb titer above the threshold of 4 log10 IC50 in at least 1 occasion during the first 3 posttransplant months. The remaining 3 cases who were unable to achieve high NAb titers received 2 or 3 low-dose IVIg infusions
What are the other uses of IVIG in transplantation?
1- varicella-zoster immune globulin [VariZIG]; cytomegalovirus immune globulin [CMVIG]) may be given to hematopoietic cell transplantation (HCT) recipients who have not yet been re-immunized against certain viral infections, as postexposure prophylaxis.
2- desensitization protocols for renal transplant recipients. IVIG causes B cell apoptosis, blocks binding of donor-reactive antibodies, and may inhibit complement activation. IVIG has been used widely in
3-Intravenous immune globulin (IVIG) has been used in combination with rituximab in lung transplant recipients who developed donor specific HLA antibodies, but did not have clinical AMR, and also to treat acute AMR .
dose of IVIG for acute AMR is 0.5 to 2 g/kg, using ideal body weight for patients with obesity, given intravenously. Doses >1 g/kg are generally divided over two days.
4-HLA desensitization protocols
pretransplant HLA desensitization using a combination of high-dose IVIG and rituximab in most patients.
Living-donor transplantation pretransplant desensitization with high-dose IVIG and rituximab.
some transplant centers use a protocol that consists of low-dose intravenous immune globulins (IVIG) in combination with alternate-day plasmapheresis
In deceased-donor transplant recipients, we administer alemtuzumab 30 mg subcutaneously and IVIG 2 g/kg (maximum dose of 140 g) at the time of transplantation. subsequently give an additional dose of IVIG 2 g/kg within 7 to 14 days after transplant. Rituximab 375 mg/m2 is also given within 7 to 14 days after transplant if it has not been received within six months of the transplant.
5-Commercially available IVIG preparations contain BKPyV-neutralizing antibodies against all major genotypes
We do not routinely administer IVIG for the treatment of BKPyVAN. However, the adjunctive use of IVIG may be considered in patients with established BKPyVAN who do not respond to a reduction in immunosuppression and who also have severe hypogammaglobulinemia (ie, immunoglobulin G [IgG] <400 mg/dL).
If used, IVIG is administered at a dose of 300 mg/kg every three weeks in conjunction with a reduction in immunosuppression. We typically administer intravenous hydration with normal saline (10 to 20 mL/kg) prior to starting the infusion to mitigate the risk of acute kidney injury (AKI).
We repeat 21-day trough IgG levels after three months of therapy with the goal of maintaining an IgG level >400 mg/dL.
Limited data are available concerning the efficacy of IVIG in patients with BKPyVAN. Some observational studies have reported clearance of BKPyV viremia following IVIG therapy . However, the findings of these studies are difficult to evaluate, since other antiviral interventions were administered concurrently.
6-ABO DESENSITIZATION
Immunomodulation — IVIG is administered by many transplant centers prior to ABOI transplantation to replace immunoglobulins that are removed with plasmapheresis or immunoadsorption. In addition, IVIG may also block Fc receptors (FcR) to prevent a rebound in anti-A/B antibody titers when the plasma cells have naked receptors and, therefore, are stimulated to make more antibody. IVIG may also have immunoregulatory properties. It should be noted, however, that IVIG products may contain detectable anti-A and anti-B isoagglutinins which should be considered if high-dose IVIG is administered.
Intravenous immunoglobulin as a preventive strategy against BK virus viremia and BKV-associated nephropathy in kidney transplant recipients Results from a proof-of-concept study.
Early IVIg administration prevents BKV replication in patients with low NAb titers.
IVIg may be a valuable strategy for preventing BKV replication, as the incidence of BKV viremia in the high-risk group treated with IVIg was similar to that of the low-risk group.
KT patients with available NAb titers measured on day 0 were deemed eligible.
Exclusion criteria were patient or graft survival lower than 3 months.
Patients with NAb titers below 4 log 10IC50 were considered high-risk.
The most common viral genotype (genotype I) was used as reference for patients with negative BKV DNA load.
The study patients (n = 174) were divided into 3 risk categories for BKV replication: –
A- High-risk patients who received IVIg treatment for second-ary immunodeficiency (SID) or AMR.
B- Low-risk patients with low NAb titers.
C- And high NAb titers who did not receive IVIg.
Secondary immunity was defined as IgG levels <400 mg/dL or 800 mg/dL in the presence of concurrent infection.
Low-risk patients were excluded due to ethical approval from DC-2013-1990.
Immunosuppressive regimens
Imunosuppressive therapy after KT included basiliximab or thymoglobulin, calcineurin inhibitor, MMF, mTOR inhibitor, and steroids.
Target trough levels of tacrolimus, ciclosporin, everolimus, and mycophenolic acid were achieved with steroid pulses at 250 mg and 1 mg/kg/day oral steroids.
Steroid ad-ministration was continued in patients at high immunological risk or with acute rejection.
Monitoring of BKV infections
Monitoring of BKV infections was conducted using a BKV quantitative real-timepolymerase chain reaction kit, with a 95% limit of detection of 2.4 log10 cop-ies per mL.
Biopsies were performed in case of graft dys-function, detection of DSA, or sustained BKV viremia.
Neutralization assay
Neutralization assays were conducted using a BKV pseudovirion system to quantify titers of antibodies that functionally neutralize the infectivity of different BKV genotypes, with a neutralization titer of 2.5 log10 IC50 as the threshold for quantification of antibody-mediated neutralization.
IVIg therapy
VIg therapy was used as a pre-ventive or curative treatment of AMR or SID, with 0.4 g/kg doses every 3 weeks depending on IgG levels
Results
41 high-risk patients received IVIg at a dose of 0.4 g/kg due to SID and preventive or curative treatment of AMR.
IVIg in absence of BKV viremia increased BKV NAb titers.
At day 0, BKV NAb titers were 3.06 (0.56) log10 IC50, increasing to 3.82 (0.61) at 1 posttransplant month.
41 patients had a high risk of BKV replication for BKV genotype I, genotype II, and genotype IV, with 29 of them reaching a BKV NAb titer above 4 log10 IC50 in at least 1 occasion during the first 3 posttransplant months.
Only 2 and 1 patients with high risk of replication achieved a BKV NAb titer above 4 log10 IC50.
High-risk patients without IVIg and BKV viremia had no significant differences in BKV NAb titers after transplantation.
Testing of BKV viruria found positive in 4 patients, potentially explaining response.
BKV viremia was observed in 27 of 174 study patients, with a median peak viral load of 4.91 log10 copies per mL.
BK genotype I and IV were identified as replicat-ing strains in 23 (85%) and 4 (15%) patients, respectively, and 41 had a BKV genotype mismatch.
The incidence of BKV viremia in the high-risk group treated with IVIg was similar to the low-risk group, but markedly lower than the untreated group.
The median peak viral load was significantly lower in the high-risk group treated with IVIg, while the use of MMF was less common in the low-risk group.
D0 Nab titers and patient group were independently associated with BKV viremia.
BKVAN incidence at 12 posttransplant months was 4.5% in high-risk groups, 2.2% in low-risk group, and 19.5% for untreated high-risk patients.
IVIg increased NAb titers against BKV genotype I, and passive immunization in early posttransplant phase was associated with lower incidence of BKV viremia and BKVAN in high-risk KTR.
The anti-BKTR neutralizing response in KTR plays a key role in protecting against BKV replication, and NAb titers against the donor’s strain are clinically useful for risk stratification of BKV-related disease.
IVIg has potential to prevent BKV replication in the first 3 post-transplant months, despite higher burden of immunosuppression caused by AMR and DSA treatment.
The incidence of BKV viremia in the high-risk group treated with IVIg was similar to that of the low-risk group.
High donor seroreactivity can act as a risk factor for BKV replication, and the incidence of BKVAN was as low as 4.5% in the high-risk group treated with IVIg.
BKV-neutralizing antibodies and B cell immunity play a key role in preventing BKV replication, while T cell immunity is preferentially involved.
IVIg may be a valuable strategy for preventing BKV replication in KTR, but its potential is debatable due to other antiviral strategies and/or immunosupression tapering.
We provide proof-of-concept evidence that IVIg administration can prevent BKV viremia and BKVAN in KTR with low NAb titers.
Regarding BKVAN, similar outcomes were seen. We come to the conclusion that IVIg may be a useful tactic for halting BKV replication.
What are the other uses of IVIG in transplantation?
Patients any age with acute rejection and antibody-mediated rejection after solid organ transplantation.
Autoimmune and Inflammatory disorders(inflammatory diseases such as Kawasaki disease, Guillain-Barre syndrome, myasthenia gravis, dermatomyositis and demyelinating polyneuropathy.)
Highly sensitized patients results in reduced allosensitization, reduced ischemia-reperfusion injuries, fewer acute rejection episodes, and higher successful long-term allograft outcomes for cardiac and renal allograft recipients.
Postexposure prophylaxis of hepatitis A and B, tetanus, rabies, diphtheria, botulism, varicella-zoster, respiratory syncytial virus, and cytomegalovirus infections.
Bone marrow transplantation and HIV infection.
Other conditions
Where IVIG therapy demonstrates benefit include toxic epidermal necrolysis and Stevens-Johnson syndrome, neonatal sepsis, birdshot retinochoroidopathy, Henoch-Schönlein purpura, and toxic shock syndrome.
Jordan SC, Vo A, Tyan D, Toyota M. Desensitization therapy with intravenous gammaglobulin (IVIG): applications in solid organ transplantation. Trans Am Clin Climatol Assoc. 2006;117:199-211.
Anti-idiotypic antibodies in IVIG, for instance, binds and neutralizes circulating autoantibodies to factor VIII
F(ab’) neutralizes C3a and C5a anaphylatoxins that mediate inflammation in autoimmune rheumatic conditions; IVIG binds to complement proteins and sequesters them away from auto-antibodies, which helps prevent the formation of membrane attack complex in dermatomyositis.
Introduction
BKV replication occurs in 30%-50% of kidney transplant recipients (KTR). BKV-associated nephropathy (BKVAN) can occur in 10% of BKV-infected KTR causing graft loss.
Regular screening and reduction of immunosuppression is the current available modalities for therapy ,in fact it succeeds in 50-80% of the cases and carries the possibility of rejection.
Intravenous immunoglobulin (IVIg) has been introduced as a preemptive treatment against
BKV infections.
BKV-neutralizing antibodies (NAb) is protective against BKV replication.
The current study evaluated the preventive role of IVIg in reduction of the incidence of BKV viremia and BKVAN in high-risk KTR. Methods
KTR in the Strasbourg University Hospital were retrospectively divided into 3 risk categories for BKV replication according to Nab titers on transplantion day:
first group were high risk patients with low NAb titers whom received IVIg during the first
3 posttransplant months
Second group are high risk patients with low NAb titers also but didnot undergo IVIg treatment Third group are low risk patients with high NAb titers without receiving IVIg. Results
1 year after transplantation , the incidence of BKV viremia and BKVAN in the high-risk group treated with IVIg and in the low-risk group was the same and markedly lower than the incidence in the untreated high-risk group . Discussion
IVIg can increase NAb titers against BKV genotype I which is the most common variant over the protective threshold of 4 log10 IC50.
Administration of IVIg as passive immunization in the early posttransplant period lead to significant decrease of the incidence of BKV viremia and BKVAN in high-risk KTR .
The possible utility of IVIg administration in the management of BKV replication is controversial due to the concomitant use of other antiviral strategies and/or immunosuppression reduction.
The strength of this study is the precise risk stratification for BKV replication due to the quantification of NAb titers against the 3 most common BKV genotypes and availability of donors’ samples.
Limitations were being a retrospective study with small number of included patients who
Took IVIg infusions, and the use of different IVIg doses and administration schedule. Conclusion
IVIg may be a promising modality for BKV replication prevention. -Other IVIG uses in Transplantation
· prevention and treatment of Antibody mediated rejection
· Desensitisation regimens
· For treatment of other infections as CMV
Reference
-Tedla FM, Roche-Recinos A, Brar A. Intravenous immunoglobulin in kidney transplantation. Curr Opin Organ Transplant. 2015 Dec;20(6):630-7
– BK virus infection is frequently observed in renal transplant recipients and is associated with BK nephropathy which can end with graft loss
– It is estimated that 30-50% of renal transplant recipient s develop BK infection, Around 10 % of patients who have BK infection, develop BK nephropathy
– Until now the only effective therapy is reduction of immunosuppression with failure rate of 20-50% and subsequent increase in the risk of graft rejection.
– Patients with high titers of BK-neutralizing antibodies were found to be at lower risk of viral replication, from this point IVIG may have a role in treatment of BK nephropathy since it can increase the neutralizing antibodies
– The current study is a retrospective study that assess the effect of early administration of IVIG (within the first 3 months after transplantation) to patients with low level of neutralizing antibodies(<4 log10 against the BKV-sgenotype 1) on BK virus replication at 1 year post transplantation.
– The study includes 174 renal transplant recipients divided into 3 groups
Group 1 includes 44 patients with low NAb titers (high-risk) who received IVIg for the first 3 months after transplantation
Group 2 includes 41 patients with low NAb titers (high-risk) who did not recive IVIG
Group 3 includes 89 patients with high NAb titers (low-risk) who did not receive IVIg
Results
IVIg were found to increase neutralizing antibodies against BK virus serotype 1 to a protective level (>4 log10)
At 1 year after transplantation, the incidence of BK viremia in high risk group receiving IVIG (8.6%) was comparable to low risk group (10.1%) but significantly lower than high risk group who did not receive IVIG (36.6%)
The incidence of BK nephropathy was higher in high risk group who did not receive IVIG compared to the other 2 groups.
Conclusion
Passive immunization with IVIG in early transplantation in high risk patients with low NAb titers may offer an effective preventive strategy to limit BK viral replication and the occurrence of BK nephropathy
What are the other uses of IVIG in transplantation?
1- ABO incompatible transplantation
2- HLA incompatible transplantation (used for desensitization)
3- Treatment of ABMR (acute and chronic)
4- Treatment of viral infections including CMV, EBV
In 30%–50% of kidney transplant patients, BK virus (BKV) replication occurs (KTR). BKVAN may cause renal failure and graft loss in up to 10% of BKV-infected KTRs.
Intravenous immunoglobulin (IVIg) has been shown to prevent and treat BKV infections. Due to substantial methodological constraints, including the small sample size, the absence of a control arm, and the concurrent use of other antiviral treatments and/or immunosuppression, the field’s research should be evaluated carefully.
Aim:
We investigated whether IVIg prevents BKV viremia and BKVAN in high-risk KTR. Day 0 NAb titers against the donor’s BKV strain determined the donor’s risk category.
Method:
This was a retrospective study based on a review of the medical records of adults (n = 174) who had kidney transplantation (KT) between July 2012 and December 2017.
Patients were classified into one of three risk categories according to the BKV replication status.
DISCUSSION:
This research found two main things: IVIg raised NAb titers against BKV genotype I, which is the most common genotype, above the protective threshold of 4 log10 IC50.
Second, early posttransplant passive IVIg vaccination reduced BKV viremia and BKVAN in high-risk KTR.
We’ve proven that KTR’s anti-BKV antibody-mediated neutralizing response protects against BKV replication.
We also showed that pre-KT NAb titers against the donor’s strain may stratify BKV-related illness risk. 85 individuals with a NAb titer <4 log10 IC50 at day 0 were at high risk for BKV replication.
We investigated whether patients getting IVIg for SID or AMR early after KT may be protected against BKV replication due to its high BKV NAb content.
Conclusion:
The results of the trial showed that IVIg helped reduce the number of people who got BKV viremia and BKV-related nephropathy. This was true for people who took part in the trial but had low NAb titers.
Strength: It can accurately classify the risk of BKV replication based on the detection of NAb titers against the 3 most common genotypes and the good availability of donor samples.
Weakness: retrospective investigation is restricted by the small number of patients who underwent IVIg infusions and the use of varied dosages and delivery schedules. However, we demonstrate that IVIg can prevent BKV viremia and BKVAN in KTR with low NAb titers. single center.
What are the other uses of IVIG in transplantation?
1- Desensetizarion before transplantation
2- chronic active antibody-mediated rejection
3- CMV infection
4- Acute antibody-mediated rejection
BK virus (BKVN) infections are very important concern in kidney transplantation
Viral replication is happening in around to 30 to 50% of all kidney transplant patients
BKVN is seen in 10% of cases, associated with renal impairment, and allograft loss
At the moment, there is no specific treatment and this study tried to investigate the role of IVIG as a pre-emptive and supportive treatment for BKV infections
The hypothesis was that ” patients with higher levels of BKV neutralizing antibodies are protected and IVIG may increase the protection against BKV replication
Methodology:
This was retrospective analysis of medical records of adult (n= 174) who received kidney transplantation (KT) at the Strasbourg University Hospital between July 2012 and December 2017.
The patients were grouped into three risk groups based on BKV replication; group one (n=44), was considered high risk due to low BKV neutralizing antibodies (NAb) titres and they were given IVIG in the first 3 months following KT. Group two (n=41), the same characteristic (low NAb titres) as group one but they were not given IVIG. Group three (n=89), they had high NAb titres and were considered low risk for BKV replication.
Results:
The investigators found that, there was no difference in the rate of BKV replication between the high and low risk groups( 6.8% vs 10.1%). However those who received IVIG had significant lower rate of BKV replication compared to those who didn’t given IVIG.
Strength: Accurate risk stratification for BKV based on PCR
Weakness: Retrospective nature of the design, small sample size, lack of standardization of IVIG doses.
Conclusion:
IVIG may be useful adjunct treatment for preventing BKV replication and BKVN in high risk KT recipients (low NAb titres)
2.What are the other uses of IVIG in transplantation?
Desensitization protocols
Acute ABMR
May be considered in other forms of severe infections in transplantation e.g.CMV
The study hypothesises that Patients with high titers of BKV-neutralizing antibodies (NAbs) are protected against BKV replication, and the intravenous immunoglobulin (IVIg) infusion can increase NAb titers, hence patients will be protected from getting the infection and the development of BKVN.
This is a retrospective analysis done for 174 adult patients who underwent KT in the Strasbourg University Hospital between July 2012 and December 2017. Patients were given IVIg as a preventive measure against BKV viremia and BKV-associated nephropathy, as illustrated below and those patients were retrospectively divided into the following 3 risk categories for BKV replication:
(1) patients with low NAb titers (“high-risk”) who received IVIg for the first 3 posttransplant months (n = 44),
(2) patients with low NAb titers (“high-risk”) who did not undergo IVIg treatment (n = 41),
(3) patients with high NAb titers (“low-risk”) who did not receive IVIg (n = 89).
At 12 post-transplant months, the incidence of BKV viremia in the high-risk group treated with IVIg (6.8%) was similar to that observed in the low-risk group (10.1%) and markedly lower than that of the untreated high-risk group (36.6%; P < .001). Similar results were observed with regard to BKVAN.
In general, BKV viremia was an early event that occurred after a median of 64 days from KT (25th-75th percentiles: 47.5-128.5 days).
Overall, the results showed that IVIg was effective in reducing the incidence of BKV viremia and BKV-associated nephropathy in the study participants with low NAb titers. However, larger studies are needed to confirm these results and to further investigate the safety and effectiveness of this approach.
Intravenous immunoglobulin (IVIg) administration has been empirically
proposed as a preemptive and supportive treatment against
BKV infections. However, the available studies in the field should be
interpreted cautiously because of major methodological limitations
– including small sample sizes, the lack of a control arm, and the concomitant use of other antiviral strategies and/or a parallel reduction
of immunosuppression.
This is a retrospectively review of the clinical records of adult patients
who underwent KT in the Strasbourg University Hospital between
July 2012 and December 2017. All cases with available neutralizing antibodies ( Nab) titers measured on day 0 were choosen.
Exclusion criteria : were patient or graft survival lower than 3 months . A 20 patients with NAb titers below 4 log10 IC50 against the donor’s strain (which was determined by measuring NAb titers in the donor’s sera) were considered at high-risk. When the donor’s specimen was unavailable, the replicating strain was considered as reference for patients showing an active BKV replication.
Based on NAb titers on day 0 and the prescription of IVIg infusion
The patients were divided into 3 risk categories for BKV replication:
(1) patients with low Nab titers (“high-risk patients”) who received IVIg treatment for secondary immunodeficiency (SID) or for prevention or treatment of antibody-mediated rejection (AMR) during the first 3 posttransplant months and before BKV replication .
(2) patients with low NAb titers (“high-risk patients”) who did not undergo IVIg treatment during the first year of KT .
(3) patients with high NAb titers (“low-risk patients”) who did not receive IVIg .
The patients received the following commercial IVIg preparations:
Privigen®, 100 mg/mL (CSL Behring GmbH, Marburg, Germany);
Octagam®, 100 mg/mL (Octapharma, Langenfeld, Germany); Clairyg®,
50 mg/mL (LFB-Biomédicaments, Courtaboeuf, France); and Kiovig®,
100 mg/mL (Baxter, Deerfield, IL). IVIg were infused either as a preventive or curative treatment of AMR or in patients diagnosed with
SID. Patients received 0.4 g/kg IVIg doses every 3 weeks – with a total
number of doses ranging from 1 to 3 – according to their IgG levels.
Patients with de novo DSA, preformed DSA, or biopsy-proven AMR
were treated with three 2 g/kg doses of IVIg every 3 weeks.
The results:
– First, IVIg were found to increase NAb titers against BKV genotype I (ie, the largely predominant genotype) over the protective threshold of 4 log10 IC50.
-Second, passive immunization with IVIg in the early posttransplant
phase was associated with a significantly lower incidence of both
BKV viremia and BKVAN in high-risk KTR.
Other uses of IVIg ; humeral rejection, plasmapheresis, TMA, some types of anemia
Summary
Introduction
This article is concerning BK virus and IVIG being treated as a preventive therapy for the infection. BKV linked nephropathy in renal recipients has also been discussed, keeping iVIG in mind.
BKV is a polyomavirus that can recur in transplant recipients frequently, and that can often lead to a fatal outcome. Sepsis and death are possible outcomes if the infection is not detected early and then treated aggressively. The theme of this article is directed towards a preventive approach in order give a better outcome following solid organ transplantation.
Discussion
The authors of this article have tried to assess whether IVIG as a preventive approach can decrease BKV and BKVAN incidence, especially in high risk cases of organ transplant.
The patients involved in the study have been given induction with basiliximab. Other immunosuppressive drugs that have been administered to these patients include cyclosporine or tacrolimus, MMF and steroids. Some patients were given everolimus.
The NAb titres (BKV genotype) were assessed in these patients and were found to be increased in those who were administered IVIG. There was also a decreased incidence of BKV viremia and BKVAN int these patients.
Conclusion
BKV and BKVAN are extremely problematic since they can frequently recur in patients and cause fatal complications such as sepsis. Early detection and aggressive treatment is vital, including monitoring for recurrence. Since the infection also has an asymptomatic phase it can be difficult to find out when it infects the patient. Focussing on prevention is a good approach, and this article finds that administration of IVIG in the early posttransplant period has a good effect in decreasing the incidence of BKV and BKVAN in kidney transplant patients, especially high risk cases.
Other uses of IVIG in transplant
Summary:
The study evaluated the clinical data of adult Strasbourg University Hospital renal transplanted patients from July 2012 to December 2017. All day 0 NAb titers were eligible.
–BKV PCR at day 0, every month in the first 6 months, and every 3 months in the first year.
-The fact that BKV replication occurs early after renal transplantation,
-IVIG was evaluated as a preventative measure in the first three months.
-After 1 year the high-risk group treated with IVIG showed 6.8% BKV viremia, equal to the low-risk group (10.1%) and much lower than the untreated high-risk group.
-The study showed that BKV neutralizing antibodies decreases BKV replication.
INTRODUCTION
BKV infections are still a major concern following kidney transplantation with BKV replication occurring in 30%-50% of all kidney transplant recipients.
BKVAN can affect up to 10% of BKV-infected KTR, potentially leading to kidney dysfunction and graft loss.
Aim of the Study:
To investigate whether the preventive administration of IVIg may reduce the incidence of BKV viremia and BKVAN in high-risk KTR.
Risk stratification was based on NAb titers against the donor’s BKV strain measured on day 0.
PATIENTS AND METHODS:
Study patients:
retrospectively the clinical records of adult patients (N=174),who underwent KT in the Strasbourg University Hospital between July 2012 and December 2017. All cases with available NAb titers measured on day 0 were deemed eligible.
patients with NAb titers below 4 log10 IC50 against the donor’s strain (which was determined by measuring NAb titers in the donor’s sera) were considered at high-risk.
Patient divided into 3 risk categories for BKV replication:
(1) patients with low NAb titers (“high-risk patients”) who received IVIg treatment for secondary immunodeficiency or for prevention or treatment of antibody-mediated rejection, during the first 3 post-transplant months and before BKV replication (n = 44),
(2) Patients with low NAb titers (“high-risk patients”) who did not undergo IVIg treatment during the first year of KT (n = 41),
(3) Patients with high NAb titers (“low-risk patients”) who did not receive IVIg (n = 89).
immunosuppressive regimens
induction therapy with basiliximab or thymoglobulin .
maintenance phase:
the patient received CNI (ciclosporin or tacrolimus) in association with mycophenolate mofetil (MMF) or a mammalian target of rapamycin (mTOR) inhibitor (everolimus) and steroids.
Monitoring of BKV infections
day 0, every month in the first 6 post transplant months, and every 3 months thereafter (until 1 year following KT).
assay
NAb titers were measured :
at day 0; at the third, sixth, and 12th posttransplant months; and at the onset of viremia. Additional measurements at the first and second post transplant months were performed in patients who received IVIg infusions.
A neutralization titer of 2.5 log10 IC50 was set as the threshold for quantification of antibody-mediated neutralization.
IVIg therapy
Patients received IVIg were infused either as a preventive or curative treatment of AMR or in patients diagnosed with SID.
Patients received 0.4 g/kg IVIg doses every 3 weeks – with a total number of doses ranging from 1 to 3 – according to their IgG levels.
Patients with de novo DSA, preformed DSA, or biopsy-proven AMR were treated with three 2 g/kg doses of IVIg every 3 week.
RESULTS:
Donor NAb titers at D0 did not differ significantly between the 3 patient groups.
IVIg administration increases BKV NAb titers in KTR
Among the 44 high-risk patients who were treated with IVIg, we identified 35 (79.5%), 7 (15.9%), and 2 (4.5%) cases in whom there was a high risk of replication for BKV genotype I, genotype II, and genotype IV, respectively.
A total of 41 patients (93.2%) received IVIg infusion at a dose of 0.4 g/kg because of SID. Of them, 28 cases (63.6%) received 3 doses. The remaining 12 (27.3%) and 1 (2.3%) patients received 2 and 1 doses, respectively.
Three (6.8%) patients received 3 IVIg infusions at a dose of 2 g/kg because of preventive or curative treatment of AMR, with IVIg being administered during the first 3 post transplant months.
The temporal course of BKV NAb titers was studied only in patients who received IVIg in the absence of BKV viremia (n = 41).
This approach allowed investigating the impact of IVIg when immune system stimulation was lacking (owing to the increased BKV NAb titers observed in KTR with BKV viremia).
At day 0, the mean BKV NAb titer was 3.06 (0.56) log10 IC50. Before the first IVIg injection, BKV NAb titers remained below 4 log10 IC50 in all patients (mean: 3.07 [0.56] log10 IC50).
At 1 post transplant month, when the majority of patients (93%) had already received the first IVIg injection, the mean NAb titers significantly increased to 3.82 (0.61) log10 IC50 and remained at these levels for the subsequent 2 months (P < .001). A decrease in NAb titers occurred afterwards, with a return to the initial levels between 6 and 12 post transplant months.
IVIg administration decreases the incidence of both BKV viremia and BKVAN in KTR.
DISCUSSION
There are 2 principal findings from this study.
First, IVIg were found to increase NAb titers against BKV genotype I (ie, the largely predominant genotype) over the protective threshold of 4 log10 IC50.
Second,
passive immunization with IVIg in the early posttransplant phase was associated with a significantly lower incidence of both BKV viremia and BKVAN in high-risk KTR.
The current study is the first to demonstrate that IVIg infusion may be a valuable strategy for preventing BKV replication in kt.
Strength
including an accurate risk stratification for BKV replication based on the quantification of NAb titers against the 3 most common BKV genotypes and a high availability of donors’ samples
.limitation:
Its retrospective design, the relatively small number of patients who received IVIg infusions, and the use of different IVIg doses and administration schedule.
Treatment of AMR.
DESNSTIZATION.
Treatment of other viral infection CMV .
Introduction:
BK Virus infection affects patients especially post kidney transplantation up to 30-50% with 10 % having nephropathy reported with possibility of graft dysfunction and loss.
We don’t have any specific treatment with exception of RIS and monitoring BKV PCR and graft function.
IV immunoglobulin is a possible additional treatment against BK Virus.
High levels of BK antibodies might be protective as low antibodies levels have been linked to increased BK infection and vice versa
Patients and methods:
Retrospectively nonrandomized study of adult patients who underwent KT between 2012 and 2017.
Exclusion criteria include:
A. patient or graft survival lower than 3 m
B. NAb titers below 10^4
C. IC50 against the donor’s strain
D. Low-risk patients who received IVIg during the first posttransplant year
Genotype I was taken as reference for patients with a negative BKV DNA load.
Patients were divided into 3 risk categories for BKV replication.
Immunosuppressive regimens:
Immunosuppressive therapy after KT consisted of:
Monitoring of BKV infections:
BKV quantitative PCR was done at day 0, monthly for the first 6 months then 3-monthly until 1 year following kidney transplantation.
graft biopsy was performed in case of graft dysfunction, sustained BKV viremia (i.e., presence of 4 log 10 copies/mL in 2 subsequent blood specimens), detection of DSA.
Neutralization assay:
NAb titers were measured at day 0; 3rd, 6th and 12th month posttransplant and at the onset of viremia.
Additional NAb titers were done at the 1st and 2nd months post-transplant for patients who had received IVIG infusions.
IVIG therapy:
IVIG was infused as preventive or a curative treatment for ABMR or in patients with secondary immunodeficiency.
IVIG can increase NAb titers.
depending on the IgG levels, patients received 0.4g/kg IVI doses every 3 weeks with the total number of doses ranging from 1 to 3.
patients with DSAs (de novo or preformed) or biopsy-proven AMR were treated with three 2g/kg doses of IVIG every 3 weeks.
Results:
At 12 posttransplant months:
The incidence of BKV viremia in the high-risk group treated with IVIg (6.8%, 3 of 44 patients) was similar to that observed in the low-risk group (10.1%, 9 of 88 patients), but significantly lower than the untreated high-risk group (36.6%; 15 of 41 patients; P < .001).
Similar figures were observed with regard to the incidence of BKVAN at 12 posttransplant months (4.5% [2 cases] in the high-risk group treated with IVIg, 2.2% [2 cases] in the low-risk group, and 19.5% [8 cases] in untreated high-risk patients; (P = .001).
Discussion:
IVIg were found to increase NAb titers against BKV genotype I (ie, the largely predominant genotype) over the protective threshold of 4 log10.
Passive immunization with IVIg in the early posttransplant phase was associated with a significantly lower incidence of both BKV viremia and BKVAN in high-risk KTR.
Strength of the study: Accurate risk stratification for BKV replication based on the quantification of NAb titers against the 3 most common BKV (I,II, and IV) genotypes and a high availability of donors’ samples.
Limitations of the study:
Retrospective study, small sample size, and different immunosuppressive protocol, not specified.
Conclusion:
IVIg administration is capable of preventing BKV viremia and BKVAN in KTR with low NAb titers.
Multicenter controlled randomized study is needed.
What are the other uses of IVIG in transplantation?
1) Desensitization protocol.
2) Treatment of AMR.
3) Prevention and treatment of infections: CMV, BKV nephropathy, and parvovirus B19 infection
In this study author retrospectively reviewed the clinical records of adult patients who underwent KT in the Strasbourg University Hospital between July 2012 and December 2017. All cases with available NAb titers measured on day 0 were deemed eligible.Based on NAb titers on day 0 and the prescription of IVIg infusion, the study patients (n = 174) were divided into the following 3 risk categories for BKV replication: (1) patients with low NAb titers (“high-risk patients”) who received IVIg treatment for secondary immunodeficiency (SID) or for prevention or treatment of antibody-mediated rejection (AMR) during the first 3 posttransplant months and before BKV replication (n = 44), (2) patients with low NAb titers (“high-risk patients”) who did not undergo IVIg treatment during the first year of KT (n = 41), and (3) patients with high NAb titers (“low-risk patients”) who did not receive IVIg (n = 89). Secondary immunodeficiency was defined either as (1) IgG levels <400 mg/dL or (2) IgG levels between 400 and 800 mg/dL in the presence of a concurrent infection. Low-risk patients who received IVIg during the first posttransplant year were not included in the study (n = 65)
Monitoring of BKV infections–Blood samples for assessing BKV viremia were collected at the following time points: day 0, every month in the first 6 posttransplant months, and every 3 months thereafter (until 1 year following KT).
Neutralization assay-NAb titers were measured at day 0; at the third, sixth, and 12th posttransplant months; and at the onset of viremia.
IVIG– Patients received 0.4 g/kg IVIg doses every 3 weeks – with a total number of doses ranging from 1 to 3 – according to their IgG levels. Patients with de novo DSA, preformed DSA, or biopsy-proven AMR were treated with three 2 g/kg doses of IVIg every 3 weeks.
Results-
IVIg administration increases BKV NAb titers in KTR.. At 12 posttransplant months, the incidence of BKV viremia in the high-risk group treated with IVIg (6.8%) was similar to that observed in the low-risk group (10.1%) and markedly lower than that of the untreated high-risk group (36.6%; P < .001). Similar results were observed with regard to BKVAN. IVIg may be a valuable strategy for preventing BKV replication
Other uses of IVIG in transplantation-
Desenitization protocol,
Treatment of AMR,
severe hypogammaglobulinemia (ie, immunoglobulin G [IgG] <400 mg/dL).
IVIG as a preventive strategy against the BK virus
Introduction;
BKVAN can affect up to 10% of BKV-infected KTR.
BKVAN is associated with a potential risk of graft dysfunction and loss.
Till today the available strategy for BKV treatment includes; IS reduction, with a regular screening of BKV viremia and viruria.
This strategy is associated with an increased risk of DSA and rejection.
IVIG
IVIG use in kidney transplantation
This article is not available
https://pubmed.ncbi.nlm.nih.gov/32741096/
IVIG AS POSSSIBLE METHOD FOR BKV INFECTION AND NEPHROPATHY IN KTR -RESULTS FROM A PROOF OF CONCEPT STUDY:
INTRODUCTION:
-BK Virus infection affects pts esp post kidney transplantation upt 30-50% with 10 % having nephropathy reported with possibility of graft dysfunction and loss.
-We don’t have any specific tx with exception of RIS and monitoring BKV PCR and graft function.
-IV immunoglobulin is a possible additional tx against BK Virus.
-High levels of BK antibodies might be protective as low antibodies levels have been linked to increased BK infection and vice versa.
METHODS:
2.IMMUNOSUPPRESION.
3.BKV MONITORING.
4.NEUTRALIZING ASSAY.
5.IV IMMUNOGLOBULIN THERAPY.
RESULTS:
-Classes ;
-IV immunoglobulin increases BKV antibody levels post transplant;
-IV immunoglobulin reduces BKV infection and nephropathy post transplant;
DISCUSSION:
-Key conclusions ;
OTHER USES OF IV IMMUNOGLOBULIN IN TRANSPLANT:
1. Summary of the article
Introduction
Patients with high titers of BKV-neutralizing antibodies (NAbs) are protected against BKV replication. Intravenous immunoglobulin (IVIg) infusion can increase NAb titers.
NAb titers against the donor’s BKV strain lower than 4 log10 IC50 at the time of transplantation (day 0) are associated with an increased risk of BKV replication following KT.
available studies on pre-emptive and supportive treatment against BKV infections can’t be validated because of limitations.
This study, investigate whether the preventive administration of IVIg reduce the incidence of BKV viremia and BKVAN in high-risk KTR, based on NAb titers against the donor’s BKV strain.
Patients and methods:
– If donor’s specimen was unavailable, the replicating strain was considered as reference
– Genotype I, being most common, was taken as reference for patients with a negative BKV DNA load
1. patients with low NAb titers (“high-risk patients”) who received IVIg treatment for secondary immunodeficiency (SID) or for prevention or treatment of AMR – during first 3 months post-transplant and before BKV replication (n = 44). (SID = IgG levels <400 mg/dL or (2) IgG levels between 400 and 800 mg/dL in the presence of a concurrent infection><400mg/dl or 400-800mg/dl with concurrent infection).
2. patients with low NAb titers (“high-risk patients”) who did not undergo IVIg treatment during the first year of KT (n = 41)
3. patients with high NAb titers “low-risk patients”) who did not receive IVIg (n = 89).
Immuno-suppression: Induction with Basiliximab or Thymoglobulin
Tripple drug maintenance regimen
Monitoring BKV infection: Blood samples for assessing BKV viremia were collected on – day 0, monthly x first 6months, then 3 monthly until 1 year post KT.
Neutralization assay:
– NAb titers measured at day 0; 1-2-3-6 and 12months post KT; at onset of viremia. Additional measurements at the first and second posttransplant months were performed in patients who received IVIg infusions.
– The neutralization titer was defined as the sample dilution that resulted in 50% inhibition of pseudovirion infectivity (IC50), expressed as log10 of IC50.
– A neutralization titer of 2.5 log10 IC50 was set as threshold for quantification of antibody-mediated neutralization.
Results:
Discussion:
Strength of the study
Limitations of the study
– Retrospective study
– Smaller sample size
– Different IVIg doses and administration schedule
2. What are other uses of IVIG in kidney transplantation
Introduction:
Material and methods:
Results:
Discussion:
Strengths:
Limitation:
Other uses of IVIG in kidney transplantation
Tedla, Fasika M.; Roche-Recinos, Andrea; Brar, Amarpali. Intravenous immunoglobulin in kidney transplantation. Current Opinion in Organ Transplantation 20(6):p 630-637, December 2015. | DOI: 10.1097/MOT.0000000000000250
IVIG AS POSSSIBLE METHOD FOR BKV INFECTION AND NEPHROPATHY IN KTR -RESULTS FROM A PROOF OF CONCEPT STUDY.
INTRODUCTION.
-BK Virus infection affects pts esp post kidney transplantation upt 30-50% with 10 % having nephropathy reported with possibility of graft dysfunction and loss.
-We don’t have any specific tx with exception of RIS and monitoring BKV PCR and graft function.
-IV immunoglobulin is a possible additional tx against BK Virus.
-High levels of BK antibodies might be protective as low antibodies levels have been linked to increased BK infection and vice versa.
METHODS.
2.IMMUNOSUPPRESION.
3.BKV MONITORING.
4.NEUTRALIZING ASSAY.
5.IV IMMUNOGLOBULIN THERAPY.
RESULTS.
-Classes ;
-IV immunoglobulin increases BKV antibody levels post transplant;
-IV immunoglobulin reduces BKV infection and nephropathy post transplant;
DISCUSSION.
-Key conclusions ;
OTHER USES OF IV IMMUNOGLOBULIN IN TRANSPLANT.
INTRODUCTION
● BKV replication occurring in 30%-50% of
KTR
● BKVAN affect 10% of BKV-infected KTR leading to kidney dysfunction and graft loss
● Regular screening of BKV viremia or viruria accompanied by RIS remains the only viable strategy to control BKV replication and successful in 50%-80%
● BKV associated with an increased risk of developing DSA and AR .
● IVIg has been proposed as a preemptive and supportive treatment against BKV infections
● limitations of these studies are :
☆ Small sample sizes
☆ Lack of a control arm
☆ The concomitant use of other antiviral strategies and/or a parallel reduction of IS
● BKV-neutralizing antibodies (NAb) having a protective effect.
● This study investigates whether IVIg may reduce the incidence of BKV viremia and BKVAN in high-risk KTR.
PATIENTS AND METHODS
● Retrospectively nonrandomized study of adult patients who underwent KT between 2012 and 2017.
● Exclusion criteria were
☆ patient or graft survival lower than 3 m
☆ NAb titers below 10^4
☆ IC50 against the donor’s strain
☆ Low-risk patients who received IVIg during the first posttransplant year
● Genotype I was taken as reference for patients with a negative BKV DNA load.
● Patients were divided into 3 risk categories for BKV replication:
1. Low NAb titers “high-risk patients” who received IVIg treatment for secondary immunodeficiency (SID) or for prevention or treatment of antibody-mediated rejection (AMR) during the first 3 posttransplant months and before BKV replication
2. low NAb titers (“high-risk patients”) who did not undergo IVIg treatment during the first year of KT
3. patients with high NAb titers “low-risk patients” who did not receive IVIg
● Secondary immunodeficiency was defined either :
1. IgG levels <400 mg/dL
2. IgG levels between 400 and 800 mg/dL in the presence of a concurrent infection.
Immunosuppressive regimens
☆ An induction therapy with basiliximab or thymoglobulin for high risk recipient’s
☆ Thymoglobulin for patients with PRA >20% and a history of ABO-incompatible kidney transplantation
☆ Maintenance with CNi , MMF or mTORi , and steroids
Monitoring of BKV infections
● Blood BKV PCR assessment at :
* Day 0
* Every month in the first 6 months posttransplant
* Every 3 months thereafter until 1 year
● Allograft biopsies in case of graft dys-
function, detection of DSA, or sustained BKV viremia
Neutralization assay
● NAb titers were measured at day 0; at the third, sixth, and 12th posttransplant months; and at the onset of viremia.
● Additional measurements at the first and second posttransplant months in patients who received IVIg infusions.
IVIg therapy
● Patients received 0.4 g/kg IVIg doses every 3 weeks with a total number of doses ranging from 1 to 3
● Patients with de novo DSA, preformed DSA, or biopsy-proven AMR were treated with three 2 g/kg doses of IVIg every 3 weeks.
RESULTS
● IVIg increases NAb titers against BKV genotype I
● Passive immunization with IVIg in the early posttransplant was associated with a significantly lower incidence of both BKV viremia and BKVAN in high-risk KTR
● BKV viremia was an early event that occurred after a median of 64 days from KT
● BK genotype I in 85% and IV in 15 %
● The frequency of viremia was higher in presence of donor/recipient BKV genotype mismatch
● The median peak viral load was higher in patients with viremia who developed BKVAN compared with those who did not ● 6.8 % of high-risk group treated with IVIg
have BKV viremia comparsion to 10.1% in the low-risk group and 36.6% in untreated high-risk group
● The median peak viral load was significantly lower in the high-risk group treated with IVIg
● Patients in the high-risk untreated group had a 24-fold increase in the risk of developing BK viremia compared with the low-risk group
● The incidence of BKVAN was 4.5% in the high-risk group treated with IVIg and (2.2%)
in the low-risk group and (19.5%) in untreated high-risk patients
● IVIg may be more useful as a preventive rather than curative strategy.
● Utility of IVIg administration in the management of BKV replication is still debatable because :
* concomitant use of other antiviral strategies
* Immunosuppression tapering
◇ The strength points of study :
● An accurate risk stratification for BKV replication based on the quantification of
NAb titers against the 3 most common BKV genotypes and a high availability of donors’ samples
● This study adds evidence showing that BKV-neutralizing antibodies and B cell immunity play a key role in the prevention of BKV replication.
● Conversely, T cell immunity is preferentially involved in the control of active BKV replication.
● There were no major intergroup differences at baseline the only exception being the use of everolimus (which was more frequent for patients who received IVIg)
● This study is the first demonstrates that IVIg infusion may be a valuable for preventing BKV replication in KT
◇ Limitations of study :
● A retrospective nonrandomized study, .
● small number of patients who received IVIg infusions so no firm conclusions
● Use of different IVIg doses and administration schedule
Other uses of IVIG in transplantation :
☆ ABMR
☆ Desensitization protocols
☆ Protection and treatment of viral infections as CMV , EBV , PKpyV , …
☆ Recurrence of FSGS
V. Intravenous immunoglobulin as a preventive strategy against BK virus viremia and BKV-associated nephropathy in kidney transplant recipients – Results from a proof-of-concept study
Summarise this article
Introduction
– BKV infections are a major concern among kidney transplant recipients (KTRs)
– BKV replications occurs in 30-50% while BKVAN can affect 10% resulting in graft dysfunction and graft loss
– currently there is no specific antiviral treatment available against BKV infections/ replication
– the mainstay of management remains reduction in immunosuppression with regular monitoring of kidney function and BKV viremia
– this treatment approach is only 50-80% successful, it does not guarantee against evolution to BKVAN and is associated with increased risk of developing DSAs and acute rejection
– IVIG is being proposed as an adjunctive preemptive and supportive treatment against BKV infections
– humoral immunity plays a critical role in preventing BKV replication in KTRs
– high titers of BKV-neutralising antibodies (NAb) have been found to have a protective effect i.e., lower NAb titers against the donor’s BKV strain at the time of transplantation is associated with an increased risk of BKV replication after kidney transplantation
– patients with high titers of BKV Nabs are protected against BKV replication
– IVIG can exert neutralizing activity against common BKV genotypes
– IVIG infusion results in increased NAb titers among KTRs
Methods
– 568 kidney transplant recipients (KTRs), 297 excluded due to lack of BKV NAb titers (BKV-neutralising antibodies), 4 were excluded (2 due to graft loss within the first 3 months of KT and 2 deaths during the first 3 months of KT)
– Inclusion criteria: – all cases with available NAb titers measured on day 0
– Exclusion criteria: – graft or patient survival less than 3 months
– high risk patients: – patients with NAb < 4 log 10 IC50 against the donor’s strain
– 271 patients with donor and recipient NAb titers were recruited; of these,
o 113 were at high risk of BKV replication (28 excluded leaving 41 high-risk untreated patients and 44 high-risk treated patients);
o 154 were at low risk of BKV replication (65 were excluded due to IVIG treatment during the 1st year of KT leaving 89 at low-risk untreated patients)
– induction therapy with basiliximab or thymoglobulin depending on the recipient’s immunological risk
– thymoglobulin was given to patients with a PRA >20% and a history of ABO-incompatible kidney transplantation
– maintenance phase: – CNI (tacrolimus or cyclosporine) + MMF or mTORi + steroids
– BKV quantitative PCR was done at day 0, monthly for the first 6 months then 3-monthly
until 1 year following kidney transplantation
– graft biopsy was performed in case of graft dysfunction, sustained BKV viremia (i.e., presence of 4 log 10 copies/mL in 2 subsequent blood specimens), detection of DSA
– NAb titers were measured at day 0; 3rd, 6th and 12th month posttransplant and at the onset of viremia
– additional NAb titers were done at the 1st and 2nd months post-transplant for patients who had received IVIG infusions
– IVIG was infused as preventive or a curative treatment for ABMR or in patients with secondary immunodeficiency
– IVIG can increase NAb titers
– depending on the IgG levels, patients received 0.4g/kg IVI doses every 3 weeks with the total number of doses ranging from 1 to 3
– patients with DSAs (de novo or preformed) or biopsy-proven AMR were treated with three 2g/kg doses of IVIG every 3 weeks
Results
– patients were divided into 3 categories for BKV replication based on the NAb titers on the day of transplantation i.e.,
o patients with low NAb titers (“high-risk”) who received IVIG for the first 3 months post-transplant (n=44)
o patients with low NAb titers (“high-risk”) who did not receive IVIG treatment (n=41)
o patients with high NAb titers (“low-risk”) who did not receive IVIG (n=89)
– the temporal course of BKV NAb titers was studied among patients who received IVIG in the absence of viremia
– it was found that with IVIG infusion, the mean NAb titers increased significantly and remained at these levels for 3 months before returning to the initial levels in 6th to 12th month post-transplant
– at 12 months following kidney transplant, the incidence of BKV viremia in the high-risk group treated with IVIG (6.8%) was similar to that observed in the low-risk group (10.1%) and markedly lower than that observed in the untreated high-risk group (36.6%)
– similar trends were observed with regard to BKVAN
Discussion
– the two main findings in this study were: –
o IVIG was found to increase the NAb titers against BKV genotype I above the protective threshold of 4 log 10
o among high-risk KTRs, passive immunization with IVIG in the early post-transplant phase was associate with a significantly lower incidence of both BKV viremia and BKVAN
Study strengths
– risk categorization of patient’s BKV replication status based on the NAb titers
Study limitations
– retrospective
– small number of patients
– different IVIG dosing and administration schedules
What are the other uses of IVIG in transplantation? (1)
– in desensitization protocols in ABO and HLA incompatible transplant pairs
– prevention and treatment of ABMR
– treatment and prevention of post-transplant infections like CMV, parvovirus B19 and BKPyV
References
1. Jordan SC, Toyoda M, Kahwaji J, Vo AA. Clinical aspects of intravenous immunoglobulin use in solid organ transplant recipients. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2011 Feb;11(2):196-202. PubMed PMID: 21219579. Epub 2011/01/12. eng.
Please summarise this article.
-BK virus (BKV) infections are still a major concern following kidney
transplantation (KT) .
-BKV-associated nephropathy (BKVAN) can lead to kidney dysfunction and graft loss.
-No specific antiviral treatment is currently available against
BKV infections but regular screening of BKV viremia or viruria
accompanied by a reduction of immunosuppressive therapy remains
the only viable strategy to control BKV replication.
-Humoral immunity plays a crucial role for the prevention of BKV
replication in KTR, with high titers of BKV-neutralizing antibodies
(NAb) having a protective effect.
-It is retrospective study between July 2012 and December 2017 in the Strasbourg University Hospital. Number of patients 174 divided into:: (1) patients with low NAb titers (“high-risk”) who received IVIg for the first 3 posttransplant months (n = 44), (2) patients with low NAb titers (“high-risk”) who did not undergo IVIg treatment (n = 41), and (3) patients with high NAb titers (“low-risk”) who did not receive IVIg (n = 89).
-NAb titers against the donor’s strain measured before KT are clinically useful for risk stratification of BKV-related disease.
– At 12 posttransplant months, the incidence of BKV viremia in the high-risk group treated with IVIg (6.8%) was similar to that observed in the low-risk group and markedly lower than that of the untreated high-risk group .
-A high donor seroreactivity can act as a risk factor for BKV replication especially in recipients with low BKV NAb titers.
-The incidence of BKVAN was as low as 4.5% in the high-risk
group treated with IVIg.
-Conversely, T cell immunity is preferentially involved in the control of active BKV replication.
-Strengths of study :an accurate risk stratification for BKV replication based on the quantification ofNAb titers against the 3 most common BKV genotypes and a high availability of donors’ samples.
-Limitation of study : retrospective design, the relatively small number of patients who received IVIg infusions, and the use of different IVIg doses and administration schedule.
What are the other uses of IVIG in transplantation?
1.An immunomodulatory agent for highly HLA sensitized patients awaiting kidney transplantation
2.Desensitization agent for heart and lung allograft recipients
3.Treatment of AMR
4. Treatment of secondary hypogammaglobulinemia and infectious complications in solid organ transplant recipients
Reference:
S.C. Jordan et al.Clinical Aspects of Intravenous Immunoglobulin Use in Solid Organ Transplant Recipients. American Journal of Transplantation
Volume 11, Issue 2, February 2011, Pages 196-202
Please summarise this article
Introduction
BKV replication occurring in 30%-50% of all kidney transplant recipients, and nephropathy affect 10% of BKV-infected recipients, contributing in renal dysfunction and graft loss.
No approved antiviral therapy for BKVN.
Screening of BKV viremia and viruria with reduction of immunosuppressive therapy is successful in 50%-80%, but does not prevent BKVAN, and associated with increased the risk of developing DSA and acute rejection.
IVIg is considered as a preemptive and supportive treatment against BKV infections, but studies were of small ample size, lacking control arm, and whether IS reduction and concomitant use of anti-viral therapy were used.
Hypothesis that Humoral immunity plays a crucial role for the prevention of BKV genotypes replication in KTR, with high titers of BKV-neutralizing antibodies (NAb) having a protective effect.
Patients and methods
A retrospective study, conducted during 2012-2017 (in Strasbourg University Hospital, France).
BKV genotyping was performed in all BKV DNA-positive recipients, the most common viral genotype (genotype I) was taken as reference for patients with a negative BKV DNA load.
Allograft biopsies were performed in case of graft dysfunction, detection of DSA, or sustained BKV viremia (defined by the presence of 4 log10 copies per mL in 2 subsequent blood specimens).
The neutralization titer—which was defined as the sample dilution that resulted in a 50% inhibition of pseudovirion infectivity (IC50) – was expressed as log10 of IC50.
Patients received 0.4 g/kg IVIg doses every 3 weeks – with a total number of doses ranging from 1 to 3 – according to their IgG levels.
BKV viremia: day 0, every month in the first 6 posttransplant months, and every 3 months thereafter (for 1 year following KT).
NAb titers: at day 0; at 3, 6, and 12th posttransplant months; and at the onset of viremia.
Study arms:
(1) patients with low NAb titers (“high-risk”) who received IVIg for the first 3 posttransplant months (n = 44)- received IVIG.
(2) patients with low NAb titers (“high-risk”) who did not undergo IVIg treatment (n = 41)- did not receive IVIG
(3) patients with high NAb titers (“low-risk”) who did not receive IVIg (n = 89)- did not receive IVIG.
Inclusion criteria: all cases with available NAb titers measured on day 0, with titers<4 log10donor’s strain considered as high risk.
Exclusion criteria: patient or graft survival lower than 3 months.
Immunosuppressive regimens:
Induction therapy with basiliximab or r-ATG based on the recipient’s immunological risk.
MMF+CNI+ low dose steroid+/- m-TORi.
Target trough levels of tacrolimus were: 10-12 ng/mL during the first 3 months, 8-10 ng/mL from month 4 to month 6, and 6-8 ng/ mL from month 6 to month 12.
Target trough levels of ciclosporin were 150-200 ng/mL during the first 6 months and 125-150 ng/mL from month 6 to month 12.
The target for the mycophenolic acid area under the concentration-time curve (AUC) from 0 to 12 hours at months 1 and 3 was 30-60 mg·h·L.
Target trough levels of everolimus were 3-8 ng/mL.
All patients received 2 steroid pulses at a dose of 250 mg followed by 1 mg/kg/day oral steroids that were progressively tapered during the first 4 posttransplant months.
Steroid administration at a dose of 0.1 mg/kg/day was continued in patients at high immunological risk or in those with a history of acute rejection.
Results
At 12 posttransplant months:
The incidence of BKV viremia in the high-risk group treated with IVIg (6.8%, 3 of 44 patients) was similar to that observed in the low-risk group (10.1%, 9 of 88 patients), but significantly lower than the untreated high-risk group (36.6%; 15 of 41 patients; P < .001).
Similar figures were observed with regard to the incidence of BKVAN at 12 posttransplant months (4.5% [2 cases] in the high-risk group treated with IVIg, 2.2% [2 cases] in the low-risk group, and 19.5% [8 cases] in untreated high-risk patients; (P = .001).
Discussion:
IVIg were found to increase NAb titers against BKV genotype I (ie, the largely predominant genotype) over the protective threshold of 4 log10.
Passive immunization with IVIg in the early posttransplant phase was associated with a significantly lower incidence of both BKV viremia and BKVAN in high-risk KTR.
Strength: Accurate risk stratification for BKV replication based on the quantification of NAb titers against the 3 most common BKV (I,II, and IV) genotypes and a high availability of donors’ samples.
Limitations:
Retrospective study, small sample size, and different immunosuppressive protocol, not specified.
Conclusions
IVIg administration is capable of preventing BKV viremia and BKVAN in KTR with low NAb titers.
Multicenter controlled randomized study are needed.
What are the other uses of IVIG in transplantation?
INTRODUCTION
BKV-associated nephropathy (BKVAN) can affect up to 10% of BKV-infected KTR, potentially leading to kidney dysfunction and graft loss; there is no specific antiviral treatment currently available against BKV infections.
Regular screening of BKV viremia or viruria accompanied by a reduction of immunosuppressive therapy remains the preventable form of BKVN , but this approach proves successful only in 50%-80% of cases, besides increase the risk of developing donor-specific antibodies (DSA) and acute rejection.
*A clinically relevant neutralizing activity against the most common BKV genotypes, with IVIg infusion resulting in increased NAb titers among KTR. This study investigates whether the preventive administration of IVIg may reduce the incidence of BKV viremia and BKVAN in high-risk KTR.
PATIENTS AND METHODS ;
– Clinical records of adult patients who underwent KT in the Strasbourg University Hospital between July 2012 and December 2017 Study patients were retrospectively reviewed.
All cases with available NAb titers measured on day 0 were deemed eligible.
Exclusion criteria:
– Patient death or graft loss less than 3 months post kidney transplant .
– Based on NAb titers on day 0 and the prescription of IVIg infusion, the study patients (n = 174) were divided into the following 3 risk categories for BKV replication:
(1) High-risk patients with low NAb titers who received IVIg treatment for secondary immunodeficiency (SID) or for prevention or treatment of antibody-mediated rejection (AMR) during the first 3 posttransplant months and before BKV replication (n = 44),
(2) High-risk patients patwith low NAb titers who did not undergo IVIg treatment during the first year of KT (n = 41), and
(3) low-risk patients with high NAb titers who did not receive IVIg (n = 89).
Ethical approval was granted from the local institutional review board , and all participants provided written informed consent.
Immunosuppressive regimens :
Immunosuppressive therapy after KT consisted of
Monitoring of BKV infections:
-BKV quantitative plasmaPCR was checked at day 0, every month in the first 6 posttransplant months, and every 3 months thereafter (until 1 year following KT.
-Allograft biopsies were performed in case of graft dysfunction, detection of DSA, or sustained BKV viremia and systematically during the third posttransplant month.
BKVAN was diagnosed and classified according to the severity of virus-induced cytopathic effects, inflammatory infiltrates, tubular atrophy, fibrosis, and through immunohistochemistry using antibodies that cross-reacted against the large T antigen of the related simian polyomavirus (SV40 antibody .BKV genotyping was performed in all BKV DNA-positive recipients as previously described.
Neutralization assay :
NAb titers were measured at day 0; at the third, sixth, and 12th posttransplant months; and at the onset of viremia.
Additional measurements at the first and second posttransplant months were performed in patients who received IVIg infusions.
-The neutralization assays were conducted using a BKV pseudovirion system that expressed the capsid proteins of BKV genotypes I, II, or IV.
IVIg therapy :
Patients received received 0.4 g/kg IVIg doses every 3 weeks – with a total number of doses ranging from 1 to 3 – according to their IgG levels.
Patients with de novo DSA, preformed DSA, or biopsy-proven AMR were treated with three 2 g/kg doses of IVIg every 3 weeks.
Data analysis :
Continuous variables are presented as means (standard deviations [SDs]) or medians and interquartile ranges (25th–75th percentiles).
Categorical variables are given as counts and percentages using the Kruskal-Wallis test.
and analyzed with the chi-square test or the Fisher’s exact test, as appropriate. The Kaplan-Meier method was used to plot BKV viremia-free survival and BKVAN-free survival .
A multivariable Cox regression analysis was performed to identify independent predictors of BKV viremia.
Results:
Patient characteristics : we have 174 patients through the study. 133 cases have available donor BKV NAb titers or genotypes of replicating BKV .
At day 0, 170 (97.7%) recipients and 120 (96.7%) donors were seropositive for at least 1 BKV genotype.
BKV genotype I—alone or in combination with other genotypes—was detected in 138 (79.3%) recipients and 100 (83.3%) donors, respectively.
Fifty-three (30.5%) recipients and 22 (18.3%) donors were seropositive for BKV genotype II, whereas 22 (12.6%) recipients and 9 (7.5%) donors were seropositive for BKV genotype IV .
Donor NAb titers at D0 did not differ significantly between the 3 patient groups .
IVIg administration increases BKV NAb titers in KTR :
At day 0 the mean BKV NAb titer was 3.06 (0.56) log10 IC50. Before the first IVIg injection, BKV NAb titers remained below 4 log10 IC50 in all patients (mean: 3.07 [0.56] log10 IC50). At 1 post transplant month, when the majority of patients (93%) had already received the first IVIg injection, the mean NAb titers significantly increased to 3.82 (0.61) log10 IC50 and remained at these levels for the subsequent 2 months (P < .001).
Twenty-nine of the 32 patients (91%) at high risk for BKV genotype I replication were capable of reaching a BKV NAb titer above the threshold of 4 log10 IC50 in at least 1 occasion during the first 3 posttransplant months. .
Only 2 and 1 patients among those with a high risk of replication for BKV genotype II and genotype IV, respectively, were capable of obtaining a BKV NAb titer above the threshold of 4 log10 IC50 .
IVIg administration decreases the incidence of both BKV viremia and BKVAN in KTR;
– BKV viremia was observed in 27 of the 174 study patients (total incidence at 1 posttransplant year: 15.5%).
At 12 posttransplant months, the incidence of BKV viremia in the high-risk group treated with IVIg (6.8%, 3 of 44 patients) was similar to that observed in the low-risk group (10.1%, 9 of 88 patients) and markedly lower than that of the untreated high-risk group (36.6%; 15 of 41 patients; P < .001; .
– Incidence of BKVAN at 12 posttransplant months (4.5% [2 cases] in the high-risk group treated with IVIg, 2.2% [2 cases] in the low-risk group, and 19.5% [8 cases] in untreated high-risk patients; P = .001;
DISCUSSION;
In this study IVIg were found to increase NAb titers against BKV genotype as well as passive immunization with IVIg in the early posttransplant phase was associated with a significantly lower incidence of both BKV viremia and BKVAN in high-risk KTR.
The anti-BKV antibody-mediated neutralizing response in KTR plays a key role in the protection against BKV replication.
NAb titers against the donor’s strain measured before KT are clinically useful for risk stratification of BKV-related disease.
BKV NAb titers against genotype I increased in a similar fashion after low or high IVIg doses despite a higher burden of immunosuppression.
The role of IVIg was examined in the first 3 posttransplant months because BKV replication generally occurs early following KT.2,24,25 At 12 posttransplant months, the incidence of BKV viremia in the high-risk group treated with IVIg (6.8%) was similar to that observed in the low-risk group (10.1%) and markedly lower than that of the untreated high-risk group (36.6%).
Incidence of BKVAN was as low as 4.5% in the high-risk group treated with IVIg. Such figures are similar to those observed in the low-risk group (2.2%) and markedly lower than those of untreated high-risk patients (19.5%).
Limitation of the study :
-Being retrospective study .
-Rather a small number of patients who are given IVIG ,
– The administration of different doses of IVIG.
Strength of the study:
-This study is the first to demonstrate that IVIg infusion may be a valuable strategy for preventing BKV replication in KTR.
Reference:
Curr Opin Organ Transplant. 2015 Dec;20(6):630-7. doi: 10.1097/MOT.0000000000000250.
IVIG as a preventive strategy against BK virus viremia and BKN in kidney transplant recipients
Summary
· The only available method to prevent BKV infection and BLN is to do screening by blood PCR for viremia and apply preemptive reduction of immunosuppression. Unfortunately, it is effective only in 50 % of cases and is accompanied with higher risk of rejection.
· IVIG prophylaxis lower the risk of BKV infection and BKN among high risk patients for BKV infection (who had lower titers of antibodies) and even they had similar risk to those with protective high titer of anti BKV antibodies (low risk for BKV infection).
· IVIG was given at dose of 400 mg/kg IVIg doses every 3 weeks – for 1 to 3 – according to their IgG levels.
· Patients with de novo DSA, preformed DSA, or biopsy-proven AMR were treated with three 2 g/kg doses of IVIg every 3 weeks.
· It seems that B cell and neutralizing antibodies have role in BKV prophylaxis, while T cell mediated immunity is crucial in treatment and control of BKV infection.
· Points of strength as risk stratification and measurement of antibody titers.
· Points of weakness as being retrospective, none standardized regimen of IVIG and small number of cases.
Uses of IVIG in transplantation
· Treatment of ABMR.
· Treatment of recurrent FSGS.
· Given as replacement therapy after course of plasmapheresis done as in recurrent FSGS and ABMR treatment
· Desensitization protocol in HLA and ABO incompatible transplantation.
· Adjuvant therapy in treatment of CMV and BKV infection (together with reduction of IS therapy)
Treatment of sepsis (none specific and immunomodulatory effect
Please summarise this article.
# The aim of the study:
To investigate whether the preventive administration of IVIg may reduce the incidence of BKV viremia and BKVAN in high-risk KTR. Risk stratification was based on NAb titers against the donor’s BKV strain measured on day0.
# Introduction:
*BKV infections are remaining a big trouble in renal transplantation, occurring in 30%-50% of all KTR.
*BKVAN can affect up to 10% of BKV-infected KTR, leading to kidney dysfunction and graft loss.
*No specific antiviral treatment is currently available against BKV infections.
* Regular screening of BKV viremia or viruria accompanied by a reduction of immunosuppressive therapy remains the only viable strategy to control BKV replication
*Administration of IVIg has been empirically planned as a preemptive and supportive treatment against BKV infections.
*Patients with high titers of BKV-neutralizing antibodies (NAbs) are protected against BKV replication, and IVIg infusion can increase NAb titers.
# The method and result:
Retrospective study reviewed the clinical records of adult patients who underwent KT in the Strasbourg University Hospital between July 2012 and December 2017. All cases with available NAb titers measured on day 0 were deemed eligible.
# Exclusion criteria:
*Patient or graft survival lower than 3 months.
*The KTR (n = 174) were retrospectively divided into the following 3 risk categories for BKV replication:
(1) patients with low NAb titers (“high-risk”) who received IVIg for the first 3 posttransplant months (n = 44).
(2) patients with low NAb titers (“high-risk”) who did not undergo IVIg treatment (n = 41).
(3) patients with high NAb titers (“low-risk”) who did not receive IVIg (n = 89).
*At 12 posttransplant months, the incidence of BKV viremia in the high-risk group treated with IVIg (6.8%) was similar to that observed in the low-risk group (10.1%) and markedly lower than that of the untreated high-risk group (36.6%; P < .001).
*Similar results were observed with regard to BKVAN.
**They concluded that IVIg may be a valuable strategy for preventing BKV replication.
# The strengths:
An accurate risk stratification for BKV replication based on the quantification of
NAb titers against the 3 most common BKV genotypes and a high availability of donors’ samples.
# The limitation:
retrospective design, the relatively small number of patients who received IVIg infusions, and the use of different IVIg doses and administration schedule.
What are the other uses of IVIG in transplantation?
*In desensitization protocols.
*As anti-rejection therapies (ABMR)
* Protection against post transplant infection (CMV, parvovirus B19)
Making Kidney Transplants Possible for More Patients
Apr 02, 2017 Cedars-Sinai Staff.
Summary of the article
Intravenous immunoglobulin as a preventive strategy against BK virus viremia and BKV-associated nephropathy in kidney transplant recipients—Results from a proof-of-concept study
This is a retrospective review of the clinical records of adult patients who underwent KT in the Strasbourg University Hospital between July 2012 and December 2017. The review investigated whether early IVIg administration prevents BKV replication in patients with low neutralizing antibodies(Nab) titers.
Results and Discussion
1. IVIg were found to increase NAb titers against BKV genotype I(ie, the largely pre- dominant genotype).
2. Passive immunization with IVIg in the early post-transplant phase was associated with a significantly lower incidence of both BKV viremia and BKVAN in high-risk KTR.
3. The incidence of BKVAN was as low as 4.5% in the high-risk group treated with IVIg.
4. The study’s results add to the growing amount of evidence showing that BKV-neutralizing antibodies and B cell immunity play a key role in the prevention of BKV replication.
Strength of the study
a) An accurate risk stratification for BKV replication based on the quantification of NAb titers against the 3 most common BKV genotypes.
b) A high availability of donors’ samples.
Limitations of the study
a) Retrospective design.
b) The relatively small number of patients who received IVIg infusions.
c) The use of different IVIg doses and administration schedule.
What are the other uses of IVIG in transplantation?
1. Use of IVIG in desensitization protocols and for treatment of antibody-mediated rejection (AMR) are supportive for kidney transplant recipients.
· Immediate pre and/or post‐transplant where donor specific antibody(s) prevent transplantation or threaten transplantation.
· Ongoing de-sensitization of patients to improve the likelihood of transplantation.
· Initial treatment of acute antibody mediated transplant rejection.
· Treatment of ongoing active antibody mediated transplant rejection.
· Treatment or prevention of graft rejection where the use of conventional immunosuppressive therapies is contraindicated or poses a threat to the graft or patient.
2. IVIG is useful in the treatment and prevention of post-transplant infectious complications including cytomegalovirus, parvovirus B19 and polyoma BK virus(1).
References
Jordan SC, Toyoda M, Kahwaji J, Vo AA. Clinical aspects of intravenous immunoglobulin use in solid organ transplant recipients. Am J Transplant. 2011 Feb;11(2):196-202. doi: 10.1111/j.1600-6143.2010.03400.x. Epub 2011 Jan 10. PMID: 21219579.
Please summarise this article.
BK virus (BKV) replication occurs in kidney transplant recipients (KTR) leading to BKV-associated nephropathy (BKVAN) and graft loss. Patients with high titers of BKV-neutralizing antibodies (NAbs) are protected against BKV replication, and intravenous immunoglobulin (IVIg) infusion can increase NAb titres.
Purpose
To investigate whether early IVIg administration prevents BKV replication in patients with low NAb titers
Methodology
KTR followed in the Strasbourg University Hospital (n = 174) were studied retrospectively.
Patients were divided into three groups
1- High risk patients with low NAb titers who received IVIg for the first 3 posttransplant months (n = 44)
2- Patients with low NAb titers (“high-risk”) who did not undergo IVIg treatment (n = 41)
3- Patients with high NAb titers (“low-risk”) who did not receive IVIg (n = 89)
BK virus replication and its effects was assessed
IVIg administration increases BKV NAb titers in KTR
At one month the patients who received IVIG had higher mean NAb titres and remained at higher levels in subsequent two months. In high risk patients without IVIG and no viremia, there was no difference in NAb titres on the day of transplant and at one year.
IVIg administration decreases the incidence of both BKV viremia and BKVAN in KTR
At 12 posttransplant months, the incidence of BKV viremia in the high-risk group treated with IVIg (6.8%) was similar to that observed in the low-risk group (10.1%) and markedly lower than that of the untreated high-risk group (36.6%; P < .001).
Conclusion
IVIG was found to increase NAb titres against BKV. Immunization with IVIG was associated with low risk BKV viremia and BKV nephropathy in high risk group.
Strengths
Accurate risk stratification for BKV replication based on the quantification of NAb titers
High availability of donors’ samples
Limitations
Retrospective design
Small number of patients who received IVIg infusions
Use of different IVIg doses and administration schedule
What are the other uses of IVIG in transplantation?
· In ABMR
· In desensitization protocols
· CMV, BKV infections
Introduction
Currently, BK virus (BKV) viremia occurs in 30-50% of all kidney transplant recipients and BKV-associated nephropathy (BKVAN) can affect up to 10% of BKV-infected kidney transplant recipients. It has the potential to lead to kidney dysfunction and graft loss. There is no specific treatment available for the treatment of BKV viremia. Screening for the infection is accompanied by reduction of immune suppression. Unfortunately, this is not always successful, and does not eliminate the evolution to BKVAN. And it is associated with increased risk of rejection. IVIg has been suggested as a treatment for BKV infection. However, there have been a few studies conducted and their results require careful interpretation. This study investigated whether the preventative use of IVIg may reduce the incidence of BKV viremia and BKVAN in kidney transplant recipients at high risk.
Patients and Methods
Study patients Patients who underwent kidney transplantation in Strasbourg University Hospital between July 2012 and December 2017. All cases with available NAb titers measured on day 0 were deemed eligible. Exclusion criteria included patient or graft survival of less than 3 months. Patients were considered at high risk if they had Nab titers of less than 4log10IC50 against the donor’s strain.
Patients were divided in to three groups:
Immunosuppressive regimens Immunosuppressive therapy after kidney transplantation consisted of an induction therapy with basiliximab or thymoglobulin. Subsequent maintenance phase included a CNI with MMF or a mTOR inhibitor and steroids.
Monitoring of BKV infectionsBlood samples for assessing BKV infection were collected at day 0 of everymonth in the first 6 months post transplantation, and every 3 months after that for 1 year post transplantation. BKV was quantitatively measured using PCR. If graft dysfunction was noted, then allograft biopsies were performed. BKV genotyping was performed in all BKV DNA-positive recipients.
Neutralization assay NAb titers were measured on day 0 at the third, sixth and twelfth month after transplantation. A neutralization titer of 2.5 log10 IC50 was set as the threshold for quantification of antibody-mediated neutralization.
IVIg therapy Patients receiving the IVIg received 0.4g/kg every 3 weeks – with a total number of doses ranging from 1-3 depending on their IgG levels. Patients with de novo DSA, preformed DSA, or biopsy-proven AMR were treated with three 2g/kg doses of IVIg every 3 weeks.
Data analysisContinuous variables were presented as medians and interquartile ranges, analyzed using the Kruskal-Wallis test. Categorical variables were given as counts and percentages, and analyzed with the chi-square test or the Fisher’s exact test.
Results
Patient characteristics At day 0, 97.7% of the recipients and 120 donors were seropositive for at least one genotype of BKV. Donor NAb titers at day 0 did not differ between the three groups.
IVIg administration increases BKV NAb titers in KTR 44 high-risk patients were treated with IVIg, 35 patients were at a high risk of replication of BKV genotype I, 7 for genotype II and 2 for genotype IV. 41 patients received IVIg due to SID. The temporal course of BKV NAb titers was studied only in patients who received IVIg in the absence of BKV viremia. This approach allowed investigating the impact of IVIg when immune system stimulation was lacking, because of the increased BKV NAb titers observed in kidney transplant recipients with BKV viremia. At day 0, the mean BKV NAb titer was 3.06 (0.56) log 10 IC50. Before the first IVIg injection, BKV NAb titers remained below 4 log 10 IC50 in all patients. After the first month post-transplant, when the majority of patients (93%) had already received the first IVIg injection, the mean NAb titers significantly increased to 3.82 (0.61) log 10 IC50 and remained at these levels for the subsequent 2 months. A decrease in NAb titers occurred later, with a return to the initial levels between the sixth and twelfth month after transplantation. Among these 41 patients, there was a high risk of replication for BKV genotype I, genotype II, and genotype IV in 32, 7, and 2 cases, respectively. Twenty-nine of the 32 patients (91%) at high risk for BKV genotype I replication were capable of reaching a BKV NAb titer above the threshold of 4 log 10 IC50 in at least 1 occasion during the first 3 post-transplant months. The remaining 3 cases who were unable to achieve high NAb titers received 2 or 3 low-dose IVIg infusions. All of them showed markedly low titers before IVIg treatment. This increased after IVIg administration.
In the 26 high-risk patients without IVIg and no BKV viremia, there were no significant differences in BKV NAb titers measured on the day of transplantation and 1 year thereafter.
IVIg administration decreases the incidence of both BKV viremia and BKVAN in KTRBKV viremia was observed in 27 of the 174 study patients. It was noted that BKV viremia was an early event that occurred after a median of 64 days from the transplant. BKV genotype I and IV were identified as the replicating strains in 23 (85%) and 4 (15%) patients, respectively, and no case showed genotype II replication. The frequency of viremia was higher in presence of donor/recipient BKV genotype mismatch, but it was not significant. Despite immunosuppressive reduction, 12 patients evolved to a biopsy-proven BKVAN.
After 12 months post-transplant, the incidence of BKV viremia in the high-risk group treated with IVIg was similar to that observed in the low-risk group and markedly lower than that of the untreated high-risk group.
Discussion
There were two main findings in this study:
These results help us better understand the evidence of BKV-neutralizing antibodies and how B cell immunity is involved in the prevention of BKV replication. This study shows that in high risk patients, IVIg may be considered as a prophylaxis against BKV infection
The strengths include an accurate risk stratification for BKV replication based on the quantification of NAb titers against the 3 most common BKV genotypes and a high availability of donors samples.
The limitations include its retrospective design, the relatively small number of patients who receive IVIg infusions and the use of different IVIg doses and administration schedule.
Other uses of IVIg in Transplantation:
Other uses of IVIg in transplantation:
1- Desensitization protocol pre-transplant in patients with DSA
2- Post transplant viral infection
3- Treatment of AMR
1- Summary:
1- High risk (n=44): Patients with low NAb titer who received IVIg treatment for secondary immunodeficiency (SID) or for prevention or treatment of antibody-
mediated rejection (AMR) during the first 3 posttransplant months.
2- High risk untreated (n=41): with low NA tite
3- Low risk (n=89): high titre and did not receive IVIg
Results:
– At 1 posttransplant month, when the majority of patients (93%) had already received the first IVIg injection, the mean NAb titers significantly increased tand remained at these levels for the subsequent 2 months. then decrease to initial level between 6-12 months.
-Twenty-nine of the 32 patients (91%) at high risk for BKV genotype I replication were capable of reaching a BKV NAb titer above the threshold. the remaining three patients received 2nd and 3rd dose of IVIg and the titer increased.
-Only 2 and 1 patients among those with a high risk of replication for BKV
genotype II and genotype IV, respectively, were capable of obtaining a
BKV NAb titer above the threshold.
At 12 posttransplant months:
Conclusion:
Please summarise this article.
INTRODUCTION
·BKV infections are a major concern following kidney transplantation, with BKV-associated nephropathy and graft loss.
·Regular screening and immunosuppressive therapy is the only viable strategy to control BKV replication, but it is associated with an increased risk of DSA and acute rejection.
·IVIg is proposed as a preventive and supportive treatment against BKV infections.
·Humoral immunity is essential for preventing BKV replication in KTR.
PATIENTS AND METHODS
Patients retrospectively divided into the following 3 risk categories for BKV replication:
RESULTS
·At 12 posttransplant months, the incidence of BKV viremia in the high-risk group treated with IVIg (6.8%) was similar to that observed in the low-risk group (10.1%) and markedly lower than that of the untreated high-risk group (36.6%; P < .001).
·Similar results were observed with regard to BKVAN.
DISCUSSION
·It was discovered that IVIg elevated NAb titers against BKV genotype I (i.e., the genotype that is mostly predominate) over the protective threshold.
·In high-risk KTR, passive vaccination with IVIg during the first posttransplant phase was linked to a considerably decreased incidence of BKV viremia and BKVAN.
·The KTR’s ability to neutralize BKV replication is greatly aided by the anti-BKV antibody-mediated reaction.
·For the clinical purpose of risk stratification of BKV-related illness, NAb titers against the donor’s strain assessed before KT are helpful.
·When recipients have low BKV NAb titers, high donor seroreactivity can increase the probability of BKV reproduction.
· BKVAN incidence in the high-risk group receiving IVIg was as low as 4.5%.
· B-cell immunity and B-cell-neutralizing antibodies are crucial in preventing BKV replication.
·The inhibition of active BKV replication is predominantly mediated by T-cell immunity.
·The potential effectiveness of IVIg administration in the treatment of BKV replication is still up for debate due to the concurrent use of other antiviral therapies and/or the tapering of immunosuppression.
·mTOR inhibitors may be protective against BKV replication.
·The current study is the first to show that IVIg infusion could be a useful tactic for stopping BKV proliferation in KTR.
=========================================================
What are the other uses of IVIG in transplantation?
Viral Inections post transplantation.
Desensitization protocol and treatment of acute rejection.
Intravenous immunoglobulin as a preventive strategy against BK virus viremia and BKV-associated nephropathy in kidney transplant recipients—Results from a proof-of-concept study.
Introduction:
BKV infection post kidney transplant is considered one of the most common viral infection and unfortunately no definitive therapy for it except reduction of immunosuppression drugs and serial screening, BKV replication occurring in 30%-50% of all kidney transplant recipients (KTR). BKV-associated nephropathy (BKVAN) can affect up to 10% of BKV-infected KTR, potentially leading to kidney dysfunction and graft loss.
Aim of the work:
we sought to know whether the preventive administration of IVIg may reduce the incidence of BKV viremia and BKVAN in high-risk KTR. Risk stratification was based on NAb titers against the donor’s BKV strain measured on day 0.
Patients and methods:
It is retrospective study which KTR followed in the Strasbourg University Hospital from July 2012 and December 2017 (n = 174) were retrospectively divided into the following 3 risk categories for BKV replication: (1) patients with low NAb titers (“high-risk”) who received IVIg for the first 3 post-transplant months (n = 44), (2) patients with low NAb titers (“high-risk”) who did not undergo IVIg treatment (n = 41), and (3) patients with high NAb titers (“low-risk”) who did not receive IVIg (n = 89), and IVIg were infused either as a preventive or curative treatment of AMR or in patients diagnosed with SID. Patients received 0.4 g/kg IVIg doses every 3 weeks – with a total number of doses ranging from 1 to 3.
RESULTS.
IVIg administration increases BKV NAb titers in KTR.
At 1 post-transplant month, when the majority of patients (93%) had already received the first IVIg injection, the mean NAb titers significantly increased to 3.82 (0.61) log10 IC50 and remained at these levels for the subsequent 2 months, in contrast In the 26 high-risk patients without IVIg and no BKV viremia, there were no significant differences in BKV NAb titers measured on the day of transplantation and 1 year thereafter.
IVIg administration decreases the incidence of both BKV viremia and BKVAN in KTR.
At 12 post-transplant months, the incidence of BKV viremia in the high-risk group treated with IVIg was similar to that observed in the low-risk group and markedly lower than that of the untreated high-risk group, and the median peak viral load was significantly lower in the high risk group treated with IVIg (4.16 log10 copies/mL) compared with the low-risk group (5.03 log10 copies/mL) and the untreated high risk group .
Conclusion:
IVIg were found to increase NAb titers against BKV genotype I over the protective threshold of 4 log10 IC50.Second, passive immunization with IVIg in the early post-transplant phase was associated with a significantly lower incidence of both BKV viremia and BKVAN in high-risk KTR.
strengths :
an accurate risk stratification for BKV replication based on the quantification of NAb titers against the 3 most common BKV genotypes and a high availability of donors samples.
Limitation:
Retrospective design.
The relatively small number of patients who received IVIg infusions.
The use of different IVIg doses and administration schedule.
Other uses of IVIG in transplantation?
-Desensitization protocol in ABO and HLA incompatible transplantation.
-Antibody mediated rejections.
-Viral infection such as (Parvovirus, CMV and BKVN).
I agree with your analysis of strengths and limitations, and summary of this article.I agree with your analysis of the level of evidence this article provides.
Intravenous immunoglobulin as a preventive strategy against BK virus viremia and BKV-associated nephropathy in kidney transplant recipients—Results from a proof-of-concept study
Introduction:
The Aim of the Study:
A retrospective nonrandomized study on 174 kidney transplant patients To investigate whether the preventive administration of IVIg may reduce the incidence of BKV viremia and BKVAN in high-risk KTR.
Inclusion criteria:
All cases with available NAb titers measured on day 0 were deemed eligible.
Exclusion criteria:
patient or graft survival lower than 3 months.
Patients with NAb titers below 4 log 10IC50 were considered high-risk.
The most common viral genotype (genotype I) was used as reference for patients with negative BKV DNA load.
The study patients (n = 174) were divided into 3 risk categories for BKV replication:
Immunosuppressive regimens:
The result:
At 12 post-transplant months:
The incidence of BKV viremia in the high-risk group treated with IVIg was similar to that observed in the low-risk group and markedly lower than that of the untreated high-risk group .
Similar results were observed regarding BKVAN.
The investigators found that, there was no difference in the rate of BKV replication between the high and low risk groups( 6.8% vs 10.1%). However, those who received IVIG had significant lower rate of BKV replication compared to those who didn’t given IVIG.
Discussion:
IVIg can increase NAb titers against BKV genotype I which is the most common variant over the protective threshold of 4 log10 IC50.
Administration of IVIg as passive immunization in the early posttransplant period lead to significant decrease of the incidence of BKV viremia and BKVAN in high-risk KTR .
The possible utility of IVIg administration in the management of BKV replication is controversial due to the concomitant use of other antiviral strategies and/or immunosuppression reduction.
The strength of this study is the precise risk stratification for BKV replication due to the quantification of NAb titers against the 3 most common BKV genotypes and availability of donors’ samples.
Limitations were being a retrospective study with small number of included patients who
Took IVIg infusions, and the use of different IVIg doses and administration schedule.
The strengths of the study :
The accurate risk stratification for BKV replication based on the quantification of NAb titer against the 3 most common BKV genotypes and a high availability of donors’ samples.
The limitations of the study :
1-Retrospective design.
2-The relatively small number of patients who received IVIg infusions.
3- The use of different IVIg doses and ad- ministration schedule.
Conclusion:
The study results add to the growing amount of evidence showing that BKV-neutralizing antibodies and B cell immunity play a key role in the prevention of BKV replication. Conversely, T cell immunity is preferentially involved in the control of active BKV replication.
IVIg may be a valuable strategy for preventing BKV replication.
What are the other uses of IVIG in transplantation?
Desensitization protocols (in ABO or HLA incompatible transplantation)
Treatment of antibody-mediated rejection (AMR).
IVIG is useful in the treatment and prevention of post-transplant infectious complications including cytomegalovirus, parvovirus B19 and polyoma BK virus.
GVHD treatment in HSCT
I note that reducing immunosuppression is the key step. I appreciate your steps when considering retransplantation. None of the drugs mentioned have any conclusive proof of their efficacy in BKV
Intravenous immunoglobulin as a preventive strategy against BK virus viremia and BKV-associated nephropathy in kidney transplant recipients—Results from a proof-of-concept study
Introduction
Aim of the study:
PATIENTS AND METHODS
This is a retrospective nonrandomized study
Inclusion criteria:
All cases with available NAb titers measured on day 0 posttransplant.
Exclusion criteria:
Patient or graft survival lower than 3 months.
IS regimen and monitoring of BKV infection
· Were as per protocol of the center of the study.
Neutralization assay
IVIg therapy
Results:
Conclusion
· IVIg administration in the early posttransplant phase decreases the incidence of both BKV viremia and BKVAN in high-risk KTR.
The limitation of the study:
Strength of the study
I agree with your analysis of strengths and limitations, and summary of this article.I agree with your analysis of the level of evidence this article provides.
1-Please summarise this article.
Introduction;
–BK virus (BKV) replication occurs frequently in kidney transplant recipients (KTR),
–Potentially leading to BKV-associated nephropathy (BKVAN) and graft loss.
–Patients with high titers of BKV-neutralizing antibodies (NAbs) are protected against BKV replication, and intravenous immunoglobulin (IVIg) infusion can increase NAb titers.
Aim;
–In current study, they sought to investigate whether the preventive administration of IVIg may reduce the incidence of BKV viremia and BKVAN in high-risk KTR.
–Risk stratification was based on NAb titers against the donor’s BKV strain measured on day 0 of transplantation.
Methods;
–Based on NAb titers on the day of transplantation (Day 0) , KTR followed in the Strasbourg University Hospital (between July 2012 and December 2017).
– (174 Patients) were retrospectively divided into the following 3 risk categories for BKV replication:
1- ( 44 ) Patients with low NAb titers (“high-risk”) who received IVIg for the first 3 post transplant months,
2- ( 41 ) Patients with low NAb titers (“high-risk”) who did not undergo IVIg treatment,
3- ( 89 ) Patients with high NAb titers (“low-risk”) who did not receive IVIg.
Results;
–At 12 post transplant months, the incidence of BKV viremia in the high-risk group treated with IVIg (6.8%) was similar to that observed in the low-risk group (10.1%) and markedly lower than that of the untreated high-risk group (36.6%; P < .001).
–Similar results were observed with regard to BKVAN.
Conclusion;
–IVIg may be more useful as a preventive – rather than curative – strategy.
–As far as published clinical studies are concerned, the potential utility of IVIg administration in the management of BKV replication is still debatable owing to the concomitant use of other antiviral strategies and/or immunosuppression tapering.
–In addition, IVIg have been previously administered with curative intent or even as a rescue treatment.
Strength;
–The current study is the first to demonstrate that IVIg infusion may be a valuable strategy for preventing BKV replication in KTR.
–Including an accurate risk stratification for BKV replication based on the quantification of NAb titers against the 3 most common BKV genotypes and a high availability of donors’ samples.
Limitation;
–Its retrospective design, the relatively small number of patients who received IVIg infusions, and the use of different IVIg doses and administration schedule.
2-What are the other uses of IVIG in transplantation?
–Desensitization protocols in (ABO or HLA incompatible transplantation).
–ABMR treatment and prevention after solid organ transplantation.
–Adjunctive therapy in post-transplant infectious complications:(CMV, parvovirus B19 , BKVAN).
–GVHD treatment in adult bone marrow transplant patients.
–De novo DSA without concurrent antibody-mediated rejection.
–Post exposure prophylaxis;of (hepatitis A and B, tetanus, rabies, diphtheria, botulism, varicella-zoster, respiratory syncytial virus, and cytomegalovirus infections).
–Autoimmune and Inflammatory disorders; (inflammatory diseases such as Kawasaki disease, Guillain-Barre syndrome, myasthenia gravis, dermatomyositis and demyelinating polyneuropathy).
–Other conditions; include (toxic epidermal necrolysis and Stevens-Johnson syndrome, neonatal sepsis , Henoch-Schönlein purpura, and toxic shock syndrome).
References;
Up To Date: Overview of intravenous immune globulin (IVIG) therapy
I agree with your analysis of strengths and limitations, and summary of this article.I agree with your analysis of the level of evidence this article provides.
Introduction:
BK virus (BKV) infections is major complication and highly prevalent among all kidney transplant recipients (KTR). It can result in BKV-associated nephropathy, potentially leading to kidney dysfunction and graft loss.
There is no specific treatment for BKV, reduction of immunosuppression is the mainstay of treatment in these conditions. This approach has variable success and may increase risk of rejection.
Previous study showed low level of BKV-Neutralizing Antibodies (Nab) increase the risk of viral replication. IVIg has been proposed as supportive treatment against BKV as it has neutralizing activity against the most common BKV genotypes.
Aim of the Study:
To investigate the the preventive role of IVIG in reducing the incidence of BKV viremia and BKVAN in KTR.
Patient And Method:
Study patients:
-Retrospectively study reviewed the clinical records of adult patients who underwent KT in the Strasbourg University Hospital between
July 2012 and December 2017.
– Included; all cases with available NAb titers measured on day 0
–Excluded; patient or graft survival lower than 3 months, those without Nab, low risk group who receive IVIG during the first year.
– Recipient with BKV- NAb titers < below 4 log10 IC50 against the donor’s strain were considered at high-risk.
– Patients divided into the following 3 risk categories for BKV replication:
(1) high-risk patients; those with low Nab titers, “who received IVIg in the first 3 months post KT for secondary immunodeficiency (SID) before BKV replication (n = 44).
(2 high-risk patients; patients with low NAb titers; who did not undergo IVIg treatment during the first year of KT (n = 41)
(3 low-risk patients; patients with high NAb titers ; who did not receive IVIg (n = 89).
-Secondary immunodeficiency (SID) was defined either as:
(1) IgG levels <400 mg/dL or
(2) IgG levels between 400 and 800 mg/dL in the presence of a concurrent infection.
IVIg therapy As a preventive or curative treatment of AMR or in patients diagnosed with SID.
Immunosuppressive regimens
-Induction with basiliximab or thymoglobulin based on the recipient’s immunological risk.
-Maintenance; a CNI (ciclosporin or tacrolimus) with (MMF) or a (mTORi)) and steroids.
Monitoring of BKV infections
– BKV plasma PCR monitored at ; day 0, monthly in the first 6, and every 3 months thereafter (until 1 year following KT).
– Allograft biopsies( including SV-40 stain) done in case of graft dysfunction, detection of DSA, or sustained BKV viremia.
– BKV genotyping was performed in all BKV DNA-positive recipients.
Neutralization assay
-NAb titers were measured at day 0; at the third, sixth, and 12th ; and at the onset of viremia. Additional measurements in patients who received IVIg infusions at the first and second posttransplant months were performed.
– Nab titer; defined as the sample dilution that resulted in a 50% inhibition of pseudovirion infectivity (IC50) – was expressed as log10 of IC50.
RESULTS
– Genotype 1 was the most prevalent among both donors ( 79%) and recipients (83%).
– High risk group who received IVIG in the absence of BKV viremia: BKV Nab titer was significantly low before IVIG and significantly increases after IVIG above the threshold of 4 log10.
-High-risk patients without IVIg and no BKV viremia, there were no significant differences in BKV NAb titers measured on the day of transplantation and 1 year thereafter.
-BKV viremia total incidence at 1 posttransplant year: 15.5%.
–IVIg administration decreases the incidence of both BKV viremia and BKVAN in KTR
– At 12 posttransplant months, the incidence of BKV viremia in the high-risk group treated with IVIg (6.8%) was similar to that observed in the low-risk group (10.1%) and markedly lower than that of the untreated high-risk group (36.6%).
– The median peak viral load was significantly lower in the high risk group treated with IVIg (4.16 log10 copies/mL) compared with
the low-risk group and the untreated high risk group.
-Multivariate analysis did not reveal significant associations between immunosuppressive therapies and the incidence of BKV viremia.
– The occurrence of BK viremia was independently associated with D0 Nab titers and patient group in multivariate analysis.
-Patients in the high-risk untreated group had a 24-fold increase in the risk of developing BK viremia compared with the low-risk group
– The incidence of BKVAN at 12 posttransplant months 4.5% in the high-risk group treated with IVIg, 2.2% in the low-risk group, and
19.5% in untreated high-risk patients.
Conclusion:
-IVIg were found to increase NAb titers against BKV genotype and significantly lower incidence of both BKV viremia and BKVAN in high-risk KTR.
Limitations:
– Retrospective nonrandomized study
– The use of everolimus was more frequent for patients who received IVIG (which may has protective against BKV replication)
– Small sample size.
– The use of different IVIg doses and administration schedule
Strength:
-The first study demonstrate role of IVIg for preventing BKV replication in KTR.
-Accurate risk stratification for BKV replication based on the quantification of NAb titers.
What are the other uses of IVIG in transplantation?
-Desensitization in ABO or HLA incompatible transplantation.
– ABMR treatment and prevention.
– Adjunctive therapy in treatment of infection: resistant CMV, parvovirus B19 ,BKVAN.
– Post exposure prophylaxis.
– GVHD treatment in HSCT
Reference;
Jordan SC, Toyoda M, Kahwaji J, Vo AA. Clinical aspects of intravenous immunoglobulin use in solid organ transplant recipients. Am J Transplant. 2011 Feb;11(2):196-202. doi: 10.1111/j.1600-6143.2010.03400.x. Epub 2011 Jan 10. PMID: 21219579.
I agree with your analysis of strengths and limitations, and summary of this article.I agree with your analysis of the level of evidence this article provides.
The Aim of the Study ;
———————————-
To investigate whether the preventive administration of IVIg may reduce the incidence of BKV viremia and BKVAN in high-risk KTR.
The type of the study ;
—————————–
a retrospective non randomized study.
The study area ;
—————————
Strasbourg University Hospital between July 2012 and December 2017.
Population ;
———————————
174 kidney transplant patients .
Inclusion criteria ;
———————————–
All cases with available NAb titers measured on day 0 were deemed eligible.
Exclusion criteria ;
——————————————
patient or graft survival lower than 3 months.
The method ;
————————
Based on NAb titers on the day of transplantation, KTR followed in the Strasbourg University Hospital (n = 174) were retrospectively divided into the following 3 risk categories for BKV replication:
(1) patients with low NAb titers (“high-risk”) who received IVIg for the first 3 posttransplant months (n = 44) .
(2) patients with low NAb titers (“high-risk”) who did not undergo IVIg treatment (n = 41).
(3) patients with high NAb titers (“low-risk”) who did not receive IVIg (n = 89).
The study examined the preventive role of IVIg in the first 3 post- transplant months because BKV replication generally occurs early following KT.
The result ;
—————————————–
At 12 post transplant months ;
1-The incidence of BKV viremia in the high-risk group treated with IVIg was similar to that observed in the low-risk group and markedly lower than that of the untreated high-risk group .
2-Similar results were observed with regard to BKVAN.
The strengths of the study ; –
—————————————-
1- an accurate risk stratification for BKV replication based on the quantification of
NAb titers against the 3 most common BKV genotypes and a high availability of donors’ samples.
The limitations of the study ;
——————————————–
1-Retrospective design .
2-The relatively small number of patients who received IVIg infusions .
3- The use of different IVIg doses and ad- ministration schedule.
Conclusion ;
——————–
1-The study results add to the growing amount of evidence showing that BKV-neutralizing antibodies and B cell immunity play a key role in the prevention of BKV replication. Conversely, T cell immunity is preferentially involved in the control of active BKV replication.
2- IVIg may be a valuable strategy for preventing BKV replication.
What are the other uses of IVIG in transplantation?
————————————————————————-
1- In desensitization protocols .
2- treatment of antibody-mediated rejection (AMR) .
3- IVIG is useful in the treatment and prevention of post transplant infectious complications including cytomegalovirus, parvovirus B19 and polyoma BK virus.
I agree with your analysis of strengths and limitations, and summary of this article.
Introduction
BK virus infections are still a major concern following Kidney transplantation, with BKV replication occurring in 30%-50% of all kidney transplant recipients (KTR).
BK virus associated nephropathy (BKVAN) can affect up to 10% of BKV -infected KTR, potentially leading to kidney dysfunction and graft loss.
No specific antiviral treatmnent is currently available against BKV
BKV infections. 4-6 Regular screening of BKV viremia or viruria accompanied by a reduction of immunosuppressive therapy re – mains the only viable strategy to control BKV replication.
NAb titers against the donor’s BKV strain lower than 4 log IC50 at the time of transplantation are associated with an increased risk of BKV replication following kidney transplantation.
Based on NAb titers on day 0 and the prescription of IVIg infusion, the study patients (n = 174) were divided into the following 3 risk categories for BKV replication, patients with low NAb.
BENOTMANE ET Al. titers (“high-risk patients”) who received IVIg treatment for second – ary immunodeficiency (SID) or for prevention or treatment of antibody-mediated rejection (AMR) during the first 3 posttransplant months and before BKV replication (n = 44), patients with low NAb titers (“high-risk patients”) who did not undergo IVIg treatment during the first year of kidney transplantation (n = 41), and patients with high NAb titers (“low-risk patients”) who did not receive IVIg (n = 89).
Induction therapy
Donor NAb and/or replicative strain available, n (%) 29 (70.7) 39 (88.6) 65 (73.0) .08.
At 1 posttransplant month, when the majority of patients (93%) had already received the first IVIg injection, the mean NAb titers significantly increased to 3.82 (0.61) log IC50 and remained at these levels for the subsequent 2 months
A decrease in NAb titers occurred afterwards, with a return to the initial levels between 6 and 12 posttransplant months
Among these 41 patients, there was a high risk of replication for BKV genotype I, genotype II, and genotype IV in 32, 7, and 2 cases, respectively.
2 and 1 patients among those with a high risk of replication for BKV genotype II and genotype IV, respectively, were capable of obtaining a BKV NAb titer above the threshold of 4 log IC50.
Genotype II
At 12 posttransplant months, the incidence of BKV viremia in the high-risk group treated with IVIg (6.8%, 3 of 44 patients) was similar to that observed in the low-risk group (10.1%, 9 of 88 patients) and markedly lower than that of the untreated high-risk group
The median peak viral load was significantly lower in the highrisk group treated with IVIg (4.16 log copies/mL) compared with the low-risk group (5.03 log copies/mL) and the untreated highrisk group
Similar figures were observed with regard to the incidence of BKVAN at 12 posttransplant months
Discussion
There are 2 principal findings from this study. First, IVIg were found to increase NAb titers against BKV genotype I (ie, the largely predominant genotype) over the protective threshold of 4 log IC50.
Because IVIg preparations contain high levels of BKV NAbs, we sought to assess whether among these patients, those receiving IVIg for SID or AMR early after kidney transplantation may be protected against BKV replication.
In the high-risk treated group, only 3 cases received high dose IVIg. Because IVIg preparations contain high levels of BKV NAbs, we sought to assess whether among these patients, those receiving IVIg for SID or AMR early after kidney transplantation may be protected against BKV replication.
In the high-risk treated group, only 3 cases received highdose IVIg
These patients were not excluded from the analysis for the following reasons: we have previously shown than BKV NAb titers against genotype I increased in a similar fashion after low or high IVIg doses22 .despite a higher burden of immunosuppression.
Days from transplantation
3 high-risk patients treated with IVIg who had evidence of BKV viremia were unable to achieve the protective threshold of 4 log IC50.
A high donor seroreactivity can act as a risk factor for BKV replication especially in recipients with low BKV NAb titers..
The donor’s serotype was unavailable for the third patient, the recipient had a NAb titer of 4.69 log IC50 at the date of first BKV viremia .
The unavailability of urine samples does not allow excluding that BKV replication may have occurred before IVIg infusion
Another important finding from our study is TA B L E 2 Characteristics of patients with BKV viremia and/or BKV -associated nephropathy according to NAb titers at the day of transplantation and the infusion of IVIg.
Findings
BKV -associated nephropathy (BKVAN) can affect up to 10% of BKV -infected KTR, potentially leading to kidney dysfunction and graft loss..
In the 26 high-risk patients without IVIg and no BKV viremia, there were no significant differences in BKV NAb titers measured on the day of transplantation and 1 year thereafter (3.1 log IC50 vs 3.2 log IC50, respectively, P = .20, Figure S2).
The median peak viral load was significantly lower in the highrisk group treated with IVIg (4.16 log copies/mL) compared with the low-risk group (5.03 log copies/mL) and the untreated highrisk group (4.97 log copies/mL, P = .025; Table 2).
Recipient NAb levels
The inhibitory effect was more pronounced when immunoglobulins were coincubated with BKV virions before experimental cell infection compared with their use in the postinfection phase
These in vitro results suggested that IVIg may be more useful as a preventive – rather than curative – strategy.
Our study is limited by its retrospective design, the relatively small number of patients who received IVIg infusions, and the use of different IVIg doses and administration schedule.
These caveats notwithstanding, we provide proof-of-concept evidence that IVIg administration is capable of preventing BKV viremia and BKVAN in KTR with low NAb titers.
Other use of IVIg
Antibody mediated rejection.
Desensitization protocol
Post transplant infection and malignancies
Handbook of Kidney Transplantation
Gabriel M. Danovitch, MD
I agree with your analysis of strengths and limitations, and summary of this article.
Intravenous immunoglobulin as a preventive strategy against BK virus viremia and BKV-associated nephropathy in kidney transplant recipients—Results from a proof-of-concept study.
_______________________________
◇ Introduction
▪︎BK virus (BKV) infections are still a major concern following kidney transplantation, with BKV replication occurring in 30%-50% of all KTR.
▪︎BKV-associated nephropathy (BKVAN) can affect up to 10% of BKV-infected KTR, potentially leading to kidney dysfunction and graft loss.
▪︎No specific antiviral treatment is currently available against BKV infections.
▪︎Regular screening of BKV viremia or viruria accompanied by a reduction of IS therapy remains the only viable strategy to control BKV replication.
▪︎It is associated with an increased risk of developing DSA and acute rejection. ▪︎Intravenous immunoglobulin (IVIg) administration has been empirically proposed as a preemptive and supportive treatment against BKV infections.
▪︎Humoral immunity plays a crucial role for the prevention of BKV replication in KTR, with high titers of BKV-neutralizing antibodies (Nab) having a protective effect.
▪︎IVIg can exert a clinically relevant neutralizing activity against the most common BKV genotypes, with IVIg infusion resulting in increased NAb titers
among KTR.
◇ Methodology:
▪︎This study investigated whether early IVIg administration prevents BKV replication in patients with low NAb titers (<4 log10 against the BKV-specific genotype).
▪︎Based on NAb titers on the day of transplantation, KTR followed in the Strasbourg University Hospital (n = 174) were retrospectively divided into the following 3 risk categories for BKV replication:
(1) patients with low NAb titers (“high-risk”) who received IVIg for the first 3 post- transplant months (n = 44)
(2) patients with low NAb titers (“high-risk”) who did not undergo IVIg treatment (n = 41), (3) patients with high NAb titers (“low-risk”) who did not receive IVIg (n = 89).
◇ Results
▪︎At 12 posttransplant months, the incidence of BKV viremia in the high-risk group treated with IVIg (6.8%) was similar to that observed in the low-risk group (10.1%) and markedly lower than that of the untreated high-risk group (36.6%; P < .001). ▪︎Similar results were observed with regard to BKVAN.
◇ Strengths of the study:
1. An accurate risk stratification for BKV replication based on the quantification of NAb titers against the 3 most common BKV genotypes
2. High availability of donors’ samples.
◇ Limitations of the study:
1. A retrospective design.
2. The relatively small number of patients who received IVIg infusions.
3. The use of different IVIg doses and administration schedule.
◇ Conclusion:
▪︎This study investigated whether the preventive administration of IVIg may reduce the incidence of BKV viremia and BKVAN in high-risk KTR.
▪︎Risk stratification was based on NAb titers against the donor’s BKV strain measured on day.
▪︎This study concluded that IVIg may be a valuable strategy for preventing BKV replication.
☆ What are the other uses of IVIG in transplantation?
IVIG can be used (1):
▪︎In desensitization protocols.
▪︎For treatment of antibody-mediated rejection (AMR)IVIG3
Also, IVIG is useful in:
▪︎Treatment and prevention of posttransplant infectious complications including cytomegalovirus, parvovirus B19.
_______________________
▪︎Reference:
(1) S C Jordan et al. . Clinical aspects of intravenous immunoglobulin use in solid organ transplant recipients. Am J Transplant. 2011 Feb.
I agree with your analysis of strengths and limitations, and summary of this article.That is a well-structured reply. Typing the whole sentence in bold amounts to shouting, however.
SUMMARY
Introduction
The reactivation of dormant BKV infection following immune suppression or transmission to the recipient after a kidney transplant has been one of the major concerns because of the possible result of allograft loss. Unfortunately, there are no specific antiviral agents against BKV infection, hence leaving more room for concern in kidney transplantation. It has been observed that patients with high titers of BKV-neutralizing antibodies (NAbs) are protected against BKV replication, and intravenous immunoglobulin (IVIg) infusion can increase NAb titers.
Aim of the study
Patient and Method
Inclusion criteria
Exclusion criteria
Classification of study group based on the NAb titre at day 0
Results
Discussion
Strength of the study
Limitations of the study
Other uses of IVIg in KTP
I agree with your analysis of strengths and limitations, and summary of this article.
1. Please summarise this article.
Introduction
The study
Main results:
Strengths:
Limitations:
Future
==============================
2. What are the other uses of IVIG in transplantation?
I agree with your analysis of strengths and limitations, and summary of this article.That is a well-structured reply.
Introduction
BK virus replication occurs in 30%–50% of kidney transplant recipients, posing a serious risk. Up to 10% of BKV-infected KTR may develop nephropathy, causing kidney failure and graft loss.
No BKV antiviral therapy exists. Only regular BKV viremia or viruria screening and immunosuppressive therapy can reduce BKV replication.
It also increases donor-specific antibodies and acute rejection risk. In this situation, novel BKV prevention methods are eagerly awaited.
Intravenous immunoglobulin has been shown to prevent and treat BKV infections. Due to methodological issues such as small sample sizes, the lack of a control arm, and the use of additional antiviral treatments and/or immunosuppression, the field’s findings should be interpreted cautiously.
Methods
Study patients
In this article, the authors retrospectively evaluated the clinical data of adult Strasbourg University Hospital KT patients from July 2012 to December 2017. All day 0 NAb titers were eligible. Patient or graft survival below 3 months is excluded. According to our prior methods, 20 individuals with NAb titers 4 log10 IC50 against the donor’s strain were high-risk.
Immunosuppressive regimens
Based on immunological risk, basiliximab or thymoglobulin induction therapy was followed by KT. Thymoglobulin treated patients with panel reactive antibodies >20% and ABO-incompatible kidney transplantation. The patient got a calcineurin inhibitor, mycophenolate mofetil, or everolimus, and steroids in the maintenance phase.
Monitoring of BKV infections
BKV viremia was measured at day 0, every month in the first 6 posttransplant months, and every 3 months afterward (until 1 year following KT). BKV quantitative real-time polymerase chain reaction measured.
Neutralization assay
At day 0, the third, sixth, and 12th posttransplant months, and at viremia, NAb titers were assessed. IVIg-infused patients were measured at the first and second posttransplant months.
IVIg therapy
According to their IgG levels, patients got one to three 0.4 g/kg IVIg doses every three weeks. De novo DSA, preformed DSA, and biopsy-proven AMR patients received three 2 g/kg IVIg doses every three weeks.
IVIg administration increases BKV NAb titers in KTR
35 (79.5%), 7 (15.9%), and 2 (4.5%) of 44 high-risk patients treated with IVIg had a significant BKV genotype I, II, or IV replication risk. 41 SID patients received 0.4 g/kg IVIg infusions. 28 (63.6%) received 3 doses. The remaining 12 (27.3%) and 1 (2.3%) patients received 2 and 1 doses. Three (6.8%) patients got three 2 g/kg IVIg infusions to prevent or cure AMR in the first three posttransplant months.
In 32, 7, and 2 of these 41 patients, respectively, there was a high chance of replication for BKV genotype I, genotype II, and genotype IV. Ninety-one percent of the 32 patients at high risk for BKV genotype I replication were able to achieve a BKV NAb titer over the threshold of 4 log10 IC50 on at least one occasion during the first three posttransplant months.
IVIg administration decreases the incidence of both BKV viremia and BKVAN in KTR
27 of 174 study patients had BKV viremia at 1 year posttransplant (15.5%). BKV viremia usually developed 64 days after KT (25th-75th percentiles: 47.5-128.5 days). Median peak viral load was 4.91 log10 copies per mL (25th-75th percentiles: 4.68-5.27). Six (22.2%) had viremia less than 90 days. In 23 (85%) and 4 (15%) patients, BK genotype I and IV replicated, while genotype II did not. 41 BKV genotype mismatches were found in 120 donor/recipient couples. Donor/recipient BKV genotype mismatch increased viremia.
Discussion
This study found two main things. First, IVIg raised BKV genotype I NAb titers above 4 log10 IC50.
Second, early posttransplant passive IVIg vaccination reduced BKV viremia and BKVAN in high-risk KTR.
85 patients with NAb titers <4 log10 IC50 at day 0 were considered high-risk for BKV replication in this investigation.
It isinvestigated whether patients getting IVIg for SID or AMR early after KT may be protected against BKV replication due to its high BKV NAb content. Only 3 high-risk cases received high-dose IVIg.
Because BKV replication occurs early after KT,2,24,25 we evaluated IVIg’s preventative function in the first three posttransplant months. At 12 posttransplant months, the high-risk group treated with IVIg had 6.8% BKV viremia, equal to the low-risk group (10.1%) and significantly lower than the untreated high-risk group (36.6%). Two of three high-risk IVIg patients with BKV viremia failed to reach the protective threshold of 4 log10 IC50.
Findings of this study strengthen the case that BKV-neutralizing antibodies and B cell immunity hinder BKV replication. T cell immunity primarily controls active BKV replication. Everolimus use was the only substantial baseline difference in this retrospective nonrandomized trial. mTOR treatments may protect against BKV replication, but our study’s small number of everolimus-treated patients prevents definitive findings.
That is a well-structured reply.
Please summarise this article
Introduction
o BKVAN affect 10% of BKV-infected KTR leading to kidney dysfunction and graft loss
o Currently, no specific antiviral treatment
o Screening of BKV accompanied by a reduction of immunosuppressive therapy is successful in only 50%-80% and does prevent BKVAN with the risk of developing DSA and acute rejection
o IVIg administration is used as a preemptive treatment against BKV infections
o High titers of BKV-neutralizing antibodies (NAb) are protective
o IVIg have a neutralizing activity against the most common BKV genotypes and resulting in increased NAb titers
o Aim of the this retrospective study: investigate whether the preventive administration of IVIg may reduce the incidence of BKV viremia and BKVAN in high-risk KTR
Patients and methods
Conducted during 2012-2017 (Strasbourg University Hospital, France)
Inclusion criteria: All cases with available NAb titers measured on day 0
Exclusion criteria: patient or graft survival lower than 3 months
Patients with NAb titers < 4 log10 against the donor’s strain were considered at high-risk
The most common viral genotype (genotype I) was taken as reference for patients with a negative BKV DNA load
Divided into 3 risk categories for BKV replication:
1. Patients with low NAb titers (high-risk patients): received IVIg treatment (0.4 g/kg IVIg doses every 3 weeks, 1-3 according to their IgG levels), (n = 41)
2. patients with low NAb titers (high-risk patients): did not recieve IVIg treatment (n = 41)
3. Patients with high NAb titers (low-risk patients):did not receive IVIg (n = 89)
BKV viremia: day 0, every month in the first 6 posttransplant months, and every 3 months thereafter (until 1 year following KT)
NAb titers: at day 0; at 3, 6, and 12th posttransplant months; and at the onset of viremia
Results
At 12 posttransplant months:
1. the incidence of BKV viremia in the high-risk group treated with IVIg (6.8%, 3 of 44 patients) was similar to that observed in the low-risk group (10.1%, 9 of 88 patients) and markedly lower than that of the untreated high-risk group (36.6%; 15 of 41 patients; P < .001)
2. Similar results with the incidence of BKVAN
Discussion
Two important findings from this study:
1. IVIg were found to increase NAb titers against BKV genotype I (ie, the largely predominant genotype) over the protective threshold of 4 log10
2. Passive immunization with IVIg in the early posttransplant phase was associated with a significantly lower incidence of both BKV viremia and BKVAN in high-risk KTR
Strengths and limitations
Strength: Accurate risk stratification for BKV replication based on the quantification of NAb titers against the 3 most common BKV genotypes and a high availability of donors’ samples
Limitations:
1. Retrospective study
2. Relatively small size
3. Use of different IVIg doses and administration schedule
Conclusions
IVIg may be valiable in the prevention of BKV replication
Further multicenter controlled randomized study are needed
What are the other uses of IVIG in transplantation?
Desensitization protocol:
As animmunomodulatory agent for highly HLA sensitizedpatients awaiting kidney transplantation
The use of IVIG was associated with acceptableoutcomes in this high risk group and was recommendedfor use in highly HLA sensitized ESRD patients to improverates of transplantation (anadian Blood Ser-vice and Canada’s National Advisory Committee on Bloodand Blood Products)
Treatment of AMR:
High-dose IVIG in treating resistant AMR episodes
There is sufficient evidence to support the use of IVIG for treatment of ARM
Prevention and treatment of infectious complications:
1. Resistant CMV infections
2. Resistant BK nephropathy
3. Chronic parvovirus B19 infections (PVB19). This includes PVB19 induced pure redcell aplasia and collapsing glomerulopathy variant of focalglomerulosclerosis
References
1. S. C. Jordan, M. Toyoda,J.Kahwaji, A.A.Vo. Clinical Aspects of Intravenous ImmunoglobulinUse in Solid Organ Transplant Recipients. American Journal of Transplantation 2011; 11: 196–202
I agree with your analysis of strengths and limitations, and summary of this article
Many thanks prof Sharma
Introduction:
Aim of the study:
Assessment of the effect of IVIg infusion as preventive measure that reduce incidence of BKV viremia & BKVAN in high risk kidney transplant recipients.
Patients & method:
Result & discussion:
Uses of IVIg in transplantation:
I agree with your analysis of strengths and limitations, and summary of this article
Aim of sudy
We have previously shown that NAb titers against the donor’s BKV strain lower than 4 log10 IC50 at the time of transplantation (day 0) are associated with an increased risk of BKV replication following KT.20 Conversely, IVIg can exerta clinically relevant neutralizing activity against the most common BKV genotypes, with IVIg infusion resulting in increased NAb titers among KTR.21,22 In this study, we sought to investigate whether the preventive administration of IVIg may reduce the incidence of BKV viremia and BKVAN in high-risk KTR. Risk stratification was based on NAb titers against the donor’s BKV strain measured on day 0
PATIENTS AND METHODS
retrospective clinical records of adult patients who underwent KT in the Strasbourg University Hospital between July 2012 and December 2017
. All cases with available NAb titers measured on day 0 were deemed eligible.
Exclusion criteria were patient or graft survival lower than 3 months
20 patients with NAb titers below 4 log10 IC50 against the donor’s strain (which was determined by measuring NAb titers in the donor’s sera) were considered at high-risk. When the donor’s specimen was unavailable, the replicating strain was considered as reference for patients showing an active BKV replication.
The most common viral genotype (genotype I) was taken as reference for patients with a negative BKV DNA load
.the study patients (n = 174) were divided into the following
3 risk categories for BKV replication:
(1) patients with low NAbtiters (“high-risk patients”) who received IVIg treatment for secondary immunodeficiency (SID) or for prevention or treatment of antibody-mediated rejection (AMR) during the first 3 posttransplant months and before BKV replication (n = 44)
(2) patients with low NAb titers (“high-risk patients”) who did not undergo IVIg treatment during the first year of KT (n = 41),
(3) patients with high NAb titers (“low-risk patients”) who did not receive IVIg (n = 89).
Allograft biopsies were performed in case of graft dysfunction, detection of DSA, or sustained BKV viremia (defined by the presence of 4 log10 copies per mL in 2 subsequent blood specimens). As of January 1, 2013, biopsies were performed systematically during the third posttransplant month. BKVAN was diagnosed and
classified according to the severity of virus-induced cytopathic effects, inflammatory infiltrates, tubular atrophy, fibrosis, and through immunohistochemistry using antib
Among the 44 high-risk patients who were treated with IVIg, we identified 35 (79.5%), 7 (15.9%), and 2 (4.5%) cases in whom there was a high risk of replication for BKV genotype I, genotype II, and genotype IV, respectively. A total of 41 patients (93.2%) received IVIg infusion at a dose of 0.4 g/kg because of SID. Of them, 28 cases (63.6%) received 3 doses. The remaining 12 (27.3%) and 1 (2.3%) patients received 2 and 1 doses, respectively. Three (6.8%) patients received 3 IVIg infusions at a dose of 2 g/kg because of preventive or curative treatment of AMR, with IVIg being administered during the first 3 posttransplant monthsodies that cross-reacted against the large T antigen of the related simian polyomavirus
Results
IVIg administration decreases the incidence of both BKV viremia and BKVAN in KTR
Among these 41 patients, there was a high risk of replication for BKV genotype I, genotype II, and genotype IV in 32, 7, and 2 cases, respectively. Twenty-nine of the 32 patients (91%) at high risk for BKV genotype I replication were capable of reaching a BKV NAb titer above the threshold of 4 log10 IC50 in at least 1 occasion during the first 3 posttransplant months. The remaining 3 cases who were unable to achieve high NAb titers received 2 or 3 low-dose IVIg infusions
What are the other uses of IVIG in transplantation?
1- varicella-zoster immune globulin [VariZIG]; cytomegalovirus immune globulin [CMVIG]) may be given to hematopoietic cell transplantation (HCT) recipients who have not yet been re-immunized against certain viral infections, as postexposure prophylaxis.
2- desensitization protocols for renal transplant recipients.
IVIG causes B cell apoptosis, blocks binding of donor-reactive antibodies, and may inhibit complement activation. IVIG has been used widely in
3-Intravenous immune globulin (IVIG) has been used in combination with rituximab in lung transplant recipients who developed donor specific HLA antibodies, but did not have clinical AMR, and also to treat acute AMR .
dose of IVIG for acute AMR is 0.5 to 2 g/kg, using ideal body weight for patients with obesity, given intravenously. Doses >1 g/kg are generally divided over two days.
4-HLA desensitization protocols
pretransplant HLA desensitization using a combination of high-dose IVIG and rituximab in most patients.
Living-donor transplantation pretransplant desensitization with high-dose IVIG and rituximab.
some transplant centers use a protocol that consists of low-dose intravenous immune globulins (IVIG) in combination with alternate-day plasmapheresis
In deceased-donor transplant recipients, we administer alemtuzumab 30 mg subcutaneously and IVIG 2 g/kg (maximum dose of 140 g) at the time of transplantation. subsequently give an additional dose of IVIG 2 g/kg within 7 to 14 days after transplant. Rituximab 375 mg/m2 is also given within 7 to 14 days after transplant if it has not been received within six months of the transplant.
5-Commercially available IVIG preparations contain BKPyV-neutralizing antibodies against all major genotypes
We do not routinely administer IVIG for the treatment of BKPyVAN. However, the adjunctive use of IVIG may be considered in patients with established BKPyVAN who do not respond to a reduction in immunosuppression and who also have severe hypogammaglobulinemia (ie, immunoglobulin G [IgG] <400 mg/dL).
If used, IVIG is administered at a dose of 300 mg/kg every three weeks in conjunction with a reduction in immunosuppression. We typically administer intravenous hydration with normal saline (10 to 20 mL/kg) prior to starting the infusion to mitigate the risk of acute kidney injury (AKI).
We repeat 21-day trough IgG levels after three months of therapy with the goal of maintaining an IgG level >400 mg/dL.
Limited data are available concerning the efficacy of IVIG in patients with BKPyVAN. Some observational studies have reported clearance of BKPyV viremia following IVIG therapy . However, the findings of these studies are difficult to evaluate, since other antiviral interventions were administered concurrently.
6-ABO DESENSITIZATION
Immunomodulation — IVIG is administered by many transplant centers prior to ABOI transplantation to replace immunoglobulins that are removed with plasmapheresis or immunoadsorption. In addition, IVIG may also block Fc receptors (FcR) to prevent a rebound in anti-A/B antibody titers when the plasma cells have naked receptors and, therefore, are stimulated to make more antibody. IVIG may also have immunoregulatory properties. It should be noted, however, that IVIG products may contain detectable anti-A and anti-B isoagglutinins which should be considered if high-dose IVIG is administered.
I like your summary of this article
THANKS FOR YOUR SUPPORT
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Please summarise this article
Introduction
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Patient and Methods
Study patients
A- High-risk patients who received IVIg treatment for second-ary immunodeficiency (SID) or AMR.
B- Low-risk patients with low NAb titers.
C- And high NAb titers who did not receive IVIg.
Immunosuppressive regimens
Monitoring of BKV infections
Neutralization assay
IVIg therapy
Results
BKV viremia was observed in 27 of 174 study patients, with a median peak viral load of 4.91 log10 copies per mL.
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Regarding BKVAN, similar outcomes were seen.
We come to the conclusion that IVIg may be a useful tactic for halting BKV replication.
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What are the other uses of IVIG in transplantation?
Other conditions
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Reference
I like your detailed summary of this article
Typing the whole sentence in bold amounts to shouting, however.
Many thanks Prof.Sharma
Introduction
BKV replication occurs in 30%-50% of kidney transplant recipients (KTR). BKV-associated nephropathy (BKVAN) can occur in 10% of BKV-infected KTR causing graft loss.
Regular screening and reduction of immunosuppression is the current available modalities for therapy ,in fact it succeeds in 50-80% of the cases and carries the possibility of rejection.
Intravenous immunoglobulin (IVIg) has been introduced as a preemptive treatment against
BKV infections.
BKV-neutralizing antibodies (NAb) is protective against BKV replication.
The current study evaluated the preventive role of IVIg in reduction of the incidence of BKV viremia and BKVAN in high-risk KTR.
Methods
KTR in the Strasbourg University Hospital were retrospectively divided into 3 risk categories for BKV replication according to Nab titers on transplantion day:
first group were high risk patients with low NAb titers whom received IVIg during the first
3 posttransplant months
Second group are high risk patients with low NAb titers also but didnot undergo IVIg treatment Third group are low risk patients with high NAb titers without receiving IVIg.
Results
1 year after transplantation , the incidence of BKV viremia and BKVAN in the high-risk group treated with IVIg and in the low-risk group was the same and markedly lower than the incidence in the untreated high-risk group .
Discussion
IVIg can increase NAb titers against BKV genotype I which is the most common variant over the protective threshold of 4 log10 IC50.
Administration of IVIg as passive immunization in the early posttransplant period lead to significant decrease of the incidence of BKV viremia and BKVAN in high-risk KTR .
The possible utility of IVIg administration in the management of BKV replication is controversial due to the concomitant use of other antiviral strategies and/or immunosuppression reduction.
The strength of this study is the precise risk stratification for BKV replication due to the quantification of NAb titers against the 3 most common BKV genotypes and availability of donors’ samples.
Limitations were being a retrospective study with small number of included patients who
Took IVIg infusions, and the use of different IVIg doses and administration schedule.
Conclusion
IVIg may be a promising modality for BKV replication prevention.
-Other IVIG uses in Transplantation
· prevention and treatment of Antibody mediated rejection
· Desensitisation regimens
· For treatment of other infections as CMV
Reference
-Tedla FM, Roche-Recinos A, Brar A. Intravenous immunoglobulin in kidney transplantation. Curr Opin Organ Transplant. 2015 Dec;20(6):630-7
I like your summary of this article
Please summarise this article.
– BK virus infection is frequently observed in renal transplant recipients and is associated with BK nephropathy which can end with graft loss
– It is estimated that 30-50% of renal transplant recipient s develop BK infection, Around 10 % of patients who have BK infection, develop BK nephropathy
– Until now the only effective therapy is reduction of immunosuppression with failure rate of 20-50% and subsequent increase in the risk of graft rejection.
– Patients with high titers of BK-neutralizing antibodies were found to be at lower risk of viral replication, from this point IVIG may have a role in treatment of BK nephropathy since it can increase the neutralizing antibodies
– The current study is a retrospective study that assess the effect of early administration of IVIG (within the first 3 months after transplantation) to patients with low level of neutralizing antibodies(<4 log10 against the BKV-sgenotype 1) on BK virus replication at 1 year post transplantation.
– The study includes 174 renal transplant recipients divided into 3 groups
Results
Conclusion
What are the other uses of IVIG in transplantation?
1- ABO incompatible transplantation
2- HLA incompatible transplantation (used for desensitization)
3- Treatment of ABMR (acute and chronic)
4- Treatment of viral infections including CMV, EBV
I like your summary of this article
INTRODUCTION:
In 30%–50% of kidney transplant patients, BK virus (BKV) replication occurs (KTR). BKVAN may cause renal failure and graft loss in up to 10% of BKV-infected KTRs.
Intravenous immunoglobulin (IVIg) has been shown to prevent and treat BKV infections. Due to substantial methodological constraints, including the small sample size, the absence of a control arm, and the concurrent use of other antiviral treatments and/or immunosuppression, the field’s research should be evaluated carefully.
Aim:
We investigated whether IVIg prevents BKV viremia and BKVAN in high-risk KTR. Day 0 NAb titers against the donor’s BKV strain determined the donor’s risk category.
Method:
This was a retrospective study based on a review of the medical records of adults (n = 174) who had kidney transplantation (KT) between July 2012 and December 2017.
Patients were classified into one of three risk categories according to the BKV replication status.
DISCUSSION:
This research found two main things: IVIg raised NAb titers against BKV genotype I, which is the most common genotype, above the protective threshold of 4 log10 IC50.
Second, early posttransplant passive IVIg vaccination reduced BKV viremia and BKVAN in high-risk KTR.
We’ve proven that KTR’s anti-BKV antibody-mediated neutralizing response protects against BKV replication.
We also showed that pre-KT NAb titers against the donor’s strain may stratify BKV-related illness risk. 85 individuals with a NAb titer <4 log10 IC50 at day 0 were at high risk for BKV replication.
We investigated whether patients getting IVIg for SID or AMR early after KT may be protected against BKV replication due to its high BKV NAb content.
Conclusion:
The results of the trial showed that IVIg helped reduce the number of people who got BKV viremia and BKV-related nephropathy. This was true for people who took part in the trial but had low NAb titers.
Strength: It can accurately classify the risk of BKV replication based on the detection of NAb titers against the 3 most common genotypes and the good availability of donor samples.
Weakness: retrospective investigation is restricted by the small number of patients who underwent IVIg infusions and the use of varied dosages and delivery schedules. However, we demonstrate that IVIg can prevent BKV viremia and BKVAN in KTR with low NAb titers. single center.
1- Desensetizarion before transplantation
2- chronic active antibody-mediated rejection
3- CMV infection
4- Acute antibody-mediated rejection
I agree with your analysis of strengths and weaknesses, and summary of this article
1-Please summarize this article.
Introduction:
Methodology:
Results:
Strength: Accurate risk stratification for BKV based on PCR
Weakness: Retrospective nature of the design, small sample size, lack of standardization of IVIG doses.
Conclusion:
2.What are the other uses of IVIG in transplantation?
I like your summary of this article
The study hypothesises that Patients with high titers of BKV-neutralizing antibodies (NAbs) are protected against BKV replication, and the intravenous immunoglobulin (IVIg) infusion can increase NAb titers, hence patients will be protected from getting the infection and the development of BKVN.
This is a retrospective analysis done for 174 adult patients who underwent KT in the Strasbourg University Hospital between July 2012 and December 2017. Patients were given IVIg as a preventive measure against BKV viremia and BKV-associated nephropathy, as illustrated below and those patients were retrospectively divided into the following 3 risk categories for BKV replication:
(1) patients with low NAb titers (“high-risk”) who received IVIg for the first 3 posttransplant months (n = 44),
(2) patients with low NAb titers (“high-risk”) who did not undergo IVIg treatment (n = 41),
(3) patients with high NAb titers (“low-risk”) who did not receive IVIg (n = 89).
At 12 post-transplant months, the incidence of BKV viremia in the high-risk group treated with IVIg (6.8%) was similar to that observed in the low-risk group (10.1%) and markedly lower than that of the untreated high-risk group (36.6%; P < .001). Similar results were observed with regard to BKVAN.
In general, BKV viremia was an early event that occurred after a median of 64 days from KT (25th-75th percentiles: 47.5-128.5 days).
Overall, the results showed that IVIg was effective in reducing the incidence of BKV viremia and BKV-associated nephropathy in the study participants with low NAb titers. However, larger studies are needed to confirm these results and to further investigate the safety and effectiveness of this approach.
I agree with your analysis, and summary this article.