News & Events
2. A 37-year-old man was admitted after one episode of haematuria. He had a successful third renal transplant 15 months ago, 212 mismatch, no DSA and negative FAXM. His creatinine has risen from 151 µmol/L to 223 µmol/L. USS showed mild dilatation of the pelvicalyceal system, not different from the previous scan. He is currently on Tacrolimus (trough 8 ng/ml), MMF 750 bd and prednisolone 5 mg od. There is BK viraemia (plasma PCR 4 log 10). The biopsy is shown below, and SV40 staining (left).
- What is your differential diagnosis?
- How do you manage this case?
- Elaborate on SV40 staining the specificity, the sensitivity and where it comes from.
208 Comments
Leave a Reply
You must be logged in to post a comment.
Copyright © 2024 World Kidney Academy. All Rights Reserved. ICOM
SV40 is specific stain for BK virus nephropathy
specificity 100%. Sensitivity 77.7%
DD :
BKV nephropathy
Acute rejection
MV nephropathy
CNI toxicity
treatment of BKV mainly to decrease MMF by 50% and to follow BK PCR if no response stop MMF ,if no response stop MMF if no response decrease tacrolimus dose Or switch to cyclosporine
Still antiviral therapy had no evidence also leflunomide ,IV IG or cidofovir
D/D: BKVN, Acute rejection, CNI toxicity.
Management: Reduction of immunosuppression is the mainstay of treatment. Reduce MMF dose by 50% & monitor BK virus PCR, if no improve, then completely stop MMF, if still no decrease in BK PCR then reduce TAC or switch to Cyc. Role of IVIG, Leflunomide, cidofovir, quinolone is controversial.
SV40 (simian virus) immunohistochemistry test: here large T antigen is stained using commercially available antibody… specificity : 100%, sensitivity: 77.7%
What is your differential diagnosis?
How do you manage this case?
Elaborate on SV40 staining the specificity, the sensitivity and where it comes from.
Reference
The patient has detectable BK virus PCR in the blood with azotaemia and mild HUN…There is no other differential after the blood tests for BK virus ..histologically BKVN can be confused with acute rejection, adenovirus infection, CMV infection….
This patient needs a detailed evaluation in the form of CBC, DSA, kidney biopsy with C4d staining, urine routine to detect urine decoy cells in the urine….there is a need to rule out acute rejection before treatment as the treatment for both are contradicting….
This patient is a high risk case with 3rd transplant and 212 mismatch….He needs a step wise reduction in the immunosuppression to weigh the balance with graft rejection….
There is no specific anti viral available…Adjunctive therapes like cidofovir, leflunoamide, fluoroquinolones are tired only after months of BK virus not clearing with reduction in immunosuppression…
SV 40 stain by immunohistochemistry in renal biopsy can identify very early changes of BK virus nephropathy befor the cytopathic changes….this SV 40 stain differentiate other virus like adenovirus… 100% specific for polyoma virus…
the origin of SV 40 is an abbreviation for simian vacuolating virus 40 or SV 40 which is a polyoma virus found in both monkeys and humans…SV 40 detects the large T antigen found on the surface of all polyoma virus especially the SV and BK virus….
It has 100% specificity for polyoma virus but it does not differential JC from BK virus.
At the present time, there is no approved treatment for PVAN. In the absence of safe, specific and efficacious antivirals, the current mainstay of intervention resides in the judicious reduction of immunosuppression similar to cytomegalovirus infection in the era before ganciclovir. More recently, switching to leflunomide, an inhibitor of pyrimidine synthesis and protein tyrosine kinase, or the newer derivative FK778 has been proposed asthese immunosuppressive drugs have also anti-viral activity in vitro.
https://www.ncbi.nlm.nih.gov/books/NBK6388/
Our differential diagnosis in this case is mostly BKVN (dilatation of pelvicalyceal system, positive serology, viral inclusion bodies “owl eye appearance” besides SV 40 positive staining on graft biopsy along with the high level of the drug level indicative of over immunosuppression).
Other diagnoses may be CMV nephropathy, ACMR or CNI nephrotoxicity (high drug level).
Management is primarily by reduction of immunosuppression, other agents can be tried as IVIG, leflunamide, quinolones, cidofovir yet their effect is still doubtful. Concerning pelvicalyceal dilatation; expert urological opinion must be sought to eliminate the need of intervention or not.
The reason of SV40 staining in BK viral nephropathy is the affinity of large T antigen in the nuclei of the renal epithelial cells for all simian viral mitochondrial ribosomal subunits to the SV40 stain.
A 37-year-old man
15 months after 3th renal transplantation
212 mismatch, no DSA, negative FAXM
Haematuria with elevated creatinine and mild dilatation of the pelvicalyceal system, not different from the previous scan.
PCR (BK) viraemia 10^4.
The biopsy is showed tubulointerstitial with cellular inclusions and positive SV40 staining that is specific for BKN.
Presence of the haematuria that can result from Hemorrhagic cystitis caused by BKV and the risk factors in our patient as the intensity of immunosuppression( 3th transplant ), male sex, possible previous rejection episodes, the high level of HLA mismatching.
● What is your differential diagnosis?
1. BKVN with possible ACMR
2. CMV nephropathy with concomitant BKV
3. ACMR
4. Drug nephrotoxicity ( CNi toxicity)
● How do you manage this case?
☆ A reduction of immunosuppression is the gold standard of treatment BKVN especially anti-metabolite that must reduce by 50 % or withdrawal for a time.
☆ Other therapies include quinolones, cidofovir, leflunomide, and (IVIG) may be useful
☆ Steroid pulses combind with RTX for treatment the rejection
. ● Elaborate on SV40 staining the specificity, the sensitivity and where it comes from.
☆ The simian virus (SV) 40 is PV that was likely introduced into the human population through contaminated vaccines ( polio vaccines) with the simian virus 40 that present in monkey kidney cells used to grow the vaccine .
☆ Infected epithelial cell nuclei stain with antibody to the large T antigen of the SV40 virus, which serves as a surrogate marker of human polyomavirus infection .
☆ SV40 antibody reacts with the large T-antigen of BK virus only at the early phases of infection and can miss cells in later stages of infection
☆ The specificity is 100 % , the sensitivity is 79%
References:
Fakhriya Alalawia,b, Hind Alnoura,b, Mohsen El Kossib,c, John Jenkinsb, Anna Takud, Ajay K. Sharma, Ahmed Halawa. BK virus infection in renal transplant recipients: an overview. Journal of The Egyptian Society of Nephrology and Transplantation 2020, 20:127–150
What is your differential diagnosis?
· This renal transplant recipient is presenting with haematuria and graft dysfunction.
· He is a high immunological risk patient (3rd transplant, 212 mismatch).
· He is maintained on triple immunosuppression with Tacrolimus, MMF and steroids.
· His plasma levels of BKV-PCR is high (4 log 10).
· Ultrasound transplanted kidney shows no urinary tract obstruction.
· Kidney biopsy shows interstitial inflammation and a positive SV40 stain on immunohistochemistry suggesting intra-nuclear viral inclusion bodies
The most likely diagnosis is BKVAN.
Other DD:
o Acute rejection
o CNI nephrotoxicity
o Urinary tract infection
o Recurrence of the basic disease
How do you manage this case?
· Detailed history and full physical examination including what Induction was used, previous rejection episodes, ABO incompatibility, causes of previous graft failure.
· Basic Investigations: FBC, U&E, urine sample to exclude infections and check for proteinuria
· There are no specific antiviral drugs targeting BKVAN (IVIG, leflunomide, cidofovir, and quinolone. They are not routinely recommended). Therefore, the key to restore the immune control of BKV replication without triggering rejection. Hence, an individualized approach is advised keeping in mind the patient’s high immunologic risk, BK viral load, the need to monitor the renal function and DSA.
Management;
· We need to exclude acute cellular rejection first. If present, this is a difficult scenario as we need to treat rejection first with high dose steroids then reduce immunosuppression after the patient response to ACR treatment evidenced by a decline in creatinine levels.
If no ACR: step wise approach
· Decrease antimetabolites by 50%, and reduce Tacrolimus to keep the trough level between 4-6 ng/ml.
· If no decrease in BK viral load within 2-4 weeks, completely stop MMF.
· A switch from Tacrolimus to cyclosporine may be also done if no decrease in viral load (keep trough level between 50-75 mcg/L).
· After BK viremia resolve, increase immunosuppression dose to previous levels to prevent rejection episodes.
Elaborate on SV40 staining the specificity, the sensitivity and where it comes from?
· After detection of viral inclusion body in the renal biopsy. An immunohistochemistry test is done. The Simian virus (SV40) large T antigen (TAg) is stained using commercially available antibody.
· The SV40 IHC have 100% specificity but low sensitivity (77.7%) in detecting polyomavirus nephropathy. Therefore, the diagnosis may be missed in 1/3 of the biopsies.
References:
1. Hirsch HH, Randhawa PS; AST Infectious Diseases Community of Practice. BK polyomavirus in solid organ transplantation-Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep; 33(9):e13528.
2. Saleh A, El Din Khedr MS, Ezzat A, Takou A, Halawa A. Update on the Management of BK Virus Infection. Exp Clin Transplant. 2020 Nov; 18(6):659-670.
3. Sawinski D, Trofe-Clark J. BK Virus Nephropathy. Clin J Am Soc Nephrol. 2018 Dec 7; 13(12):1893-1896. doi: 10.2215/CJN.04080318. Epub 2018 Sep 21.
4. Shanmugham S, Bhadauria D, Agrawal V, Jain M, Yaccha M, Kaul A, Vamsidhar V, Meyyappan J, Prasad N. The diagnostic and therapeutic dilemma of the co-existence of BK virus nephropathy with acute rejection – an experience from a single Centre and review of the literature. Transpl Immunol. 2022 Jun;72:1015814
Q1: pathology of allograft biopsy shows inclusion bodies and interstitial proliferation with positiveSV40 staining by IHC.
Clinical picture is allograft dysfunction and dilation of system.
So the diagnosis would be BK virus nephropathy.
Q2: first of all diagnostic test such as CBC, U/A for decoy cell, U/C, ESR, CRP, LDH and other biochemistry.
BK PCR viral load in blood and even urine.
Would be diagnostic and useful for F/W.
The first step of treatment is reduction of immunosuppression.
Stop the antimetabolite start
mTOR inhibitor as anti-proliferative. Other treatments such as quinolones, leflunomide, and IVIG have been used for the treatment of BKVN but, they are not yet approved by large RCTs. there is no specific antiviral treatment, however, cidofovir was used by some clinicians with high nephrotoxicity.
Q3: SV40 staining by IHC shows infected epithelial cell nuclei which stain with antibody to the large T antigen of the SV40 virus which is a surrogate marker of human polyomavirus infection. It has 100% specificity but about 70% sensitivity. Hence, in 30% of cases, this staining would be negative.
Reference:
Prof. Ahmad Halawa lecture- module 4 clinical fellowship of transplantation, BK in kidney transplantation.
Present Biopsy picture shows-Enlargement of Tubular cells ,intranuclear inclusion along with tubulitis and interstitial inflammation.It also have SV40 positivity.Thus present biospy picture with BK viremia of high degree (plasma PCR 4 log 10),confirms it to be a case of BK virus nephropathy.
A definitive diagnosis of BKPyVAN requires the following findings on kidney biopsy –
Characteristic histological changes.
plus
Positive immunohistochemistry tests using antibodies directed specifically against BKPyV or against the cross-reacting SV40 large T antigen.
Differntial diagnosis-
Other viruses-Herpes simplex virus, adenovirus, CMV, Epstein–Barr virus (EBV) should also be considered in differential diagnosis as they may cause similar histologic findings- Viral particles of BKV are characteristically 30–50nm in diameter and occasionally form crystalloid structures, whereas inclusions due to family of herpesviridae (including Herpes simplex, EBV and CMV) and adenoviruses are bigger in size (120–150nm and 70–90nm respectively).BK virus have intranuclear inclusion,CMV has cytoplasmic inclusions, and HSV has both intranuclear and cytoplasmic inclusions.Adenovirus has basophilic nuclear inclusions and is associated with interstitial hemorrhage, necrosis, and rarely granulomas. CMV typically infects endothelial cells.HSV is typically associated with multinucleated giant cells with nuclear inclusions and may cause hemorrhagic interstitial nephritis.
Acute Rejection-. BKPyVAN is generally distinguished from rejection by the presence of BKPyV inclusions and immunohistologic or in situ hybridization evidence of virally infected cells, which are usually tubular epithelial cells, rather than podocytes or endothelial cells . It is important to correlate the histologic findings with PCR evidence of viremia. Establishing a diagnosis of concomitant T cell-mediated rejection in a biopsy that has BKPyVAN is difficult since both the histologic features and transcriptional profiles of these two disorders are similar In general, the presence of extensive tubulitis in areas remote from the viral cytopathic changes suggests that acute rejection is present, in addition to BKPyVAN. The combined presence of endarteritis, fibrinoid vascular necrosis, glomerulitis, and C4d deposits along peritubular capillaries is conclusive evidence of concurrent rejection.
Managment–
Since there are no specific antiviral therapies for BK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN), the cornerstone of management is to decrease immunosuppressive medications .Prior to reducing immunosuppression, we obtain a plasma BKPyV quantitative polymerase chain reaction (PCR) and subsequently monitor the plasma quantitative PCR every one to two weeks until BKPyV DNA is undetectable for two consecutive tests obtained at least one week apart. In addition, we monitor the serum creatinine level weekly. If the serum creatinine level increases by ≥25 percent from baseline at any time while immunosuppression is being reduced, the patient should be evaluated for the possibility of acute rejection.
In patients who are on a triple immunosuppression therapy consisting of a calcineurin inhibitor an antimetabolite and prednisone , we initially reduce the dose of the antimetabolite by 50 percent. If the BKPyV viral load does not decrease within two to four weeks, we completely discontinue the antimetabolite. If there is still no decrease in viral load after another two weeks, we decrease the dose of the calcineurin inhibitor by 25 to 50 percent, targeting a whole blood tacrolimus trough level of 4 to 6 ng/mL or a whole blood cyclosporine trough level of 60 to 100 ng/mL.
Elaborate on SV40 staining the specificity, the sensitivity and where it comes from.–Due to focal pattern of PVBKN involvement, at least two biopsy cores, including medullary tissue are needed,.In 10 to 30% of the patients, sampling error can occur. So a negative result does not exclude PVBKN.Infected epithelial cell nuclei stain with antibody to the large T antigen of the SV40 virus, which serves as a surrogate marker of human polyomavirus infection. Positive staining may be seen in the absence of nuclear enlargement or inclusions.,thus increases sensitivity above the histological finding alone.In various studies SV40 large T antigen staining found to have Sensitivity around 77% and specificy-`100%
This patient is a high immunological risk patient with 212 mismatch on CNI, MMF and steroids
Presented with AKI and hematuria with biopsy showing interstitial inflamation and positive SV40, yet no evidence of back pressure changes.
DD on top is BK virus
CNI toxicity
UTI
Recurrence of original disease
Management of this case
Is a step wise approach
Exclude the evidence of rejection, other wise treat rejection first
Then reduce MMF to 50 %
Reduction of dose of CNI with trough level 4-6 ng per ml
Stop MMF
Change Tacrolimus to CNI
Adjuvant therapy : IVIG, leflunomide, fluoroquinolones
With monitor of BK levels every 2 weeks
Once BK virus is cleared, return back to usual immunosuppression to avoid rejection
The sensitivity, specificity, positive predictive value and negative predictive value of immunohistochemistry in diagnosis of BK virus associated nephropathy is 77.7%, 100%, 100%, and 98.4%
· What is your differential diagnosis?
37y male, 3rd RTx 15 months ago, MM 212, no DSA, negative FCXM, presented with Hematuria and AKI. USS: Dilated Pelvi-calyceal system, BK viremia
Biopsy: interstitial inflammation and viral inclusion bodies, SV40 staining.
DD:
1- BK nephropathy (most likely).
2- Acute Rejection.
3- CNI toxicity (Tacrolimus level was within target).
4- UTI.
· How do you manage this case?
1- Full report of Kidney biopsy.
2- Urine dip and urine culture.
3- BKV nephropathy is treated by reduction of immunosuppression, no single agent has deemed effective for treating BKV nephropathy.
4- Continuous monitoring of BKV level and renal function tests.
· Elaborate on SV40 staining the specificity, the sensitivity and where it comes from.
Sensitivity of SV40 to stain intranuclear viral inclusion bodies 77%
Specificity of SV40 to stain intra-nuclear viral inclusion bodies 100%.
References:
hanmugham S, Bhadauria D, Agrawal V, Jain M, Yaccha M, Kaul A, Vamsidhar V, Meyyappan J, Prasad N. The diagnostic and therapeutic dilemma of the co-existence of BK virus nephropathy with acute rejection – an experience from a single Centre and review of the literature. Transpl Immunol. 2022 Jun;72:101581. doi: 10.1016/j.trim.2022.101581. Epub 2022 Mar 14. PMID: 35301106.
Saleh A, El Din Khedr MS, Ezzat A, Takou A, Halawa A. Update on the Management of BK Virus Infection. Exp Clin Transplant. 2020 Nov;18(6):659-670. doi: 10.6002/ect.2019.0254. Epub 2020 Jun 16. PMID: 32552624.
Diffrential diagnosis
Management of the case;
SV40 staining the specificity, the sensitivity, and where it comes from.
References
· What is your differential diagnosis?
Viral infection ,polyoma virus ( JC, and BK) most likely BK from the scenario.
· How do you manage this case?
· Reduction of immunosuppression, reduce MMF by 50% and monitor serum creatinine and viral load every 2 weeks , if viral load is not reduced then stop MMF.
· if viral load continue to rise inspite of that then we have to reduce tacrolimus in order to maintain the trough level between 4-6 ng/ml
· however maintaining tacrolimus will reduce the risk of acute rejection.
· Elaborate on SV40 staining the specificity, the sensitivity and where it comes from.
SV40 This stain can highlight cells in the early stages of infection, before viral cytopathic changes may be detectable on routine stains .This stain may also help differentiate PVN from other viral nephropathies seen in immunocompromised patients, such as adenovirus infection.
It has 100% specificity for polyoma virus but it does not differential JC from BK virus.
The origin of SV40 is an abbreviation for simian vacuolating virus 40 or simian virus 40, a polyomavirus that is found in both monkeys and humans. Like other polyomaviruses, SV40 is a DNA virus that has the potential to cause tumors in animals, but most often persists as a latent infection. SV40 has been widely studied as a model eukaryotic virus, leading to many early discoveries in eukaryotic DNA replication and transcription.
Reference:
Kant, S.; Dasgupta, A.; Bagnasco, S.; Brennan, D.C. BK Virus Nephropathy in Kidney Transplantation: A State-of-the-Art Review. Viruses 2022, 14, 1616. https://doi.org/10.3390/v14081616
biospy shows tubular cells with inclusion body s/o BKV nephropathy
reduction in IS like MMF and CNI is the best option till viremia is cleared
anti viral and IVIG is not recommended at present
SV( SIMIAN VIRUS ) 40 stain is used initially to identify tumor virus contamination of polio vaccine in USA
Here it is proxy for HAUFEN body s/o BKV particles
anti viral like leflunamide , cidofovir quinolones are studied but not recommended based on limited trials
This a BK nephritis evidenced by tubular atrophy and interstitial fibrosis with positive SV40 stain which confirms the diagnosis
Mangment include reduction of immunosuppressive medication and replacement of CNI with mTOR inhibitors
BKVAN evidenced by BKV viremia and positive SV 40 stain and interstitial inflammation.
Acute rejection
Acute interstitial Nephritis
MANAGEMENT
Reduction of immunosupression is the most important step
Mostly Antimetabolite is reduced to 50% and them BKV is monitored by PCR load . Further tailoring of immunosupression is done according to clinical condition.
Few people recommend reducing Tacrolimus to 10 to 20% as well
Switching MMF to mToR has been one of dealing with this difficult situation.
A simian polyomavirus virus (SV40) was discovered in 1960 as a contaminant of poliovirus and adenovirus vaccines and has been used as an experimental model of a DNA tumor virus and cell transformation.
Despite human exposure to SV40 through contaminated attenuated poliovirus and adenovirus vaccines in the past, and possibly in wildlife reserves and animal facilities serologic data do not support the independent circulation of SV40 in humans. Its possible role in human diseases including cancer has been controversial.
Positive SV40 staining is useful as it is associated with a specificity of almost 100 percent for polyomavirus nephropathy (PVN), although it does not distinguish between BKPyV- and JC virus (JCV)-associated cases.
DD
1- BKVN : confirmed by presence of viremia ,presence of interstitial infiltration and positive SV 40 stain on graft biopsy and pelvicalceal system dilatation that could be due to ureteric structure , beside presence of heamaturia mostly from heamorragic cystitis. The level of IS drugs is elevated which is the commonest risk factor for BKV reactivation.
Other potential DD
– CMV nephritis .
– Drug induced TIN.
– Graft rejection.
2- Management of this case:
A- For BKVN:
1-Decrease the dose of IS by 25-50 % for tacrolimus and 50% for MMF with close monitoring of graft function to detect early signs of rejection . If no improvement in graft function, consider further IS reduction , switch from MMF to mTOR.
2- Antiviral drugs
– Cidofovir
– Leflunamide
– IVIG
– Quinolones
3- SV40 :
Immunehistochemical staining for antibody against large T antigen of simian virus 40 is used to confirm the diagnosis of BKVN specially in early stages where the characterstic histological changes and inclusion bodies are still absent and also due to focal nature of BKVN that could be missed if only one core biopsy was taken . SV40 stain has fair predictive value for diagnosis of BKVN estimated as Sensitivity = 77.7%. Specifity =100%. PPV: True positive/ (True positive + false positive) 100%. And NPV = 98.4%
Ref:
Nili F, Mohammadhoseini M, Khatami SM, Seirafi G, Haghzare M. Routine immunohistochemistry study for polyomavirus BK nephropathy in transplanted kidney biopsies, is it recommended? BMC Nephrol. 2021 Jun 18;22(1):226.
On H&E stain there is extensive interstitial fibrosis & tubular atrophy (pattern C) with intanuclear inclusion.
On SV40 stain there is positive sv40 stain with marked interstitial inflammatory cell & fibrosis (confirm polyoma virus infection)
So my differential diagnosis are:
a) BKV nephropathy
b) BKV haemorrhagic cystitis
c) BKV ureteric stricture
d) CMV disease
Investigation
– Urinary cytology for decoy cell
– Blood PCR for BKV
– Urine PCR for BKV
– Renal biopsy (histology given)- Gold standard
Treatment
– Lower the dose of tacrolimus (25- 50%)
– Lower the dose of glucocorticoids
– Lower the dose of mycophenolate mofetil (50%)
Adjuvant treatment- May consider
-Leflunomide
– Cidifovir
– Quinolone
Treatment of acute rejection
-Intravenous steroid or IVIg
Differential diagnosis:
BK virus nephropathy
CMV virus
Cellular Rejection
Management:
Reduction of immunosuppression.
Tacrolimus to cyclosporin switch or CNI to mTOR switch
Stopping MMF/AZA
CNI levels
Monitoring for rejection
Antiviral agents:
May consider adjunctive antiviral agents in BKV-associated disease refractory to reduction or manipulation of immunosuppression although benefit is unclear.
Elaborate on SV40 staining the specificity, the sensitivity and where it comes from.
The SV40 IHC stain detects the large T antigen which is expressed by all polyoma viruses pathogenic in humans (BK,SV and JC).
Specificity of 100% and Sensitivity is of 70 %.
It also help differentiate BKVAN from other viral nephropathies seen in immunocompromised patients
Differential diagnosis:
· The likely diagnosis is BKCN, Other differentials are:
· Acute tubular injury,
· Drug induced acute interstitial nephritis,
· Acute T-cell mediated rejection,
· CMV nephritis.
How do you manage this case:
· The key treatment of BKV management is immunosuppression modification,
· Corticosteroid dose reduction,
· Tacrolimus dose reduction by 25 to 50%,
· MMF dose reduction by 50%, however, if no response and persistent increase in viral load and still symptomatic then hold antimetabolite and can switch to mTORi, although there is no consolidated evidence, but there published articles.
· Other options are IVIG and other drugs like leflonemide, cidofivir, but no consensus and no recommendation in using all these drugs.
Elaborate on SV40 staining the specificity, the sensitivity and where it comes from:
SV40 antigen is present on polymaviRUS, therefore, the antibody for SV40 will positive against the antigen.
This is used to confirm the diagnosis of BKVN in early stages when the histological changes for BKV are not appeared yet, it can differentiate between BKVN and other viral infection causing nephropathy.
The sensitivity and specificity for SV40 is 77 to 100% and 100% respectively.
Refrences:
1. https://europepmc.org/article/med/30896679.
2. uptodate :Prevention and management of BK virus-induced (polyomavirus-induced) nephropathy in kidney transplantation.
3. https://academic.oup.com/ndt/article/30/2/209/2337134.
What is your differential diagnosis?
15months post 3rd KT – use of induction agent, heavy immunosuppression
Allograft dysfunction associated with BKV viremia
PCS dilation – could be due to ureter stenosis / stricture
Tubular injury, flatten epithelium, tubulitis, epithelial cells with viral inclusion (Owl’s eye)
lymphoplasmacytic interstitial inflammation, and positive SV40 IHC stain
· Most likely BKV Nephropathy, due to typical clinical scenario with and histo-patho finding
Other D/D
· Acute Rejection
· Tubulointerstitial nephritis
· CMV Nephritis – Owl eye inclusion body
· Bacterial infection- Pyelonephritis
How do you manage this case?
Antivirals drugs are not so effective
· Reduction of immune suppression is main stay of treatment
– Reduce MMF by 50 % and monitor by BKV PCR log
– Reduce Tacrolimus to minimum dose (target Tac C0 @4-5 ng/ml)
– If no improvement à to stop MMF
o may switched to mTORi – Sirolimus
o with Everolimus, Tac dose can be kept further low (C0 2-3ng/ml)
· Drugs which can be tried, but have limited success include Cidovofir, Leflunamide and IVIg.
· Treatment of Acute Rejection – if initial treatment of BKVN does not improve graft function
Elaborate on SV40 staining the specificity, the sensitivity and where it comes from.
· It is the special immunohistochemical staining using Antibody against the Large T antigen of the Simian Virus 40, which serves as a surrogate marker of human polyomavirus infection.
· Infected epithelial cell nuclei are stained with this IHC marker and can be seen on fixed block of specimen or on flow cytometry
· Positive staining can be seen in the absence of inclusions or nuclear enlargement, even in early stage of BKV nephropathy.
Sensitivity-77%
Specificity- 100%
This is a 37 year old S/P renal transplantation presented with AKI , hematuria , mild dilatation of the pelvicalyceal system , He receive ATG induction therapy as mismatch with the donor was 2 1 2 so on the top of the differential is :
1- BKVN : Kidney biopsy shows viral inclusion bodies found in tubular epithelium associated with fibrosis and atrophy,and positive SV40 stain
2- Other viral infection such as CMV , adenovirus, and herpes simplex
3- Rejection
4- CNI toxicity
5- Urethral cancer
according to Prof Ahmad Halawah lecture the mainstay of treatment is reduction of maintenance Immunosuppression
1- Lower the dose of tacrolimus by 25-50 %
2- lower the dose of prednisilone
3- lower the dose of MMF by 50 %
4- consider changing of MMF to mTOR inhibitor ( may have some benefits )
5- Follow up blood PCR should be done every 2-4 weeks until the viral load fall below the threshold value and preferably to undetected level
6- Close follow up of kidney function looking for any evidence of rejection
7- urological evaluation to rule out uretric stricture which may need intervention
8- Some adjuvent treatment such as cidofovir , IVIG , leflonomide and Quinolones no enough RCT supporting this medication
SV40 staining has a specificity of 100%, and pathognomonic for BKV infection , about sensitivity a diagnosis of BKV in a renal biopsy could be missed in about 30% of cases because BKV has a focal tropism in the medulla rather than in the cortex, making an initial biopsy not enough to exclude .
References :
1) Prof Ahmed Halawa Lecture
2) Update on the Management of BK Virus Infection Ahmed Saleh,1,4,5 Mohamed Salah El Din Khedr,1 Abeer Ezzat,2 Anna Takou,3 Ahmed Halawa
This third transplant patient has increased creatinine probably due to BKV nephropathy.
Management of this case:
Hirsch HH, Randhawa PS, AST Infectious Diseases Community of Practice. BK polyomavirus in solid organ transplantation—Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clinical transplantation. 2019 Sep;33(9):e13528.
Kant S, Dasgupta A, Bagnasco S, Brennan DC. BK Virus Nephropathy in Kidney Transplantation: A State-of-the-Art Review. Viruses. 2022 Jul 25;14(8):1616.
· What is your differential diagnosis?
· The likely diagnosis is BKCN, other differentials are,
· Acute tubular injury,
· Drug induced acute interstitial nephritis,
· Acute T-cell mediated rejection,
· CMV nephritis.
· How do you manage this case?
· The key treatment of BKV management is immunosuppression modification,
· Corticosteroid dose reduction,
· Tacrolimus dose reduction by 25 to 50%,
· MMF dose reduction by 50%, however, if no response and persistent increase in viral load and still symptomatic then hold antimetabolite and can switch to mTORi, although there is no consolidated evidence, but there published articles.
· Other options are IVIG and other drugs like leflonemide, cidofivir, but no consensus and no recommendation in using all these drugs.
· Elaborate on SV40 staining the specificity, the sensitivity and where it comes from.
SV40 antigen is present on polymavisur, therefore, the antibody for SV40 will positive against the antigen.
This is used to confirm the diagnosis of BKVN in early stages when the histological changes for BKV are not appeared yet, it can differentiate between BKVN and other viral infection causing nephropathy.
The sensitivity and specificity for SV40 is 77 to 100% and 100% respectively.
Refrences;
1. https://europepmc.org/article/med/30896679.
2. uptodate :Prevention and management of BK virus-induced (polyomavirus-induced) nephropathy in kidney transplantation.
3. https://academic.oup.com/ndt/article/30/2/209/2337134.
BKPyV-associated nephropathy.
JCPyV is a rare cause of nephropathy.
ACR.
Adenovirus infection
SV40 was isolated from normal monkey kidney cells, stocks of the Sabin poliovirus vaccine, and an adenovirus vaccine. The last two reagents were prepared in primary kidney cell cultures derived from rhesus monkeys.These observations raised concerns that vaccinated people worldwide may have been inadvertently exposed to an oncogenic virus.
SV40 study on all transplanted kidney biopsies of the patients with new onset of allograft dysfunction, can improve the sensitivity of PVBKN pathologic diagnosis.
Sensitivity: 77.7%.
Specifity: 100%.
PPV: 100%.
NPV: 98.4%
Treatment:
Deduction of IS 50 %MM F, follow up after 2 weeks if no improve stop MMF.
Maintain Tac trough at 4-6ng/ml.
Reference
Fatemeh Nili et al .Routine immunohistochemistry study for polyomavirus BK nephropathy in transplanted kidney biopsies, is it recommended. BMC Nephrology volume 22, Article number: 226 (2021
What is your differential diagnosis?
The differentials will include –
· BK virus nephropathy
· Tubulointerstitial nephritis
· CMV Nephritis
· Graft Rejection
· Bacterial infection- Pyelonephritis
BK virus nephropathy is highly due to BKV viremia, Interstitial infiltrates and SV 40 staining on biopsy. There is dilatation of Pelvicalyceal system which can be due to Ureteric stricture.
How do you manage this case?
For BKVN-
Reduction of immune suppression – Reduce Tacrolimus to achieve TAC levels between 4-6 ng/ml
Reduce MMF by 50 % and monitor by BKV PCR log
If no improvement then MMF can be stopped and mTORi can be started
Other drugs can be used but may have limited success and main stay of treatment is reduction of immune suppression. These include Cidovofir, Leflunamide, Quinolones and IVIG.
Elaborate on SV40 staining the specificity, the sensitivity and where it comes from.
Infected epithelial cell nuclei stain with antibody to the large T antigen of the SV40 virus, which serves as a surrogate marker of human polyomavirus infection. Positive staining can be seen in the absence of inclusions or nuclear enlargement.
Sensitivity-77%
Specificity- 100%
Nili, F., Mohammadhoseini, M., Khatami, S.M. et al. Routine immunohistochemistry study for polyomavirus BK nephropathy in transplanted kidney biopsies, is it recommended?. BMC Nephrol 22, 226 ;2021.
it is a case of hematuria one episode in immunosuppressed patient ( transplanted since 15 months), with deteriorated graft function, with positive BK PCR
DD:
1- BKN
2-drug induced interstitial nephritis
3-CNI toxicity
4-urothelial malignancy
5-other infections like bacterial, viral or fungal
6-pelonephritis
7-graft rejection
management:
1- urine analysis and culture
2-CBC
3-DSA
4-treat BK by reduction of immunosuppression RIS , reduce MMF by 50%, decrease dose of steroid and decrease the dose of tacrolimus to lower its concentration by 25-50%
5-other adjuvant treatment like cidofovir, lefluonamide, ivig, and quinolones
6-no role except for RIS
SV40 stain can detect BK in early phase as it binds large T antigen on BK virus, so the diagnosis can be missed in late stage of infection
references:
1- DR AHMED HALAWA LECTURE
2- Wendy N Wiesend , Raviparasenna Parasuraman, Wei Li, Maryam A Farinola, Michele T Rooney, Sharon K Hick, Dilip Samarapungavan, Steven R Cohn, Gampala H Reddy, Leslie L Rocher, Francis Dumler, Fan Lin, Ping L Zhang. Adjuvant role of p53 immunostaining in detecting BK viral infection in renal allograft biopsies. Ann Clin Lab Sci. 2010 Fall;40(4):324-9.
Differential Diagnosis
1) BK virus associated Nephropathy
2) Acute cellular Rejection
How do you manage this case
Acute cellular Rejection is the close differential diagnosis of BK virus Associated Nephropathy (BKVAN). Presence of BK viremia 4 log 10 copies per ml, Cytopathic Changes ( hyaline intraneuclar inclusions ) And IHC positive for SV 40 confirm the diagnosis of BKVAN.
Reduction in immunosuppression is mainstay of treatment.
Reduce the dose of MMF by 50 %.
Monitor the renal Function and Plasma BK PCR level every 2 weeks from same lab.
If no reduction in Plasma BK viral Load, we will proceed with complete cessation of MMF
Next step is to reduce the CNI trough level if no reduction in plasma BK viral load by 4 weeks after complete cessation of MMF(Anti- metabolites) to Tacrolimus 4-6 ng/L and cyclopsorine 50-100 ng/L.
Adjunctive Therapies.
1) IvIg
2) Cidofovir
3) Quinolones
4) Leflunomide
Upcoming Therapeutic Trials
1) human monoclonal antibody (IgG1)
2) multivirus-specific T Cells
Elaborate on SV40 staining the specificity, the sensitivity and where it comes from
A Characteristic cytopathic changes on the renal biopsy plus positive immunohistochemistry (against BKV or against SV40 large T antigens), which has a specificity of 100% and Sensitivity is of 70 %.
It can miss the diagnosis of BKVAN in 30 % owing to focal tropism in medulla rather than the renal cortex.
The SV40 IHC stain detects the large T antigen which is expressed by all polyoma viruses pathogenic in humans (SV, JC, and BK).
This stain also help differentiate BKVAN from other viral nephropathies seen in immunocompromised patients, such as adenovirus infection.
BK virus nephropathy
Drug induced interstitial nephritis
Acute cellular mediated rejection
Reducing immunosuppressive therapy dose
In case of BK virus reduce anti metabolite to half and monitoring graft function and viral load in plasma and urine. If continuous viremia reduce calcinurine inhibitors to half and consider intravenous immunoglobulin
there’s no role of anti viral therapy
immunohistochemical (IHC) stain for the viral SV40 large T antigen, although in situ hybridization (ISH) for viral DNA is used in some centers. It’s showed 88% sensitivity and 79% specificity for diagnosis and confirm BKV.
Differential diagnosis:
–BK nephropathy ;most probable.
–T-cell mediated rejection.
– Combined BKN with T cell mediated Rejection.
–Drug-induced interstitial nephritis
-other viral infections.
-Management:
high immunological risk patient with previous latent BK infection
– Early surveillance policy.
-Reduction in the intensity of immunosuppression is the mainstay for treatment of BK viremia and BKVAN.
– No therapeutic agent to treat this virus-associated disease.
-Reduction of MMF to 250 mg bid; if PCR still > 1000 after 2 weeks, MMF to be stopped.
-Reduction of tacrolimus targeting trough of 5-7 ng/ml.
-Monitoring graft function and PCR every 2-4 weeks; viral clearance may need 20 weeks.
-SV 40:
-Simian Virus 40: is immunohistochemistry stain for all transplant biopsies where PVN is suspected without definitive features.
-It detects the large T antigen expressed by all pathogenic polyoma viruses in humans (SV, JC, and BK).
-It can highlight cells in the early stages of infection.
-It helps to differentiate PVN from other viral nephropathies such as adenovirus infection.
–Specificity (100%) and sensitivity 77%.
What is your differential diagnosis?
1. BKVN
2. Other viruses, CMV, HSV and adenovirus nephropathy
3. BKVN plus ACR
Management of this patient:
Every center has its own protocol of management of BKVN
Since this patient is biopsy proven BKVAN
· I would stop MMF, continue with tacrolimus and steroids and add leflonamide because of its antiviral and IS properties. It is the only adjuvant therapy showing benefit,(observational trials)
· Continue monitoring serum creatinine and BKV PCR in the same lab every two weeks
· If viral load continues to rise despite stopping MMF, reducing the CNI and adding leflunomide Stop CNI and ADD sirolimus.
· Repeat BK viral load every 2 weeks.
· When viral load is undetectable for 2 readings, consider gradually resuming IS with close motoring of PCR.
· We should put in mind that with reduction of IS treatment there is a possibility of AR. Although Kidney transplant recipients maintained on tacrolimus-based regimes had lower rates of rejection.
· If AR occur as indicated by increase in serum creatinine with reduction of IS treatment, consider giving pulse steroids
Elaborate on SV40 staining:
· Infected epithelial cell nuclei are stained with antibody to the large T antigen of the SV40 virus, which serve as a surrogate marker human plyomavirus infection. Cannot differentiate between the three viruses, BKV, SV and JCV. it is used to confirm the diagnosis of BKVN
· It is 100% specific and 77% sensitive
Refrences
1. BK Virus (BKV) Management Guideline: July 2017
2. Sam Kant etal, BK Virus Nephropathy in Kidney Transplantation: A State-of-the-Art Review, Viruses 2022, 14, 1616
3. Mark A etal, AJKD Atlas of renal pathology: Polyomavirus Nephropathy, American Journal of Kidney Dis 2016,68(6)
What is your differential diagnosis?
The case scenario addressed the followings:
a) successful third renal transplant 15 months ago.
b) Expected intense immunosuppression because of 2-1-2 mismatch and history of 2 previous transplant. TAC level exceeding the target for the age of the transplant.
c) Episode of hematuria and deteriorating KFT in the background of BK viremia and biopsy findings are suggestive of BKVN.
d) USS feature of mild dilatation of the pelvicalyceal system in the presence of BKV infection raised a suspicion of ureteral stenosis as a cause of this dilatation.
The most likely differential diagnoses for this scenario:
· BKVN
· ACR
· Tubule-interstitial diseases due to drugs.
· Other viral infection; CMV
How do you manage this case?
The most likely diagnosis is BKVN with allograft dysfunction and the management plan for this patient is as follows:
A. Diagnosis of BKV(1):
a) Laboratory findings;elevated serum creatinine and urine analysis with pyuria, hematuria, and findings consistent with interstitial nephritis.
b) The presence of decoy cells in the urine analysis increases the suspicion of BKV nephritis.
c) Quantitative PCR is used to diagnose BKV viremia(a blood quantitative PCR showing > 60 to 100 BKV copies).
d) A tissue (renal) biopsy is needed for a definitive diagnosis of BKVN(may be missed in the tissue obtained because viropathic lesions are patchy.)
B. Treatment plan(2):
1. Reduction of immunosuppression although may increase the risk of DSA formation and further rejection episode.
a) I will reduce the dose of antimetabolite(MMF) by half while continuing on the same doses of calcineurin inhibitor and/or prednisone.
b) If viral loads continue to be at similar levels or increase, proceed with complete cessation of anti-metabolite(MMF).
c) The next step is to reduce calcineurin-inhibitor trough goals if viral loads do not reduce over 4 weeks despite cessation of anti-metabolite (4–6 ng/mL for tacrolimus and 50–100 ng/L for cyclosporine).
2. Intravenous immunoglobulin (IVIG): IVIG administration appeared to be safe and effective in treating BK viremia and BKVN and in preventing graft loss in patients who had inadequate response to immunosuppression reduction and leflunomide therapy(3,4).
3. Other adjunctive therapies utilized to treat BK virus infection include quinolones, cidofovir andleflunomide. These are associated with severe adverse effects.
4. However, a specific antiviral agent to treat BKVN does not exist. Leflunomide has both antiviral and immunosuppressive effects, however, a phase II randomized trial did not support this effectand the efficacy of leflunomide remains controversial(5).
5. For pelvicalyceal dilatation, ureteric stricture and stenosis need to be ruled out and a urologist opinion is crucial.
Elaborate on SV40 staining the specificity, the sensitivity and where it comes from.
A. What’s SV40:
SV40 large T antigen (Simian Vacuolating Virus 40 TAg) is a small hexamer protein, DNA-containing tumour virus. One of its gene products, the large tumour antigen (T-ag), is essential for both viral replication and cell transformation. SV40 T-ag can be considered a dual oncogene protein; it is a composite transforming protein that provides distinct functions at different subcellular locations(6).
B. IHC staining for SV40: Routine IHC study for SV40 in all transplanted kidney biopsy samples with new onset of allograft dysfunction, will enhance the diagnostic sensitivity of early stage disease detection(7).
a) IHC or In Situ Hybridization (ISH) assays can confirm PVBK infection(8).
b) Sensitivity, Specifity, PPV and NPV of morphologic histopathological assay without IHC for detection of PVBKN was 77.7, 100, 100 and 98.4% respectively(7).
c) ISH showed 88% sensitivity and 79% specificity and, as an alternative test, could confirm the presence of BKV tissue in presumed BKpyVAN and rule out BKV as the causative agent in JC virus nephropathy(9).
References
1. Saleh A, El Din Khedr MS, Ezzat A, Takou A, Halawa A. Update on the Management of BK Virus Infection. Exp Clin Transplant. 2020 Nov;18(6):659-670. doi: 10.6002/ect.2019.0254. Epub 2020 Jun 16. PMID: 32552624.
2. Kant S, Dasgupta A, Bagnasco S, Brennan DC. BK Virus Nephropathy in Kidney Transplantation: A State-of-the-Art Review. Viruses. 2022 Jul 25;14(8):1616. doi: 10.3390/v14081616. PMID: 35893681; PMCID: PMC9330039.
3. Shah T, Vu D, Naraghi R, Campbell A, Min D. Efficacy of Intravenous Immunoglobulin in the Treatment of Persistent BK Viremia and BK Virus Nephropathy in Renal Transplant Recipients.Clin Transpl. 2014:109-16. PMID: 26281134.
4. Benotmane I, Solis M, Velay A, Cognard N, Olagne J, Gautier Vargas G, Perrin P, Marx D, Soulier E, Gallais F, Moulin B, Fafi-Kremer S, Caillard S. 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. Am J Transplant. 2021 Jan;21(1):329-337. doi: 10.1111/ajt.16233. Epub 2020 Aug 27. PMID: 32741096.
5. Yamazaki T, Shirai H, Tojimbara T. Use of Leflunomide as an Antiviral Agent with Everolimus for BK Virus Nephropathy Patients After Kidney Transplantation: A Case Series. Am J Case Rep. 2020 Nov 25;21:e927367. doi: 10.12659/AJCR.927367. PMID: 33235184; PMCID: PMC7701375.
6. Butel JS. SV40 large T-antigen: dual oncogene. Cancer Surv. 1986;5(2):343-65. PMID: 3022925.
7. Nili, F., Mohammadhoseini, M., Khatami, S.M. et al. Routine immunohistochemistry study for polyomavirus BK nephropathy in transplanted kidney biopsies, is it recommended?.BMC Nephrol 22, 226 (2021). https://doi.org/10.1186/s12882-021-02444-5.
8. Liptak P, Kemeny E, Ivanyi B. Primer: histopathology of polyomavirus-associated nephropathy in renal allografts. Nat Clin Pract Nephrol. 2006;2(11):631–6.
9. Costigliolo F, Lombardo K, Arend LJ, Rosenberg AZ, Matoso A, Carter-Monroe N, Bagnasco SM. BK Virus RNA in Renal Allograft Biopsies. J Histochem Cytochem. 2020 May;68(5):319-325. doi: 10.1369/0022155420922604. Epub 2020 Apr 30. PMID: 32352851; PMCID: PMC7226623.
What is your differential diagnosis?
Patient presented with hematouira ,rising s creatinine, tacrolitmus trough level is 8 ng/ml, on third transplantation, with 212 mismatch, BK viraemia
DD includes
-BK nephropathy.
– Acute T cell mediated rejection
– CMV nephropathy.
– urologic cause of hematuria as ureteric stone .
-JC virus nephropathy:Should be considered in patients with BK viremia loads inconsistent with strong SV40 staining in renal biopsy samples
-High grade urothelial carcinoma:
Causes confusion especially in urine cytology, presence of Haufen in urine cytology and SV40 immunohistochemistry is diagnostic;
*Biopsy shows:
Its difficult to distinguish histologically between BKVAN and acute rejection but the presence of endarteritis, glomerulitis, and C4d deposits along peritubular capillaries is suggestive of concurrent rejection.
Due to focal pattern of PVBKN involvement, at least two biopsy cores, including medullary tissue are needed, to conduct IHC and ISH assays.
In 10 to 30% of the patients, sampling error can occur.
So a negative result does not exclude PVBKN.
First slide:
Tubulo-interstitial inflammation and nuclear viral inclusion bodies in tubular epithelium characteristic for BKVAN.
Second slide
Tubular epithelial cells with positive immunohistochemical stain for SV40 T antigen within nuclei
Therefor its mostly a case of BK virus nephropathy
How do you manage this case?
Risk Factors for BKVN:
– intensity of immunosuppression.
-transplanting kidney from BKV seropositive donor to seronegative donor.
– number of HLA mismatches, ABO-incompatibility.
-ischemia reperfusion injury.
– Recipient factors include old age, male sex, desensitization, and prior kidney transplant with PVN.
-The mainstay of treatment of PVN is immunosuppression reduction. A wide variation in treatment practices is available based on individual clinician experience.
Most centers monitor BKV post-transplant at 3, 6, 9, and 12 months.
But with more intense induction regimen or in those with risk factors, perform routine surveillance monthly in the first 12 months following transplant.
PVN is difficult to treat since there is no BKV-specific anti-viral therapy.
PVN is treated by stimulating host immune response by IS reduction; however, there is a risk of acute rejection following virus clearance, further complicating treatment options since rejection treatment requires escalation of IS which often results in BKV recurrence.
Immunosuppression Reduction and Antiviral Therapy
-For BKV viral load <10,000 copies/mL, IS dose reduction should be considered.
-For viral loads >10,000 copies/mL, a common initial approach involves calcineurin inhibitor dose reduction by 25–50% to reach tacrolimus trough level of 4 to 6 ng/mL.
-keep the same dose of steroids.
-Switching to Cyclosporine A (CsA) has been shown to have some benefit as well.
Switching from Tacrolimus to CsA is a common approach used.
-Failure of reduction in viral load should prompt reduction of MMF by 50%, or discontinuation of MMF if no response in 2-3 weeks switching to an mTOR inhibitor.
The practices vary by center and physician experience.
-There is no strong evidence supporting antiviral treatment for PVN
In refractory cases, most common therapeutic option is Cidofovir, use of which is limited by its nephrotoxicity.
– Brincidofovir is a prodrug of cidofovir and has also been used with limited success.
-IVIG preparations have high titers of neutralizing antibodies to BK virus and can help virus clearance and have been used as a useful adjunctive therapy.
– Fluoroquinolones have been tried but failed to show therapeutic benefit.
– for Concurrent BKVN and acute rejection
There are no clear protocol for management Some centres recommend treating acute rejection first then reduce immunosuppression after decline of s creat with close monitoring of the viremia.
Elaborate on SV40 staining the specificity, the sensitivity and where it comes from.
Immunohistochemistry stain to confirm BKVAN
Large T antigen (LTAg), one of the proteins encoded by the BK polyomavirus genome shares sequence homology with the LTAg of the simian virus (SV40)
Anti-SV40 antibody directed against the SV40 T antigen, hence crossreacts with the BK polyomavirus LTAg and is used to identify BK polyomavirus
This antibody also crossreacts with the JC polyomavirus
At least two biopsy cores, including the medulla, since the virus is more likely to be present in the medulla.
SV40 is highly specific up to 90- 100%, but
Lower sensitivity around 70%.and 30 % false negative results may occur.
-Positive stains for BKVAN in renal biopsy
-In situ hybridization for BK virus DNA
-Anti-BK polyomavirus VP1 recombinant antibody, immunohistochemistry: a novel monoclonal antibody directed against the viral VP1 capsid protein. (Am J Transplant 2007;7:1552).
Another suggested biomarker
Singh and colleagues suggested a non-invasive novel biomarker for assessment of PVBKN.
It is based on the detection of three-dimensional polyomavirus aggregates in voided urine samples by negative staining electron microscopy.
The presence of these urinary cast-like structures named “Haufen” has positive and negative predictive values over 90% by far more than other screening tests.
But this method is not available in most of the centers
Reference
1 Rajeev Sharma, Mareena Zachariah.BK Virus Nephropathy: Prevalence, Impact and Management Strategies.International Journal of Nephrology and Renovascular Disease.2020:13 187–192
2 Fatemeh Nili, Maliheh Mohammadhoseini.Routine immunohistochemistry study for polyomavirus BK nephropathy in transplanted kidney biopsies, is it recommended?.BMC Nephrology volume 22, Article number: 226 (2021)
3 Francesca Costigliolo, Kara Lombardo. BK Virus RNA in Renal Allograft Biopsies.Journal of Histochemistry & Cytochemistry 2020
What is your differential diagnosis?
———————————————————
1- BK virus infection.BKN
2- Other types of viral infections (CMV)
3- TCMR
4- Acute interstitial nephritis .
5- Acute pyelonephritis
How do you manage this case?
———————————————————
1-Diagnosis ;
——————–
1-Clinical manifestations :
In presenting case ;the patient is heavily immune suppressed ,haematuria ,slow rising serum creatinine and radiological finding suggestive of BKN.
2-Histological diagnosis ;
The kidney biopsy(of the presented case) result showed tubulointerstitial nephritis with marked lymphocytic infiltration in addition to postive SV40 stain for polyoma virus (confirm the diagnosis of BKN.
2-Treatment ;
————————–
1-A reduction in the intensity of immunosuppression ;
A-The first step ;
Reduction of MM dose by 50% and the calcineurin to the corresponding therapeutic level(5-7ng/mL) and continue the same dose of prednisone.
Monitor serum creatinine and serial plasma BK PCR levels every 2 weeks .
B.The second step ;
If viral loads continue to be at similar levels or increase, proceed with complete cessation of anti-metabolite.
C.The third step ;
Is to reduce calcineurin-inhibitor trough goals if viral loads do not reduce over 4 weeks despite cessation of anti-metabolite (4–6 ng/mL for tacrolimus0 .
2-Other adjunctive therapies utilized to treat BK virus infection include quinolones, cidofovir, leflunomide, and intravenous immunoglobulin (IVIG).
Elaborate on SV40 staining the specificity, the sensitivity and where it comes from.
—————————————————————————————————–
SV40 is a monkey polyomavirus isolated originally in 1960 as a natural contaminant of early poliomyelitis vaccines, including both the Salk intramuscular inactivated vaccine and the Sabin oral attenuated vaccine . The SV40-encoded large Tag is an essential protein required for viral replication, transformation, and oncogenicity .
The SV40 IHC stain detects the large T antigen expressed by all polyoma viruses pathogenic in humans (SV, JC, and BK). This stain can highlight cells in the early stages of infection, before viral cytopathic changes may be detectable on routine stains .
This stain may also help differentiate PVN from other viral nephropathies seen in immunocompromised patients, such as adenovirus infection. Sensitivity (77.7%) / Specificity (100%).
Reference ;
1-Update on the Management of BK Virus Infection Ahmed Saleh, 1,4,5 Mohamed Salah El Din Khedr,1 Abeer Ezzat, Anna Takou, 3 Ahmed Halawa4.
2-Review BK Virus Nephropathy in Kidney Transplantation A State-of-the-Art Review Sam Kant 1,2,* , Alana Dasgupta 3, Serena Bagnasco 3 and Daniel C. Brennan 1,2
3-PLoS One. 2016; 11(1): e0145720. Published online 2016 Jan 5. doi: 10.1371/journal.pone.0145720 PMCID: PMC4701414 PMID: 26731525 Specific Antibodies Reacting with SV40 Large T Antigen Mimotopes in Serum Samples of Healthy Subject
_The index case is high immunological risk (3rd transplant with 212 mismatch, so most probably recieved induction therapy (may be ATG) , I’m addition to tripple maintenance therapy including tacrolimus and MMF
_ so, he is high risk for infection
_presence of hematuria, together with dilated pelvicalyceal system (may suggest ureteric stricture) and presence of BKV viremia all suggest BKV infection
_The provided biopsy shows marked lymphocytic infiltration In the interstitium in addition to postive SV40 stain for polyoma virus (suggest BKN).
👉 Differential diagnosis:.
1.BKN
2_ concomitant TCMR (as BKN can trigger or associate rejection).
3_ Drug induced interstitial nephritis.
4_ acute pyelonephritis.
👉 Management of the case:
_ first step is to decrease immunosupression (reduce MMF by 50% or even stop it , reduce CNI by 50%).
_additional IVIg and leflunamide may be tried if viral load not decrease with reduction of immunosupressives alone
_ The problem in treatment of concurrent rejection if present , as rejection can be treated with pulse steroids which causes flare up of BKN and BKN is treated with reduction of immunosupression which is against treatment of TCMR
-so close monitoring of graft function and protinuria is essential during reduction of IS to early detect rejection.
👉 SV40 is immunohistochemistry tissue staining of 100% specificity to polyoma virus and about 77% sensitivity.
-It stains T antigen of polyoma virus.
It is named after simian virus
1-What is your differential diagnosis?
–BK nephropathy (BKVN) (most likely).
–T-cell mediated Rejection.
–Other viral infections (CMV, herpes simplex virus , adenovirus).
–BKN with T cell mediated Rejection.
–Drug-inuced interstitial nephritis.
2-How do you manage this case?
(This case is third renal transplant 15 months ago, 212 mismatch with Tacrolimus (trough 8 ng/ml) / There is BK viraemia (plasma PCR 4 log 10). The biopsy is shown BKVN, and SV40 staining)
-Considering this patient high immunological risk patient ; probably with a previous latent BK infection
-An early surveillance policy followed in some centers by non invasive methods is highly indicated in this case.
-Reduction in the intensity of immunosuppression is the overarching principle for the treatment of BK viremia and BKVAN.
-There is no therapeutic agent available to treat this virus-associated disease, with many agents lacking conclusive efficacy in the reduction in viral loads.
-Multiple protocols have been developed for a reduction in immunosuppressions.
In current case i will start treatment as the following;
1-Reduce MMF to 250 mg bid , and if PCR still > 1000 after 2 weeks; I will stop MMF.
2-Reduce the dose of tacrolimus to attain a trough of (5-7 ng/ml).
3-Continue on the same steroid dose 5 mg od.
4-Monitoring graft function and F/U PCR every 2-4 weeks, it may need up to 20 weeks for viral clearance.
5-No need to shift to sirolimus (m-TOR).
6-I.D. referral for other adjunctive therapies utilized to treat BK virus infection include; quinolones, cidofovir, leflunomide, and intravenous immunoglobulin (IVIG).
3-Elaborate on SV40 staining the specificity, the sensitivity and where it comes from.
-Simian Virus 40 (SV40); is an immunohistochemistry (IHC) stain be performed on all transplant biopsies where PVN is suspected clinically, but no definitive features of PVN are seen.
-The SV40 IHC stain detects the large T antigen expressed by all polyoma viruses pathogenic in humans (SV, JC, and BK).
-This stain can highlight cells in the early stages of infection, before viral cytopathic changes may be detectable on routine stains.
-This stain may also help differentiate PVN from other viral nephropathies seen in immunocompromised patients, such as adenovirus infection.
–Sensitivity (77.7%) / Specificity (100%)
References;
-Nickeleit, V.; Singh, H.K.; Randhawa, P.; Drachenberg, C.B.; Bhatnagar, R.; Bracamonte, E.; Chang, A.; Chon, W.J.; Dadhania, D.; Davis, V.G.; et al. The Banff Working Group Classification of Definitive Polyomavirus Nephropathy: Morphologic Definitions and Clinical Correlations. J. Am. Soc. Nephrol. 2018, 29, 680–693.
-Hardinger, K.L.; Koch, M.J.; Bohl, D.J.; Storch, G.A.; Brennan, D.C. BK-Virus and the Impact of Pre-Emptive Immunosuppression Reduction: 5-Year Results. Am. J. Transplant. 2010, 10, 407–415.
-Ginevri, F.; Azzi, A.; Hirsch, H.H.; Basso, S.; Fontana, I.; Cioni, M.; Bodaghi, S.; Salotti, V.; Rinieri, A.; Botti, G.; et al. Prospective Monitoring of Polyomavirus BK Replication and Impact of Pre-Emptive Intervention in Pediatric Kidney Recipients. Am. J. Transplant. 2007, 7, 2727–2735.
That is a well thought reply
What is your differential diagnosis?
The patient had 3rd transplant( history sensitization) with 212 mismatches although there was no DSA and negative FAXM, I assume the patient would have given induction with possibility of Thymol or alemtuzumab ( potent induction therapy)
He had Tacrolimus and MMF combination as maintenance therapy.
With possibility of potent induction and MMF-Tac combination, patient has risk for infections.
My differential will be:
How do you manage this case?
USS showed mild dilatation of the pelvicalyceal system, but it has been found previously.
BK viraemia was found and SV 40 stained showed pattern B histology of BKVN.
It will be good to categorize PVN according to Histologic classification system of PVN for the Banff Working Group Classification of Definitive Polyomavirus Nephropathy.
The pvl score is calculated on the extend of virally induced changes identified on H&E or via SV40 IHC staining. Score for pvl are calculated as follows:
Pvl:<1% of all tubules / ducts with viral replication;pvl2>1 to 10% of all tubules / ducts with viral replication; pvl3:.10% of all tubules /ducts with viral replication.
The ci score is calculated using Banff Classification of Renal Allograft Pathology.
I would like to see any ejection along with the evidences of BKVN: DSA, C4d staining of renal tissue and Banff classification for renal histopathology.
Treatment of BKVN:
Elaborate on SV40 staining the specificity, the sensitivity and where it comes from.
Positive SV40 staining is useful as it is associated with a specificity of almost 100 percent for polyomavirus nephropathy; although, it does not distinguish between BKV and JC virus (JCV).
Some literature stated that it will still give around 30% false negative results.
SV40 consists of an unenveloped icosahedral virion with a closed circular double-stranded DNA genome of 5.2 kb. The virion adheres to cell surface receptors of MHC class I by the virion glycoprotein VP1. Penetration into the cell is through a caveolin vesicle.
Kant, S.; Dasgupta, A.;Bagnasco, S.; Brennan, D.C. BK Virus
Nephropathy in KidneyTransplantation: A State-of-the-Art Review. Viruses 2022, 14, 1616.https://doi.org/10.3390/v14081616
I like your structured response
What is your differential diagnosis?
Most likely diagnosis is BKVAN evidenced by the positive SV40, interstitial inflammation and BKV viremia.
Differentials to consider:
T cell mediated rejection
Drug induced interstitial nephritis
CMV nephritis.
How do you manage this case?
This patient 15 months post third transplant presents with raised Scr, U/S showing mild dilatation of the pericalyceal system, BKV viremia and histology findings of positive SV40, tubulitis and interstitial inflammation.
The mainstay of treatment is reduced immunosuppression.
The first to reduce/ withdraw is the antimetabolite(MMF).
It should reduced by 25-50% as monitoring of the plasma PCR and Scr continues in intervals of 2 weeks.
Failure of the viral loads to drop should warrant complete removal of the antimetabolite.
Rising or viral loads that are not decreasing despite withdrawal of the antimetabolite calls for reduce trough levels of the CNI targeting trough levels of 3-6ng/ml.
Other treatment options that can be used is IVIG in non-responders who have their immunosuppression maximally reduced.
Currently other treatments like cidofovir, leflunomide, quinolones are not recommended and further research on their use is required.
Elaborate on SV40 staining the specificity, the sensitivity and where it comes fromSV40?
SV40 T antigen is an antigen presents on the polyomaviruses, hence IHC SV40 tests for antibodies targeted against this antigen.
The sensitivity of IHC SV40 positive with characteristic biopsy findings for BKVAN ranges between 77-100%. It has specificity of 100% and it can differentiate nephropathy caused by the polyomavirus from those of other viruses like CMV, adenoviruses.
However its interpretation should be take with caution since one it doesn’t differentiate between the polyomaviruses and secondly it may be confounded with the latency of the virus in the kidneys.
References
BK Virus Nephropathy in Kidney Transplantation: A State-of-the-Art Review Sam Kant, Alana Dasgupta, Serena Bagnasco and Daniel C. Brennan
BK Virus RNA in Renal Allograft Biopsies Francesca Costigliolo, Kara Lombardo, […] and Serena M. BagnascoRoutine immunohistochemistry study for polyomavirus BK nephropathy in transplanted kidney biopsies, is it recommended? Fatemeh Nili, Maliheh Mohammadhoseini, Seyed Mohammadreza Khatami, Golnar Seirafi & Majidreza Haghzare
I wish you could type references as in Vancouver style
DD
1- BKVN : confirmed by presence of viremia ,presence of interstitial infiltration and positive SV 40 stain on graft biopsy and pelvicalceal system dilatation that could be due to ureteric structure , beside presence of heamaturia mostly from heamorragic cystitis. The level of IS drugs is elevated which is the commonest risk factor for BKV reactivation.
Other potential DD
– CMV nephritis .
– Drug induced TIN.
– Graft rejection.
2- Management of this case:
A- For BKVN:
1-Decrease the dose of IS by 25-50 % for tacrolimus and 50% for MMF with close monitoring of graft function to detect early signs of rejection . If no improvement in graft function, consider further IS reduction , switch from MMF to mTOR.
2- Antiviral drugs : their efficacy in treatment of BK is not conclusive ,but could be tried if reducing IS dose wasnot sufficient to control BK infection . including
– Cidofovir
– Leflunamide
– IVIG
– Quinolones
3- SV40 :
Immunehistochemical staining for antibody against large T antigen expressed by all polyoma viruses specially BK ,SV and JC. This stain is used to confirm the diagnosis of BKVN specially in early stages where the characterstic histological changes and inclusion bodies are still absent and also due to focal nature of BKVN that could be missed if only one core biopsy was taken . It can also differntiate between BKVNand other viral nephropathies as adenovirus infection.
SV40 stain has fair predictive value for diagnosis of BKVN estimated as
Sensitivity 77 %, Specifity of 100%
PPV of 100% and NPV of 98.4%
Ref:
Nili F, Mohammadhoseini M, Khatami SM, Seirafi G, Haghzare M. Routine immunohistochemistry study for polyomavirus BK nephropathy in transplanted kidney biopsies, is it recommended? BMC Nephrol. 2021 Jun 18;22(1):226.
Yes, reduction of immunosuppression is the key. One may have to discontinue MMF for some time
A 37-year-old man was admitted after one episode of haematuria. He had a successful third renal transplant 15 months ago, 212 mismatch, no DSA and negative FAXM. His creatinine has risen from 151 µmol/L to 223 µmol/L. USS showed mild dilatation of the pelvicalyceal system, not different from the previous scan. He is currently on Tacrolimus (trough 8 ng/ml), MMF 750 bd and prednisolone 5 mg od. There is BK viraemia (plasma PCR 4 log 10). The biopsy is shown below, and SV40 staining (left).What is your differential diagnosis?1-BKN.
2- Acute cellular rejection.
3-CMV nephropathy.
4- Acute pydonephmitis.
5 – Hemorrhagic cystitis.
6- Drugs induced interstitial nephritis.
How you manage this case?
Firstly diagnosis is made by :-
* demonstration of viral cytopathic effects.
* demonstration of virus itself.
* demonstration of immunity to virus.
* histologic findings:-
> immenoperoxidase staining for SV40 large T antigen.
> decoy cells ( enlarged nucleus with a single large basophilic intranuclear inclusion.
Then management:
– decrease dose of TAC with aiming to decrease concentration by 25-50%.
– decrease dose of steroids.
– decrease dose of MMF by 50%.
* some studies suggested that mTOR inhibitors has a role to decrease BKV
and we must consider change MMF to mTOR inhibitors.
– increase creatinine more than 200 ummol has a higher incidence of a graft loss so we must consider decrease immunosuppression.
Elaborate on SV40 staining the specificity, the sensitivity and where it comes from.
Positive immunohistochemistry tests using antibodies directed specifically against BKV or against the cross-reacting SV40 large T antigen. Positive SV40 staining is useful as it is associated with a specificity of almost 100 percent for polyomavirus nephropathy despite it does not distinguish between BKV and JC virus .
References:-
1. Prof Ahmed Halawa lecture.
2. Knoll G., Humar A., Fergusson D., Johnston O., House A.A., Kim S.J., Ramsay T., Chassé M., Pang X., Zaltzman J., et al. Levofloxacin for BK Virus Prophylaxis Following Kidney Transplantation. JAMA. 2014;312:2106–2114. doi: 10.1001/jama.2014.14721.
3. Lee B.T., Gabardi S., Grafals M., Hofmann R.M., Akalin E., Aljanabi A., Mandelbrot D.A., Adey D.B., Heher E., Fan P.-Y., et al. Efficacy of Levofloxacin in the Treatment of BK Viremia: A Multicenter, Double-Blinded, Randomized, Placebo-Controlled Trial. Clin. J. Am. Soc. Nephrol. 2014;9:583–589. doi: 10.2215/CJN.04230413.
4. Meier P., Dautheville-Guibal S., Ronco P.M., Rossert J. Cidofovir-induced end-stage renal failure. Nephrol. Dial. Transplant. 2002;17:148–149. doi: 10.1093/ndt/17.1.148.
Yes, reduction of immunosuppression is the key. One may have to discontinue MMF for some time
1- Diagnosis:
BKVN ( BK viraemia, intranuclear basophilic inclusion body, positive Sv-40, impaired graft function)
2- Management:
First start with reduction of MMF to half dose and maintain tacrolimus and predinsolone. with monitoring of renal function and viral load after 2 weeks.
if viral load maintained or increased, stop MMF
IF no decrease of viral load by 4 weeks, reduce tacrolimus dose (target trough level 406 ng/ml)
3- SV40 staining:
Immunohistochemical staining using antibodies directed specifically against
the cross-reacting SV40 large T antigen.
Positive SV40 staining is useful
It is associated with a specificity of almost 100 % for polyomavirus nephropathy
(PVN); although, it does not distinguish between BKV and JCV.
Yes, reduction of immunosuppression is the key. One may have to discontinue MMF for some time. I would not wait for watching the effect of MMF reduction
We can see pattern B staining for SV40 staining (intensive infiltrates). Acute rejection solely or as result is main differential diagnois here. Tubules are not atrophied. tubulitis is per cent on the left side image.
Key management is decreasing the immunosuppression. Mainly decreasingor stopping MMF. If nor responsive Tacrolimus can be reduced to safer trough level with monitoring of virmeia , viruria and RFTs.
As adjuvant treatment some patients may benifit from Leuflomide (ARAVA) or IVIG. Some centres may prefer cidofovir
Swedish group in the paper published in 2019 (according to W4 lecture) suggest lowering Tacrolimus by %25-50, Lowering MMF by 505 and lowering steroid dose.
Early treatment is effective. At early stage immunosuppression can help
—–
SV40 staining may not differentiate BK from JC but we usually see BK in renal transplant patients
I agree that a reduction of immunosuppression is the key. One may have to discontinue MMF for some time. I would not wait for watching the effect of MMF reduction
This 37 year patient underwent 3rd successful kidney transplant and developed asymptomatic rising in serum creatinine . He is on tacrolimus with trough level 8ng/ml plus MMF and prednisolone .There is BK viraemia (plasma PCR 4 log 10). Kidney biopsy showed evidence of tubulointerstitial nephritis with intracellular inclusion that proved SV40 positive staining .So the first differential is BK nephropathy.
Other differentials include :
–CNI toxicity
-Acute rejection
– Cmv nephropathy .
-Hemorrhagic cystitis
*Management approaches differ and can include :
-Dose reduction of the calcineurin inhibitor (CNI) by 25–50% targeting significantly lower levels (tacrolimus 3–4 ng/mL and cyclosporine 50–100 ng/mL, or even less) or switching from tacrolimus to cyclosporine .
-Discontinuation of the anti-metabolite such as MMF is the most common approach, but a recent study suggests that both tacrolimus and cyclosporine can inhibit anti-BK T Cell responses in vitro, challenging this practice.
The resolution of viremia may take several months. An alternative approach that is used by others is to decrease the mycophenolate dose by 50 %, followed by a 50 % decrease in the calcineurin inhibitor at three months if decoy cells persist. If using this approach, the target serum tacrolimus trough level is 4 to 6, and the target serum cyclosporine trough level is 60 to 100 ng/mL.
Antiviral therapies :
– Currently, there are no available specific antiviral medications against BKV, but for patients who have progressive allograft dysfunction, despite a maximal decrease in immunosuppressive therapy for a period of several weeks to months, we may try agents that may have antiviral activity like leflunomide, cidofovir ,ciprofloxacin, rapamycin or intravenous immunoglobulin , although the efficacy of this approach has not been proven .
Regardless of the treatment strategy employed, rapid viral reduction has been associated with stable or improving glomerular filtration rate (GFR).
SV40 large T antigen (Simian Vacuolating Virus 40 TAg) is a hexamer protein that is a dominant-acting oncoprotein derived from the polyomavirus SV40. TAg is capable of inducing malignant transformation of a variety of cell types.
Positive immunohistochemistry tests using antibodies directed specifically against BK or against the cross-reacting SV40 large T antigen. Positive SV40 staining is useful as it is associated with a specificity of almost 100 % and sensitivity of 77.7% for polyomavirus nephropathy, although it does not distinguish between BKV and JCV-associated cases.
Reference :
1.Nephrol Dial Transplant (2015) 30: 209–217 doi: 10.1093/ndt/gfu023
2. uptodate :Prevention and management of BK virus-induced (polyomavirus-induced) nephropathy in kidney transplantation.
3. Saleh A, El Din Khedr MS, Ezzat A, Takou A, Halawa A. Update on the Management of BK Virus Infection. Exp Clin Transplant. 2020 Nov;18(6):659-670. doi: 10.6002/ect.2019.0254. Epub 2020 Jun 16. PMID: 32552624.
4. BMC Nephrology volume22, Article number: 226 (2021)
One may have to discontinue MMF for some time. I would not wait for watching the effect of MMF reduction
yes thank you prof Ajay Sharma i already mention this .
Discontinuation of the anti-metabolite such as MMF is the most common approach, but a recent study suggests that both tacrolimus and cyclosporine can inhibit anti-BK T Cell responses in vitro, challenging this practice.
1- BKV nephropathy is the most likely diagnosis
Differential diagnosis
Acute cell mediated rejection
Viral infection as CMV infection,HSV ,adenovirus ,EBV infection
2- Management
Investigations
Urine cytology for decoy cells,
It is recommended to do screening for decoy cells in all renal transplant recipients every 3 months during the first 2 years after transplantation and annually for the following 3 years, as well as in allograft dysfunction
urine PCR for BK viruria
serum PCR for BK viraemia
BK viraemia in titres of >10 000 copies/ml is in itself a marker of BKV nephropathy.
Renal biopsy is suggestive of BKV allograft nephropathy as the pathognomonic intranulclear inclusion bodies are seen in tubular epithelium and second image shows positive SV40 staining
BKV–induced allograft nephropathy is more common in patients who are treated with tacrolimus and MMF
The main treatment modality is reduction of immunosuppression but risk for rejection need to be considered.
Lower the dose of tacrolimus by 25–50%
Lower the dose of mycophenolate mofetil by 50%.
Lower the dose of glucocorticoids.
If there is no improvement in the levels of BKV DNA in serum/plasma, the doses of tacrolimus or mycophenolate mofetil can be reduced even more, with the possible of complete discontinuation of mycophenolate mofetil and glucocorticoid treatment.
Changing mycophenolate mofetil to an mTOR-inhibitor can also be considered.
Viral levels can be checked within 2–4-weeks.
follow-up of renal function and drug levels.
A new renal biopsy should be considered if the serum creatinine worsened during the adjustment of the patient’s immunosuppression
There is no strong evidence for antiviral treatment of BKV. Several agents have been tried, although not in the context of controlled studies.
Cidofovir, at reduced doses (10–20% of the recommended dose) has been reported as being effective in clearing the virus from the blood and renal parenchyma in BKV nephropathy with resulting improvement in the renal function
Brincidofovir is a prodrug of cidofovir. It results in higher concentrations of cidofovir, but less renal toxicity
Leflunomide, an immunosuppressant commonly used in rheumatoid arthritis has been tried in BKV nephropathy with persistence of cytopathic effects in repeat biopsy
Intravenous immunoglobulin (IVIG) administration had shown conflicting results
Evidence for the use of antiviral and antibiotic agents is limited and requires further study and studies examining a diagnostic schema for early detection of this condition are needed.
3-The SV40 IHC stain detects the large T antigen expressed by all polyoma viruses pathogenic in humans (SV, JC, and BK). This stain can highlight cells in the early stages of infection, before viral cytopathic changes may be detectable . This stain may also help differentiate PVN from other viral nephropathies seen in immunocompromised patients, such as adenovirus infection.
Positive SV40 staining is specific of almost 100 % for polyomavirus nephropathy (PVN) and nearly77.7% sensitive
Reference
-M. Bairy, A. Sett, S. Bhandari, E. Long, Obstruction or renal allograft rejection—potential clinical markers of BK virus nephropathy, QJM: An International Journal of Medicine, Volume 101, Issue 7, July 2008, Pages 594–598
-Bardaka S etal. BK virus nephropathy in a renal transplant patient: Potential role of electron microscopy in diagnosis. nefrologia 2016Vol. 36. Issue.5.pages 465-582
-Tina Dalianis, Britt-Marie Eriksson, Marie Felldin, Vanda Friman, Anna-Lena Hammarin, Maria Herthelius, Per Ljungman, Johan Mölne, Lars Wennberg & Lisa Swartling (2019) Management of BK-virus infection – Swedish recommendations, Infectious Diseases, 51:7, 479-484,
-Kant S, Dasgupta A, Bagnasco S, Brennan DC. BK Virus Nephropathy in Kidney Transplantation: A State-of-the-Art Review. Viruses. 2022;14(8):1616. Published 2022 Jul 25.
-Nili, F., Mohammadhoseini, M., Khatami, S.M. et al. Routine immunohistochemistry study for polyomavirus BK nephropathy in transplanted kidney biopsies, is it recommended?. BMC Nephrol 22, 226 (2021).
Even though you have numbered your contents, it is not easy to read. I wish you could type headings and sub-headings as underline or in bold.
What is your differential diagnosis?
– The biopsy showed (1st slide) intranuclear inclusions and (2nd slide) positiveSV40 staining and interstitial inflammation→BKV nephropathy
-Acute rejection
-CMV infection (Tissue-invasive CMV disease)
How do you manage this case?
-management of BK virus replication and BKN involves reduction of immunosuppression with close monitoring for rejection.
-Recommended protocols include either 50% reduction or cessation of mycophenolate mofetil, followed by dose reduction of CNI if this change is not effective.
– Although a variety of medical therapies including fluoroquinolones, leflunomide, and cidofovir have been proposed for prevention or treatment of BK viremia and BKN, none has demonstrated clear benefit.
– There is limited data to suggest the possible benefit of IVIG in treatment of BKN.
Elaborate on SV40 staining the specificity, the sensitivity and where it comes from.
-A definitive diagnosis of BKVN requires characteristic cytopathic changes on the renal biopsy plus positive immunohistochemistry (against BKV or against SV40 large T antigens), which has a specificity of
100%, and pathognomonic results for BKV infection.
-The HPyV genome encodes early small-t/large-T antigens as well as
late structural proteins called VP1, VP2, VP3, and agnoprotein.
References:
– Ahmed Saleh, et al. Update on the Management of BK Virus Infection. Experimental and Clinical Transplantation (2020) 6: 659-670
– Jorge Levican ,et al. Role of BK human polyomavirus in cancer. Infectious Agents and Cancer (2018) 13:12
– Danovitch G.M .Handbook of kidney transplantation. sixth edition. Wolters Kluwer .Press:2017.
One may have to discontinue MMF for some time. I would not wait for watching the effect of MMF reduction
differential diagnosis
the corner stone of management of BKVN is reduction of immunosupression
-stop MMF
consider reduction of tacrolimus if no response to MMF withdrawal
no strong evidence for other adjuvant ttt(antiviral , IVIG. cidofovir, leflunamide
SV40.
has a specificity of 100%, however in 30 % of cases diagnosis could be missed (pathchy lesion in medulla )
I agree that one may have to discontinue MMF for some time.
2. A 37-year-old man was admitted after one episode of haematuria. He had a successful third renal transplant 15 months ago, 212 mismatch, no DSA and negative FAXM. His creatinine has risen from 151 µmol/L to 223 µmol/L. USS showed mild dilatation of the pelvicalyceal system, not different from the previous scan. He is currently on Tacrolimus (trough 8 ng/ml), MMF 750 bd and prednisolone 5 mg od. There is BK viraemia (plasma PCR 4 log 10). The biopsy and SV40 staining were done.
What is your differential diagnosis?
-BKVAN (BK virus associated nephropathy) ± Ureteral stenosis
-Acute cellular rejection
-Pyelonephritis
-Other viral infections – CMV
-Recurrence of primary kidney disease
How do you manage this case?
Current issues: –
– comprehensive history – induction therapy, anti-rejection therapy (i.e., ATG exposure), ABO incompatibility, ureteral stent placement, delayed graft function
– detailed physical examination
– baseline investigations i.e., complete blood count, ESR, CRP, LFTs, blood sugar, urinalysis (pyuria, hematuria, cellular casts)
– there are no specific antiviral drugs targeting BKVAN hence immunosuppression reduction is the standard of care – the aim is to restore the immunity and immune control of BKV replication without triggering rejection (1, 2)
– however, the effectiveness of this strategy (immunosuppression reduction) has not been evaluated in RCTs
– an individualized approach to immunosuppression modification is advised putting into consideration the patient’s high immunologic risk, need for close monitoring of GFR, BK viral load, DSAs
Management: –
– in view of the biopsy findings which are suggestive of BKVAN we should consider de-escalating his immunosuppression i.e., reduce MMF by 50% initially, maintain prednisone at 5mg OD and monitor the viral load
– if the BKV viral load does not decrease in 2-4 weeks discontinue MMF altogether
– if the BKV viral load still does not decrease in another 2-4 weeks then decrease the CNI dose by 25-50% (target tacrolimus trough level 4-6ng/mL)
– continue monitoring BKV viral load every 1-2 weeks until BKV DNA is undetectable on two occasions done at least 1 week apart (3)
– this patient has a high immunologic risk hence the possibility of a rejection cannot be ignored
– monitor BKV viral load trends every 2 weeks, as well as the serum creatinine (sCr) trends – if there is a more than 25% rise in sCr then evaluate the patient for possible rejection and manage appropriately
– it is prudent to distinguish BKVAN from rejection since management of one will worsen the other; also correlate the histologic findings with the PCR viral loads
– we should bear in mind that rejection and BKVAN can actually co-exist though this remains controversial
– unfortunately, the histologic features of these two states (BKVAN and rejection) are similar (4)
– acute rejection is suspected when there is extensive tubilitis in areas away from the viral cytopathic changes
– evidence of concurrent rejection includes: – glomerulitis, endarteritis, fibrinoid vascular necrosis, C4d deposits along the peritubular capillaries (5)
– immunosuppression reduction is the cornerstone of management in BKVAN but it increases the risk for development of DSA and acute rejection episodes
– this highlights the need for targeted anti-BKV therapy
Concurrent BKVAN and acute rejection: – (2, 6)
– coexistence of BKVAN and rejection remains controversial
– there is no data to guide treatment approach in patients with both BKVAN and acute rejection
– some centers suggest treatment of the rejection first with pulse corticosteroids then subsequently tapering down the immunosuppression once the patient’s serum creatinine has reduced
– other centers opt not to augment immunosuppression but instead reduce the maintenance immunosuppression and monitor the BKV viral load and serum creatinine
Acute rejection following reduction in immunosuppression: – (7)
– suspect acute rejection in patients whose serum creatinine increases following immunosuppression reduction
– a kidney biopsy might not add diagnostic value given that sometimes it is difficult to distinguish between rejection and BKVAN
– there is no defined approach to management but consider avoiding immunosuppression augmentation i.e., maintain immunosuppression at the level at which the patient developed rejection
Adjunctive therapies: – (3)
– there are other emerging treatment options described in literature although not backed up with sufficient evidence (lack RCTs hence cannot be recommended) include: –
– in summary, from the list above, there is no specific immunomodulatory or antiviral therapy that is effective for routine use against BKV
Prognosis
– BKVAN is associated with graft dysfunction, graft loss, reduced graft survival, development of Class II de novo DSAs (15)
– kidney re-transplantation remains a viable option – confirm absence of BKV replication prior to re-transplantation (15)
– Management of BKVAN has great cost implications due to the close monitoring done i.e., BKV viral load, graft biopsies, SAB assays to assess for DSAs
– BKVAN remains a challenging cause of graft dysfunction. Screening and early detection of viral replication and BKVAN is key so as to institute the appropriate preventive measures before graft damage ensues. (16)
– there is a link between BKV and development of genitourinary cancers in animal models but this is yet to be established in humans
Elaborate on SV40 staining the specificity, the sensitivity and where it comes from (2, 17)
– the sensitivity, specificity, positive predictive value and negative predictive value of IHC (immunohistochemistry) in the diagnosis of BKVAN is 77.7%, 100%, 100% and 98.4% respectively
– the cross-reacting monoclonal antibodies against SV40 are used for IHC staining of the intranuclear viral inclusion bodies in the kidney tubules
– positive SV40 staining cannot distinguish between BKV- and JC virus-associated nephropathy
References
1. KDIGO clinical practice guideline for the care of kidney transplant recipients. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2009 Nov;9 Suppl 3:S1-155. PubMed PMID: 19845597. Epub 2009/10/23. eng.
2. Hirsch HH, Randhawa PS. BK polyomavirus in solid organ transplantation-Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clinical transplantation. 2019 Sep;33(9):e13528. PubMed PMID: 30859620. Epub 2019/03/13. eng.
3. Johnston O, Jaswal D, Gill JS, Doucette S, Fergusson DA, Knoll GA. Treatment of polyomavirus infection in kidney transplant recipients: a systematic review. Transplantation. 2010 May 15;89(9):1057-70. PubMed PMID: 20090569. Epub 2010/01/22. eng.
4. Randhawa PS, Finkelstein S, Scantlebury V, Shapiro R, Vivas C, Jordan M, et al. Human polyoma virus-associated interstitial nephritis in the allograft kidney. Transplantation. 1999 Jan 15;67(1):103-9. PubMed PMID: 9921805. Epub 1999/01/28. eng.
5. Hirsch HH, Brennan DC, Drachenberg CB, Ginevri F, Gordon J, Limaye AP, et al. Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation. 2005 May 27;79(10):1277-86. PubMed PMID: 15912088. Epub 2005/05/25. eng.
6. Kayler LK, Batal I, Mohanka R, Morgan C, Basu A, Shapiro R, et al. Antirejection treatment in kidney transplant patients with BK viruria. Transplantation. 2008 Sep 27;86(6):797-803. PubMed PMID: 18813104. Pubmed Central PMCID: PMC2730026. Epub 2008/09/25. eng.
7. Hardinger KL, Koch MJ, Bohl DJ, Storch GA, Brennan DC. BK-virus and the impact of pre-emptive immunosuppression reduction: 5-year results. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2010 Feb;10(2):407-15. PubMed PMID: 20055811. Pubmed Central PMCID: PMC3188431. Epub 2010/01/09. eng.
8. Hirsch HH, Yakhontova K, Lu M, Manzetti J. BK Polyomavirus Replication in Renal Tubular Epithelial Cells Is Inhibited by Sirolimus, but Activated by Tacrolimus Through a Pathway Involving FKBP-12. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2016 Mar;16(3):821-32. PubMed PMID: 26639422. Pubmed Central PMCID: PMC5064607. Epub 2015/12/08. eng.
9. Jacobi J, Prignitz A, Büttner M, Korn K, Weidemann A, Hilgers KF, et al. BK viremia and polyomavirus nephropathy in 352 kidney transplants; risk factors and potential role of mTOR inhibition. BMC Nephrol. 2013 Oct 2;14:207. PubMed PMID: 24088187. Pubmed Central PMCID: PMC3850699. Epub 2013/10/04. eng.
10. Kuypers DR, Vandooren AK, Lerut E, Evenepoel P, Claes K, Snoeck R, et al. Adjuvant low-dose cidofovir therapy for BK polyomavirus interstitial nephritis in renal transplant recipients. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2005 Aug;5(8):1997-2004. PubMed PMID: 15996251. Epub 2005/07/06. eng.
11. Krisl JC, Taber DJ, Pilch N, Chavin K, Bratton C, Thomas B, et al. Leflunomide efficacy and pharmacodynamics for the treatment of BK viral infection. Clinical journal of the American Society of Nephrology : CJASN. 2012 Jun;7(6):1003-9. PubMed PMID: 22461534. Epub 2012/03/31. eng.
12. Lee BT, Gabardi S, Grafals M, Hofmann RM, Akalin E, Aljanabi A, et al. Efficacy of levofloxacin in the treatment of BK viremia: a multicenter, double-blinded, randomized, placebo-controlled trial. Clinical journal of the American Society of Nephrology : CJASN. 2014 Mar;9(3):583-9. PubMed PMID: 24482066. Pubmed Central PMCID: PMC3944757. Epub 2014/02/01. eng.
13. Kable K, Davies CD, O’Connell P J, Chapman JR, Nankivell BJ. Clearance of BK Virus Nephropathy by Combination Antiviral Therapy With Intravenous Immunoglobulin. Transplantation direct. 2017 Apr;3(4):e142. PubMed PMID: 28405598. Pubmed Central PMCID: PMC5381735. Epub 2017/04/14. eng.
14. Davies SI, Muranski P. T cell therapies for human polyomavirus diseases. Cytotherapy. 2017 Nov;19(11):1302-16. PubMed PMID: 28927823. Epub 2017/09/21. eng.
15. Schold JD, Rehman S, Kayle LK, Magliocca J, Srinivas TR, Meier-Kriesche HU. Treatment for BK virus: incidence, risk factors and outcomes for kidney transplant recipients in the United States. Transplant international : official journal of the European Society for Organ Transplantation. 2009 Jun;22(6):626-34. PubMed PMID: 19207187. Epub 2009/02/12. eng.
16. Cohen-Bucay A, Ramirez-Andrade SE, Gordon CE, Francis JM, Chitalia VC. Advances in BK Virus Complications in Organ Transplantation and Beyond. Kidney medicine. 2020 Nov-Dec;2(6):771-86. PubMed PMID: 33319201. Pubmed Central PMCID: PMC7729234. Epub 2020/12/16. eng.
17. Nili F, Mohammadhoseini M, Khatami SM, Seirafi G, Haghzare M. Routine immunohistochemistry study for polyomavirus BK nephropathy in transplanted kidney biopsies, is it recommended? BMC Nephrology. 2021 2021/06/18;22(1):226.
I like your comprehensive reply
Thank you Prof.
Latent reactivation of BKV with likely BKV nephropathy, the main risk factor, in this case, is the intense Immunosuppression with tacrolimus and antimetabolites MMF so the diagnosis is BKV nephropathy(BKVN) as the kidney biopsy shows SV40 IHC staining highlighting infected tubular epithelial cells with the focal dense area of interstitial inflammation by immunostaining with no evidence of tubultitis or tubular atrophy or interstitial fibrosis, while the other slide with trichrome stain shows very clear enlarged, hyperchromatic nuclei and “ground glass” intranuclear inclusions suspicious of viral inclusion bodies, either CMV or BKV nephropathy in the context of 3rd kidney transplant with intense immunosuppression tacrolimus trough level 8 ( upper limit ) and MMF 750mg BID, and maybe induction with T cells depleting agents like ATG and alemtuzumab so t likely diagnosis of this indexed case is BKVN, we need to ask about previous BKV viremia or viruria in previous transplantation after this 3rd transplantation which is likely latent reactivated with intense immunosuppression with dysfunctional cellular immune response.
BKV viral load was > 4 log as per evidence BK viral loads >4 log10 c/mL are associated with higher rates of biopsy-proven BKVAN and loads peaking above 6 log10 c/mL are predictive of extensive BKVN pathology measured by SV40 immunohistochemistry and associated inflammatory infiltrates (2,3).
So, this is BKVAN
How do you manage this case?
We need to send in addition to BKV PCR, CMV PCR, the DSA level C4D Staining, urine protein/ creatinine ratio, and the US looking for any hydronephrosis, obstruction
If confirmed BKVN only with this progressive graft dysfunction the treatment will be a combination of a 50% reduction of MMF or stop MMF plus IVIG, reduction of CNI dose with target tacrolimus trough level with lower trough level target 4-6 ng, and close monitoring, BKV PCR every two weeks, u&E, tacrolimus trough level, urine p/c ratio, and DSA level as the patient at risk of rejection with reduction of IS, alternative protocol again if no evidence e of rejection and no proteinuria can consider modification of Maintenance IS to everolimus plus minimization of CNI dose and discontinue MMF with close monitoring by BKV PCR every two weeks and graft function test. limited evidence supporting the use of ciprofloxacin, cidofovir, and leflunomide for BKV infection .
Our local protocol for BKV nephropathy with such histological findings and graft dysfunction will go for a 50% reduction of MMF or stop it, if no response will use further tacrolimus dose reduction by 25-50% and IVIG 0.5mg /kg every 3 weeks till clearance of the viral infection, IVIG contains BK neutralizing antibodies in addition to its immunomodulating effect with a reduction in BKV viral load (evidence limited to observational trails (1). We need close monitoring for rejection if no proteinuria will add everolimus plus CNI minimization with target trough level 4-6 ng provided there is no rejection.
Upcoming Therapeutic Trials
Agreed on the absence of therapies existing for the treatment of BK infection, the two following trials involving modified T cells and monoclonal antibodies are currently underway:
A randomized, double-blind, placebo-controlled study to assess the safety, pharmacokinetics, and efficacy of MAU868—a human monoclonal antibody (IgG1) that binds the viral capsid protein, VP1, which is responsible for binding to the surface of host cells (ClinicalTrials.gov identifier: NCT04294472).
A phase 2 multicenter, randomized, double-blind, study of the safety, tolerability, and effectiveness of adoptively transferred posoleuccel (ALVR105) multi-virus-specific T Cells in kidney transplant recipients with either high or low levels of BK viremia (ClinicalTrials.gov identifier: NCT04605484)(1).
Elaborate on SV40 staining the specificity, the sensitivity, and where it comes from.
The SV40 IHC stain detects the large T antigen expressed by all polyomaviruses pathogenic in humans (SV, JC, and BK). This stain can highlight cells in the early stages of infection, before viral cytopathic changes may be detectable on routine stains.
This stain may also help differentiate PVN from other viral nephropathies like adenovirus infection. Quantitative PCR for PV can also be performed on tissue samples
EM needed as PV can be identified on electron microscopy by the presence of 40 nm paracrystalline viral particles within the nuclei of tubular cells.
References:
1.Kant S, Dasgupta A, Bagnasco S, Brennan DC. BK Virus Nephropathy in Kidney Transplantation: A State-of-the-Art Review. Viruses. 2022 Jul 25;14(8):1616. doi: 10.3390/v14081616. PMID: 35893681; PMCID: PMC9330039.
2. Höcker B., Schneble L., Murer L., Carraro A., Pape L., Kranz B., Oh J., Zirngibl M., Strologo L.D., Büscher A., et al. Epidemiology of and Risk Factors for BK Polyomavirus Replication and Nephropathy in Pediatric Renal Transplant Recipients: An International CERTAIN Registry Study. Transplantation. 2019;103:1224–1233.
3.Babel N., Fendt J., Karaivanov S., Bold G., Arnold S., Sefrin A., Lieske E., Hoffzimmer M., Dziubianau M., Bethke N., et al. Sustained BK Viruria as an Early Marker for the Development of BKV-Associated Nephropathy: Analysis of 4128 Urine and Serum Samples. Transplantation. 2009;88:89–95.
4. Pollara C.P., Corbellini S., Chiappini S., Sandrini S., De Tomasi D., Bonfanti C., Manca N. Quantitative viral load measurement for BKV infection in renal transplant recipients as a predictive tool for BKVAN. New Microbiol. 2011;34:165–171.
I like your comprehensive reply
OUR CASE;
37 YR OLD KTR.
X1 episode of hematuria.
x3 renal transplants, last done 15/12 ago.
212 mismatch ,no DSA, neg FAXM
Cr increase from 151 to 223
US – mild dilatation of pelvicalyceal system.
Meds- tac- 8ng/ml, MMF 750 mg BD,PDL 5mg OD
BK plasma PCR 4 log 10.
Biopsy- SV 40 staining.
DX.
DDX.
MANAGEMENT.
This will be varied i.e
1.With No concurrent ACR.
-RIS;
2.Other therapies;
2.Concurrent BK Nephropathy + ACR.
-This is a difficult one to treat. In our center we treat ACR first with high dose steroids then RIS as next step once the pt has responded to ACR tx evidenced by a decline in creatinine levels.
3.ACR after RIS.
-An allograft biopsy will be needed to establish rejection after RIS. We maintain the same immunosuppressive medication dose as when the pt manifested features of rejection and monitor.
SV 40 ORIGIN,SENSITIVITY AND SPECIFICITY.
SV 40-Simian virus 40- Infected cells stain with antibodies to large T antigens of SV 40 virus that acts as a surrogate marker of human polyomavirus dx. It has a specificity of 100% with no clear distinction between BK & JC virus. It has a low sensitivity of ~70%
REFERENCES.
What is your differential diagnosis?
How do you manage this case?
1- Decreasing the dose of Tacrolimus or conversion to Cyclosporin or Sirolimus.
2- Holding MMF for 2 weeks.
3- Renogram by DTPA for evaluation of the pelvicalyceal system dilatation.
Elaborate on SV40 staining the specificity, the sensitivity and where it comes from?
The index patient is a 37-year-old, 3rd renal transplant recipient (15 months ago), presenting with hematuria and graft dysfunction. He is a high immunological risk patient (3rd transplant, 212 mismatch). His current immunosuppression is tacrolimus, MMF and steroids. His plasma BK virus PCR is high (4 log 10), and kidney biopsy shows features of interstitial inflammation and a positive Simian virus 40 (SV40) stain on immunohistochemistry of tubular cross-section, suggesting intranuclear viral inclusion bodies (1). Ultrasound graft kidney does not show any new features of urinary tract obstruction.
In view of and laboratory parameters, the most likely diagnosis is BK virus associated nephropathy. Other differential diagnosis, which need to be kept in such a scenario include acute rejection, calcineurin inhibitor toxicity, urinary tract infection, and recurrence of the basic disease (2).
The patient requires additional laboratory testing in form of complete blood count, donor specific antibodies (DSA), detailed kidney biopsy including c4d staining, urine examination (routine microscopic examination, and urine protein creatinine ratio), as well as urine culture.
In case, a concurrent acute rejection is detected, first the acute rejection needs to be treated, and management for BK virus associated nephropathy should be done after 2 weeks once there is clinical and laboratory response to anti-rejection treatment (1,3).
If there is no rejection, the treatment of BK virus associated nephropathy includes reduction in immunosuppression and continuous monitoring of BKV plasma PCR, as well the graft function (2,4).
This patient is a high immunological risk (3rd transplant, 212 mismatch). The stepwise approach includes:
1) The dose of anti-metabolite (MMF) should be reduced by 50%. Monitor plasma BKV PCR every 2 weeks. If no reduction, then step 2.
2) The dose of calcineurin inhibitor (Tacrolimus) should be reduced to attain target trough level 4-66 ng/ml. Monitor plasma BKV PCR every 2 weeks. If no reduction, then step 3.
3) Stop anti-metabolite (MMF). Monitor plasma BKV PCR every 2 weeks. If no reduction, then step 4.
4) Shift from Tacrolimus to Cyclosporine (trough level 50-75 microg/l) or Sirolimus (1). A trend towards decreased incidence of BK virus associated nephropathy is seen in patients on mTOR inhibitors (5).
5) Use of adjunctive therapies (IVIG, Cidofovir, Leflunomide, Fluoroquinolones) can be considered in case of sustained BK viremia despite immunosuppression reduction (1). But the evidence regarding role of antivirals is weak (4).
Return to routine maintenance immunosuppression should be considered (to prevent rejection) once BK viremia has been cleared with careful and close monitoring of BK virus PCR levels. If acute rejection takes place while reducing immunosuppression, it should be treated as per standard protocols (1).
Cross-reacting monoclonal antibodies against simian virus 40 (SV40) large T antigen are used for immunohistochemical staining of the intranuclear viral inclusion bodies in renal tubules (1). The sensitivity, specificity, positive predictive value and negative predictive value of immunohistochemistry in diagnosis of BK virus associated nephropathy is 77.7%, 100%, 100%, and 98.4% (6).
References:
1) Hirsch HH, Randhawa PS; AST Infectious Diseases Community of Practice. BK polyomavirus in solid organ transplantation-Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13528. doi: 10.1111/ctr.13528. Epub 2019 Apr 10. PMID: 30859620.
2) Sawinski D, Trofe-Clark J. BK Virus Nephropathy. Clin J Am Soc Nephrol. 2018 Dec 7;13(12):1893-1896. doi: 10.2215/CJN.04080318. Epub 2018 Sep 21. PMID: 30242026; PMCID: PMC6302319.
3) Shanmugham S, Bhadauria D, Agrawal V, Jain M, Yaccha M, Kaul A, Vamsidhar V, Meyyappan J, Prasad N. The diagnostic and therapeutic dilemma of the co-existence of BK virus nephropathy with acute rejection – an experience from a single Centre and review of the literature. Transpl Immunol. 2022 Jun;72:101581. doi: 10.1016/j.trim.2022.101581. Epub 2022 Mar 14. PMID: 35301106.
4) Saleh A, El Din Khedr MS, Ezzat A, Takou A, Halawa A. Update on the Management of BK Virus Infection. Exp Clin Transplant. 2020 Nov;18(6):659-670. doi: 10.6002/ect.2019.0254. Epub 2020 Jun 16. PMID: 32552624.
5) Mallat SG, Tanios BY, Itani HS, Lotfi T, McMullan C, Gabardi S, Akl EA, Azzi JR. CMV and BKPyV Infections in Renal Transplant Recipients Receiving an mTOR Inhibitor-Based Regimen Versus a CNI-Based Regimen: A Systematic Review and Meta-Analysis of Randomized, Controlled Trials. Clin J Am Soc Nephrol. 2017 Aug 7;12(8):1321-1336. doi: 10.2215/CJN.13221216. Epub 2017 Jun 2. PMID: 28576905; PMCID: PMC5544521.
6) Nili F, Mohammadhoseini M, Khatami SM, Seirafi G, Haghzare M. Routine immunohistochemistry study for polyomavirus BK nephropathy in transplanted kidney biopsies, is it recommended? BMC Nephrol. 2021 Jun 18;22(1):226. doi: 10.1186/s12882-021-02444-5. PMID: 34139999; PMCID: PMC8212535.
Yes, reduction of immunosuppression is the key. One may have to discontinue MMF for some time
What is your differential diagnosis?
-BKVN
-CMV Nephropathy
-Adenovirus Nephropathy
-ACR
-Ureteric obstruction
How do manage this case ?
After confirming the diagnosis of BKVN the management plan will be :
RI
25% reduction of Tacrolimus
50% reduction of MMF
Maintain low dose steroid
mTORi can be replaced MMF .
Leflunomide , IVIG , floruoquinolone are tried.
Cellular immunotherapy is promising .
Elaborate on SV40 staining the specificity, the sensitivity and where it comes from.
Polyomavirus (PV) nephropathy has been attributed to reactivation of BK virus (BKV) or more rarely JC virus (JCV). The simian virus (SV) 40 is PV that was likely introduced into the human population through contaminated vaccines.
Simian virus 40 is a little DNA virus with 5.2 kb of double-stranded DNA used for its genetic code. The only viral protein necessary for SV40 replication is SV40 big T antigen (T-ag), an 85 kD multifunctional phosphoprotein. The host cell that has been infected supplies all other components. T-ag transforms vulnerable cell lines in addition to aiding in the replication of the SV40 DNA. The replication and transformation fractions of T-ag can be separated, according to studies on several mutant T-ag proteins. This protein’s multifunctionality has led to its usage as a model system across many different academic fields. SV40 T-ag uses feedback inhibition to negatively regulate the transcription of SV40 early mRNA and positively regulates transcription from the late promoter. T-ag is involved in viral DNA replication in addition to transcriptional control. High-affinity binding to locations inside the viral origin of DNA synthesis, as well as ATPase and helicase activity, are specific biochemical processes necessary for DNA synthesis that are unique to the T-ag. T-ag is also credited with cellular transformation, inducing the creation of cellular DNA and rRNA, as well as providing a host-range role for viral replication. However, a variety of post-translational changes, such as phosphorylation, glycosylation, acetylation, acylation, and adenylation, have an impact on all of T-functions. ag’s T-ag is a tumor suppressor protein that can be found in monomeric and polymeric forms, and it associates with p53 and Rb (retinoblastoma protein). A minor portion of T-ag is localized at the cell surface, but the majority of it is carried to the nucleus.
The SV40 IHC have 100% specificity but low sensitivity in detecting polyomavirus nephropathy.but it can not differentiate between BKVN and JCV .
Reference:
-Ahmed Saleh,1,4,5 Mohamed Salah El Din Khedr,1 Abeer Ezzat,2 Anna Takou,3 Ahmed Halawa4. Update on the Management of BK Virus Infection.
-SV40 Antibody Staining Protocol for Immunohistochemistry
IHCWORLD
Lifescience Produdes & Survives
One may have to discontinue MMF for some time. I would not wait to see the effect of reducing antimetabolites
The most likely diagnosis is BK nephropathy suggestive by:
Viral cytopathic changes in tubular epithelial cells
SV40 immunostain nuclear positivity
The presence of BK viremia
High Tac level
3rd transplant, HLA mismatch
DD of allograft tubulointerstitial nephritis:
Concurrent acute T cell mediated rejection
Pyelonephritis
CMV and other viral infection
Drug induced interstitial nephritis
Recurrence of primary disease
Rarely fungal or mycobacterial infection
Management
Distinguishing BK nephropathy from acute/ Concurrent rejection is important. History to assess compliance with immunosuppression and absorption.
Urine cytology for decloy cells.
DSA
MSU
CMV PCR
Stablishing a diagnosis of concomitant T cell-mediated rejection in a biopsy that has BKPyVAN is difficult as histologic features are similar. In general, the presence of extensive tubulitis in areas remote from the viral cytopathic changes suggests that acute rejection is present, in addition to BKPyVAN. The combined presence of endarteritis, fibrinoid vascular necrosis, glomerulitis, and C4d deposits along peritubular capillaries is conclusive evidence of concurrent rejection, although some patients with BKPyVAN without concurrent rejection may have C4d deposits in the tubular basement membrane
Among some patients, it may only be possible to distinguish BK nephropathy from rejection by empirically altering IS and observing the clinical response.
In patients who do not have concurrent acute rejection
Reduction of immunosuppression: is the cornerstone; The optimal approach has not been defined; protocols vary among transplant centers.
We initially reduce the antimetabolite by 50%. If the BK viral load does not decrease within two to four weeks, we discontinue the antimetabolite. If still no decrease in viral load after another two weeks, we decrease the CNI by 25 to 50 %, targeting tacrolimus trough level of 4 to 6 ng/mL
An alternative approach is to first decrease CNI by 25 to 50% in one or two steps, followed by reducing the antimetabolite by 50%, followed by discontinuing the antimetabolite.
mTORi: They might be some role for mTORi, esp switching MMF to mTORi.
IVIG: For patients with progressive allograft dysfunction despite maximal decrease in immunosuppression for several weeks, we may try agents that have antiviral and/or immunomodulatory activity, such as IVIG, However, the efficacy of it has not been proven.
Cidofovir: should only be considered for treatment when other interventions have failed.
Concurrent BKPyVAN and acute rejection
There are no data to guide optimal management of concurrent BKPyVAN and acute rejection. Some experts advocate for treating acute rejection first (eg, with pulse glucocorticoids) and then subsequently reducing immunosuppression once the patient had a clinical response (ie, a decrease in serum creatinine level). By contrast, other experts avoid augmented immunosuppression and favor a reduction in immunosuppression alone. If immunosuppression is augmented, more frequent monitoring of BKPyV viremia may be warranted.
Monitor the plasma PCR every one to two weeks until BK is undetectable for two consecutive tests at least one week apart
Monitor the serum creatinine.
Following resolution of viremia or biopsy-proven BKVAN, the decision to increase immunosuppression should take into account the risk of rejection as well as the risk of recurrent BK nephropathy
SV40 staining:
This is a form of immunohistochemistry test that uses antibodies directed specifically against BK polyomavirus or against the cross-reacting SV40 large T antigen.
A positive SV40 test on immunohistochemistry of kidney biopsy is associated with a specificity of 100 percent for polyomavirus nephropathy, however, a distinction still has to be made between BK and JC virus.
Because of the focal nature of early BKVAN, the diagnosis may be missed on one-third of biopsies and this will be reflected in the sensitivity of SV40 to be low. As a result, at least two biopsy cores, preferably including the medulla, since the virus is more likely to be present in the medulla.
Many thanks for a comprehensive reply
What is the differential diagnosis?
The biopsy tissue shows interstitial inflammation with infilterates. Co-relating with the history the likely differential diagnosis is:
How do you manage the case?
The principals of management of the case are as follows:
Tacrolimus dose to be reduced to reach 50% of the target blood levels
MMF dose to be reduced to half
Looking to the severity of infiltrate in biopsy tissue the chances of graft loss are high and patient and family requires counselling regarding the same.
Elaborate on SV40 staining the specificity, the sensitivity and where it comes from.
SV40 staining is a technique based on principals of immunohistochemistry (IHC). In this procedure, SV40 large T antigen (TAg) is stained using comercially available antibody.
Sensitivity – 77.7%
Specificity – 100%
REF:
That is a well-structured reply.
1-BK nephropathy type B
2-ACR
3-ATN
For BK nephropathy, which it the most likely diagnoses in this case. As he is heavily immunosuppressed with 3rd kidney transplant, relatively high tacrolimus level. Also has positive viremia and typical biopsy findings.
The standard of care is reduction of immunosuppression. Which includes:
1-Cutting MMF by 50% or stopping it altogether if no response in 2-3 weeks. However, this patient, had 2 previoustransplantsn, so we need to keep some MMF on board as the risk of rejection is relatively higher.
2-Reducing level of tacrolimus to 3-5 instead of 8
3-Continue prednisone as it is.
If no response we may consider Leflunomide and Cidofovir, sirolimus, IVIG or quinolones. But each of them has some limitations and none of them is shown in good studies to have persistent effect.
Quinolones did not show a good response and in some cases associated with drug resistance.
Leflunomide is associated with liver toxicity.
Cidofovir is associated with nephrotoxicity and crystal nephropathy.
Sirolimus: is not good in patient with moderate graft dysfunction, proteinuria and significant interstitial fibrosis.
IVIG: could be useful if there is association with rejection, but could inter act with an
Antibody screening for few weeks.
The diagnosis of PVAN is highly suggested by the detection of viral inclusion bodies on kidney biopsy but is confirmed with immunohistochemical staining for simian virus 40 (SV40) large T antigen and/or in situ hybridization for BK virus genetic sequences.
BK polyomavirus genome shares about 72% nucleotide homology with JC virus and 70% with SV40.
SV40 specificity is almost 100%, but sensitivity around 67%
.
Co-localization of SV40 and p53 was identified in cells that had characteristic nuclear features of BK virus infection by histology. The sensitivity and specificity for using p53 . staining to identify BK infected cells was 92% and 86 %, respectively. SV40 alone is not ideal.
References:
1-BK Polyomavirus and the Transplanted Kidney: Immunopathology and Therapeutic Approaches Transplantation November 2016 Volume 100 Number 11
2-Adjuvant role of p53 immunostaining in detecting BK viral infection in renal allograft biopsies Ann Clin Lab Sci 2010 Fall;40(4):324-9.
That is a well-structured reply.
What is your differential diagnosis?
Given the clinical scenario, and the histopathology presented are highly suggestive of BK virus infection in the form of nephropathy presented with dilatation of pevicalyceal system.
Differential diagnosis:
Viral infections: CMV, Herpes simplex virus and Adenovirus.
Acute cellular rejection.
Pyelonephritis.
Acute interstitial nephritis- drug induced!
How do you manage this case?
Do full clinical examination, and detailed medical history.
Laboratory testing: CBC- looking for any leukopenia, anemia and/or thrombocytopenia, Urinalysis- pyuria, hematuria and cellular casts, presence of decoy cells by electron microscopy and urine culture.
Liver function testing, coagulation profile, CRP, ESR, and LDH.
Blood for BKV PCR, as well as urine BKV PCR- as baseline to evaluate treatment later on.
Haufen by electron microscopy 100% specific and 99% sensitive.
The mainstay of treatment is reduction of immunosuppressive medications, antimetabolites (MMF), CNI (Tacrolimus) by 50% of the current dosage used, but keeping him with the current low dose steroid. With frequent follow up of kidney function.
If no improvement then will consider stopping the MMF, while keeping on steroid and low CNI dose, but m-TOR inhibitors could be used as the patient carry a high immunological risk.
Cidofovir, leflunomide, quinolones show anti-viral activity but of low clinical evidence., cidofovir- nephrotoxicity, leflunomide- hepatic injury.
Intravenous immunoglobulins may be used, but with little clinical evidence.
Adoptive immunotherapy is a promising tool for BKV treatment.
Monitoring of treatment by doing blood viral PCR every one to two weeks, if the viral load decreasing, it is fine with management plan, if continues to rise in spite of the above mentioned treatment plan then will consider doing another kidney biopsy for better evaluation and classification of disease.
Elaborate on SV40 staining the specificity, the sensitivity and where it comes from.
Simian virus 40 large T antigen, The T antigen is responsible for cell immortalization and the establishment of latent infection, it is one of the early nonstructural or enzymatic proteins, and can be found by immunohistochemistry, it is 100% specific but may be not identified in 30% of the kidney biopsy as the virus more in medullary region. (disease specific diagnostic tool).
References:
(1) Prof. Ahmad Halawa lecture- module 4 clinical fellowship of transplantation, BK in kidney transplantation.
(2) Saleh A, El Din Khedr MS, Ezzat A, Takou A, Halawa A. Update on the Management of BK Virus Infection. Exp Clin Transplant. 2020 Nov;18(6):659-670. doi: 10.6002/ect.2019.0254. Epub 2020 Jun 16. PMID: 32552624.
(3) UpToDate- Kidney transplantation in adults: BK polyomavirus associated nephropathy.
That is a well-structured reply.
What is your differential diagnosis?
Diagnosis is BKVN: a definitive diagnosis of BKVN
1. Cytopathic changes on the renal biopsy (possible pattern B)
2. And positive immunohistochemistry against SV40 large T antigens
Other differential diagnoses:
1. Concurrent acute rejection
2. Other viral infections (CMV, herpes simplex virus, adenovirus)
3. Drug-inuced interstitial nephritis
How do you manage this case?
· High risk of BKV infection
· Before commencing treatment, obtain a baseline blood BK virus quantitative PCR for assessment of response to treatment
· The aim is to suppress viral replication without triggering acute rejection:
1. Discontinue the anti-metabolite (mycophenolate or azathioprine)
2. Reduce calcineurin inhibitor (Target trough levels: Tacrolimus 4 to 6ng/ml, cyclosporin 50 to 100ng/ml)
3. Maintain low-dose prednisolone (<10mg/day)
· Renal function should be monitored weekly initially and blood BK virus PCR for viral load should be performed monthly
· Specific agents such as intravenous immunoglobulin, quinolones, cidofovir (nephrotoxicity) and leflunomide (thrombotic microangiopathy, hepatitis, and bone marrow suppression) have been shown to have anti-viral activity but there is no definitive evidence to show that they offer any advantage over simply reducing the total immunosuppressive burden
Elaborate on SV40 staining the specificity, the sensitivity and where it comes from.
· SV staining is an immunohistochemistry test using antibodies directed specifically against the cross-reacting SV40 large T antigen
· Specificity is around 100% for BK nephropathy
· Not differentiate between BK virus and JC virus
References
1. BKV in Kidney Transplantation By Ahmed Halawa (lecture), consultant Transplant Surgeon Associate Professor, University of Liverpool –UK, 2023.
2. Alalawi F, Alnour H, El Kossi M, Jenkins J, Taku A, Sharma AK, Halawa A. BK virus infection in renal transplant recipients: an overview. J Egypt Soc Nephrol Transplant 2020;20:127-50
3. Kant S, Dasgupta A, Bagnasco S, Brennan DC. BK Virus Nephropathy in Kidney Transplantation: A State-of-the-Art Review. Viruses. 2022 Jul 25;14(8):1616. doi: 10.3390/v14081616. PMID: 35893681; PMCID: PMC9330039.
4. BK Polyomavirus Interstitial Nephritis in Renal Transplant UHL Renal Transplant Guideline
That is a well-structured reply.
*The index patient is 15 months post 3rd-KT.
*HLA mismatch.
*Presented with hematuria
*Deterioration in graft function.
*On triple IS with high Tacrolimus level ( for 15 months post Tx)
*USS showed mild pelvicalyceal dilatation ( stable)
*BKV PCR; 4 log 10.
-Viremia is present in nearly all patients with BKAN.
-It has a positive predictive value of approximately 40 to 65 percent for the development of BKAN
-BKAN can quickly follow viremia (eg, within 1-2 weeks) and cause damage to the graft can be irreversible
*Biopsy showed:
-LM showed tubular epithelial cells with enlarged, hyperchromatic nuclei and granular intranuclear inclusions (clumps), and interstitial lymphocytic infiltrate with intrstitial fibrosis.
Area of disrupted flatted tubular epithelia cells with slough cell into the tubular lumen
-IHC showed interstitial lymphocytic infiltrate and infected cell stained against SV-40.
Differential diagnosis:
– BKAN.
– Acute cellular rejection.
– Other viral infection: CMV nephritis, HSV, Adenovirus infection .
The diagnosis of BKAN in this patient based on:
-The presence of cytopathic changes in allograft biopsy.
-Positive IHC stainging for SV-40.
-The presence of BK viremia PCR 4 log 10.
-The risk for BKV replication is increased in his setting:
– Cummulitve exposure to IS is high 3rd KT.
– HLA mismatch.
Patient is a high immunological risk, therefore surveillance is recommended;
-As early detection of viremia and preemptive reduction in immunosuppression prevent progression to BKPyVAN in the majority of patients.
– Screening monthly for the first six months following transplant, then every three months until two years posttransplant, and then annually until five years posttransplant
–At any point if kidney allograft dysfunction occurs.
– plasma PCR; the preferred screening method for screening asviremia has more PPV for BKAN, sensitivity can approach 100% and specificity is ∼90%, with a PPV of 50% and negative predictive value (NPV) of 100%,
-Urine PCR is more sensitive than urine cytology for detection and diagnosis of BKVN.
How do you manage this case?
– There is no specific antiviral therapy against BKV infection
– Reduction of immunosuppression is the mainstay to restor immunity and control viral replication.
– There is no generally accepted regimen for reduction of IS,
– IS reduction comes with the risk of rejection, which can be difficult to distinguish clinically from progressive BKAN, as in the index case, high immunological risk ( 3rd KT, HLA- mismatch).
-Therefore, IS should be tailored for each patient according to the clinical situation
*Step 1
– Reduce MMF dose to 250 mg BD
– Reduction CNI by 25–50% targeting lower level to 6.
– while continuing on the same doses of prednisone.
– Close monitoring of viral load and renal function every 2 weeks.
*Step 2; If no improvement in viral load in 2 week
-Discontinuation of the anti-metabolite
*Step3; if viral loads do not reduce over 4 weeks despite cessation of anti-metabolite
-Reduce calcineurin-inhibitor trough goals 3–5
-Additional strategies have been:
switching from tacrolimus to low-dose cyclosporine
or switching from the CNI to low-dose sirolimus
or switching from MMF to leflunomide or to low-dose sirolimus
Successful outcomes have been reported using each of these different interventions in small case series, but there is to date no randomized controlled trial recommending one over the other strategy.
*In patients with sustained high-level plasma BKV load despite adequately reduced immunosuppression, the adjunctive use of antiviral agents may be considered; quinolones, cidofovir, leflunomide, and IVIG.
Meta-analysis has demonstrated that there is no difference in graft outcomes when the strategy of reduction
in immunosuppression is compared with a combination of immunosuppression with leflunomide or cidofovir
– Cidofovir; No RCT, associated with nephrotoxicity
– Brincidofovir; prodrug, less nephrotoxic, successful outcomes in renal and HSCT.
– Leflunomide; IS and antiviral properties.
– IVIG neutralizing antibodies, used as adjunctive therapy, immunomodulatory
effects may guard against allograft rejection in the context of reducing IS.
– Fluoroquinolone; inhibit replication of BKV or SV40.
– Adoptive cellular immunotherapy; may carry potential hope
The co-existence of BKVN and AR:
Diagnostic and therapeutic dilemma unfolds when these two conditions coexist. Careful assessment of graft biopsy may allow renal pathologists to differentiate AR from BKV nephropathy, as both share some similar histopathological features.
The diagnosis of acute rejection concurrent with PyVAN is only considered secure if one finds endarteritis, fibrinoid vascular necrosis, glomerulitis, or C4d deposits along peritubular capillaries.
In such cases, therapeutically reducing immunosuppression for treating BKVN can aggravate AR, whereas enhancement may cause an increase in BKV replication and tubulointerstitial injury leading to worsening graft function.
The literature on coexistent BKVN and AR management and outcome is scarce, ranging from case reports to a few cases series.
Some physicians support the treatment of the AR first (Puls glucocorticoids) accompanied by lowering of immunosuppression as a second step, following clinical response to anti-rejection treatment (i.e., improvement of GFR). On the other hand, some physicians avoid immunosuppression enhancement and advocate a reduction only
Recent study suggested intensifying immunosuppression to treat AR followed by gradual reduction of maintenance immunosuppression and perhaps IVIG seems an optimal strategy to control viral proliferation and showed good long-term graft survival.
Elaborate on SV40 staining the specificity, the sensitivity and where it comes from
– It is recommended that SV40 IHC stain be performed on all transplant biopsies where PVN is suspected
-The SV40 IHC stain detects the large T antigen expressed by all polyoma viruses pathogenic in humans
(SV, JC, and BK).
-This stain can highlight cells in the early stages of infection, before viral cytopathic changes may be detectable on routine stains
-This stain may also help differentiate PVN from other viral nephropathies seen in immunocompromised
patients, such as adenovirus infection.
– it is associated with a specificity of almost 100 percent for polyomavirus nephropathy, although, it does not distinguish between BKV and JC virus (JCV
References:
– Hirsch HH, Randhawa P; AST Infectious Diseases Community of Practice. BK polyomavirus in solid organ transplantation. Am J Transplant. 2013 Mar;13 Suppl 4:179-88. doi: 10.1111/ajt.12110. PMID: 23465010.
-Shanmugham S, Bhadauria D, Agrawal V, Jain M, Yaccha M, Kaul A, Vamsidhar V, Meyyappan J, Prasad N. The diagnostic and therapeutic dilemma of the co-existence of BK virus nephropathy with acute rejection – an experience from a single Centre and review of the literature. Transpl Immunol. 2022 Jun;72:101581. doi: 10.1016/j.trim.2022.101581. Epub 2022 Mar 14. PMID: 35301106.
-Hirsch HH, Randhawa P; AST Infectious Diseases Community of Practice. BK polyomavirus in solid organ transplantation. Am J
Transplant. 2013;13 Suppl 4:179-88. doi:10.1111/ajt.12110
-Saleh A, El Din Khedr MS, Ezzat A, Takou A, Halawa A. Update on the Management of BK Virus Infection. Exp Clin Transplant. 2020 Nov;18(6):659-670. doi: 10.6002/ect.2019.0254. Epub 2020 Jun 16. PMID: 32552624.
-Kant S, Dasgupta A, Bagnasco S, Brennan DC. BK Virus Nephropathy in Kidney Transplantation: A State-of-the-Art Review. Viruses. 2022 Jul 25;14(8):1616. doi: 10.3390/v14081616. PMID: 35893681; PMCID: PMC9330039.
Many thanks for a comprehensive reply
Differential diagnosis of allograft tubulointerstitial nephritis:
1] BKPN
2[CMVN
3]Acute pyelonephritis.
4] Acute cell mediated rejection ACMR
5] Acute antibody mediated rejection ABMR.
6]Covid19 – nephropathy..
How to manage this case:
Clinically, the constellation of symptoms and clinical features of hematuria, hydronephrosis , deterioration of renal function, and interstitial nephritis is consistent mostly with BKPN.
Diagnosis is depending on identifying the BKPV as an intranuclear inclusions in renal tubular epithelial cells and Bowman’s capsule epithelial cells.
Diagnosis :
Depend on identifying SV40 large T antigen which is shared antigen between SV, BKPV and JCV..
Managment:
It depends on minimizing immune suppression.
Hence, mycophenolate and Azathioprim have to be withheld and CNi to reduced 25 -50%.Close follow up of renal function and BKPV viremia and vireuria every 2-4 weeks have to be contemplated as ACMR might be eventuated in the aftermath. Vireuria is suspected to be cleared in 7-80% of patients and from 40% -97% of viremia.
Leflunomide along with immunosuppression reduction was suggested in patients who continued to show deterioration of renal function with persistent viremia.
Other medications are controversially used in treatment.
reference:
1-Cristina Costa and Rossana Cavallo. Polyomavirus-associated nephropathy.World J Transplant. 2012 Dec 24; 2(6): 84–94.
That is a well-structured reply.
Differential diagnosis of allograft tubulointerstitial nephritis:
1] BKPN
2[CMVN
3]Acute pyelonephritis.
4] Acute cell mediated rejection ACMR
5] Acute antibody mediated rejection ABMR.
6]Covid19 – nephropathy..
How to manage this case:
Clinically, the constellation of symptoms and clinical features of hematuria, hydronephrosis , deterioration of renal function, and interstitial nephritis is consistent mostly with BKPN.
Diagnosis is depending on identifying the BKPV as an intranuclear inclusions in renal tubular epithelial cells and Bowman’s capsule epithelial cells.
Diagnosis :
Depend on identifying SV40 large T antigen which is shared antigen between SV, BKPV and JCV..
Managment:
It depends on minimizing immune suppression.
Hence, mycophenolate and Azathioprim have to be withheld and CNi to reduced 25 -50%.Close follow up of renal function and BKPV viremia and vireuria every 2-4 weeks have to be contemplated as ACMR might be eventuated in the aftermath. Vireuria is suspected to be cleared in 7-80% of patients and from 40% -97% of viremia.
Leflunomide along with immunosuppression reduction was suggested in patients who continued to show deterioration of renal function with persistent viremia.
Other medications are controversially used in treatment.
reference:
1-Cristina Costa and Rossana Cavallo. Polyomavirus-associated nephropathy.World J Transplant. 2012 Dec 24; 2(6): 84–94.
That is a well-structured reply.
DDX.:
-viral infections ,on the top of list BKV ,then other viruses
How do you manage this case?
this case nearly confirmed BKV ….
Elaborate on SV40 staining the specificity, the sensitivity and where it comes from.
SV40 staining associated with high sensitivity and specificity.
Short and precise.
References?
Sir,
the answer from listening of proff. Ahmad halawa lectures, common sense , general background reading and clinical ( surgical) practice in our center
37 years male with his third renal transplant presented with;
Slow rising creatinine and hematiria
Ultrasound dilatation of Pelvicalyceal system
Medication; Tac/MMF/pred.
BK PCR 4 log 10
Graft biopsy shows viral inclusion bodies found in tubular epithelium associated with fibrosis and atrophy, no vessel and glom. Tubules are dilated.
Immunohistochemistry SV 40 +ve is involved in interstitial inflammation and fibrosis.
Differential are; BK virus nephropathy,
Acute cellular rejection, CNI toxicity, herpes simplex, adenovirus,CMV
Treatment
There aren’t many controlled trials that can help us manage BKV infection in renal transplants.
However, a number of papers have proposed potential anti-BKV medications. Only uncontrolled retrospective observational studies have documented the simultaneous use of these drugs with immunosuppression decrease;
1. Immunosuppression is decreased
Although lowering immunosuppression has been the cornerstone of treating BKV infection, doing so comes with a larger risk of rejection, which makes this choice difficult.
2. Cidofovir
The advantages of combining cidofovir with immunosuppression reduction have been discussed in numerous single-center studies and case series.However, there are no randomized controlled trials available to back this strategy.
3.Brincidofovir (CMX001)
Because of the nephrotoxicity with cidofovir,scientists had developed brincidofovir, which is a
prodrug of cidofovir that is administered orally. Phase 3 clinical trials have shown a lower incidence
of nephrotoxicity with brincidofovir.
4. Leflunomide
Leflunomide is an immunosuppressant agent that also has antiviral properties against BKV in vitro.
Leflunomide and BKV viral load have been significantly correlated in these trials; however, the source of the BKV viral load (i.e., whether it is a result of decreased immunosuppression or because of the antiviral characteristics of leflunomide) is not reflected by this.
5. intravenous immunoglobulin Intravenous immunoglobulin (IVIG)
contains neu- tralizing antibodies against BKV, which makes it a good choice in the management of BKVN. no controlled studies have been reported.
6. Role of cellular immunotherapy in the management of BKv infection
The majority of BK virus infections occur in children, after which the virus goes dormant until it is reactivated during immunosuppressive therapy due to the inability of BKV-reactive T cells to prevent viral replication.
Elaborate on SV40 staining the specificity, the sensitivity and where it comes from.
The rhesus macaque is the simian virus 40 (SV40natural )’s host, and it is usually kept there as a chronic infection of the kidney epithelium and other tissues.
Positive immunohistochemistry, with a 100% specificity and pathognomonic findings for BKV infection (against BKV or against SV40 large T antigens).
References
1.Malaria and Some Polyomaviruses (SV40, BK, JC, and Merkel Cell Viruses).2. Update on the Management of BK Virus Infection
Ahmed Saleh, 1,4,5 Mohamed Salah El Din Khedr,1 Abeer Ezzat,2 Anna Takou, 3 Ahmed Halawa4,
That is a well-structured reply.
DEAR ALL.
Please consider the following points in this particular R.
Third TX ,212 mismatch,Tac level 8ng/ml.
15 months post TX
He is a high risk patient probably with a previous LATENT BK infection
An early SURVEILLANCE POLICY followed in some centers by non invasive methods is highly indicated in this case.
Thank you, all
I’m not impressed by the answers of some colleagues. They did not listen to the lecture and kept copying and pasting without reflection.
Is there any role of antiviral agents in the treatment of BKV infection?
sir,
the role of antiviral not conclusive ….
the main step of treatment is reduction of antimetabolite +/- CNI medications
Yes
Thanks sir
Thanks very much Prof.Halawa
Treatment of BKV nephropathy is problematic. No antiviral drug is
approved, and none has been appropriately studied in a PRCT.
BKV in Renal Transplantation By Ahmed Halawa Consultant Transplant Surgeon Associate Professor, University of Liverpool – UK.
I agree
Thanks alot Prof.Sharma
No. Mainstay of treatment is reduction of immunosuppression especially the antimetabolites.
Yes
thanks
the ministry treatment of BKV-associated nephropathy is depend on immunosuppression reduction but the role of antiviral (cidofovir) there is no RCT available .
Yes
Thank you Prof. Ahmad Halawa.
Cidofovir, Leflunomide, are of limited evidence needs further studies.
Intravenous immunoglobulins, are of limited evidence may be used.
Fluoroquinolone, in vitro there is some inhibitory effects, in vivo no evidence, but may be protective of BK virema.
Saleh A, El Din Khedr MS, Ezzat A, Takou A, Halawa A. Update on the Management of BK Virus Infection. Exp Clin Transplant. 2020 Nov;18(6):659-670. doi: 10.6002/ect.2019.0254. Epub 2020 Jun 16. PMID: 32552624.
I agree
Thank you prof,
I note
Reduction of immunosuppression is the mainstay of treatmnet.
So far, there is s no specific antiviral therapy against BKV infection
Other antiviral as cidofovir, leflunomide ; there is no strong evidence for routine use of these drugs.
Yes
Currently, there are no available antiviral medications against BKV.
The mainstay of BKVN treatment is immunosuppression reduction. The role of antivirals is not conclusive due to lack of evidence in form of structured RCTs.
Yes
I agree
Is there any role of antiviral agents in the treatment of BKV infection?
– No there is no role.
– The mainstay of treatment is reduction in immunosuppression (1, 2)
– Several adjunctive therapies have been shown to have in vitro activity against BKV activity but the efficacy of these agents has not been established neither have they been shown to be superior to immunosuppression reduction (3)
References
1. Hirsch HH, Randhawa PS. BK polyomavirus in solid organ transplantation-Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clinical transplantation. 2019 Sep;33(9):e13528. PubMed PMID: 30859620. Epub 2019/03/13. eng.
2. KDIGO clinical practice guideline for the care of kidney transplant recipients. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2009 Nov;9 Suppl 3:S1-155. PubMed PMID: 19845597. Epub 2009/10/23. eng.
3. Johnston O, Jaswal D, Gill JS, Doucette S, Fergusson DA, Knoll GA. Treatment of polyomavirus infection in kidney transplant recipients: a systematic review. Transplantation. 2010 May 15;89(9):1057-70. PubMed PMID: 20090569. Epub 2010/01/22. eng.
I agree
There is no strong evidence for antiviral treatment of BKV. Several agents have been tried, although not in the context of controlled studies
Cidofovir, at reduced doses (10–20% of the recommended dose) has been reported as being effective in clearing the virus from the blood and renal parenchyma in BKV nephropathy with resulting improvement in the renal function
Brincidofovir is a prodrug of cidofovir. It results in higher concentrations of cidofovir, but less renal toxicity
Leflunomide, an immunosuppressant commonly used in rheumatoid arthritis has been tried in BKV nephropathy with persistence of cytopathic effects in repeat biopsy
Reference
Tina Dalianis, Britt-Marie Eriksson, Marie Felldin, Vanda Friman, Anna-Lena Hammarin, Maria Herthelius, Per Ljungman, Johan Mölne, Lars Wennberg & Lisa Swartling (2019) Management of BK-virus infection – Swedish recommendations, Infectious Diseases, 51:7, 479-484,
I like you understanding of ‘no evidence of antivirals in BK’.
Other antiviral” adjunctive therapies used to treat BK virus infection include quinolones, cidofovir, leflunomide, and IVIG.
A meta-analysis has demonstrated that there is no difference in graft outcomes when the strategy of reduction in immunosuppression is compared with a combination of immunosuppression with leflunomide or cidofovir.
Intravenous immunoglobulin is probably the only viable adjunctive therapy. IVIG utilized when there is no response to a maximal reduction in immunosuppression in comparison to risk of rejection. The rationale for use is the presence of BK-neutralizing antibodies in IVIG preparations.
five observational studies have demonstrated a reduction in BK viral loads; however, other anti-viral agents were administered at the same time .
Quinolones: Despite demonstrating anti-viral properties in vitro, randomized trials failed to show efficacy as prophylaxis in the immediate post-transplant period or treatment for BK viremia.
In the levofloxacin prophylaxis trial, a higher incidence of resistant bacterial infection was seen in the quinolone group.
Cidofovir: A nucleotide analog of cytosine has demonstrated activity agains polyomaviridae in vitro.
Studies showed no benefit with cidofovir use,while a significant risk of kidney dysfunction was noted.
Cidofovir has already been shown to be associated with proteinuria, proximal tubular dysfunction, and kidney disease.
Leflunomide: A prodrug that converts to an active metabolite, A77 1726, which has demonstrated both immunosuppressive and anti-viral properties. Despite some studies suggested its use in BK virus infection based on a case series but a pharmacodynamic and prospective open-label study showed no benefit . Another metabolite, FK778, did not demonstrate efficacy in a phase 2 , a randomized, open-label, parallel-group, 6-month study in kidney transplant patients when compared with a reduction in immunosuppression .
References:-
1. Benotmane I., Solis M., Velay A., Cognard N., Olagne J., Vargas G.G., Perrin P., Marx D., Soulier E., Gallais F., et al. 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. Am. J. Transplant. 2021;21:329–337. doi: 10.1111/ajt.16233.
2.Vu D., Shah T., Ansari J., Naraghi R., Min D. Efficacy of Intravenous Immunoglobulin in the Treatment of Persistent BK Viremia and BK Virus Nephropathy in Renal Transplant Recipients. Transplant. Proc. 2015;47:394–398. doi: 10.1016/j.transproceed.2015.01.012.
3.Sharma A.P., Moussa M., Casier S., Rehman F., Filler G., Grimmer J. Intravenous immunoglobulin as rescue therapy for BK virus nephropathy. Pediatr. Transplant. 2009;13:123–129. doi: 10.1111/j.1399-3046.2008.00958.x.
I like you understanding of ‘no evidence of antivirals in BK’.
Several agents were tried in the treatment of BK nephropathy due to their in vitro anti-BKPyV activity, including IVIG, leflunomide, cidofovir, and quinolone. All these are not routinely recommended as there is no clear evidence of their superiority on reduction of immunosuppression alone.
I like you understanding of ‘no evidence of antivirals in BK’.
The main treatment of BKVN is reducing immunesuppresion ,the role of other drugs including antiviral , IVIG ,quinolones and leflunamied is not conclusive and these drugs are not approved for BKV treament ,but due to their in vivo antiviral effect, they could be used as adjuncative therapy if graft function continue to deterirate despite reducing immunesuppresion.
I like you understanding of ‘no evidence of antivirals in BK’.
-A variety of medical therapies including fluoroquinolones, leflunomide, and cidofovir have been proposed for prevention or treatment of BK viremia and BKN, none has demonstrated clear benefit.
Yes
-Thank you,our;Prof.
-Reduction in the intensity of immunosuppression is the overarching principle for the treatment of BK viremia and BKVAN.
-There is no therapeutic agent available to treat this virus-associated disease, with many agents lacking conclusive efficacy in the reduction in viral loads.
I agree
Cidofovir:
A nucleotide analog of cytosine has demonstrated activity against Polyomavirida in-vitro Studies have shown no benefit with cidofovir use, not with standing that a significant risk of kidney dysfunction was noted has already been shown to be associated with proteinuria, proximal tubular dysfunction,and kidney disease
Leflunomide
A prodrug that converts to an active metabolite, A77 1726demonstrated both immunosuppressive and anti-viral propertiesWhile there was initial enthusiasm for its use in BK virus infection based on a case series, a pharmacodynamic and prospective open-label study showed no benefit
FK778
did not demonstrate efficacy in a phase 2, proof-of-concept, randomized, open-label, parallel-group, 6-month study in kidney transplant patients when compared with a reduction in immunosuppression
Meta-analysis has demonstrated that there is no difference in graft outcomes when the strategy of reduction in immunosuppression is compared with a combination of immunosuppression with leflunomide or cidofovir
Intravenous immunoglobulin is probably the only viable adjunctive therapy
IVIG
utilized in the setting of non-response to a maximal reduction in immunosuppression(balancing with risk of rejection).The rationale for use is the presence of BK-neutralizing antibodies in IVIG preparations. Data from five observational studies have demonstrated a reduction in BK viral loads; however, other anti-viral agents were administered at the same time as well
Kant, S.; Dasgupta, A.;Bagnasco, S.; Brennan, D.C. BK Virus
Nephropathy in KidneyTransplantation: A State-of-the-Art Review. Viruses 2022, 14, 1616.https://doi.org/10.3390/v14081616
I like you understanding of ‘no evidence of antivirals in BK’.
What is your differential diagnosis?
– BKVN
-other infection as CMV
-acut interstitial nephritis
How do you manage this case?
It is mostly BKV nephropathy can be treated by :
• reduction of immunosuppressive drugs: reduce MMF by 50% and follow up but if still high stop MMF
• If still viral load not reduced after 4 weeks of stopping MMF, reduce CNI with level of tac at blood 4-6 and cyclosporine 50-100.
• Others : IVIG , leflunamide, quinolones, cidofovir but their role is not conclusive
• As regard pelvi-calcyeal dilation : uretral stenosis must be ruled out
Reference ;
Saleh A, El Din Khedr MS, Ezzat A, Takou A, Halawa A. Update on the Management of BK Virus Infection. Exp Clin Transplant. 2020 Nov;18(6):659-670. doi: 10.6002/ect.2019.0254. Epub 2020 Jun 16. PMID: 32552624.
_ The role of various antiviral drugs as cidofovir and leflunamide (just proved by invitro studies to have anti BKV activity), but they don’t have clear benefit superior to reduction of immunosupression alone.
Yes
Currently, there are no available specific antiviral medications against BKV, the antiviral agents which are tried like leflunomide, cidofovir ,ciprofloxacin, rapamycin or intravenous immunoglobulin , has not been proven to be effective so the main stay of treatment is reduction of immunosuppressant .
I agree
There is no strong evidence supporting antiviral treatment for PVN
In refractory cases, most common therapeutic option is Cidofovir, use of which is limited by its nephrotoxicity.
– Brincidofovir is a prodrug of cidofovir and has also been used with limited success.
The main management of BK virus is reducing immunosuppressive therapy especially anti metabolites (cellcept), and still not proved anti viral is effective in treatment of BKV.
There are no antiviral medications that have been authorized yet to treat BKV infections. Reducing the dosage of immunosuppressive medication is a reliable therapy for these immunocompromised kidney transplant patients. However, this raises the possibility of acute or chronic transplant rejection and loss.
Reduction of immunosuppression is the cornerstone of management.
There is no specific antiviral or immunomodulatory therapy sufficiently effective for
routine use.
no role of anything except RIS
We are yet to get an express approval for use of anti virals in BKV treatment.Main treatment is RIS.
The role of antiviral is controversial and no enough RCT is available , the only proved treatment is reduction of immunosupression .
Until now there is no evidence of the antiviral agent in the treatment of BKV infection
The mainstay of the management is immunosuppression reduction
There is no strong evidence supporting antiviral treatment for PVN
In refractory cases, most common therapeutic option is Cidofovir, use of which is limited by its nephrotoxicity.
Brincidofovir is a prodrug of cidofovir and has also been used with limited success.
Thank you Sir.
There is significant effect of antiviral (cidofovir) in clearing viruria or viraemia ( other studies reported clearance of viraemia in 50 to 100% of the cases).
The pronounced nephrotoxicity limits the use of cidofovir & adequate. hydration is required.
Several agents have been shown to have in vitro anti-BKPyV activity.Leflunomide,cidofovir, Quinolone antibiotics and ivig.However, we do not routinely use any of these agents for the treatment of BKPyV infection, given that the efficacy of these agents has not been established and use of these therapies has not been clearly shown to be superior to reduction in immunosuppression alone .
There is no approved role for antivirals like cidofovir in BK virus infection. The main-stone of treatment is immunosuppressive reduction.
Dear Prof. , reduction of immunosuppression is the only current evidenced path for management , antivirals role is of unproven evidence, yet .
What is your differential diagnosis?
The histopathological image showing a section of renal tubules with abundunt inflammatory cells infiltrates and viral cytopathic changes can be due to:
-BKV nephropathy:
In the left side slide which is stained with H&E stain showing tubular epithelial cells with Intranuclear basophilic viral inclusions without a surrounding halo.These changes can be caused by CMV with the difference in Intranuclear basophilic viral inclusions with surrounding halo (Owl eye appearance) as well as it can be with other viral infections like adenovirus, and herpes simplex virus (HSV) infection.Specific immunostaining will distinguish between these infections from polyomavirus-related infection.
Right side slide which is Immunohistochemical staining against the SV-40 T-antigen. This type of stain which confirm diagnosis of BK nephroppathy and highly specific for all polymaviruses.Staining against the SV-40 T-antigen is a sign of active viral replication.There is extensive interstatial inflammatory cells infiltrate and fibrosis.
How do you manage this case?
-Management of BK nephropathy:
There are no specific antiviral therapies for BK polyomavirus associated nephropathy , the cornerstone of management is reduction of immunosuppressive medications and this applied for both prevention of patients with BKPyV viremia detected by routine screening and the treatment of patients with established BKPyVAN.
The optimal approach for immunosuppression reduction is not defined and centre dependent ,in general it is individualized and the goal to to restore immunity against BKPyV without triggering rejection with close monitoring.We optain BK PCR before reducing immunosppression and follow up with quanitative BK PCR every one to two weeks until BKPyV DNA is undetectable for two consecutive tests obtained at least one week apart.If the serum creatinine level increases by ≥25 percent from baseline at any time while immunosuppression is being reduced, the patient should be evaluated for the possibility of acute rejection.
-Reduction of Immunosuppressin as following:
Initially reduce the dose of the antimetabolite by 50 %. If the BKPyV viral load does not decrease within two to four weeks, we completely discontinue the antimetabolite. If there is still no decrease in viral load after another two weeks, we decrease the dose of the calcineurin inhibitor by 25 to 50 %, targeting a whole blood tacrolimus trough level of 4 to 6 ng/mL or a whole cyclosporine trough level of 60 to 100 ng/mL.
Adjunctive therapies :Has no specific role in management of BKVAN
Intravenous immune globulin:administered at a dose of 300 mg/kg every three weeks in conjunction with a reduction in immunosuppression.
Leflunomide:With the the potential for hematologic toxicity and hepatotoxicity.
Cidofovir is potentially highly nephrotoxic, resulting in proteinuria and kidney failure in 20 percent of patients.
Elaborate on SV40 staining the specificity, the sensitivity and where it comes from.
Diagnosis of BKVN is proved with use of immunohistochemical detection of the large T-antigen which is most commonly used and has sensitivity of 100% in diagnosis of BKVN. The sensitivity and specificity of the histological diagnosis of PVAN is complicated by the patchy pattern of renal involvement, particularly early in the disease (pattern A).Immunohistochemical stain with an antibody directed against the outer polyomavirus capsid protein VP-1. This stain marks virions (in contrast to antibodies directed against polyomavirus large T antigen that is found within nuclei during viral replication).
References:
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009; 9 Suppl 3:S1
Drachenberg CB, Beskow CO, Cangro CB, et al. Human polyoma virus in renal allograft biopsies: morphological findings and correlation with urine cytology. Hum Pathol 1999; 30:970.
Hirsch HH, Knowles W, Dickenmann M. et al. Prospective study of polyomavirus type BK replication and nephropathy in renal-transplant recipients. N Engl J Med. 2002;347:488–496.
Well done .
Since the risk of rejection is high with IS reduction :
What is the controvercial position of Steroid pulse here?
IvIG role is questionable as it has an immunemodulatory role which has an effect on total IS.
A 37-year-old man was admitted after one episode of haematuria. He had a successful third renal transplant 15 months ago, 212 mismatch, no DSA and negative FAXM. His creatinine has risen from 151 µmol/L to 223 µmol/L. USS showed mild dilatation of the pelvicalyceal system, not different from the previous scan. He is currently on Tacrolimus (trough 8 ng/ml), MMF 750 bd and prednisolone 5 mg od. There is BK viraemia (plasma PCR 4 log 10). The biopsy is shown below, and SV40 staining (left).
What is your differential diagnosis?
The Left image showed ===> LM showed a tubular cell with BK viral inclusions with interstitial fibrosis (bluish) and infiltration with lymphocytes & neutrophils, Intranuclear basophilic viral inclusions without a surrounding halo, hyperchromasia, and chromatin clumping of infected cells, Interstitial cell infiltrates in the areas of tubular damage , Tubular injury, characterized by cell drop out, desquamation and flattened epithelial lining, Tubulitis.
The Right image showed => SV40 immunostaining shows positive staining for enlarged nuclear inclusion of polyomavirus.
DD:
– BKVN
– ACR/BKVN
– Hgic Cystitis
– CNI Nephrotoxicity (AIN)
How do you manage this case?
– Blood BKV PCR ===> viral load >10,000 copies /ml.
Taqman DNA PCR of urine copies/ml >107
PPV 67%
NPV 100%
Taqman DNA PCR of blood copies/ml >104
sensitive 100% , specificity 95%
PPV 85%
NPV 100%
– Kidney Allograft Biopsy=> Definitive diagnosis
TREATMENT:
Guideline 8.6.2 – KTR: BK nephropathy
Robust evidence supports
– Decrease
• Tacrolimus trough level to less than 6 ng/mL
• MMF dose to less than or equal to 1g/d
• CsA trough level to 100 to 150 ng/mL
– Switch
• Tacrolimus to CsA (trough level 100–150 ng/mL)
• CsA/MMF to CsA/ steroids or tacrolimus/steroids
– ? Conversion from MMF to an mTOR inhibitor
Guidelines – We suggest:
– Immunosuppression should be reduced when the serum BKV load exceeds 104
copies/ml (2C)
– There is no established specific treatment for BK nephropathy. (2D)
– Re-transplantation can safely be considered in patients who have BK nephropathy
diagnosed in an earlier graft (2C)
Hirsch HH et al. Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation. 2005 May 27;79(10):1277-86
Summary Treatment:
Decrease immunosuppression medication (1st step)
MMF 50% reduction of MMF or completely discontinue the MMF if no response within two weeks.
Decrease the dose of CNI by 25% to 50% to target blood trough level Tac. of 4 to 6bng/m; and cyclo.in 60 to 100ng/ml
IVIG if no respond to a reduction in IS and who have hypogammaglobinemia IgG <400ng/dl====>IVIG treatment 0.5 gm /kg EOD for 4 doses, to avoid confounding result when DSA is checked., to check DSA do it 2-3 week after IVIG .
Leflunomide==>.Replacing anti-proliferative. ==> is an IS drug used to treat rheumatoid arthritis, but with antiviral properties, BK viraemia cleared in some patients with 10 or 20mg daily
► side effects include ↑BP, hepatotoxicity, haemolysis and TMA)
Adjunctive therapies – Leflunomide
Switch MMF / MPA to Leflunomide 40-60 mg /day to therapeutic level 50-100 mcg/ml
Prodrug whose anti-metabolite, A77 1726, has both immunosuppressive and anti-viral activity.
Dosage: 100mg/d X 5 days followed by 20–60 mg daily
target trough blood level 50–100 mg/ml
10-20mg/daily (>40µg/ml)
85% clearance of viraemia <2500copies/ml
Study 1:
12/13 pts treated – exchanging leflunomide for MMF & lowering trough level of calcineurin-inhibitor cleared the virus.[1]
Study 2:
5/12 pts treated – exchanging leflunomide for MMF & decreasing immunosuppression cleared the virus.[2]
[1] Teschner S et al. Transplant Proc. 2009 Jul-Aug;41(6):2533-8.
[2] Faguer S. Transpl Int. 2007 Nov;20(11):962-9. Epub 2007 Jul 30.
Johnston O et al. Transplantation. 2010 May 15;89(9):1057-70
Krisl J et al CJASN June 2012
Cidofovir ==> is an antiviral drug used to treat resistant CMV disease. It is nephrotoxic, but low doses may clear BK viraemia in some patients. Reported doses are 0.25–1mg/kg given IV once each 1–3 weeks
A nucleotide analogue of cytosine that is active against various DNA viruses. Ooriginally used for CMV retinitis in patients with AIDS
– Has in vitro activity against BK virus
– Dosage: 0.25-0.33mg/kg/dose X 1-3 doses every 2-3 weeks
– IV Cidovir – 0.25-1mg/Kg IV weekly ? 5 doses
– Problem with cidofovir – NEPHROTOXIC, P& D RTA, Crystal deposition & vascular injury
– A few studies have shown improvement in patients treated with cidofovir, but no RCTs.[1-3]
– In one study patients treated with cidofovir had no decline in BKV & had decreased renal function compared to those not treated.[4]
1 Vats A et al. Transplantation 2003; 75: 105.
2 Kadambi PV et al. Am J Transplant 2003; 3: 186.
3 Vats A et al. Am J Transplantation 2003; 3: 190 (Abstract #148).
4 Pallet N. Transplantation. 2010 Jun 27;89(12):1542-4.
5 Hirsch HH et al. Transplantation. 2005 May 27;79(10):1277-86.
Quinolone Antibiotics ==> (antiviral activity by inhibiting DNA helicase), for example
ciprofloxacin 500mg BD for 10 days
mTOR inhibitors, (antiproliferative) ==> Few studies have recommended its use in lowering the rate of BKV, especially by switching from antimetabolites to mTORi in viral infection that occurs in solid organ transplantation
Elaborate on SV40 staining the specificity, the sensitivity, and where it comes from:
Simian virus 40 (SV40) is a small DNA tumor virus of monkey origin. This polyomavirus was administered to human populations mainly through contaminated polio vaccines, which were produced in naturally infected SV40 monkey cells.
The immune histochemistry tests is using antibodies directed specifically against BKV or against the cross-reacting SV 40 large T antigen.
Sv40 staining immunohistochemistry test specificity is 100% and sensitivity is low
it can’t distinguish between BKV & JCV (low sensitivity).
References:
BKV in Kidney Transplantation lecture By Ahmed Halawa
Nickeleit V et al. N Engl J Med. 2000; 342:1309-1315.
Hirsch HH. Transplantation 2005 May 27;79(10):1277-86
Uptodate
Well done.
-What is your differential diagnosis?
-How do you manage this case?
The main stay of the management is reduction of immune suppression
-Elaborate on SV40 staining the specificity, the sensitivity and where it comes from?
Source; prof Halwa lecture, update on BKV infection by Ahmed Saleh et. al, BKN in kidney transplant by Sam Kant et.al. Association Between Simian Virus 40 and Human Tumors
https://www.frontiersin.org › fonc.2019.00670 › full
Well done
DD:
BK nephropathy, T-cell mediated rejection, both combined and CMV infection.
Management:
-Reduction of 50% of MMF dose in addition to keeping CNI dose, with close monitoring of serum creatinine together with BK viral PCR every 2 weeks.
-If no response , MMF to be stopped.
-reduce CNI trough target ;TAC 4-6ng/ml, Cyclosporin 50-100ng/l; if BK PCR still persisting after 4 weeks.
-IVIG as adjuvant therapy.
-increase of steroid dose to cover possibility of T cell mediated rejection.
SV 40 Staining test: has specificity of 100%for polyoma virus nephropathy, however cannot distinguish between BKN and JCV; with low sensitivity.
1-BK-associated nephropathy.
2-BKV-associated nephropathy associated with acute rejection.
3- hemorrhagic cystitis caused by the BK virus.
4-CMV induced nephropathy
diagnosis by plasma PCR, the detection of BKPYV viremia is highly sensitive 100% and specific 88% for the diagnosis of BKVPYVAN. but urine cytology (decoys cells) is less sensitive and specific for the diagnosis of BKPYVAN.
kidney allograft biopsy is the gold standard for diagnosing BKPYVAN,however, diagnosis is made based upon viremia plasma BKPYV viral load>10,000 copies /ml.
TREATMENT
1-No specific antiviral therapies for BKPYV-associated nephropathy. is to decrease
2-The cornerstone of management is to decrease immunosuppression medication.
the optimal approach to reducing immunosuppression has not been defined protocols, vary among transplant centres and are often individualized.
3-50% reduction of antimetabolite(MMF375 mg bid)
if BKPYV viral load does not decrease within two to four weeks we completely discontinue the MMF,
4-if still no decrease in viral load after another two weeks we decrease the dose of CNI by 25% to 50% to target blood trough level of 4 to 6bng/m; and in 60 to 100ng/ml
5-IVIG use in patients who do not res.
pond to a reduction in immunosuppression and who have hypogammaglobinemia IgG <400ng/dl
6-leflunomide we do not use for the treatment of BKPYV infection its uncertain efficacy.
7-cidofovir only consider for the treatment of BKVPYVAN when another intervention has failed.
8-quinolone antibiotics,we do not use quinolone antibiotics an adjunct therapy to treat BKYVAN infection
Well done.
What is your differential diagnosis?
The LM image showed tubular cells BK viral inclusions with interstitial infiltrate composed of lymphocytes & neutrophils.
SV40 immunostaining shows positive staining for enlarged nuclear inclusion of polyomavirus.
Differential diagnoses include:
BKVN with probable ACR.
How do you manage this case?
· Continue with tacrolimus and steroids.
· Reduce/withheld MMF or replace MMF with leflunomide or mTOR I.
Elaborate on SV40 staining the specificity, the sensitivity and where it comes from
Infected epithelial cell nuclei stain with antibody to the large T antigen of the SV40 virus, which serves as a surrogate marker of human polyomavirus infection. However, given the focality of replicating BKV in the kidney, SV40 stain can be negative in the allograft biopsy in 10% to 30% of patients with sustained viremia.
Reference: Costigliolo F, Lombardo K, Arend LJ, Rosenberg AZ, Matoso A, Carter-Monroe N, Bagnasco SM. BK Virus RNA in Renal Allograft Biopsies. J Histochem Cytochem. 2020 May;68(5):319-325. doi: 10.1369/0022155420922604. Epub 2020 Apr 30. PMID: 32352851; PMCID: PMC7226623.
The question will rise if you have a documented ACR!
You mentione STEROID PUSE !
IvIG
Can you elaborate on their role.
Remember steroid pulses were accused of being a risk factor!!
It is a very difficult situation.!!!
The Rx is really challenging and no specific recommendations could be made.
IVIGs is used here for its immunomodulatory effects. Additionally, IVIG has potent neutralizing antibodies and is able to neutralize all major BK viral genotypes.
The IVIG with a concurrent decrease in immunosuppressive medications has been successful in treating BKVN with concurrent acute rejection; however, the efficiency of IVIG is uncertain, as it has been given with concomitant reduction in immunosuppression.
This is a high risk transplant patients who is on triple immunosuppression. He has had one episode of hematuria and has graft dysfunction with a graft US thats similar to one done previously and a high BK viral PCR
The biopsy shows tubular injury with intranuclear inclusion bodies within the tubular cells and increased inflammation in the interstitium. The SV40 stain is positive
The differential diagnosis includes:
Management of this case:
Lowering immunosuppression is key in management of BKVAN.
The tacrolimus dose should be lowered by 25-50%
The MMF dose should be lowered by 50%
The glucocorticoids dose should be lowered
The graft function and the BK viral PCR should be followed closely
If there is no reduction in the PCR, then the MMF should be stopped. It can be replaced by an mTOR inhibitor or leflunamide
IVIG has also been used in some case series although the evidence is not robust for its efficacy
SV40
SV40 is a polyoma virus that is 70% homologous to the BK and JC virus. It mainly affects monkeys but cases were reported from a contaminated polio vaccine
The staining uses immunohistochemistry and utilizes antibodies against the large T Ag
The viral inclusion bodies stain brown
It has a specificity of 100% but the sensitivity is lower
Am J Kidney Dis. 2016;68(6):e37-e38
Nephrology 21 (2016) 647-654
Ellaborate more about use of antivirals.
A 37-year man had Third renal transplant 15 months ago with 212 mismatch ,no DSA ,negative FAXM, on triple immunosuppression ,admitted with hematuria. USS showed mild dilatation of the pelvicalyceal system, BK viraemia and allograft biopsy showing viral inclusions in the tubular epithelium and surrounding interstitium containing mixed inflammatory infiltrates, and mild fibrosis and tubular atrophy. Left figure showing SV 40 positive in in the tubular epithelial cells .Likely diagnosis is BK Polyoma virus nephropathy. Other differentials which need to be considered include:CMV infection and acute Rejection.
How do you manage this case?
Diagnosis is already confirmed via urine for decoy cells ,PCR for BK virus and finally allograft biopsy(gold standard). First thing in the management will be to reduce the immunsupression without increasing the risk of rejection. Tacrolimus should be reduced to maintain trough level of 4-6ng/ml followed by reduction of Antimetabolite i.e., Mycophenolate mofetil to 50% and also reduction of steroids .Sometimes MMF can be switched to mTOR inhibitor as in few cases ,lower rates of BKV has been seen .Adjunctive therapies like Cidofovir,Leflunomide can be tried. Monitoring with PCR BKV till the virus is undetectable.
Elaborate on SV40 staining the specificity, the sensitivity, and where it comes from
SV40 staining is done with the immunohistochemistry that utilizes antibodies targeted against SV-40 Large T Antigen or BK polyomavirus. It does not differentiate between BK virus and JC virus and is not sensitive as injury in BVN is focal and can be missed on biopsy .Specificity is around 100 % for polyomavirus nephropathy.
REFERENCES:
1-BKV in Kidney Transplantation lecture By Ahmed Halawa.
2- Deirdre Sawinski and Simin Goral, BK virus infection: an update on diagnosis and treatment, Nephrol Dial Transplant (2015) 30: 209–217
Well done.
please ellaborate on the use of the antivirals!
What is your differential diagnosis?
Differential diagnoses include:
===========================
How do you manage this case?
===========================
Elaborate on SV40 staining the specificity, the sensitivity and where it comes from.
References
Well done
Pros. and Cons of the OTHER DRUGS!!
THANK YOU, DEAR PROF DAWLAT
Pros & Cons of other drugs:
2. Quinolones:
3. Cidofovir:
4. Leflunomide:
5. Rapamycin:
Reference
Differential diagnosis:
Management:
This patient viral load >10000 copy/ml, and receive ATG in the past so plan of treatment:
SV40 staining:
References:
Can you justify:
CNI toxicity!
Acute pyelonephritis.
more information for antivirals!!
Sir cellular infiltrates in biopsy makes it one of the Diff Diagnosis
similarly, infections and drug toxicity(CNI) should always be in your mind in treating post Transplant rise in creatinine
regarding AntiViral therapy only reduction in IS have been effective in reduction in viral load otherwise all other options like Cidofovair, leflunamide, ciprofloxacin have been tried but clinical evidence and RCT are lacking.
2.How do you manage this case?
3 .Elaborate on SV40 staining the specificity, the sensitivity and where it comes from,
Pyelonephritis ?!
pros. and cons of other antiviral drugs.
History
====================================================================
What is your differential diagnosis?
====================================================================
How do you manage this case?
If viral load is between 1000 and 5000 copies/mL:
If viral load is greater than 5000 copies/mL:
If viral load continues to increase and patient is still on MMF:
If viral load continues to increase and patient is not on MMF, reduce CNI by 25-50%:
If viral load continues to rise despite stopping MMF, reducing the CNI and adding leflunomide:
If biopsy proven BK virus nephropathy (BKVN)
====================================================================
Elaborate on SV40 staining the specificity, the sensitivity and where it comes from.
===================================================================
Reference
What are the side effects of Lefloneamide?
Thankyou for mentioning of TIMELY diagnosis in suce a scenario.
Otherwise well done.
Thanks alot Prof.Dawlat
More common
Less common
Incidence not known
Drug information provided by: IBM Micromedex.Mayo Clinic
Many thanks Prof.Dawlat
What are the side effects of Lefloneamide?
More common
Rare
Thanks alot Prof.Dawlat
What are the side effects of Lefloneamide?
Side effects include thrombotic microangiopathy, hepatitis, and bone marrow suppression.
Differential diagnosis:
Management:
This patient had viral load >10000 copy/ml, and receive ATG during treatment of acute cellular rejection, so plan of treatment:
SV40 staining:
References:
You need to revise all your adjunctive therapies including steroid pulses.
What is your differential diagnosis?
1- Acute BK nephropathy class II (positive BK PCR, graft dysfunction, characteristic cytopathy, SV40 staining)
2- Associated acute rejection
3- CNI toxicity
Diagnosis of BK nephropathy
The diagnosis of BK nephropathy requires the presence of the following:
A- Characteristic cytopathy (not specific) including
And
B- positive IHC test for SV40 antigen
How do you manage this case?
1- All patients with viremia (viral load > 1000 copies/ml) are indicated for reduction of immunosuppression
2- Monitor viral load (plasma PCR) /2-4 weeks, clearance of viremia precedes viruria by weeks to months so monitoring of viruria has no clinical implication in follow up. Target PCR is < 1000 copies/ml
3- Monitor renal functions/2-4 weeks
4- If there is concurrent BK nephropathy and AR the treatment is debatable some recommend given pulse steroids without reduction of immunosuppression then reduce immunosuppression after treating rejection, others reduce immunosuppression and do not treat AR.
5- If patient develop AR after reduction of immunosuppression it is generally not recommended to augment immunosuppression again if there is biopsy proven BK nephropathy
6- Several agents were tried in the treatment of BK nephropathy due to their in vitro anti-BKPyV activity, including IVIG, leflunomide, cidofovir, and quinolone. All these are not routinely recommended as there is no clear evidence of their superiority on reduction of immunosuppression alone.
So … in the current high immunological risk case (third transplant, 212 mismatch), I will do the following:
Elaborate on SV40 staining the specificity, the sensitivity and where it comes from.
References
1. Cavallo R, Costa C, Bergallo M, Messina M, Mazzucco G, Segoloni GP. A case of ureteral lesions in a renal transplant recipient with a co-infection of BK virus and JC virus. Nephrol Dial Transplant 2007;22:1275. Back to cited text no. 2
2. Rajpoot DK, Gomez A, Tsang W, Shanberg A. Ureteric and urethral stenosis: A complication of BK virus infection in a pediatric renal transplant patient. Pediatr Transplant 2007;11:433-5. Back to cited text no.
3. Hwang YY, Sim J, Leung AY, Lie AK, Kwong YL. BK virus-associated bilateral ureteric stenosis after haematopoietic SCT: Viral kinetics and successful treatment. Bone Marrow Transplant 2013;48:745-6. Back to cited text no. 4
4. Khan H, Oberoi S, Mahvash A, Sharma M, Rondon G, Alousi A, et al. Reversible ureteral obstruction due to polyomavirus infection after percutaneous nephrostomy catheter placement. Biol Blood Marrow Transplant 2011;17:1551-5. Back to cited text no. 5
5. Helle F, Brochot E, Handala L, et al. Biology of the BKPyV: An Update. Viruses 2017; 9.
6. Nankivell BJ, Renthawa J, Sharma RN, et al. BK Virus Nephropathy: Histological Evolution by Sequential Pathology. Am J Transplant 2017; 17:2065.
Well done this is an exellent answer:
What is the value and impact of the early NON INVASIVE diagnosis inthis particullar HIGH RISK recipient.
Appart from this patient a SURVEILLANCE policy for patients used in some centers to detect early viruria can be very rewarding in prevention of BKVN.
BK associated nephropathy
Rejection of the allograft
Nephrotoxicity is caused by CNI.
Acute interstitial nephritis
Thrombotic microangiopathy.
blockage of the urinary tract.
infection with the virus CMV
Recurrence of original kidney disease
First, the patient has a high baseline level of creatinine. We need to know more about the cause of this high baseline creatinine. The level of tacrolimus is high after 15 months of transplantation. Maybe he has underlying CNI toxicity, and this is one of the risk factors, along with an HLA mismatch, for developing BKAN.
In the treatment of BK viremia and BKVAN, the overriding concept that must be adhered to is the lowering of the severity of immunosuppression. There is currently no curative medication available for the treatment of this illness caused by a virus.
Stop the antimetabolites (in our center, we replace MMF with leflunomide). Reduce the calcineurin inhibitor (4–6 ng/mL for tacrolimus). and continue to take prednisone. Serum creatinine must be monitored.
In the meantime, repeated plasma BK PCR values from the same lab every 2 weeks.
Reduce the calcineurin-inhibitor trough level. objectives if viral loads do not decrease after 4 weeks despite stopping the antimetabolite.
Although it has a specificity of one hundred percent for polyomavirus nephropathy, it is still difficult to differentiate between BK and JC viruses, and it has a poor sensitivity with only one core since nephropathy is mostly patchy in its distribution.
Antibodies that are directed exclusively against BK polyomavirus or against the cross-reacting SV40 big T antigen are used in the immunoperoxidase stain for SV-40 large T antigen.
To start with the logical DD you mentioned are :
associated ACR
CMV
Back preasure due to obstruction.
The rest are very far fetched.
Otherwise welldone.
· What is your differential diagnosis?
1. BKV Nephropathy
2. Adenovirus associated Nephropathy
3. CMV infection
4. Graft rejection
· How do you manage this case?
After confirming diagnosis of BKVN I will manage this case as;
a) Maintain low dose steroids 5m/day.
b) Decrease Tac by 25% and monitoring trough level.
c) Decrease MMF by 50% with BK viral load monitoring, if dose not decreases within 4 weeks will completely stop MMF.
d) If no reduction in viral load despite stopping MMF, will reduced Tac by another 25-50% (4-6ng/ml) with close monitoring of creatinine if more than 25% of baseline will have to evaluate for acute rejection.
e) Following resolution of BK Viremia, will either maintain low doses immunosuppression if GFR is stable or increases IS if required.
f) No role of adjunctive therapies proven as of yet.
· Elaborate on SV40 staining the specificity, the sensitivity and where it comes from.
Immunoperoxidase stain for SV 40 large T antigen which is antibody against BK polyomavirus having specificity of 100% for polyomavirus nephropathy but couldn’t differentiate between BK and JC.
Reference UpTo Date
In this high risk patient what would have been the role of EARLLIAR NON INVASIVE SURVEILLANCE .
Could have identified BKVN in this high risk patient with subsequent reduction in IS. At this stage need to monitor DNA PCR bi weekly to assess the response to IS reduction
First picture :
BK virus-infected cells with the tubular epithelium showing marked nuclear enlargement and anisonucleosis. The nuclear chromatin has a homogenous basophilic appearance. A mild mixed inflammatory infiltrates is present in the interstitium
second picture :
Immunoperoxidase staining with anti-SV40 antibody showing BK virus antigens within infected nuclei of tubular epithelium.
Based on history and ultrasound which shows hydronephrosis BKVN is the most likely diagnosis
patient with BKV usually presents with an asymptomatic slowly increase in creatinine concentration.
urine analysis may show hematuria, proteinuria, and cellular cast.
Diagnosis requires the presence of characteristic cytopathic chances and positive immunohistochemistry tests using antibodies directly against BK or again the crossreacting SV40 which is a large-T antigen .
1- Allograft rejection
2-CNI nephrotoxicity.
3-Thrombotic microangiopathy.
4-Recurrent primary disorder.
5-Renal artery stenosis.
6-Urinary obstruction.
7-viral infection: CMV
8-De Novo glomerular disease.
Specificity of almost 100 percent, but it doesn’t distinguish between BK and JCV cases.
Simian virus 40 (SV40) is a small DNA tumor virus of monkey origin. This polyomavirus was administered to human populations mainly through contaminated polio vaccines, which were produced in naturally infected SV40 monkey cells.
Diagnosis requires the presence of characteristic cytopathic chances and positive immunohistochemistry tests using antibodies directly against BK or again the crossreacting SV40 which is a large-T antigen .
Infected epithelial cell nuclei stain with antibody to the large T antigen of the SV40 virus, which serves as a surrogate marker of human polyomavirus infection. Positive staining may be seen in the absence of nuclear enlargement or inclusions.
The number of SV40-T-antigen-positive epithelial cells was counted in the cytopreparations and compared to the findings in routine urine cytology and transplant histology. Immunostaining of urine cytology with SV40-T-ab demonstrated clearly that the infected epithelial cells and the rate of infection could be estimated by semiquantitative counting. There was a strong correlation between the findings in the urine and in the biopsies, but in the urine preparations, the number of infected cells was much higher than in the biopsies.
The high number of SV40-positive cells in the urine also correlated to the severity of clinical infection and the transplant state. Immunostaining of urine cytology with SV40-T-antibody seems to be useful in the diagnosis and follow-up of polyomavirus reactivation disease in transplant patients, especially in children with renal transplants.
reference :
1-E. von Willebrand et al.
Thrombocyte aggregates in renal allograftsAnalysis by the fine needle aspiration biopsy and monoclonal anti-thrombocyte antibodies2- uptodate .
I agree with your differentials
What is your differential diagnosis?
My primary diagnosis is BK Virus Nephropathy (Polyomavirus)
Differential diagnosis includes
– Graft rejection
– CMV Infection
– JC virus infection
How do you manage this case?
– Tacrolimus dose reduction by 25 to 50% with strict monitoring of its levels;
– 50% decrease in the dose of Mycophenolate (consider the possibility of switching to mTOR inhibitors)
– Dosage of the viral load of the BK virus to monitor its levels. In case of a drop of two logs, consider that the treatment is adequate and tends to become negative within 20 weeks. If levels increase or there is no response, consider adjuvant treatments and individualize their indication (Cidofovir, Leflunomide, IVIG);
– In case of treatment failure consider nephrectomy and graft loss. New biopsies may be necessary to assess disease progression (in this case, it is at level B).
Elaborate on SV40 staining the specificity, the sensitivity, and where it comes from.
They are antibodies with specific markers for polyomavirus, making their samples positive by binding to a specific protein, but being unable to differentiate the different species of Polyomavirus
Stopping MMF is the key step.
Thank you, Filipe
What are the roles of antiviral treatment and mTORi in the treatment of BK nephropathy?
We do not have effective antivirals to control the virus. Some medications are used due to their small antiviral effect (cidofovir and leflunomide), improvement of immunity (IVIG and decrease in immunosuppressants), and change of immunity axis (mTOR having an effect on a different axis of immunosuppression that favors the reactivation of the BK Virus in addition to an effect additional antiviral).
The combination of these measures must be individualized and discussed with a multidisciplinary team.
A 37-year-old man was admitted after one episode of hematuria.
1-Third renal transplant 15 months ago, 212 mismatch, no DSA and negative FAXM and on Tacrolimus (trough 8 ng/ml), MMF 750 bd and prednisolone 5 mg od (highly immunosuppressed ).
2-Deranged renal function and USS showed mild dilatation of the pelvicalyceal system.
3-There is BK viremia (plasma PCR 4 log 10).
4-Renal biopsy on left hand side shown mononuclear cell infiltrate
with nuclear inclusions in the epithelial cells of the tubules and Viral cytopathic changes with varying degrees of inflammation, tubular atrophy, and mild fibrosis.
On the left hand side picture shown SV 40 LT positive cells in collecting ducts.
What is your differential diagnosis?
It is a case of BK Polyoma virus nephropathy with proximal ureteric dilatation and hemorrhagic cystitis.
Adenovirus associated nephropathy.
Other viral associated nephropathy.
How do you manage this case?
1-BK viral PCR and urine decoy cell to confirm diagnosis and to get base for PCR unless renal biopsy is considered the gold standard for diagnosis.
2-The corner stone in treatment plan is to reduce the immunosuppression drugs such as lowering the dose of tacrolimus as tacrolimus level here is high around 8 and targeted around 3-5 ng/ml, lower the dose of glucocorticoids, and lower the dose of Mycophenolate mofetil usually by 50% and strictly follow up the renal functions to avoid the risk of rejections.
3-Changing Mycophenolate mofetil to an mTORinhibitor can also be considered.
4-We can use adjuvant therapy such as Cidofovir, Quinolones, Leflunomide and or IVIG.
5- monitoring should be performed by blood BKV PCR, until the viral level is undetectable.
Elaborate on SV40 staining the specificity, the sensitivity and where it comes from.
Immunoperoxidase stain for SV-40 Large T Antigen which is antibodies directed specifically against BK polyomavirus or against the cross-reacting SV40 large T antigen.
Associated with a specificity of 100 % for polyomavirus nephropathy, however, it is still difficult differentiating between BK and JC virus and low sensitivity with one core as nephropathy mainly patchy in distribution.
References:
1- BKV in Kidney Transplantation lecture By Ahmed Halawa, ASNRT.
2- Sood P, Senanayake S, Sujeet K, et al. Management and outcome of BK viremia in renal transplant recipients: a prospective single-center study. Transplantation. 2012;94(8):814-821. doi:10.1097/TP.0b013e31826690c6.
3- Overview and virology of JC polyomavirus, BK polyomavirus, and other polyomavirus infections, Up To Date, 2023.
Thanks for mentioning adjuvant therapy but i have not seen anyone benefitting from these drugs,
Thank you, Mohamed
What are the roles of antiviral treatment and mTORi in the treatment of BK nephropathy?
Thanks professor .
The most current data to highlight the role of mTORis in the management of viral infections after solid organ transplant, as the mTORis play a clear role in the management of cytomegalovirus, and have data supporting their potential use for BK virus and human herpesvirus 8-related Kaposi sarcoma. No data definitively supports mTORis for use in Epstein-Barr virus-mediated posttransplant lymphoproliferative disorder.
In some studies been associated with lower rates of BKV.
References:
Bowman LJ, Brueckner AJ, Doligalski CT. The Role of mTOR Inhibitors in the Management of Viral Infections: A Review of Current Literature. Transplantation. 2018;102(2S Suppl 1):S50-S59. doi:10.1097/TP.0000000000001777
What is your differential diagnosis?The provided kidney biopsy staining shows tubular injury manifested as cellular desquamation, cell drop out and flattened epithelial lining as well as intranuclear viral inclusions of tubular epithelial cells. The SV40 staining is positive in the tubular epithelial cells. Having previous multiple kidney transplantations, significant HLA mismatch, aggressive induction and maintenance immunosuppression, patient is at high risk for infections and malignancy.Clinical scenario and kidney biopsy is diagnostic of BKPyVN.
How do you manage this case?The mainstay of care is to reduce immunosuppressive medicines because there are no particular antiviral therapies for BK polyomavirus-associated nephropathy. This strategy is generally applicable to the treatment of patients with BKPyVAN that has already developed as well as the prevention of BKPyVAN in patients with BKPyV viremia found by regular screening. There is no established method for lowering immunosuppression; instead, regimens vary between transplant facilities and are frequently customized.
For the majority of kidney transplant recipients who have detectable BKPyV viremia or biopsy-proven BKPyVAN, it is advised to minimize maintenance immunosuppressive. Restoring immunity against BKPyV without inciting rejection is the aim of immunosuppression reduction, in particular in this high risk patient for acute reduction.
Prior to lowering immunosuppression, we take a plasma BKPyV quantitative PCR and monitor it every one to two weeks until BKPyV DNA is undetectable in at least two consecutive tests done at least one week apart. In addition, the serum creatinine level is monitored weekly.
In this particular case, as the patient has high Tacrolimus trough level, reduction in tacrolimus dose is mandatory to achieve lower levels, MMF can also be decreased to 500 mg BID. Stopping either agent put the patient at high risk of acute rejection.
Elaborate on SV40 staining the specificity, the sensitivity and where it comes from.Utilizing antibodies specifically targeted against BKV or the cross-reacting SV40 large T antigen, positive immunohistochemistry tests. Positive SV40 staining is helpful since it has a nearly 100% specificity for polyomavirus nephropathy, however, it cannot differentiate between BKV and JC virus.
References:
UpToDate
Dr Ahmed Halawa Lecture
Kant S, Dasgupta A, Bagnasco S, Brennan DC. BK Virus Nephropathy in Kidney Transplantation: A State-of-the-Art Review. Viruses. 2022 Jul 25;14(8):1616. doi: 10.3390/v14081616. PMID: 35893681; PMCID: PMC9330039.
I agree with your plan for reducing immunosuppression.
Thank you, Mohamed
What are the roles of antiviral treatment and mTORi in the treatment of BK nephropathy?
Thank You Dr
Cidofovir is an antiviral medication that should be considered for the treatment of BKPyVAN only if other treatments have failed. Few uncontrolled trials have assessed the effectiveness of cidofovir in treating BKPyVAN.
In contrast, a small randomized trial of kidney transplant recipients with BKPyVAN reported that treatment with cidofovir had little effect on the BKPyV virus load in plasma or urine when compared to a placebo.
Other treatments have also been used in the treatment of BKPyVN not responding to a reduction in immunosuppression, such as leflunamide and IVIG.
The role of mTORi in the treatment of BK nephropathy is due to its lower immunosuppressive effect compared to CNI and antimetabolites. By better activation of T cell and subsequent activation of immune system, BK virus is rapidly cleared from blood and urine.
What is your differential diagnosis?
a) risk factors
-third kidney transplant
-poor mismatch
-use of Tacrolimus with a high Tac level for the graft age
-use of MMF
b) Persistent plasma PCR >4 log 10 has been shown to be shown with a strong association with BKVAN
c) Combination of histological findings with SV40 Tantigen staining
Other differentials.
How do you manage BKVAN?
Additional Investigations
-urine PCR quantification of BKV
-urine cytology for identification of Decoy’s cell and EM Haufen cell
-urine cytokine: IL-3 and IL-6
Treatment
Note: this is a late BKVAN because the creatinine is > 200umol/l and the possibility of graft rejection is high
Also, no specific antiviral drug agent has been found to be active against BKVAN
Antiviral that has been tried with variable outcomes are;
Antibiotics like levofloxacin.
SV40 Staining
This is a form of immunohistochemistry test that uses antibodies directed specifically against BK polyomavirus or against the cross-reacting SV40 large T antigen.
A positive SV40 test on immunohistochemistry of kidney biopsy is associated with a specificity of 100 percent for polyomavirus nephropathy, however, a distinction still has to be made between BK and JC virus.
Because of the focal nature of early BKVAN, the diagnosis may be missed on one-third of biopsies and this will be reflected in the sensitivity of SV40 to be low. As a result, at least two biopsy cores, preferably including the medulla, since the virus is more likely to be present in the medulla.
References
I agree with your plan for stopping MMF
Thank you
Thank you, Isaac
What are the roles of antiviral treatment and mTORi in the treatment of BK nephropathy?
Thank you, prof, for the response,
The antivirals that have been used in the treatment are ;
Leflunomide
CIdofovir
mTORi