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4. A 68-year-old woman was admitted with a deterioration of kidney function. She had a cadaveric renal transplant 3 months ago for ESRD secondary to APKD. She received a kidney from CMV positive donor (she was also CMV-positive at the time of transplantation). She received ATG for steroid-resistant acute cell-mediated rejection (ACR) 3 weeks after transplantation. A routine infection screen and USS of her kidney were normal. A second Kidney biopsy for another deterioration of the kidney function
- What is your differential diagnosis?
- How do you manage this case?
- The pathologist queried grade 1 ACR. Would your management differ?
- What is the association between this condition and ACR?
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Differential diagnosis
CMV
BK nephropathy
ACR
the presence of viral inclusion bodies within the biopsy with characteristic Owl eye appearance support the diagnosis of CMV kidney invasive disease
How to manage
Complete investigations ( CBC,KFT,LFT, CMV and Bk PCR)
Reduction of immunosuppression
Antiviral medications IV GANCICLOVIR followed by oral Valganciclovir
Acute cellular rejection
Give pulse steroids for 3 to 5 days
No ATG can cause widespread infection
The association between CMV and ACR
ACR is an indirect effect of CMV infection
Differential diagnosis is rejection vs CMV viral infection vs BK nephropathy.
The biopsy displays characteristic viral inclusion bodies with the famous OWL eye sign.
Along with the fever and history of rejection with heavy immunosuppression recently directs the diagnosis to CMV infection.
This can be confirmed by performing CMV and BK virus PCR in addition to the biopsy.
Management of such case necessitates reduction of immunosuppression along with the use of antiviral therapy renally adjusted doses.
IVIG can be of help being immunomodulatory, anti rejection agent and antiviral.
Grade 1 ACR if coexisted in this situation pulse steroids and IVIG would offer better choices. No need to use other heavy immunosuppressive agents.
The common association between CMV and ACR, is that CMV causes rejection as it leads to upregulation of costimulatory molecules on antigen presenting cells and T lymphocytes (producing MHC 1 & 2 ) resulting in acute rejection. Also the presence of CMV urges clinicians to reduce immunosuppression doses thus facilitating rejection as well.
Light microscopy biopsy picture showing-patchy interstitial pleomorphic infiltrate with Tubulitis is present, with characteristic intranuclear inclusions with surrounding halo (owl’s eye-type inclusion) and marked increase in the size of the cell – tubular epithelial cells.
What is your differential diagnosis
Cytomegalovirus infection
Acute cellular Rejection
Bk virus nephropathy
How do you manage this case?
Present clinical features,use of ATG and biopsy indicates this is a case of cytomegalovirus infection. We administer valganciclovir 900 mg orally twice daily, with dose adjustment for kidney function. We generally treat until both symptoms and CMV viremia have resolved (ie, CMV is undetectable or lower than the limits of a sensitive assay in two quantitative PCR tests drawn one week apart). The typical duration of therapy is 21 days but is often longer, particularly for patients with tissue invasive disease .
The pathologist queried grade 1 ACR. Would your management differ?
In addition to valganciclovir ,we have to give pulse IV methyprednisolone at 3 to 5 mg/kg daily for three to five doses, with a maximum daily dose of 500 mg. No ATG should be given even if it is Banff IB ,considering the fact ,patient is also suffering from Cytomegalovirus. ATG in this case may lead to widespread cmv infection.
What is the association between this condition and ACR?
Indirect effects of CMV infection are upregulation of human leukocyte antigens and adhesion molecules that can promote acute allograft rejection.
What is your differential diagnosis?
In the above patient ,Histopathology slide revealed infiltration of tubules with lymphocyte along with peri tubular capillaritits,mild interstitial inflammation and characteristic owl’s eye appearance(viral inclusions).Differentials which should be considered include CMV nephritis, BK nephropathy or cellular rejection.
How do you manage this case?
Likely cause in the above case is CMV nephritis-First confirmation should be done with PCR in tissue and blood. Then MDT including infectious disease specialist along with renal transplant physician,and transplant surgeon should be involved . Immunosuppression should be reduced i.e., antimetabolite to half first and then completely stopping if no response clinically and also no decrease in viral load.CNIs level should be kept at lower level(5-7ng/ml).Patient should be counseled in detail about the chances of rejection and graft loss because of reduction in immunosuppression. Start I/V gancyclovir in a dose of 5mg/kg/12 hours(renal adjusted dose in renal impairment) for the first 5 days ,followed by oral valgancyclovir(900 mg twice daily) to complete the duration of at least 21 days or PCR is negative for 2 consecutive samples o1 week apart. Close monitoring of CBC needed while on antiviral due to side effect of bone marrow suppression. PCR weekly done .Graft function monitoring also needed due to chances of rejection. Prophylaxis to be started immediately after treatment for at least 3 months.
The pathologist queried grade 1 ACR. Would your management differ?
Treatment will be high dose steroids i.e., methylprednisolone (5-7 mg/kg/day) along with reduction of antimetabolite , CNIs and commencement of antivirals i.e., ganciclovir.
What is the association between this condition and ACR?
Both types of rejection(ACR, ABMR) are increased in the presence of CMV infection as interferon gamma increases the expression of co-stimulatory molecules on vascular endothelial and tubular epithelial cells, leading to immune response activation to graft. The Impact study revealed 16-18% allograft failure within1-2 years.
REFERENCES:
1-CMV in kidney transplantation Lecture by Ahmed Halawa.
2-Ana carina Ferreira, David Navaro. Cytomegalovirus nephropathy in transplant patients. Nephrology Dialysis Transplantation. 2021; 36:777-778
What is your differential diagnosis?
· CMV nephritis with characteristic owls’ eye inclusions in glomerular capillaries (High immunological risk ; D+/R+ for CMV and also received ATG to treat ACR)
· ACR+CMV nephritis
· BK nephropathy
How do you manage this case?
· A challenging case with active tissue invasive CMV that may be coupled with ACR
· MDT approach including ID and the Transplant team
· Simple basic investigations (FBC, U&E), TAC trough level, CRP, UPCR + CMV PCR), best supportive treatment including hydration and proper counseling of the patient about this challenging situation and the chances of graft loss with reduction in immunosuppression.
· Immunosuppression modification: Stop anti-metabolites and reduce CNIs by 25-50%. Titrate steroids upwards(pulse steroids can be given to treat ACR if present) and monitor graft function. Antimetabolites can be reintroduced once infection has cleared at a lower dose but if CMV recurs stop antimetabolites completely)
· Antiviral treatment: IV ganciclovir 5 mg/kg (adjust dose according to Creatinine clearance) for 2 weeks then change to oral valganciclovir 900mg BID with weekly CMV PCR monitoring, graft function and FBC. Treatment is continued until 2 negative PCR results are obtained coupled with resolution of symptoms. In case of Ganciclovir resistance (no response after 2 weeks)switch to second line treatment with consideration to their side effects( Foscarnet, Letermovir, Maribavir or Cidofovir). IVIG or CMV IG to be considered.
· Initiate PCP and fungal prophylaxis
The pathologist queried grade 1 ACR. Would your management differ?
· There would be no difference in the treatment as ATG for steroid resistant ACR was already given.
· The patient will continue treatment for CMV with antiviral treatment coupled with modification of immunosuppression. Pulse steroids can be given during that time. IVIG or CMV IG to be considered.
What is the association between this condition and ACR?
· CMV is an important risk factor for ACR and AMR. CMV disease appeared to influence long term graft survival but only when coupled with the occurrence of acute rejection.
· CMV has been associated with increased co stimulatory molecules on antigen presenting cells, tubular epithelial cells and T lymphocytes which mediate acute rejection. Also, CMV can result in the production of MHC 1 AND 2 molecules on T cell surface which led to acute rejection.
References:
1. Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13512.
2) Kotton CN, Kumar D, Caliendo AM, Huprikar S, Chou S, Danziger-Isakov L, Humar A; The Transplantation Society International CMV Consensus Group. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation. 2018 Jun;102(6):900-931.
30 Aziz F, Djamali A. Post-Transplant CMV Glomerulitis. Clin J Am Soc Nephrol. 2021 Jun;16(6):957-959. doi: 10.2215/CJN.19061220.
This patient has infection with CMV as demonstrated by owel eye appearance in histopathology of renal biopsy with tubulitis, rejection is also a possibility
management include :
1- IV valganciclovir
2- optimization of immunosuppression
3- consider pulse methylprednisolone
CMV cause immune modulation hence leading to rejection
68-year-old woman
admitted with a deterioration of kidney function.
3 months ago a cadaveric renal transplant
ESRD secondary to APKD.
CMV D+/R-
She received ATG for steroid-resistant acute cell-mediated rejection (ACR) 3 weeks after transplantation.
A routine infection screen and USS of her kidney were normal.
A second Kidney biopsy for another deterioration of the kidney function
● What is your differential diagnosis?
The graft biopsy showed ” owl eyes ” with Interstitial inflammation and mild tubulitis that characters CMV infection with possibility of Acute cellular rejection
● How do you manage this case?
☆ First we need complete laboratory evaluation: full blood count, electrolytes, liver tests, urine analysis, and blood PCR(CMV).
☆ Maintained patient hydration and electrolytes .
☆ Reduction of immunotherapy carefully because of high risk of rejection.
☆ Antiviral therapy with IV GCV then switching to VGCV when patient is stable and his condition has improved , and continuing VGCV at least for 2-3 weeks.
☆ Monitoring graft function and PCR ( CMV) to detect resistant CMV infection
☆ In case of resistant CMV we can switch to foscarnet or zidovudine with CMV IVIG that may be useful.
☆ MP cycle for associated ACR
● The pathologist queried grade 1 ACR. Would your management differ?
MP + previous Management
● What is the association between this condition and ACR?
CMV infection is a risk factor for ACR
References:
4. Seung Hyuk Yim , Mun Chae Choi , Deok-Gie Kim , Eun-Ki Min , Jae Geun Lee , Dong Jin Joo and Myoung Soo Kim.Risk Factors for Cytomegalovirus Infection and Its Impact on Survival after Living Donor Liver Transplantation in South Korea: A Nested Case-Control Study.Pathogens 27 march 2023, 12, 521.
5. UK Guidelines on prevention and Management of cytomegalovirus (CMV) infection and disease following solid organ
transplantation . British Transplantation Society.April 2022.
kidney biopsy showed:
renal tubule contains large, intra-nuclear inclusion bodies typical characteristic for CMV , The typical Owl eye picture of intra-cellular
basophilic inclusions with surrounding halo of CMV infection
with mild Tubulitis and focal Interstitial inflammation.
What is your differential diagnosis?
-CMV infection ( CMV Nephropathy).
– BK nephropathy.
– ACR
Investigation:
-CBC, CRP
-KFTs
-PCR for detection of CMV ,EBV and BKV
-Tacrolimus trough Level
-DSA level
– Biopsy from the graft with immunohistochemistry.
How do you manage this case?
This patient has Receive graft from CMV positive donor, ATG was given so high risk for CMV nephropathy , together with biopsy findings so most probable diagnosis is CMV nephritis.
Treatment depend on antiviral drugs together with reduction of IS:
-Stop MMF
-Reduce CNI by 25-5- %, with close monitor of graft function due to high risk of rejection, keep tacrolimus trough level around 5 .
counselling the patient about the risk of infection it self in immunocompromised patient, risk of associated ACR and rejection
– methylprednisolone pulse for acute cellular rejection.
Antiviral therapy:
Treatment is indicated in active infection as CMV viral syndrome or case of tissue-invasive CMV disease.
-IV ganciclovir is the gold standard treatment of CMV disease.
-In mild and moderate cases of the disease, oral valganciclovir is effective as IV.
-severe disease must be treated with IV ganciclovir.
-Acyclovir and valacyclovir are not used for treatment.
– intravenous ganciclovir (5mg/kg IV 12 hourly, to be adjusted according to creatinine clearance). It should be continued for minimum 2 weeks and until improvement of graft dysfunction with clearance of CMV viral load confirmed by PCR.
-oral Valganciclovir continue for 2-3 weeks after clearing viraemia and 2 negative PCR 2 weeks apart.
– resistance is suspected with clinical progression and /or persistent viral replication 2–3 weeks after treatment.
Resistant is observed in 1–2% of KTRs, Drug resistance commonly develops in CMV D+/R− recipients, also in long antiviral therapy, high viral load and high level of immunosuppression, viral mutants (UL97) is also associated with resistance
-Drug-resistant and refractory disease may responds to increased dose of ganciclovir with adjustment according to graft function .
-in resistant cases(IVIG) should be considered.
The pathologist queried grade 1 ACR. Would your management differ?
In presence of ACR , pulse methylprednisolone 500mg IV for 3-5 days is recommended to reduce risk of rejection associated with IS reduction, together with antiviral TTT.
CMV disease increase risk for acute cellular rejection, and ABMR
modulation of the immune system response against the allograft (CMV may express molecules similar to MHC class I and II antigens priming the immune ).
is important effect of CMV infection on transplanted kidney, rather than CMV nephritis. It promotes rejection by T-cell-mediated response .
references
Željka VH, Nika K. Viral Infections after Kidney Transplantation: CMV and BK [Internet]. Perioperative Care for Organ Transplant Recipient. Intech Open; 2019.
Gardiner BJ, Chow JK, Price LL, Nierenberg NE, Kent DM, Snydman DR. Role of secondary prophylaxis with valganciclovir in the prevention of recurrent cytomegalovirus disease in solid organ transplant recipients. Clinical Infectious Diseases. 2017;65(12):2000-2007.
Aslani HR, Ziaie S, Salamzadeh J, Zaheri S, Samadian F, Mastoor-Tehrani S. Incidence of ganciclovir resistance in CMV-positive renal transplant recipients and its association with UL97 gene mutations. Iranian Journal of Pharmaceutical Research. 2017;16(2):805-810
What is your differential diagnosis?
The differential diagnosis is of CMV nephritis, PTLD, BK virus nephropathy.
How do you manage this case?
Alteration in immunosuppressive drugs by Reduction or stopping of immunosuppressants. IV Ganciclovir 5 mg should be started.
The pathologist queried grade 1 ACR. Would your management differ?
Yes, there is no need to reduce immunosuppression immediately.
What is the association between this condition and ACR?
CMV infection is the predisposing factor for ACR induction.
Q1: This Kidney shows a characteristic owl’s eye inclusion body which indicates CMV nephritis. In addition, fabulists are seen which indicated acute cellular rejection.
BK virus nephropathy, drug-related interstitial nephritis or even PTLD may be the other differential diagnosis.
Q2: anti-CMV therapy with IV ganciclovir 5 mg/kg/dose BD (adjusted according to kidney function) should be started. CMV viral load should be monitored weekly. At least 5 days of IV therapy is recommended. After two negative results for CMV PCR, the treatment could be stopped. Oral valganciclovir could replace IV ganciclovir after clinical improvement.
For resistant or refractory CMV with no response after two weeks of adequate IV ganciclovir, IV foscarnet or IV cidofovir or oral maribavir are alternatives.
Q3: for this high-risk patient, methylprednisolone pulses should be used to treat ACR.
Q4: CMV infection or disease has indirect effects on immunity that can trigger acute rejection.
Thanks for this case
I had a similar case at my work and it was managed as per Dr Halwa recommendations
IV steroids for ACR
Treatment of CMV
This is a challenging case of CMV infection in patient has already treated with ATG for steroid-resistant acute cell-mediated rejection (ACR)
I want to share this study that mentioned the relation between prior ACR and CMV infection
“rejection is a risk factor for CMV infection that appears to persist for 1 year. Preceding rejection events increased risk of graft loss and mortality in CMV patients. Given this, prolonged surveillance monitoring for CMV after rejection may be warranted. Studies are needed investigating optimal monitoring strategies.”
for this scenario the differential diagnosis
CMV infection
BK
CMR Or AMR
The management start with distinguish between a statu of CMV + AR
OR AR without CMV
laboratory evaluation:
Regular renal function monitoring
PCR CMV
PCR BK
c4d staining in renal biopsy samples
de novo DSA
Other steps of management
Anti-viral drug:
Reduce immunosuppression
The pathologist queried grade 1 ACR. Would your management differ?
this most probaply is CMV invasive tissue with owel eye appearance
This patient first of all need to reduce the MMF to 50% percent and then start the anti virla gancyclovir iv then shift to oral valgancyclovir
we need to confirme the diagnosis by doing the CMV PCR
yes will start this patient on iv steroid for the queries of ACR ,
in this case we need to manage first the CMV invasion disease amd the benifits outway the risk ,that mean if we will be agrresive in managing the ACR then will end up with severe CMV invasion and we may end up with death of the patient .
CMV is an immunomudulater virus and increase the expression of MHC and anti endothelial Ab and increase the risk of AMR and ACR
CMV owl eye appearance
ACR
AMR
CBC ,KFT ,LFT ,Coagulation profile,viral pcr
Stress dose steroid ,decreasing MMF to 50 %,decreasing CNI to lower level
Starting IV ganciclovir till undetectable viral load and continue oral valgancyclovir for at least 6 months with monitoring of viral load.
No ,the same management
CMV nephritis increase the risk of both ABMR and ACR
What is your differential diagnosis?
Gram positive donor tx to gram positive recipient with tissue biopsy showing Owel eye appearance of intracellular inclusion bodies.
So most probably the diagnosis is CMV tissue invasive disease.
How do you manage this case?
First confirm the diagnosis of CMV invasive tissue disease through
Basic investigations, CMV PCR
Management include
First supportive therapy
Treatment of CMV invasive disease
Gangiclovir 5 mg iv every 12 hours for minimum of 2 weeks followed by 1 to 2 months of vanganciclovir
Dose adjustment of ganciclovir according to Creatinine clearance
Reduction of immunosuppression esp MMF which should be stopped or decreased by 50 %
Pulse steroids may be initiated
The pathologist queried grade 1 ACR. Would your management differ?
Antiviral treatment with ganciclovir in addition to pulse steroids
What is the association between this condition and ACR?
CMV may induce ACR through various mechanisms e.g increase expression of MHC or anti Endothelial antibodies
1- Q1-What is your differential diagnosis?
A- CMV infection . histopathlogy slide show OWL,S eye sign .
B- Acute cell mediated rejection .
C- BK virus nephropathy .
2- Q2 – How do you manage this case?
A- Admission to hospital with close monitoring of vital signs .
B- Supportive care .
C- Baseline investigation (CBC , GUE , B UREA , S CREATININE , RBS , LFT, )
D- QNAT (CMV PCR ) .
E- PCR for BK virus , decoy cell .
F- TCROLIMUS OR CYCLOSPORINE blood level .
G- For suspected ACR 3-5 doses of 500 mg methylprednisolone should be used .
H- Anti-viral therapy in case of confirmed CMV: IV gancycolvir 5mg/kg bid for 5 days followed by oral valgancyclovir 900 mg od until 2 X PCR negative. Adjust the drug doses according to the renal function.
3- The pathologist queried grade 1 ACR. Would your management differ?
Yes, this information impact the line of treatment . in the absence of any sign of rejection the usual step of treatment is to manipulate the the immune- suppressive medication ( especially stopping the anti proliferative agent – MMF, Azathioprine ) . but with a sign of ACR the opposite action will needed ie intensification of immunosuppression .
4- What is the association between this condition and ACR?
CMV is an immune modulating virus it induce adhesive molecules and can precipitate ACR.
REFFERENCES:
A T Borchers 1, R Perez, G Kaysen, A A Ansari, M E Gershwin. Role of cytomegalovirus infection in allograft rejection: a review of possible mechanisms. 1999 Jun;7(2):75-82. doi: 10.1016/s0966-3274(99)80023-9.
Differential Diagnosis:
1. CMV infection: owl eye appearance
2. ACR
3. BK nephropathy.
Management:
For CMV:
1. CMV PCR
2. Reduction of immunosuppression: stop MMF/AZA, continue CNI and steroids, and discuss the risk of rejection.
3. CNI levels
4. IV ganciclovir and monitoring of CMV PCR.
The pathologist queried grade 1 ACR. Would your management differ?
Yes, In ACR no reduction of immunosuppression, continuation of AZA/MMF, monitoring CNI levels.
IV Methylprednisolone 500mg daily for 3-5 days.
What is the association between this condition and ACR?
CMV is an immunomodulatory virus and can therefore induce ACR.
The owl eye appearance with the rejection draws the attention of CMV as a cause.
We need to treat CMV by iv gancyclovir, followed by oral valganciclovir for a total of 3-4 weeks, together with pulse steroid.
CMV infection can result in an upregulation of adhesion molecules on vascular endothelium and increase the infiltration of lymphocytes, thereby facilitating the inflammatory process.
—–
https://pubmed.ncbi.nlm.nih.gov/10544437/
In the picture of renal histology showing characteristic owl’ s eye inclusion body with inflammatory infiltrate in the renal tubule. From the picture & given scenerio i have following differentials:
-CMV nephropathy
– Acute cell mediated rejection(ACR)
– Bk viral nephropathy
Investigation:
– CBC, LFT, Urea, creatinine, electrolytes
– CMV DNA PCR, BK viral PCR of blood & urine,
– Urine for decoy cell
Treatment:
According to cause
CMV nephropathy:
– Reduction of immunosuppression
– Anti CMV therapy ( I/V gancyclovir followed by oral valgancyclovir)- dose reduction according to renal function & continue after 2 weeks of CMV PCR negative.
– Monitoring of graft function
Yes there is difference.
– No immediate reduction of immunosuppression.
– I/ V methylprednisolone 500mg daily for 3 days. Consider increasing oral prednisolone to 0.3 mg/kg/ day to max. 20 mg, then taper by 5mg weekly to previous dose.
-Optimize maintenance immunosuppression ( switch cyclosporin to tacrolimus, target trough 10-12 ug/L)
– Few weeks later consider reduction of immunosuppression
CMV infection can cause immunomodulation & induce ACR by activation of T cell.
Differential diagnosis:
1. CMV infection is most probable diagnosis as typical sign, owls’ eye is there.
2. ACR
3. BK nephropathy
Management:
Further investigation to confirm diagnosis:
– Plasma for CMV PCR
– Plasma for BK virus
– SV-40 staining for BK virus
Treatment after confirm diagnosis
This Histological findings highly suggestive of CMV nephropathy, so treatment for CMV disease can be started.
The pathologist queried grade 1 ACR. Would your management differ:
The initial treatment with steroids pulse therapy, reduction of MMF along with antiviral therapy.
What is the association between this condition and ACR:
CMV infection is important predisposing factor for acute allograft rejection after kidney transplantation.
Reference:
Boshra Hasanzamani et al. The effect of cytomegalovirus infection on acute rejection in kidney transplanted patients, J Renal Inj Prev. 2016 May 16;5(2):85-8.
The differential diagnosis include:
CMV Nephropathy
BK Nephropathy
ACR
The graft biopsy revealed the characteristics owls eyes inclusions highly suggestive of CMV nephritis, with the presence of tubulitis and inflammatory cells infiltration suggestive of ACR grade 1.
This is a challenging case with concomitant ACR and CMV nephritis.
The management plan start by pulse steroid with antiviral drug gancyclovir iv , with monitoring of the viral load.then after a short period of time we consider reduction of immunosuppression.
The CMV infection highly associated with acute rejection episode of around 30%.
D/D: CMV nephropathy associated ACR
Mx: start oral ganciclovir with pulse MP, continue the ongoing immunosuppresive drugs ( not taper, up to CMV treatment while careful monitoring of renal function).
CMV is associated with acute graft rejection & decresed geaft survival.
1- CMV infection ( Typical owl’s eye inclusion bodies in kidney biopsy )
2- PK virus
3- ACR in combined with CMV infection ( Lymphocytic infiltration plus tubulitis )
This is a complicated case becuase he had both CMV infection with evidence of ACR
so treatment should be reduction of MMF , give pulse steroid for 3 days and start intravenous ganciclovir (5 mg/kg every 12 hours). Patients with CMV disease should receive at least weekly monitoring of blood viral load, and antiviral therapy should be continued until there is suppression of viremia, typically 14 to 21 days. After successful suppression of viral replication, an additional course of suppressive therapy, valganciclovir 900 mg once daily, may be continued for an additional 1 to 3 months, or longer if indicatedand start IV ganciclovir 5 mg/kg and the dose can be adjusted according to the graft function for two weeks then change to oral valganciclovir 900mg BID for a total 3 weeks course with weekly CMV PCR monitoring, graft function monitoring .
CMV replication is associated with indirect effects of immune modulation and dysregulation, and can culminate in opportunistic infection and allograft injury or rejection.
References :
1) Hand Book of kidney transplantation 6th Edition .
1. What is your differential diagnosis?
Allograft biopsy showing typical “Owl eye” inclusions body characteristic of tissue invasive CMV disease. Also seen are lymphocytic infiltration in tubules (Tubulitis), interstitium, flatten tubular epithelium, peritubular capillaries, glomerulus and sub-endothelium of blood vessels suggestive of ACR + AMR.
Diagnosis – CMV nephropathy + ACR (recovering) + ABMR.
Cadaveric transplant -must have received induction and heavy immunosuppression
Steroid resistant ACR already treated with ATG – improved initially.
CMV serostatus D+/R- leads to primary CMV infection, CMV disease involving renal allograft and a second time renal dysfunction.
2. How do you manage this case?
Evaluation: C4d immune-staining of biopsy sample
Also review the previous biopsy (prior to ATG) to compare grade
Blood tests – CBC, RBS, CNI drug (C0) level, CMV quantitative PCR (baseline + for monitoring response to therapy)
Treatment:
Aggressive antiviral therapy is the mainstay of treatment, shall improve renal function (to some extent).
Frequent monitoring serum Creatinine, can guide to decide further treatment of Rejection.
ACR may be in recovery phase following recent ATG administration – better to watch and wait. Further administration of ATG can be detrimental.
Pulse Methyl prednisone may not work (recent steroid resistant ACR) – may be tried with sugar control.
· Oral Valgancyclovir 900mg twice daily (dose adjusted ac/to GFR) for 2weeks – till symptoms improve, resolution of graft dysfunction + clearance of CMV viremia (CMV DNA negative on 2 consecutive PCR done at 7days apart).
Except for graft dysfunction, this patient does not have any systemic illness, thus cumbersome administration of IV Gancyclovir therapy and its side effects can be avoided.
Oral Valgancyclovir is as effective as IV Gancyclovir for clearance of viremia, is better tolerated, has less side effects and resistance to CMV – (VICTOR trial)
· Monitoring Ser Creatinine, CBC and CMV viremia weekly. If no satisfactory response within 2 weeks -> Inj Foscarnet + CMV- immunoglobulin should be considered.
· ABMR can be treated simultaneously with IVIg. Clearing of CMV, would improve allograft function and pulse steroid may treat initial ABMR to some extent.
– Once CMV is cleared, and patient’s condition stable, Plasma exchange with IVIg +/- Retuximab may be tried.
· Secondary prophylaxis after viral clearance, with oral valganciclovir 900mg daily for 6 months should be given to prevent relapse.
· Immunosuppression Reduction at present can aggravate rejection. However, reduction of MMF (50%) and CNI to minimal dose can be considered after successful treatment of rejection.
References:
1. Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9).
2.UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION. bts.org.uk 05 July 2022
3. Anders Åsberg , Atul Humar , Halvor Rollag, et al. Lessons Learned From a Randomized Study of Oral Valganciclovir Versus Parenteral Ganciclovir Treatment of Cytomegalovirus Disease in Solid Organ Transplant Recipients: The VICTOR Trial. Clin Infect Dis. 2016 May 1;62(9):1154-60.
3. The pathologist queried grade 1 ACR. Would your management differ?
· CMV nephropathy + Gr1 ACR + AMR – situation is complex, difficult to treat CMV as well as rejection simultaneously, but we have to prioritise the treatment decision.
· Treatment of CMV takes priority, as it can be life-threatening if not treated adequately. Aggressive antiviral therapy (IV Gancyclovir) or Oral Valgancyclovir + CMV-Ig should be administered with monitoring CBC, CMV viremia and creatinine.
· Also review the previous biopsy (prior to ATG) to compare grade and see if it is improving (recovery phase)
– As the patient had h/o steroid resistant ACR 2months back, Pulse Methyl Prednisone may not work; but it can be tried, if serum creatinine remains elevated after 2 weeks of antiviral.
· Quick Treatment of ABMR, also needed to have good response and to prevent graft loss.
4. What is the association between this condition and ACR?
CMV disease involving the renal allograft, cause graft dysfunction30-40% cases, which usually recovers once CMV infection is cleared after treatment.
Persistent CMV viremia can mimic the immune modulation by expression of MHC class I & II and thus increases risk of acute cellular rejection.
CMV infection can mimic production of anti-endothelial antibodies, cause ABMR.
Thus, CMV infection can aggravate both ACR and ABMR of renal allograft.
There are literature, also negating the direct association of CMV with rejection or graft loss.
References
n CMV infection is important predisposing factor for acute allograft rejection after kidney transplantation and control of CMV infection could decrease episodes of acute kidney rejection.
– Boshra Hasanzamani, Maryam Hami, Vajihe Zolfaghari, et al.
The effect of cytomegalovirus infection on acute rejection in kidney transplanted patients.
J Renal Injury Prevention. 2016; 5(2): 85-88. DOI: 10.15171/jrip.2016.18
n pCMV infection was not proven to increase the risk for acute rejection or allograft loss. However, it increased the risk for rejection-associated allograft loss. In remaining functioning allografts, it was not significantly associated with decline in function nor with presence of IF/TA.
– Clinical consequences of primary CMV infection after renal transplantation: a case–control study Ramandeep Singh, Hessel Peters-Sengers, Ester B.M. Remmerswaal, et al. Transplant International 2020; 33: 1116–1127
n Our data suggests that the link between CMV and AR is far less significant than previously thought. Outcome in patients with CMV may be more determined by coexisting conditions like high donor age and delayed graft function.
– Uta Erdbruegger, Irina Scheffner, Michael Mengel, et al.
Impact of CMV infection on acute rejection and long-term renal allograft function: a systematic analysis in patients with protocol biopsies and indicated biopsies
Nephrol Dial Transplant (2012) 27: 435–443
The diagnosis of the patient is a post renal transplant recipient due to ADPKD and CKD V who received a kidney from CMV positive donor and patient was also CMV + recipient.. The patient has steroid resistant rejection in the past and received ATG for the same… she is currently admitted for deterioration in her renal function…
Graft biopsy was done and it showed typical owl eye inclusion in the WBC with tubulitis and interstitial inflammation… The risk factors for CMV in this patient are 3 months after cadaver transplant with history off ATG use of rejection and transplant between CMV+d/R+ status….
In the background of the above she is first suspected to have invasive CMV disease with CMV nephropathy…Immunohistochemistry for CMV DNA stain can be done in the renal biopsy and can be diagnosed as CMV disease… A mere detection of CMV viral load will prove only CMV infection but not disease…
Differential diagnosis of cellular infiltrate in the interstitium after renal transplant are acute cellular rejection, Acute CMV disease, Acute interstitial nephritis due to drugs, BK virus nephropathy, rarely PTLD also
But the typical owl eye appearance and the CMV DNA histochemistry will clinch the diagnosis….
Management includes IV hydration.. CBC, Tacrolimus trough levels monitoring, LFT should be done as a routine.. It is important to detect occult bacterial sepsis in renal transplant patients by sending cultures and start empirical antibiotics…I would start the patient on IV Ganciclovir 5mg/kg IV every 12th hourly according to the creatinine clearance…It should be continued for 14 days and atleast IV for 5 days and later oral valganciclovir to continue the treatment till there is recovery of graft function…CBC shoudl be monitored every alternate days and the dose should be reduced if there is marrow suppression….GMCSF can be added for leucopenia…If there is no response in 2 weeks we should suspect Ganciclovir resistance and test for the same and add Foscarnet with CMV specific IVIG….
After completion of the treatment I would place the patient on Oral Valganciclovir prophylaxis’s 900mg once a day for 3 months..
Immunosuppression needs to be reduced…Antimetabolites need to be stopped…CNI can be reduced
Although pathologist expressed concerns of acute cellular rejection class 1, It is important to treat the CMV first and then think about rejection…
There is increased risk of Acute cellular rejection with CMV disease..CMV virus can cause immune dysregulation and this can cause problems in terms of acute cellular rejection as evidenced by many studies…
Few other studies show that CMV disease is a risk factor for rejection, but not CMV infection..Few other studies proved that CMV infection was not associated with increased risk of rejection after 5 years
Sagedal S, Nordal KP, Hartmann A, Sund S, Scott H, Degré M. et al. The impact of cytomegalovirus infection and disease on rejection episodes in renal allograft recipients. Am J Transplant. 2002;2:850–6.
Toupance O, Bouedjoro-Camus MC, Carquin J, Novella JL, Lavaud S, Wynckel A. et al. Cytomegalovirus-related disease and risk of acute rejection in renal transplant recipients: a cohort study with case-control analyses. Transplant Int. 2000;13:413–9.
Differential diagnosis:
(i) CMV infection is most probable diagnosis as typical sign, owls’ eye is there.
(ii) ACR
(iii) BK nephropathy
Management:
Further investigation to confirm diagnosis-
– Plasma for CMV PCR
– Plasma for BK virus
– SV-40 staining for BK virus
Treatment after confirm diagnosis-
This Histological findings highly suggestive of CMV nephropathy, so treatment for CMV disease can be started.
The pathologist queried grade 1 ACR. Would your management differ?
The initial treatment with steroids pulse therapy, reduction of MMF along with antiviral therapy.
What is the association between this condition and ACR?
CMV infection is important predisposing factor for acute allograft rejection after kidney transplantation.
Reference:
Boshra Hasanzamani et al. The effect of cytomegalovirus infection on acute rejection in kidney transplanted patients, J Renal Inj Prev. 2016 May 16;5(2):85-8.
This lady has
The biopsy is suggestive of “owl-eye” appearance bodies suggestive of CMV nephropathy.
This a very challenging situation, where we need to treat rejection, which in turn would worsen CMV infection.
Mangement:
Complete blood count, renal function test, urine protein levels, blood CNI levels and blood CMV PCR.
The pathologist queried grade 1 ACR. Would your management differ?
IV pulse steroid should be given to manage the ACR.
ATG is not required and if given may be lethal for patient, as it will flare up CMV infection.
What is the association between this condition and ACR?
CMV is associated with increased risk of acute rejections.
Toupance O, Bouedjoro-Camus MC, Carquin J, Novella JL, Lavaud S, Wynckel A, Jolly D, Chanard J. Cytomegalovirus-related disease and risk of acute rejection in renal transplant recipients: a cohort study with case-control analyses. Transpl Int. 2000;13(6):413-9. doi: 10.1007/s001470050723. PMID: 11140239.
· What is your differential diagnosis?
· This is a recent transplant with history of rejection, ATG, CMV positive.
This is a second biopsy with histological findings suggest CMV nephropathy, the other differentials could be,
Acute cellular rejection,
BK infection & nephropathy,
Other viral infection.
Bacterial infection.
· How do you manage this case?
General management,
. IV fluid,
. Antipyretics,
. CMV PCR if confirmed then can start antiviral gencyclovir 5mg/kg BD.
. Monitor CMV viral load.
. if not responding give IVIG, and switch to second line agent.
. Immunosuppression modification reduction by 50% (antimetabolite),
Specific management,
. Treat rejection with and Pulse with steroid,
. IVIG
. Plamapheresis,
· The pathologist queried grade 1 ACR. Would your management differ?
. Would be a difficult case to treat because there is history of rejection, ATG and CMV positive these will increases the risk and challenges the management.
. But according to Banff criteria I would suggest only treat infection and pulse with methylprednisolone for possible ACR.
· What is the association between this condition and ACR?
. The CMV infection increases the risk acute cellular rejection antibody mediated too.
. Persistent viremia can mimic the immune modulation by expression of MHC class I & II and increases the risk of rejection.
. CMV infection can mimic production of anti endothelial antibodies.
we will send full investigation[CBC,RFT,S.electrolytic,CMV PCR,BK Virus PCR].
start CMV virus treatment ganciclovir vial 5mg\kg bid according to renal function for 10 to 14 days after that valganciclovir tab 900 mg daily if renal function goof monitoring renal function and CMV PCR .
👉 The current case has deterioration of kidney function, with biopsy shows owl eye appearance (inclusion bodies of CMV infection) that means tissue invasive disease (mostly occurs after treatment of steroid resistant ACR with ATG).
👉 Differential diagnosis:
_CMV invasive disease with nephritis.
_Interstitial nephritis
_ACMR (Marked interstitial infiltration with lymphocytes).
_BKN.
👉 Management of the case:.
_ Treatment of CMV with IV ganciclovir followed by oral ganciclovir is essential. And should be continued for 2 weeks after clearance of CMV from the blood by 2 negative PCR
_Close monitoring of graft function and protinuria as risk of acute rejection is increased as CMV invites rejection.
_Reduction of IS must be very cautious and gradually for fear of rejection.
_FU CMV PCR is essential to guide treatment plan.
👉 The management plan will differ with ACR...we can use pulse steroids to treat rejection as the patient had history of steroid resistant TCMR that occured early post transplant.
While it is contraindicated to use ATG as it will cause T cell depletion and causes flairing up of CMV infection.
⭐ The association between CMV and rejection …CMV infection can trigger or invites rejection through upregulation of cytokinesis expression and increased MHC class I and II expression on the tubular epithelial cells and in the endothelium and on the other hand occurance of acute rejection and the subsequent anti rejection therapy can increase risk of CMV infection and tissue invasive disease.
The presence of typical owls eye sign is suggestive of tissue invasive CMV. The associated interstitial inflammation reflects possible ACR which can be triggered by CMV .
In such scenario management of of CMV with immediate IV Ganciclovir followed by oral valganciclovir is the key. A repeat biopsy and CMV PCR can be done as follow up of management.
The renal histopathology showed:
It is a hematoxylin and eosin stain)
Lypmphoplasmacytic infiltrate with tubulitis
Viral cytopathic changes with enlarged tubular epithelial cells and owl’s eye type nuclear inclusions.
So, my differential will be.
How do you manage this case?
What is the association between this condition and ACR?
CMV infection has been associated with upregulation of cytokines, adhesion molecules
Prof Halawa lecture – CMV in kidney Transplantation.
Uptodate – CMV post renal transplant ; diagnosis and treatment
The presence of inclusion bodies and cellular infiltration point out to CMV-associated ACR
also, interstitial nephritis should be considered
Management
cbc crp LFT
CMV PCR
CMV serology
culture
If confirmed anti viral therapy should be started IV gancyclover 5mg/kg /12h for 5 days followed by 900 mg BID valcyte until two negative PCR s
Regarding associated ACR
antiviral therapy should be continued under coverage of pulse steroids
close monitoring of KFT and rebiopsy
the association is mostly due to reactivation of a latent virus secondary to ATG
The biopsy showed characteristic owl’s eye intranuclear inclusion bodies and lymphocytic infiltration, glomerulitis and capillaritis in the kidney of patient with suspected disseminated cytomegalovirus infection, so differential diagnosis mainly:
CMV with ACR
ABMR
BKV
The management
C4d, SBA, PCR for CMV, decoy cells in urinary sediment
Treat the CMV under cover of methylprednisolone, continue the CNI when there is no life threading condition otherwise stop or reduce it, stop or reduce the MMF, give I/V ganciclovir or valganciclovir for at least 2 weeks and monitor the virus load, the treatment should be continued for 2 weeks after disappearance of the virus from the blood.
In case of ABMR give IVIG + PE.
The pathologist queried grade 1 ACR. Would your management differ?
The patient can be cover with methylprednisolone and anti CMV therapy.
What is the association between this condition and ACR?
The CMV infection leads to immunomodulation via activation of T-lymphocyte and inflamation that may result in ACR
Handbook of Kidney Transplantation
496 Pages · 2009 · 6.1 MB · 2,126 by Gabriel M. Danovitch
What is your differential diagnosis?
This slide shows Owl eye sign, suggesting CMV disease
The differentials include-
· CMV nephritis
· BK nephropathy
· Acute Cellular rejection
How do you manage this case?
I will like to do blood tests like full blood count, renal functions, liver functions, CMV PCR
I will start CMV treatment and monitor it. I will start with IV ganciclovir according to renal functions and monitor the treatment.
I will check viral load at 2 week and then weekly.
I will halt the treatment once symptoms have resolved and two negative CMV PCR are achieved.
I will also give pulsed Intravenous methylprednisolone
I will carefully watch for any opportunistic infections
The pathologist queried grade 1 ACR. Would your management differ?
No. I will continue both ganciclovir and steroids and maintain immune suppression.
What is the association between this condition and ACR?
CMV infection can alter immune response which can result in acute cellular rejection. Viral reactivation can reduce cellular immunity.
References-
Al Atbee MYN, Tuama HS. Cytomegalovirus infection after renal transplantation. J Med Life. 2022 Jan;15(1):71-77.
Hasanzamani B, Hami M, Zolfaghari V, Torkamani M, Ghorban Sabagh M, Ahmadi Simab S. The effect of cytomegalovirus infection on acute rejection in kidney transplanted patients. J Renal Inj Prev. 2016 May 16;5(2):85-8.
What is your differential diagnosis?
1-CMV nephropathy
Presence of Owl Eye sign in renal biopsy (inclusion bodies )
2-Acute rejection
Tubulitis and interstitial infiltration
How do you manage this case?
1-serology, quantitative polymerase chain reaction(PCR), pp65 antigenemia, culture, and histopathology
CBC,
RFT,
CNI drugs level
– The standard therapy for TCMR remans intravenous steroids and T cell depletion.
but as Administration of ATG increases the risk of worsening CMV disease therefore would be to treat cmv infection with IVIG and pulse steroid
CMV association with ACR;
-CMV has been associated with increased co stimulatory molecules on antigen presenting cells, tubular epithelial cells and T lymphocytes which mediate rejection.
-CMV infection along with previous episodes of Rejection with augmentation of IS might have led to Rejection
REF;
Prof Halawa lecture – CMV in kidney Transplantation.
Uptodate – CMV post renal transplant ; diagnosis and treatment
The graft biopsy shows typical “Owl eye” picture of intracellular inclusions characteristic of CMV infection and mild to moderate tubulitis with interstitial inflammation; ie tissue-invasive CMV disease: CMV nephropathy .CMV antigen detection by immunohistochemistry can help in diagnosis.
Acute rejection (acute cellular rejection as well as antibody mediated rejection) should be included in DD.
Management:
Routine lab work up in addition to CNI trough levels& CMV PCR in blood.
– IV ganciclovir (5mg/kg IV 12 hourly, adjusted according to creatinine clearance, continued for minimum 2 weeks ;to be changed to oral valganciclovir, if symptoms improve and until resolution of graft dysfunction with clearance of CMV in blood.
– Complete blood count and serum creatinine monitoring weekly during the treatment. If no response within 2 weeks, shift to Foscarnet and additional CMV immunoglobulin or IVIG should be considered.
-Secondary prophylaxis: oral valganciclovir post-treatment can be given for 1-2 months in case of high-risk of relapse.
– Antimetabolites should be reduced by 50% ,but with recent acute rejection, it is not possible due to high risk of rejection . IV methylprednisolone pulse can be used to treat acute cellular rejection. CNI trough levels should be checked.
GI ACR:
The most important measure in is to treat CMV disease. IV methylprednisolone can be used in addition to anti-viral treatment.
-Relation to ACR:
CMV disease is a risk factor for acute tubulointerstitial rejection in renal transplant recipients.
References:
Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9).
What is your differential diagnosis?
-The biopsy showed Owl eye sign →Tissue-invasive CMV disease
-ACR and CMV nephritis
-BK nephropathy
How do you manage this case?
– CBC ,CMV PCR and RFT.
– Started IV ganciclovir for a duration of at least 2 weeks and adjust the dose of ganciclovir according creatinine clearance.
.Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days and Consider stopping treatment for CMV disease after resolution of symptoms and two consecutive, CMV viral load tests that confirm that CMV is not detected.
-Iv pulse steroid.
The pathologist queried grade 1 ACR. Would your management differ?
No,continue on methylprednisolone and IV ganciclovir.
What is the association between this condition and ACR?
CMV infection has been associated with upregulation of cytokines, adhesion molecules and increased expression of MHC class II surface markers that may result in AR.
References:
1. UK GUIDELINE ON PREVENTION AND MANAGEMENTOF CYTOMEGALOVIRUS (CMV) INFECTION ANDDISEASE FOLLOWING SOLID ORGANTRANSPLANTATION.
2. Uta Erdbruegger et al.Impact of CMV infection on acute rejection and long-term renal allograft function: a systematic analysis in patients with protocol biopsies and indicated biopsies .Nephrology Dialysis Transplantation, Volume 27, Issue 1, January 2012, Pages 435–443, https://doi.org/10.1093/ndt/gfr306
I like your DD.
4. A 68-year-old woman was admitted with a deterioration of kidney function. She had a cadaveric renal transplant 3 months ago for ESRD secondary to APKD. She received a kidney from CMV positive donor (she was also CMV-positive at the time of transplantation). She received ATG for steroid-resistant acute cell-mediated rejection (ACR) 3 weeks after transplantation. A routine infection screen and USS of her kidney were normal. A second kidney biopsy for another deterioration of the kidney function
What is your differential diagnosis? (1)
– CMV nephropathy
– CMV-associated interstitial nephritis
– Acute T-cell mediated rejection
– BK nephropathy
How do you manage this case? (1, 2)
– Detailed history e.g., diarrhoea, nausea, vomiting, odynophagia, dysphagia, oral ulcers, dyspnoea, cough
– Thorough physical examination.
– Baseline investigations e.g., FHG, UECs and extended electrolytes, LFTs, blood sugar, urinalysis, CMV viral load (qualitative PCR), BKV viral load (qualitative PCR), immunohistochemistry (C4d, SV40), DSAs
– Multidisciplinary approach i.e., involve renal pathologist, infectious disease specialist.
– AKI management i.e., volume repletion if the patient is volume depleted.
– Antiviral therapy – initiate IV ganciclovir (especially in patients with severe disease or patients who cannot tolerate oral medication) then transition to oral valganciclovir (dose adjusted according to the renal function) while monitoring the CMV viral load. The duration of treatment is usually 3 weeks then followed by 3months of prophylaxis with valganciclovir.
– Treatment should continue for an extra 14days once the patient has two negative PCRs.
– If resistant to ganciclovir (as evidenced by failure of a log drop in the viral load two weeks into treatment) other options can be considered e.g., letermovir, maribavir, foscarnet or cidofovir.
– It is important to keep in mind that foscarnet and cidofovir are nephrotoxic.
– Immunosuppressive therapy – a delicate balance has to be struck between controlling the infection and preventing a possible rejection i.e., ideally, we should discontinue the antimetabolite or reduce the dose by 50% (i.e., mycophenolic analogues, azathioprine) especially in the setting of leucopenia but continue with prednisone and CNI
– In case of severe neutropenia, GMCSF injections can be offered.
– Once the CMV infection has cleared the antimetabolite can be introduced at a small dose and thereafter titrated to target dose as guided by patient’s tolerance/ response.
– Counsel the patient on the possible graft outcomes i.e., further decline in graft function due to the reduction in immunosuppressive doses.
The pathologist queried grade 1 ACR. Would your management differ? (3)
– The standard therapy for TCMR remans intravenous steroids and T cell depletion.
– It is important to bear in mind that this patient had received ATG for steroid-resistant ACR 3 weeks post-transplant and currently has a diagnosis of CMV. Administration of ATG increases the risk of worsening CMV disease.
– The safest bet would be another pulse therapy with methyl prednisone keeping a close eye on the possibility of developing other opportunistic infections due to the depressed immune status.
What is the association between this condition and ACR? (4-6)
– CMV infection has been associated with acute rejection, increased morbidity, mortality and in some instances, decreased graft survival.
– If CMV prophylaxis is not offered, CMV infection can occur in the first month post-kidney transplant.
– Administration of immunosuppressive agents to prevent rejection, increases the risk of CMV infection.
References
1. Rane S, Nada R, Minz M, Sakhuja V, Joshi K. Spectrum of cytomegalovirus-induced renal pathology in renal allograft recipients. Transplantation proceedings. 2012 Apr;44(3):713-6. PubMed PMID: 22483475. Epub 2012/04/10. eng.
2. Vichot AA, Formica RN, Jr., Moeckel GW. Cytomegalovirus glomerulopathy and cytomegalovirus interstitial nephritis on sequential transplant kidney biopsies. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2014 Mar;63(3):536-9. PubMed PMID: 24568687. Pubmed Central PMCID: PMC7210789. Epub 2014/02/27. eng.
3. Cooper JE. Evaluation and Treatment of Acute Rejection in Kidney Allografts. Clinical journal of the American Society of Nephrology : CJASN. 2020 Mar 6;15(3):430-8. PubMed PMID: 32066593. Pubmed Central PMCID: PMC7057293. Epub 2020/02/19. eng.
4. Hasanzamani B, Hami M, Zolfaghari V, Torkamani M, Ghorban Sabagh M, Ahmadi Simab S. The effect of cytomegalovirus infection on acute rejection in kidney transplanted patients. Journal of renal injury prevention. 2016;5(2):85-8. PubMed PMID: 27471740. Pubmed Central PMCID: PMC4962675. Epub 2016/07/30. eng.
5. Hartmann A, Sagedal S, Hjelmesaeth J. The natural course of cytomegalovirus infection and disease in renal transplant recipients. Transplantation. 2006 Jul 27;82(2 Suppl):S15-7. PubMed PMID: 16858268. Epub 2006/07/22. eng.
6. Sagedal S, Nordal KP, Hartmann A, Sund S, Scott H, Degré M, et al. The impact of cytomegalovirus infection and disease on rejection episodes in renal allograft recipients. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2002 Oct;2(9):850-6. PubMed PMID: 12392291. Epub 2002/10/24. eng.
I like your DD.
Thank you Prof.
1-CMV nephropathy
Presence of Owl Eye sign in renal biopsy (inclusion bodies )
2-ACM rejection
Tubulitis and interstitial infiltration
1-serology, quantitative polymerase chain reaction
(PCR), pp65 antigenemia, culture, and histopathology
CBC, RFT, CNI drugs level
1-reduce immunosuppression kidney transplant recipients with CMV disease. (decrease the dose of MMF to 50% and continue on CNI
patients who are at increased risk of rejection (eg, those who have undergone retransplantation or have a prior history of rejection), introduce the antimetabolite at a lower dose.monitor the blood for CMV replication with PCR at weekly intervals for four weeks to ensure that CMV does not reactivate at the lower antimetabolite dose.
2-Antiviral therapy Ganciclovir or its oral derivative, valganciclovir, is the preferred agent for most patients with CMV viremia or CMV disease. Oral maribavir, intravenous (IV) foscarnet, and IV cidofovir are alternatives and are primarily used for patients with known or suspected infection with resistant or refractory CMV
The selection of antiviral treatment is determined by the severity of illness, initial viral load, ability to tolerate oral medication, and the ability to administer IV therapies at home. The selection of antiviral therapy is not stratified depending upon whether the patient has CMV syndrome or tissue-invasive CMV disease
Both CMV syndrome and tissue-invasive disease may be associated with significant clinical manifestations and high viral loads.
generally continue one of the antiviral regimens until the clinical signs and symptoms of CMV disease have completely resolved and there is no evidence of CMV viremia in two blood polymerase chain reaction (PCR) tests at least one week apart. The typical duration of therapy is 21 days but is often longer, particularly for patients with tissue invasive disease
I will continue on CMV treatment that mentioned above with additional of 3 doses of methylprednisolone
In recipients that carry the virus there may be viral reactivation, and the primary risk factors identified are the use of anti-lymphocyte antibodies .Reactivation is related to reduction of cellular immune activity, especially of CD8+ cells, as result of the immunosuppressed state, and also due to activity of cytokines that induce the virus to move from the state of latency, especially tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β).
Reference
1-up to date
2- Lúcio Roberto Requião-Moura1, Ana Cristina Carvalho de Matos1, Alvaro Pacheco-Silva2.
Cytomegalovirus infection in renal transplantation: clinical aspects, management and the perspectives. einstein. 2015;13(1):142-8
I like your 2 differential diagnoses but the list is not complete.
What is your differential diagnosis?
Considering the followings:
a) KTR with pre-transplant serostatus for CMV D+/R-.
b) ATG for steroid-resistant acute cell-mediated rejection (ACR).
c) Kidney biopsy after deterioration of the kidney function showed the appearance of an “owl’s eye” which goes with tissue invasive CMV.
The likely differential diagnosis:
1. Tissue invasive CMV
· CMV Nephritis(Tubulo-interstitial nephritis). Patients with tubulointerstitial CMV nephritis were significantly more likely to have rejection at the time of biopsy (50% vs. 0%, p < 0.05) compared to those with glomerular CMV nephritis(1).
· CMV glomerulopathy.
2. Infection related Rejection( CMV infection is known to trigger immune responses with subsequent rejection).
3. ACR or ABMR.
4. BK nephropathy.
How do you manage this case?
1. Hospital admission.
2. Detailed history and relevant clinical examination.
3. Investigations
a) CBC, RFT, LFT, urinalysis, septic screen, LDH and RBG.
b) for diagnosing CMV;
· Serologic tests that detect CMV antibodies (IgM and IgG) via ELISA.
· Detection of the CMV pp65 antigen in leukocytes.
· Quantitative CMV PCR (COBAS Amplicor Monitor Test).
c) Investigations for BK virus; urine for decoy cells and urine for BK DNA by PCR.
d) Investigations regarding expected rejection: DSA level and tissue examination for C4d deposition.
4. Treatment:
a) For CMV ganciclovir or Valganciclovir beside manipulation of MMF/AZA.
b) For concomitant rejection to consider methylprednisolone pulses to induce remission.
The pathologist queried grade 1 ACR. Would your management differ?
For ACR:
· I will consider pulses of methylprednisolone.
· Immunosuppression level to be at the lowest acceptable level.
· Treatment of CMV with anti-viral, Ganciclovir or Valganciclovir. .
What is the association between this condition and ACR?
CMV infection is known to trigger immune responses with subsequent rejection. It has been known for a long time that CMV reactivation and disease are associated with graft rejection, possibly due to overexpression of HLA molecules that would induce viral replication.
References
1. Swanson KJ, Djamali A, Jorgenson MR, Misch EA, Ghaffar A, Zhong W, Aziz F, Garg N, Mohamed M, Mandelbrot D, Parajuli S. Cytomegalovirus nephritis in kidney transplant recipients: Epidemiology and outcomes of an uncommon diagnosis. Transpl Infect Dis. 2021 Oct;23(5):e13702. doi: 10.1111/tid.13702. Epub 2021 Aug 7. PMID: 34324253.
There is contradiction in your reply:
‘I will consider pulses of methylprednisolone’ and ‘Immunosuppression level to be at the lowest acceptable level’.
This patient’s kidney biopsy showed an owl’s eye and features of lymphocyte infiltration along with ACR, and he is CMv positive before RTX and received a kidney from a positive donor as well, which put him at risk of CMV infection.
so I think this patient will need to start his CMV infection by iv Gancyclovir and, at the same time, need to treat his ACR with iv methylprednisolone, which will treat both.
ATG heavily immunosuppresses these patients, and reducing the IS will diffiently end up bu rejection, so I think we may need to reduce the antimetabolites agent (MMF).
yes, THis is may give me a chance to treat the CMV first and reduce the MMF.
one of the approaches is to use IVIG, which can help him with both CMV Infection and ACR.
There is a strong association between ACR and CMV infection, and what happened so far in this histopathology could be only CMV infection which triggered ACR and in this case treating the CMV is the crucial principle.
CMV and induce ACR By one of the coming :
references
pro Halawa lectuer
As much as I adore my academic twin brother Ahmed Halawa, referring to his lecture can not be considered as a reference in a scientific writing.
IVIg would not be a dependable treatment of CMV.
Differential diagnosis,
1.CMV nephritis
2.ACR with CMV
3. BKN
Management :
1.CMV PCR for viral load and treatment monetring,
IV gaincylovir 5mg/kg bid or adjusted for GFR. Repeat PCR weekly and see clinical response, gaincylovir resistance should be consider in Case of no response otherwise give for 21days or two negative PCRs tests.
2. Maintain Immunosuppressant due to ACR or reduce if poor/no reduction in viral load especially antimetabolites MMF/AZA.
3. Consider CMV specific ivig or ivig.
CMV disease is associated with increases mortality and allograft loss.
I like your DD
What is your differtial diagnosis?
This patient is at risk of developing CMV disease as he is:
The differtial diagnosis is
Management:
Accordingto the biopsy result the possibility of coexisting ACR should be put in mind in the management of this patient.
This case carries no diagnostic challenge. The main challenge is the management of this patient.
First:
in this patient survival is the main concern rather than graft survival. Putting in mind that the outcome of CMV nephropathy is not lethal in most cases
For the treatment of ACR:
we give methylpredinsiolone as it is the first line treatment of ACR an we may find good response with the treatment of CMV as it may be an association.
ATG is not an option in this patient with evidence of CMV disease and it may not be needed.
The association between CMV and ACR:
CMV increases the risk of ACR. The mechanism is not fly understood. Some evidence that CMV up regulates the immune systemm
There is contradiction in your reply. One one hand you state that ‘to reduce the immunosuppression’, and then in next para you suggest methyl pred pulse therapy?
I appreciate that ATG is not an option as mentioned by you.
1- The biopsy showed the characteristic Owl’s eyes and inflammatory cell infiltrate
(CMV infection and associate ACR)
2- Management:
3- Presence of associated ACR is expected with severe CMV infection and makes it more challenging. pulse steroid will be a good option for management of ACR. we have to consider the cones and pros of reduction of antimetabolites.
4- Association between CMV and ACR:
CMV can induce rejection by the following mechanisms:
There is contradiction in your reply. One one hand you state that ‘we can consider reduction of antimetaboltes’, and then in next para you suggest methyl pred pulse therapy?
The biopsy showed owls eye sign with inflammatory cells infiltrate the glomeruli both recipient and donor are CMV positive before kidney transplantation , in addition of ACR that managed by ATG due to steroid resistant all these put the patient at high risk of opportunistic infection esp CMV disease , the most likely diagnosis in this patient is CMV nephritis associated with ACR .
Other differential include
– ACR associated with CMV infection
-Acute interstitial nephritis
– BK virus infection
After proper history and examination
Investigations: full blood count ,renal function test and liver function test , urine (analysis ,culture and protein creatinine ratio ) , CMV IgM and PCR .
Treatment of this case is challenging because of recent ACR and increased risk of another ACR due to immunogenicity of CMV and triggering of ACR .
Ideally the treatment will be reduction of immunosuppression and antiviral therapy 2 weeks course iv ganciclovir 5 mg/kg with dose adjustment according to renal function followed by oral valgancyclovir 900 mg bid for total of 3 weeks reduction of antimetabolite by 50% and continuation of CNI with observation of trough level following renal graft function, urine PCR and full blood count .
Yes I will add pulse methylprednisolone and discuss with the immunologist and clinical pharmacist regarding resuming the usual dose of immunosuppressant .
CMV infection and disease are independent risk factors for clinical acute rejection in kidney allograft recipients. CMV may express molecules similar to MHC class 1 and 11 antigens triggering the immune response against the allograft .
reference:
1.Prof Ahmed Halawa lecture of CMV in kidney transplantation.
2. Am J Transplant. 2002 Oct;2(9):850-6. doi: 10.1034/j.1600-6143.2002.20907.x.
There is contradiction in your reply. One one hand you state that ‘ideally the treatment will be reduction of immunosuppression’, and then in next para you suggest methyl pred pulse therapy?
Thank you for your for your replies
This case was treated with the routine CMV treatment with a pulse steroid cover. No immediate immunosuppression reduction was done a few weeks after discontinuation of the CMV treatment.
ATG will treat the ACR by will flair up CMV which could be life-threatening. You will end up with a successful treatment of the ACR and fist degree murder (dead patient).
IVIg treatment is acceptable, but it is not the best option as it is more expensive and also its effect on ACR is questionable
Noted Prof.Thanks
OK Sir
The clinical risk for CMV infection is high because;
1-She received a kidney from CMV positive donor (she was also CMV-positive at the time of transplantation).
2- She received ATG for steroid-resistant acute cell-mediated rejection (ACR) 3 weeks after transplantation.
The histopathology showed ;
1-Interstial lympocytic infiltration .
2-Tubulitis with intranuclear owl’s eye-type inclusion .
What is your differential diagnosis?
————————————————————–
1-CMV nephritis .
2-ACR.
3-ABMR.
4-Bk nephropathy .
How do you manage this case?
———————————————
1-The diagnosis ;
The kidney biopsy showed the histological hallmark of CMV infection is the “Owl Eye Inclusions”. We need to rule out coexistence rejection ;
a-DSA
b-C4d staining
C- Tests of antigenemia or DNAemia ;It help in confirmation of the diagnosis and treatment monitoring .
2-Treatment ;
A-Antiviral therapy;
1-IV ganciclovir is preferred drug for treatment of severe or life-threatening CMV disease or in those with questionable gastrointestinal absorption .In this case with severe disease associated with renal impairment ,we use IV Ganciclovir and the dose will be adjusted according to the creatinine clearance .
2-The duration of antiviral therapy should be guided by resolution of clinical symptoms and viral load monitoring (for 14-21 days, stop date determined by 2 x PCR negative).
B-Reduction of immunosuppression ;
CMV occurs as a result of an over-immunocompromised state, hence, the reduction
in immunosuppression will allow for the recovery or the gen- eration of CMV-specific immunity that will allow longer-lasting control of the virus infection.
1-The guidelines suggest a dose reduction of either calcineurin inhibitor or mycophenolate mofetil / azathioprine [1C] .
2-In the setting of leucopenia , the guidelines suggest reducing or stopping MMF or azathioprine 2C .
The pathologist queried grade 1 ACR. Would your management differ?
———————————————————————————————-
Yes
Immunologically this patient is high risk for both rejection and CMV infection .
Acute cellular rejection does not have viral cytopathic changes or positive CMV staining.
This is a very complex case ,there are some reports regarding uses of IV Ig in such cases in combination with anti viral therapy .
What is the association between this condition and ACR?
————————————————————————
The cause of acute kidney transplant rejection after CMV infection is unknown, but immune modulation after infection can play as a major factor. There are some evidences suggest, CMV infection stimulates the immune system. Some studies indicate that CMV infection can induce up-regulation of adhesion molecules on endothelial cell of vessels. This up-regulation can enhance the inflammatory process .
Referance ;
1- AJKD Atlas of Renal Pathology: Cytomegalovirus Infectionhttps://www.ajkd.org › article › fulltext .
2- De Keyzer K, Van Laecke S, Peeters P, et al. Human cytomegalovirus and kidney transplantation: A clinician’s update. Am J Kidney Dis 2011;58:118-26. 10.1053/j.ajkd.2011.04.010 [PubMed] [CrossRef] [Google Scholar]
3-UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION3-von Willebrand E, Petterson E, Atonen J, Hayry P. CMV infection, class I1 antigen expression and human kidney allograft rejection. Transplantation. 1986;42:364–7. [PubMed] [Google Scholar].
Thank you for your answer
We have a cheaper option and more effective. I do not think that IVIg would help that much in ACR. Could you wait for my replay later?
Thanks professor
I agree
What is your differential diagnosis?
Cmv nephritis and Glomerulitis and owls’ eye inclusions in glomerular capillaries.
Combination of CMV nephritis and ACR (as shown in LM with tubultitis ‘
BKV nephropathy
A high immunological risk patient received ATG for ACMR and she received KT from CMV +D /R+. The graft biopsy for LM BY H&E stain shows the typical Cowdry Type A viral inclusions, also called “Owl
Eye Inclusions” this is CMV nephritis in combination with tubulitis CMV glomerulitis and nephritis are uncommon but important manifestations of the CMV tissue-invasive disease.
The key pathological features of CMV nephritis include
1. Patchy lymphoplasmacytic infiltrate with tubulitis
2. Viral cytopathic changes with enlarged tubular epithelial cells and owl’s eye-type nuclear inclusions
3. CMV immunostaining
4. characteristic electron microscopy morphology (dense core and thick capsule) may be present in nuclei and cytoplasm, bulls eyes(3).
will ask for CMV PCR and immunohistochemical staining for CMV, SV40 staining, & BKV PCR level, CNI trough level, c4d staining, FBC
How do you manage this case?
Very challenging case to treat active CMV infection should be treated with antiviral, immunosuppression reduction plus immunomodulation agents like IVIG
active CMV nephritis with ACR, still will be treated with IV ganciclovir 5 mg/kg and the dose can be adjusted according to the graft function for two weeks then change to oral valganciclovir 900mg BID for a total 3 weeks course with weekly CMV PCR monitoring, graft function monitoring, full blood count for side effects and continue on tacrolimus-based IS with target trough level 6-8 ng and still can reduce MMF by 50% or stopped
The pathologist queried grade 1 ACR. Would your management differ?
Again very challenging condition and still will go for CMV treatment with IV ganciclovir for 3 weeks, PMP, and weekly monitoring of the CMV PCR titer, another option of change to everolimus with CNI combination and stop MMF with close monitoring as M tor inhibitors still have a higher rate of rejection but less infection rate.
the role of IVIG in the treatment of CMV is debated, and there is literature to support its immunomodulatory properties, which may prevent rejection in the setting of withholding maintenance immunosuppression during the treatment of CMV disease (1).
What is the association between this condition and ACR?
CMV infection can trigger acute rejection.CMV viremia is found in up to 60% after kidney TX and can trigger acute allograft rejection and can affect the T – cell immunity Memory NK cells and NK-like CD28–CD8+ T cells were associated with control of viremia. These findings suggest that signatures of innate activation may be prognostic for CMV reactivation after transplant, while CD8+ T cell functionality is critical for effective control of CMV(4).
References
1. Aziz F, Djamali A. Post-Transplant CMV Glomerulitis. Clin J Am Soc Nephrol. 2021 Jun;16(6):957-959. doi: 10.2215/CJN.19061220. Epub 2021 Feb 10. PMID: 33568381; PMCID: PMC8216621.
2. Morgantetti GF, Balancin ML, de Medeiros GA, Dantas M, Silva GEB. Cytomegalovirus infection in kidney allografts: a review of literature. Transl Androl Urol. 2019 May;8(Suppl 2):S192-S197. doi: 10.21037/tau.2018.10.14. PMID: 31236337; PMCID: PMC6559934.
3. Agnes B. Fogo, Mark A. Lusco, Behzad Najafian, and Charles E. Alpers, AJKD Atlas of Renal Pathology: Cytomegalovirus Infection
4.Pickering H, Sen S, Arakawa-Hoyt J, Ishiyama K, Sun Y, Parmar R, Ahn RS, Sunga G, Llamas M, Hoffmann A, Deng M, Bunnapradist S, Schaenman JM, Gjertson DW, Rossetti M, Lanier LL, Reed EF; CMV Systems Immunobiology Group. NK and CD8+ T cell phenotypes predict the onset and control of CMV viremia after kidney transplant. JCI Insight. 2021 Nov 8;6(21):e153175. doi: 10.1172/jci.insight.153175. PMID: 34609965; PMCID: PMC8663544.
5.
Thank you for your answer
We have a cheaper option and more effective. I do not think that IVIg would help that much in ACR. Could you wait for my reply later?
OUR CASE;
65 YR old woman.
ESRD from ADPKD.
Cadaveric transplant from CMV +VE donor.
CMV +VE recipient.
ATG induction for ACR 3/52 Post transplant.
2nd kidney biopsy- owls eye appearance- typical of CMV.
RISK CATEGORY.
High risk ; D+/R+ for CMV
ATG tx post transplant.
Failing Kidney
DDX;
CMV nephritis
BK nephropathy
ACR
MGT.
1.Multidisciplinary- Transplant team and Infectious Disease team (High risk of infection with increased immunosuppressive meds use in patient post transplant for the rejections)
2.Counsel the patient of the high risk status and that increasing immunosuppression increases more risk of CMV and other viral infections while decreasing it increases risk of both T Cell and antibody mediated rejection.
3.Immunosuppressive meds + Antivirals;
>RIS – Stop anti metabolites followed by reduction in CNI by 25-50% and monitor graft function. Antimetabolites can be reintroduced once infection has cleared at a lower dose and CMV reinfection monitored 3 weekly, if it recurs we stop it completely if, it doesn’t recur, we continue it at the lower dose.
-Titrate steroids upwards with graft function to concurrently monitor the ACR.
>Antiviral Tx – Initiate antivirals, PO valganciclovir 900 mg BD for 21/7 then OD until X2 PCR neg results and resolution of symptoms, Alternatively or for those with severe disease or sick to tolerate oral meds, IV ganciclovir 5mg/kg BD for 5-7/7 followed by PO valganciclovir OD until x2 negative PCR results and resolution of symptoms. These should all be renal dosed appropriately. Presence of leukopenia will prompt inv for other causes of leukopenia apart from the anti virals.GM-CSF should be started and attempts to reduce antiviral doses be resisted or be last option to avoid exposing pt to subtherapeutic drug levels that will increase risk of resistance.
>Failure of CMV VL to decrease by x1 viral load ,2 weeks post treatment with an appropriate dose of antiviral meds is a potential pointer to resistance and resistance testing needs to be done and alternative tx considered depending on results and with consideration to their side effects; Foscarnet, Cidofovir,Letermovir, Maribavir and CytoGam.
Grade 1 ACR.
Our pt already had ATG for steroid resistant ACR, Going with recommendations for ACR treatment ,grade 1 and the fact the patient is over immunosuppressed with CMV infection insitu, We would use steroid monotherapy (Pulse steroids),be reluctant to add the other immunotherapy medications ,initiate PCP and fungal prophylaxis, Maintain CMV treatment and monitor graft function.
CMV association with ACR;
-CMV has been associated with increased co stimulatory molecules on antigen presenting cells, tubular epithelial cells and T lymphocytes which mediate rejection.
-CMV infection,x2 rejection ,over immunosuppression with the hx of ATG use, might have led to CMV reactivation with production of MHC 1 AND 2 molecules on T cell surface which led to acute rejection.
REF;
Prof Halawa lecture – CMV in kidney Transplantation.
Uptodate – CMV post renal transplant ; diagnosis and treatment
Sagedal et al; The impact of CMV infection and disease on rejection episodes in renal allograft recipient. J transplant.2002 oct;2(9);852-6
Michael Klompas; Treatment of ganciclovir resistant CMV rejection.
Thank you for your EXCELLENT answer
This case was treated with the routine CMV treatment with a pulse steroid cover. No immediate immunosuppression reduction was done a few weeks after discontinuation of the CMV treatment.
Thank you Prof.
A 68-year-old woman was admitted with a deterioration of kidney function. She had a cadaveric renal transplant 3 months ago for ESRD secondary to APKD. She received a kidney from CMV positive donor (she was also CMV-positive at the time of transplantation). She received ATG for steroid-resistant acute cell-mediated rejection (ACR) 3 weeks after transplantation. A routine infection screen and USS of her kidney were normal. A second Kidney biopsy for another deterioration of the kidney function;
The kidney biopsy showed:
A peri- glomerular renal tubule contains large, intra-nuclear viral inclusion bodies typical
of those found in cells infected with CMV , The typical “Owl eye” picture of intra-cellular
basophilic inclusions with surrounding halo {owl’s eye-type inclusion} of CMV infection in
the renal tubule, also Tubulitis => mild to moderate Tubulitis with (cytomegaly).and
Interstitial inflammation => interstitial infiltrate with lymphocytes.
What is your differential diagnosis?
1- CMV infection(CMV Nephropathy), most common typical diagnosis to our case senario
2- ACR
3- ACR/ CMV Nephritis
4- AIN / ATIN
Investigation:
CBC, RFTs, LFTs, CRP
Septic screen ; blood , Urine cs
ACR %
PCR %
CMV blood PCR
EBV, BKV Blood PCR
Tacrolimus Level
DSA level
Transplant Doppler U/S
Kidney Transplant Biopsy
How do you manage this case?
There is evident CMV infection , so should be treated as it is itself a higher risk for ACR
which may not be resolved, so, will treat CMV undercover of methylprednisolone and will
decrease MMF by 50% and continue CNI if there is no life threatening condition
Management of CMV nephritis:
IS management :
Stop or reduce MMF by 50%
Do not discontinue CNI unless there is evidence of life-threatening infection, keep level
of Tacrolimus ~ 5.
Corticosteroids => Pulse Steroid as ACR is highly suspected
Monitor graft function as the risk of rejection will increase.
Antiviral therapy:
IV ganciclovir or its prodrug, oral valganciclovir, is the first-line treatment for CMV
illness, These medications work by preventing viral DNA polymerase from extending DNA.
IV Ganciclovir 5mg/kg bid (Cr CL) for minimum of 14 days followed by oral Valganciclovir
for 2-3 weeks after clearing of CMV viraemia or until 2 x CMV DNA by PCR are
negative, Then continue VGCV prophylaxis for 3 months
Monitoring of CMV viral load, RF, CBC, LFT is required
If CMV PCR count has not fallen by ≥ 1 log copies/ml after two weeks of therapy or if there is no clinical improvement despite treatment===========>>>>>>
= Ganciclovir/ VGCV resistance; viral gene typing, ====>
====> Switch to second line therapy:
===> Foscarnet (nephrotoxic; it can result in metabolic changes as well as cardiac arrhythmias and genital ulcerations).
==> Cidovir (nephrotoxic and causes neutropenia, metabolic acidosis and ocular hypotony).
==>Letermovir is a newly approved anti-CMV antiviral which inhibits the viral terminase
complex.
It interacts with immunosuppression, requires dose adjustment in renal and hepatic
impairment and can be used with other anti-CMV medications.
==> Maribavir is a promising new antiviral against the viral UL97 kinase.
Co-administration of with GCV is not advised as Maribavir is an inhibitor of the UL97
enzyme required for anabolism of the latter.Reduction in immunosuppression
CMVIG can be used to induce a passive immunity. Resistant infection and side effects to
VGC .
Request genotypic resistance and
Adoptive immunotherapy
Prophylaxis
D+/R+ 100 days of valganciclovir.
The pathologist queried grade 1 ACR. Would your management differ?
Managing CMV nephritis with ACR
The management is challenging; treating the infection by reducing IS will further
increase the risk of rejection. In this situation, Pulse steroids will help to control ACR,
while reducing IS.
For patients with biopsy-proven Banff grade IA TCMR (with no evidence of antibody-
mediated rejection [ABMR), we suggest treatment with glucocorticoids.
IV Pulse methylprednisolone at 3 to 5 mg/kg daily for three to five doses, with a maximum daily dose of 500 mg.
Should start antiviral gancyclovir 5mg/kg/ day twice a day for 2 weeks
Decrease MMF by 50%
Reduce calcinurine inhibitors to level ~ 5.
Prophylaxis by valgancyclovir 450 mg for 6 months
What is the association between this condition and ACR?
CMV infection will increase the risk of both ACR and ABMR by Production of interferon-Υ
during the inflammatory process increases the expression of major histocompatibility
(MHC) class I and II molecules on both vascular endothelial and tubular epithelial cells.
CMV may express molecules similar to MHC class I and II antigens priming the immune
response against the allograft.
Enhances the alloantigen independent pathway of rejection by increasing co- stimulatory
molecules on APCs, vascular endothelial cells, tubular epithelial cells and T
lymphocytes.
Elevated anti- endothelial cell antibodies have been reported in a small group of renal
and cardiac allograft recipients coincident with CMV infection.
This may indicate an increased risk of humoral response.
Potent IS used in treatment of Rejection will increase the risk for CMV infection.
Persistence intra-graft CMV was independent risk factor for lower clearance at 1 and 2
years , hence reducing survival.
CMV disease appeared to influence long term graft survival but only when coupled with
the occurrence of acute rejection.
CMV is an important cause of morbidity and mortality in individuals whose immune
system is compromised.
Reference:
CMV in Kidney Transplantation lecture by Prof. Ahmed Halawa
Solez K, Axelsen RA, Benediktsson H, et al. International standardization of criteria for the histologic diagnosis of renal allograft rejection: the Banff working classification of kidney transplant pathology. Kidney Int. 1993;44:411–422.
CMV in Renal Transplantation By Ahmed Halawa Consultant Transplant Surgeon Associate Professor, University of Liverpool – UK.
UK guideline on prevention and management of cytomegalovirus (CMV) infection and disease. following solid organ transplantation April 2022.
Fishman JA , Rubin RH . Infection in organ-transplant recipients , N Engl J Med ,1998 , vol. 338 (pg. 1741 -1751
Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13512. doi: 10.1111/ctr.13512. Epub 2019 Mar 28. PMID: 30817026.
Up To Date.
Thank you for your EXCELLENT answer
This case was treated with the routine CMV treatment with a pulse steroid cover. No immediate immunosuppression reduction was done a few weeks after discontinuation of the CMV treatment.
The index case is
a) A recent (3 month back) cadaveric renal transplant recipient
b) CMV D+/R+ status
c) She developed steroid resistant cellular rejection 3 weeks post-transplant which was treated with injection ATG.
Now she developed renal graft dysfunction.
A graft biopsy was performed. It showed typical “Owl eye” picture of intra-cellular inclusions characteristic of CMV infection with tubulitis (mild to moderate), and interstitial inflammation.
In the light of the clinical features and the histopathology, this patient is having tissue-invasive CMV disease: CMV nephropathy (1). CMV antigen detection by immunohistochemistry of the biopsy specimen can help in diagnosis.
Acute rejection (acute cellular rejection as well as antibody mediated rejection) should be kept in differential diagnosis in such a scenario.
The patient would laboratory testing including a complete blood count, renal function tests, urine routine examination, urine protein creatinine ratio spot, CNI trough levels, CMV PCR in blood.
This case of tissue-invasive CMV is managed by:
1) Supportive therapy: Maintain adequate hydration.
2) Treatment with intravenous ganciclovir (5mg/kg IV 12 hourly, to be adjusted according to creatinine clearance). It should be continued for minimum 2 weeks (can be changed to oral valganciclovir, if symptoms improve earlier), and until resolution of graft dysfunction with clearance of CMV in blood, if present (3,4).
3) Complete blood count and serum creatinine should be monitored weekly during the treatment. If no response in 2 weeks, assessment for ganciclovir resistance and shift to Foscarnet and additional CMV immunoglobulin or intravenous immunoglobulin (IVIG) should be considered (3).
4) Secondary prophylaxis with oral valganciclovir post-treatment can be given for 1-2 months in patients with high-risk of relapse.
5) Immunosuppression reduction: Ideally antimetabolites should be stopped/ reduced by 50%. But in view of recent acute rejection, it would be difficult due to high risk of rejection (3). Injection methylprednisolone pulse can be used to treat the concomitant acute cellular rejection. The CNI levels should be checked.
6) Patient should be counselled regarding the risk of rejection in such a scenario when the dose of immunosuppression is being reduced.
The most important initial measure in the scenario is to treat CMV disease. Injection methylprednisolone cover can be used with the anti-viral treatment.
CMV disease is a risk factor for clinical and biopsy proven acute tubulointerstitial rejection in renal transplant recipients (5).
References:
1) Aziz F, Djamali A. Post-Transplant CMV Glomerulitis. Clin J Am Soc Nephrol. 2021 Jun;16(6):957-959. doi: 10.2215/CJN.19061220. Epub 2021 Feb 10. PMID: 33568381; PMCID: PMC8216621.
2) Fogo AB, Lusco MA, Najafian B, Alpers CE. AJKD Atlas of Renal Pathology: Cytomegalovirus Infection. Am J Kidney Dis. 2016 Dec;68(6):e35-e36. doi: 10.1053/j.ajkd.2016.10.008. PMID: 27884284.
3) Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13512. doi: 10.1111/ctr.13512. Epub 2019 Mar 28. PMID: 30817026.
4) Kotton CN, Kumar D, Caliendo AM, Huprikar S, Chou S, Danziger-Isakov L, Humar A; The Transplantation Society International CMV Consensus Group. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation. 2018 Jun;102(6):900-931. doi: 10.1097/TP.0000000000002191. PMID: 29596116.
5) Sagedal S, Nordal KP, Hartmann A, Sund S, Scott H, Degré M, Foss A, Leivestad T, Osnes K, Fauchald P, Rollag H. The impact of cytomegalovirus infection and disease on rejection episodes in renal allograft recipients. Am J Transplant. 2002 Oct;2(9):850-6. doi: 10.1034/j.1600-6143.2002.20907.x. PMID: 12392291.
Thank you for your EXCELLENT answer
This case was treated with the routine CMV treatment with a pulse steroid cover. No immediate immunosuppression reduction was done a few weeks after discontinuation of the CMV treatment.
Differential diagnosis:
Management of the case:
The patient is categorized as high risk due to the;
So, management should include the following :
2. Anti-viral treatment:
G1 Acute Cellular Rejection:
Challengeable case:
Association between the condition and ACR:
BK nephropathy presents with the same histological feature and acute rejection.
References:
The immune response to human CMV. Corinna La Rosa and Don J Diamond* Future Virol. 2012 Mar 1; 7(3): 279–293.doi: 10.2217/fvl.12.8 2. Anglicheau D, Lautrette A, Scieux C, Thervet E, et al. Lowering immunosuppression is safe and effective to treat altered pattern of CMV infection in renal transplant recipients on valaciclovir prophylaxis. Transplant Proc. 2002;34(7):2826-7.
American Journal of Transplantation 2009; 9 (Suppl 3): S21–S2
Thank you for your EXCELLENT answer
This case was treated with the routine CMV treatment with a pulse steroid cover. No immediate immunosuppression reduction was done a few weeks after discontinuation of the CMV treatment.
Differential diagnosis
Management
Blood works including CBC, renal function, liver function test
CMV and BK PCR.
Staining of the biopsy for SV40 and C4d.
Then reduction of her immunosuppression.
She needs to be started on valganciclovir that is renal dosed.
After 2 weeks of treatment she should have CMV viral loads done then after in intervals of 1 week.
Treatment should be stopped when there is resolution of symptoms plus 2 CMV viral loads below threshold.
CBC monitoring should be done since valganciclovir causes leucopenia.
Pathologist queried grade 1 ACR. Would your management differ?
This is a challenging case the fact the patient has CMV nephritis and reduced renal function and a queried diagnosis of ACR.
One hand the CMV requires reduced immunosuppression while pulsing for the ACR.
This would require a consultation with others in field.
However I think this would be a case that would benefit from leflunomide.
Leflunomide has both immunomodulatory and antiviral properties.
Studies on SOT with a failing allograft with the use of leflunomide were able to reduce the immunosuppressive dose with no further episodes of allograft rejection.
So yes, my management would change. I would stop the CNI and antimetabolites, pulse with steroids. After pulsing give leflomide.
What is the association of this condition and ACR?
One patients recently treated for acute rejection are at high risk of CMV disease due to the intensive immunosuppression.
Two treatment for CMV disease which involves reduced immunosuppression increases the risk of rejection.
CMV has both direct and indirect effects, in the indirect effects it can cause allograft rejection
References
CMV in Kidney Transplantation By Ahmed Halawa (lecture), consultant Transplant Surgeon Associate Professor, University of Liverpool –UK, 2023.
Treatment of Ganciclovir Resistant Cytomegalovirus Infection
Michael Klompas
Thank you for your answer. I do not think that leflonamide would be effective in this case. It is a weak immunosuppressive drug.
This case was treated with the routine CMV treatment with a pulse steroid cover. No immediate immunosuppression reduction was done a few weeks after discontinuation of the CMV treatment.
What is your differential diagnosis?
=============================
How do you manage this case?
Treatment of CMV disease
=============================
The pathologist queried grade 1 ACR. Would your management differ?
=============================
What is the association between this condition and ACR?
References
Your answer is still not clear regarding the association of ACR
This case was treated with the routine CMV treatment with a pulse steroid cover. No immediate immunosuppression reduction was done a few weeks after discontinuation of the CMV treatment.
Dear All
Thank you for your comments. Clearly this is a tricky and challenging situation when you would like to treat an ongoing infection and boost overall immunological response whilst you face a rejection event when you want to damp the immune response because of the rejection episode.
I did not see many of you made any comment on the histological picture
Thank you Prof Mohsen,
Thank you Professor.
The kidney biopsy field shows:
a) The typical “Owl eye” picture of intra-cellular inclusions characteristic of CMV infection in the renal tubule.
b) Tubulitis: mild to moderate.
c) Interstitial inflammation.
Comment on the histological picture
– intranuclear inclusions with nuclei surrounded by a clear circumferential halo (owl’s eye)
– tubulitis
1-What is your differential diagnosis?
most patients with acute rejection are asymptomatic and present only with an elevated creatinine
In patients who present with fever, malaise, oliguria, and/or graft pain or tenderness, the diagnosis of infection, urinary leak, and obstruction should also be considered.
posttransplant lymphoproliferative disease (PTLD), cytomegalovirus (CMV) disease, BK (polyomavirus) nephropathy, interstitial nephritis, and pyelonephritis, may have similar histologic findings to allograft rejection:
CMV infection may manifest as an increased serum creatinine, with a kidney biopsy histologic appearance similar to rejection.
In one study, treatment of the CMV rather than antirejection treatment was associated with “reversal” of rejection and improvement in graft function in 17 of 21 patients
In general, whole blood or plasma CMV viral load testing will identify patients with active CMV disease.
BK nephropathy – The histologic appearance of BK nephropathy may mimic the tubulitis and/or arteritis classically associated with rejection
Among such patients, it is extremely important to attempt to differentiate BK nephropathy from rejection as the two treatments are diametrically opposed, and increased immunosuppression in the setting of BK nephropathy will lead to further viral proliferation and potential allograft loss. However, distinguishing BK nephropathy from acute rejection on the basis of histology is not always possible, and, in some patients, the two diagnoses may simultaneously overlap.
Among all patients, special stains for BK should be performed on the biopsy sample if there is concern for BK nephropathy, even in the absence of typical viral inclusions on the biopsy. It is essential that medullary tissue be available for analysis since BK is tropic for medullary tubules more than cortical tubules.
Drug- or infection-related interstitial nephritis may also mimic rejection. Peripheral eosinophilia may suggest drug-induced acute interstitial nephritis, although its absence does not exclude its presence.
Transplant pyelonephritis can cause an elevation in serum creatinine as well as interstitial and tubular infiltrates. However, the infiltrate mostly consists of polymorphonuclear cells rather than lymphocytes. Urine culture will usually be positive for gram-negative organisms, although gram-positive bacteria can cause urinary tract infections (UTIs) in rare cases.
PTLD is suggested by a diffuse lymphocytic infiltrate of such severity that it is difficult to visualize tubular architecture, which can occasionally be observed in patients with severe T cell-mediated rejection (TCMR) (frequently secondary to noncompliance with immunosuppression).
Since the treatment options for rejection and PTLD are markedly different, additional studies must be performed to differentiate the two possibilities. Studies include special stains for T and B cell populations, Epstein-Barr virus (EBV) antigens, and monoclonal light chains, as well as quantitative EBV polymerase chain reaction (PCR) and serum and urine protein electrophoresis. Imaging of the graft should also include the abdomen, pelvis, and any other clinically relevant areas . Detection of specific cell markers for T cells, B cells, plasma cells, and monocytes may also be useful to guide rejection therapy in the setting of a significant cellular infiltrate with graft dysfunction.
2-How do you manage this case?
it is recommended that, in addition to histology, C4d staining and the presence of DSA be evaluated in suspected cases of rejection.
Prevention of opportunistic infections — In all patients who are treated with rATG-Thymoglobulin (or alemtuzumab) and high-dose glucocorticoids
PCP prophylaxis
CMV prophylaxis
Antifungal prophylaxis
Universal prophylaxis (high risk) — For all kidney transplant recipients who are CMV seropositive or who have received an organ from a CMV-seropositive donor (CMV D+/R+, D-/R+, D+/R-), we suggest universal prophylaxis rather than preemptive therapy. We prefer universal prophylaxis over preemptive therapy, given its ease of administration and prevention of potentially harmful low-level CMV replication.
For prophylaxis, we suggest valganciclovir rather than valacyclovir, oral ganciclovir, or other antiviral agents because of its efficacy and high oral bioavailability
For CMV D+/R- patients, we use valganciclovir at 900 mg orally once daily for six months following transplantation, with the dose adjusted for kidney function.
For CMV R+ patients, we use valganciclovir at 900 mg orally once daily for three months following transplantation, with the dose adjusted for kidney function.
Longer durations of prophylaxis may be preferred since shorter courses have been associated with an increased risk of late-onset CMV disease
One trial showed that valganciclovir given for 200 days decreased the rate of active CMV infection and disease in CMV D+/R- patients compared with valganciclovir given for 100 days
The toxicity profile of valganciclovir is similar to that of its parent compound, ganciclovir. Hematologic suppression, in particular leukopenia (including neutropenia), appears to be the most significant and common adverse event associated with these agents. When leukopenia occurs, dose reduction of valganciclovir should be avoided, given the risk of promoting resistance. Patients should be evaluated for other potential causes of leukopenia (eg, mycophenolate, trimethoprim-sulfamethoxazole). The addition of granulocyte colony-stimulating factor should be considered before discontinuing valganciclovir.
Reduction of immunosuppression
stop the antimetabolite immunosuppressant (ie, mycophenolate or azathioprine).
do not restart it at the conclusion of CMV treatment (ie, when symptoms have resolved and PCR is undetectable or less than the lower limit of a sensitive assay),
However, occasionally, among patients who are at increased risk of rejection (eg, those who have undergone retransplantation or have a prior history of rejection),
we reintroduce the antimetabolite at a lower dose. We monitor the blood for CMV replication with PCR at weekly intervals for four weeks to ensure that CMV does not reactivate at the lower antimetabolite dose
. If CMV recurs, we discontinue the antimetabolite indefinitely and restart treatment with antiviral therapy.
If CMV reactivation does not occur, we continue the antimetabolite at the reduced dose.
Antiviral therapy — Ganciclovir or its oral derivative, valganciclovir, is the preferred agent for most patients with CMV viremia or CMV disease
. Oral maribavir, intravenous (IV) foscarnet, and IV cidofovir are alternatives and are primarily used for patients with known or suspected infection with resistant or refractory CMV
3-The pathologist queried grade 1 ACR. Would your management differ?
YES
GRADE 1 A MANAGMENT WITH PULSE STREOID’
GRADE 1 B MANAGMENT WITH PULSE STERIOD +alemtuzumab
OUR PATIENT ALREADY GIVEN PREVIOUS DOSE OF ATG ‘
For patients who cannot receive rATG-Thymoglobulin, we give alemtuzumab as a single IV dose of 30 mg. Such patients include those with a known history of allergic reaction to rATG-Thymoglobulin (such as during induction therapy or during previous treatment of rejection) or those with a white blood cell count less than 2000/microL or a platelet count less than 75,000/microL. We also give alemtuzumab, rather than rATG-Thymoglobulin, to patients who have a previous history of significant rabbit exposure (ie, history of having raised or ingested rabbits) and, therefore, may be at risk for developing serum sickness after treatment with rATG-Thymoglobulin
4-What is the association between this condition and ACR?
Acute TCMR occurs most commonly within the first year after transplantation
Risk factors for the development of acute rejection include pre-sensitization (ie, presence of donor-specific antibodies [DSAs] or a high panel reactive antibody [PRA]), human leukocyte antigen (HLA) mismatches, blood group incompatibility, prolonged cold ischemia time, and delayed graft function (DGF).
Your answer is still not clear regarding the association of ACR
This case was treated with the routine CMV treatment with a pulse steroid cover. No immediate immunosuppression reduction was done a few weeks after discontinuation of the CMV treatment.
What is your differential diagnosis?
· Acute cellular rejection reoccurrence along with CMV nephritis
· CMV nephritis
· Acute cellular rejection reoccurrence
· BK nephropathy
· Acute antibody mediated rejection
But ACR with CMV nephritis is most likely diagnosis due to multiple risk factors :
-according to the history of transplantation 3 months ago from a CMV D+/R+ either due to superinfection with the donor virus or reactivation of the recipient’s virus
-ATG given for ACR 3weeks post transplant increasing risk of CMV infection
-renal graft biopsy showing Cowdry Type A viral inclusions, “Owl Eye Inclusions’’ (CMV inclusion bodies) with lymphocytic tubular infiltration
-deterioration of KFT
How do you manage this case?
Detailed history
Full lab tests
-Virological status evaluation by CMV PCR with viral load assessment
-The graft function needs evaluation by KFT , eGFR ,urine analysis ,US was normal and biopsy revealed CMV inclusion bodies and ACR findings
– basic lab ;CBC ,LFT, Inflammatory markers, blood and urine cultures
-Immunosuppressive levels
Treatment
Is challenging in this case as balancing immunosuppressive drugs for ACR in the face of antiviral agents for CMV infection is crucial.
MDT team must be involved with patient counselling
A combination of antiviral therapy, reduction of immunosuppression and immunomodulation
-Antiviral therapy is mandatory for invasive CMV regardless of the viral load ,till CMV DNA is undetectable in the forum of IV Ganciclovir (renal dose adjustment)
-stopping or reducing 50% of the dose of MMF /Azathioprine/Myfortic
-CNI will be stopped in life threatening infection
-Steroids are continued
-IL2R antagonist can be used instead of lymphocyte depleting agents
-graft function must be closely monitored as well as CMV viral load tracing
The pathologist queried grade 1 ACR. Would your management differ?
CNI and MMF can be stopped and pulse steroids can be given under cover of anti viral therapy
What is the association between this condition and ACR?
The cause of association of ACR with CMV infection is unknown, CMV caused immune modulation can be a major factor as CMV infection stimulates the immune system by up-regulating the adhesion molecules on endothelial cell of vessels thereby provoking the inflammatory process leading to ACR
Reference
Morgantetti GF, Balancin ML, de Medeiros GA, Dantas M, Silva GEB. Cytomegalovirus infection in kidney allografts: a review of literature. Transl Androl Urol. 2019;8(Suppl 2):S192-S197.
Hasanzamani B, Hami M, Zolfaghari V, Torkamani M, Ghorban Sabagh M, Ahmadi Simab S. The effect of cytomegalovirus infection on acute rejection in kidney transplanted patients. J Renal Inj Prev. 2016;5(2):85-88. Published 2016 May 16. doi:10.15171/jrip.2016.18
Thank you for your EXCELLENT answer
This case was treated with the routine CMV treatment with a pulse steroid cover. No immediate immunosuppression reduction was done a few weeks after discontinuation of the CMV treatment.
History
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What is your differential diagnosis?
====================================================================
How do you manage this case?
Investigation
Treatment
Ganciclovir Resistance
1-Exclude other causes of symptoms
Switch to second line
Prophylaxis
====================================================================
The pathologist queried grade 1 ACR. Would your management differ?
====================================================================
What is the association between this condition and ACR?
====================================================================
Reference
Thank you for your EXCELLENT answer
This case was treated with the routine CMV treatment with a pulse steroid cover. No immediate immunosuppression reduction was done a few weeks after discontinuation of the CMV treatment.
Many thanks for you our Prof.Halawa
Differential diagnosis:
1-CMV infection
2-BK virus
3- ACR
4 AMR
The possible diagnosis based on histopathology( owls’ eye inclusion bodies) is CMV nephritis .
Management :
IV Ganciclovir
Reduced MMF
The pathologist queried grade 1 ACR.:
1- Pulse methyel predisilone daily for 3 days ,followed by oral predisilone
What is the association between this condition and ACR?:
The use of ATG and steroid in treatment of ACR strongly correlates with CMV reactivation and disease
Reference :
Hand book of kidney transplant
Congratulations
You killed the patient as you helped to flare up the CMV infection by giving ATG
-The patient has deterioration in KF and diagnosed to have steroid resistance ACR, therefore, she received ATG.
-Both donor and recipient are CMV positive; risk for of superinfection with donor virus or reactivation of recipient virus, CMV prophylaxis after treatment for ACR is recommended in this condition.
-Kidney biopsy showed; interstitial infiltrate with lymphocytes. Tubulitis with characteristic intranuclear glassy-appearing basophilic inclusions with surrounding halo (owl’s eye-type inclusion) and marked increase in the size of the cell (cytomegaly).
What is your differential diagnosis?
-The diagnosis is CMV nephropathy supported by biopsy finding.
– Also to consider ;
-ACR.
– ABMR
– BK nephropathy.
How do you manage this case?
Work up:
– CBC, CRP,LFT, blood culture.
– RF and drug level Tacrolimus.
– Viral load PCR CMV, EBV, BK.
– DSA level.
– USS done already (normal)
– include in the biopsy; C4d staining, IHC for CMV, BK SV-40 staining.
Management of CMV nephritis:
This patient should be treated as tissue invasive CMV disease, irrespective of viral load.
IS management :
– Stop/reduce (by 50%) azathioprine/MMF/myofortic
– Do not discontinue CNI unless there is evidence of life-threatening infection, keep level of Tacrolimus 3-5.
– Corticosteroids are generally continued ( IVMP as ACR is highly suspected), then increase baseline steroids.
– Monitor graft function as the risk of rejection will increase.
Antiviral therapy:
– IV GCV for minimum of 14 days followed by oral vGCV for 2-3 weeks after clearing of CMV viraemia or until 2 x CMV DNA by PCR are negative
-The doses should be adjusted to renal function
-Monitoring of CMV viral load, RF, CBC, LFT is required
-In vGCV/GCV resistance; viral gene typing, second line therapy with help of ID team.
– After completing the treatment, continue VGCV prophylaxis for 3 months.
– CMV Ig and IVIG adjunctive therapies
The pathologist queried grade 1 ACR. Would your management differ?
Managing CMV nephritis with ACR
The management is challenging; treating the infection by reducing IS will further increase the risk of rejection. In this situation, Pulse steroids will help to control ACR, while reducing IS.
What is the association between this condition and ACR?
CMV infection will increase the risk of both ACR and ABMR by priming the immune response against the allograft by expressing molecules similar to MHC -I and II ; enhances the alloantigen independent pathway of rejection by increasing costimulatory molecules, and elevated anti- endothelial cell antibodies.
Potent IS used in treatment of Rejection will increase the risk for CMV infection.
Persistence intra-graft CMV was independent risk factor for lower clearance at 1 and 2 years , hence reducing survival.
CMV disease appeared to influence long term graft survival but only when coupled with the occurrence of acute rejection.
References:
– CMV in Kidney Transplantation lecture by Prof. Ahmed Halawa
– Eid, A.J., Razonable, R.R. New Developments in the Management of Cytomegalovirus Infection after Solid Organ Transplantation. Drugs 70, 965–981 (2010).
-UpTODate.
You did not say anything regarding the treatment of CMV associated with ACR. See my answer above and confirm
Thank you Prof.
May be it was not clear. may answer was;
In this situation, Pulse steroids will help to control ACR, while reducing IS.
Absolutely covering patient with pulse steroid plus usual CMV treatment. If viremia did not improve we may need to reduce IS otherwise, after completing CMV treatment will reduce IS
1. Limaye AP, Bakthavatsalam R, Kim HW, Randolph SE, Halldorson JB, Healy PJ. et al. Impact of cytomegalovirus in organ transplant recipients in the era of antiviral prophylaxis. Transplantation. 2006;81:1645–52. doi: 10.1097/01.tp.0000226071.12562.1a. [PubMed] [CrossRef] [Google Scholar]
You did not say anything regarding the treatment of CMV associated with ACR. See my answer above and confirm
thanks
in this case, the treated CMV infection in this recipient should receive pulse steroid for possible ACR and reduction in immunosuppression therapy so MMF should be reduced by 50% of the given dose in this case in addition to anti CMV viral medication
1-What is your differential diagnosis?
–CMV infection (CMV Nephropathy) most likely
(Owl eye appearance in the graft biopsy)
-ACMR (Acute-cell mediated Rejection)
-ABMR (Acute antibody mediated Rejection)
-BK nephropathy
-Interstitial nephritis
-Pyelonephritis (less likely)
2-How do you manage this case?
–PCR test for CMV and Polyoma virus.
–C4d staining for evidence of peri-tubular and glomerular capillaritis, for associated acute AMR.
If we deal with acase of (CMV Nephritis)
-Immunosuppressions:
-Reduce (by 50%) or stop azathioprine/MMF/myofortic (discontinue CNI only if there is evidence of life-threatening infection).
-Monitor graft function closely and discuss the risk of acute rejection with the patient.
-Review the dosing of immunosuppression following resolution of CMV disease.
–Antiviral:
-Treatment is mandatory regardless to viral load if confirmed to be CMV-tissue invasive (nephritis)
-Give intravenous GCV 5mg/kg bd (tissue-invasive) for a minimum of of 14 days and continue until resolution of symptoms and two tests of CMV DNA by PCR are negative.
-Do viral load first after 2 weeks and then weekly.Adjustment the dose according eGFR,
-Follow up CBC, renal function test and CMV PCR weekly during treatment.
-Be aware of ganciclovir resistance if there is no clinical improvement despite treatment or CMV PCR count has not fallen by ≥ 1 log copies/ml after two weeks.
-If confirmed, stop ganciclovir and give Intravenous Foscarnet for at least 3 weeks after virology advice (newer agents Letermovir and Maribavir may be an alternative).
– Prophylaxis by Valgancyclovir 450 mg for 3-6 months depending on serology status of the recipient.
3-The pathologist queried grade 1 ACR. Would your management differ?
–For kidney transplant recipients with Banff grade IA rejection,
-We suggest glucocorticoids alone, rather than glucocorticoids plus other immunosuppressive therapies .
-For patients with Banff grade IB rejection,
-We suggest treatment with (rATG)-Thymoglobulin in addition to pulse glucocorticoids, rather than glucocorticoids alone,
-But in this case because use ATG may reactivate CMV virus. I will continue with the same medications without reduction in immune suppressants, but I might consider steroids in high doses with valganciclovir, with monitoring graft functions.(after review Bx with the Histopathologist).
4-What is the association between this condition and ACR?
-CMV reactivation lead to production of gamma interferon which lead to activation of MHC molecules I , II on T cell surface which predispose to acute cellular rejection.
-High dose of immunosuppressive drug and use of ATG for treatment of ACR may reactivating CMV virus.
-Allograft rejection. failure has been found in about 16-18% within 12 -24 months in those with CMV infection according to the IMPACT study.
-References;.
–Up To Date,
–CMV in kidney transplantation Lecture by Ahmed Halawa,
–Cytomegalovirus-related disease and risk of acute rejection in renal transplant recipients: a cohort study with case-control analyses. Transpl Int. 2000;13(6):413-9.
Congratulations
You killed the patient as you helped to flare up the CMV infection by giving ATG
Thanks; Prof
Sorry; I didn’t mention to give ATG
This my answer;
But in this case because use ATG may reactivate CMV virus. I will continue with the same medications without reduction in immune suppressants, but I might consider steroids in high doses with valganciclovir, with monitoring graft functions.(after review Bx with the Histopathologist).
· What is your differential diagnosis?
This immunocompromised patient got two steroid inductions and two ATG inductions within the first few months after transplantation, putting him at increased risk for infections and cancer. The clinical presentation and kidney biopsy are suggestive with CMV nephropathy, Bk-Polyomavirus nephropathy, and acute cellular rejection. There are several risk factors present in the index patient that include: positive CMV donor, use of ATG, old age.
The presence of OWL eyes in the kidney biopsy is highly suggestive of CMV disease.
· How do you manage this case?
As the patient has histological description of ACR grade 1, steroids therapy should be initiated despite previous episode of steroid resistance ACR.
At the same time, having highly specific histological findings compatible with CMV nephropathy, treatment for CMD disease should be initiated.
BK-Polyomavirus Nephropathy can also present with histological features of acute cellular rejection/tubulitis and tubular vacuolization. So SV-40 staining should be performed to rule in/out BK virus.
C4D staining also important to check for concomitant antibody mediated rejection.
· The pathologist queried grade 1 ACR. Would your management differ?
The initial treatment is steroids pulse therapy, reduction in antimetabolite by 50%, and antiviral therapy.
· What is the association between this condition and ACR?
Acute CMV nephropathy may resembles acute cellular rejection histologically, and should be treated with both antiviral and steroids.
Thank you for your EXCELLENT answer
This case was treated with the routine CMV treatment with a pulse steroid cover. No immediate immunosuppression reduction was done a few weeks after discontinuation of the CMV treatment.
This is a patient who has received ATG for ACR 3 weeks after kidney transplant. She has now presented with graft dysfunction with normal graft US and negative infection screen
The kidney biopsy is showing the classic owls eye inclusion bodies pointing towards CMV nephritis. There is also tubulitis with lymphocytes and interstitial inflammation
The differential diagnosis would include:
To confirm the diagnosis of CMV disease, we will need to do a quantitative CMV PCR. This will also help for monitoring response to therapy.
Management
The management of this case is very complex. This patient has already had ACR for which she was given ATG which predisposed her to CMV. In a normal case, one would immediately reduce the immunosuppression and stop the antimetabolite. In this patient’s case, we should have a discussion with the patient about the risk of rejection if we reduce immunosuppression and the risk of not clearing the CMV infection if we dont reduce immunosuppression.
There are features of early grade ACR as evidenced by tubulitis. She will need to have IV ganciclovir therapy which should be dose adjusted for her kidney function. Her blood parameters should be monitored closely as ganciclovir can cause bone marrow suppression. Based on the suspicion of ACR, I would have the ID team consulted and discuss the benefits and the risks of pulsing with intravenous methylprednisolone.
CMV and Rejection
CMV has been associated with rejection via several mechanisms:
Thank you for your EXCELLENT answer
This case was treated with the routine CMV treatment with a pulse steroid cover. No immediate immunosuppression reduction was done a few weeks after discontinuation of the CMV treatment.
renal function deterioration after renal transplantations make the possibility of all aspects such as:
in this case scenario…most of the work up has been done…..
the histology showing owl eye inclusion body going with viral infections of CMV (patient already high risk for CMV / D+ & R- ,also induction with ATG.
Yes requred management of both CMV infection plus ACR simultaneously .which make the patient risk of progression of his infection further
there is a debate about their exact associations but generally CMV infections increases episodes of ACR via multifactorial mechanisms
Thank you, but you did not give us an answer regarding the management of CMV in association of ACR
· What is your differential diagnosis?
Glomerular inflammatory cell infiltration ,with MCV Owle eyes appearance inclusion bodies suggest of
CMV glomerulonephritis.
EBV infection.
BK nephropathy.
Adenovirus .
· How do you manage this case?
Plasma CMV PCR.
Plasma BK .
SV-40 T antigen.
C4D staining.
· Valganciclovir.
· cessations of antimetabolite.
· The pathologist queried grade 1 ACR. Would your management differ?
High dose of corticosteroid for 3days.
Reduce immunotherapy.
· What is the association between this condition and ACR?
CMV nephritis may be associated with acute rejection in 30% of the cases.(1).
References:
1-panelS. Rane , R. Nada , M. Minz , V. Sakhuja , K. Joshi.Spectrum of Cytomegalovirus-Induced Renal Pathology in Renal Allograft Recipients. Transplantation Proceedings .Volume 44, Issue 3, April 2012, Pages 713-716.
Thank you for your EXCELLENT answer
This case was treated with the routine CMV treatment with a pulse steroid cover. No immediate immunosuppression reduction was done a few weeks after discontinuation of the CMV treatment.
thank prof.
Renal biopsy of a post-kidney transplant recipient who was treated with ATG due to resistant ACR, which revealed interstitial and glomerular inflammatory cell infiltration with plasma cells and epithelial tubular cells with nuclear and cytoplasmic viral inclusion bodies with Owle eyes appearance (plasma cell rich rejection).
Therefore, I believe it to be an instance of acute cellular rejection (plasma cell rich rejection) combined with CMV-induced nephritis.
– Nephritis caused by ACR/CMV.
-Nephritis caused by the BK virus.
Other viral-induced kidney disease
Acute cellular rejection
How do you manage this case?
1-CMV DNA PCR
2-Immune suppression is lessened, for example, by ceasing to use antimetabolites like MMF or AZA for at least one month.
3-Discuss the potential for rejection if the immune system is weakened.
4-For the purpose of determining medicine doses and monitoring, be aware of your baseline SCr (eGFR) and FBC.
5-Antiviral treatment: 5 mg/kg IV gancyclovir for 5 days, then 20 mg/day oral valcyclovir till 2 X PCR negative
6-Review immune suppression following CMV resolution.
Would your management differ?
While ACR calls for maintaining enough IS, CMV treatment calls for a reduction or even a cessation of IS.
If graft performance continues to decline, CMV IVIG may be utilized since it has been shown to be effective in treating CMV infection in lung transplant patients, maintain graft function, and increase patient survival.
Because CMV nephritis stimulates the immune response and is associated with an inflammatory state, it raises the risk of both ACMR and ABMR in kidney transplant recipients.
1- CMV in Kidney Transplantation By Ahmed Halawa (lecture), consultant Transplant.
2-Cytomegalovirus in solid organ transplant recipients— Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice
Thank you, BUT the treatment of CMV in association with ACR by IVIg is not the best option
This case was treated with the routine CMV treatment with a pulse steroid cover. No immediate immunosuppression reduction was done a few weeks after discontinuation of the CMV treatment.
The slide shows CMV inclusion bodies at 12 O’clock , with lymphocyte infiltrate of tubules, glomerulitis and peri tubular capillaritits. No significant interstitial inflammation in the section shown.
These finding is diagnostic for CMV disease in addition to acute rejection. Acute cellular rejection 1 A plus probable antibody mediated rejection ( AMR). We need C4d stain and single antibody screen to complete the criteria for AMR.
Another possibility to be considered is BK virus nephritis.
To confirm the diagnoses, we need CMV PCR, DSA, BK virus screening, routine investigation.
Having both rejection and infection in the kidney transplant patient is very challenging as the management is opposing each other.
We need to start ganciclovir or oral valganciclovir if the patient can take it orally. Or Given 5mg bid or 900mg bid, respectively adjusted for kidney function.
To treat the rejection we need to increase immunosuppression, however with infection at the same time, keeping immunosuppressive medications at their level is better. If patient became very sick, shocked we may need to reduce the immunosuppressive medications starting with the antimetabolite, then CNI and lastly steroid and changing it to stress dose hydrocortisone or methylprednisone. We may consider giving CMV IVIG, if no improvement or if AMR is confirmed with the addition of plasmapheresis.
As mentioned above, in this case it will be very challenging. Depending on severity of infection and rejection we may continue same immunosuppressive medications without reduction or giving iv steroid 3-5mg/kg for 3 days with antiviral treatment coverage at same time if infection is mild.
It is well known that CMV infection will alter immune system, causing immunomodulation and can induce rejection by activation of T cells.
References:
1-Handbook of kidney transplantation 6th edition Gabriel Danovitch
2-Fundamentals of renal pathology by Agnes B Fog 2006
Thank you for your EXCELLENT answer
This case was treated with the routine CMV treatment with a pulse steroid cover. No immediate immunosuppression reduction was done a few weeks after discontinuation of the CMV treatment.
-CMV-infected renal transplant(Owel eye)
-TMA
-BK nephropathy
-ACR(biopsy is inadequate)
-ATN
Send for blood for culture, virology (CMV, BK virus), U&E, LFT, FBC, and tacrolimus/CyA level. Urinalysis and urine for culture.
If the PCR for CMV is positive or there is a CMV-positive stain in the biopsy:
Patients with CMV disease (syndrome or tissue-invasive disease), should receive antiviral treatment for a minimum of 2 weeks. Therapy should be continued until the viral load is undetectable in two consecutive samples.
IV gancyclovir in a dose of 5 mg/kg/24 hours or valganciclovir in a dose of 900 mg twice daily, adjusted to the GFR.
As the patient is at high risk for rejection, I will continue treatment of CMV while he is on antirejection therapy. I will avoid the reduction of immunosuppressive medication except if the patient has a life-threatening condition (CMV pneumonitis).
The priority for the treatment is the treatment of rejection
grade 1 ACR, usually responds to steroids. I will give pulse steroid under the cover of valganciclovir
If steroid-resistant, ATG under cover of valganciclovir and continue for 3 months after completion of ATG
-CMV may express molecules similar to MHC class I and II antigens priming the immune response against the allograft
-Enhances the alloantigen-independent pathway of rejection by increasing the co-stimulatory molecular level.
Interferon, during the inflammatory process, increases the expression of major histocompatibility complex (MHC) class I and II molecules on both vascular endothelial and tubular epithelial cells.
References:
Handbook of kidney transplantation.
–Cytomegalovirus in solid organ transplant recipients— Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice
Your DD includes TMA.ATN ,both have different etiologies and pathologies and far from the supplied pathology report.
The biopsy provided is insufficient.
CMV infection is one of the causes of TMA post-transplantation.
Usually, CMV is insidious in its effect on the kidney.
A kidney biopsy shows interstitial infalamation with owel’s eye appearance, the golerulus shows mesangial hypercellularity and a thickened GBM.
What is your differential diagnosis?
CMV disease – owl’s eye
The risk factors in our case are old age of the recipient, received ATG after evident ACR.
Cellular rejection
Diabetic nephropathy
Light chain disease
How do you manage this case?
Investigations:
CBC, Kidney function test (BUN, creat, Na, K, Cl), Liver function test, LDH, serum calcium, total protein and albumin, urinalysis, CRP, ESR, RF.
Serology and viral PCR
Treatment:
Reduce immunosuppressive medications: MMF by 50%, keep lower therapeutic CNI level, continue on steroid, with careful follow up of kidney function.
Anti CMV viral therapy iv ganciclovir till the viral load undetectable then oral valgancyclovir for at least 6 months with continued monitoring of viral load.
IVIG/MCVIG is a good option to treat CMV, and may reduce the inflammation.
The use of m-TOR inhibitor might be of value.
The pathologist queried grade 1 ACR. Would your management differ?
No, as the patient is known to had steroid resistant ACR, and had received ATG lastly. I would not give him another shot of ATG.
However; the prognosis is poor with this old age recipient, and impaired graft function.
What is the association between this condition and ACR?
It was thought that patients with CMV experience more ACR episodes, but lately this was eliminated by a systemic analysis of the CMV associated ACR, that showed slight non-significant increased ACR with CMV infection either by protocol biopsy or indicated biopsies.
The etiology of CMV induced rejection are:
– Production of interferon-ϒ during the inflammatory process increases the expression of major histocompatibility (MHC) class I and II molecules on both vascular endothelial and tubular epithelial cells.
– CMV may express molecules similar to MHC class I and II antigens priming the immune response against the allograft.
– the alloantigen independent pathway of rejection by increasing co[1]stimulatory molecules on APCs, vascular endothelial cells, tubular epithelial cells and T-lymphocytes.
– Elevated anti- endothelial cell antibodies have been reported in a small group of renal and cardiac allograft recipients coincident with CMV infection. This may indicate an increased risk of humoral response.
References:
(1) CMV in Kidney Transplantation By Ahmed Halawa (lecture), consultant Transplant Surgeon Associate Professor, University of Liverpool –UK, 2023.
(2) Erdbruegger U, Scheffner I, Mengel M, Schwarz A, Verhagen W, Haller H, Gwinner W. Impact of CMV infection on acute rejection and long-term renal allograft function: a systematic analysis in patients with protocol biopsies and indicated biopsies. Nephrol Dial Transplant. 2012 Jan;27(1):435-43. doi: 10.1093/ndt/gfr306. Epub 2011 Jun 28. PMID: 21712490.
Differntial diagnosis
1- CMV nephritis
2- PKV nephritis
3- ATIN ACMR
Management :
1- CBC : for leucopenia , thrombocytopenia supporting the diagnosis of CMV .
2-CRP ,procalcinonon to monitor inflammatory process.
Exclude other potential cuases :
– CMV PCR in blood and tissue cultures
– PKV PCR
– C4d stain to exclude concomitant ABMR.
Treatment:
– decrease the dose of IS drugs and stop antiproliferative drugs as MMF and AZA
– Monitoring of graft function for detection of early graft rejection .
– IV fluid with maintaining adequate fluid balance .
It’s mostly a case of CMV nephritis ( as biopsy show characterstic owl eye appearance and CMV R+D+ status with heavy immunesuppresion after the attackof acute rejection that was treated with ATG ).Start treatment with IV gancyclovir 5 mg /kg bdIV for14-21 days followed by oral valgancyclovir with monitoring of CMV PCR . Treatment should continue for at least 2 weeks after obtaining 2 negative CMV PCR results.
The pathologist queried grade 1 ACR. Would your management differ?
For treatment of CMV associated rejection requires careful balancing of the IS drugs as
1- CMV treatment needs decrease or even stop IS while ACR requires maintaining adequate IS . If graft function continue to deterirate , CMV IVIG can be used as these IVIG were evaluated in lung transplant patients with CMV infection and yield good results regarding CMV treatment ,maintain graft function and improve patient survival . Other potential treatments include plasmapharesis and rituximab
CMV nephritis increase the risk of both ACMR and ABMR in kidney transplant recipent due to stimulating immune respponse and associated inflammatory status
Ref:
· Cytomegalovirus (CMV) Treatment & Management Cedeno-Mendoza R. Jul 07, 2021 .Medescap
What is your differential diagnosis?
Kidney biopsy demonstrated the characteristic ‘Owl’s Eye’ CMV Inclusion bodies in the tubules, (prominent enlargement of tubular epithelial cells and their nuclei). Peri-tubular inflammatory cells?
Differential diagnoses could be:
1. CMV nephritis
2. ACR
Risk of superinfection with donor virus or reactivation of recipient virus (re-activation/super-infection)
Risk factors of CMV infection in this patient include:
1. Age
2. Degree of MHC complex mismatch (high immunological risk): risk for both CMV and ACR
3. Amount of immunosuppression the patient received
4. Depleting antibodies (ATG)
How do you manage this case?
Management of pure CMV nephritis
Immunosuppressions:
*Reduce (by 50%) or stop azathioprine/MMF/myofortic (discontinue CNI only if there is evidence of life-threatening infection)
*Monitor graft function closely and discuss the risk of acute rejection with the patient
* Review the dosing of immunosuppression following resolution of CMV disease
Antiviral:
* Treatment is mandatory regardless to viral load if confirmed to be CMV-tissue invasive (nephritis)
* Give intravenous GCV 5mg/kg bd (tissue-invasive) for a minimum of of 14 days and continue until resolution of symptoms and two tests of CMV DNA by PCR are negative. Do viral load first after 2 weeks and then weekly. Reduce the dose in renal impairment
* Do CBC twice weekly (neutropenia)
* Be aware of ganciclovir resistance if there is no clinical improvement despite treatment or CMV PCR count has not fallen by ≥ 1 log copies/ml after two weeks. If confirmed, stop ganciclovir and give Intravenous Foscarnet for at least 3 weeks after virology advice (newer agents Letermovir and Maribavir may be an alternative)
*Prophylaxix: D+/R+ (100 days of valganciclovir)
The pathologist queried grade 1 ACR. Would your management differ?
How to manage ACR and CMV disease?
*CMV is a risk factor of ACR
*Combined CMV disease and ACR increase the risk of allograft loss
*Control of CMV disease may decrease episodes of acute rejection
*So, I will treat CMV disease and optimize immunosuprresions as is a high immunological risk (shift to potent immunosuppressions tacrolimus/MMF) with close monitoring of kidney function and adverse effect of ant-viral and biopsy re-evaluation
*At the end of CMV treatment, I will give CMV prophylaxis for 100 days (Sheffield protocol)
What is the association between this condition and ACR?
Effect of rejection on CMV:
Intense immunosuppression and use of depleting antibodies are risk factors of CMV
CMV and rejection:
*CMV disease is a risk factor of acute renal transplant rejection
*Production of interferon-ϒ during the inflammatory process increases the expression of major histocompatibility (MHC) class I and II molecules on both vascular endothelial and tubular epithelial cells
*CMV may express molecules similar to MHC class I and II antigens priming the immune response against the allograft
*Enhances the alloantigen independent pathway of rejection by increasing co-stimulatory molecules on APCs, vascular endothelial cells, tubular epithelial cells and T-lymphocytes
References
1. UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION. BTS, 2022.
2. CMV in Kidney Transplantation By Ahmed Halawa (lecture), consultant Transplant Surgeon Associate Professor, University of Liverpool –UK, 2023
3. Ramandeep Singh et al. clinical consequences of primary CMV infection after renal transplantation: a case control study. Transplant Internatinal, 2020.
What is your differential diagnosis?
How do you manage this case?
The pathologist queried grade 1 ACR. Would your management differ?
What is the association between this condition and ACR?
· What is your differential diagnosis?
It is a renal biopsy of post kidney transplant recipient, was treated by ATG due to resistant ACR that shown epithelial tubular cell with nuclear and cytoplasmic viral inclusion bodies with Owle eyes appearance with interstitial and glomerular inflammatory cell infiltration with plasma cells which may be the cause of resistance to steroid treatment (plasma cell rich rejection).
So, I think it is a case of Acute cellular rejection ((plasma cell rich rejection) with CMV induced nephritis.
– Association of ACR/CMV induced nephritis.
-BK virus induced nephritis.
-Acute cellular rejection.
-0ther viral induced nephritis.
How do you manage this case?
-We should be aware about the TT matching , DSA, and the first kidney biopsy.
-If our patient received her prophylactic treatment for viral infection e.g. CMV
-To send CMV and BKV PCR.
-Staining the biopsy with SV 40 staining.
-Regular follow up for Renal function tests.
-We should decrease antiproliferative treatment such as MMF or allopurinol.
-Start GCV according to e GFR and continue prophylactic treatment 200 days after ATG with IVIG to treat associated ACR.
-Continue treatment until viral load of CMV not be detected for 2 weeks.
-F/U CBC and keep in mind GCV side effects and use CSF indications once indicated.
· The pathologist queried grade 1 ACR. Would your management differ?
As I mentioned before, we should avoid more immunosuppression pulses in the form of steroid or ATG as this may lead to more opportunistic infections or disseminated CMV.
I think it is wise to keep our decision balanced between our care about the graft and the patient survival .
The role of IVIG is appearing her in the scene.
· What is the association between this condition and ACR?
CMV disease, but not asymptomatic viremia, is a risk factor of acute renal transplant rejection. Which may be due to the viral replication and the diffuse inflammatory process are implicated in acute graft rejection.
References:-
1- CMV in Kidney Transplantation Lecture By: professor Ahmed Halawa.
2-Clinical Aspects of Intravenous Immunoglobulin Use in Solid Organ Transplant Recipients, S.C. Jordan a, M. Toyoda a b, J. Kahwaji a, A.A. Vo a
3- Toupance O, Bouedjoro-Camus MC, Carquin J, et al. Cytomegalovirus-related disease and risk of acute rejection in renal transplant recipients: a cohort study with case-control analyses. Transpl Int. 2000;13(6):413-419. doi:10.1007/s001470050723.
4- Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant patients, Up To Date 2023.
Dear All
Thank you, for your answers.
I’m not impressed. Your answer lacks a careful consideration of the high immunological risk of this case and the possibility of ACR.
Thanks alot Prof.Halawa
-What is your differential diagnosis?
-How do you manage this case?
Management is MDT and the principle are;
-The pathologist queried grade 1 ACR. Would your management differ?
-What is the association between this condition and ACR?
Source, Prof Halawa lecture, Sheffield protocol, Medscape, Oxford hand book of nephrology & hypertension 2th edition
Note: steroid -resistant ACR may actually represent ABMR, this should be keep in mind as a differential diagnosis because the management is completely different here. Further evaluations are needed e.g. C4d staining , molecular classifiers, and DSA. Failure to recognize ABMR is associated with poor outcomes.
Thank you, Ben
You said you treat with pulse steroid later. Do you mean after progression of ACR and failure of the graft?
Most welcome prof;
1-DD:
1- resistant acute cellular rejection
2-antibody mediated rejection
3-CMV infection
by graft biopsy: it is ACR with CMV infection (owl eye appearance in the graft biopsy)
2-management:
PCR CMV should be done
3&4- no will not differ because CMV infection may precipitate ACR, so, CMV should be treated appropriately.
Thank you, Riham
Will you reduce immunosuppression in this patient?
You mentioned”. Will you justify your answer please given the high immunological risk of this patient?
in this case there is evident CMV infection , so should be treated as it is itself a higher risk for ACR which may not be resolved
so, will treat CMV undercover of methylprednisolone and may decrease MMF by 50% and continue CNI if there is no life threatening condition
Excellent, Riham
It’s CMV nephropathy due to presence of Owl’s bodies in interstitial tissue of kidney ( Tissue invasive CMV disease )
Other diagnosis is Interstitial nephritis
HIV nephropathy
Cell mediated rejection
Positive recipient and donor for CMV / PCR and blood culture
Drug level and serial DSA level
CBC and ESR CRP
should be start antiviral gancyclovir 5mg/kg/ day twice a day for 2 weeks
Stop azathioprine and MMF
Reduce calcinurine inhibitors to half
prophylaxis by gancyclovir or valgancyclovir 450 mg for 6 months
High dose of steroid because ATG may reactivate CMV virus
CMV reactivation lead to production of gamma interferon which lead to activation of MHC molecules I , II on T cell surface which predispose to acute cellular rejection
High dose of immunosuppressive drug and use of ATG for treatment of ACR may reactivating CMV virus
Thank you, Sahar
Will you reduce immunosuppression in this patient?
You mentioned”. Will you justify your answer please given the high immunological risk of this patient?
1- There are Owl inclusion bodies suggestive of CMV disease, particularly since this patient is heavily immune suppressed and recently had ATG. CMV PCR should be monitored.
2- If CMV PCR is positive, and considering the result of kidney biopsy, Treatment is mandatory in all cases of suspected tissue-invasive CMV disease, irrespective of viral load. Appropriate reduction in immunosuppression should be considered. Valganciclovir should be started.
3- Then I will continue with the same medications without reduction in immune suppressants, but I might consider steroids in high doses with valganciclovir.
4- The relationship between cytomegalovirus (CMV) infection and the acute rejection of a renal transplant is not well established. CMV disease, but not asymptomatic viremia, is a risk factor for acute renal transplant rejection. On epidemiological grounds, these results support the hypothesis that factors controlling both the viral replication and the diffuse inflammatory process are implicated in acute graft rejection.
Toupance O, Bouedjoro-Camus MC, Carquin J, Novella JL, Lavaud S, Wynckel A, Jolly D, Chanard J. Cytomegalovirus-related disease and risk of acute rejection in renal transplant recipients: a cohort study with case-control analyses. Transpl Int. 2000;13(6):413-9.
Thank you,Fakhriya
This is a good answer but is not the best. What would you do about the ACR?
this is a challenging situation since CMV can signify over the immune impression, but if there is a concomitant ACR I will give pulse steroids therapy with IV ganciclovir and continue with the same doses of other immune suppressants. how you will treat Prof Halawa??
What is your differential diagnosis?
CMV nephropathy, as there was worsening of renal function associated with histopathological findings suggestive of CMV (owl eyes). The patient is considered at risk because the donor is positive for CMV and, in addition, there was a need for anti lymphocyte drug (rATG) to control cell-mediated rejection and increase the risk of CMV reactivation.
How do you manage this case?
– Reduce immunosuppressants (if possible remove MMF or Azathioprine)
– Measure the dosage of immunosuppressants
– Measure serum PCR levels for CMV at least twice a week
– Start Ganciclovir 5mg/kg/dose twice a day until you get two consecutive negative viral loads for at least fourteen days
– Consider CMV-enriched IVIG, Foscarnet, Cidofovir, or Maribavir if there is no sustained viral response
– Scheduled biopsies and aggressive kidney function checks
The pathologist queried grade 1 ACR. Would your management differ?
I would avoid the use of anti-lymphocytes due to the high risk of CMV reactivation, preferring to use high doses of corticosteroid therapy.
What is the association between this condition and ACR?
CMV reactivation can trigger an increase in Interferon Gamma, resulting in an increase in histocompatibility complex I and II in epithelial and endothelial cells, resulting in stimuli for increased activation of antigen-presenting cells and T lymphocytes, increasing the risk of rejection.
Functional T cells, mismatch of the MHC complex, and important immunosuppression favor CMV reactivation.
Thank you, Filipe
Will you reduce immunosuppression in this patient?
You mentioned”. Will you justify your answer please given the high immunological risk of this patient?
Professor, there is a high risk of rejection if there is a progression of the disease by CMV. Would I dose the CNI to maintain therapeutic doses and evaluate the reduction of MMF/AZA or would I switch to another class (mTOR inhibitors)
But at the time of diagnosis, I would definitely use high doses of corticosteroids to decrease the risk of rejection
What is your differential diagnosis?
How do you manage this case?
If the case proved to be CMV nephropathy (PCR in tissue and blood, IHC positive for CMV antigen)
The pathologist queried grade 1 ACR. Would your management differ?
What is the association between this condition and ACR?
1- CMV may increase the risk of ACR due to the following:
2- CMV nephropathy may be misdiagnosed as cellular rejection since biopsy can mimic ACR, and the main diagnostic difference is the detection of the virus in blood and/ or by IHC.
3- Treatment of ACR with ATG may predispose to the development of CMV nephropathy due to aggressive immunosuppression used in the treatment of rejection
4- Once treatment for CMV nephropathy is established, reduction of immunosuppression may cause the development of acute rejection leading to further allograft damage.
Thank you, Sherif
Will you reduce immunosuppression in this patient?
You mentioned”. Will you justify your answer please given the high immunological risk of this patient?
No universal acceptance of a single approach in this type of patient with high immunological risk, it is difficult to adjust the risk of rejection and benefit of viral clearance.
I will reduce MMF by 50%, keep CNI and increase steroid dose since there is high risk of rejection.
if rejection proved I will use high dose steroids.
I will not stop MMF except if no reduction of the viral load, at that time I should stop MMF and resume low dose after PCR is negative for 2 successive samples 1 weeks apart
Thank you, Sherif
Your answer lacks clarity. You should treat CMV under pulse steroid cover
Differential Diagnosis
CMV Nephropathy – the presence of an owl’s eye intranuclear inclusion in the interstitium of kidney histology
Risk factors in the index patient
Management
other investigations
Treatment
Would the treatment change with ACR
Association between CMV nephropathy and ACR
Allograft rejection. failure has been found in about 16-18% within 12 -24 months in those with CMV infection according to the IMPACT study
References
Thank you, Isaac
Will you reduce immunosuppression in this patient?
You mentioned”. Will you justify your answer please giving the high immunological risk of this patient?
Thank you prof Halawa for the response.
I agree with you that reducing the immunosuppressive in this patient with high immunological risk may lead to graft loss.
However, allowing the immunosuppressives to stay as it is will enhance the proliferation of the CMV virus and coupled with the fact CNI inhibitors could be nephrotoxic. So I will rather prefer to lose the graft than to lose the patient since there is another chance for another kidney transplantation if the patient still remains alive
Thank you, Isaac
This is definitely the WRONG answer. You should treat CMV under pulse steroid cover
Thank you prof, for the response
The patient had acute cell mediated allograft rejection , received corticosteroid which was non effective, and rejection was deemed steroid resistant , hence ATG was administered .
she had another deterioration of renal function for which kidney biopsy repeated and revealed glomerular and tubulo-interstitial infiltration with mono-nuclear and poly-nuclear cells. Tubular cells were swollen with enlarged nuclei.
Differential diagnosis :
1] BKpolyoma kidney disease
2] Covid Nephritis.
3] CMV nephritis
4] HIV nephritis
5] Acute cell mediated rejection.
6] Acute interstitial nephritis.
Management:
Establishing the diagnosis by having immune -histochemistry IHC and tissue PCR. Blood PCR and PP65 protein might be investigated as well.
ACR and CMV nephritis:
The excessive immunosuppression status followed treatment with ATG for steroid resistant CMR .
CMV nephritis is often associated with ACR, furthermore, it might predispose to ACMR by enhancing the inflammatory reaction and activate immune system.
Primary treatment of CMV nephritis is advocated with intravenous Ganciclovir 5 mg/kg for 14 days.
close observation of renal function, with re-biopsy to ascertain the status of ACMR progression.
Anti-rejection therapy might be warranted if no improvement was documented.
long term management:
CMV prophylaxis is indicated with oral Valganciclovir 450 mg bid for 3-6 months depending on serology status of the recipient.
reference:
1]Giuliano Ferreira Morgantetti et al.Cytomegalovirus infection in kidney allografts: a review of literature.Transl Androl Urol. 2019 May; 8(Suppl 2): S192–S197.
Thank you, Wael
Please describe what is shown on the biopsy
What are the diseases that give this picture?
Will you reduce immunosuppression?
Thank you prof. Ahmed .
The picture features infiltration of glomeruli and tubulo- interstitium with mononuclear and polynuclear cells consistent with tubulointerstitial nephritis or acute cellular rejection. giving the high risk of cellular rejection in this context , i will not reduce the immune suppression meanwhile .
OWL eye (CMV inclusion bodies).
You should treat CMV under pulse steroid cover.
The most common risk factors for CMV infection include-
use of lymphocyte-depleting agents for induction or rejection therapy
donor-recipient mismatching
co-morbid infection and illness
BK virus nephropathy
Acute cellular rejection
ABMR
OWL eye inclusions seen in renal biopsy .
it is also seen in Hodgkins lymphoma.in view of ACR i will start inj methylprednisolone pulses and iv ganciclovir .
pulse methylprednisolone along with iv gangiclovir followed by valganciclovir for a total till 2 weekly CMV PCR tests are negative .
CMV disease is a risk factor for acute allograft rejection in patients with kidney transplantation.
CMV disease can cause dysregulation in immune system and may increase the risk of transplant rejection
Sagedal et al evaluated 477 kidney transplant patients and demonstrated that CMV disease is a predictor of rejection . Toupance et al reported that CMV disease but not viremia, is a major risk factor for acute rejection in renal transplant recipients . on the other hand Michael et al, concluded that, after 5 years follow-up, CMV infection was not a risk factor for acute or chronic rejection .
Sagedal S, Nordal KP, Hartmann A, Sund S, Scott H, Degré M. et al. The impact of cytomegalovirus infection and disease on rejection episodes in renal allograft recipients. Am J Transplant. 2002;2:850–6. doi: 10.1034/j.1600-6143.2002.20907.x
Toupance O, Bouedjoro-Camus MC, Carquin J, Novella JL, Lavaud S, Wynckel A. et al. Cytomegalovirus-related disease and risk of acute rejection in renal transplant recipients: a cohort study with case-control analyses. Transplant Int. 2000;13:413–9. doi: 10.1007/s001470050723
Dickenmann MJ, Cathomas G, Steiger J, Mihatsch MJ, Thiel G, Tamm M. Cytomegalovirus infection and graft rejection in renal transplantation. Transplantation. 2001;71:764–7