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5. A 48-year-old woman was admitted with epigastric pain and deterioration of kidney function 2 months after ABOi kidney transplantation. A routine infection screen and USS of her kidney were normal. USS of the liver and gall bladder was also reported normal. Anti-A IgG titre has risen from 1/8 to 1/512. CMV positive/CMV negative transplantation on Valganciclovir® 900 mg/daily. Kidney biopsy and C4d staining are shown below:
OGD and biopsy are shown below:
- Describe the finding.
- How do you manage the case?
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A case of resistant CMV infection and Antibody mediated rejection
Treatment of AMR :IVIG and plasmapheresis and may be rituximab
treatment of resistant CMV infection:/
Leflunoamide
IV foscarnet
IV ganciclivur can be tried
cidofvir
IVIG can be another option
send genetic study for UL97 and UL 54
The biopsy shows acute interstitial inflammation and vacuolization,C4d +ve ; ABMR
Upper endoscopy shows hyperemic gastric mucosa with ulcerations with
intranuclear inclusion bodies with Owl eye appearance of CMV .
Treatment of ABMR and the Gancyclovir resistant CMV disease :
-IV Steroids, Plasma exchange ,IVIG , Mabthera.
-CMV quantitative analysis by PCR and genotyping to exclude mutations .
-Stop Ganciclovir and start Foscarnet or Cidovofir.
The kidney biopsy showed evidence of tubulitis and positive C4d staining (ABMR) along with lymphocytic infiltration and presence of inclusion bodies likely CMV.
OGD (the gross finding are erythema, swollen hyperemic margins and inflammation) CMV gastritis possibly.
Management of this case:
This is a case of concomitant antibody mediated rejection evident by serological rising of antibody titre and biopsy proven C4D combined with heavy viral resistant GIT CMV gastritis resistant to antiviral therapy due to heavy immunosuppressive load.
Reduction of immunosuppressive load is to be considered, with conversion from CNI to mTORi better with holding antimetabolites for a while.
IVIG could offer some help to overcome both viral infection and rejection being a potent immunomodulator.
Plasma IgG to reduce viral burden.
CMV genotype analysis.
● Describe the finding.
This is a case of resistant CMV disease associated with AMR
● How do you manage the case?
◇ Resistant CMV infection
☆ The frequency of CMV resistance in the SOT after GCV therapy is < 5%.
☆ The risk factor is the lack of prior CMV immunity ( D+/R-) , inadequate antiviral drug dose , intense immunosuppressive therapy and exposure to therapeutic antiviral drugs with a lower barrier to resistance.
☆ Treatment include :
** Reducing immunosuppression therapy
** High-dose GCV (from 7.5 to 10 mg/kg every 12 h in normal renal function)
** For severe, life-threatening, or sight-threatening disease use foscarnet with a mortality of 31% and with renal toxicity
** Maribavir is a safe and effective therapeutic agent The main side effect was dysgeusia in 37%.
** But in retinitis or encephalitis foscarnet is preferred because of poor maribavir penetration . So In such patients it is preferred to use foscarnet induction therapy followed by maribavir treatment
** Letermovir approved for prophylaxis after stem cell transplant but not as treatment agent. it is probably better used as prophylaxis
** CMV immunoglobulin may be useful.
** infusions of CMV-specific T cells may improve antiviral host defenses
** Prophylaxis after treatment of R/R CMV
letermovir
Other options include :
CMV immunoglobulin
cidofovir every 2 weeks.
◇ Treatment AMR:
Plasma exchange, IVIG, cycles of Mp.
Describe the finding.
1st picture–Showing glomerulitis with peritubular capillaritis -suggestive of AMR
2nd picture-Diffuse linear C4D staining -Suggestive of AMR
3rd picture-Mucosal inflammation and mucosal ulcer
4th picture–Intranuclear inclusion and owl eye
3 and 4 th picture indicates cmv infections.
Overall These clinical and histological picture indicates AMR in ABOi kidney transplantation and Valganciclovir resistant CMV infection.
How do you manage the case?
Managment of GANCICLOVIR RESISTANT CMV-
Genotype testing should be performed to identify specific resistance mutations-UL97 and UL54.A significant number of patients with clinically ganciclovir-resistant CMV disease have no detectable mutation.Maribavir a new drug,is active against CMV with UL97 and UL54 mutations. Maribavir is dosed at 400 mg orally twice daily for eight weeks. Foscarnet is active against CMV with UL97 and UL54 mutations. Foscarnet is dosed at 60 mg/kg IV every 8 hours or 90 mg/kg every 12 hours, with dose adjustment for kidney function impairment. Foscarnet is highly nephrotoxic .Cidofovir is active against CMV with UL97 mutations but not against CMV with UL54 mutations.Cidofovir can be dosed at 1 mg/kg IV three times a week. It is highly nephrotoxic.If Maribavir is available ,it should be preferred.
Managment of Associated AMR-
Considering the Risk of graft loss with ABMR ,i will not decrease his immunosuppression Taq level and Area under curve of mycophenolate should be checked. Here we have to decrease high Anti A IgG titre quickly.Plasmapheresis is performed daily or every other day for a maximum of six sessions or until the serum creatinine is within 20 to 30 percent of the baseline. intravenous (IV) methyprednisolone at a dose of 300 to 500 mg daily for three to five days, followed by a rapid oral prednisolone taper to the patient’s previous maintenance dose of prednisone.IVIG at a dose of 100 mg/kg after each session of plasmapheresis. with a total cumulative target dose of at least 1000 mg/kg of IVIG.
Ganciclovir resistance usually occurs in 1-2% of the patients, more common in lung and pancreatic transplant with least prevalence in liver and renal transplant cases. Patients who are CMV D+/R- ,have been administered intensive immunosuppression and have very high viral load are more prone to develop resistance .It is defined as persistence or elevation of the viral load after 2 weeks of appropriate treatment .Genotypic resistance testing should be done whenever it is suspected .Various genetic mutations are responsible but usually UL97 and UL54 gene mutations are responsible. Treatment in such cases includes: reduction of immunosuppression followed by IV Foscarnet, Combination therapy with reduced doses of ganciclovir and foscarnet , , Cidofovir, Leflunomide and CMV hyperimmune globulin.
The above case has resistant CMV infection with AMR ,so treatment in this case will be to reduce immunosuppression with close monitoring of graft function and start pulse steroids, plasmapheresis with IVIG +/- Rituximab for ABMR and treatment of CMV with IV foscarnet or combination therapy with reduced doses of ganciclovir foscarnet or trial of high doses of Ganciclovir or CMV hyperimmune globulin.Duration of treatment -3 weeks.Close monitoring of LFT,RFTs and CBC needed.After treatment,prophylaxis with valganciclovir for 3 mths
REFERENCES:
UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATIONTreatment of Ganciclovir Resistant Cytomegalovirus Infection
This patient is challenging case he has ABMR which require more aggressive IS and resistant CMV disease on prophylactic ganciclovir which require reduction of IS
Ganciclovir resistance may occur due to prolonged antiviral ttt, intensive immunosuppression, induction with and T-cell depletion, viral genetic mutation such as UL97 .
Management will be by reduction of immunosuppression ,reduce MMF by 50% and optimize the dose tacrolimus keep trough level at 5 to be stopped if life threatening condition occurred .
With cover by pulse methylprednisone 500mg for 5 days with IVIG and PLEX .
Antiviral therapy treatment
Increase the dose of ganciclovir (up to 10 mg/kg twice daily may give good response
If gentic testing revealed UL97 mutation foscarnet is suggested with monitor of graft function .
Ciodovir can be used with carful monitoring of liver and kidney function The doses should be adjusted to renal function
Q1: kidney biopsy shows acute tubular necrosis and peritubular capillaritis and arteritis and c4d positive immunofluorescent indicating ABMR
GI endoscopy shows ulcerative gastritis with inflammatory infiltrations.
Q2: It is difficult to treat ABMR and CMV tissue-invasive (gastritis) disease at the same time, especially when the patient had been taking prophylaxis which shows that it might be a resistant CM disease.
Plan:
· Multidisciplinary management
· Lubtest: CMV PCR (may be negative), CBC, LFT, biochemistry, LFT, renal function tests
· Methylprednisolone pulses for 3 days
· Plasma exchange and IVIG infusion for ABMR treatment
· IV ganciclovir (high dose) and monitoring for CMV disease. If no response, IV foscarnet, and genotype assay are necessary
· Reduction of MMF by 50%
The histologic stain showing peritubular lymphocytic cell infiltration with tubulitis, and tubular vacuolation.
The Immunofluorescences: diffuse C4d positive – likely AMR.
The OGD and biopsy are showing: gastric tissue with hyperemic and superficial mucosal ulceration, with histologic shown intranuclear inclusion bodies with CMV infection appearance.
– Schedule tests for UL97 and UL54 mutations.
– Decrease immunosuppression;
– Evaluate treatment dose if adjustment is possible
– Assess whether there may have been failure to adhere to treatment
– If there is no dose adjustment or treatment adherence failure, it will be necessary to stop Valganciclovir and start Foscarnet for 3 weeks
REFERENCE:
– Uk Guideline on Prevention and Management of Cytomegalovirus (CMV) Infection and Disease following Solid Organ Transplantation
· Describe the finding:
Renal biopsy and OGD.
First image: LM, H&E stain: dilated tubules with vacuolation, inflammatory cells in PTC, no glomeruli seen. ATI+ PTC suggest acute AMR.
Second image: IF stain, C4d positive, in presence of rising anti-A IgG titer from 1/8 to 1/512 suggest acute AMR.
Third image: esophageal red mucosa.
Fourth image: Biopsy of mucosa showing inclusion bodies in the endothelial cells suggestive of CMV infection.
This is a case of AMR associated with CMV infection.
· How do you manage the case?
ABOi, CMV D+/R-, 2 months post RTx. Rising anti-A IgG from 1/8 to 1/512. Acute graft dysfunction.
OGD: CMV esophagitis. On Valganciclovir 900mg–à> resistant CMV
RTx biopsy: ? acute AMR?
1- Routine investigations: U&Es, LFT, FBC, CRP, Urine dip.
2- CNI level
3- DSA.
4- CMV PCR and check for genotype and sensitivity to antivirals.
5- Treatment of AMR:
A- Pulse Methyl-prednisolone.
B- Plasma exchange 5 sessions, followed by IVIG till anti-A IgG Titer below 1:16.
C- IV rituximab after last Plasma exchange.
6- Treatment of Tissue invasive CMV (in resistant strain):
a- IV Ganciclovir for at least 2 weeks then can be switched to oral valganciclovir. Continue monitor CMV PCR.
b- Consider using Foscarnet or CMV IG or IVIG if resistant CMV strain.
7- Secondary prophylaxis against PJP, maintain well hydration.
Describe the finding.
The kidney biopsy showed evidence of tubulitis and positive C4d staining (ABMR).
OGD (the gross finding are erythema and inflammation ) CMV gastritis ? and the biopsy showed lymphocytic infiltration and inclusion bodies suggestive of CMV disease .
How do you manage the case?
This is a case of vGCV and the management can be done through ;
1-Ask for CMV genotype
2-Consider further reduction in immunosuppression .
3-Switch to the second line of treatment .
4-Consider CMV immunoglobulin
Regarding Acute rejection methyl prednsolone can be initiated in conjunction with treatment of CMV disease .
References
1.Bruminhent J, Rotjanapan P, Watcharananan SP. Epidemiology and Outcome of Ganciclovir-Resistant Cytomegalovirus Infection After Solid Organ Transplantation: A Single Transplant Center Experience in Thailand. Transplant Proc. 2017 Jun;49(5):1048-1052.
1. Describe the finding.
The first two images –
Graft biopsy- Showing acute interstitial inflammation & vacuolization
C4d staining- suggestive of ABMR
3rd and 4th image-
UGIE showing hyperemic gastric mucosa with ulcerations
Histology showing intranuclear inclusion bodies with Owl eye appearance – suggestive of CMV infection.
2. How do you manage the case?
These finding are suggestive of Renal allograft ABMR and CMV disease with gastritis – in spite of using Val Ganciclovir, suggesting Ganciclovir resistant CMV disease.
Treatment of ABMR
· Retuximab + Plasma exchange + IVIG
· Monitoring RFT; follow up biopsy may be required.
Treatment of Ganciclovir resistant CMV disease
· CMV PCR and genotyping – exclude mutations UL97
· Therapeutic options: Foscarnet / Cidofovir; Leflunomide.
– monitoring for nephrotoxicity.
· Immunosuppression reduction – MMF by 50%, minimize CNI dose; monitoring RFT for rejection
References:
1. 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. Iran J Pharm Res. 2017 Spring;16(2):805-810.
2. Koslik MA, Friebus-Kardash J, Heinemann FM, Kribben A, Bräsen JH, Eisenberger U. Differential Treatment Effects for Renal Transplant Recipients With DSA-Positive or DSA-Negative Antibody-Mediated Rejection. Front Med (Lausanne). 2022 Jan 31; 9: 816555.
The patient has resistant CMV infection and evidence of ABMR..
Clinically, antiviral drug resistance is suspected in this patient because of progressive CMV disease while on prophylactic valganciclovir for 2-month post kidney transplant.
Reassurance of treatment adherence
testing for CMV antiviral resistance, UL97 and UL54 gene mutations.
Start IV Foscarnet for at least 3 weeks till viral load negative
Stop/reduce (by 25-50%) MMF
continue CNI unless there is evidence of a life-threatening infection
Monitor graft function
For ABMR,
IV pulse methyl prednisone
PLEX every other day 6-10 sessions
IVIG after each session of plasmapheresis
Rituximab if needed
Hand book of transplantation ,6th edition
This a resistance CMV infection with an episode of AMR , we need to start gancyclovir to treat the infection and the same time we need to treat the rejection; the best option in this scenario is High dose IVIG which can treat both
Kidney biopsy
– LM & H&E stain- Features of acute interstitial inflammation and tubular vacuolization.
– IM stain- c4d staining positive
Dx- ABMR as high titer of Anti-A IgG
OGD and biopsy
– Diffuse erythema, erosion and superficial ulceration
– Giant cell and intranuclear inclusion
Dx- As patient on Valgancyclovir, this is a case gancyclovir resistant CMV infection
Resistant CMV infection
– Consider reduction in immunosuppression
– Consider Ig
– 2nd line therapy (Foscarnet, cidofovir, letermovir, maribavir)
ABMR
-IV pulse steroid
– IV Ig
– Plasma exchange
Management of ganciclovir resistance CMV
Antiviral therapy:
Check medication compliance
Viral gene typing.
Stop Valganciclovir
Start IV Foscarnet for 3 weeks
leflunomide
Investigation:
Monitor renal function, CBC, and LFT
After completing the treatment, continue valganciclovir prophylaxis for three months.
CMV Ig and IVIG
Immunosuppression
Stop/reduce (by 50%) MMF/AZA
Continue CNI unless life-threatening infection; level of Tacrolimus should be 6.
Corticosteroids are continued IVMP pulse steroids for the co-existence of ABMR.
ABMR management:
IV methyl prednisolone pulse
Plasmapheresis every other day 6-10 sessions
IVIG after each session of plasmapheresis
Rituximab
· Describe the finding.
This is a examination of upper GI tract the findings are hyperemia mucosa with signs of colitis, on histological examination there is lymphocytic infiltrates with inclusion bodies.
IF is positive for C4d.
· How do you manage the case?
· C4d positivity and lymphocytic infiltrates are signs of antibody mediated rejection, on the basis of evidence CMV infection which has direct and indirect effect on graft, signs of rejection, I will treat ABMR.
· Second, CMV infection not responding to antiviral therapy. Suspicion of drug resistant infection.
· Qualitative PCR and genotyping and look for mutation UL54 and UL97.
· Increase dose of genciclovir up-to 7.5mg/kg if responds, otherwise switch to second line agents like Foscarnet, Cidofovir, and Marabavir.
· Others to treat both ABMR and resistant infection with high does IVIG, plasmapheresis, and +/- rituximab.
Refrences;
1. UK guidelines on prevention and CMV Infection and disease following SOT -April 2022.
2. Uptodate – Clinical manifestations, diagnosis and management of CMV in KTR.
48 year old women has undergone an ABOi renal transplantation…She had presented with epigastric pain and deterioration in kidney function…..The kidney was received from CMV positive to CMV negative recipient…. Septic screen and USG were normal… this patient was on CMV prophylaxis….
Patient underwent renal biopsy… Light microscopy shows ATN with peritubular capillairitis…. C4d stain is positive…. raising Anti A IgG titre to 1:512 suggests antibody mediated rejection…. Patient renal biopsy also shows owl eye nuclear inclusions in the interstitium…. Colonoscopy showed few ulcers in the colon…
The given patient has developed ABMR and Resistant CMV infection while on Valganciclovir prophylaxis’s…..
Management of the case:
This presents a challenging situation in which there is ABMR and tissue invasive CMV… Patient needs CBC, RFT, Liver function test, Procalcitonin and blood culture to detect concomitant bacterial sepsis…Patient needs to get checked the CMV viral load…CMV resistance needs to be checked for UL97 and UL54 gene mutations…I will also look into the sensitization history in the past and look SAB DSA by Luminex now….
Patient needs treatment for ABMR as the raising titres are alarming… Patients needs plasmaphresis atleast 5 settings with pre plasma monitoring of anti IgA titres and DSA titres if needed… Patient needs IVIg that is CMV specific as he has CMV invasive disease and these antibodies can be used to replenish the IG that are being replaced.. Patient should be treated with IV Rituximab 500mg at least 2 doses 1 week apart… She also needs to be reduced on antimetabolites/ I will reduce the dose to 50% first and then see the response of the CMV and then decide on stopping as we need to maintain the immunosuppression for rejection….High tacrolimus level needs to be maintained in view of ABMR….
Patient needs to be started on IV ganciclovir 15-20mg/Kg IV twice a day for 21 days..Atleast 5 days of IV then followed by oral therapy with valganciclovir 900mg twice daily is needed for CMV …CMV specific IVIG given post plasmaphresis will help ….If there is UL97 and UL54 mutations IV foscarnet needs to be started..
Describe the finding:
Renal Biopsy:
Light Microscopy: shows tubular vacuolization peritubular and capillary infiltration with lymphocytes.
Immunofluorescence: shows positive C4d staining in the peritubular capillaries.
Endoscopy:
Show ulcerative and congested mucosa with gastric erosion.
Biopsy showed CMV inclusion bodies with interstitial infiltrates owl eye appearance, characteristic to CMV gastritis.
Management:
This ABO incompatibility with the above findings diagnosed as acute antibody mediated rejection (AMR) with Valgancyclovir resistant CMV disease.
AMR: IV pulse steroid, IVIG, & plasma exchange.
Resistant CMV: following gene typing testing for CMV antiviral resistance
– Foscarnet need close monitoring for nephrotoxicity
– Cidofovir monitoring for nephrotoxicvity is needed
– Newer options, Letermovir, and Brincidofovir
Immunosupressive management:
– Stop/reduce antimetabolites by 50%.
– Keep CNI within therapeutic level (4-6 ng/ml)
References:
(i) Cooper JE. Evaluation and Treatment of Acute Rejection in Kidney Allografts. Clin J Am Soc Nephrol. 2020 Mar 6;15(3):430-438. doi: 10.2215/CJN.11991019. Epub 2020 Feb 17. PMID: 32066593; PMCID: PMC7057293.
(ii) 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.
(iii)Hand book of transplanatation ,6th eidtion
The patient has resistant CMV infection and evidence of ABMR
Clinically, antiviral drug resistance is suspected in this patient because of progressive CMV disease while on prophylactic valganciclovir for 2-month post kidney transplant.
Reassurance of treatment adherence
testing for CMV antiviral resistance, UL97 and UL54 gene mutations.
Start IV Foscarnet for at least 3 weeks till viral load negative
Stop/reduce (by 25-50%) MMF
continue CNI unless there is evidence of a life-threatening infection
Monitor graft function
For ABMR,
IV pulse methyl prednisone
PLEX every other day 6-10 sessions
IVIG after each session of plasmapheresis
Rituximab if needed
Hand book of transplantation ,6th edition
This patient is suffering from probable resistant CMV infection with underlying ABMR post ABOi transplant.
Points in favour of ABMR:
Post ABOi transplant with worsening graft function
Anti-A IgG titres have significantly increased
C4D stain may be positive in post-ABOi transplant, but this picture fits acute rejection.
DSAs would be helpful.
Management of ABMR in CMV diseased patient with Valganciclovir resistance:
before managing resistance, confirm:
Treatment of CMV gastritis: Intravenous Foscarnet for at least 3 weeks
Stop MMF and continue CNI. As stopping CNI, would further worsen the acute rejection.
Management of ABMR:
Plasmapheresis, IVIG, Rituximab
Source:
UK Guideline On Prevention And Management Of Cytomegalovirus (Cmv) Infection And Disease Following Solid Organ Transplantation
Djamali A, Kaufman DB, Ellis TM, Zhong W, Matas A, Samaniego M. Diagnosis and management of antibody-mediated rejection: current status and novel approaches. Am J Transplant. 2014 Feb;14(2):255-71. doi: 10.1111/ajt.12589. Epub 2014 Jan 8. PMID: 24401076; PMCID: PMC4285166.
iABO case- HIGH chances of AMR
CMV D+/R- HIGHEST CHANCES OF CMV INFECTION AND ALSO RESISTANCE TO GANCICLOVIR
top two slides are suggestive of AMR
OGD- stomach mucosal lesion and haemorrages
two issues are important here
AMR – need PLEX, AND PULSE STEROID AND REASSESS with antibody titres
GANCICLOVIR RESISTANCE due to UL97 mutation , can be detected on plaque reduction assay
rish factors – D+/R-, prolonged anti=CMV drugs, degree of IS, magnitude of viremia, pancres transplant ( highest incidence )
valganciclovir is 10 times more potent and can reduce the resistance compared to ganciclovir
forcarnet
can be used
work in UL97 mutation but not in UL54 mutation
toxicity – renal , electrolytes imbalance , seizures
cidofovir
need phosporylation before the action
iv once a week
renal toxicity
here in this high risk case , patient life is at risk due to resitant CMV and graft is at loss due to AMR
tricky balance need to be maintained
LIFE OF PATIENT TAKE PRECEDENCE OVER GRAFT
There is acute tubular injury, heavy infiltration by neutrophils and mononuclear cells in the peritubular capillaries. There are areas of fibrinoid necrosis. The next slide showed diffuse and intense C4d staining (>50%).
Though it is common to find positive C4d on protocol biopsies in ABO-incompatible transplant, as compared to HLA incompatible transplant, however, given the clinical scenario of graft dysfunction accompanied with a rise in the Anti-A IgG titre from 1/8 to 1/512, with the histology picture shown above, all signify a presence of acute AMR. She should be re-initiated on plasmapheresis and IVIG. In addition, the slide also shows owl bodies and given that she has CMV positive/CMV negative transplantation and her endoscopy shows oesophageal erythema, therefore she has an active CMV disease. Currently she is on prophylactic Valganciclovir® 900 mg/daily. The dose should be modified to b therapeutic regimen. Patients with CMV infection should receive intravenous ganciclovir or oral valganciclovir for a minimum of 14 days until resolution of symptoms.
5. A 48-year-old woman was admitted with epigastric pain and deterioration of kidney function 2 months after ABOi kidney transplantation. A routine infection screen and USS of her kidney were normal. USS of the liver and gall bladder was also reported normal. Anti-A IgG titer has risen from 1/8 to 1/512. CMV positive/CMV negative transplantation on Valganciclovir® 900 mg/daily. Kidney biopsy and C4d staining are shown below:
issues/ concerns
– 48yo lady, epigastric pain
– deteriorating kidney function
– ABOi kidney transplantation done 2months ago
– normal infection screen, normal liver and GB ultrasound, normal graft ultrasound
– rising anti-A IgG titer from 1/8 to 1/512
– CMV+/ CMV- serostatus on Valganciclovir 900mg OD
Describe the findings: –
– Kidney biopsy findings: – tubulitis, peritubular capillaritis, C4d positive staining suggestive of ABMR
– OGD and biopsy findings: – mucosal inflammation, gastric erosion, CMV inclusion bodies, interstitial infiltrates suggestive of CMV disease
How do you manage the case?
– patient most probably has antibody mediated rejection (ABMR) and CMV disease involving the GI
– multidisciplinary approach – gastroenterologist, infectious disease specialist, pathologist
– comprehensive history – altered stool patterns/ diarrhoea, vomiting, weight loss, epigastric pains, urine output, lower limb/ facial swelling, chest symptoms, night sweats, fevers, induction therapy, any rejection episodes, compliance to medication,
– thorough physical examination – pallor, lymphadenopathy, abdominal tenderness, graft tenderness
– Investigations: – CBC, ESR, CRP, UECs, LFTs, urinalysis, blood sugar, CMV viral load (quantitative PCR), BKV viral load (quantitative PCR), CNI trough levels, DSA levels
– Management: – (1-3)
– the goal of therapy in ABMR is to reduce the DSA levels, get rid of the B cells or plasma cells that are responsible for the production of the DSAs, prevent complement activation, reduce endothelial injury and to preserve graft function
– the recommendation is a combination of: –
– markers of response to treatment include: –
– if the patient responds to the above management, then maintain the augmented maintenance dose and continue routine monitoring
– if there is no response, consider doing a repeat graft biopsy to exclude ongoing rejection, extensive interstitial fibrosis or an alternative diagnosis
– for patients treated for active ABMR, reinitiate antiviral, antifungal and antimicrobial prophylaxis i.e., prophylaxis against PCP, CMV, HSV, at doses similar to those administered in the immediate post-transplant period
– rituximab can be considered in: –
– for patients with refractory ABMR i.e., patients who fail to respond to the pulse corticosteroids, plasmapheresis, IVIG, rituximab combination the other viable rescue therapies include complement inhibitors, proteosome inhibitors
– less commonly used therapies in refractory ABMR include immunoadsorption and splenectomy
– ABMR increases the risk for subsequent rejection, chronic ABMR and eventually graft failure (4)
– Management of CMV disease involving the GI system: – (5, 6)
References
1. Schinstock CA, Mannon RB, Budde K, Chong AS, Haas M, Knechtle S, et al. Recommended Treatment for Antibody-mediated Rejection After Kidney Transplantation: The 2019 Expert Consensus From the Transplantion Society Working Group. Transplantation. 2020 May;104(5):911-22.
2. Wan SS, Ying TD, Wyburn K, Roberts DM, Wyld M, Chadban SJ. The Treatment of Antibody-Mediated Rejection in Kidney Transplantation: An Updated Systematic Review and Meta-Analysis. Transplantation. 2018 Apr;102(4):557-68. PubMed PMID: 29315141. Epub 2018/01/10. eng.
3. Cornell LD, Schinstock CA, Gandhi MJ, Kremers WK, Stegall MD. Positive crossmatch kidney transplant recipients treated with eculizumab: outcomes beyond 1 year. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2015 May;15(5):1293-302. PubMed PMID: 25731800. Epub 2015/03/04. eng.
4. Dunn TB, Noreen H, Gillingham K, Maurer D, Ozturk OG, Pruett TL, et al. Revisiting traditional risk factors for rejection and graft loss after kidney transplantation. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2011 Oct;11(10):2132-43. PubMed PMID: 21812918. Pubmed Central PMCID: PMC3184338. Epub 2011/08/05. eng.
5. 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.
6. 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.
A bidirectional “synergistic” relationship between acute rejection and CMV disease can occur after SOT. TNF-α and other Pro-inflammatory cytokines released during acute rejection are potent trans-activators of CMV.
In one study, acute rejection increased the risk of CMV disease by sixfold in a cohort of CMV D+/R− liver and kidney recipients.
On the other hand, CMV increases the risk of acute and chronic rejection.
Antiviral prophylaxis has been associated in some studies to reduce not only the incidence of CMV disease but also acute rejection.
Regarding this case scenario, a resistant strain is suspected as the pt developed an invasive disease while receiving Valcyte prophylaxis so testing for these strains by genotyping is advised, while awaiting the results, antimetabolites should be stooped or taken in a reduced dose, CNI will continue in an optimized dose
I will start pulse steroids and PLEX on alternate days with IVIG after each session
increased dose of IV ganciclovir up to 10 mg/kg BID in combination with Foscarnet can be used empirically.
Describe the finding.
The first two images –
Graft biopsy- Showing acute interstitial inflammation & vacuolization
C4d staining- suggestive of ABMR
3rd and 4th image-
OGD showing hyperemic gastric mucosa with ulcerations
Histology showing intranuclear inclusion bodies with Owl eye appearance. It is suggestive of CMV infection.
How do you manage the case?
These finding are suggestive of ABMR and CMV disease with gastritis in spite of using Val Ganciclovir suggesting Ganciclovir resistant CMV disease.
Treatment of ABMR
· Steroids
· Plasma exchange
· IVIG
· Follow up required
Treatment of Ganciclovir resistant CMV disease
· CMV PCR and genotyping to exclude mutations like UL97 protein kinase
· Stop Ganciclovir
· Therapeutic options include Lefunamide, Foscarnet and Cidovofir. All these drugs require monitoring for nephrotoxicity.
· Modification of immune suppression.
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. Iran J Pharm Res. 2017 Spring;16(2):805-810.
Koslik MA, Friebus-Kardash J, Heinemann FM, Kribben A, Bräsen JH, Eisenberger U. Differential Treatment Effects for Renal Transplant Recipients With DSA-Positive or DSA-Negative Antibody-Mediated Rejection. Front Med (Lausanne). 2022 Jan 31;9:816555.
OUR CASE;
FINDINGS;
MANAGEMENT;
ABMR < 1YR POST TRANSPLANT.
-Therapy to include steroids + plasmapharesis + IVIG +/- Rituximab.
CMV RESISITANCE.
-Choice of therapy; Marabavir, foscarnet and cidofovir.
-We will check for resistance before commencing treatment.-UL97 and UL54 Mutations.
-Treatment;
>No detectable mutation;
>Detectable mutation;
>Other therapies for life threatening dx;
REFERENCES.
CMV GASTRITIES :
Non specific symptoms :
Fever ,nausea, epigastric pain ,and bleeding
Endoscopic :
Normal mucosa ,diffuse erythema, nodules ,pseudo tumors ,necrosis and ulcers.
Detection of intra nuclear inclusion in the biopsy is the hall mark of CMV..
Treatment
:Reduction in immunosuppressive agents .
Immunoglobulin CMV IG can be used to induced passive immunity
Request genotype resistance
Medication can be used :
1-Foscavet
2-Cidovir
3-leteromovir
4- Maribavir
Treatment of AMR :
1-rituximab
2-Plasma exchange
3- IVIG .
4- Steroid
Rituximab and intravenous Ig (IVIG) are commonly used for desensitization of HLA and blood group–incompatible (ABOi) transplants. However, serious infections have been noted in association with rituximab administration
the anti-infective properties of IVIG might account for reduced infections
IVIG contains anti-CMV IgG
References
1- Desensitization in Crossmatch-positive Kidney Transplant Candidates
Transplantation 2022; Publish Ahead of Print.
review-article
2- prof ahmed halawa lecture
A 48-year-old woman has epigastric pain and deterioration of kidney function 2 months after ABOi kidney transplantation.
Anti-A IgG titer has risen from 1/8 to 1/512. (suspected rejection)
CMV positive/CMV negative transplantation on Val ganciclovir 900 mg/daily. (high risk for CMV infection.
Describe the finding.
Kidney biopsy:
The left side image showing:
L/M :Inadequate biopsy not showing glomeruli and stained with H&E stain showing peritubular lymphocytic cell infiltration with tubulitis, Tubular vacuolation.
Immunofluorescences: diffuse C4d positive
This findings are characteristic of ABMR.
The right side image showing:
Immunofluorescences: diffuse C4d positive
This findings are characteristic of ABMR.
The second two photos showing
Gastric tissue ;hyperemic with superficial mucosal ulceration, second one shown intranuclear inclusion bodies with owl eye appearance which mainly matched with CMV infection.
How do you manage the case?
It is a case of ABMR with CMV gastritis CMV disease despite Val ganciclovir prophylaxis, explaining ganciclovir-resistant CMV infection.
Treatment of CMV disease:
1-CMV PCR with CMV genotyping to exclude mutations in the viral such as UL97 protein kinase.
2- leflunomide is a reasonable option in ganciclovir-resistant infection in kidney transplant recipients.
3-Foscarnet;Monitor for nephrotoxicity.
4-Cidofovir; Monitor for nephrotoxicity.
5-Reduction of anti-proliferative therapy.
Treatment option of ABMR:
Pulse steroid .
PEX.
IVIG.
Follow-up of renal function and anti-A/B titer.
References:
1- Andrei G, Van Loon E, Lerut E, et al. Persistent primary cytomegalovirus infection in a kidney transplant recipient: Multi-drug resistant and compartmentalized infection leading to graft loss. Antiviral Res. 2019;168:203-209. doi:10.1016/j.antiviral.2019.06.004.
2- Ciszek M, Mucha K, Foroncewicz B, Chmura A, Pączek L. Leflunomide as a rescue treatment in ganciclovir-resistant cytomegalovirus infection in a seronegative renal transplant recipient–a case report. Ann Transplant. 2014;19:60-63. Published 2014 Jan 30. doi:10.12659/AOT.884035.
3- . Davis S, Cooper JE. Acute antibody-mediated rejection in kidney transplant recipients. Transplant Rev (Orlando). 2017; 31:47–54.
4- Haas M, Loupy A, Lefaucheur C, Roufosse C, Glotz D, Seron D, et al. The Banff 2017 Kidney Meeting Report: revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials. Am J Transplant. 2018; 18:293–307.
5- Djamali A, Kaufman DB, Ellis TM, Zhong W, Matas A, Samaniego M. Diagnosis and management of antibody-mediated rejection: current status and novel approaches. Am J Transplant. 2014;14(2):255-271. doi:10.1111/ajt.12589.
Descripe the findings
a- Graft biopsy
– LM with H&E stain reveal acute interstitial inflammation and tubular vacuolization .
– IF : C4d deposit
– Thses findings together with rebound increase in level of anti A Ig G consistant with diagnosis of ABMR.
b- OGD : hyperemic mucosa with superficial ulcerations .
– Biopsy :Owl eye characteristic CMV inclusion bodies , consistant with tissue invasive CMV infection despite being treated with vangalcyclovir suggesting resistant CMV infection that in turn increases the risk of ABMR .
– Treatment of Refractory CMV infection :
I-Identify the risk factors for CMV resistance :
1- Host factors :
a- Previous treatment with CMV antiviral drugs or prolonged treatment courses.
b- Decrease drug bioavilabilty,absorption and patient non compliance.
c- Congentital immunedeffiency syndrome
d- Also ,young age , induction with ATG are risk factors.
2- Viral related factors :
a- Recurrent CMV infection .
b- Delayed viral clearance .
c- Genetic mutation :UL97 mutation causes resistance to gancycovir while UL54 mutation causes multidrug resistance .
II- Correct the reversablle risk factors as
– Patient compliance
– Genetic analysis to diagnose genetic mutation .
III- Management :
Data regarding treatment of resistant CMV infection are not conclusive and include trial of
1- Foscarnet for at least 3 weeks .
2- Leflunamde :has immunmodulatory and antiviral effects
3- Cidofovir
4- Stop Valganciclovir ,in patients with evidence of ganciclovir resistance.
5- Decrease the dose of IS , stop antiproliferative drugs.monitoring of graft function
6- In the current case: concomitant CMV and ABMR may benefit from Iv pulse methyl prednisolone , plasma exchange and IVIG .
Ref:
1- Chemaly RF, Chou S, Einsele H, Griffiths P, Avery R, Razonable RR, Mullane KM, Kotton C, Lundgren J, Komatsu TE, Lischka P, Josephson F, Douglas CM, Umeh O, Miller V, Ljungman P; Resistant Definitions Working Group of the Cytomegalovirus Drug Development Forum. Definitions of Resistant and Refractory Cytomegalovirus Infection and Disease in Transplant Recipients for Use in Clinical Trials. Clin Infect Dis. 2019 Apr 8;68(8):1420-1426.
2- UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION.july ,2022
Prof Halawa s disappointment is genuine as we missed the fact that this is tissue invasive CMV Inspite of valganciclovir 900 mg for two months raising strong possibility of Resistant CMV disease.
This merits to first confirm our diagnosis by checking for UL 97 and UL 54 gene mutations which we can’t do at our center.
Refractory CMV disease is defined as persistent and/or progressive infection despite antiviral agents and reduction of immunosuppression and can be due to ganciclovir resistance. Ganciclovir resistance should be suspected in patients who have rising or persistently elevated viral loads despite treatment with appropriately dosed ganciclovir for more than two weeks .
It occurs in 1 to 2 percent of kidney transplant recipients with CMV infection or disease and typically develops in CMV D+/R- patients.
Common resistance mutations include those in the genes that encode UL97 phosphotransferase, which performs the initial phosphorylation of ganciclovir (which is required for its antiviral activity), and the viral DNA polymerase gene UL54.
UL 97 is more common accounting for 80% of resistant cases where as UL 54 is less common.
In this case concomitant treatment for both CMV and ABMR is needed keeping a critical balance.
Treatment of drug-resistant CMV
Maribavir – An oral drug that inhibits UL97 phosphotransferase .
Maribavir cannot be coadministered with ganciclovir or valganciclovir. Key advantages of maribavir over other agents are lack of bone marrow and kidney toxicity. Due to a drug interaction with calcineurin inhibitors and mammalian (mechanistic) target of rapamycin (mTOR) inhibitors, close monitoring of these immunosuppressive agents is required.
Foscarnet – A pyrophosphate analog that inhibits viral replication by selectively binding to viral DNA polymerase and requires IV administration. Foscarnet is active against CMV with UL97 and UL54 mutations. Foscarnet is dosed at 60 mg/kg IV every 8 hours or 90 mg/kg every 12 hours, with dose adjustment for kidney function impairment. Foscarnet is highly nephrotoxic and patients should receive pre- and postinfusion hydration, and close monitoring of electrolytes, creatinine, magnesium, and phosphorus is essential given that acute kidney injury is common with foscarnet.
Other drugs mentioned in literature are CIDOFOVIR
Reductions of immunosupression mainly anti metabolite ( stopping) is first key step in this context but at cost of worsening ABMR.
PLEX and IVIG should be used to maintain that balance
In either case it’s a tough Scenario and there will come a time to decide to SAVE THE PATIENT OR KIDNEY
The kidney biopsy shows ATN with peritubular capillaritis and +ve C4d plus rising iso titer to 512 which diagnose AMR.
The EGD shows inflamed mucosa and the biopsy showed typical CMV inclusion body.
So, this patient has both AMR and CMV infection while on prophylaxis=?resistant CMV .
Managing both rejection and infection simultaneously is challenging as we need to reduce immunosuppressive medication and to increase them for rejection. However, their occurrence is not a surprise as it is well known that infection, notably viral infection can induce immunomodulation that can increase the risk of rejection.
For AMR post ABO incompatible transplant we can start plasmapheresis and IVIG both of which has little or no feared risk of flaring the existing CMV infection. Not only that, but CMV IVIG could be helpful in controlling circulating the virus. While on treatment we need to monitor anti Ig G titer and kidney function.
The immunosuppressive medications can be kept in the same range if the infection related symptoms are not sever. If not, then priority is for infection treatment over rejection and we can reduce anti-metabolite by 50% or even stop them all together if needed.
For CMV infection, we need to ensure the compliance to the prophylactic valganciclovir. Since this raises the concern of ganciclovir resistance if treatment was given for 2weeks in adequate dose.
BTS guidelines state that: Consider resistance to Ganciclovir if:
• There is a persistent or increasing viral load or symptomatic disease after
a normally effective dosage and duration (e.g.; 2-4 weeks) of Ganciclovir
or Valganciclovir [1A]
In people with suspected resistance to Ganciclovir:
• Confirm that dosing is adequate
• Consider adherence to treatment plan and absorption
• Offer testing for Human CMV (HCMV) antiviral resistance
o UL97 and UL54 gene mutations [1A]
o Use either whole blood or plasma [1A].
In people with evidence of ganciclovir resistance:
• Stop Valganciclovir (or Ganciclovir) [1A]
• Offer Intravenous Foscarnet for at least 3 weeks [1B]
o Seek specialist virology advice before commencing treatment with Foscarnet [1D].
References:
1-UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION April 2022
This case is high risk because of D+/R- donation despite an effective prophylaxis dose of daily vGCV of 900 mg. Here we have documented CMV gastritis as we can see owl’s eyes inclusion bodies. As an ABOI transplantation, this patient received heavy immunosuppression preceded by desensitization followed by high-dose depleting agents. Her ABM rejection documented by biopsy needs to be addressed parrel with potent anti-CMV treatment
We can apply Rituximab, IVIG, and plasmapheresis for ejection combined with iv 5mg/kg Valcyclovir (adjusted for eGFR). With a serial follow-up of CMV-PCR vila load and control OGD, if available other potent antiviral therapy can be used (Letermovir!)
This is a case of resistant CMV infection associated with ABMR
– Describe the finding.
Renal biopsy:
Ø L/M : peritubular capillaritis , tubulitis with neutrophils infiltration.
Ø I/F : positive c4d staining in peritubular capillaritis.
OGD shows signs of inflammation & hyperaemia with tissue biopsy showing owls eye appearance with CMV inclusion body
How do you manage the case?
Simultaneous management of the AMR with management of CMV infection
1- Pulse steroid.
2- IVIG with plasmapheresis
3- Hold antimetabolites at time being
4- Keep tacrolimus trough level within 6-8
5- Management of resistant CMV infection (table ):
Ø ganciclovir dose escalation
Ø ganciclovir and foscarnet combination
Ø adjunct therapy such as CMV-specific cytotoxic T-lymphocyte infusions.
(How I treat resistant cytomegalovirus infection in hematopoietic cell transplantation recipients
Firas El Chaer, Dimpy P. Shah, Roy F. Chemaly, Blood (2016) 128 (23): 2624–2636.)
file:///C:/Users/abosa/AppData/Local/Temp/msohtmlclip1/01/clip_image001.jpg
Management of resistant CMV infection (table )
The above case is of ABMR in case of ABOi Transplantation with CMV drug resistant infection involving gastrointestinal system.
FIRST: DISCUSSION ON ABMR IN ABOi TRANSPLANT
SECOND: DISCUSSION ON DRUG RESISTANT CMV INFECTION
REF:
This has clear evidence of CMV invasive disease despite on valgaincyclovir and AMR on biopsy, would mandate for Resistance testing.
Though lack of decrease in viral load during the first two weeks of therapy is a good marker but not reliable indicator for testing.
All drugs intended for treatment of CMV target DNA polymerase including Gaincyclovir, foscarnet and cidofovir.
Resistance to Gaincyclovir occurs in mutation of initial phophorylation UL97. Mutation in UL97 phosphotransferase gene could conferred by increasing dose of gancyclovir while having both mutation of UL97 and UL54 could not be conferred by increasing dose.
Mutation in UL54 can occur as second step who already has UL97 mutation. UL54 DNA polymerase mutation can cause various combination of resistance to gainclycovir, foscarnet and cidofovir.
Testing by gene sequencing should be done for both UL97 and UL54 in this case and therapy should be consider according to results, Options are;
foscarnet or cidofovir if resistance to UL97 mutation only.combination of foscarnet and and gaincyclovir.Maribavir efficacy not proven.Letermovir optimal therapy no determined and risk of resistance while on therapy.ivig in this case as patient is having evidance of AMR.References
UpToDate
48 years, epigastric pain and deteriorating kidney function, ABOI Tx, Anti A IgG rising , CMV IgG D+ R- and on valganciclovir prophylactic dose
1 . Describe the findings
Renal biopsy: LM: showed interstitial inflammatory cells with tubular vacuolization
IF: Positive for C4d
Gastroscopy: erythema with ulceration
Gasteric biopsy: Characteristic CMV inclusion bodies
So this most probably a case of CMV infection with ABMR. ABMR is a risk factor for CMV infection in renal transplant patients.
How to manage this case?
Treatment
Treating of ABR:
References
1. Filippone, Edward J, et al Histologic Antibody Mediate Kidney Allograft rejection in the Absence of Donor Specific –HLA antibodies. Transplantation 105(11): pe190-, November 2021.
2. Camille N. Kotton et al, International Consensus Guidelines on the Management of Cytomegalovirus in Solid Organ Transplantation, Transplantation • Volume 89, Number 7, April 15, 2010
3. Giuliano etal CMV Infection in Kidney Allograft: A review of literature, Trans Androl Urol. 2019 May,8 S192-S197
4. Karthik et al Management of ganciclovir resistant CMV with hyperimmune globulin and leflonamide in seven cardiothorathic transplant recipients. Transpl Infect Dis.2022 Feb
4. Miae Kim et al Antibody Mediated Rejection in Kidney Transplant Recipient , Pharmacotherapy 2014 July, 34(7:733-44)
Describe the finding.
GRAFT BIOPSY
Light microscopy showing antibody-mediated rejection in renal transplant biopsy, ATN, and polymorphonuclear leukocytes
The glomerular capillary loops in this biopsy with hyperacute rejection show strong staining for IgG.
Well developed hyperacute rejection with fibrinoid necrosis of the glomeruli,
OGD and biopsy
Cytomegalovirus Gastritis
multiple discrete lesions appear
gastric mucosa findings fold thickening, exudates
How do you manage the case?
serologic markers for HIV, hepatitis A, B, and C viruses
T-lymphocytes count came back as CD4 of 588 and CD8 of 1649.
Thyroid tests]
Computed tomography scan of abdomen and pelvis
Echocardiogram
Antigen detection: Specimens can be stained by specific immunofluorescent antibodies to detect viral antigens or viral DNA – CMV
Patients who are ≤1 year posttransplant — For most patients who are diagnosed with active ABMR within the first year posttransplant (early onset),
Initial therapy with the combination of glucocorticoids, plasmapheresis, and IVIG rather than other therapies. In addition, some experts administer rituximab if the patient is younger (eg, age <70 years), has better allograft function (eg, estimated glomerular filtration rate [eGFR] ≥20 mL/min/1.73 m2 and lower chronicity scores on biopsy [ie, interstitial fibrosis + tubular atrophy + fibrous intimal thickening + allograft glomerulopathy <8]), and has evidence of severe disease (eg, higher DSA, diffuse C4d staining, or more extensive microvascular inflammation [ie, glomerulitis score + peritubular capillary score ≥4] on biopsy) .
Dosing of glucocorticoids –
intravenous (IV) methylprednisolone at a dose of 300 to 500 mg daily for three to five days, followed by a rapid oral prednisone taper to the patient’s previous maintenance dose of prednisone
Plasmapheresis regimen – Plasmapheresis is performed daily or every other day for a maximum of six sessions or until the serum creatinine is within 20 to 30 percent of the baseline. The initial treatment is typically a one-and-one-half-volume exchange with albumin, and subsequent treatments are a one-volume exchange with albumin.
Dosing of IVIG –
administer IVIG at a dose of 100 mg/kg after each session of plasmapheresis. typically give 500 mg/kg per day for one to two days after the final session
Dosing of rituximab – If rituximab is given,
administer a single dose of either 200 mg or 375 mg/m2 after completion of plasmapheresis and IVIG
–
not routinely use immunoadsorption, proteasome inhibitors, interleukin (IL)-6 blockade, complement inhibitors, or splenectomy in the initial treatment of patients with ABMR. However, some these therapies can be considered in patients who do not respond to initial treatment.
For patients with tissue-invasive disease (eg moderate to severe gastrointestinal disease IV ganciclovir rather than oral valganciclovir.
administer ganciclovir 5 mg/kg IV every 12 hours, with dose adjustment for kidney function
Reduction of immunosuppression — reduce immunosuppression in all kidney transplant recipients with CMV disease. stop the antimetabolite immunosuppressant (ie, mycophenolate or azathioprine)
First slide is LM of renal tubules shows tubulitis and interstitial inflammation
Second slide is immunoflorescence shows C4d staining along peritubular membrane
3Th one is redness and inflammation of gastric mucosa (erosive gastritis)
renal biopsy shows inclusion bodies characteristics of Owls body indicates CMV infection with presence of ABMR
Treat rejection by pulse therapy of steroid and rituximab with plasmapheresis on alternative day and IV immunoglobulin and stop ganciclovir and shift to foscarnet because of refractory CMV infection and consider cidofovir
Serial monitoring of RFT and viral load and drug level of calcinurine inhibitors.
Findings description:
-LM of kidney biopsy H&E stain revealing peritubular capillaritis ,tubular vacuolation & sloughing of epithelial cells and infiltration with mononuclear cells .
IF study : Showing diffuse tubular and peritubular C4D Ab staining .
EGD : Showed hypremic ulcerating gastric mucosa .
– Gastric biopsy revealing owl’s eye sign which indicates CMV viral infection.
Treatment of ABMR: entails Plasma exchange to remove antibodies, IVIg ,rituximab and pulse steroids.
Treatment of resistant CMV:
-High dose of ganciclovir or foscarnet .
-Cautious reduction of immunosuppression.
-Addition of IVIG.
-Genotypic resistance testing:UL97 or UL54 gene mutation.
Kidney biopsy peri tubular and interstitial inflammation and diffuse C4d deposits
OGD inflamed tissue with ulceration and biopsy inclusion bodies suggestive of viral CMV infection
We are dealing with both AMR and CMV gastroenteritis so treatment of both at the same time
For CMV
Oral valganciclovir (900 mg twice daily) has been demonstrated to have comparable safety and efficacy to intravenous ganciclovir for clearing CMV viremia and resolving clinical disease in solid-organ transplant patients with mild-to-moderate CMV disease.
Patients with high CMV viral loads (e.g., >5 × 10 5 IU/mL) or severe tissue-invasive disease, and those who fail to achieve a reduction in viral load after 7 or more days of oral valganciclovir treatment should be treated with 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 indicated. Dose adjustments are indicated for renal insufficiency.
Foscarnet is indicated for treatment of UL97-mutant ganciclovir-resistant CMV disease; however, caution is indicated because of nephrotoxicity.
Cidofovir is a third-line agent for CMV disease treatment for ganciclovir-resistant CMV strains, and should also be used with caution because of nephrotoxicity, especially with concurrent use of CNIs.
New anti-CMV compounds in Phase III trials include letermovir and brincidofovir, which may offer avenues for effective treatment without bone marrow suppression.
For AMR
Current strategies for the treatment of AMR include antibody depletion with plasmapheresis (PLEX), immunoadsorption (IA), immunomodulation with intravenous immunoglobulin (IVIG), and rituximab
In the current scenario of 48 years old woman with history of ABOi kidney transplantation presented with acute allograft dysfunction, significant rising Anti -A IgG titre to 1/512.CMV positive to CMV negative status on prophylactic valganciclovir 900 mg daily. Complaining of epigastric pain.
The work up to diagnose underlying causes of cute allograft dysfunction including:
-High Anti -A IgG titre to 1/512
-Kidney biopsy:
1-The left side image showing: section of tubules stained with H&E stain with picture of acute tubular injury with loss of brush borders, thinning of tubular epithelial cells cytoplasm, shedding of tubular epithelium, and focal loss of nuclei.
2-The right side image showing: Diffuse C4d by immunofluorescence.
– Esophagogastroduodenoscopy (OGD) showing: gastritis with evidence of inflammation and ulceration which most probably in the current scenario due to CMV gastritis (Stomach ,colon and small intestine are the most common sites of its gastrointestinal infection).
-The fourth image showing: Section of tubules stained with H&E stain revealed tubular cells with viral cytopathic changes , enlarged tubular epithelial cells and owl’s eye-type nuclear inclusions with surrounding halo (appears just in one part).
From all the previous data we have:
1-Most probably Picture of active ABMR with acute allograft dysfunction,significant rising isoagglutinin titre ,Acute tubular injury and diffuse C4d staining (the presence of other histopathological picture of ABMR is against immunologic accommodation).
2-Picture of CMV invasive disease despite prophylactic anti-viral medication? (Valganciclovir dose 900 mg daily is prophylactic dose). The question here I could not found answer; can CMV disease occurs in spite of ongoing prophylaxis?? implementation of CMV prophylaxis has been shown to reduce CMV‐associated morbidity and mortality, primary CMV infection may still occur after discontinuation of CMV prophylaxis.
How do you manage the case?
Really it is a complicated case needs extensive evaluation:
In fact, CMV IgG seronegative recipients may experience primary CMV infection after transplantation with a renal allograft obtained from a CMV IgG seropositive donor. There is a relationship between CMV infection and allograft injury in the form of rejection has been observed in experimental studies.
-Will order for CMV PCR to prove infection (is the preferred test for detecting viremia).
1-Treatment of CMV tissue invasive disease: Which is generally considered severe with clinical evidence of organ dysfunction.Commence IV ganciclovir (rather than oral valganciclovir) 5 mg/kg IV every 12 hours with dose adjustment for kidney function.
Duration of therapy: treatment until both symptoms and CMV viremia have been resolved with undetectable CMV titre 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 or can be longer.
If we considered it as a case of resistant CMV infection, which defined as persistent and/or progressive infection despite treatment with appropriately dosed ganciclovir for more than two weeks plus reduction of immunosuppression and can be due to ganciclovir resistance.(treatment protocol for drug-resistant CMV).
So what I understood from the current scenario that prolonged reduction of immunosuppression led to incidence of ABMR.
2-Treatment of active ABMR including :
Pulse steroids,IV IG,plasmapheresis and may be Rituximab in case of resistant ABMR.
My another question;is acute allograft dysfunction secondary to CMV infection or ABMR?
Renal biopsy: Light M H&E stain showed peritubullar capillaritis, inflammatory cells infiltration in the interstitium, vacuolation of the tubules with sloughing of tubular mucosa . IF shows PTC C4d staining with CMV immunohistochemistry.
OGD and biopsy: patchy areas of erythema, edema, inflammation with ulceration of the gastric mucosa. The biopsy shows giant cell with inclusion inside ( owls eye ) characteristics of CMV infection.
So this is a very challenging scenario for lady with graft dysfunction after 2 months of ABOi KT to D+/R- serostatus of CMV presented with epigastric pain and high isoagglutinin titer > 1:16 .
So high anti A IgG in ABOi KT associated with deranged renal function mostly indicates ABMR with CMV infection ( either the cause or the results).putting in our mind that the patient is already on CMV prophylaxis,this heightened the suspicion of CMV resistance infection.
The management plant :
Complete work up include CBC , CRP, ESR, RFT,LFT,Blood CMV PCR and tissue PCR, drug level, DSA level.
Treatment plan :
General supportive measures start from admission to hospital, IVF , AB , prophylactic LMWH.
The decision now is to focus on ABMR or CMV infection treatment ??
The best action is to balance between the 2 diagnosis by managing IS by reducing antimetabolites to 50% , decrease Tac to a trough level between 5-7ng/ ml, give steroid pulse, remove the DSA by TPE , give IVIG which is effective for both , RTx .
Antiviral treatment:
Stop valgancyclovir and start ganciclovir Iv 5 mg / kg for 5 days then valgancyclovir 900 mg twice daily orally for 3 wks .
During this time monitoring of CMV viral load after 2 weeks then after week , if No response, So consider alternative items after sending the patient for genotyping for mutations .
Ganciclovir act by inhibition of CMV DNA polymerase.
Mutations arising in UL97 phosphotransferase lead to ganciclovir resistance. Also mutations arising in the DNA polymerase gene UL54 also confer resistance to ganciclovir.
Different UL97 mutations are associated with different degrees of ganciclovir resistance.
Most patients develop only UL97 mutations, but prolonged exposure to ganciclovir can give rise to simultaneous UL54 and UL97 mutations.
This is associated with higher level resistance to ganciclovir.
UL54 mutations can confer cross- resistance to foscarnet and cidofovir since these agents also target CMV DNA polymerase.
resistance can be assayed either phenotypically or genotypically.
The “gold standard” test is the plaque reduction assay using specimen from the patient.
resistance can also be detected via genotype analysis to assess for known mutations in the UL54 and UL97 genes.
Detection of resistance via gene mutations is attractive since it is less labour intensive, need less time and is not limited by the need to culture CMV from patient specimens.
Risk factors for the development of ganciclovir resistance include CMV seronegativity at transplant when receiving a seropositive organ, degree of IS, magnitude of CMV viremia, and prolonged exposure to anti-CMV medication. Seronegative recipients of seropositive organs appear to be at particular risk of both CMV infection and ganciclovir resistance.
The alternative drugs used in CMV resistance include:
Foscarnet, Combination therapy with dose reduced ganciclovir and foscarnet.
Cidofovir, and Leflunomide .
Reference:
Treatment of Ganciclovir Resistant Cytomegalovirus Infection
Michael Klompas.
Management:
1- Treatment of ganciclovir resistant CMV disease:
2- Treatment of associated AMR:
I’m not impressed with many answers. This is a case of resistant CMV infection associated with evidence of AMR.
Many of you treated it as a non-resistant CMV infection ignoring the evidence of AMR.
UNFORTUNATELY, we have to repeat this scenario again.
Management of ganciclovir resistance CMV
Antiviral therapy:
In people with evidence of resistance
-Check treatment adherence
-Viral gene typing, testing for CMV antiviral resistance, UL97 and UL54 gene mutations.
-Stop Valganciclovir (or Ganciclovir).
-Start IV Foscarnet for at least 3 weeks , till resolution of symptoms. ( as the viral load is negative)
-Seek specialist virology advice and ID team opinion.
–leflunomide can be considered for both potentiates immunosuppression (ABMR) and suppresses CMV reproduction.
-Ciodovir is another option.
-The doses should be adjusted to renal function
-Monitor RF, CBC, and LFT is required
– After completing the treatment, continue VGCV prophylaxis for three months.
– CMV Ig and IVIG as adjunctive therapies ( in the setting of rising antibody titer and ABMR)
IS management :
– Stop/reduce (by 50%) antimetabolites.
– Do not discontinue CNI unless there is evidence of a life-threatening infection; keep the level of Tacrolimus 6.
– Corticosteroids are generally continued IVMP pulse steroids for the co-existence of ABMR.
– Monitor graft function.
ABMR management:
– IVMP pulse steroid
– Plasmapheresis every other day 6-10 sessions
– IVIG after each session of plasmapheresis with help also in controlling CMV disease.
– Rituximab.
-Monitor isoagglutinin titer and renal function.
GCV-resistant CMV infection in SOT recipients is an emerging clinical problem in a resource-limited country. Those with UL97 mutation CMV infection have a prolonged duration of CMV DNAemia, usually, they tried higher doses of GCV or second-line treatment like foscarnet, and cidofovir with poor outcomes, I was not aware of the testing for UL97 mutation before and I wonder about if any of you doing this test for suspected cases of CMV resistant cases and the second question came to my mind in limited resources centers like ours its worth to take the risk of transplanting CMV positive donor to CMV negative recipient taken in consideration the antiviral therapy and prophylaxis it’s very expensive, thanks prof Halawa for this scenario
References
1.Bruminhent J, Rotjanapan P, Watcharananan SP. Epidemiology and Outcome of Ganciclovir-Resistant Cytomegalovirus Infection After Solid Organ Transplantation: A Single Transplant Center Experience in Thailand. Transplant Proc. 2017 Jun;49(5):1048-1052.
Thank you Prof. Ahmad Halawa,
Gancyclovir resistant CMV defined as a plaque reduction or DNA hybridization IC50 of > 6µg/ml, or via genotype analysis to assess for known mutations in the UL54 and UL97 genes.( less labour intensive, less time consuming, and is not limited by the need to culture). In our case no evidence of resistance in the text However, high risk of CMV resistance is there including the patient already on valgancyclovir prophylaxis, and D+/R- serostatus, so we should be looked for.
Almost 60% of patients treated for resistant CMV, suffered allograft loss, foscarnet nephrotoxicity, or rejection.
However, I stated in my answer that CMV resistance should be considered, and the treatment options are letermovir, foscarnet, leflunamide, cidofovir (nephrotoxic)- so, i would not use in this case with deteriorated kidney function, and IVIG.
In our case with AMR, IVIG would be the best treatment for both rejection and CMV infection.
Acute rejection may be a consequence of strong recipient derived cytotoxic T lymphocyte response to CMV infection.
The high titers of anti-endothelial cell antibodies, suggest a humoral rejection pathogenesis, the occurrence of these antibodies found in 80% in kidney and heart transplant recipients.
References:
(1) Treatment of Ganciclovir Resistant Cytomegalovirus Infection Michael Klompas.
(2) Rolling KE, Jorgenson MR, Descourouez JL, Mandelbrot DA, Redfield RR, Smith JA. Ganciclovir-Resistant Cytomegalovirus Infection in Abdominal Solid Organ Transplant Recipients: Case Series and Review of the Literature. Pharmacotherapy. 2017 Oct;37(10):1258-1271. doi: 10.1002/phar.1987. Epub 2017 Sep 3. PMID: 28699311.
(3) Einollahi B. Antibody mediated acute rejection in kidney transplant recipients with CMV infection. Fukushima J Med Sci. 2012;58(1):88; author reply 89. doi: 10.5387/fms.58.88. PMID: 22790898.
Resistant CMV & AMR:
1.Lines of management of AMR:
2.Resistant CMV: Possible options
Source; Hand book of transplanatation ,6th eidtion
Many thanks Prof.Halawa
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Reference
This is a case of resistant CMV infection associated with evidence of AMR
Clinically, antiviral drug resistance is suspected in this patient because of progressive CMV disease while on prophylactic valganciclovir for 2 month post kidney transplant.
-A genotypic resistance test is recommended .
This patient has ABMR with tissue invasive CMV the first therapeutic intervention is reduction of immunosuppression ,reduce antimetabolite by 50% and optimize the dose of CNI .
Antiviral therapy :
Depending on the severity of the CMV disease (whether life or sight threatening) and host risk factors (D+R−, lung transplantation, and severe immunosuppression), an empiric therapy is begun, pending return of genotypic resistance test data.
*In a high-risk clinical setting, empiric combination ganciclovir and foscarnet therapy is reasonable (at either partial or standard doses) or foscarnet alone.
*Alternatively, for more mild CMV disease, ganciclovir can be increased to higher than standard doses (up to 10 mg/kg twice daily for normal renal function).
* If genotypic resistance testing reveals a major UL97 mutation (>5-fold increased ganciclovir resistance), a switch to foscarnet is suggested.
* UL97 mutations conferring lesser degrees of resistance may permit the continued use of ganciclovir at higher doses (between 5 and 10 mg/kg twice daily for normal renal function), but genotypic testing for a viral UL54 pol mutation is suggested.
* Because of the demonstrated frequency of ganciclovir-cidofovir cross-resistance from pol mutations, cidofovir is not recommended as an alternate therapy for ganciclovir-resistant CMV, unless pol mutations are shown to be absent and the disease is not clinically severe.
Reference :
Picture of CMV invasive disease despite prophylactic anti-viral medication? (Valganciclovir dose 900 mg daily is a prophylactic dose). The question here I could not found answer; can CMV disease occurs in spite of ongoing prophylaxis?? implementation of CMV prophylaxis has been shown to reduce CMV‐associated morbidity and mortality, primary CMV infection may still occur after discontinuation of CMV prophylaxis.
The patient is on a prophylaxis dose of valganciclovir and he developed tissue invasive disease. start IV gancyclovir for 5 days and continue on valganciclovir for 21 days.
Ganciclovir-resistant individuals:
Check dosing.
Consider treatment compliance and absorption. Test for HCMV antiviral resistance. UL97/UL54 mutations
Ganciclovir-resistant people:
Stop Valganciclovir (or Ganciclovir)
intravenous foscarnet for three weeks.
Before starting Foscarnet, consult a virologist.
We ought to get started treating AMR and CMV illnesses at the same time, but the general weakening of immune suppression ought to come after therapy for AMR.
Treatment of AMR:
– Plasmapheresis every other day with follow-up of renal function and anti-A/B titer.
– IVIG after each session of plasmapheresis(as a line of treatment for rejection and CMV).
rapid reduction of immunosuppressives I will stop the MMF and continue on tacrolimus and prednisolone. and for further reduction of the tacrolimus dose if CMV persists.
UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION
– Ganciclovir resistance is defined as persistence or elevation of the viral load after 2 weeks of appropriate treatment (patient should receive the appropriate dosing at appropriate timing for appropriate duration)
– Ganciclovir acts by inhibiting CMV DNA polymerase, and in order to be activated it needs phosphorylation by phosphotransferase produced by the gene UL97.
– UL97 and UL54 gene mutations are responsible for ganciclovir resistance
Risk factors for gancyclovir resistance
Type of organ transplant: the prevalence of ganciclovir resistance is ranging from 0 up to 15% with the highest prevalence occur with lung and pancreas and the lowest prevalence occurring with liver and renal transplantation
Patients receiving long or suboptimal courses of treatment (including infection occurring on top of prophylaxis)
Very high viral load(D+/R-) transplantation
Patients receiving aggressive ATG for acute rejection
In the current case infection develop in a CMV negative recipient receiving graft from CMV positive donor and occur while receiving prophylactic therapy, so gancyclovir resistance is highly suspected
Diagnosis of ganciclovir resistance
Plaque reduction assay (gold standard test) in which human fibroblasts are cultured with ganciclovir at different concentrations, and CMV growth is assessed by counting the viral plaques or DNA hybridization technique. Gancyclovir resistance is defined as plaque reduction or DNA hybridization IC 50 of > 6µg/ml.
Detection of UL97 and UL54 gene mutations.
Treatment of Ganciclovir Resistant CMV Infection
I- More reduction of immunosuppression
II- IV Foscarent
It is a direct competitive inhibitor of DNA polymerase but it needs no phosphorylation to be active so not affected by UL97 mutation but may be affected by UL54 gene mutationsIt is given in a dose of 60mg/kg IV every 8h for 2 weeks followed by 90mg/kg/day
Its effect is comparable to IV ganciclovir
– Associated with renal and GIT toxicity and electrolyte imbalance and seizures, genital ulcers and infusion related symptoms
Neutropenia is less common with Foscarent than with gancyclovir
III- Combination therapy with reduced doses of ganciclovir and foscarnet
The regimen include the use of half the dose of IV ganciclovir (5mg/kg IV q24h) and 2/3 the dose of foscarnet (125mg/kg IV q24h)
Associated with comparable efficacy and less side effects
IV- Cidofovir
Effective
Given IV twice weekly
Associated with high incidence of nephrotoxicity (50% of cases), myelosuppression and ocular disease( iritis, uveitis, and vitreous hypotonicity).
V- Leflunamide
It has immunosuppressive and antiviral activity at the same time, so it may provide the balance between treating virus and avoid reduction of immunosuppression
It is given in a loading dose then maintenance dosePersist in the blood for very long time after stopping the medication (up to 2 years)
Side effects includes, hepatitis, myelosuppression, hypertension, GI side effects, alopecia and skin rash
To conclude the management of the current case (resistant CMV infection associated with evidence of AMR) includes
Screening of UL97 and UL54 gene mutations
More reduction of immunosuppression is required which may be problematic in this case of ABMR so switching from MMF to leflunamide may be an option
Switching to IV foscarnet or combination therapy with reduced doses of ganciclovir and foscarnet for 3 weeks under the guidance of virology expert
Treatment of ABMR with pulse steroids, plasmapheresis (till the titer decrease < 1:16), and IVIG
References
UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATIONTreatment of Ganciclovir Resistant Cytomegalovirus Infection
CMV resistance usually develops after prolonged drug exposure for more than 6 weeks.
CMV resistance defines as persistence elevation of viral load while on appropriate therapy. or rebound viral load after the initial. response.
CMV mutation both UL97 and UL54 mutation high-level ganciclovir resistance.
UL54 DNA polymerase mutation confers various combinations of resistance to ganciclovir, foscarnet, and or cidofovir.
IgG for CMV is adjuvant therapy .
reference
uptodate
Refractory CMV disease is defined as persistent and/or progressive infection despite antiviral agents and reduction of immunosuppression and can be due to ganciclovir resistance. It occurs in 1 to 2 percent of kidney transplant recipients with CMV infection or disease and typically develops in CMV D+/R- patients.
When ganciclovir-resistant infection or disease is suspected, genotype testing should be performed to identify specific resistance mutations.
Treatment of drug-resistant CMV: Antiviral therapies for patients with ganciclovir-resistant or refractory CMV include maribavir, foscarnet, and cidofovir. Selection among antiviral agents is guided by disease severity and the results of genotypic testing. Previous medications can be used with UL97 gene mutations and UL54 mutations.
On the other hand, if no detectable mutations, then the dose of ganciclovir can be increased to 7.5 mg/kg IV twice daily and recheck a viral load in one week rather than switching to another agent.
I will not reduce immune suppressants in this case since there is AMR.
Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant patients – UpToDate
Management of resistant CMV infection associated with evidence of AMR
Management of resistant CMV infection (1, 2)
– Ganciclovir-resistant CMV is an emerging clinical challenge in SOT recipients especially kidney, pancreas and lung transplant recipients
– it is a late post-transplant complication and is commonly observed among CMV D+/ CMV R- pairs especially among recipients on intensive immunosuppression and who have been exposed to ganciclovir for a long time
– if you clinically suspect ganciclovir resistance start empiric treatment with IV Foscarnet, CMV hyperimmune globulin and consider reduction in immunosuppressive therapy
– in cases of multidrug resistance CMV (i.e., CMV resistant to ganciclovir, cidofovir, foscarnet) another option is use of high-dose CMV IVIG and switch to mTORi as an alternative to high-dose ganciclovir and foscarnet
– letermovir and maribavir are yet to be approved for therapy in kidney transplant recipients
Management of AMR (3)
– AMR is an important complication of kidney transplantation and is associated with a poor prognosis
– the standard of care involves: –
– other agents that can be used in AMR treatment include: –
References
1. Limaye AP. Ganciclovir-resistant cytomegalovirus in organ transplant recipients. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2002 Oct 1;35(7):866-72. PubMed PMID: 12228824. Epub 2002/09/14. eng.
2. Wiening V, Schmidt T, Dahmen M, Siam S, Reuter S, Pavenstädt HJ, et al. Case Report: Management of a Multidrug-Resistant CMV-Strain in a Renal Transplant Recipient by High-Dose CMV-Specific Immunoglobulins, Modulation in Immunosuppression, and Induction of CMV-Specific Cellular Immunity. Frontiers in immunology. 2020;11:623178. PubMed PMID: 33569064. Pubmed Central PMCID: PMC7868410. Epub 2021/02/12. eng.
3. Kim M, Martin ST, Townsend KR, Gabardi S. Antibody-mediated rejection in kidney transplantation: a review of pathophysiology, diagnosis, and treatment options. Pharmacotherapy. 2014 Jul;34(7):733-44. PubMed PMID: 24753207. Epub 2014/04/23. eng.
Refractory CMV disease is defined as persistent and/or progressive infection despite antiviral agents and reduction of immunosuppression and can be due to ganciclovir resistance. It occurs in 1 to 2 percent of kidney transplant recipients with CMV infection or disease and typically develops in CMV D+/R- patients.
When ganciclovir-resistant infection or disease is suspected, genotype testing should be performed to identify specific resistance mutations.
Treatment of drug-resistant CMV: Antiviral therapies for patients with ganciclovir-resistant or refractory CMV include maribavir, foscarnet, and cidofovir. Selection among antiviral agents is guided by disease severity and the results of genotypic testing. Previous medications can be used with UL97 gene mutations and UL54 mutations.
On the other hand, if no detectable mutations, then the dose of ganciclovir can be increased to 7.5 mg/kg IV twice daily and recheck a viral load in one week rather than switching to another agent.
I will not reduce immune suppressants in this case since there is AMR.
Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant patients – UpToDate
I have a question here …
Treatment of ABMR due to isoagglutinin related to ABO Incompatibility is the same as for HLA DSA related ABMR (plasmapheresis, IVIG, Rituximab and pulse steroids) or just plasmapheresis is sufficient
The treatment is mainly to remove the OFFENDING ANTIBODIES as soon as possible to avoid DIC, AKI by PX.
IVIG comes next, Retuximab
Steroids as anti inflamatory.
So they are basically the same.
Thanks alot prof
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Describe the finding.
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How do you manage the case?
Plan
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Reference
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Well done
Many thanks Prof.Dawlat
Thank you, Mahmoud
Are you treating AMR or CMR with steroid pulses?
Many thanks Prof.Halawa
Steroid pulse
That is applicable in both scenarios. AMR or cAMR.
Describe finding
LM of the kidney
H&E stain no glomeruli appreciated hence this is an insufficient sample.
Other findings: Interstitial infiltration with inflammatory infiltrates
Tubulitis
Peritubular capillaritis
Tubular vacuolation.
Immunoflourescence: C4d positive
This findings are characteristic of ABMR.
OGD and biopsy findings
OGD-inflammation and ulceration
Biopsy- Inclusion bodies that are characteristic for CMV
Management
Detailed history and physical examination.
Investigations:CBC, UECS, LFT, CMV PCR, CNI trough levels, BK PCR
Treatment
This patient has both ABMR and CMV disease hence requires pulsing with methylprednisolone, plasmapheresis can also be done to reduce the DSA titers.
For the CMV, reduction of the antimetabolite by 50%, switching the ganciclovir to IV valganciclovir 5mg/kg for at least 5 days. After the patient can be put on PO valganciclovir 900mg bd for at least 2 weeks this should be discontinued when 2 consecutive CMV PCR are negative.
CMV PCR and UECS monitoring should be done every 2 weeks.
Patient will require CMV prophylaxis with ganciclovir after treatment.
References
Wan SS, Ying TD, Wyburn K, Roberts DM, Wyld M, Chadban SJ. The Treatment of Antibody-Mediated Rejection in Kidney Transplantation: An Updated Systematic Review and Meta-Analysis. Transplantation. 2018 Apr;102(4):557-568. doi:10.1097/TP.0000000000002049. PMID: 29315141
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.
Well done
Case Problem list:
Two months post ABOi kidney transplantation abdominal pain, and deteriorated kidney function.
D+/R- serology, on prophylaxis valgancyclovior 900 mg/day.
Describe the finding.
Kidney biopsy: by light microscopy there interstitial, peritubular inflammation, with tubular isometric vaculation, on immunofluorescence there is diffuse c4d deposits this may be an allograft accommodation phenomenon in ABOi kidney transplant detected in almost 70% of these patients.
OGD+ biopsy: ulcerative lesions with inflammation, biopsy indicates lymphocytic infiltrates with inclusion bodies (indicates viral infection mostly CMV).
How do you manage the case?
Detailed history and revision of medical chart, full physical examination.
Laboratory evaluation: CBC, ALT,AST, Bilirubin, PT, PTT,INR, blood sugar, CRP, Urinalysis, serum electrolytes, stool analysis, and tacrolimus level.
DSA level monitoring.
QUANTIFERON GAMMA ASSAY for viruses including CMV, parvovirus 19…. Etc.
Send the biopsy taken by endoscopy for viral PCR to detect the affecting virus, as this tissue invasive disease could be missed by serum CMV PCR testing.
Serum PCR for CMV, BKV, Parvovirus-19 … etc
It is a complicated case with serious AMR, and concurrent CMV gastritis.
Treatment of AMR include iv methylprednisolone, plasma exchange, IVIG and rituximab or eclizumab, not to give ATG as a treatment. These models of treatment should be carried out with treatment of CMV infection, and twice monthly monitoring of immunoglobulins, viral load, and kidney function.
To stop or reduce the dose of antimetabolites (MMF) by 50%, continue on CNI and put on stress dose (pulse steroid), start on iv ganciclovir for 5 days then oral valgancyclovir with frequent monitoring of CMV PCR till having two negative tests, then to keep on CMV prophylaxis for at least 6 months later, if no response then consider resistant CMV strains and use other antiviral therapy such as letermovir, foscarnet, cidofovir (nephrotoxic), and leflunamide, IVIG considered a good option for treatment of both CMV and AMR.
For AMR will consider plasma exchange +IVIG and rituximab.
References:
(1) Wan SS, Ying TD, Wyburn K, Roberts DM, Wyld M, Chadban SJ. The Treatment of Antibody-Mediated Rejection in Kidney Transplantation: An Updated Systematic Review and Meta-Analysis. Transplantation. 2018 Apr;102(4):557-568. doi: 10.1097/TP.0000000000002049. PMID: 29315141.
(2) Ortiz F, Lempinen M, Aaltonen S, Koivuviita N, Helanterä I. Letermovir treatment for CMV infection in kidney and pancreas transplantation: A valuable option for complicated cases. Clin Transplant. 2022 Feb;36(2):e14537. doi: 10.1111/ctr.14537. Epub 2021 Dec 7. PMID: 34797574.
(3) Hellemans R, Abramowicz D. Cytomegalovirus after kidney transplantation in 2020: moving towards personalized prevention. Nephrol Dial Transplant. 2022 Apr 25;37(5):810-816. doi: 10.1093/ndt/gfaa249. PMID: 33280028.
Thankyou for the detailed answer BUT:
The vaculations are not isometric so they could be due to IvIG among other causes.
In accomodation there is +C4D but no signs of rejection with stable graft function ( not mentioned in this case).
Thank you Prof. Dawlat
Describe the finding
I have a disclaimer here: my ability to interpret slides is limited. The possible view I may have is as follows:
Kidney biopsy LM
Kidney biopsy IF
OGD
OGD biopsy
Impression: ABMR with CMV gastritis
How do you manage the case?
Describe the finding.
-This patient underwent a kidney transplant from ABOi donor. It is also CMV positive /CMV negative transplantation on valganciclovir prophylaxis , developed epigastric pain ,deterioration of kidney function and rising anti-A IgG titer .
-LM of kidney biopsy H&E stain showed peritubular capillaritis ,tubular vacuolation and sloughing of epithelial cells and infiltration with mononuclear cells .
Immunofluorescence study : Showed diffuse tubular and peritubular C4D Ab staining .
-OGD : Showed congested and ulcerating gastric mucosa possible CMV gastritis .
– Gastric biopsy showed an owl’s eye sign that indicates CMV
-This patient has ABMR with tissue invasive CMV infection needs: Admission , supportive, treatment ,by MDTs (Nephrology , gastroenterologist , ID , Clinical pharmacist)
–Full blood count and peripheral blood picture , graft function and liver function test .
– Serum CMV PCR .
Reference :
1- Renal biopsies show: dilated tubules with denuded epithelial lining (tubulitis) and pericapilaritis and C4d positive in immunoflourescence. Associated increased anti-A IgG suggest the diagnosis of AMR
2- Management:
It is a challenging case of concomitant CMV and AMR
The goal is to save patient life by treating CMV infection and try to preserve the graft function.
Describe the finding.
1. Background: ABOiKT with pre-transplant CMV serostatus D+/R-. ABMR may be a risk factor for CMV(1) and CMV infection may trigger immunological responses and predisposes to rejection.CMV infection is important predisposing factor for acute allograft rejection after kidney transplantation(2).
2. Kidney biopsy showed linear staining of PTC for C4d. Haas et al. described a positive C4d staining in peritubular capillaries without any correlation with histologic changes suggestive of ABMR in 80% of protocol kidney biopsies performed during the first year posttransplant in ABOi transplant recipients, while PTC C4d deposition indicates probable AMR in biopsies of HLA-incompatible grafts, including protocol biopsies(3).
3. Anti-A IgG titre has risen from 1/8 to 1/512: Most of the DSA post-transplantation disappear without any immunological damage. Proteinuria is a clear indication for biopsy and also significant deterioration of the kidney function (>15% rise in creatinine). The rise of ABOi antibody titre to 2 dilutions or more is another indication of biopsy.
4. OGD and biopsy: the OGD after epigastric pain showed esophageal bleeding. Biopsy finding revealed cellular infiltration and intracellular inclusion(appearance of an “owl’s eye”) suggestive of tissue invasive CMV.
5. Deteriorating kidney function: may be explained by gastritis and pre-renal issues of fluid loss, CMV nephritis or glomerulopathy and infection-triggered rejection.
How do you manage the case?
1. The control of CMV infection could decrease episodes of acute kidney rejection.
2. Investigations:
· CBC, LFT, RFT, LDH and RBG.
· CMV IgG and IgM plus PCR for CMV.
· DSA level.
3. Treating CMV Infection and Disease (4)
a) To offer treatment with oral Valganciclovir for a duration of at least 2 weeks. Most commonly valganciclovir 900mg twice daily has been used as treatment dose, adjusted for level of kidney function.
b) To adjust the dose of Valganciclovir according to licensed dosing recommendations if creatinine clearance is less than 60ml/minute.
c) I will be aware of the potential development of ganciclovir resistance.
d) I will assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days.
e) I will consider stopping treatment for CMV disease after resolution of symptoms, two consecutive CMV viral load tests that confirm that CMV is not detected.
4.IVIG and pulses of methylprednisolone will be considered for the treatment of ABMR if no response to initial supportive measures and CMV treatment.
References
1. Los-Arcos I, Len O, Perello M, Torres IB, Codina G, Esperalba J, Sellarés J, Moreso F, Seron D, Gavaldà J. Is antibody-mediated rejection in kidney transplant recipients a risk factor for developing cytomegalovirus or BK virus infection? Results from a case-control study. J Clin Virol. 2019 Jan;110:45-50. doi: 10.1016/j.jcv.2018.11.010. Epub 2018 Dec 1. PMID: 30537648.
2. 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. doi: 10.15171/jrip.2016.18. PMID: 27471740; PMCID: PMC4962675.
3. Haas M, Rahman MH, Racusen LC, Kraus ES, Bagnasco SM, Segev DL, Simpkins CE, Warren DS, King KE, Zachary AA, Montgomery RA. C4d and C3d staining in biopsies of ABO- and HLA-incompatible renal allografts: correlation with histologic findings. Am J Transplant. 2006 Aug;6(8):1829-40. doi: 10.1111/j.1600-6143.2006.01356.x. PMID: 16889542.
4. UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION
Thank you, but remember it is a resistant CMV. How would you treat it?
The recipient have concamitant CMV infection and AMR
The finding;
Management of the case;
itis a chalengeable to manaegme such cases with concomitant different and opposite direction and modality of treatment.
The core and goal of treatment is to kept graft survival while treating CMV, to prevent complication and to reduce overall mortality.
For CMV;
Reffrences:
⭐ The first image of renal biopsy shows acute tubular injury (denuded epithelial cells and dilated tubules), no glomeruli or vessels (insufficient biopsy)
👉 IF staining in 2nd image shows peritubular c4d staining together with rising IgG titre to 1/512 is considered as ABMR (rather than accomodation phenomena in ABO I transplantation.
👉 Gross picture of stomach in upper endoscopy shows erythema and inflammation, suggestive of CMV gastritis on the background of D+/R_ transplantation
👉 gastric biopsy shows lymphocytic infiltration and inclusion bodies suggestive of CMV tissue invasive disease
👌 Management of the case is tricky
_start with IV ganciclovir guided by blood CMV PCR
_start also treatment of ABMR under cover of ganciclovir.
_treament of ABMR includes plasmapheresis and IVIG
_close monitoring of CBC, graft function and IgG titre are essential during therapy.
_I thing reduction of immunosupression is not wise here.
Thank you, but remember it is a resistant CMV. How would you treat it?
Describe the finding:
How do you manage the case?
Thank you, this a deficient answer Ibrahim
The findings shown include a renal biopsy (light microscopy – hematoxylin and eosin stain, and C4d stain).
Light microscopic image of the renal biopsy is an inadequate image to comment. The biopsy involves only tubule without any glomerulus. It shows tubular dilatation, vacuolation, and sloughing of tubular epithelial cells. It also reveals congestion and presence of inflammatory cells in the peritubular capillaries (peritubular capillaritis). These findings point towards acute tubular injury, which in light of other findings, could be a part of Acute antibody mediated rejection. C4d stain is positive (which could be due to ABO incompatible transplant). There is a rapid rise in anti-A IgG titres. The differential diagnosis with these findings in a patient with graft dysfunction should include an antibody mediated rejection (AMR).
OGD revealed erythematous lesions in the esophagus. Biopsy revealed intranuclear inclusions in the endothelial cells, characteristic of cytomegalovirus (CMV) tissue-invasive disease.
Hence this patient has a combination of acute antibody mediated rejection, and a cytomegalovirus tissue-invasive disease.
The index patient is a recent (2 month back) ABO incompatible, CMV D+/R- renal transplant recipient, now presenting with epigastric pain and graft dysfunction. Routine infection screen, ultrasound abdomen including graft kidney is normal. Anti-A antibody titres have risen.
The patient requires investigations including complete blood count, urine routine examination, urine protein creatinine ratio, calcineurin inhibitor trough levels, Donor specific antibody (DSA), a detailed kidney biopsy (as the images provided are inadequate) and Blood CMV PCR.
In the light of the clinical features and the histopathology, this patient is having an acute antibody mediated rejection (which could be due to ABO incompatibility alone, or due to presence of DSA), with a tissue-invasive CMV disease: gastrointestinal CMV (despite being on valganciclovir prophylaxis). CMV antigen detection by immunohistochemistry of the biopsy specimen can help in diagnosis.
AMR should be treated with (1):
1. Injection methylprednisolone 500 mg intravenous pulse for 3 days
2. Minimum 5 sessions of Plasma exchange followed by IVIG 100-200 mg/kg following each plasma exchange, till the anti A antibody titres fall to <1:16.
3. Inj Rituximab 375 mg/m2 after last session of plasmapheresis
The 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 (2,3).
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 (2).
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 until rejection has been treated (2). 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.
7) Patient should be given pneumocystis prophylaxis with trimethoprim-sulfamethoxazole post-treatment of rejection.
References:
Thank you, but remember it is a resistant CMV. How would you treat it?
If there is no response in 2 weeks, assessment for ganciclovir resistance should be done. Genotype testing to identify the specific mutations should be done.
First step is to increase the dose of Ganciclovir to 10 mg/kg 12 hourly (dose should be adjusted as per creatinine clearance), and, if no reponse, then shift to Foscarnet and additional CMV immunoglobulin or intravenous immunoglobulin (IVIG) should be considered (1). Cidofovir, Maribavir, and Letermovir have also been used.
Cautious decrease in immunosuppression with shift to mTOR inhibitor based regimen should be undertaken (1).
Reference:
Describe the finding.
kidney biopsy:
showed tubular lymphocytic infiltration with some vaculations in the tubules.
Immunofluorecence:
Show CD4 positive especially in this ABO incompatible kidney transplantation.
OGD:
Show ulcerative and congested mucosa.
How do you manage the case?
This ABO incompatibility with the above findings diagnosed as acute antibody mediated rejection (AMR) with CMV disease.
Management as :
Plasmapharesis
Iv methylprednisolone
IVIG
IV ganciclovir
After treatment of CMV we need to reduce immunosupressions especially anti metabolites.
REFERENCES
1.Asberg A, Humar a, Rollag H, Jardine AG, Mouas H, Pescovitz MD, et al. Oral valganciclovir is non inferior to intravenous ganciclovir for the treatment of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant. 2007;7((9)):2106–13. doi: 10.1111/ajt.2007.7.issue-9. [PubMed] [CrossRef] [Google Scholar]
2.Humer A, Snydman D, and the AST Infectious Diseases Community of Practice. Cytomegalovirus in solid organ transplant recipients. Am J Transplant 2009; 9(S4): S78-861
Thank you, but remember it is a resistant CMV. How would you treat it?
H&E stain showed; isometric vacuolization of tubules with acute tubular injury and peritubular capillaritis. IHC showed linear C4d staining.
OGD showed inflamed mucosa with diffuse erythema.
Biopsy revealed a giant cell with a characteristic inclusion body of CMV
gastritis.
KTR with high immunological risk ABOi, CMV
mismatch D+/R- with CMV invasive disease along with ABMR
CMV disease :
-CMV infection will increase the risk of ACR
and ABMR by priming the immune response against the allograft.
-Negative CMV PCR does not exclude the
diagnosis. PCR had 85% sensitivity and 95% specificity to diagnose CMV GI
disease; sensitivity was highest in the D+/R− patients (100%) and lowest in the
D+/R+ patients (72.7%).
-Potent IS used in the treatment of
Rejection will increase the risk for CMV infection.
-CMV disease appeared to influence long-term
graft survival but only when coupled with acute rejection.
– Recipients of ABOI kidneys may be at
higher risk for infectious complications compared with non-ABOI
recipients.
ABOi & ABMR:
-One study showed C4d-positive staining was
present in 80 % of protocol ABOI allograft biopsies. There was no correlation
between this finding and histologic evidence of ABMR or graft injury.
The presence of detectable isoagglutinin titers and positive PTC C4d staining,
despite the absence
of any histologic evidence of ABMR, has been thought to represent ABOI immunologic
accommodation, and initiation of therapy is not recommended.
In patients with isoagglutinin titer ≥1:16
and kidney biopsy showed histologic manifestations associated with ABMR and
PTC C4d is likely to be positive, treatment is highly indicated.
The co-existence of CMV and AR:
Diagnostic and therapeutic dilemma. In such
cases, therapeutically reducing immunosuppression for treating CMV can
aggravate AR, whereas enhancement may cause an increase in CMV replication.
The management for CMV and ABMR should be
started simultaneously.
Frequent monitoring for graft function and
IgG A titer.
How do you manage this case?
-Coordinate the management with GIT the
infectious disease team.
Work up:
– CBC, CRP, LFT.
– RF and drug level Tacrolimus.
– Viral load PCR CMV, EBV.
– Monitor IgG A titer.
– DSA monitoring.
General consideration:
– Admission.
– Fluid management, especially if
dehydrated.
– Detailed clinical history and
medication history, compliance with
anti-viral therapy.
Management of CMV gastritis:
This patient should be treated as
tissue-invasive CMV disease, irrespective of viral load.
Antiviral therapy:
– IV GCV for a minimum of 14 days followed
by oral vGCV for 2-3 weeks after resolution of symptoms. ( as the viral load is
negative)
-The doses should be adjusted to renal
function
-Monitor RF, CBC, and LFT is
required
-In vGCV/GCV resistance, viral gene typing,
second-line therapy with the help of ID team.
– After completing the treatment, continue
VGCV prophylaxis for three months.
– CMV Ig and IVIG as adjunctive
therapies ( in the setting of rising antibody titer and ABMR)
IS management :
– Stop/reduce (by 50%)
antimetabolites.
– Do not discontinue CNI unless there is
evidence of a life-threatening infection; keep the level of Tacrolimus 6.
– Corticosteroids are generally continued
IVMP pulse steroids for the co-existence of ABMR.
– Monitor graft function.
ABMR management:
– IVMP pulse steroid
– Plasmapheresis
– IVIG after each session of
plasmapheresis with help also in controlling CMV disease.
– Rituximab can be considered
PCP prophylaxis.
References;
-Ison MG. Diagnosis of gastrointestinal
cytomegalovirus infections: an imperfect science. Clin Infect Dis. 2013
Dec;57(11):1560-1. doi: 10.1093/cid/cit524. Epub 2013 Aug 15. PMID: 23956171.
– Angarone M, Snydman DR; AST ID Community of Practice. Diagnosis and management of diarrhea in solid-organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13550. doi: 10.1111/ctr.13550. Epub 2019 Apr 10. PMID: 30913334.
-Haas M, Rahman MH, Racusen LC, Kraus ES, Bagnasco SM, Segev DL, Simpkins CE, Warren DS, King KE, Zachary AA, Montgomery RA. C4d and C3d staining in biopsies of ABO- and HLA-incompatible renal allografts: correlation with histologic findings. Am J Transplant. 2006 Aug;6(8):1829-40. doi: 10.1111/j.1600-6143.2006.01356.x. PMID: 16889542.
-Yamada C, Ramon DS, Cascalho M, Sung RS, Leichtman AB, Samaniego M, Davenport RD. Efficacy of plasmapheresis on donor-specific antibody reduction by HLA specificity in post-kidney transplant recipients. Transfusion. 2015 Apr;55(4):727-35; quiz 726. doi: 10.1111/trf.12923. Epub 2014 Nov 11. PMID: 25385678; PMCID: PMC4911015.
Thank you, but remember it is a resistant CMV. How would you treat it?
Thank you prof.
In people with evidence of resistance
-Check treatment adherence, offer testing for CMV antiviral resistance, UL97 and UL54 gene mutations.
-Stop Valganciclovir (or Ganciclovir).
-Start IV Foscarnet for at least 3 weeks
-Seek specialist virology advice.
–leflunomide can be considered for both potentiates immunosuppression (ABMR) and suppresses CMV reproduction.
1-Describe the finding.
Renal Biopsy;
L.M.; shows tubular vacuolization, peritubular capillary infiltration with mononuclear cells,
Peritubular capillaritis , Acute tubular injury , lymphocytic infiltrates.
I.F.; shows positive C4d staining in the peritubular capillaries.
Endoscopy;
L.M.; showed gastric erosion with inflamed ulcerated mucosa.
Biopsy; showed CMV inclusion bodies with interstitial infiltrates (owl eye appearance) which characteristic to CMV gastritis.
2-How do you manage the case?
In current patient;
-ABOi kidney transplantation,
-Anti-A IgG titre has risen from 1/8 to 1/512,
-Kidney biopsy and C4d staining,
-CMV positive/CMV negative transplantation
-Epigastric pain
-S/P EGD with biopsy (CMV gastritis)
My impression; Antibody mediated rejection (ABMR) with CMV gastritis
Initial investigation;
-CBC – CRP – LFTS – RFTS
-CMV PCR (pt is high risk)
-DSA (single antigen I,II) R/O anti HLA abs.
Management;
-Review by MDTs (Nephrology , ID , GIT , Histopathologist , Clinical pharmacist),
Treatment of ABMR;
-Will not postponed till full coarse of CMV therapy; so starting,
-IV Pulse steroid,
-Plasma pharesis and IVIg,
-Review the dose of anti-metabolite with reducing by 50%,
-Keep CNI within therapeutic level (4-6 ng/ml).
Under cover of anti CMV;
-Stop valganciclovir prophylaxis and initiate CMV treatment,
-IV ganciclovir (5mg/kg twice daily) for 14-21 days, OR use IV ganciclovir for 5 days, then switch to valganciclovir 900 mg twice daily for 2-3 weeks,
-Monitoring weekly CMV-PCR, and stop treatment after 21 days if the patient is symptom-free and PCR-negative in two consecutive tests.
-After completion of treatment, continue prophylaxis with 900 mg of valganciclovir once daily for 1-3 months.
-Review the dose of valganciclovir based on creatinine clearance (guided by clinical pharmacist).
Description of biopsy and analysis
This is a case of high risk kidney transplantation being ABOi, and high risk for CMV being CMV+ to CMV-.
Kidney biopsy shows desquamation and sloughing of tubular cells, peritubular inflammatory cells.
The presence of peritubular capillaritis associated with diffuse C4d staining and high isoagglutinin titers, is consistent with ABMR. However, in ABOi transplantation diffuse C4d staining- accommodation is expected.
The likelihood of CMV gastritis is increased by hyperemia, inflammation of the stomach mucosa, gastric ulceration, and presence of OWL eyes appearance on histology.
Standard laboratory tests, including CBC, CRP, liver and kidney function tests, should be performed. CMV PCR in the blood, in the gastric biopsy sample and in the kidney. Using PCR, monitor BK virus load. The level of Tacrolimus should be measured. DSA should be followed to rule out the presence of HLA DSA as an alternative etiology of ABMR.
In this clinical scenario, there is invasive CMV disease and ABMR dur to ABOi transplantation.
Plan:
Plasmapheresis daily till the titer decrease < 1: 16
Reduce MMF dose by 50 %
Keep CNI within therapeutic level
Immediately stop valgancyclovir prophylaxis and initiate CMV treatment:
Use IV gancyclovir for 5 days, then switch to valgancyclovir 900 mg twice daily with weekly PCR monitoring, and discontinue treatment after 21 days if the patient is symptom-free and PCR-negative in two consecutive tests.
After completion of treatment, continue prophylaxis with 900 mg of valgancyclovir once day for 1 to 3 months.
–The findings
ABOi kidney transplantation CMV +/CMV – recipient presenting with deterioration of kidney function 2 months post transplant on Valganciclovir® 900 mg/daily.
Kidney biopsy shows infiltration of inflammatory cells in the peritubular capillaries with possibility of Antibody mediated rejection with C4d staining are shown below
The gastrointestinal tract is the most common site of tissue-invasive CMV infection,
Upper GIT endoscopy shows gastric erosions and inflammation , and biopsy shows cells infected with CMV with a thickened nuclear membrane and granular intracytoplasmic inclusions representing owl’s eyes finding
Mostly a case of tissue invasive CMV gastritis and ABMR
– Management
Despite the use of antiviral prophylaxis, CMV viraemia in transplant recipients remains a significant concern
CMV quantification in the blood samples using PCR
quantitative nucleic acid testing (NAT)or pp65 antigenemia
IV GCV 5 mg/kg twice daily for 14 days then oral VGCV 900 mg twice daily, adjusted for renal function with monitoring of viremia level .
MMF need to be suspended, mTOR can be introduced as having less risk of CMV infection but less potent effect on graft rejection
IV pulse steroids ,plasmapheresis and human immunoglobulin can be introduced.
Genotypic resistance testing can be to guide treatment of CMV drug-resistant infection and reduce the risk of treatment failure and drug toxicity.
Increased doses of Ganciclovir and a combination of antiviral agents may be used to resolve GCV-resistant CMV infection
Reference
–Selvey, L.A., Lim, W.H., Boan, P. et al. Cytomegalovirus viraemia and mortality in renal transplant recipients in the era of antiviral prophylaxis. Lessons from the western Australian experience. BMC Infect Dis 17, 501 (2017).
-Ardalan M. Rare presentations of cytomegalovirus infection in renal allograft recipients. Nephrourol Mon. 2012;4(2):431-436.
– Raquel Vaz, Francisca Barros, Isabel Tavares, Manuela Bustorff, Inês Ferreira, Manuel Pestana, Ganciclovir-resistant cytomegalovirus infection in renal transplantation, Clinical Kidney Journal, Volume 7, Issue 2, April 2014, Pages 210–213
Renal findings:
Tubular necrosis with tubulo-interstitial infiltration by both monoclonal and poly-clonal white blood cells.Immune florescent study revealed diffuse glomerular capillaries deposition of C4d.
OGD findings :
Patchy mucosal inflammation and ulceration with bleeding spots.
Biopsy findings:
Mucosal epithelial infiltration with monoclonal and polyclonal WBCs .
A cell with enlarged nucleous and intra-nuclear inclusions is shown .
clinically:
ABOi kidney transplant recipient who developed allograft deterioration in the context of acute gastroentritis .
CMV positive to CMV negative patient on Valgancyclovir
increasing Anti-A IgG antibodies titer from 1/8 to 1/512.
Impression;
Acute CMV nephropathy CMVN. CMV gastroentritis
Accommodation of Anti-A IgG .
plan:
For CMV PCR.
IHC for CMV virus detection
To start her on Intravenous Gancyclovir for 14 days.
References:
1] Sócrates Bezerra de Matos, Roberto Meyer,2 and Fernanda Washington de Mendonça Lima . . Cytomegalovirus Infection after Renal Transplantation: Occurrence, Clinical Features, and the Cutoff for Antigenemia in a University Hospital in Brazil.Infect Chemother. 2017 Dec; 49(4): 255–261.
This is a patient who has undergone ABOi transplantation and CMV+/CMV- transplant putting her at an extremely high risk of CMV infection and CMV disease
She has been on valganciclovir prophylaxis. She has developed epigastric pain and a rise in creatinine 2 months after the transplant with a rise in the anti-A IgG titers
Describe the images
Management
The management of CMV disease is:
Describe the finding.
Top RT light microscopic of graft biopsy with typical ATN and PTC, top LT-IF staining positive for C4D
Lower RT Gross appearance by colonoscopy shows focal area of inflammation with bleeding (patchy or focal inflammation , ulceration (CMV colitis) and lt lower slide of LM for graft biopsy with typical inclusion bodies
The CMV infection or disease following transplant is determined mainly by the donor and recipient CMV sero-status (from highest D+/R−, like the indexed case) followed by D+/R+, D−/R+, D−/R−) (1).the intensity of immunosuppression , again he is ABO I kidney transplantation and need to know about his induction agents ( ATG , Alemtuzumab , is he underwent desensitization with rituximab, prolonged lymphopenia
How do you manage the case?
Very challenging case of ABO I transplantation with raising titer of anti IgG and biopsy confirmed acute ABM rejection with CMV tissue invasive disease , including CMV colitis which carry high morbidity and mortality and need prompt treatment, despite this patient was on valganciclovir 900mg /daily on back ground of seropositive CMV donor to seronegative recipient and ABO I transplantation ( means he underwent intense IS including potent T cells depleting agents like ATG , and B cells depleting agent like rituximab and he is still at high risk of latent reactivation of CMV disease. CMV has a preference to cause allograft nephritis. CMV also have immunomodulatory effects and can increase risk of activation of other herpes viruses, EBV-mediated PTLD, allograft rejection& associated with higher risk of mortality and graft loss (2).
We need MDT approach including transplant nephrologist, infectious disease and gastroenterologist input.
we need further investigations including FBC and monitoring for any hematological side effects after treatment initiation like bone marrow suppression and thrombocytopenia , Liver function test, CMV PCR ( however is less sensitive for tissue invasive CMV disease like gut and retina , lung, and preferred tissue biopsy to confirm the CMV inclusion Abs , BKV PCR, tacrolimus trough level , DSA level by SAB and anti IgG titer every 2weeks, IFN-γ release assays (QuantiFERON-CMV, ELISpot) and intracellular cytokine staining for IFN-γ have been shown to predict both CMV viremia and disease(3).
The treatment will be directed for both ABMR and CMV colitis includes PMP, Plasmapheresis and IVIG , and stop MMF , and further decisions based on the immunological risk and patient response .Antiviral including valganciclovir or preferred IV ganciclovir for CMV colitis , hold MMF while continue on CNI with target level of 6-8ng , monitor with anti IgG titer and CMV PCR trend ( however may remain negative so we will Fu by clinical response , frequent hematological monitoring for drug side effects and response . also might need fu with repeat colonoscopy. IF no responsive after 2 weeks from IV ganciclovir consider ganciclovir resistance and need to send for Genotypic assays for resistance (4), and consider second line treatment like foscarnet, high dose ganciclovir, cidofovir, and CMV Ig. Adoptive transfer of CMV‐specific T cells may be considered as adjunctive therapies for resistant CMV, in teamwork with transplant infectious disease experts(1).
References
1.Razonable RR, Humar A: Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Disease Community of Practice. Clin Transplant 33: e13512, 2019 .
2.Agrawal A, Ison MG, Danziger-Isakov L. Long-Term Infectious Complications of Kidney Transplantation. Clin J Am Soc Nephrol. 2022 Feb;17(2):286-295. doi: 10.2215/CJN.15971020. Epub 2021 Apr 20. PMID: 33879502; PMCID: PMC8823942.
3. Kumar D, Chin-Hong P, Kayler L, Wojciechowski D, Limaye AP, Osama Gaber A, Ball S, Mehta AK, Cooper M, Blanchard T, MacDougall J, Kotton CN: A prospective multicenter observational study of cell-mediated immunity as a predictor for cytomegalovirus infection in kidney transplant recipients. Am J Transplant 19: 2505–2516, 2019 [PubMed] [Google Scholar].
4. Lurain NS, Chou S: Antiviral drug resistance of human cytomegalovirus. Clin Microbiol Rev 23: 689–712, 2010
Agrawal A, Ison MG, Danziger-Isakov L. Long-Term Infectious Complications of Kidney Transplantation. Clin J Am Soc Nephrol. 2022 Feb;17(2):286-295. doi: 10.2215/CJN.15971020. Epub 2021 Apr 20. PMID: 33879502; PMCID: PMC8823942.
Top left slide – shows tubular atrophy, tubulitis, lymphocytic infiltrates.
Top right slide – shows positive C4d staining.
Bottom left slide – shows gastric erosion.
Bottom right slide – shows CMV inclusion bodies with interstitial infiltrates.
Overall impression – Antibody mediated rejection with GI CMV disease.
Management
Renal biopsy :
Show tubulitis.
Tubular vacuolization
Sloughing.
IF show C4d stain.
OGD shows congested mucosa with possible ulceration.
And biopsy. Shows inclusion body’s. In D+/R- patient ,most likely. Diagnosis is CMV
infection with ABMR.
Management :
PF,IVIG, Methyl prednisolone.
IV ganciclovir.
acute AMR in AIT is in the first 2 weeks after transplantation. If graft loss from rejection occurs during the first 4 weeks, it will often be found that the onset of rejection was during the first 2 weeks The patient has a High titer of A/B antibodies and high renal function. this is require PP with IV Ig. IVIg is considered a line of treatment for CMV.
Treatment of AMR is a priority as it is catastrophic, but because of the presence of CMV. I will reduce the immunosuppressive medication rapidly after PP and start the CMV on the first day.
needs confirmation first of the biopsy GIT stain for CMV virus and sends for blood PCR for CMV. as the patient is high risk.
If confirmed as infiltrative CMV colitis
I will treat the patient with IV valacyclovir for 5 days and continue on valganciclovir for another 2 weeks or until 2 results of PCR are negative.
close monitoring of serum creatinine, CMV PCR, and AntiA/B titer.
British Transplantation Society Guidelines(Guidelines for Antibody Incompatible Transplantation).
You are right the tubules show non isometric vaculation probably due to Iv Ig treatment.
ABMR will not wait for the full coarse of CMV therapy so both should start. px. IvIg,steroids ,NO ATG,.UNDER COVER of anti CMV.
CMV With AMR is very challenging
First will start with CMV treatment as following;
(Dose adjustments are indicated for renal insufficiency.)
* In mild-to-moderate CMV disease ;
Oral valganciclovir (900 mg twice daily) has been demonstrated to have comparable safety and efficacy to intravenous ganciclovir for clearing CMV viremia and resolving clinical disease in solid-organ transplant patients.
* In Patients with high CMV viral loads (e.g., >5 × 105 IU/mL) or severe tissue-invasive disease and those who fail to achieve a reduction in viral load after 7 or more days of oral valganciclovir treatment;
-should be treated with intravenous ganciclovir (5 mg/kg every 12 hours)
-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 indicated.
AMR treatment including :Plasma Exchange and IVIG with Rituximab, a B-cell–depleting agent with monitoring to renal function, DSA.
Reference SIXTH EDITION
Handbook of
Kidney
Transplantation
Edited by
Gabriel M. Danovitch, MD
You mentioned a full correct coarse of CMV treatment but:
are you going to wait for 2 to 3 weeks with ABMR going on.?
-Describe the finding.
1.Renal biopsy
A.Light microscopy (LM) on the left upper images:
B.Immune fluorescence microscopy (IF) on the right upper images:
Conclusion:
OGD & biopsy:
OGD:
Biopsy
-How do you manage the case?
Management is tricky, you have two conditions their management goes in opposite directions.
Principle:
Treatment of ABMR:
Treatment of CMV
Reduction of immune suppression after treatment of CMV: start by 50% anti metabolites and monitor for the response & rejection
Source;
Oxford handbook of nephrology, 2 nd edition, hand book of kidney transplantaion, 6 th edition
Thank you for your reply
Will you treat CMV and AMR at the same time or one at a time?
Note; The reduction of immune suppression comes after full treatment of ABMR
Describe the finding.
Upper GIT endoscopy: erythematous, friable with erosions and ulcers
Upper GIT endoscopy biopsy: intranuclear inclusions bodies of CMV
Kidney biopsy: peritubular inflammatory cells
Immunoflourescence: C4d deposit (peritubular)
It is a case of concomitant CMV-invasive gastritis and ABMR (high nti-A IgG titre, kidney biopsy and IF)
Ø High immunological risk with intense immunosuppression and use of depleting antibodies are risk factors of CMV
Ø CMV disease is a risk factor of acute renal transplant rejection
Ø 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
Ø CMV may express molecules similar to MHC class I and II antigens priming the immune response against the allograft
Ø Enhances the alloantigen independent pathway of rejection by increasing co-stimulatory molecules on APCs, vascular endothelial cells, tubular epithelial cells and T-lymphocytes
How do you manage the case?
*complete history and examinations
*Lab tests: CBC, RFT and electrolytes, LFT, RBS, urine analysis, ESR, CRP
*CMV viral load (a negative plasma or whole-blood does not exclude tissue-invasive disease)
Treatment:
This is tissue-invasive gastritis
Immunosuppressions:
This high immunological risk
I will treat CMV disease and reduce antimetabolite immunosuprresions with a pulse steroid and close monitoring of kidney function and adverse effect of ant-viral and biopsy re-evaluation. Monitor DSA and isoagglutinin titres
Antiviral:
* Treatment is mandatory regardless to viral load if confirmed to be CMV-tissue invasive
* Give intravenous GCV (5mg/kg bd) for a minimum of of 14 days and for 2 weeks 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)
* Valganciclovir prophylaxis (200 days after ATG)
References
1. CMV in Kidney Transplantation By Ahmed Halawa (lecture), consultant Transplant Surgeon Associate Professor, University of Liverpool –UK, 2023
2. Ison MG. Diagnosis of gastrointestinal cytomegalovirus infections: an imperfect science. Clin Infect Dis. 2013 Dec;57(11):1560-1. doi: 10.1093/cid/cit524. Epub 2013 Aug 15. PMID: 23956171.
3. UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION. BTS, 2022.
Thank you for your reply
Will you treat CMV and AMR at the same time or one at a time?
Thank you prof
I will treat CMV and AMR at the same time, I will not wait to start acute rejection treatment after CMV treatment. Options for AMR include plasmapheresis, IvIg and steroids
Describe the findings
The first histology shows peritubular capillaritis with inflammatory cells and dilatation of the tubule with hemorrhages around the interstitium
The immunofluorescence demonstrated diffuse C4d staining around the peritubular capillaries
The endoscopic finding shows hyperemic changes, while the last histology shows dilated tules with the presence of basophilic intranuclear bodies surrounded by clear holo
How do you manage this case?
Diagnosis
– CMV disease and antibody-mediated rejection
Investigations
Treatments
This is a difficult double edge sword in which the treatment of CMV disease may result in complete graft loss, while treatment of antibody-mediated rejection may worse CMV disease.
References
Thank you for your reply
Will you treat CMV and AMR at the same time or one at a time?
Thank you Proffor the response,
This is a very challenging case, but I will rather treat the CMV first to keep the patient since another transplant can always be done even if the kidney graft is lost while treating to reduce immunosuppression
Kidney biopsy
H&E stain showed cmv inclusion.
IF, diffuse and intense deposits peritubular (c4d) (positive in ABOi)(4)
Endoscopy showed red inflamed ulcerated mucosa and biopsy showed owl eye appearance which characteristic to CMV
Management:
1- Iv ganciclovir (for invasive cmv) for 2-3 weeks , cmv pcr after 2 weeks if negative continue till 1 more week, 2 consecutive sample of cmv pcr negative is needed to complete the treatment, then valganciclovir 900 mg with renal dose adjustment for 3-6 months (secondary prophylaxis). In this case of tissue invasive longer course is warrant 4 to 6 weeks (2)
2- Stop mmf in treatment period(2)
3- Monitor graft function
4- increasing titer of igg may not be of any significance after 6 weeks (5)
5- PJP prophylaxis (lecture)
6- DSA
Second line therapy for resistant case (3)
Foscarnet
Cidovir
Letermovir
Maribavir
Reference
1)UK guideline on prevention and management of cytomegalovirus (cmv) infection and disease following solid organ transplantation.
2)Kotton, Camille N. MD1; Kumar, Deepali MD2; Caliendo, Angela M. MD, PhD3; Huprikar, Shirish MD4; Chou, Sunwen MD5; Danziger-Isakov, Lara MD, MPH6; Humar, Atul MD7 on behalf of the The Transplantation Society International CMV Consensus Group. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation 102(6):p 900-931, June 2018. | DOI: 10.1097/TP.0000000000002191
3)Stern A, Papanicolaou GA. CMV Prevention and Treatment in Transplantation: What’s New in 2019. Curr Infect Dis Rep. 2019 Nov 15;21(11):45. doi: 10.1007/s11908-019-0699-0. PMID: 31732823; PMCID: PMC8142836.
4).Mark Haas,Dorry L. Segev, Lorraine C. Racusen, Serena M. Bagnasco, Jayme E. Locke, Daniel S. Warren, Christopher E. Simpkins, Diane Lepley, Karen E. King, Edward S. Kraus, Robert A. Montgomery. C4d Deposition without Rejection Correlates with Reduced Early Scarring in ABO-Incompatible Renal Allografts. J Am Soc Nephrol. 2009 Jan; 20(1): 197–204.
5).Shah BV, Rajput P, Virani ZA, Warghade S. Baseline Anti-blood Group Antibody Titers and their Response to Desensitization and Kidney Transplantation. Indian J Nephrol. 2017 May-Jun;27(3):195-198. doi: 10.4103/0971-4065.202402. PMID: 28553039; PMCID: PMC5434685.
Thank you for your reply
Do you think that there is an AMR as well?
How would you confirm it?
Please explain the renal biopsy.
thank you for the question prof.
With given scenario i cannot confirm there is AMR as well.
To confirm i would like to know about the patient DSA and also would like to see whole adequate biopsy.
Renal biopsy
Light microscopy
H&E stain
Showed tubules, no gloms, & no vessels
Dilatation and vacoulization of some tubules
Peritubular capillary infitration by mononeular cells
Acute tubular injury
Immune fluorescence microscopy
Showed diffuse CD4 +ve staining in the peritubular capillaries.
Describe the finding.
This is a case of graft dysfunction, biopsy is showing peritubular capillaritis associated with C4d staining and high isoagglutinin titers, this is consistent with ABMR Hyperemia and inflammation of gastric mucosa with gastric ulceration, histology is showing owl eye appearance, raising the probability of CMV gastritis
Diagnosis
Routine lab should be done including CBC, C reactive protein, liver and kidney function testCMV PCR in blood, PCR in gastric biopsy and in renal biopsy (occasionally PCR is negative in tissue invasive disease and the only way for diagnosis is tissue biopsy and histopathological examination)Monitor BK viral by PCRTacrolimus level.DSA should be monitored to exclude the presence of HLA DSA
Treatment
I- General measures
Hospital admissionAdjust fluid status, IV fluids can be given if there is signs of dehydrationLMWH prophylactic dose
II- Specific treatment
A- Adjustment of immunosuppression if CMV detected
In the form of reduction of the dose (by 50%) or stopping the antimetabolite (in severe and non-responding disease) since kidney can survive without antimetaboliteIn ABO I transplantation tacrolimus should be maintained at 8-12 ng/ml for first month then 5-10 thereafter, in the current case i will keep CNI at lower trough around 5-7 ng/ml (do not play with CNI)Pulse steroidsClose follow up of graft functionB- Antimicrobial therapy
In case of CMV gastritis, stop valgancyclovir prophylaxis and start IV gancyclovir for 5 days then switch to valgancyclovir 900 mg twice daily with follow up of PCR weekly and stop treatment after 21 days of treatment provided the patient is symptom free and PCR negative for 2 successive samples. Then continue on once daily valgancyclovir in a dose of 900 mg daily for 1-3 months to prevent recurrenceC- Regarding ABMR with high of isoagglutinin titers
In case of ABO I transplantation monitoring of isoagglutinin titers is recommended, daily till discharge form the hospital, then 2-3 times per week for the first month then weekly till 3 m post-transplant then annually, and at any time of graft dysfunction.If posttransplant isoagglutinin titer is ≥1:16, patient should be considered for therapeutic plasmapheresis (if there is biopsy proven ABMR ), but some recommended doing preemptive plasmapheresis if only rising titer is detected.So in the current case, plasmapheresis is indicated daily till the titer decrease < 1: 16
Thank you for your reply
Will you treat CMV and AMR at the same time or one at a time?
Will you treat CMV and AMR at the same time or one at a time?
In the presence of both CMV infection and ABMR it is difficult to obtain balance between reduction of immunosuppression (to decrease CMV viremia) and treatment of ABMR which will need augmentation of immunosuppression.
But in the current case, I will treat both at the same time as follow:
Describe the finding.
How do you manage the case?
Diagnosis
Treatment
General measures
Specific treatment
A- Adjustment of immunosuppression if CMV detected
B- Antimicrobial therapy
C- Regarding ABMR with high of isoagglutinin titers
kidney biopsy by H&E stain showed inflammatory cells peritubular with homogenous material deposited between tubules
by IF, diffuse and intense deposits peritubular ( c4d )
endoscopy showed red inflamed ulcerated mucosa and biopsy showed owl eye appearance which characteristic to CMV
c4d deposit may not indicate ABMR, and can be present in incompatible ABO renal allograft
the case is CMV disease with associated cellular rejection as caused by CMV
also ABMR can be a risk factor to CMV
management:
1- iv ganciclovir for 2-3 weeks then valganciclovir 900 mg with renal dose adjustment for 3-6 months
2-cover with iv methylprednisolone as a pulse therapy
3-reduce MMF dose to 50%
4-monitore graft function and IgG antibody titer
5-we may need ivig if the titer is not decreased and graft function worsen
6- CMV PCR should be done as a baseline and for follow up
Mark Haas,Dorry L. Segev, Lorraine C. Racusen, Serena M. Bagnasco, Jayme E. Locke, Daniel S. Warren, Christopher E. Simpkins, Diane Lepley, Karen E. King, Edward S. Kraus, Robert A. Montgomery. C4d Deposition without Rejection Correlates with Reduced Early Scarring in ABO-Incompatible Renal Allografts. J Am Soc Nephrol. 2009 Jan; 20(1): 197–204.
Ibai Los-Arcos , Oscar Len, Manel Perello , Irina B Torres , Gemma Codina , Juliana Esperalba , Joana Sellarés , Francesc Moreso , Daniel Seron , Joan Gavaldà. Is antibody-mediated rejection in kidney transplant recipients a risk factor for developing cytomegalovirus or BK virus infection? Results from a case-control study. J Clin Virol. 2019 Jan;110:45-50.
Thank you for your reply
Describe the finding.
============================
How do you manage the case?
Treatment of CMV:
Treatment of ABMR:
Treatment options include:
References
Thank you for your reply
Will you treat CMV and AMR at the same time or one at a time?
Thank you, dear Prof, Halawa
I believe that providing a hasty response to this issue is a difficult task.
If I had to guess, though, I would either choose to treat them both at the same time or, failing that, I would weigh their respective seriousness to choose which should be treated first.
A 48-year-old woman was admitted with epigastric pain and deterioration of kidney function 2 months after ABOi kidney transplantation. A routine infection screen and USS of her kidney were normal. USS of the liver and gall bladder was also reported normal. Anti-A IgG titre has risen from 1/8 to 1/512. CMV positive/CMV negative transplantation on Valganciclovir® 900 mg/daily. Kidney biopsy and C4d staining ate shown below:
Describe the finding:
The kidney allograft biopsy showed: ABMR H&E Stain :
Renal tubules demostrating PTCs , the PTCs are dilated and filled with inflammatory cells, amongest which neutrophils , monocytes & lymphocytes ca be also seen ,
The renal tubule, also Tubulitis => mild to moderate Tubulitis with (cytomegaly).and Interstitial inflammation => interstitial infiltrate with lymphocytes.
C4D IF Staining of PTC
OGD and biopsy showing:
Macroscopic appearance of GIT Mucosal injury of CMV haemorrahagic Invasive Gastritis
Histopathology with H& E => Cytomegalic endothelial cells, with CMV large basophilic intranuclear Inclusions (circles)
How do you manage the case?
What is your differential diagnosis Of Allograft Biopsy ?
Anti-A IgG titre has risen from 1/8 to 1/512==> AMR.
1- ABMR
2- ABMR // CMV Nephritis
4- AIN / ATIN
What is your differential diagnosis Of OGD ? CMV MM: ==>
1- CMV Colitis (tissue invasive disease)
2. Inflammatory bowl disease(IBD)
3. Clostridium Difficile(CD)
4. Drug (MMF) induced colitis
5. Other infectious cause of colitis
6. Malignancy : Colon cancer, PTLD
Differential diagnosis
Infectious colitis:============>
Adenovirus: ===> Commonly infects surface epithelial cells Homogenous glassy amphophilic nuclear inclusions
HSV1, HSV2: ===> Chromatin margination, multinucleation, nuclear molding
Graft versus host disease:=====>
Crypt apoptosis
Crypt dropout
Ulceration
No cytomegalic inclusions
May coexist with CMV infection
Inflammatory bowel disease:====>
No inclusions
Ulcerative colitis, Crohn’s disease
Mycophenolate mofetyl induced colitis:====>
No inclusions
Increased apoptosis
Increased lamina propria eosinophils
ABR :=========>
Alloimmune reaction to donor specific antigens resulting in damage to the kidney allograft
Mediated by antibodies produced by B cells and hence referred to as antibody mediated rejection (ABMR) in the Banff 2019 classification (Am J Transplant 2020;20:2318)
Has 3 major subcategories:====>
Active antibody mediated rejection: characterized by an acute immunologic reaction
Chronic active antibody mediated rejection: chronic renal injury due to persistent / recurrent ABMR
Chronic (inactive) ABMR: chronic renal injury due to prior active / chronic active ABMR
Essential features
Evidence of microvascular / endothelial damage
Peritubular capillaritis, glomerulitis, microthrombosis and acute tubular injury (active component)
Transplant glomerulopathy and multilayering of the tubular basement membrane (signs of chronicity)
C4d positivity (a complement degradation product) along peritubular capillaries
Pathophysiology:
Due to circulating antibodies against donor HLA, non-HLA or ABO antigens, i.e. donor specific antibodies (DSA) (Clin Biochem 2016;49:320)
DSAs can be preformed (in which case antibody mediated rejection occurs during the very early posttransplant period – hyperacute / accelerated rejection) or may develop de novo after transplantation (usually due to inadequate immunosuppression or nonadherence)
These antibodies bind to donor specific antigens on the vascular endothelium of the graft and result in complement activation
This leads to activation of polymorphonuclear inflammatory cells, NK cell and monocyte recruitment and inflammation, as well as activation of the coagulation cascade
This in turn leads to widespread microvascular injury evident as peritubular capillaritis, glomerulitis and microvascular thrombosis
Eventually, transplant glomerulopathy develops (chronic phase) due to recurrent injury and repair (manifested as proteinuria) – glomerular basement membrane remodeling, mesangial matrix expansion, capillary obliteration, foot process effacement
References: Transplant Rev (Orlando) 2017;31:257, Transplant Rev (Orlando) 2017;31:47
Clinical features
Acute antibody mediated rejection (ABMR):
Usually seen during the first few weeks after transplantation but can occur later, usually associated with decreased immunosuppression or noncompliance
Presents with acute renal failure or oliguria, sometimes severe enough to require dialysis
Chronic / chronic active ABMR: chronic renal failure with proteinuria
Subclinical ABMR: stable creatinine but histological evidence of ABMR
Reference: J Transplant 2012;2012:193724
Diagnosis ABMR :
Active antibody mediated rejection (ABMR): all 3 criteria must be met for diagnosis
Histologic evidence of acute tissue injury; 1+ of the following should be present:
Microvascular inflammation (g > 0 or ptc > 0), in the absence of recurrent or de novo glomerulonephritis; ptc ≥ 1 alone is not sufficient and g must be ≥ 1 if:
Borderline infiltrate is present
Acute T cell mediated rejection is also present
Infection is present
Intimal or transmural arteritis (v > 0)
Acute thrombotic microangiopathy (in the absence of any other cause)
Acute tubular injury (in the absence of any other cause)
Evidence of current / recent antibody interaction with vascular endothelium; 1+ of the following should be present:
Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by immunoflourescence on frozen sections or C4d > 0 by immunohistochemistry on paraffin sections)
At least moderate microvascular inflammation ([g + ptc] ≥ 2) in the absence of recurrent or de novo glomerulonephritis; ptc ≥ 2 alone is not sufficient and g must be ≥ 1 if:
Chronic active ABMR: all 3 criteria must be met for diagnosis
Morphologic evidence of chronic tissue injury; 1+ of the following should be present:
Transplant glomerulopathy (cg > 0) if no evidence of chronic thrombotic microangiopathy or chronic recurrent / de novo glomerulonephritis; includes changes evident by electron microscopy alone (cg1a)
Severe peritubular capillary basement membrane multilayering (requires electron microscopy)
Arterial intimal fibrosis of new onset, excluding other causes (leukocytes within the sclerotic intima favor chronic ABMR if there is no prior history of T cell mediated rejection but are not required)
Chronic (inactive) ABMR
Transplant glomerulopathy (cg > 0) or severe peritubular capillary basement membrane multilayering
Absence of criterion 2 for active ABMR
Prior documented active or chronic active ABMR
C4d staining without evidence of rejection: all 4 features must be present for diagnosis
Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by immunoflorescence on frozen sections or C4d > 0 by immunohistochemistry on paraffin sections)
Laboratory:
Acute antibody mediated rejection (ABMR): acute increase in serum creatinine levels
Chronic active ABMR: chronic increase in serum creatinine levels along with proteinuria, usually nephrotic range
Serum donor specific antibodies: anti-HLA or non-HLA antibodies (J Transplant 2012;2012:193724)
Radiology description
Contrast enhanced ultrasound has been shown to be of diagnostic value in identifying cases of vascular rejection (Clin Hemorheol Microcirc 2018;69:77)
New technologies for identification of acute rejection are at the experimental stage (Am J Nucl Med Mol Imaging 2019;9:110)
Imaging seems to rely on analysis of changes in blood flow, which decreases with acute rejection induced inflammation and detection of recruitment of activated leucocytes with 18F-fluoro-deoxy-glucose positron emission tomography (Clin Kidney J 2017;10:97)
Prognostic factors
Chronic active antibody mediated rejection is associated with poor graft survival and is today the leading cause of graft scarring and loss (Am J Transplant 2009;9:2520)
Work UP:
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
Microscopic (histologic) description
Hyperacute antibody mediated rejection (ABMR):
Transmural vasculitis
Severe cortical necrosis
Active ABMR:
Peritubular capillaritis: presence of inflammatory cells within the lumens of the capillaries – most prominently neutrophils and monocytes
Glomerulitis: inflammatory cells within glomerular capillary lumens
Intimal or transmural arteritis: inflammatory cells within the intima or walls of vessels
Thrombotic microangiopathy and fibrinoid necrosis of vessel walls
Acute tubular injury: dilatation of the tubular lumen, flattening of tubular epithelial cells, loss of nuclear staining of tubular epithelial cells, shedding of tubular epithelial cells into the lumen and denudation, regenerative changes in tubular epithelial cells such as nucleolar enlargement and hyperchromasia
Linear C4d staining along peritubular capillaries
Chronic active ABMR: in addition to above mentioned changes for active ABMR, changes associated with chronic injury are present
Transplant glomerulopathy: double contours along the glomerular basement membrane, expansion of mesangium and obliteration of capillary lumina; usually accompanied by linear C4d staining along the glomerular basement membrane
Peritubular basement membrane multilayering (with electron microscopy)
Arterial intimal fibrosis with presence of inflammatory cells (transplant arteriopathy)
Interstitial fibrosis and tubular atrophy
Chronic ABMR:
Transplant glomerulopathy: double contours along the glomerular basement membrane, expansion of mesangium and obliteration of capillary lumina; usually accompanied by linear C4d staining along the glomerular basement membrane
Peritubular basement membrane multilayering (with electron microscopy)
Arterial intimal fibrosis with presence of inflammatory cells (transplant arteriopathy)
Interstitial fibrosis and tubular atrophy
References: Transplant Rev (Orlando) 2017;31:47, Mod Pathol 2018;31:235, Transplantation 2018;102:1795
Banff scoring of histological lesions
v – vascular inflammation: the most severely affected artery dictates the score; an asterisk is added to the v score if interstitial hemorrhage or infarct present
v0: no arteritis
v1: intimal arteritis with < 25% luminal area lost (minimum = 1 cell, 1 artery)
v2: intimal arteritis with ≥ 25% of luminal area lost in 1+ arteries
v3: transmural arteritis or fibrinoid necrosis (medial smooth muscle necrosis) with lymphocyte infiltrate in vessels
g – glomerulitis: percentage of glomerular capillaries partially or completely occluded by inflammatory cells (polymorphonuclear leucocytes and mononuclear cells) and endothelial cell enlargement
g0: no glomerulitis
g1: < 25% of glomeruli involved (mostly segmental)
g2: 25 – 75% of glomeruli involved (segmental to global)
g3: > 75% of glomeruli involved (mostly global)
ptc – peritubular capillaritis: the most severely affected peritubular capillary (PTC) dictates the score; an asterisk is added to the ptc score if neutrophils are lacking / only mononuclear cells are present
ptc0: < 3 cells/PTC
ptc1: 1+ inflammatory cells in > 10% of cortical PTCs with 3 – 4 cells in most severely involved PTC
ptc2: 1+ inflammatory cells in > 10% of cortical PTCs with 5 – 10 cells in most severely involved PTC
ptc3: 1+ inflammatory cells in > 10% of cortical PTCs with > 10 cells in most severely involved PTC
C4d: percentage of PTC (or vasa recta in the medulla) that has linear circumferential staining, scored in at least 5 high powered fields of cortex or medulla without scarring or infarct
C4d0: no staining of PTC and medullary vasa recta
C4d1: < 10% of PTC and medullary vasa recta
C4d2: 10 – 50% of PTC and medullary vasa recta
C4d3: > 50% of PTC and medullary vasa recta
cg – transplant glomerulopathy: percentage of glomerular capillary loops with duplication of glomerular basement membrane in most affected nonsclerotic glomerulus
cg0: none by light microscopy (LM) and electron microscopy
cg1a: only by electron microscopy in 3+ glomerular capillaries
cg1b: ≤ 25% by LM (1+ glomerular capillaries with glomerular basement membrane double contours by LM)
cg2: 26 – 50% by LM
cg3: > 50% by LM
cv – transplant arteriopathy: arterial fibrointimal thickening; percentage of narrowing of lumen of most severely affected artery
cv0: none
cv1: ≤ 25% of the luminal area
cv2: 26 – 50% of the luminal area
cv3: > 50% of the luminal area
Peritubular capillary basement membrane multilayering (ptclm) – electron microscopic evaluation of the most affected PTC
ptclm 1: 1 PTC with ≥ 7 layers +2 PTC with ≥ 5 layers
Reference: Transplantation 2018;102:1795
How do you manage this case? ABMR plus Invasive CMV GIT ???
You should reduce immunosuppression?
You should treat CMV under pulse steroid , PLEX then IVIG
Plasmapheresis (J Transplant 2012;2012:193724)
Intravenous immunoglobulin
Rituximab – efficacy unclear
Bortezomid – efficacy unclear
Proteosome inhibition – efficacy unclear
Complement inhibition
References: Am J Transplant 2018;18 Suppl 3:3, Transplantation 2018;102:557
CMV :
There is evident CMV infection (CMV MM), so should be treated as it is itself a higher risk for AMR 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
Cytomegalovirus (CMV) is a double stranded DNA virus and a member of human herpes virus family
Also known as herpes virus type 5.
3 patterns of CMV infection:
Latent infection
Most common, immunocompetent patients
Mononucleosis-like syndrome
Immunocompetent patients
Tissue invasive disease
Immunocompromised patients
Tissue invasive disease
Gastrointestinal tract is most commonly involved (30% of tissue invasive cases) (Virol J 2008;5:47)
Essential features
Double stranded DNA virus and a member of human herpes virus family
Tissue invasive disease, usually seen in immunocompromised patients
Most common sites of infection in gastrointestinal tract:
Colon
Esophagus
Symptoms:
Rectal bleeding (most common)
Diarrhea
Abdominal pain
Fever
Weight loss
Microscopy:
Cytomegalic cells with owl’s eye intranuclear viral inclusions
CMV immunohistochemistry is the gold standard for diagnosis
Sites
Can involve any part of the gastrointestinal tract
Most common sites:
Colon
Esophagus
Pathophysiology
Spread by saliva, urine, respiratory droplets, sexual contact, breast milk and blood transfusions (Clin Microbiol Rev 1989;2:204, Nihon Rinsho 1998;56:179)
After initial infection, CMV resides latently in monocytes, fibroblasts, myeloid cells and endothelial cells
Tissue invasive disease in colon can lead to ulcerative changes, erosion into blood vessels (causing bloody diarrhea), inflammatory polyps, severe inflammation and vasculitis leading to ischemia and transmural necrosis
Etiology
Cytomegalovirus (CMV)
Most commonly in immunocompromised patients
History of AIDS, organ transplantation, hematologic malignancy, cancer therapy and corticosteroid therapy
Risk factors in immunocompetent patients:
Renal disease
Hemodialysis
Neurological disease
Rheumatic disease
Exposure to antibiotics
Antacids
Corticosteroid
Red blood cell transfusion within 1 month of diagnosis of colitis (Clin Infect Dis 2015;60:e20)
Severe ulcerative colitis (patients treated with high dose corticosteroids)
Clinical features
Rectal bleeding (most common)
Diarrhea, abdominal pain, fever, weight loss (StatPearls: Cytomegalovirus Colitis [Accessed 12 November 2021])
Diagnosis
Surgical resection specimen or biopsy: histopathologic diagnosis
Clinical symptoms, endoscopic findings, serologic testing, polymerase chain reaction (PCR) and culture
Laboratory
Histology:
Gold standard test
Immunohistochemistry (IHC) for CMV
Greater sensitivity than hematoxylin & eosin (H&E)
H&E can detect CMV infected cells
Cells larger than normal, containing intranuclear or intracytoplasmic inclusions
CMV infected cells can be confirmed by IHC staining
Serology:
Acute infection
CMV IgM antibodies
4 times increase in titer of CMV IgG specific antibodies 2 – 4 weeks apart
CMV antigenemia
Predictor of clinical outcomes
Less sensitive for diagnosis of CMV colitis
Real time polymerase chain reaction (PCR) / CMV DNA quantification
Positive in only 50% of patients with biopsy proven CMV colitis / enteritis
CMV culture
High sensitivity and specificity for diagnosis of CMV colitis
Takes longer to obtain results (1 – 3 weeks)
May delay diagnosis and timely treatment (J Clin Microbiol 1993;31:2851)
Radiology description
Computed tomography:
Nonspecific findings
Bowel wall thickening
Mural edema
Pericolonic fat stranding
Free fluid, free air
Lymphadenopathy (Radiology 1985;155:585)
Endoscopic findings:
Easy bleeding, loss of vascular pattern, mucosal edema, erythema, mucinous exudate and wide mucosal defect
Mucosal defects, punched out ulcers (most common), longitudinal ulcers, irregular ulceration or cobblestone appearance (Emerg Radiol 2020;27:277)
Prognostic factors
Excellent overall prognosis
Factors associated with poor prognosis and higher mortality (immunocompetent patients)
M > F
Age > 55 years
Patients requiring surgery
CMV colitis reactivation with ulcerative colitis, tends to have poorer prognosis
Timely diagnosis and treatment greatly improves clinical outcomes (StatPearls: Cytomegalovirus Colitis [Accessed 12 November 2021])
Microscopic (histologic) description
Most commonly affected cells:
Endothelial cells
Mesenchymal cells
Macrophages
Larger (cytomegalic) cells:
Usually 25 – 35 micrometers
Typically 2 – 4 times larger than normal
Owl’s eye:
Large ovoid or pleomorphic nucleus with basophilic intranuclear inclusions (Cowdry bodies) surrounded by a clear halo (Arch Pathol Lab Med 2016;140:854)
Thickened nuclear membrane
Coarse red intracytoplasmic granules (Int Med Case Rep J 2011;4:55)
Increased apoptotic bodies
Expansion of lamina propria by mixed inflammatory plasma cell rich infiltrate
Neutrophilic inflammation
Should raise suspicion for CMV infection in graft versus host disease and mycophenolate injury (Int J Surg Pathol 2018;26:347, J Clin Pathol 2013;66:8)
Deep fissuring ulcers, cryptitis, crypt abscess, architectural distortion and pseudopolyp formation
May mimic inflammatory bowel disease (Am Surg 2007;73:58)
Submucosal vasculitis and thrombosis of
Management of CMV nephritis:
IS management :
Stop or reduce MMF by 50% For a ~ 2 week
Do not discontinue CNI unless there is evidence of life-threatening infection, keep level
of Tacrolimus ~ 5.
Corticosteroids => Pulse Steroid as AMR is highly suspected
Monitor graft function as the risk of rejection will increase.
Treatment as Sever CMV è IV Valganciclovir recommended dose as 5mg/kg iv for 5 days then 900 mg bid for 14 – 21 days and , recommended OGD after one month for tissue biopsy again.
Continue valganciclovir prophylaxis for another 6 month from clearance of the virus by tissue biopsy.
Consider resuming MMF after 1-2 weeks for confirmed pathology clearance of the virus by half the dose and titrate it to usual doe 1000 mg bid from 1-2 month .
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:
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
==> 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.
Managing CMV nephritis with AMR
•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 AM
while reducing IS.
•For patients with biopsy-proven they 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 450-900 mg for 6 months
What is the association between CMV and AMR ?
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.
Am J Transplant. 2007 Sep;7(9):2106-13. doi: 10.1111/j.1600-6143.2007.01910.x. Epub 2007 Jul 19
Am J Transplant 2018;18 Suppl 3:3, Transplantation 2018;102:557
Transplant Rev (Orlando) 2017;31:257, Transplant Rev (Orlando) 2017;31:47
J Transplant 2012;2012:193724
Up To Date.
Thank you very much
THIS IS AN EXHAUSTIVE REPLY. I WOULD BE VERY GRATEFUL IF YOU CAN SUMMERISE IT BETTER.
I’m not impressed
Increases in Anti-A titers above 1/32 are suggestive of antibody-mediated rejection, requiring plasmapheresis/Plasma Exchange to decrease titer values.
If there is no graft injury with circulating DSA, it may be related to the phenomenon of accommodation, without the need for specific treatment.
The patient in question has a high risk of developing gastrointestinal CMV (in this case, serum RT-PCR rarely tends to be positive) and the clinical findings associated with the macroscopic findings of digestive endoscopy are sufficient for empirical treatment (Positive donor/Negative recipient).
Rituximab in this case has a high risk of worsening the CMV condition, and IVIg should be the drug of choice for both rejection and adjuvant treatment of CMV. Start therapeutic intravenous ganciclovir associated with IVIg.
So,
How do you confirm AMR? Is the rising titre enough?
Please describe the biopsy of the kidney and the stomach.
It can be accommodation without having compromised kidney or kidney function. I’m honest in saying that I have difficulty interpreting the slides. The titer is high, which worries me (and that’s why IVIg would do it) to serve both for CMV and to reduce titers
Biopsy shows peritubular capillaritis and c4d staining is positive.C4d staining is positive in post ABOi transplant renal biopsy.Still the biopsy avours ABMR ,DSA needs to be done.
Treatment for ABMR
Plasmapheresis alternate day till recovery .
IvIg 100mg/kg after each plasmapheresis.
Iv rituximab if refractory .
Recommended Treatment for Antibody-mediated Rejection After Kidney Transplantation: The 2019 Expert Consensus From the Transplantion Society Working Group
Schinstock et al
Valganciclovir resistant CMV
The “gold standard” definition of resistance to ganciclovir is dependent on the demonstration of reduced susceptibility of a CMV isolate to ganciclovir in vitro (typically, an IC50 >6 µM) by use of a plaque reduction assay.
But not practically possible .
So Absence of a reduction or an increase in virus load, persistence of blood culture positivity, or failure to show clinical improvement after ganciclovir has been administered intravenously twice daily for 14 days appear to be helpful in the identification of SOT recipients who have a higher likelihood of having GanR CMV as a cause of their clinical or virologic failure
Stop MMF
Iv foscarnet can be given .
Safety and efficacy data for patients with baseline serum creatinine levels greater than 2.8 mg/dL or measured 24-hour creatinine clearances < 50 mL/min are limited.
Renal function must be monitored carefully at baseline and during induction and maintenance therapy with appropriate dose adjustment.
Foscarnet is not recommended in patients undergoing hemodialysis.
Cidofovir can be given .
Patient must meet the following criteria first:
serum creatinine ≤ 1.5
CRCL >55ml/min and urine protein < 100 mg/dL).
Induction: 5 mg/kg qweek x 2.
Maintenance: 5 mg/kg q2weeks.
The maintenance dose of cidofovir must be reduced from 5 mg/kg to 3 mg/kg for an increase in serum creatinine of 0.3 – 0.4 mg/dL above baseline. cidofovir therapy must be discontinued for an increase in serum creatinine of ≥ 0.5 mg/dL above baseline or development of ≥ 3+ proteinuria.
Maribavir 400mg bd can be given.
No dose adjustment is needed unless Crcl <12,below which not given.
Good option to treat index case but not available in india.
Use of Cidofovir for Cytomegalovirus Disease Refractory to Ganciclovir in Solid Organ Recipients
Hugo Bonatti et al
Ganciclovir-Resistant CMV Colitis in a Donor-Seronegative/Recipient-Seronegative Liver Transplant Patient
Samuel O. Igbinedion et al
Maribavir for Refractory Cytomegalovirus Infections With or Without Resistance Post-Transplant: Results From a Phase 3 Randomized Clinical Trial
Robin K Avery et al