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6. 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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Renal biopsy results are displayed (light microscopy – hematoxylin and eosin stain, and C4d stain).
The light microscopic image of the renal biopsy is insufficient for commenting. The biopsy only includes tubule and no glomerulus. It exhibits tubular dilatation, vacuolation, and tubular epithelial cell shedding. It also demonstrates congestion and inflammatory cell presence in the peritubular capillaries (peritubular capillaritis). These findings indicate acute tubular injury, which, based on other findings, may be a component of acute antibody-mediated rejection. Positive C4d stain (which may be owing to an ABO-incompatible transplant). There is an exponential increase in anti-A IgG titres. Antibody-mediated rejection (AMR) should be considered in the differential diagnosis for this patient with graft dysfunction.
Esophageal erythematous lesions were discovered by OGD. Endothelial cell biopsies revealed intranuclear inclusions, which are indicative of cytomegalovirus (CMV) tissue-invasive disease.
This patient has a combination of acute antibody-mediated rejection and tissue-invasive cytomegalovirus disease.
The index patient is a two-month-old recipient of an ABO-incompatible, CMV D+/R- renal transplant who is currently experiencing epigastric discomfort and graft dysfunction. Routine infection screening and abdominal ultrasound, including the grafted kidney, are normal. Antibody titres against A have increased.
The patient requires a complete blood count, urine routine examination, urine protein creatinine ratio, calcineurin inhibitor trough levels, Donor specific antibody (DSA), a detailed kidney biopsy (as the supplied images are insufficient), and Blood CMV PCR.
In light of the clinical characteristics and the histopathology, this patient has an acute antibody-mediated rejection (which could be due to ABO incompatibility alone or the presence of DSA) with a tissue-invasive CMV disease (gastrointestinal CMV) that appears to be ganciclovir resistant (CMV developing despite an adequate prophylactic dose of valganciclovir). Using immunohistochemistry to detect CMV antigen in a biopsy specimen can aid in the diagnosis.
AMR should be managed by (1):
Minimum of 5 plasma exchange sessions, followed by 100-200 mg/kg of IVIG after each plasma exchange, until anti-A antibody titres are 1:16.
2. Inject Rituximab 375 mg/m2 after the final plasmapheresis session.
3. Methylprednisolone 500 mg intravenous pulse for three days (if a biopsy reveals evidence of concomitant T cell rejection).
The management of tissue-invasive CMV involves:
Maintain adequate hydration as a component of supportive care.
2) Resistance to ganciclovir ought to be evaluated. It is necessary to conduct genotype testing to identify the specific mutations.
3) The initial step is to administer an increased dose of intravenous Ganciclovir (10 mg/kg 12 hourly) as opposed to the standard dose of 5 mg/kg 12 hourly (dose should be adjusted according to creatinine clearance), and if the patient responds, the treatment should be continued for a minimum of two weeks, and until resolution of graft dysfunction and clearance of CMV in the blood, if present (2,3). In the absence of any genetic mutation, an increase in ganciclovir dosage would be sufficient.
4) Shift to intravenous Foscarnet (90 mg/kg 12 hourly, dose to be adjusted per renal clearance) for 3 weeks and contemplate additional CMV immunoglobulin or intravenous immunoglobulin (IVIG) (2) if there is no response or UL97 and UL54 mutations.
5) Cidofovir (1 mg/kg intravenously three times per week): May be administered in the presence of UL97 mutation alone (not effective in the presence of UL54 mutation).
6) Maribavir (400 mg twice daily for eight weeks) is effective against UL97 and UL54 mutations.
Letermovir has also been utilised.
8) Patients with a high risk of relapse may receive secondary prophylaxis with oral valganciclovir for 1 to 2 months after treatment. But in the presence of ganciclovir resistance, it may be ineffective.
9) Immunosuppression reduction: Ideally, 50% of antimetabolites should be discontinued or reduced. However, given the recent onset of acute rejection, it would be challenging until the rejection has been treated (2). The levels of CNI should be evaluated. Reduce immunosuppression with caution when switching to a regimen based on mTOR inhibitors (2).
10) The patient should be counselled regarding the risk of rejection when the dose of immunosuppression is reduced in such a scenario.
11) Pneumocystis prophylaxis with trimethoprim-sulfamethoxazole should be administered to the patient following rejection treatment.
Maribavir was approved by the U.S. Food and Drug Administration in November 2021 for the treatment of adult and pediatric patients with post-transplant cytomegalovirus (CMV) infection/disease that is refractory to treatment (with or without genotypic resistance) with ganciclovir, valganciclovir, cidofovir, or foscarnet. Maribavir is an oral benzimidazole riboside with potent and selective multimodal anti-CMV activity. It utilizes a novel mechanism of action which confers activity against CMV strains that are resistant to traditional anti-CMV agents, and also offers a more favorable safety profile relative to the dose-limiting side effects of previously available therapies.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9487637/
First picture showed slide with H and E staining having ATN ,loss of brush border of tubules and shedding of tubular cells.
Second picture-IF showing diffuse staining of C4d
Third picture-inflammation of gastric mucosa with erosion and ulceration.
Fourth picture- CMV inclusion(owl’s eye)bodies, enlarged tubular epithelial cells and interstitial inflammation.
First thing in the management will be to reduction in immunosuppressant especially anti-metabolite –MMF or azathioprine that is to be reduced or sometimes stopped, while CNIs to be halved .However, steroids can be increased or continued at the same dose. Then specific treatment is according to the cause. As in the above case likely diagnosis GI CMV resistant disease(rising titer of anti-IgG despite on valganciclovir),so IV Ganciclovir in a dose of 5 mg/kg per day for minimum 02 weeks or until two consecutive viral loads are undetectable should be started and continued till the resistance testing available. Close monitoring of blood counts and allograft function needed as antivirals causes bone marrow suppression. Weekly PCR for CMV DNA also needed to monitor the response or to check for resistance mainly UL97 and UL54 mutation. IV Foscarnet, Combination therapy with reduced doses of ganciclovir and foscarnet , , Cidofovir, Leflunomide and CMV hyperimmune globulin are the options for resistant CMV disease. Duration of treatment is for about 21 days.
Patient can be switched to oral valganciclovir once the patient start tolerating oral intake. Frequent monitoring of drug levels to detect rejection early and weekly levels of PCR for CMV DNA needed .
ABMR treatment involves Plasmapheresis – total 06 seessions performed either daily or every other day till the serum creatinine is 20 to 30% of baseline value or titer <1:16 with IVIg – given at 100mg/kg after each plasmapheresis and +IV rituximab
REFERENCES:
Uk Guideline on Prevention and Management of Cytomegalovirus (CMV) Infection and Disease following Solid Organ Transplantation
De Keyzer K, Van Laecke S, Peeters P, et al. Human cytomegalovirus and kidney transplantation: a clinician’s update. Am J Kidney Dis. 2011;58:118–126.
● This is a case of resistant CMV disease associated with AMR
◇ 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
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.
Maribavir is approved for treatment of resistant cases not for prophylaxis.
To treat ABMR: IV methylprednisolone, plasmapheresis and IVIG should be considered.
Reference:
Einollahi, B. (2012). Antibody mediated acute rejection in kidney transplant recipients with CMV infection. In Fukushima journal of medical science (Vol. 58, Issue 1). https://doi.org/10.5387/fms.58.88
Allograft biopsy shows peritubular capillaritis and c4d positive staining in case of ABOi RT and high o agglutination antibodies with the diagnosis of ABMR.
In addition, gastric mucosa inflammation and inclusion bodies with owl’s eye shape shows CMV gastritis.
Q2 Because of possibility of negative results in tissue-invasive disease. CMV disease could be considered even without CMV positive PCR in a D+, R- ABOi kidney transplantation simultaneously with ABMR.
Because of receiving valganciclovir prophylaxis, this case is considered resistant CMV
In spite of two-week treatment with full dose ganciclovir, if viral load increase or persists ganciclovir resistant CMV infection is likely.
Defining genetic mutation for UL97, UL54 is necessary by sending a sample from blood or viral culture of tissue. The first step is reduction of immunosuppression therapy.
In this case 50% reduction in MMF dose or switching to siro.limus is recommended. Maintaining tacrolimus level to a logical level is the next option for severe diseases. Maribavir has recently approved in the USA for resistant cases
This oral drug is safe with no considerate side effects.
Some experts suggest using foscarnet induction therapy followed by maribavir.
This drug treats only CMV and for treatment of varicella and herpes reactivation, acyclovir should be considered.
Letermovir is used just for prophylaxis after HSCT.
Maribavir is not approved for prophylaxis. So letermovir is considered for prophylaxis after treatment of resistant CMV disease.
Other options include: CMV immunoglobulin and cidofovir every 2 weeks.
To treat ABMR:
1- IV methyl prednisolone pulse.
2- Therapeutic plasmaphresis.
3-IVIG until the isoglutinin titer decrease below 1/16.
Reference:
Kotton, C. N., & Kamar, N. (2023). New Insights on CMV Management in Solid Organ Transplant Patients: Prevention, Treatment, and Management of Resistant/Refractory Disease. In Infectious Diseases and Therapy (Vol. 12, Issue 2). https://doi.org/10.1007/s40121-022-00746-1
The histologic stain showing peritubular lymphocytic cell infiltration with tubulitis, and tubular vacuolation.
The Immunofluorescences: diffuse C4d positive – likely ABMR.
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:
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 if there is evidence of concomitant T cell rejection on biopsy,
IVIG after each session of plasmapheresis(as a line of treatment for rejection and CMV), & Minimum 5 sessions plasma exchange.
The FDA has approved 2021 the Maribavir in CMV resistant cases
Kidney biopsy with H&E stain showing tubular dilatation, vacuolation and sloughing of tubular epithelial cell. Inflmmatory infiltrate in peritubular capillary.
Kidney biopsy with IF staining showing C4d staing
Comment on renal biopsy: Acute antibody mediated rejection
OGD showing haemorrhagic gastritis and in the histology there is giant cell inclusion body with inflammatory infiltrate
Comment: CMV gastritis
1. Reduction of immunosuppresion ( stop / reduce (by 50%) MMF/ myfortic/azathioprine)
2. Continue corticosteroid
3. CNI can be continue unless life threatening infection.
4. Plasma exchange and IV Ig
5. I/V gancyclovir 5mg/ kg for 14-21 days.
6. Monitoring of renal function
1. The first histology slide shows dilatation of the tubule, mononuclear inflammatory cells in peritubular capillaries (capillaritis) with interstitial inflammation.
2. The second slide (immunofluorescence for C4d-IHC) demonstrated diffuse C4d staining around the peritubular capillaries
3. The endoscopic finding shows hyperaemic gastric mucosa with ulceration, suggestive of CMV gastritis (Invasive CMV disease)
4. The last histology slide shows dilated tubules with the presence of basophilic inclusion surrounded by clear hallo (Owl Eye appearance) – CMV inclusion body.
The above findings are suggestive of invasive CMV disease (drug resistant, patient being already on prophylaxis) with subclinical ABMR of renal allograft (post-ABOi- transplant).
How do you manage the case?
· CMV infection in spite of being on valganciclovir prophylaxis
This is very likely to be a case of CMV resistance, which usually occurs due to
– CMV seronegative recipients receiving SDOT from seropositive donors (D+/R-): infection with a new strain of virus
– Intensive immunosuppression (T-cell depleting agent, treatment with high dose Thymoglobulin for acute rejection)
– prolonged courses / sub-therapeutic dose of anti-CMV antiviral
– Recipients of lung transplants
The index case being ABOi, must have received intense immunosuppression, including Retuximab and Thymoglobulin induction. Patient’s compliance to valganciclovir dose needs to be assessed.
CMV viral load (PCR), Genotype assay for UL97, UL57 mutation (drug resistance)
Diagnosis of CMV resistance
CMV resistance to ganciclovir can result from either modification of pUL97 or alteration of pUL54.
All approved CMV antivirals inhibit pUL54 as a final target. UL54 mutations induce various patterns of cross-resistance among all these drugs.
Genotypic assays have the advantages of rapid diagnosis of drug resistance and ability to differentiate drug resistance from clinical resistance secondary to host factors. However readily availability and cost are main issues.
Treatment options of Ganciclovir resistant CMV infection:
After confirmation of CMV resistance, IV foscarnet or Cidofovir or Brincidofovir (if available) should be administered with close monitoring for nephrotoxicity. Monitoring CMV viral load guides treatment duration.
– Newer agent Maribavir or Letermovir has better results with less adverse effects.
Foscarnet:
Cidofovir: nucleotide analogue of cytosine with potent activity against CMV.
Brincidofovir: oral lipid conjugate of cidofovir; more potent, less nephrotoxic, and achieves higher serum concentrations than cidofovir.
Maribavir:
Letermovir:
CMV-specific Cytotoxic T cell CTLs (Cellular adoptive immunotherapy):
Leflunomide:
CSJ148 (combination of 2 newly discovered monoclonal antibodies against CMV):
Management of ABMR :
Diagnosis
Raised Anti-A IgG titre (1:8 à 1:512) associated with Graft dysfunction
Diffuse capillary positive C4d immune-stain
Positive or high DSA would be diagnostic.
Usually associated with “Proteinuria” – which can be used to assess treatment response, and recurrence of ABMR on follow up.
Treatment of ABMR: combination of Plasma exchange + IVIG
Immunosuppression modification:
Situation is complicated, as the patient harbours 2 different scenarios, requiring treatment extremely opposite to each other – CMV infection requires lowering IS load, whereas ABMR treatment requires increasing dose of immunosuppressive drugs.
Invasive CMV (Gastritis) disease is life threatening and also it could be major contributor for renal dysfunction. CMV can trigger and invite rejection, so treatment of CMV can help in treatment of rejection.
ABMR could be subclinical, as rising Anti-ABO titre, late in the follow up, usually does not affect graft function.
Thus, CMV infection should be treated on priority with effective antiviral drugs (Intravenous Foscarnet x3 weeks or Brincidofovir), or preferably novel agents, along with reduced dose of MMF, till CMV DNA becomes nondetectable.
To properly adjust the immunosuppressive medications, we must closely monitor CMV viral load, IgG anti-A antibody levels, drug levels, RFT, CBC, Proteinuria and DSA.
References
1. Daniel C Brennan, Tarek Alhamad, FASNAndrew Malone. Kidney Transplantation in adult: Clinical Features and diagnosis of acute renal rejection — UpToDate.
2. Molinaa MG, Estebana PR, Caballero A, et al. Immune response and histology of humoral rejection in kidney transplantation. Nefrologia 2016; 36(4): 354–367.
3. Reboredo JMM, Reboredo IM, Martul E V,et al. Diagnostic criteria of antibody-mediated rejection in kidney transplants. Nefrologia 2011 Apr; 10: 10740 DOI: 10.3265 /2011. Apr.10740
4. Sung-Hyun S, Hyukyong K, Kitae K, et al. ANTI-ABO ANTIBODY- VERSUS ANTI-HLA ANTIBODY-INDUCED ANTIBODY MEDIATED REJECTION IN ABO-INCOMPATIBLE KIDNEY TRANSPLANT PATIENTS: RELATIVE INCIDENCE AND PHENOTYPE DIFFERENCE. Transplantation 2020 Sep; 104 (S3): S338 DOI: 10.1097/01. Tp 0000700232. 54143.3e
5. UK Guideline on Prevention and Management of Cytomegalovirus Infection and Disease following Solid Organ Transplantation. British Transplant Society.
6. Chaer FE, Shah D P, Chemaly RF. How I treat resistant cytomegalovirus infection in in hematopoietic cell transplantation patients, BLOOD 2016 Dec8; 128 (23):
7. Rolling KE, Jorgenson MR, Descourouez JL, et al. 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.
8. Chou S, Song K, Wu J, et al. Drug Resistance Mutations and Associated Phenotypes Detected in Clinical Trials of Maribavir for Treatment of Cytomegalovirus infection. J infect Dis 2022; 226: 576.
Describe the finding:
Picture on above is light microscopy – hematoxylin and eosin stain, and immunofluorescent microscopy -C4d stain of kidney biopsy. Light microscopic showing tubular dilatation, tubular epithelial cells destruction, peritubular capillaritis and no glomeruli or blood vessels (inadequate biopsy which could be a part of acute ABMR but the problem is C4d stain positivity in ABO incompatible transplant maybe part of accommodation especially we are 2months post-transplant. OGD showing erythematous lesions and Biopsy revealed cytopathic changes characteristic of cytomegalovirus (CMV) tissue-invasive disease.
Hence this patient has cytomegalovirus tissue-invasive disease with or without acute ABMR.
· How do you manage the case?
1. Admit the patient.
2. Start IV fluids to avoid prerenal element.
3. Accurate monitoring of his urine output.
4. Requested investigations includes complete blood count, tacrolimus level, Donor specific antibody (DSA), Blood CMV PCR.
5. Stop MMF and keep tacrolimus level on the lower side from 5-7ng/l
6. Start valganciclovir 5-10mg/kg with frequent monitoring of his CBC and weekly monitoring of CMV PCR (risk of CMV resistance) if no response in form of clinical worsen or PCR viral log is not improving next line treatment should be considered as foscarnet or cidofovir.
7. If AMR proven by re-biopsy or DSA: 5-7 sessions of plasma exchange followed by IVIG 2grams/kg total dose (with or without rituximab and with or without shifting to mTOR) according to viral response and patient’s clinical condition.
References:
Maribavir inhibits ATP binding to UL97 and UL54 ,active against UL97 and UL54 mutations which are key in pathogenesis of CMV resistance while on ganciclovir and Foscarnet. Due to DI, we monitor MTORi and CNIs trough levels while on treatment. Some resistance while on maribavir has been documented. It has demonstrated superiority in clearing viremia with fewer side effects compared to ganciclovir and valganciclovir.
REF;
Ganthi R et al; Evaluating safety of maribavir for tx of CMV. The clin Risk Manag.2022 mar 12;18;223-232.
Robin K et al; Maribavir for refractory CMV with or without resistance post transplant ;Results from a phase 3 RCT.
Uptodate ; Clinical manifestations, diagnosis and management of CMV in KTR.
According to data available in the scenario, increase in IgG titer, and typical appearance on OGD supported by owl eye in the biopsy, the most probable (definite) diagnosis is CMV gastritis. C4d staining and the acute AMBR relate to the degree of aggressive immunosuppression planned for ABOİ donation.
Management should be parallel, treating the infection with foscarnet or mabiravir (supposing this patient is still under prophylaxis of CMV.
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 renal biopsy shows: LM with E&H stain , inadequate core , Tubules, no glomeruli , no vessels. Tubular dilatation with vacuolization and sloughing of epithelial lining.
There is peritubular inflammatory cells infiltration.
IF staining shows diffuse C4d staining.
OGD and biopsy :
OGD : shows erythematous area with ulceration and inflammation in the gastric mucosa.
biopsy: shows viral inclusion bodies ( owls eyes), suggesting CMV disease.
Comment: patient with renal function derangement associated with elevated anti IgG AB titter and diffuse C4d staining in the PTC , with viral inclusions in gastric mucosa in spite of being on valgancyclovir prophylactic for 2 months suggested AMR with drug-resistance CMV disease.
For treatment we should treat both problems together, starting by PE, IVIG, steroids pulses and if no response give RTx.
For CMV we should send for CMV PCR and genotype to confirm the resistance, treat the virus with the new alternative maribavir, which is a novel agent . If not available we can use one of these agents: foscarnet, cidofovir, leflunamide.
Monitor for nephrotocisity , DSA , and anti IGG AB level , CMV PCR viral load.
renal biopsy is suggestive of AMR
also antibody titres are rising
OGD- gastritis leading to symptoms , likey cmv resistant to gancyclovir
PLEX is the best way to treat AMR
REPEAT ANTIBODY TITRE
TARGET antibody is 1/8
Pulse steroid is generally given if the biopsy findings are not available and to buy time but for established AMR PLEX is the choice
for resistant CMV options are cidofovir , foscarnet and Mirabavir
Mirabavir is noval antiviral drugs approved by FDA for resistant CMV
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
Describe the finding.
48 y old lady had ABOi renal transplant 2 months ago, CMV D+/R-, presented with epigastric pain associated with AKI in her graft function.
USS abdomen and pelvis revealed normal liver, GB and kidney.
anti-A IgG increased from 1/8 to 1/512 while being already on valganciclovir 900mg daily.
She had an OGD and renal graft biopsy done showing the following results:
OGD: mucosal inflammation, and erythema is suggestive of gastritis in picture 3
Renal graft biopsy:
1- H&E stained section: ATI with loss of brush border, peri-tubular capillaritis and lymphocytic infiltrates in picture 1
2- IF: Diffuse C4d staining. In picture 2.
3- H&E stain: owl’s eye inclusions surrounded by halo.
This lady has evidence of:
1- CMV infection while on valganciclovir prophylaxis evidenced by high anti-A CMV IgG titer and owel’s eye inclusions in the biopsy.
2- Deranged graft function with histo-pathological findings suggestive of anti-body mediated rejection with diffuse C4d staining.
How do you manage the case?
· High anti-A titers above 1/32, and positive C4d direct attention to check DSA and anti-agglutinins which if they are positive will confirm diagnosis of ABMR
· Treatment of active ABMR: Pulse steroids, IVIG, plasma exchange till the anti-A falls below 1/16.
· IVIG is highly recommended so it will be useful for treatment of ABMR and CMV infection.
· Rituximab can be considered in case of resistant ABMR. However, it will increase the risk of worsening CMV infection
· Request CMV PCR and CMV genotyping (UL97 mutation and UL54 mutation)
· Treatment of CMV tissue invasive disease:
· 1- IVIG + IV Ganciclovir 5 mg/Kg every 12 hours, dose should be adjusted according to GFR, duration of treatment is usually 3 weeks but can be longer until asymptomatic and undetectable CMV viremia in 2 PCR tests drawn one week apart.
· 2- Resistant CMV infection: according to vailability and local protocol; Maribavir, Foscarnet and Cidofovir.
· Foscarnet is effective with UL97 gene mutation but not effective against UL54 gene mutation.
· Foscarnet dosage: IV, 60mg/Kg tds for 2 weeks then 90mg/Kg/day for one week.
· Combined regimen of Foscarnet + Ganciclovir is available.
· Cidofovir: IV, twice/week, monitor for side effects.
· Maribavir: 400mg bd, for 6 weeks, is effective in clearing viremia.
· Maribavir tends to increase the level of CNI, and m-TOR inhibitors.
· Maribavir was superior to older anti CMV medications (Ganciclovir, Valganciclovir, Foscarnet and Cidofovir) in clearing CMV viremia, controlling symptoms and signs in post SOT recipients with refractory CMV infection. Maribavir side effects were less as well.
References:
Clinical Infectious Diseases, Volume 76, Issue 3, 1 February 2023, Page 560.
Morgantetti GF, Balancin ML, de Medeiros GA, Dantas M, Silva GEB. Cytomegalovirus infection in kidney allografts: a review of literature. Transl Androl Urol. 2019;8(Suppl 2):S192-S197. doi:10.21037/tau.2018.10.14
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).
Santhanakrishnan K, Yonan N, Iyer K, Callan P, Al-Aloul M, Venkateswaran R. Management of ganciclovir resistance cytomegalovirus infection with CMV hyperimmune globulin and leflunomide in seven cardiothoracic transplant recipients and literature review. Transpl Infect Dis. 2022 Feb;24(1):e13733.
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.
Describe the finding.
Picture on above is light microscopy – hematoxylin and eosin stain, and immunofluorescent microscopy -C4d stain of kidney biopsy. Light microscopic showing tubular dilatation, tubular epithelial cells destruction, peritubular capillaritis and no glomeruli or blood vessels (inadequate biopsy which could be a part of acute ABMR but the problem is C4d stain positivity in ABO incompatible transplant maybe part of accommodation especially we are 2months post-transplant. OGD showing erythematous lesions and Biopsy revealed cytopathic changes characteristic of cytomegalovirus (CMV) tissue-invasive disease.
Hence this patient has cytomegalovirus tissue-invasive disease with or without acute ABMR.
· How do you manage the case?
1. Admit the patient.
2. Start IV fluids to avoid prerenal element.
3. Accurate monitoring of his urine output.
4. Requested investigations includes complete blood count, tacrolimus level, Donor specific antibody (DSA), Blood CMV PCR.
5. Stop MMF and keep tacrolimus level on the lower side from 5-7ng/l
6. Start valganciclovir 5-10mg/kg with frequent monitoring of his CBC and weekly monitoring of CMV PCR (risk of CMV resistance) if no response in form of clinical worsen or PCR viral log is not improving next line treatment should be considered as foscarnet or cidofovir.
7. If AMR proven by re-biopsy or DSA: 5-7 sessions of plasma exchange followed by IVIG 2grams/kg total dose (with or without rituximab and with or without shifting to mTOR) according to viral response and patient’s clinical condition.
References:
Renal biopsy:
Show tubulitis.
Tubular vacuolization
Sloughing.
IF show C4d stain.
OGD shows congested mucosa with possible ulceration.
And biopsy. Shows inclusion bodies.
In D+/R- patient, most likely. Diagnosis is CMV
Infection with ABMR.
Management:
PF, IVIG, Methylprednisolone.
Stop MMF, maintain CNI at 4-6ng.ml.
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.
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 UL97 and UL54 gene mutations Use either whole blood or plasma.
In people with evidence of ganciclovir resistance:
Stop Valganciclovir (or Ganciclovir)
Offer Intravenous Foscarnet for at least 3 weeks.
Consider use Leflunomide.
Specialist virology advice before commencing treatment with Foscarnet.
DESCRIBE THE FINDINGS.
MGT;
ABMR – < 1YR POST TRANSPLANT.
CMV RESISTANCE;
REF;
UK guidelines on prevention and management of CMV infection and disease following SOT -April 2022.
Upto-date -Clinical manifestations, Diagnosis and treatment of CMV Disease in kidney transplant recipients.
Describe the finding
Kidney biopsy H&E stain no glomeruli appreciated there is increased interstitial inflammatory cells with tubilitis.
Immunofluorescence positive C4d staining that is diffuse.
Inflamed gastric mucosa.
Histology of gastric mucosa shows inclusion bodies (owl eye appearance) with increased inflammatory infiltrate.
How would you manage this case?
Kidney transplant recipient presents 2 months after transplantation with rising titers and worsening kidney function.
Patient was a high risk of CMV disease D+/R- and was on valganciclovir prophylaxis.
Now presents with CMV disease and ABMR evidenced by the histology findings.
CMV disease
This is a challenging scenario because treatment of CMV disease requires reduction of the immunosuppressive agents however this patient has also ABMR.
This patient highly likely has CMV resistant disease since she developed resistance while on valganciclovir, thus paramount to test for CMV mutations.
UL 97 is the most common mutation against ganciclovir, however they may also have UL54 resistance which confers cross resistance to cidofovir and forscanet.
Forscanent is the primary alternative to ganciclovir however it is nephrotoxic can cause electrolyte abnormalities and seizure.
Hence if patient only has UL 97 resistance forscanet can be used though its nephrotoxic.
Maribavir is another alternative that can be used, it is less nephrotoxic than forscanet, it has a multimodal mechanism of action hence active against CMV with UL97 and UL 54 resistance.
ABMR
Treatment involves removal of the existent antibodies and prevention of their redevelopment.
KDIGO recommends the use of either plasma exchange, IVIG, rituximab and lymphocyte depleting antibody.
This patient with concomitant CMV disease I would recommend plasmapheresis minimum 5 session with IVIG to suppress further antibody production.
However there are no treatment protocol to determine which modality is superior to the other.
References
Treatment of Ganciclovir Resistant Cytomegalovirus InfectionMichael Klompas
Maribavir for Refractory Cytomegalovirus Infections With or Without Resistance Post-Transplant: Results From a Phase 3 Randomized Clinical Trial
Robin K Avery, Sophie Alain, […], and SOLSTICE Trial Investigators
Diagnosis and Management of Antibody-Mediated Rejection: Current Status and Novel Approaches.A Djamali, D B Kaufman, […], and M Sam
KDIGO clinical practice guideline for the care of kidney transplant recipient
PMID: 19845597 DOI: 10.1111/j.1600-6143.2009.02834.x
Describe the finding.
The Rt top LM shows nonisometric vacuolization flatting of the tubules which indicate acute tubular injury with an area of PTCs, and the LT top IHC staining for diffuse C4D positive deposit.
the rt lower endoscopic gross appearance of the focal area of ulceration with bleeding and the biopsy confirm typical viral cytopathic changes with enlarged tubular epithelial cells and owl’s eye-type nuclear inclusions likely in the indexed case, it’s a combination of CMV colitis (tissue invasive disease) with acute AMR. however, this LM biopsy is inadequate as we can’t comment on the glomeruli, IFTA, and EM as well for any evidence of transplant glomerulitis , DSA level by SAB
How do you manage the case?
This patient high risk for CMV Infection, seropositive donor-to-recipient negative (D+/R-VE), Despite the chemoprophylaxis with valganciclovir 900mg od, ABO I transplantation with raising antibodies titer put him at risk of ABMR, especially with CO-CMV Infection and intense Immunosuppression, which mainly affect the innate cellular immune response and the TLR2, TLR3, TLR4, and TLR9 are pattern recognition receptors with a key role in innate immunity against viral infections. Accordingly, TLR genetic polymorphisms have been reported to impact the course of CMV infection, and LR4 polymorphisms are associated with an increased risk of CMV disease in the kidney transplant cohort ( 4).
A combination of CMV colitis and AMR on the background of ABO I kidney transplantation, a very challenging case and carries high morbidity and mortality, we should balance the risk and benefit while deciding the treatment line, based on this biopsy results which are limited to tubules and we don’t have any evidence of chronic changes still we can direct the treatment for both AMR and invasive CMV Disease after MDT discussion with the transplant nephrologist, ID team, and gastroenterologist team taken in consideration the possibility of CMV resistant as this patient was on valganciclovir, prophylaxis ganciclovir or valganciclovir has been the standard of care for high-risk SOT recipients for decades. Valganciclovir is more potent compared to oral ganciclovir and has less risk of CMV resistance infection. However, ganciclovir resistance mutations in UL97 were found in 9.5% of patients and should be checked in a suspected case like the indexed case also T-cell immune functional assays such as ELISpot or QuantiFERON assays have shown an association with a higher incidence of CMV infection in high-risk SOT recipient. and may benefit from prolonged prophylaxis or even lifelong prophylaxis depending on the type of transplant.
Treatment
for AMR
Plasmapheresis with IVIG 2gm /kg, followed by triple maintenance IS, rituximab I would delay it till the CMV disease is under control
CMV colitis trial of High dose IV ganciclovir for 3 weeks if no response within the first 5-6 days may consider CMV resistant and use second-line therapy like Foscarnet is associated with renal toxicity, electrolyte abnormalities, and seizures, and its use is restricted due to the intolerance and side effects alternative the combination of both foscarnet and ganciclovir with CMV immunoglobulin
cidofovir and its use is limited by its adverse effects
Novel therapeutic options for drug-resistant or refractory CMV infection, including maribavir, letermovir, and adoptive T-cell transfer.
References
1. Haidar G, Boeckh M, Singh N. Cytomegalovirus Infection in Solid Organ and Hematopoietic Cell Transplantation: State of the Evidence. J Infect Dis. 2020 Mar 5;221(Suppl 1 ):S23-S31.
2. Bai G, Cui N, Wang H, Cheng W, Han W, Chen J, Guo Y, Wang F. T-lymphocyte subtyping: an early warning and a potential prognostic indicator of active cytomegalovirus infection in patients with sepsis. Immunol Cell Biol. 2022 Nov;100(10):777-790. doi: 10.1111/imcb.12586. Epub 2022 Oct 12. PMID: 36106958; PMCID: PMC9828035.
3. Manuel O, Avery RK. Update on cytomegalovirus in transplant recipients: new agents, prophylaxis, and cell-mediated immunity. Curr Opin Infect Dis. 2021 Aug 1;34(4):307-313
4. Bodro M, Cervera C, Linares L, Suárez B, Llopis J, Sanclemente G, Casadó-Llombart S, Fernández-Ruiz M, Fariñas MC, Cantisan S, Montejo M, Cordero E, Oriol I, Marcos MA, Lozano F, Moreno A; GESITRA-IC/SEIMC/REIPI investigators. Polygenic Innate Immunity Score to Predict the Risk of Cytomegalovirus Infection in CMV D+/R- Transplant Recipients. A Prospective Multicenter Cohort Study. Front Immunol. 2022 Aug 9;13:897912.
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:
a challenging case of AMR and associated ganciclovir resistant GI CMV.
1- Treatment of ganciclovir resistant CMV disease:
-Combined foscarnet and valganciclovir
-Cidofovir or leflumomide (rare available clinical data)
2- Treatment of associated AMR:
3- After completion of treatment:
re-start CMV prophylaxis
6. 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:
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 of acute rejection: – (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 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:
Findings Description:-
LM :Loss of tubular brush border, tubulitis, tubular atrophy.
IF : positive C4d staining.
OGD Scope : gastric erosion and ulceration
LM : CMV inclusion bodies, interstitial cellular infiltrates
Treatment of GI CMV Disease:
1) Reduce immunosuppression => stop the antimetabolites until viral load is not detectable, then consider restarting at a low dose , Weekly monitoring of PCR viral DNA levels to be sure there is no recurrence of viremia.
If the CMV recurs, it’s better to discontinue the antimetabolite indefinitely. However, in this patient with suspected refractory disease from likely resistance to ganciclovir, it’s better not to restart. Additionally, doses of prednisolone can and CNI can be reduced when the resistance is confirmed.
2) Convert to IV ganciclovir at 5mg/kg 12 hourly with renal dose adjustment pending the determination of drug resistance testing. Check the complete blood count to monitor for bone marrow toxicity.
3) Refractory cases if persistent and or progressive infection despite antiviral agents and reduction of immunosuppression and can be due to ganciclovir resistance, of more than 2 weeks at appropriate doses treatment. (Drugs Resistent Mutation => UL97 and UL54 gene mutations => according to the result of resistance testing, options include mabavir, foscarnet and cidofovir.
Mabavir: this is active against UL97 and UL54 mutation. Given at 400mg bd po for 8 weeks. Close monitoring of CNI doses due to drug interaction is necessary.
Foscarnet :active against UL97 and UL54 mutation. It’s dosed at 60mg/kg IV 8 hourly with renal dose adjustment. Pre-hydration and close monitoring of electrolytes is necessary due to its nephrotoxic effect.
Cidofovir : Active against UL97 mutation only. Dose is 1mg/kg IV three times weekly or 5mg/kg IV for 2 weeks intensive phase and 5mg/kg every other week.
Treatment of antibody mediated rejection:
1) For All Acute Rejection IV methylprednisolone 500mg daily for 3 days or 5mg/kg for 3
days , then oral prednisolone 1mg/kg tapered to 10mg daily.
2) Plasmapheresis – either daily or every other day for a maximum of 6 sessions or until
serum creatinine is 20 to 30% of baseline value.
3) IVIg – given at 100mg/kg after each plasmapheresis (or 2gm/kg after the Last PLEX).
4) IV rituximab – 200mg after each dose of plasmapheresis
Reference:
Up to Date
Thanks Professor Ahmed Halawa
Any evidence to support the use of Maribavir for ganciclovir-resistant CMV?
Drug is approved by FDA 2021.
It inhibits UL97 phosphotransferase and stops viral maturation.
It is active against CMV with UL97 and UL54 mutations.
Dose 400 mg orally twice daily for eight weeks.
It is shown to be superior to valganciclovir/ ganciclovir, foscarnet or cidofovir in patient
with CMV infection with or without resistance with respect to viremia control and
symptom control.
Who treats AMR with methylprednisolone pulses?
KDIGO suggest to treat ABMR with one or more of the following:
(PEX, IVIG, Anti-CD20 and lymphocyte depleting agents) and no specific role for steroid.
But clinically in our program we are given Pulse steroids 5 mg/kg to either ACR or ABMR for three days as a 1st line of treatment
References:
* Avery RK, Alain S, Alexander BD, et al. Maribavir for Refractory Cytomegalovirus Infections With or Without Resistance Post-Transplant: Results From a Phase 3 Randomized Clinical Trial [published correction appears in Clin Infect Dis. 2023 Feb 8;76(3):560]. Clin Infect Dis. 2022;75(4):690-701. doi:10.1093/cid/ciab988.
*KDIGO guidelines for the care of kidney transplant recipients.
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
· Describe the finding.
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.
· How do you manage the case?
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) which seems to be ganciclovir resistant (CMV developing despite on adequate prophylactic dose of valganciclovir). CMV antigen detection by immunohistochemistry of the biopsy specimen can help in diagnosis.
AMR should be treated with (1):
1. 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.
2. Inj Rituximab 375 mg/m2 after last session of plasmapheresis.
3. Injection methylprednisolone 500 mg intravenous pulse for 3 days (if there is evidence of concomitant T cell rejection on biopsy).
The tissue-invasive CMV is managed by:
1) Supportive therapy: Maintain adequate hydration.
2) Assessment for ganciclovir resistance should be done. Genotype testing to identify the specific mutations should be done.
3) First step is to give increased dose of intravenous Ganciclovir (10 mg/kg 12 hourly) rather than the standard dose of 5 mg/kg 12 hourly (dose should be adjusted as per creatinine clearance), and if responds, then It should be continued for minimum 2 weeks, and until resolution of graft dysfunction with clearance of CMV in blood, if present (2,3). In absence of any genetic mutation, increasing the dose of ganciclovir would suffice.
4) if no response, or if there is UL97 and UL54 mutation: Shift to intravenous Foscarnet (90 mg/kg 12 hourly, dose to be adjusted as per renal clearance) for 3 weeks and additional CMV immunoglobulin or intravenous immunoglobulin (IVIG) should be considered (2).
5) Cidofovir (1mg.kg intravenous 3 times a week): Can be given in presence of UL97 mutation alone (not effective in UL54 mutation).
6) Maribavir (400 mg twice a day for 8 weeks): Active against both UL97 and UL54 mutations.
7) Letermovir have also been used.
8) Secondary prophylaxis with oral valganciclovir post-treatment can be given for 1-2 months in patients with high-risk of relapse. But in presence of ganciclovir resistance, it might not be useful.
9) 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. Cautious decrease in immunosuppression with shift to mTOR inhibitor based regimen should be undertaken (2).
10) Patient should be counselled regarding the risk of rejection in such a scenario when the dose of immunosuppression is being reduced.
11) Patient should be given pneumocystis prophylaxis with trimethoprim-sulfamethoxazole post-treatment of rejection.
References:
Describe the finding.
There is deterioration of renal functions post ABOI renal transplant and Anti-A IgG titre has risen from 1/8 to 1/512. This indicates possible rejection. There is high risk of CMV infection and despite being on Val Ganciclovir there is possible CMV gastritis. It indicates Ganciclovir resistant CMV disease.
The first image is a kidney biopsy showing tubulitis and tubular vacuolation.
The second image shows immunofluorescence C4d staining.
The third and fourth image shows inflamed gastric mucosa on OGD and histology shows intranuclear inclusion bodies with Owl eye appearance.
How do you manage the case?
This is a case of ABMR and Ganciclovir resistant CMV infection.
CMV PCR
CMV Genotyping- for mutations like UL97 Protein kinase
Treatment option include-
Maribavir 400 mg twice daily
Reduction of immune suppression
Other options include-
Lefunomide
Foscarnet
Cidofovir
Strict monitoring is need for nephrotoxicity
For AMBR one of these options can be used
PEX
IVIG
Anto CD 20 Rituximab.
El Chaer F, Shah DP, Chemaly RF. How I treat resistant cytomegalovirus infection in hematopoietic cell transplantation recipients. Blood. 2016 Dec 8;128(23):2624-2636. doi: 10.1182/blood-2016-06-688432.
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.
Describe the finding.
Immune fluorescence Renal biopsy
This LM that stained H and E, show vacuolization of the renal tubules with lymphocytic infiltration of the interstitium,dilated tubules and back to back ,generally in adequate biopsy but this finding go with acute tubular necrosis.
Heavyd diffuse CD4 count staining in peritubular capillaries which is normal in ABO
Incompatibility transplantation due to graft accomudation ,together with rising level of igG with this CD4 deposition all favour dignosing of ABMR.
OGD
Hyperemic ,ulcerated of superficial mucusa ,other one show inclusion bodies with owel eye appearance which is matched with CMV infection.
How do you manage the case?
This case is ABMR with CMV infection inspite of that on ganciclovir diagnosed as ganciclovir resistance CMV disease.
Treatment of CMV disease.
We must do PCR for CMV genotype to exclude mutations
Maribavir 400mg twice daily for 6 weeks.
Foscarnet (moniter nephrotoxicity)
Cidofovir (moniter nephrotoxicity)
Reduce immune suppression.
Treatment of ABMR
Plasma exchange .
IVIG
Rituximab .
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.Avery RK, Alain S, Alexander BD, et al. Maribavir for Refractory Cytomegalovirus Infections With or Without Resistance Post-Transplant: Results From a Phase 3 Randomized Clinical Trial [published correction appears in Clin Infect Dis. 2023 Feb.
Thank you very much Prof Halawa for this case as we have a lot of points to learn.
First of all he is ABOi compatible WITH HIGH TITER OF Anti A 1/512 but this is not reflected on his kidney function yet and he may have subclinical AMR as we are not relay on positive C4d in the case of ABOi.
The first problem of this patient is having CMV resistance despite on prophylactic treatment and he had the kidney from a positive donor, adding to he is now 2 months post RTX and presenter with features of CMV disease and tissue invasion.
First of all we may try to combine treating both conditions with the special scale as follows:
Resistant CMV will hold VAlgancyclovir and will start managing him by FOScarnet and IVIG (which will help in subclinical AMR).
next will keep him on the same dose of CNI but will hold MMF
Prednisolone can be increased and will help in both AMR and in even rejection due to CMV .
I will do PEX to reduce the titer of Anti A AB tite without giving rituximab for now , along with following for the Anti A titer .
will follow CMV PCR load and decide accordingly regarding being very aggressive in treating the rejection.
It is risky to give IS in such case of R/R CMV.
references
uptodate
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- Maribavir 400 mg, twice daily in solid-organ (SOT), clearing viremia within 6 weeks in patients with refractory CMV infection
3- Leflunomide is a reasonable option in ganciclovir-resistant infection in kidney transplant recipients.
4-Foscarnet;Monitor for nephrotoxicity.
5-Cidofovir; Monitor for nephrotoxicity.
6-Reduction of anti-proliferative therapy.
Treatment option of ABMR:
One or more of the following can be used for ABMR treatment:
PEX.
IVIG.
Anti-CD 20 such as Rituximab and lymphocyte depleting agents.
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.
6- Avery RK, Alain S, Alexander BD, et al. Maribavir for Refractory Cytomegalovirus Infections With or Without Resistance Post-Transplant: Results From a Phase 3 Randomized Clinical Trial [published correction appears in Clin Infect Dis. 2023 Feb.
Description of the clinical scenario and images provided
This is a case of high-risk kidney transplantation being ABOi and high-risk CMV being CMV+ to CMV-.
A kidney biopsy shows desquamation and sloughing of tubular cells and peritubular inflammatory cells.
The presence of peritubular capillaritis associated with diffuse C4d staining and high isoagglutinin titers is consistent with ABMR. However, in ABO-i transplantation, diffuse C4d staining means accommodation is expected.
The likelihood of CMV gastritis is suggested by the EGD findings of hyperemia, inflammation of the gastric mucosa, gastric ulceration, and the presence of OWL eyes 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 the 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 due to ABOi transplantation.
The occurrence of CMV infection in this recipient of an ABOi donor early after transplantation, who ideally should still be maintained on Valganciclovir, raises the suspicion of resistance to ganciclovir, the active metabolite of Valganciclovir.
Resistance to treatment with correctly dosed ganciclovir for longer than two weeks along with a reduction in immunosuppression is referred to as “resistant CMV infection.”
Plan of treatment of invasive CMV disease and AMR
Plasmapheresis daily till the titer decrease < 1: 16
Reduce MMF dose by 50 %
Keep CNI within therapeutic level
Immediately stop valganciclovir prophylaxis and initiate CMV treatment.
Use IV ganciclovir for 21 days. Discontinue ganciclovir if the patient is symptom-free and PCR-negative in two consecutive tests. If symptoms persist despite treatment, alternative therapy is recommended. Maribavir, foscarnet, and cidofovir are antiviral treatments for patients with ganciclovir-resistant or refractory CMV.
After completion of treatment, continue prophylaxis with 900 mg of valganciclovir once a day for 1 to 3 months.
Describe the finding.
===========================
How do you manage the case?
Treatment of resistant CMV infection:
Treatment options
Foscarnet:
Cidofovir:
Maribavir
Brincidofovir:
Letermovir:
CMV-specific CTLs (Cellular adoptive immunotherapy):
Leflunomide:
Artesunate:
Sirolimus and everolimus:
CSJ148 (a combination of 2 newly discovered monoclonal antibodies against CMV):
Treatment options for ABMR include:
References
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:
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 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.
There is higher risk for resistant CMV infection:
D+/R- serostatus, and already on Valgancyclovir prophylaxis, and tissue invasive virus.
To stop or reduce the dose of antimetabolites (MMF) by 50%, continue on CNI and put on stress dose (pulse steroid), and can use other antiviral therapy such as letermovir, foscarnet, cidofovir (nephrotoxic), and leflunamide.
Mribavir (slavage treatment) can be used with less side effect profile (no nephortoxicity/bone marrow suppression) no dose adjustment required in the index case.
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.
(4) 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: 2279089.
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.
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
Dear All
Any evidence to support the use of Maribavir for ganciclovir-resistant CMV?
Also, who treats AMR with methylprednisolone pulses?
I have read some of the colleagues in this scenario doing this. What is the rationale?
Maribavir is a good alternative when traditional drugs fail in the treatment of drug-resistant CMV infection in combination with changes in immunosuppression.
-Maribavir is superior to ( valganciclovir/ganciclovir, foscarnet, or cidofovir) for cytomegalovirus viremia clearance plus symptom control maintained post-therapy in transplant recipients with refractory cytomegalovirus infection .
-Maribavir had fewer adverse events than(valganciclovir/ganciclovir, foscarnet, or cidofovir) .
Thank you
Many thanks Prof . Halawa
Use with Immunosuppressant Drugs
Reference
Cite this: FDA Approves First Drug for Treatment of Resistant Cytomegalovirus Infection – Medscape – Nov 24, 2021.
Thank you
Thank you Prof. Ahmad Halawa.
=========================
Any evidence to support the use of Maribavir for ganciclovir-resistant CMV?
Maribavir is a Novel agent with anti-CMV effect- used for valgancyclovir resistant/refractory CMV, FDA approved in 2021, with good safety profile, dose not need dose adjustment in mild and moderate renal impairment.
Who treats AMR with methylprednisolone pulses?What is the rationale?
I would give him a pulse steroid, as CMV infection per se, put him in high risk for acute rejection either ACR or AMR, in both scenarios pulse steroid is a mainstay of tretament.
in index case S/P ABOi kdieny transplant C4d +ve, can be seen with no rejection, and found in almost 70% of ABOi transplants due to allograft accommodation phenomenon.
so; i would review the biopsy with an expert renal pathologist to better know the rejection status, and might ask for anti-endothelial cell anti bodies- indicates humoral rejection.
The risk of rejection in CMV is due to:
If rejection ensue i would treat with IVIG + plasma exchange and Rituximab.
Refernces:
(1) Gandhi RG, Kotton CN. Evaluating the Safety of Maribavir for the Treatment of Cytomegalovirus. Ther Clin Risk Manag. 2022 Mar 12;18:223-232. doi: 10.2147/TCRM.S303052. PMID: 35308097; PMCID: PMC8926008.
(2) 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.
Thank you
Maribavir:
-It is a potent, selective, orally bioavailable benzimidazole riboside that is active against CMV infection in humans.
-It blocks nuclear egress of viral capsids through the inhibition of protein kinase UL97.
-Active in vitro against CMV strains that are resistant to ganciclovir, foscarnet, or cidofovir.
-It has a favorable safety profile, without associated myelosuppression or nephrotoxicity
Recent study concluded:
Maribavir was superior to (valganciclovir/ganciclovir, foscarnet, or cidofovir) for CMV viremia clearance and viremia clearance plus symptom control maintained post-therapy in transplant recipients with CMV resistance.
It had fewer AEs
Reference:
Avery RK, SOLSTICE Trial Investigators. Maribavir for Refractory Cytomegalovirus Infections With or Without Resistance Post-Transplant: Results From a Phase 3 Randomized Clinical Trial. Clin Infect Dis. 2022 Sep 10;75(4):690-701. doi: 10.1093/cid/ciab988. Erratum in: Clin Infect Dis. 2023 Feb 8;76(3):560. PMID: 34864943; PMCID: PMC9464078.
Thank you
Thanks prof, Halawa.
1-Maribavir has multimodal anti-cytomegalovirus activity through the inhibition of UL97 protein kinase and it is effective against CMV infection with and without resistance. Drug is approved by FDA 2021.
2-KDIGO suggest to treat ABMR with one or more of the following:
(PEX, IVIG, Anti-CD20 and lymphocyte depleting agents) and no specific role for steroid.
References:
1- Avery RK, Alain S, Alexander BD, et al. Maribavir for Refractory Cytomegalovirus Infections With or Without Resistance Post-Transplant: Results From a Phase 3 Randomized Clinical Trial [published correction appears in Clin Infect Dis. 2023 Feb 8;76(3):560]. Clin Infect Dis. 2022;75(4):690-701. doi:10.1093/cid/ciab988.
2- Gandhi RG, Kotton CN. Evaluating the Safety of Maribavir for the Treatment of Cytomegalovirus. Ther Clin Risk Manag. 2022;18:223-232. Published 2022 Mar 12. doi:10.2147/TCRM.S303052.
3- KDIGO guidelines for the care of kidney transplant recipients.
Thank you
Maribavir;
–An oral drug that inhibits UL97 phosphotransferase and stops viral maturation.
-It is active against CMV with UL97 and UL54 mutations.
-Maribavir is dosed at 400 mg orally twice daily for eight weeks.
-Dysgeusia is a frequent side effect, and 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 target of rapamycin (mTOR) inhibitors, close monitoring of these immunosuppressive agents is required.
-Resistance to maribavir has also been reported to emerge while on therapy.
References;
-Chou S, Song K, Wu J, et al.Drug Resistance Mutations and Associated Phenotypes Detected in CLinical Trials of Maribavir for Treatment of Cytomegalovirus infection. J infect Dis 2022; 226:576 .
Thank you
Maribavir is used for CMV resistance as approved by FDA and has no B.M suppression and no nephrotoxcity
Thank you
This is a very short response, Manal.
IV methylprednisolone is not effective in treatment of ABMR. We just use it in presumed rejection (prior to or until result of allograft biopsy) , and if it is ABMR it will be resistant to pulse steroids. So, treatment will be PEX (if early in 1st year) , IVIg and rituximab
Maribavir has been shown to be superior to valganciclovir/ ganciclovir, foscarnet or cidofovir in patient with CMV infection with or without resistance with respect to viremia control and symptom control.
Reference:
Avery RK, Alain S, Alexander BD, Blumberg EA, Chemaly RF, Cordonnier C, Duarte RF, Florescu DF, Kamar N, Kumar D, Maertens J, Marty FM, Papanicolaou GA, Silveira FP, Witzke O, Wu J, Sundberg AK, Fournier M; SOLSTICE Trial Investigators. Maribavir for Refractory Cytomegalovirus Infections With or Without Resistance Post-Transplant: Results From a Phase 3 Randomized Clinical Trial. Clin Infect Dis. 2022 Sep 10;75(4):690-701. doi: 10.1093/cid/ciab988. Erratum in: Clin Infect Dis. 2023 Feb 8;76(3):560. PMID: 34864943; PMCID: PMC9464078.
The role of methylprednisolone pulses in acute antibody mediated rejection arises in presence of concomitant T cell rejection.
Reference:
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.
Maribavir was superior to valganciclovir/ganciclovir, foscarnet, or cidofovir for cytomegalovirus viremia clearance and viremia clearance plus symptom control maintained post-therapy in transplant recipients with resistant cytomegalovirus. Maribavir had fewer treatment discontinuations due to treatment-emergent adverse events than valganciclovir/ganciclovir, foscarnet, or cidofovir.
Robin K Avery, Sophie Alain, Barbara D Alexander, Emily A Blumberg, Roy F Chemaly, Catherine Cordonnier, et al. SOLSTICE Trial Investigators, Maribavir for Refractory Cytomegalovirus Infections With or Without Resistance Post-Transplant: Results From a Phase 3 Randomized Clinical Trial, Clinical Infectious Diseases, Volume 75, Issue 4, 15 August 2022, Pages 690–701.
Choice of antiviral therapy – Antiviral therapies for patients with ganciclovir-resistant or refractory CMV include maribavir, foscarnet, and cidofovir.
•
Maribavir – An oral drug that inhibits UL97 phosphotransferase and stops viral maturation and egress. Maribavir is active against CMV with UL97 and UL54 mutations. Maribavir is dosed at 400 mg orally twice daily for eight weeks. Dysgeusia is a frequent side effect, and 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. Resistance to maribavir has also been reported to emerge while on therapy
Reference
Drug Resistance Mutations and Associated Phenotypes Detected in Clinical Trials of Maribavir for Treatment of Cytomegalovirus Infection. Chou S, Song K, Wu J, Bo T, Crumpacker C
J Infect Dis. 2022;226(4):576.
the European Union, maribavir is indicated for the treatment of cytomegalovirus (CMV) infection and/or disease that are refractory (with or without resistance) to one or more prior therapies, including ganciclovir ,valgancyclovir, cidofovir or foscarnet in adults who have undergone a hematopoietic stem cell transplant (HSCT) or solid organ transplant (SOT).
Maribavir inhibits ATP binding to UL97 and UL54 ,active against UL97 and UL54 mutations which are key in pathogenesis of CMV resistance while on ganciclovir and Foscarnet. Due to DI, we monitor MTORi and CNIs trough levels while on treatment. Some resistance while on maribavir has been documented. It has demonstrated superiority in clearing viremia with fewer side effects compared to ganciclovir and valganciclovir.
REF;
Ganthi R et al; Evaluating safety of maribavir for tx of CMV. The clin Risk Manag.2022 mar 12;18;223-232.
Robin K et al; Maribavir for refractory CMV with or without resistance post transplant ;Results from a phase 3 RCT.
Uptodate ; Clinical manifestations, diagnosis and management of CMV in KTR.
Light microscopy (LM)
H&E stain
Inadequate biopsy
Dilatation of some tubules
Vacoulization of some tubules
Sloughing of the tubular epithelial cells
Peritubular capillary infiltration by mononeular cells
Immune fluorescence microscopy (IF)
IF showed diffuse CD4 +ve staining in the peritubular capillaries
OGD:
Showed edema, erythema of mucosa
Biopsy
Viral inclusion body
Need to see post-transplant DSA to confirm rejection.
How do you manage the case?
Treatment of AMR and invasive cmv infection
Need to take into consideration CMV is life threatening and AMR is only kidney threatening
Need to treat simultaneously, later reduction of immunosuppression after treatment of AMR
For AMR:
Plasma exchange 3 to 5 session followed by CMV IVIG after each session of plasmapheresis, iv pulse steroid (to treat concurrent TCMR). Instead of rituximab I would like to give leflunomide in this patient which will work for AMR and CMV as well.
Stop MMF, continue tacrolimus to drug level (7-10)
Invasive CMV infection:
First, we will check CMV PCR viral load and do viral genotyping as patient had cmv infection in spite of valacyclovir prophylaxis.
(In our part we don’t have genotyping and foscarnet) so will rely of viral load for treatment)
We have 2 approach.
1) Give iv ganciclovir 5-10 mg/kg (according to GFR) and see the viral load weekly and observe clinical symptoms (I need to use this option as we don’t have CMV genotyping and foscarnet)
2) As in this case we can’t wait to see whether ganciclovir work or not as we have to treat rejection as well so start foscarnet for 3 to 4 week then give every 48hrly with valganciclovir. Continue foscarnet till therapeutic level of Valganciclovir have been achieved, then can discontinue foscarnet.
In case of foscarnet resistant can use cidofovir
Leflunomide to be use as adjuvant drug.
Reference
Eid AJ, Arthurs SK, Deziel PJ, Wilhelm MP, Razonable RR. Emergence of drug-resistant cytomegalovirus in the era of valganciclovir prophylaxis: therapeutic implications and outcomes. Clin Transplant. 2008 Mar-Apr;22(2):162-70. doi: 10.1111/j.1399-0012.2007.00761.x. PMID: 18339135.
El Chaer F, Shah DP, Chemaly RF. How I treat resistant cytomegalovirus infection in hematopoietic cell transplantation recipients. Blood. 2016 Dec 8;128(23):2624-2636. doi: 10.1182/blood-2016-06-688432. Epub 2016 Oct 19. PMID: 27760756; PMCID: PMC5146744.
Sola E, Vega E, Gutiérrez C, López V, Cabello M, Burgos D, González Molina M, Siles J. Enfermedad por CMV resistente a ganciclovir. Está indicado monitorizar niveles plasmáticos de valganciclovir en pacientes de alto riesgo? [Disease by CMV resistant to Ganciclovir. Should plasma valganciclovir levels be monitored in high risk patients?]. Nefrologia. 2009;29(2):180-1. Spanish. doi: 10.3265/Nefrologia.2009.29.2.4889.en.full. PMID: 19396331.-(Editorial)
Excellent
Thank you Prof.
Findings description:
-LM of kidney biopsy H&E stain revealing peritubular capillaritis ,tubular vacuolation and sloughing of epithelial cells with infiltration with mononuclear cells .
IF testing : Showing diffuse tubular and peritubular C4D Ab staining (ABMR).
EGD : Showed hypraemic ulcerating gastric mucosa .
– Gastric biopsy revealing owl’s eye sign which indicates CMV viral infection.
Treatment of ABMR: comprise :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.
👉 LM of renal biopsy shows evidence of tubulitis, sheded epithelial cells and IF shows linear deposits of peritubular c4d (together with rising titre of isoagglutinin and impaired graft function) are highly suggestive of ABMR, rather than accomodation phenomenon of ABO incompatible transplantation.
👉 Presence of gastritis by NE of upper endoscopy together with viral inclusion bodies in the biopsy are suggestive of CMV tissue invasive disease.
👉 Treatment of such case is tricky, as management if CMV by reduction of immunosupression is opposing to treatment of aggressive ABMR by augmentation of IS plus IVIG , PEx and rituximab.
👉 Treatment of ABMR by PEX followed by IVIG are essential.
👉 treatment of CMV by foscarnet IV (as the case has valganciclovir resistance (evidenced by infection while on its chemoprophylaxis).
👉 Close follow up of graft function as foscarnet is nephrotoxic and follow up CNI trough level
👉 decrease MMf dose or it’s stoppage, while keeping on CNI and steroids are essential.
👉 As CMV can trigger and invite rejection, so treatment of CMV can help in treatment of rejection.
⭐ I think use of rituximab in such case of CMV invasive disease is not wise and risky.
Excellent
Thanks dear professor
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 :
Describe the finding
Upper GIT endoscopy: erythematous, friable with erosions and ulcers
Upper GIT endoscopy biopsy: stained with H&E revealed enlarged tubular cells with intranuclear inclusions bodies of CMV
Kidney biopsy: stained with H&E stain and revealed tubular injury and peritubular inflammatory cells
Immunoflourescence: C4d deposit (peritubular)
This patient has evidence of AMR:
1. Morphological evidence of acute tissue injury (acute tubular injury)
2. C4d staining
3. and serology (rising titre of isoagglutinin)
Also has CMV-invasive gastritis: (although she is on Valganciclovir prophylaxis)
GIT symptoms, GIT endoscopy and biopsy
So, it is a case of concomitant CMV-invasive gastritis and ABMR
It is a case of concomitant CMV-invasive gastritis and ABMR
How do you manage the case?
Tissue-invasive gastritis
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)
Ganciclovir resistance
CMV disease that is refractory to treatment with Ganciclovir or Valganciclovir and is reported to occur in up to 3% of SOT recipients (Deteced via genotype analysis to assess for UL54 and UL97 genes)
Risk factors include:
1. R-/D+
2. Degree of immunosuppression
3. Magnitude of CMV viremia
4. Prolonged exposure to anti-CMV medication, or subtherapeutic antiviral dosing
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
If resistance to Ganciclovir is suspected:
1. Confirm that dosing is adequate
2. Consider adherence to treatment plan and absorption
3. Offer testing for Human CMV (HCMV) antiviral resistance: UL97 and UL54 gene mutations. Use either whole blood or plasma
When there is evidence of ganciclovir resistance:
1. Stop Valganciclovir (or Ganciclovir)
2. Offer Intravenous Foscarnet for at least 3 weeks. Seek specialist virology advice before commencing treatment with Foscarnet
Newer agents Letermovir and Maribavir may be associated with less drug toxicity
Maribavir has FDA approval and is currently being assessed by the NICE
AMR treatment
1. Methylpredisolone
2. Plasma exchange (PEX)
3. IVIg
4. Rituximab (initially when there is severe histological changes or ongoing AMR despite PEX and IVIg)
References
1. CMV in Kidney Transplantation By Ahmed Halawa (lecture), consultant Transplant Surgeon Associate Professor, University of Liverpool –UK, 2023
2. Treatment of Ganciclovir Resistant Cytomegalovirus Infection, Michael Klompas.
3. 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.
4. UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION. BTS, 2022.
The above case is of AMR in case of ABOi Transplantation with CMV drug resistant infection involving gastrointestinal system.
AMR IN ABOi TRANSPLANT
DRUG RESISTANT CMV INFECTION
REF:
The above case is of AMR in case of ABOi Transplantation with CMV drug resistant infection involving gastrointestinal system.
FIRST: DISCUSSION ON AMR IN ABOi TRANSPLANT
SECOND: DISCUSSION ON DRUG RESISTANT CMV INFECTION
REF:
Thanks
–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 seen
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 ganciclovir resistant CMV infection with CMV gastritis, and ABMR
– Management
Despite the use of antiviral Valganciclovir prophylaxis, CMV viraemia progressed in the current transplant recipients indicating
Ganciclovir resistant CMV infection
Investigations
CMV quantification in the blood samples using PCR quantitative nucleic acid testing (NAT)or pp65 antigenemia
Genotypic resistance testing as UL89 ,C607 Y mutation can be used to guide treatment of CMV drug-resistant infection and reduce the risk of treatment failure and drug toxicity.
Treatment includes
· IV Foscarnet or IV Cidofovir use is on limited bases due to their nephrotoxic and neurotoxic effect.
· Lefluonamide as immunomodulatory was used in CMV infection therapy
· CMV immunoglobulin to neutralize viral particle .
· Lefluonamide and CMV Ig therapy can be used together
· Newer agents ; Letermovir ,Maribavir and Brincidofovir.
Viral load need to be monitored to adjust antiviral therapy and immunosuppression accordingly
MMF need to be suspended, mTOR can be introduced as having less risk of CMV infection but less potent effect on graft rejection
For AMR
Diagnosis
Renal biopsy shows
ABMR diagnostic Banff revised criteria 2017
(all three criteria must be met for diagnosis)
· Histologic evidence of acute tissue injury including one or more of microvascular inflammation MVI,Intimal or transmural arteritis ,Acute Thrombotic microangiopathy,
· Evidence of current/recent antibody interaction with vascular
endothelium as Linear C4d staining in PTC and vasa recta , moderate MVI ,Increased expression of gene transcripts/classifiers
· Serologic evidence of DSA to HLA or other antigens.
In fact C4d deposition in Peri Tubular Capillaries without evidence of rejection is commonly seen in biopsies of ABO‑incompatible allografts, in which it may represent graft accommodation. Hence, C4d lacks its utility as a marker for ABMR in ABOi allografts.
Diagnostic criteria for C4d‑negative ABMR were incorporated
into the 2013 Banff update, as moderate microvascular
inflammation or presence of endothelial activation and injury
transcripts (ENDATs), in the absence of C4d byIF and C4d by IHC, with coexistent histologic evidence of tissue injury and presence of DSA
Treatment
IV pulse steroids ,
plasmapheresis and
human immunoglobulin can be introduced .
Rituximab in resistant cases
Conclusively this is a challenging case therefore
ABMR therapy has to be started with monitor of graft function and at the same time undercover of Ganciclovir resistant antiviral therapy with viral load monitoring as well.
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
-Santhanakrishnan K, Yonan N, Iyer K, Callan P, Al-Aloul M, Venkateswaran R. Management of ganciclovir resistance cytomegalovirus infection with CMV hyperimmune globulin and leflunomide in seven cardiothoracic transplant recipients and literature review. Transpl Infect Dis. 2022 Feb;24(1):e13733.
– Etta, Praveen Kumar. C4d Staining and Antibody-Mediated Rejection in Renal Transplantation: Current Status. Indian Journal of Transplantation 14(3):p 197-201, Jul–Sep 2020.
– Perrottet N, Fernández-Ruiz M, Binet I, et al. Infectious complications and graft outcome following treatment of acute antibody-mediated rejection after kidney transplantation: A nationwide cohort study. PLoS One. 2021;16(4):e0250829.
Excellent
Thanks Professor Halawa
2 months after ABOi kidney transplantation, the patient presented with epigastric pain and diarrhea with deterioration of allograft function. In his background, He is CMV negative, and the donor is CMV positive. The investigations revealed significant rise of Anti A antibodies from 1/8 to 1/512. importantly, the patient was on CMV prophylaxis with Valgancyclovir 900 mg/day.
upper endoscopy revealed epithelial infiltration with ulceration and hemorrhage. Histopathologically, showcased, epithelial cells with enlarged nucleus and intra nuclear inclusion bodies.
Kidney biopsy with H&E and immunofluorescent study features tubular necrosis, infiltration of peritubular capillaries with polymorphonuclear leukocytes.
Immunofluorescent study disclosed capillary deposition of C4D.
Impressions:
CMV infection, denoting CMV resistant infection as, he was already on prophylactic anti -CMV.
C4d deposition in peri-tubular capillaries .
Gastroentritis secondary to CMV infection.
Discussion:
There is a debatable opinion of a combination of CMVN predisposing to ACMR. no report of increasing risk of ABMR in association with CMVN. However its mainly ABMR rather than ACMR .Nevertheless, the recurrence of Anti A antibodies and its interaction and predisposition for C4D deposition might be a indicative of a concomitant accommodation phenomena , as after desensitization protocol at time of transplantation and reduction of anti A antibodies to 1/8 titer there is increasing risk of rebound and drastic ABMR encountered during the first 2 weeks after transplantation and never afterwards, therefore the presence of C4D deposition in peritubular capillaries might be indicative of accommodation only which is reflecting resistance of the allograft to immunologic stimulation. Nevertheless, ABMR can’t be excluded on solid base and we need to investigate for anti HLA DSAs preformed or de novo to fulfil the criteria of ABMR. As far as CMVN eventuated despite being on prophylactic Valgancyclovir then second line therapy has to be implicated, meanwhile testing for Human CMV antiviral resistance is advocated. treatment with Foscarnet for 3 weeks is implemented when resistance to vagancyclovir is detected. Simultaneously, treating the ABMR with plasma pheresis, IVIG, Rituximab and pulse steroid is recommended to tackle both of the apparent underlying etiology.
References:
1] Maritati F et al.Current Perspectives in ABO-Incompatible Kidney Transplant. Journal of Inflammation Research; 25 May 2022 Volume 2022:15 Pages 3095—3103.2] UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION.bts.org.uk
Excellent
====================================================================
Describe the finding.
====================================================================
Risk factors for CMV resistance in HCT recipients
Host factors
Prolonged antiviral CMV drug exposure (>3 mo)
Previous antiviral CMV drug exposure
Recurrent CMV infection
Inadequate antiviral CMV drug absorption and bioavailability
Inadequate antiviral CMV oral prodrug conversion
Variation in antiviral CMV drug clearance
Subtherapeutic antiviral CMV drug level
Poor compliance
T-cell depletion
Haploidentical, allogeneic, and cord blood HCT
Delayed immune reconstitution
In people with suspected resistance to Ganciclovir:
====================================================================
How do you manage the case?
Plan
====================================================================
In people with evidence of ganciclovir resistance: •
Use with Immunosuppressant Drugs
. Treatment of ABMR
====================================================================
Reference
Excellent
Many thanks for you Prof.Halawa
The case is challenging as the treatment of one disease can be against the other, so treatment should base on avoiding risk for patient survival by controlling CMV invasive disease and treating AMR.
CMV infection was proved to increase the antibody and non-antibody mediated rejection, so an effort to keep graft survival by controlling both CMV and AMR.
Treatment of AMR;
Treatment of CMV disease
C4d is present both in AMR and in ABOi condition, and a new diagnosis of C4d -ve AMR has been focused in renal allograft pathology.
So any 2 of the following can diagnose AMR
References
De Keyzer K, Van Laecke S, Peeters P, et al. Human cytomegalovirus and kidney transplantation: a clinician’s update. Am J Kidney Dis. 2011;58:118–126.
2. Taherimahmoudi M, Ahmadi H, Baradaran N, et al. Cytomegalovirus infection and disease following renal transplantation: preliminary report of incidence and potential risk factors. Transplant Proc. 2009;41:2841–2844.
Significance of C4d deposition in antibody-mediated rejectionAsami Takeda 1, Yasuhiro Otsuka, Keiji Horike, Daijo Inaguma, Takahisa Hiramitsu, Takayuki Yamamoto, Koji Nanmoku, Norihiko Goto, Yoshihiko Watarai, Kazuharu Uchida, Kunio Morozumi, Takaaki Kobayashi
I appreciate your comprehensive reply well supported by references.
There is acute tubular injury, and 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 by 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 be a therapeutic regimen. Patients with CMV infection should receive intravenous ganciclovir or oral valganciclovir for a minimum of 14 days until the resolution of symptoms.
Adherence to valacyte should be checked. If patient is compliant to medication, then probably she has medication Refractory CMV disease, which 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
What will you do for AMR? That aspect of management is missing from your reply.
What will you do for AMR? That aspect of management is missing from your reply.
In the current case of ABMR with high isoagglutinin titer, I will do the following after confirmation of the diagnosis of CMV by PCR (blood or tissue)
Reduction of immunosuppression is required ( problematic in this case of ABMR), 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 antimetabolite, Keeping CNI at lower trough around 5-7 ng/ml (do not play with CNI), and close follow up of graft function
Treatment of ABMR with pulse steroids, plasmapheresis (till the titer decrease < 1: 16), and IVIG
Regarding CMV infection, I may give a trial of ganciclovir with appropriate dosing together with reduction of immunosuppression and, if the patient remain symptomatic or there is no reduction of viral load by ≥ 1 log copies /ml after 2 weeks of treatment I will consider ganciclovir resistance and I will switch to alternative therapy such as IV foscarent for 3 weeks under the guidance of virology expert, at that time shifting from MMF to leflunamide may be effective as it has antiviral activity
I am not sure about the utility of leflunamide in this situation, though I am aware of reports of its possible utility.
Findings.
Upper left – Loss of tubular brush border, tubulitis, tubular atrophy.
Upper right – positive C4d staining.
Lower left – gastric erosion and ulceration
Lower right – CMV inclusion bodies, interstitial cellular infiltrates
Treatment of GI CMV Disease
Treatment of antibody mediated rejection
Reference
Carlos AQ et al. Clinical manifestations, diagnosis and management of cytomegalovirus disease in kidney transplant recipient. Up to Date.
Snadesh P et al. Kidney transplantation in adults: Prevention and treatment of antibody-mediated rejection. Up to Date.
I like your detailed summary.
antibody-mediated rejection in kidney transplant recipients a risk factor for developing cytomegalovirus infection
cytomegalovirus (CMV) infections remain one of the most common complications affecting solid organ transplant recipients, conveying higher risks of complications, graft loss, morbidity, and mortality
Refractory or drug-resistant CMV
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
genotype testing should be performed to identify specific resistance mutations. 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.
Antiviral therapies for patients with ganciclovir-resistant or refractory CMV include maribavir, foscarnet, and cidofovir.
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,
C4d deposition
OGD and biopsy
Cytomegalovirus Gastritis
multiple discrete lesions appear
gastric mucosa findings fold thickening, exudates
How do you manage the case?
investigations
serologic markers for HIV, hepatitis A, B, and C viruses
Computed tomography scan of abdomen and pelvis
Antigen detection: Specimens can be stained by specific immunofluorescent antibodies to detect viral antigens or viral DNA – CMV
mangment of cmv infection
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)
mangment of AMR
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.
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
rituximab – If rituximab is given,
administer a single dose of either 200 mg or 375 mg/m2 after completion of plasmapheresis and IVIG
I appreciate your comprehensive reply. I wish you could add references.
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
To confirm diagnosis the following are required:
The most probable diagnosis in this case is resistant CMV infection associated with evidence of AMR
Gancyclovir resistance
Risk factors for gancyclovir resistance
In the current case infection develop in a CMV negative recipient receiving graft from CMV positive donor and occur while receiving prophylactic therapy, so ganciclovir resistance is highly suspected
To confirm diagnosis of gancyclovir resistance one of the following is required
Treatment
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.
A- Adjustment of immunosuppression
B- Treatment of gancyclovir resistant CMV (antiviral therapy)
1- IV Foscarent
2- Combination therapy with reduced doses of ganciclovir and foscarnet
3- Cidofovir
4- leflunamide
C- Regarding ABMR with high of isoagglutinin titers
To conclude the management of the current case (resistant CMV infection associated with evidence of AMR) includes
Well done.
In this patient I may give trial of ganciclovir with appropriate dosing together with reduction of immunosuppression and, if the patient remain symptomatic or there is no reduction of viral load by ≥ 1 log copies /ml after 2 weeks of treatment I will consider ganciclovir resistance and I will switch to alternative therapy
If there is a rejection, it would be AMR rather than ACR
Increases in Anti-A titers above 1/32 associated with C4d+ are suggestive of antibody-mediated rejection, requiring plasmapheresis/Plasma Exchange to decrease titer values.
Peritubular capillaritis, Acute tubular injury, lymphocytic infiltrates.
Immunofluorescence shows positive C4d staining in the peritubular capillaries
CMV infection in spite of being on a prophylactic dose of valganciclovir.
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).
Biopsy showing owl eyes on immunohistochemistry.
Genotypic resistance testing (UL97 mutation & UL54 mutations)
How would you diagnose AMR in case of ABOi transplantation where C4d staining is not diagnostic?
Anti-A titers above 1/32
Desensitized patients should measure DSA and anti-agglutinins regardless of the positivity of C4d. Positivity suggests ABMR and is related to dysfunction and rapid loss of the graft, requiring early therapy.
You need to put a clear strategy for the treatment addressing the 2 pathologies.
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.
Thanks, Filipe
How reliable C4d in this case?
How would you define ganciclovir-resistant CMV?
14 days of Ganciclovir treatment with symptoms and/or positive viral load
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 resistant CMV gastritis
Initial investigation;
-CBC – CRP – LFTS – RFTS
-CMV PCR (pt is high risk)
-DSA (single antigen I,II) R/O anti HLA abs.
-Genotypic resistance testing (UL97 mutation & UL54 mutations).
Management;
-Review by MDTs (Nephrology , ID , GIT , Histopathologist , Clinical pharmacist),
Treatment of ABMR;
-Will not postponed till full coarse of CMV therapy; so starting,
-Plasma pharesis and IVIg,
-IV Pulse steroid,
-Rituximab (may have role)
-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.
-This current case has clear evidence of CMV invasive disease despite on valgaincyclovir and AMR on biopsy, would mandate for Resistance testing.
With evidence of resistance;
-Offer testing for CMV antiviral resistance, UL97 and UL54 gene mutations.
-Check treatment adherence,
-Stop ganciclovir and give Intravenous Foscarnet for at least 3 weeks after specialist virology advice (newer agents Letermovir and Maribavir may be an alternative).
-It is important to note that nephrotoxicity is common when foscarnet is given in combination with cyclosporine or tacrolimus. Electrolyte disturbances are also common with foscarnet.
-Switching the immunosuppressive regimen to one that includes an mTOR inhibitor (eg, sirolimus, everolimus).
-An alternative to foscarnet is cidofovir, but there is less clinical experience with this agent for treating resistant CMV infection, and its use is limited by the potential for severe nephrotoxicity.
-leflunomide can be considered for both potentiates immunosuppression (ABMR) and suppresses CMV reproduction.
-After completion of treatment, continue prophylaxis with 900 mg of valganciclovir once daily for 3-6 months depending on serology status of the recipient.
References;
-UK guidelines on prevention and management of (CMV) infection and disease following SOT;5 Juli 2022.
-McGavin JK, Goa KL. Ganciclovir. An update of its use in the prevention of cytomegalovirus infection and disease in transplant recipients. Drugs 2001;61:1153-83.
This is a repetition
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 ABMR 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.
Thanks, Riham
How would you define ganciclovir-resistant CMV?
(1) a high virus load provides a greater opportunity for selection of resistant mutants
(2) ganciclovir resistance rarely develops after a short duration of exposure to ganciclovir
(3) ganciclovir resistance develops more commonly after exposure to oral versus intravenous ganciclovir
(4) phenotypic laboratory methods may underestimate the true prevalence of resistance.
Ajit P. Limaye. Ganciclovir-Resistant Cytomegalovirus in Organ Transplant Recipients. Clinical Infectious Diseases, Volume 35, Issue 7, 1 October 2002, Pages 866–872.
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-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).
As per Banff classification for diagnosis of active ABMR where in 3 criteria needed to diagnose ABMR:
-Histologic evidence of acute tissue injury: there is evidence of acute tubular injury by kidney biopsy.
– Evidence of current/recent antibody interaction with vascular endothelium which presented by C4d staining in peritubular capillaries by IF.
– Serologic evidence of donor-specific antibodies (DSA to HLA or other antigens like ABO antigens): high isoagglutinin titres.
2-Picture of CMV invasive disease despite prophylactic anti-viral medication? (Valganciclovir dose 900 mg daily is prophylactic dose). 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:
Antiviral therapies for patients with ganciclovir-resistant or refractory CMV include maribavir, foscarnet, and cidofovir.
So what I understood from the current scenario that prolonged reduction of immunosuppression as management of resistant CMV disease has been 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.
Excellent answer Mohamed
Will you consider the current dose this patient receiving as an indication of treatment failure (drug resistance)?
No,that because drug resistant or treatment failure is by definition:persistent or progression of infection despite on appropriate dose of IV ganciclovir.
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
Dear All
I have repeated this scenario due to a lack of understanding of the following:
Confirming the diagnosis of rejection;
-The standard for the diagnosis of renal allograft rejection is a renal allograft biopsy, which is used to accurately grade the severity of rejection, differentiate between T cell-mediated rejection (TCMR) and ABMR, and determine the degree of irreversible kidney damage (interstitial fibrosis/tubular atrophy [IF/TA]).
-Biopsy of the renal allograft can also reveal other causes of renal inflammation and injury, including cytomegalovirus (CMV) disease, BK (polyomavirus) nephropathy, interstitial nephritis, pyelonephritis, de novo or recurrent glomerular disease, and post-transplant lymphoproliferative disease (PTLD).
Active (acute) antibody-mediated rejection;
-ABMR is thought to be caused by the binding of circulating antibodies to donor alloantigens on graft endothelial cells, which results in inflammation, cell damage, and, ultimately, graft dysfunction.
-Such antigens most commonly include human leukocyte antigen (HLA) class I and class II antigens and, in recipients of ABO-incompatible transplants, ABO blood group antigens; other non-major histocompatibility complex (MHC) alloantigens on the endothelium may also be targeted.
-The diagnosis of ABMR requires three components:
●Histologic evidence of acute tissue injury,
●Evidence of antibody interaction with vascular endothelium (eg, C4d staining in peritubular capillaries [PTCs]),
●Serologic evidence of circulating DSAs.
Histologic findings;
-Histologic features of ABMR include capillary endothelial swelling, arteriolar fibrinoid necrosis, fibrin thrombi in glomerular capillaries (GC), and, in severe cases, frank cortical necrosis.
-Severe vasculitis, glomerulitis with neutrophils in the GC and PTCs, fibrin thrombi, fibrinoid necrosis, and interstitial hemorrhage are more commonly seen with ABMR compared with TCMR.
-In some cases, ABMR may present only with evidence of acute tubular necrosis (ATN).
-The presence of linear staining for C4d, a degradation product of the complement pathway that binds covalently to the endothelium, is highly suggestive of ABMR.
References;
-Up To Date; Kidney transplantation in adults: Clinical features and diagnosis of acute renal allograft rejection: Sep 09, 2021.
Thank you, but you did not reflect on the case. How would you treat the index case?
Treatment of ABMR;
-Plasma pharesis and IVIg,
-IV Pulse steroid,
-Rituximab (may have role if resistant ABMR).
Treatment of CMV gastritis ;
-This current case has clear evidence of CMV invasive disease despite on valganciclovir and AMR on biopsy, would mandate for Resistance testing.
-Offer testing for CMV antiviral resistance, UL97 and UL54 gene mutations.
With evidence of resistance;
-Stop valganciclovir or ganciclovir and give Intravenous Foscarnet for at least 3 weeks after specialist virology advice (newer agents Letermovir and Maribavir may be an alternative).
-It is important to note that nephrotoxicity is common when foscarnet is given in combination with cyclosporine or tacrolimus. Electrolyte disturbances are also common with foscarnet.
-An alternative to foscarnet is cidofovir, but there is less clinical experience with this agent for treating resistant CMV infection, and its use is limited by the potential for severe nephrotoxicity.
-leflunomide can be considered for both potentiates immunosuppression (ABMR) and suppresses CMV reproduction.
-After completion of treatment, continue prophylaxis with 900 mg of valganciclovir once daily for 3-6 months depending on serology status of the recipient.
To continue prophylaxis with Valganciclovir will take you back to square 1 as she has resistance.!
noted;Thanks so much
but resistence not confirmed yet; and may be from non adherence to proper dose and proper duration of treatment.
Thankyou for finding a way out but:
Clinically he has been on Valgan. for 2 months (with complience) and ended up with that lesion.
If you perform the genetic mutation study(unlikely).
If he is going to be treated with alternative drugs well and good.
Then what prophylaxis will follow! I personally dont know.
Well done Dr Mohamed Abou Elenein
You referred to ‘After completion of treatment, continue prophylaxis with 900 mg of valganciclovir once daily for 3-6 months depending on serology status of the recipient’
What did you mean by serologic status? What is the difference between IgG + and – cases for prophylaxis? Obviously this dose will also depend on creatinine clearance
Thank Dr Abou Elenein
As prof Halawa mentioned you did not reflect on the case and another point you did not refer to endoscopic findings? What is the relation of this to the case?
Thanks so much; our Prof. Mohsen
Sorry; I had comment on endoscopic findings in the main comment below and I don’t repeat it because of the comment of our Prof Dr. Halawa.
Acute AMR in AIT occurs 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.
Treatment of AMR:
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.
Treatment of AMR is a priority as it is catastrophic, but also because of the presence of CMV. I will reduce the immunosuppressive medication rapidly after PP and start the CMV treatment on the same day as the treatment for rejection.
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 21 days or until 2 results of PCR are negative.
close monitoring of serum creatinine, CMV PCR, and AntiA/B titer.
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.
Cidofovir is an alternate treatment option to foscarnet.
References:
British Transplantation Society Guidelines(Guidelines for Antibody Incompatible Transplantation).
UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION
Typing whole sentence in capitals amounts to shouting.
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?
Resistant CMV & AMR:
1.Lines of management of AMR:
2.Resistant CMV:
First order for CMV PCR & viral genotyping
Possible line of treatments are :
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
I appreciate your comment, “This is a very tricky case because management of either of these condition is opposite the other one”.
Thnxs prof
Treatment of GI CMV Disease
Treatment of antibody mediated rejection
Diagnosis question – Positive DSAs can be used for diagnosis of ABMR if features of tissue injury is present in C4d negative cases. This is because the tissue injury might be mediated by other pathways (such as antibody dependent and cell mediated cytotoxicity) not necessarily complement pathway which classically result in C4d deposition.
Reference
Carlos AQ et al. Clinical manifestations, diagnosis and management of cytomegalovirus disease in kidney transplant recipient. Up to Date.
Snadesh P et al. Kidney transplantation in adults: Prevention and treatment of antibody-mediated rejection. Up to Date.
I appreciate your comprehensive reply well-supported by references.
Do you treat AMR with steroid pulses?
I’m not impressed with this answer
I- Renal biopsy :
LM with H&E stain show no glomeruli or blood vessels , only tubules so its insufficient biopsy. The examined tubules are dilated with vacuolization indicating acute tubular injury .
IF : C4d deposit in peritubular capillaries that are normal finding in ABO I transplantation due to graft accomudation ,but in this index case presence of acute tubular injury together with rising level of anti A IgG and C4d deposit all favour the diagnosis of ABMR. Further confirmation of ABMR could be through increased gene transcript or classifier on renal biopsy.
Diagnosis of ABMRrequires threecriteria
1- Histological evidence of tissue injury
a-Microvascular inflammation in absence of GN
b- Intimal or transmural arteritis.
c-Acute TMA.
d- Acute tubular injury.
2- Evidence of current Ab interaction with vascular endothelium
a- Peritubular C4d linear deposit.
b- Moderate microvascular injury
c- Increase gene transcript expression on biopsy.
3- Serological evidence :
A- DSA
b-C4d staining .
I- OGE :hyperemic mucosa with ulceration consistant with gastritis.
Gastric biopsy : CMV viralinclusion bodies , consistant with tissue invasive CMV tiisue invasion.
This is a case of combined refractory CMV ( as tissue invasion occurred despite being on prophylactic valgancyclovir) and active ABMR.
Treatment :
1- For Refractory CMV
a- Confirm patient compliance to antiviral treatment.
b- Genetic studies to diagnose genetic mutation associated with resistant to valgancyclovir and gancyclovir as UL97 and UL54 mutations.
c- In case of genetic mutation : stop valgancyclovir , shift to foscarnet for at least 3 weeks under expert supervision .
d- Adjuvant antiviral drugs as leflunamide and cidofovir can be tried.
e- Modify IS drugs: stop MMF .
f- Monitor graft function.
2- For ABMR : in presence of associated CMV , the relatively safe options are
a- Pulse steroid.
b- Plasmapharesis followed by IVIG.
I appreciate your comprehensive reply. I wish you could add references.
In the current case of ABMR with high isoagglutinin titer, I will do the following after confirmation of the diagnosis of CMV by PCR (blood or tissue)
I appreciate your comprehensive reply. I wish you could add references.
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
CMV infection in spite of being on a prophylactic dose of valganciclovir
This is very likely to be a case of CMV resistance and it can occur as a result of the following conditions in transplants patient:
In this index case, the most likely cause of CMV resistance may be due to the use of intensive immunosuppressant as a result of ABOi transplantation provided the patient is also adherent to the prophylactic treatment
Diagnosis of AMR in ABOi transplantation where C4d staining is not diagnostic
The following are the cardinal point in diagnosing AMR
A negative C4d staining AMR may be an injury that occurred through a complement-independent mechanism or non-HLA antibodies is responsible for the injury
Treatment of the CMV resistance
This should first be confirmed by offering tests for human CMV antiviral resistance UL97 and UL57 using either whole blood or plasma
Treatment of AMR
References
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:
IV pulse steroid
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.
H&E stain showed; vacuolization of tubules with acute tubular injury, sloughing of tubular cells and peritubular capillaritis .
IHC; showed diffuse linear C4d staining.
OGD showed inflamed mucosa with diffuse erythema. Biopsy revealed a giant cell with a characteristic inclusion body of CMV gastritis.
KTR is a high immunological risk ABOi, CMV mismatch D+/R-
Diagnosis:
-CMV invasive disease ( CMV gastritis) confirmed histologically, despite being on prophylactic Valganciclovir, indicative for CMV resistant disease.
-ABMR ( histologically; AKI, positive C4d staining, and increasing anti-A IgG titer)
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 influence long-term graft survival when coupled with acute rejection.
– Recipients of ABOI kidneys may be at higher risk for infectious complications compared with non-ABOI recipients.
Refractory and resistant CMV:
-It is considered refractory if CMV viral load increases or persist the same after or if there is no resolution/ lack of improvement after at least 2 weeks of appropriately dosed antiviral therapy
– The incidence of ganciclovir‐resistant CMV infection after SOT is 0%‐3%.
– Risk factors are prolonged subtherapeutic dose of antiviral drugs (eg, mini‐dosing), D+/ R− serostatus, intense immunosuppression, and lung transplantation.
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 resistant disease, irrespective of viral load.
CMV- resistance disease;
– Check treatment adherence.
– Offer testing for CMV antiviral resistance, UL97 and UL54 gene mutations.
– Seek specialist virology advice.
-Definitive antiviral treatment should be guided by results of genotypic
– Stop Valganciclovir.
– Some recommend giving a trial of IV ganciclovir appropriate dose before considering alternative options.
– Foscarnet IV for at least 3 weeks till resolution of symptoms as viral load is negative ( monitor electrolytes imbalance and kidney function)
-leflunomide can be considered for both potentiates immunosuppression (ABMR) and suppresses CMV replication.
– Cidofovir ( nephrotoxicity limits its use) off‐label letermovir , Maribavir
– CMV Ig or IVIG may be used as an adjunct to antiviral drugs in transplant recipients with resistant CMV disease (in the setting of rising antibody titer and ABMR)
– The doses should be adjusted to renal function
– Monitor RF, CBC, and LFT is required
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.
– Consider switching to sirolimus‐containing regimen may be an option due to the reportedly lower risk of CMV disease in patients receiving mTOR inhibitors
– 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
– Monitor isoagglutinin titer and renal function
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.
Describe the finding.
How do you manage the case?