|Year : 2017 | Volume
| Issue : 4 | Page : 204-207
Coinfection of BK virus and cytomegalovirus in renal transplant recipients
Rudreshwar Prabakaran1, Georgi Abraham1, Milly Mathew1, Rajeevalochana Parthasarathy1, Priyanka Koshy2, Anusha Rohit3
1 Department of Nephrology, Institute of Kidney Diseases, Urology and Organ Transplantation, Madras Medical Mission, Chennai, Tamil Nadu, India
2 Department of Pathology, Institute of Kidney Diseases, Urology and Organ Transplantation, Madras Medical Mission, Chennai, Tamil Nadu, India
3 Department of Microbiology, Institute of Kidney Diseases, Urology and Organ Transplantation, Madras Medical Mission, Chennai, Tamil Nadu, India
|Date of Web Publication||28-Dec-2017|
Institute of Kidney Diseases, Urology and Organ Transplantation, Madras Medical Mission, Chennai - 600 037, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Viral infections are common opportunistic infections in renal transplant recipients which can cause allograft dysfunction and are often a major cause of graft dysfunction in the South Asian region. Cytomegalovirus (CMV) and BK viral infections are often seen in the early and late posttransplant periods, respectively. Coinfection of both these viruses is rare and hence early diagnosis is the key to prevent graft loss. We present the cases of two male renal transplant recipients with CMV and BKV coinfection with diverse outcomes.
Keywords: Allograft dysfunction, BK virus, cytomegalovirus
|How to cite this article:|
Prabakaran R, Abraham G, Mathew M, Parthasarathy R, Koshy P, Rohit A. Coinfection of BK virus and cytomegalovirus in renal transplant recipients. Indian J Transplant 2017;11:204-7
|How to cite this URL:|
Prabakaran R, Abraham G, Mathew M, Parthasarathy R, Koshy P, Rohit A. Coinfection of BK virus and cytomegalovirus in renal transplant recipients. Indian J Transplant [serial online] 2017 [cited 2022 Sep 25];11:204-7. Available from: https://www.ijtonline.in/text.asp?2017/11/4/204/221855
| Introduction|| |
Cytomegalovirus (CMV) and BK polyoma virus (BKV) are ubiquitous infections in childhood which remain dormant and may get reactivated in organ transplant recipients. These infections can coexist, mimic, or cause immunomodulation, which may result in graft rejection., Definitive treatment is available for CMV but not for BK virus infection. BKV nephritis in patients with coexisting systemic CMV infection is very rare.,, We report the cases of two patients who presented with systemic CMV disease and associated BK virus nephropathy (BKVAN) leading to graft dysfunction.
| Case Reports|| |
A gentleman aged 21 years, nondiabetic, normotensive, a recipient of living-related kidney transplant (inducted with single-dose thymoglobulin 50 mg 4 years ago with baseline serum creatinine of 1.1 mg/dl) on triple immunosuppression with tacrolimus, sirolimus, and prednisolone, presented with persistent diarrhea, vomiting, and intermittent fever with chills for 10 days. He complained of significant weight loss. His CMV status pretransplant was D+R+. He had received CMV prophylaxis with oral valganciclovir for 3 months' posttransplant.
On admission, his hemoglobin was 11.8 g%, and other cell counts were normal. His serum urea was 30 mg/dl and creatinine was 3.3 mg/dl. Urine analysis showed 1+ albumin and no active sediments. Given acute graft dysfunction, renal allograft biopsy was done which showed 16 glomeruli, 4 of which were globally sclerosed. Viable glomeruli showed an increase in mesangial cellularity with segmental sclerosis seen in two glomeruli. Patchy interstitial fibrosis and tubular atrophy (IFTA) involved 25%–30% of the core. Fibrous intimal proliferation of the arteries was seen. Tubulitis and crescents were absent. Tubular epithelial cells showed nuclear inclusions which were suggestive of BKV infection [Figure 1]. Immunofluorescence revealed 3+ staining of IgA and 2+ staining for C3 in the mesangium, which was suggestive of IgA nephropathy, CD4 was negative. Immunohistochemistry of the biopsy was positive for SV40 staining and Decoy cells were found in the urine BKVAN. Quantitative real-time polymerase chain reaction (PCR) for BK virus in the blood was 2000 copies/ml.
|Figure 1: Black arrow showing BK polyoma viral inclusion in the renal tubular epithelial cell (PAS, ×200)|
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Immunosuppression was tapered gradually and the tacrolimus was stopped and low-dose prednisolone was continued.
The patient continued to have diarrhea and vomiting in view of which an upper gastrointestinal (GI) endoscopy was done which showed edematous duodenal mucosa. Antral mucosal biopsy was done which revealed CMV inclusion bodies [Figure 2].
|Figure 2: Nuclear positivity in the endothelial cells of gastric antral mucosa (immunohistochemistry – anti CMV, ×200)|
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Quantitative real-time DNA PCR in the blood for CMV  and HIV serology was negative. In view of tissue-invasive CMV disease, the patient was initiated on renal dose-adjusted oral valganciclovir for 21 days and other supportive therapies.
Three days later, the patient developed acute respiratory distress syndrome. Bronchoscopy and lavage specimen showed heavy growth of Pseudomonas aeruginosa for which intravenous (IV) carbapenem was given with which he improved. The patient's serum creatinine gradually decreased to 1.6 mg/dl after 1 month and was discharged. He was continued on valganciclovir for additional 3 months as a secondary prophylaxis.
Two years later, he presented with worsening of graft function with serum creatinine of 4.62 mg/dl. Repeat allograft renal biopsy was done which showed 15 glomeruli, of which five showed global glomerulosclerosis, moderate IFTA, and moderate arteriosclerosis [Table 1]. Anti-CMV and SV40 stains were negative. At present, the patient has chronic allograft dysfunction and is awaiting a second transplant.
A 36-year-old male had a live unrelated renal transplantation and was inducted with basiliximab. CMV status pretransplant was not known and he was on triple immunosuppression with prednisolone, sodium salt of mycophenolate mofetil, and tacrolimus, with a baseline serum creatinine of 1.1 mg/dl. Three months later, he developed Varicella zoster infection for which he was treated with IV acyclovir for a fortnight. Later, 5 months' posttransplant, he presented with the complaints of vomiting, oral thrush, anemia, and a serum creatinine of 3.5 mg/dl. Allograft biopsy was done which showed features of acute tubular necrosis, was negative for viral inclusions, and had no features of rejection. In view of persistent severe nausea and vomiting, upper GI endoscopy was done which revealed few curdy white adherent plaques and irregular-shaped superficial ulcers with hazy margin and base overlaid with exudates noted in the upper esophagus. The antrum had prominent mucosal folds with surface erythema and erosions. Esophageal and antral mucosal biopsy was done which showed ulcers with CMV inclusions [Figure 3]. CMV DNA viral load in the blood was 57,000 copies/ml by quantitative real-time PCR. Fungal staining and culture of the esophageal plaques revealed Candida albicans which was treated with oral fluconazole for 2 weeks.
|Figure 3: Numerous cytomegalovirus inclusions within the endothelial cells in the esophagus biopsy (H and E, ×200)|
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In view of tissue-invasive CMV disease, immunosuppression was tapered. IV ganciclovir was given for 3 weeks till subsequent testing for CMV DNA by real-time quantitative PCR was undetectable. His allograft function improved and serum creatinine reduced to 1.2 mg/dl. Secondary prophylaxis with valganciclovir was continued for 3 months. The patient was discharged on double immunosuppression with prednisone and tacrolimus. After a month, he presented again with graft dysfunction (serum creatinine: 3 mg/dl) for which second allograft biopsy was performed after ruling out pre- and postrenal causes of acute kidney injury. It showed features of acute cellular rejection (Type IA), and CD4 staining was negative. There was IFTA [Table 1]. Immunohistochemistry of the graft biopsy revealed strong SV40 positivity, suggestive of BKV nephropathy [Figure 4]. Anti-CMV staining was negative.
|Figure 4: Nuclear positivity for BK polyoma virus in the renal tubular epithelial cells (immunohistochemistry – SV40, ×200)|
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Real-time quantitative PCR for BK virus in the blood showed 4690 copies/ml. In view of BKVAN, oral leflunomide was started and steroid was continued at a tapering dose, and tacrolimus was switched over to low-dose cyclosporine. Serum creatinine gradually improved and remained stable at 2 mg/dl.
| Discussion|| |
CMV manifests most commonly within 100 days of renal transplant and BK virus infection in the first year of renal transplant. The effect of viruses on renal allograft can range from a direct cytopathic effect to indirect effects such as rejection, oncogenesis, and augmentation of immunosuppression as demonstrated in both our cases in whom both CMV and BKV could have predisposed to graft dysfunction and fungal and bacterial infection.
Both our patients had GI and renal manifestations of CMV disease. Probable risk factors in our patients could have been increased immunosuppression and unknown CMV status in the second patient.
The gold standard for the diagnosis of CMV tissue-invasive disease is identification of CMV inclusions or CMV-specific immunohistochemistry staining on histopathology. Negative blood PCR does not rule out tissue-invasive disease.
Invasive disease should be initially treated with IV ganciclovir. Oral valganciclovir can be used for a minimum of 21 days in patients with mild or asymptomatic infection. Patients should be monitored with weekly CMV PCR for 4 weeks after the CMV PCR becomes undetectable. We could not do weekly CMV PCR for our patients due to financial constraints. Treatment must be continued for 1 month after the CMV PCR becomes undetectable. Secondary prophylaxis is recommended for a duration of 3 months after the initial therapy in patients with high risk of recurrence such as donor positive/recipient negative or in HLA-DR mismatches.
BK polyoma infection occurs in 15% of recipients with allograft failure in 15%–50% of affected individuals.,,
Renal allograft biopsy is the gold standard test for BK virus nephropathy. Biopsy is indicated if the plasma BK virus load is >104 copies/ml with or without an elevated serum creatinine.
Our second case could be easily misdiagnosed as an episode of acute cellular rejection in the posttransplant setting since both cellular rejection and BK virus nephropathy share many similar histopathological features.
Reduction of immunosuppression is the mainstay for BK virus nephropathy treatment which can involve discontinuing the antimetabolites or reducing the dose of calcineurin inhibitors by 25%-50%. Other alternative treatment strategies include IV immunoglobulin (IVIG), leflunomide, cidofovir, and rapamycin.
Case reports of renal allograft patients having BK virus nephritis with CMV coinfection affecting other systems such as GI tract have been rarely reported.,, Proposed mechanisms for coinfection include CMV-induced polyoma virus amplification, DNA replication,, and BK virus large T antigen enhancing the expression of immediate early and early genes. All renal transplant patients presenting with recurrent infections should be screened for the presence of CMV and BK virus in the blood or in the relevant biopsy specimens. High level of suspicion of CMV and BKV is needed in all cases of renal allograft dysfunction with known risk factors to both viruses since early treatment and avoidance of excessive immunosuppression can prevent permanent graft loss, especially in a resource-poor setting where the cost of recurrent hospitalization is high and the availability of advanced diagnostic modalities is low.
| Conclusion|| |
Clinicians are often tempted to increase immunosuppression when an allograft biopsy shows features of acute cellular rejection. While such measures can prevent graft loss, increasing immunosuppression can also lead to permanent graft dysfunction. Measures to rule out viral causes of graft dysfunction which mimic cellular rejection in light microscopy such as immunohistochemistry for SV40 can prevent overzealous use of immunosuppression and permanent graft dysfunction.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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