QJM Advance Access originally published online on April 29, 2008
QJM 2008 101(7):594-598; doi:10.1093/qjmed/hcn051
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Obstruction or renal allograft rejection—potential clinical markers of BK virus nephropathy
Sir,BK virus (BKV)-associated nephropathy in renal transplant recipients is an emerging cause of allograft dysfunction and transplant loss.1,2 BKV is a human polyomavirus which is a member of the Papovaviridae family. These are non-enveloped viruses of small virion size with a closed, circular double DNA-stranded genome.3 Polyomaviruses are ubiquitous in nature and were first isolated from the urine of a renal transplant patient who developed ureteral stenosis post-operatively.3 Up to 80% of adults are seropositive for BKV with the virus subsequently remaining dormant in the uroepithelium. The majority of primary infections are asymptomatic or minimally symptomatic. The incidence of BKV nephropathy among renal transplant recipients is as high as 5%.1 The majority of infections occur within the first 3 months after transplant; however, infections occurring >2 years after transplantation have been reported.4 BKV disease is associated with haemorrhagic and non-haemorrhagic cystitis, ureteric stenosis and tubulointerstitial nephritis.4 Between 30% and 50% of patients with BKV nephropathy develop progressive renal dysfunction leading to eventual allograft loss.5 The risk factors for BKV are not known but it is suggested to be a disease associated with modern day immunosuppression. Apart from the histopathological likeness to acute rejection and hence misdiagnosis, BKV infection can also manifest as ureteric stenosis during the early post-transplant period.1 Reduction in immunosuppression has yielded varying results and evidence with cidofovir and ciprofloxacin are promising.4–8
Cases
We report two cases of BKV in renal transplant patients to highlight important teaching points in BKV nephropathy. The first patient was treated for ureteric stenosis and was later diagnosed to have BKV nephropathy resulting in graft loss despite the use of cidofovir and the other developed chronic allograft nephropathy (CAN), which stabilized with immunosuppression reduction.
Case 1
A 53-year-old female with end stage kidney disease of uncertain cause received a cadaveric renal transplant from a standard criteria deceased donor in January 2004. Induction therapy was not used and Tacrolimus (0.1 mg/kg b.i.d.) and Mycophenolate mofetil (MMF) (1 g b.i.d.) constituted the immunosuppression regimen. The target tacrolimus trough level for the first 3 months was in the range 10–14 µg/l and after that, 5–10 µg/l. The achieved trough levels in the first 3 months was in the range 10–20 µg/l (median 13 µg/l) and subsequently were in the range of 5–10 µg/l (median 7 µg/l). Fluconazole and cotrimoxazole were used in appropriate doses as fungal and pneumocystis carini prophylaxis, respectively. Cytomegalovirus (CMV) prophylaxis was not given as both the donor and recipient were sero-negative at the time of transplantation.
Graft function was satisfactory with a serum creatinine of 126 µmol/l 2 weeks after the transplant. A week later, the creatinine rose to 266 µmol/l and hydronephrosis of the transplant kidney was demonstrated on sonography (Figure 1).
|
Renal function promptly improved after a nephrostomy was inserted. The JJ stent previously placed intra-operatively over the anastomotic site was removed as it was thought to be blocked. A nephrostogram performed the next day revealed partial obstruction and narrowing of the transplant ureter. The stent was replaced, but a week later the hydronephrosis had recurred and the serum creatinine was 233 µmol/l. At this stage, the transplant ureter was resected and the pelvi-ureteric junction (PUJ) was anastomosed to the urinary bladder with a Boari flap reconstruction. Renal function improved (serum creatinine 107 µmol/l) and repeated scans showed no evidence of obstruction. Nine months after the transplant, the serum creatinine rose to 160 µmol/l and a transplant biopsy was performed. Histological examination showed features suggestive of acute tubulo-interstitial rejection (Banff grade1A), but minor nuclear abnormalities of the tubular epithelial cells were also noted. CMV polymerase chain reaction (PCR) was negative. She was treated with intravenous methylprednisolone and oral steroids were added to the immunosuppressant regimen. Renal function however did not improve and repeat biopsy now showed damaged tubular epithelial cells with enlarged, pleomorphic nuclei showing smudged chromatin patterns (Figure 2), immunohistochemical staining demonstrated positive nuclear staining for BKV (Figure 3). Urine was positive for ‘decoy’ cells and BKV viraemia was demonstrated. MMF was stopped, and the dose of tacrolimus was reduced to maintain a trough level of 4–6 µg/l. Renal function deteriorated despite further reduction in steroid and tacrolimus doses. A third biopsy was performed to exclude rejection. BK nephropathy changes were more prominent and there was no evidence of rejection. BKV PCR of the serum remained positive. She was therefore commenced on intravenous Cidofovir (0.25 µg/kg/dose) with saline prehydration. Two weeks later the serum creatinine had risen to 619 µmol/l and another biopsy showed widespread positivity for BKV on immunohistochemistry and no evidence of rejection. Renal function continued to deteriorate leading to commencement of renal replacement therapy. Cidofovir was discontinued, renal function continued to deteriorate and a transplant nephrectomy was carried out 2 weeks later.
|
|
Case 2
A 73-year-old male with end stage renal disease due to Goodpastures glomerular basement membrane disease received a cadaveric renal transplant from a standard criteria deceased donor in February 2004. Induction therapy was not used and immunosuppression consisted of Tacrolimus (0.1 mg/kg b.i.d.) and MMF (1 g b.i.d.). The target tacrolimus trough levels were as for Case 1. A median trough level of 14 µg/l (range 10–14) was achieved in the first 3 months and subsequently the trough levels were in the range of 6–10 µg/l (median 8 µg/l). Prophylactic fluconazole and cotrimoxazole were again used. CMV prophylaxis was not given as both the donor and recipient were again sero-negative at the time of transplantation. Renal function had stabilized to a serum creatinine of 161 µmol/l a month after the transplant. Two months later an episode of neutropenia coincided with symptoms of viral illness and a high CMV PCR titre. The MMF dose was reduced to 0.5 g b.i.d. and he was treated with intravenous Ganciclovir with a prompt fall in the viral titres. Serum creatinine stabilized at 191 µmol/l.
The serum creatinine was 197 µmol/l in November 2004 and rose steadily to 317 µmol/l in February 2005. A renal biopsy revealed immunohistochemical nuclear positivity for BKV within tubular epithelial cells, which was confirmed by ultra-structural demonstration of the characteristic viral particles (Figure 4). MMF was stopped and Tacrolimus dose was reduced to maintain levels of 4–6 µg/l. The creatinine peaked at 403 µmol/l and dropped to 361 µmol/l a month later and has since been stable.
|
Discussion
The increasing frequency of BKV in renal transplants since the first case diagnosed in 2001 perhaps still remains under recognized. These cases highlight the clinical spectrum of BKV and aspects of diagnosis and potential treatment of renal transplant BKV infection. These cases are a timely reminder of a potentially growing epidemic in the era of modern immunosuppressant therapy.
The diagnosis of BKV nephropathy hinges on the histology but urine cytology and BK viral PCR of the urine and serum each have a role to play in possible ‘pre-emptive’ diagnosis. Recently, PCR testing of plasma samples obtained from recipients of renal allograft transplants has proven to be a sensitive (100%) and specific (88%) means to determine BKV–associated nephropathy9 in addition to biopsy confirmation. This stems from the observation that persistence of ‘decoy’ cells in the urine in large numbers after 3 months post-transplant and BK viraemia indicate reactivation and active replication of the virus in the renal epithelium.10–12 Intense immunosuppression as in the current anti-rejection regimes facilitates the reactivation and replication of the BKV already present in the renal tubules. There has been considerable debate about the influence of the induction agent on the incidence of BKV nephropathy but a large series reported recently by Khamash et al.13 found that the use and type of induction agent were not linked to the risk of developing BKV nephropathy. These investigators performed surveillance biopsies in 1027 kidney transplant recipients and detected 74 grafts with BKV nephropathy over a median follow-up period of 30 months. Female gender and older age were risk factors for development of BKV nephropathy. The type of induction agent, Tacrolimus vs. sirolimus, the number of HLA mismatches and the frequency of acute rejection were not linked with a higher incidence of BKV disease. Up to 30% of renal transplant patients shed ‘decoy’ cells in the urine in the first 3 months. Rupture of infected tubular cells and migration of the virus into tubular capillaries results in viraemia. Though acute rejection is hypothesized to facilitate viral migration by causing tubular injury, rejection has not been found to be a risk factor in the largest series of BKV Nephropathy studied.1 However, tubulointerstitial changes due to BKV in the absence of prominent cytopathic effects could resemble acute rejection prompting further immunosuppression thus facilitating viral replication. The use of the various diagnostic tests for BKV nehropathy such as urine cytology for decoy cells, urine PCR for BK viruria and serum PCR for BK viraemia and their correlation with histological proven disease has been investigated in recent years.10–12,14 When urine cytology was compared with PCR15 it was found that decoy cells had a sensitivity of 42% and a negative predictive value of 83% as a marker of BK viruria while urine PCR had 100% specificity and positive predictive value. False negative results are found in samples with low viral load, sub-optimal cellularity and vaginal contamination. Therefore urine cytology has a lower sensitivity than PCR and cannot distinguish between BK and JC virus.
Drachenberg et al.16 followed 349 patients over 27 months with concurrent evaluation of urine cytology, urine PCR and viral load in blood and correlated each with the histological diagnosis of BKV nephropathy. The urine tests were both useful for screening purposes but the authors felt that it was not necessary to perform the tests simultaneously other than for the purpose of distinguishing JC virus from BKV by urine PCR. Also, the quantitative estimation of viral load in blood did not add to the diagnostic capability in the absence of viruria. On the other hand, BK viraemia in titres of >10 000 copies/ml is in itself a marker of BKV nephropathy.11 Hence, it is recommended that screening for decoy cells should be performed in all renal transplant recipients every 3 months during the first 2 years after transplantation and annually for the following 3 years, as well as in those patients who develop allograft dysfunction.17 A positive screening result should be followed by a quantitative PCR for BKV DNA in plasma. If this test is positive, a renal biopsy is indicated.
BK viraemia correlates well with viral replication and nephropathy and thus is a useful diagnostic and monitoring tool7,10,14 but only 
50% of patients with viraemia have histological changes.14 The cut off point for the viral count in the serum has been difficult to ascertain but protocols for surveillance biopsies such as the one followed in The University of Maryland Hospital (C.B. Drachenberg) have used 10 000 copies/ml as the level triggering a renal biopsy.12 Falling BKV titres in the serum certainly correlate with histological resolution in treated cases.7,11
BKV infection is not commonly considered in the differential diagnosis of ureteric stenosis in the early post-transplant period though the incidence was as high as 8.9% in the largest series of BKV nephropathy reported.1 Our first patient most likely had ureteric stricture due to reactivation of BKV in the graft 6 weeks after the transplantation though ureteric tissue is not available for confirmation. BKV infection could have been diagnosed at that early stage if quantitative viral studies for BKV in the blood and the urine had been carried out. Serial viral load assessment was not possible in these cases as quantitative estimation was not available. However one would expect with treatment to see a rapid fall in viral load with the initiation of treatment or therapeutic interventions. Others have demonstrated this when immunosuppression is reduced.11 Reducing the dose of immunosuppressive therapy has currently been the best approach in treating BKV in transplant recipients.1,18 BKV–induced allograft nephropathy may be more common in patients who are treated with certain immunosuppressive regimens. Some supportive evidence exists for an association with tacrolimus13,19,20 and MMF,21 although prospective data are lacking to corroborate these findings.
Cidofovir, at reduced doses (10–20% of the recommended dose) has been reported as being effective in clearing the virus from the blood and renal parenchyma in BKV nephropathy with resulting improvement in the renal function.4–8,18 Our first patient did not respond to reduction in immunosuppression and subsequent cidofovir. Leflunomide, an immunosuppressant commonly used in rheumatoid arthritis has been tried in BKV nephropathy22 in a dose of 100 mg/day for 5 days then 20–60 mg/day aiming for levels of 40–50 µg/ml. However the persistence of cytopathic affects in repeat biopsy usually carries a poor prognosis of graft survival. More recently use of ciprofloxacin has shown some promise for virus eradication.23
In conclusion, the rising incidence of BKV nephropathy and its impact on graft survival highlights the importance of a low threshold for diagnostic tests for the virus in all renal transplant patients. A steadily increasing creatinine with rejection like changes on the biopsy should alert the clinician to this possibility. Ureteric stenosis in the early post-transplant period is an uncommon but important manifestation of this condition. Evidence for the use of antiviral and antibiotic agents is limited and requires further study and studies examining a diagnostic schema for early detection of this condition are needed.
Conflict of interest: None declared.
Department of Renal Medicine
Consultant Nephrologist/Honorary Clinical Reader
Hull and East Yorkshire Hospitals
NHS Trust and Hull York Medical School
email: Sunil.bhandari{at}hey.nhs.uk
Department of Pathology
Hull and East Yorkshire Hospitals NHS Trust
Hull Royal Infirmary
Kingston upon Hull
HU32JZ, UK
References
1. Ramos E, Drachenberg CB, Papadimitriou JC, Hamze O, Fink JC, Klassen DK, et al. Clinical course of polyoma virus nephropathy in 67 renal transplant patients. J Am Soc Nephrol (2002) 13:2145–51.
2. Mylonakis E, Goes N, Rubin RH, Cosimi AB, Colvin RB, Fishman JA. BK virus in solid organ transplant recipients: an emerging syndrome. Transplantation (2001) 72:1586–92.
3. Demeter LM. JC, BK and other polyomaviruses; progressive multifocal leukoencephalopathy. In: Mandell, Douglas and Bennett's Principles and Practice of Infectious Diseases.—Mandell GL, Bennett JE, Dolin, eds. (1995) 2, 24th. New York, NY: Churchill Livingstone. 1400–6.
4. Bjorang O, Tveitan H, Midtvedt K, Broch LU, Scott H, Andersen PA. Treatment of polyoma virus infection with cidofovir in a renal transplant recipient. Nephrol Dial Transplant (2002) 17:2023–5.
5. Keller LS, Peh CA, Nolan J, Bannister KM, Clarkson AR, Faull RJ. BK transplant nephropathy successfully treated with cidofovir. Nephol Dial Transplant (2003) 18:1013–4.
6. Lim WH, Mathew TH, Cooper JE, Bowden S, Russ GR. Use of cidofovir in polyoma virus BK viral nephropathy in two renal allograft recipients. Nephrology (2003) 8:318–23.[CrossRef][Medline]
7. Vats A, Shapiro R, Randhawa P, Scantleburg V, Tuzuner A, Saxena M, et al. Quantitative viral load monitoring and cidofovir therapy for the management of BK virus-associated nephropathy in children and adults. Transplantation (2003) 75:105–12.[CrossRef][Web of Science][Medline]
8. Kadambi PV, Josephson MA, Williams J, Corey L, Jerome KR, Meehan SM, et al. Treatment of refractory BK virus associated nephropathy with cidofovir. Am J Transplant (2003) 3:186–91.[CrossRef][Web of Science][Medline]
9. Nickeleit V, Klimkait T, Binet IF, Dalquen P, Delzenero V, Thiel G, et al. Testing for polyomavirus type BK DNA in plasma to identify renal-allograft recipients with viral nephropathy. N Engl J Med (2000) 342:1309–15.
10. Limaye AP, Jerome KR, Davis CL, Ferrenberg J, Huang ML, Davis CL, et al. Quantification of BK virus load in serum for the diagnosis of BK virus-associated nephropathy in renal transplant recipients. J Infect Dis (2001) 183:1669–72.[CrossRef][Web of Science][Medline]
11. Randhawa P, Andrew H, Shapiro R, Vats A, Swalsky P, Finkelstein S, et al. Correlates of quantitative measurement of BKV DNA with clinical course of BKV infection in renal transplant patients. J Clin Microbiol (2004) 42:1176–80.
12. Drachenberg RC, Drachenberg CB, Papadimitriou JC, Ramos E, Fink JC, Wali R, et al. Morphological spectrum of polyoma virus disease in renal allografts. Diagnostic accuracy of urine cytology. Am J Transpant (2001) 1:373–81.
13. Khamash HA, Wadei HM, Mahale AS, Larson TS, Stegall MD, Cosio FG, et al. Polyomavirus-associated nephropathy risk in kidney transplants: the influence of recipient age and donor gender. Kidney Int (2007) 71:1302–9.[CrossRef][Web of Science][Medline]
14. Hirsch HH, Knowles W, Dickenmann M, Passweg J, Klimkait T, Mihatsch MJ, et al. Prospective study of polyoma virus type BK replication and nephropathy in renal transplant recipients. N Engl J Med (2002) 347:488–96.
15. Randhawa P, Vats A, Shapiro R. Monitoring for polyomavirus BK and JC in urine: comparison of quantitative polymerase chain reaction with urine cytology. Transplantation (2005) 79:984–6.[CrossRef][Web of Science][Medline]
16. Drachenberg C, Hirsh HH, Papadimitriou JC, Mozafari P, Wali R, McKinney JD, et al. Cost efficiency in the prospective diagnosis and follow-up of polyoma virus allograft nephropathy. Transplantation Proc (2004) 36:3028–31.[CrossRef][Web of Science][Medline]
17. Blanckaert K, De Vriese A. Current recommendations for diagnosis and management of polyoma BK virus nephropathy in renal transplant recipients. Nephrol Dial Transplant (2006) 21:3364–7.
18. Hirsch HH, Brennan DC, Drachenberg CB, Ginevri F, Gordon J, Limaye AP, et al. Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation (2005) 79:1277–86.[CrossRef][Web of Science][Medline]
19. Nickeleit V, Hirsch HH, Binet IF, Gudat F, Prince O, Dalquen P, et al. Polyomavirus infection of renal allograft recipients: from latent infection to manifest disease. J Am Soc Nephrol (1999) 10:1080–9.
20. Binet IF, Nickeleit V, Hirsch HH, Prince O, Dalquen P, Gudat F, et al. Polyoma virus disease under new immunosuppressive drugs: a cause of renal graft dysfunction and graft loss. Transplantation (1999) 67:918–22.[CrossRef][Web of Science][Medline]
21. Howell DN, Smith SR, Butterly DW, Klassen PS, Krigman HR, Burchette JL, et al. Diagnosis and management of BK polyomavirus interstitial nephritis in renal transplant recipients. Transplantation (1999) 68:1279–88.[CrossRef][Web of Science][Medline]
22. Josephson MA, Gillen D, Javaid B, Kadambi PV, Meehan S, Foster P, et al. Treatment of renal allograft polyoma BK virus infection with Leflunomide. Transplanation (2006) 81:704–10.[CrossRef]
23. Ramos E. Treatment – which works and what doesn't. In: Symposium at American Transplant Congress. (2007) (Communication).
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||