The First Case of Jc Virus Allograft Nephropathy

There are two known human polyomaviruses: BK virus (BKV) and JC virus (JCV). BKV-induced nephropathy is well defined and JCV is considered the etiologic agent of progressive multifocal leukoencephalopathy. A 37-year-old man with chronic renal failure caused by malformative uropathy first underwent transplantation in August 1991. He presented acute rejection refractory to treatment and returned on hemodialysis in 1993. A second renal transplantation was performed in June 1994. He received antithymocyte globulin, cyclosporine A, azathioprine, and prednisone. In June 1995, he presented severe distal ureteral stenosis with graft hydronephrosis necessitating ureterovesical reimplantation. In August 1995, his graft function deteriorated rapidly. Renal biopsy showed nonspecific mild tubulointerstitial lesions. In 1998, he presented a new episode of deterioration of renal function. Renal biopsy revealed severe chronic tubulointerstitial lesions without any evidence of viral infection. Decoy cells were present in urine, but polymerase chain reaction (PCR)-based analysis of BKV in serum was negative. We decided to replace azathioprine with mycophenolate mofetil and reduce the dose of cyclosporine A to decrease the risk of cyclosporine A nephrotoxicity. The third episode of allograft dysfunction occurred in August 2000, with a serum creatinine level increasing to over 300 μmol/L. Decoy cells were always present in the urine. Renal biopsy disclosed inflammatory lesions in the medulla associated with epithelial cells containing intranuclear inclusion bodies, which were partially shed into tubular lumens and produced several focal desquamative necrotic lesions (Fig. 1). The histologic aspect was consistent with polyomavirus interstitial nephritis. However, PCR assay of DNA remained negative for BKV in serum. Figure 1: Allograft biopsy. Inflammatory interstitial lesions: peritubular lymphocytic infiltrate associated with focal tubular atrophy and dystrophic epithelial cells showing enlarged irregular nuclei and intranuclear inclusion bodies (hematoxylin-erythrocin-safran; magnification ×250).The histologic specimens were sent to expert pathologists who confirmed the diagnosis of polyomavirus-induced nephritis. Analysis of the allograft by in situ hybridization confirmed the presence of JCV and the absence of BKV (Fig. 2). For this analysis, neutral formalin-fixed tissue sections were treated with 0.04% proteinase K solution (DAKO Corp., Carpinteria, CA) for 8 min at room temperature. A solution of 1 μg/mL biotinylated DNA probe JCV or BKV (DAKO) was applied and the slides were placed for 5 min onto a hot plate at 94°C and then incubated overnight in a humidified chamber at 37°C. An avidin-alkaline phosphatase complex (Biomeda Corp., Foster City, CA) was applied for 20 min at room temperature followed by Fast Red (Roche Diagnostics, Mannheim, Germany) as chromogen. Control slides were done by replacement of specific probe with hybridization buffer only. For positive controls, we used paraffin-embedded cell pellets containing approximately 20% positive cells for SV40 virus. Figure 2: In situ hybridization with JCV probe in allograft biopsy specimen. Intense red coloration of some desquamating tubular cells revealing the presence of viral nucleic acid (Avidin-Alkaline Phosphatase complex-fast red; magnification ×400).PCR assay for JCV DNA in serum was shown also to be positive. For PCR analysis of DNA extracted from serum, we amplified a short sequence located in the large T-antigen gene of the JCV and BKV. PCR products were identified by a colorimetric immunoassay (Hybridowell Universel, Argene-Biosoft, France) with two biotinylated probes, respectively, specific for JCV and BKV (1). PCR products were also digested with Bam HI, run on agarose gel, and visualized after ethidium bromide staining by exposure to ultraviolet light. Therefore, the 173-base pair (bp) JCV sequence was cut once in fragments of 120 and 53 bp, and the 178-bp BKV sequence was not cut. Evolution of histobiologic markers is summarized in Table 1. We concluded that our patient presented allograft nephropathy caused by polyomavirus type JCV and decided to minimize immunosuppression by stopping mycophenolate mofetil and continuing cyclosporine A and prednisone at a lower dosage. He presented no symptoms or signs of neurologic involvement. After 26 months, graft function continues to deteriorate slowly, with a serum creatinine level of approximately 400 μmol/L.Table 1: Histobiologic markers of PVNJCV is detectable in a subset of allograft kidneys with established BKV nephropathy (2). However, the role of JCV as an independent etiologic agent of renal allograft dysfunction remains unclear (3). In this patient, the third biopsy revealed the characteristic histologic findings consistent with polyomavirus nephropathy. The decoy cells were present in the urine several months before the biopsy. The clinical course was also consistent with this diagnosis. In addition, he presented ureteral stenosis, a known complication of BKV infection (4). However, there were no signs of BKV replication in allograft or serum, confirmed by negative in situ hybridization and PCR assay of DNA, respectively. In contrast to BKV, biologic markers confirmed the presence of JCV in allograft and in serum. As far as we know, this is the first case of polyomavirus nephropathy in which JCV is the only agent present in the allograft and there exist no biologic signs of BKV concurrent infection. Amir Kazory Didier Ducloux Jean-Marc Chalopin Régis Angonin Bernard Fontanière Hélène Moret