Polyomavirus Interstitial Nephritis Research Articles

Urinary HLA-DR and CD54 expression—indicators for inflammatory activity in decoy cell shedding patients

Polyomavirus (PV) nephropathy may coexist with or follow acute renal transplant rejection. The aim of this study was to evaluate whether HLA-DR and CD54 are useful cellular markers for surveillance of acute rejection in PV-infected patients. A prospective study was conducted using 205 renal transplant patients. Urine samples were collected at a regular interval post-transplantation for routine cytology and immunocytochemistry. Urinary levels of tumour necrosis factor alpha, soluble interleukin-2 receptor and interleukin-6 were used as adjunctive markers for acute rejection. Of the 699 total samples, decoy cells were identified in 100 samples of 50 patients. Patients with decoy cell-positive (DCP) samples had higher serum creatinine levels than decoy cell-negative (DCN) samples (1.55 vs 1.41 mg/dl, respectively; P = 0.006). DCP samples were also more likely to be HLA-DR positive (50.0 vs 32.4%; P = 0.029), as well as CD54 positive (17.4 vs 6.9%; P = 0.038). However, serum creatinine levels did not correlate with HLA-DR or CD54 positivity among DCP samples. Instead, CD54 positivity correlated with decoy cell grades. Immunosuppression decreased in 11 DCP patients, and HLA-DR was negatively converted in three of them. None of the patients developed acute clinical rejection. Urinary cytokine levels did not correlate with serum creatinine levels, nor did they correlate with HLA-DR or CD54 status among DCP patients. Urinary tubular HLA-DR and CD54 expression increased in decoy cell shedding patients but did not indicate a concomitant acute rejection. These markers may instead indicate renal inflammatory activity associated with viral reactivation, which has the potential to progress to PV interstitial nephritis.

Polyomavirus interstitial nephritis and concurrent post-transplant lymphoma in a renal allograft: coincidence or more?

We describe a case of an Epstein-Barr virus (EBV)-negative post-transplant large B-cell non-Hodgkin lymphoma located in the renal allograft, spleen, liver and left inguinal lymph node of a renal recipient and accompanied by a simultaneous polyomavirus-associated nephropathy. To our knowledge, this is the first report of a simultaneous polyomavirus infection and post-transplant lymphoproliferative disorder.

Conversion to sirolimus-based maintenance immunosuppression using daclizumab bridge therapy in renal transplant recipients.

Conversion from calcineurin inhibitor (CI)-based maintenance immunosuppression to sirolimus (SRL)-based immunosuppression may be beneficial in selected renal transplant recipients. The purpose of this study was to evaluate the safety and efficacy of a daclizumab (DAC) bridge protocol in patients converted from CI- to SRL-based maintenance immunosuppression. We conducted a retrospective chart review of renal transplant recipients who were converted to SRL at least 2 months post-transplant. The protocol consisted of an abrupt discontinuation of either cyclosporin (CsA) or tacrolimus (TAC), initiation of SRL within 48 h of CI discontinuation, and DAC 2 mg/kg at the time of CI discontinuation and again at 14 d (depending on the SRL serum concentration). The SRL starting dose was based on risk stratification in each patient. Twenty-one renal transplant patients were converted to SRL (11 from TAC, 10 from CsA) between October 2001 and July 2003. Conversion occurred at a mean of 23 months post-transplant. Indications for SRL conversion included 12 for chronic allograft nephropathy (CAN), four for CI-associated neurotoxicity, two for thrombotic microangiopathy (TMA), two for post-transplant diabetes mellitus (PTDM), and one for polyomavirus interstitial nephritis (PVN). Mean follow-up was 16 months from time of conversion. Therapeutic SRL levels were reached at a mean of 14 d. Total serum cholesterol levels increased from a mean of 205 (+/- 47) to 234 (+/- 55) mg/dL (P = 0.014), and serum triglyceride levels increased from a mean of 186 (+/- 66) to 257 (+/- 88) mg/dL (P = 0.002). In addition, mean haemoglobin level decreased from 12.0 (+/- 2.3) to 10.5 (+/- 2.1) g/dL (P = 0.002); total white blood cell count decreased from 8300 (+/- 4300) to 4700 (+/- 1400)/mm(3) (P < 0.001); and platelet count decreased from 238 000 (+/- 72 800) to 186 000 (+/- 51 900)/mm(3) (P = 0.002) from before to after conversion. Patients experienced the following side-effects while taking SRL: diarrhoea (n = 6), peripheral oedema (n = 5), arthralgias (n = 4), anaemia (n = 4), oral ulcers (n = 1), deep vein thrombosis (n = 1), shortness of breath (n = 1), and mild increase in serum transaminases (n = 1). Two patients (9.5%) discontinued SRL due to side-effects, both secondary to severe arthralgias. There were two serious infections noted after conversion: one Pseudomonas aeruginosa urosepsis, and one PVN (that was ongoing prior to conversion). Patient survival was 100%, and kidney graft survival was 76%. Five patients (24%) lost their allograft after conversion due to progression of CAN (n = 2), persistent TMA in the kidney (n = 1), patient self-discontinuation of sirolimus (n = 1), and preexisting PVN unresponsive to cidofovir therapy (n = 1). Of the five patients who lost their allograft, the mean serum creatinine at the time of conversion was 3.5 (+/-1.1) mg/dL compared with 2.2 (+/- 0.8) mg/dL in patients who did not lose their allograft (P = 0.034). No acute rejection episodes occurred after conversion to sirolimus. DAC bridge therapy provides safe and effective immunosuppressive coverage while converting renal transplant recipients from CI- to SRL-based maintenance immunosuppressive therapy. A pharmacoeconomic analysis, however, is necessary to determine the cost-effectiveness of this conversion protocol.

BK Polyomavirus Interstitial Nephritis in a Renal Allograft Recipient

Human polyomavirus (PV) interstitial nephritis has recently been recognized as a cause of severe renal allograft dysfunction. It occurs in immunosuppressed patients after reactivation of the latent virus PV type BK (BK virus) in the renal epithelium. BK disease is defined as a morphologically manifest renal infection with cytopathic signs accompanied by varying degrees of interstitial inflammatory cell infiltrates and functional impairment. It is also identified by the presence of cells containing viral inclusion bodies (decoy cells) in the urine. The authors report a case of BK PV interstitial nephritis in a 36-year-old renal allograft recipient. Under light microscopy the chief diagnostic indicator was detection of intranuclear viral inclusions, which were found exclusively in tubular epithelial cells. Cells with viral changes were often enlarged with nuclear atypia and chromatin basophilia. Widespread interstitial plasma cell infiltrates associated with tubulitis were present. Intranuclear paracrystalline arrays of virus particles 35-38 nm in diameter were present as characteristic ultrastructural indicators. Urine samples revealed decoy cells with ground-glass-type intranuclear inclusions positive for BK virus by electron microcopy.

Successful retransplantation after renal allograft loss to polyoma virus interstitial nephritis

Poduval et al. (1) have reported on successful retransplantation after renal-allograft loss to polyoma virus nephritis. They conclude that previous graft loss secondary to polyoma virus infection is not a contraindication to retransplantation. Although we do agree that retransplantation should be considered as a therapeutic option, our experience suggests that specific circumstances and actions may be indispensable for long-term success. A 35-year-old man with end-stage renal failure caused by diabetic nephropathy underwent a simultaneous pancreas and kidney transplantation from a six antigen-mismatched cadaveric donor on January 11, 1999. Immunosuppression consisted of antithymocyte globulin (ATG) induction, tacrolimus, mycophenolate mofetil (MMF), and prednisone (discontinued at posttransplant month [PTM] 5). Except for prolonged wound healing, the postoperative course was uneventful with an excellent function of both organs. On PTM 11 and 16, short courses of methylprednisolone were given because of creatinine increases with borderline changes and acute rejection (type 1A, Banff 97) on kidney biopsy, respectively. On PTM 20, after another biopsy revealed tubular-cell intranuclear inclusions, polyoma virus nephritis was suspected and tacrolimus and MMF doses were reduced. However, the deterioration of renal function was not halted, and thus, because of full function of the bladder-drained pancreatic graft and past intolerance of dialysis treatment, a decision on preemptive renal retransplantation was undertaken. Retransplantation was performed on April 22, 2001 with the kidney graft harvested from a 2 antigen-matched cadaveric donor. The removed graft showed interstitial nephritis of viral etiology with intranuclear inclusions (polyoma virus confirmed by immunohistochemistry: SV40 T-Ag, Oncogene Research Products, San Diego, CA). The postoperative period was complicated by delayed graft function with a creatinine level of 198 μmol/L (2.2 mg/dL) at time of hospital discharge. Prednisone was added to tacrolimus and MMF in the early postoperative period. An increase of creatinine necessitated a kidney biopsy at PTM 3, which showed only mild benign nephrosclerosis and no signs of acute rejection. At PTM 5, immunosuppression was changed to low-dose tacrolimus and sirolimus in an attempt to minimize nephrotoxicity and reduce risk of recurrence of viral nephritis. Another biopsy done at PTM 5 for progressive deterioration of graft function showed nonsuppurative tubulointerstitial nephritis of viral origin (polyoma etiology was confirmed by immunohistochemistry with urinalysis being negative for decoy cells). A short course of steroid therapy was tried with some transient effect because of a simultaneous finding of 1B rejection. However, polyoma virus nephritis was reconfirmed by biopsy at PTM 8, and graft function further declined later with dialysis treatment restarted at PTM 12. As suggested by others (2), retransplantation in patients with graft loss caused by polyoma nephritis should be considered only in cases where evidence of lytic infection is no longer present. Qualitative or quantitative plasma or urine polymerase chain reaction (PCR) monitoring (3) (unfortunately unavailable to us in the described case) may be necessary, while urine cytology is probably of insufficient sensitivity. These and other important preconditions, such as preceding allograft nephrectomy and specific adjustments of immunosuppression, will have to be defined more precisely to ensure a lasting success of kidney retransplantation in cases of polyoma nephritis. Petr Boucek1 Ludek Voska2 Frantisek Saudek1

Molecular genotyping of BK and JC viruses in human polyomavirus[ndash ]associated interstitial nephritis after renal transplantation

The human polyomaviruses BK virus (BKV) and JC virus (JCV) have been linked to ureteric stenosis and allograft interstitial nephritis, but molecular characterization of the species involved has not been performed. We studied paraffin-embedded renal tissue from 19 cases of allograft viral interstitial nephritis. Histological sections were subjected to polymerase chain reaction amplification using consensus, BKV-, and JCV-specific primers, with subsequent DNA sequencing for strain determination. BKV was present in all (100%) interstitial nephritis kidneys and placed in genotypes corresponding to serological groups I (n [equals] 11), II (n [equals] 1), and IV (n [equals] 5). Fourteen of 17 isolates (82%) showed sequence variations in the viral capsid protein-1 (VP1) capsid region, with predicted changes in the encoded amino acids and sometimes with potential implications for the secondary and tertiary structure of the corresponding protein molecules. An additional case showed a previously reported glutamine[rarr ]leucine T-antigen region mutation. JCV was seen in seven interstitial nephritis kidneys (37%), with types 4 (n [equals] 3), 3A (n [equals] 2), and 2A (n [equals] 1) identified. Most white individuals with asymptomatic infection are reported to shed type 1 JCV in the urine. Simian 40 polyomavirus was not identified in any case. These observations may have pathogenic relevance to the development of an extremely refractory form of polyomavirus interstitial nephritis seen after kidney transplantation. [copy ] 2001 by the National Kidney Foundation, Inc.

Polyomavirus interstitial nephritis in a patient with EBV-Negative B-Cell posttransplantation lymphoproliferative disorder

Polyomavirus interstitial nephritis in a patient with EBV-Negative B-Cell posttransplantation lymphoproliferative disorder

Massive Exfoliation of Markedly Atypical Cells in Urine Resulting from Polyoma Virus Interstitial Nephritis.

Polyoma virus nephritis is increasingly being recognized as a cause of allograft dysfunction in renal transplant patients. We describe and illustrate the findings in a renal biopsy and a concurrent urine sample from a patient with polyoma virus nephritis. The urine cytology findings were highly suggestive of a tumor due to the presence of large number of atypical cells with marked hyperchromasia, high nuclear/cytoplasmic ratio in a necrotic background. Scattered cells with viral cytopathic changes were also identified, therefore indicating an infectious process with associated reactive cellular changes rather than a tumor. The cytological findings could thus be explained by the viral cytopathic and cytolytic changes, as well as marked reactive and degenerative changes in tubular epithelial cells. Int J Surg Pathol 8(4):329-331, 2000

Human polyoma virus in renal allograft biopsies: Morphological findings and correlation with urine cytology

Human polyoma virus (PV) interstitial nephritis occurs in immunosuppressed patients after reactivation of latent virus in renal epithelium. Currently, there is neither general consensus about the incidence of clinically significant PV infection in renal transplants nor conclusive evidence determining its significance in the long-term graft outcome. We evaluated 601 renal transplant biopsy specimens (from 365 patients) by routine light microscopy and immunoperoxidase stains with antibody against SV40 (which cross reacts with PV). We also examined urine samples from 200 patients (100 obtained concurrently with a renal biopsy in patients presenting with acute graft dysfunction and 100 from patients with stable graft function). Electron microscopic evaluation was performed in 50 renal biopsy specimens and in 23% of all urine samples. PV was identified in 1.8% biopsy specimens (1.9% of patients). PV interstitial nephritis showed the typical viral cytopathic changes in tubular epithelial cells associated with marked tubular damage and a disproportionately mild degree of tubulitis. There was no difference in the incidence of PV in the urine of patients with acutely deteriorating versus stable renal function (18% and 19%, respectively); however, urines with large numbers of infected cells (> 10/cytospin) and inflammatory changes in the sediments corresponded invariably to patients with acute allograft dysfunction (8 of 8), and in most cases to biopsy specimens showing PV interstitial nephritis (7 of 8). Based on these findings, urine samples seem to be the most sensitive and cost-effective screening method for PV infection; only urine samples with inflamed sediments and abundant infected cells correlate with clinically significant disease. In these cases, examination of a renal biopsy is indicated. Immunohistochemical stains are useful to confirm the presence of PV but do not increase the sensitivity of diagnosis of PV if this is not already suspected on routine light microscopy. In our material, immunostains were helpful ruling out the presence of PV in a small number of biopsy specimens (2%) that showed markedly reactive tubular cells resembling PV infection. Most patients with PV interstitial nephritis responded to decreased immunosuppression; however, the decay in graft function (based on creatinine slopes) was significantly more rapid in these patients than in matched controls. Evidence of PV infection should be systematically sought in renal biopsy specimens and urine samples from renal allograft recipients.