sirolimus and Polyomavirus-Infections

Cytomegalovirus (CMV) and BK polyomavirus (BKPyV) infections after kidney transplant have become increasingly prevalent. Based on previous studies, the mammalian target of rapamycin (mTOR) inhibitors seem like attractive alternatives with antiviral activity. The objective of this systematic review and meta-analysis was to investigate the incidence of CMV and BKPyV infections in kidney transplantation recipients receiving mTOR inhibitors. This meta-analysis included three comparisons of immunosuppressant regimens commonly used after kidney transplantation: Comparison 1: mTOR inhibitors versus calcineurin inhibitors (CNI); Comparison 2: mTOR inhibitors versus antimetabolites (AM); and Comparison 3: mTOR inhibitors plus a reduced-dose of CNI versus AM plus a standard-dose of CNI. The group containing mTOR inhibitors was the study group and the remaining one was the control group. The incidence of CMV or BKPyV infection defined by positive culture, serology, or polymerase chain reaction testing was the primary outcome. A total of 61 studies involving 13,609 patients were included. As compared with the control group, a significantly decreased risk of CMV and BKPyV infections favoring the mTOR inhibitors-based group was shown in comparisons 1, 2, and 3 (p < 0.05). Compared with the control group in all three comparisons, mTOR inhibitors made no difference in regard to death and graft loss (p > 0.05). Compared with CNI, the incidence of biopsy-proven acute rejection (BPAR) and anemia was higher with mTOR inhibitors (p < 0.05). In comparisons 2 and 3, the risk of new-onset diabetes mellitus (NODM) was higher with mTOR inhibitors (p < 0.05). Early introduction of mTOR inhibitors reduced more CMV infections in comparisons 1 and 2 (p < 0.05). The mTOR inhibitor-based regimen is an attractive alternative with lower risk of CMV and BKPyV infections in kidney transplant recipients. The combination regimen is more appropriate and acceptable than the mTOR-inhibitor monotherapy-based regimen. Early introduction of mTOR inhibitors is recommended, although it is worth noting that attention should be paid to wound healing when mTOR inhibitors are introduced early.

Topics: Calcineurin Inhibitors; Cytomegalovirus; Cytomegalovirus Infections; Humans; Incidence; Kidney Transplantation; MTOR Inhibitors; Polyomavirus Infections; Sirolimus; TOR Serine-Threonine Kinases

JC polyomavirus-associated nephropathy (JC-PVAN) is a rare but challenging cause of renal dysfunction. We report JC-PVAN in a renal allograft recipient and highlight the obstacles in definitive diagnosis of this disease entity. A deceased-donor renal transplant recipient was diagnosed with JC polyomavirus nephritis 4 years after transplantation. Immunosuppressive agents were subsequently reduced, resulting in an initial stabilization of renal function. We present this interesting case and discuss the challenges with diagnosing and treating this rare entity.

Topics: Biopsy; BK Virus; Creatinine; Graft Rejection; Humans; Immunoglobulins, Intravenous; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Isoxazoles; JC Virus; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Leflunomide; Male; Middle Aged; Mycophenolic Acid; Nephritis; Polymerase Chain Reaction; Polyomavirus Infections; Sirolimus; Tacrolimus; Transplantation, Homologous; Viremia

Polyomavirus-associated graft nephropathy (PAN) has emerged as a significant risk factor for kidney graft loss. We analyzed intracellular cytokine responses for possible protective versus permissive immunologic effects on BK-virus replication. One hundred five renal transplant patients included in a prospective single-center study were randomized to receive cyclosporine mycophenolate mofetil (MMF) (CM: n = 31), tacrolimus (Tac)/MMF (TM: n = 32) or Tac/MMF with conversion to everolimus (TErl; n = 32). Ten patients were not randomized (NR) due to contraindications to MMF. The immunosuppressive therapy was monitored pre- and posttransplantation at 4, 12, and 24 months using triple fluorescence flow cytometry for intracellular interleukin (Il)-2 Il-4 and interferon (IFN)-γ production in phorbol myristate acetate- and lipopolysaccharide- stimulated lymphocyte cultures. BK viremia screening was performed by reverse-transcriptase polymerase chain reaction testing on days 0, 14, 30, 60, 90, 120, 180, 270, 360, and 720. Seven of 105 (6.7%) patients developed biopsy-proven PAN (CM: n = 1, TM: n = 3, TErl: n = 2, NR: n = 1), among whom 4 lost their grafts (TM: n = 1, TErl: n = 2, NR: n = 1). Twenty-one of 105 (20.0%) patients had documented BK viremia. BK viremia which preceded PAN in all cases, was significantly associated with TM immunosuppression: 4/31 (12.9%) CM: 11/32 (34.4%) TM; 5/32 (15.6%) TErl, and 1/10 (10.0%) NR patients (P = .034). BK-viremic patients showed significantly diminished CD8(+) T-cell Il-2 production at 120 days (P = .011) and 1 year posttransplantation (P = .014) compared with non-BK-viremic patients. Patients with PAN displayed significantly lower CD4(+) T-cell Il-4 responses at 1 and 2 years after transplantation (1 year: P = .007; 2 years: P = .001) with diminished IFN-γ responses at 1 year after transplantation (P = .011). Our analysis showed the incidence of BK viremia to be increased among patients with defective cytotoxic CD8(+) T-cell -dependent immune reactivity. Recipients who progressed from BK viremia to overt PAN showed an additional immunologic defect in CD4(+) T-cell function. Patients on a Tac- plus MMF-based immunosuppression were at higher risk to develop BK viremia.

Topics: BK Virus; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cyclosporine; Everolimus; Flow Cytometry; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Polyomavirus Infections; Prospective Studies; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Sirolimus; Tacrolimus; Viremia

BK polyomavirus infection has been reported in 10% to 60% of renal transplant recipients with progression to BK nephropathy (BKN) occurring in 1% to 5% of patients. Graft loss occurs in up to 60% of renal transplant recipients with BKN. Because BK polyomavirus infection is believed, in part, to be a manifestation of overimmunosuppression, the current standard of care involves the reduction of immunosuppressants. This strategy has been associated with clearance of viral load, preservation of renal function, and improvement in graft survival; however, this may come at a risk of rejection. A safe and effective immunosuppressive agent that does not predispose to viral infection is needed in transplantation.. In a phase 2, proof-of-concept, randomized, open-label, parallel-group, 6-month study in renal transplant patients, FK778 (an investigational immunosuppressant from the malononitrilamides class) was compared with the current standard of care (reduction of immunosuppression) for treatment of newly diagnosed or untreated BKN, which was confirmed by renal biopsy.. Demographic characteristics were similar between the two groups, except there were numerically more females in the FK778 group than in the standard care group. Although the treatment with FK778 decreased BK viral load in this study, it was associated with a less favorable rejection profile and renal function and a higher incidence of serious adverse events compared with reduction of immunosuppression.. Data from this study are consistent with the findings of previous studies that found no benefit of drug therapy in the treatment of BKN in kidney transplant recipients.

Topics: Algorithms; Alkynes; Creatinine; Cyclosporine; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Isoxazoles; Kidney Transplantation; Mycophenolic Acid; Nitriles; Patient Compliance; Polyomavirus Infections; Sirolimus; Tacrolimus; Time Factors; Viral Load

This study aimed to determine the predictive factors of BK virus viremia/nephropathy in kidney transplant recipients and to evaluate the effects of low-dose tacrolimus plus everolimus.. This study included 3654 kidney transplant recipients. The patients were divided into 2 groups: group 1 were BK virus negative (n = 3525, 96.5%) and group 2 were BK virus positive (n = 129, viremia 3.5%, nephropathy 1%). Predictive factors were determined by receiver operating characteristic curve analysis and logistic regression models.We also divided and analyzed patients with BK virus viremia/nephropathy into 2 groups according to immunosuppressive changes. Group 2a had been switched to low-dose tacrolimus plus everolimus (n = 54, 41.9%), and group 2b had been switched to other immunosuppressive protocols (n = 75, 58.1%).. We found that use of anti-T-cell lymphocyte globulin and tacrolimus, deceased donor transplant, and rejection were predictive factors for BK virus viremia/nephropathy. In addition, patients who had low-dose calcineurin inhibitor plus mammalian target of rapamycin inhibitor regimens showed a low rate of BK virus development(only 6.2% of all cases). In Group 2a, both the BK polyomavirus-associated nephropathy rate (n = 23 [42.6%] vs n = 12 [16%] in group 2b; P = .001) and viral load (DNA > 104 copies/mL) (n = 49 [90.7%] vs n = 27 [36%] in group 2b; P = .001) were increased versus group 2b. Graft function, graft survival, viral clearance, and rejection rate were similar between the groups after protocol change.. BK virus viremia/nephropathy rate was lower in patients who received low-dose calcineurin inhibitor plus mammalian target of rapamycin inhibitor protocols; the low-dose tacrolimus plus everolimus switch protocol after BK virus was more effective and safe than other protocols.

Topics: BK Virus; Calcineurin Inhibitors; Everolimus; Humans; Immunosuppressive Agents; Kidney Transplantation; Nephritis, Interstitial; Polyomavirus Infections; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases; Transplant Recipients; Tumor Virus Infections; Viremia

Human polyomavirus BK (BKPyV) is the etiologic agent of polyomavirus-associated nephropathy, a leading cause of kidney transplant dysfunction. Because of the lack of antiviral therapies, immunosuppression minimization is the recommended treatment. This strategy offers suboptimal outcomes and entails a significant risk of rejection. Our aim was to evaluate the effect of different immunosuppressive drugs (leflunomide, tacrolimus, mycophenolic acid, sirolimus, and everolimus) and their combinations in an in vitro model of BKPyV infection.. Human renal tubular epithelial cells were infected with BKPyV and treated with leflunomide, tacrolimus, mycophenolic acid, sirolimus, and everolimus, administered alone or in some combination thereof. Viral replication was assessed every 24 hours (up to 72 hours) by BKPyV-specific quantitative real-time polymerized chain reaction for the VIRAL PROTEIN 1 sequence in cell supernatants and by western blot analysis targeting the viral protein 1 and the glyceraldehyde 3-phosphate dehydrogenase on total protein lysates. Results were described as viral copies/mL and compared between treatments at any prespecified time point of the study.. The highest inhibitory effects were observed using leflunomide or everolimus plus mycophenolic acid (mean BKPyV replication log reduction 0.28). The antiviral effect of everolimus persisted when it was used in combination with tacrolimus (mean BKPyV replication log reduction 0.27).. Our experience confirms that everolimus has anti-BKPyV properties and prompts future research to investigate possible mechanisms of action. It also provides a rational basis for targeted clinical trials evaluating alternative immunosuppressive modification strategies.

Topics: Antiviral Agents; BK Virus; Everolimus; Humans; Immunosuppressive Agents; Kidney Transplantation; Leflunomide; Mycophenolic Acid; Polyomavirus Infections; Sirolimus; Tacrolimus; Tumor Virus Infections; Viral Proteins

Human polyomaviruses can reactivate in transplant patients, causing nephropathy, progressive multifocal leukoencephalopathy, Merkel cell carcinoma, pruritic, rash or trichodysplasia spinulosa. Sirolimus and related mechanistic target of rapamycin (mTOR) inhibitors are transplant immunosuppressants. It is unknown if they directly reactivate polyomavirus replication from latency beyond their general effects on immunosuppression.. In vitro expression and turnover of large T (LT) proteins from BK virus, JC virus (JCV), Merkel cell polyomavirus (MCV), human polyomavirus 7 (HPyV7), and trichodysplasia spinulosa polyomavirus (TSV) after drug treatment were determined by immunoblotting, proximity ligation, replicon DNA replication, and whole virus immunofluorescence assays.. mTOR inhibition increased LT protein expression for all 5 pathogenic polyomaviruses tested. This correlated with LT stabilization, decrease in the S-phase kinase-associated protein 2 (Skp2) E3 ligase targeting these LT proteins for degradation, and increase in virus replication for JCV, MCV, TSV, and HPyV7. Treatment with sirolimus, but not the calcineurin inhibitor tacrolimus, at levels routinely achieved in patients, resulted in a dose-dependent increase in viral DNA replication for BKV, MCV, and HPyV7.. mTOR inhibitors, at therapeutic levels, directly activate polyomavirus replication through a Skp2-dependent mechanism, revealing a proteostatic latency mechanism common to polyomaviruses. Modifying existing drug regimens for transplant patients with polyomavirus-associated diseases may reduce symptomatic polyomavirus replication while maintaining allograft-sparing immunosuppression.

Topics: BK Virus; DNA Replication; DNA, Viral; Humans; JC Virus; Merkel cell polyomavirus; MTOR Inhibitors; Polyomavirus; Polyomavirus Infections; S-Phase Kinase-Associated Proteins; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases; Virus Replication

Reactivation of the BK-Polyomavirus (BKPyV) can cause a polyomavirus associated nephropathy in approx. 10% of kidney transplant recipients. In these cases, current therapy is based on the reduction of immunosuppression. Since BKPyV-transcription is driven by the Non-Coding-Control-Region (NCCR) we were interested whether NCCR-activity is affected by immunosuppressive agents.. Plasma samples from 45 BKPyV-positive patients after renal transplantation were subjected to PCR-analysis. NCCR-amplicons were cloned into a plasmid that allows the quantification of early and late NCCR-activity by tdTomato and eGFP expression, respectively. HEK293T-cells were transfected with the reporter-plasmids, treated with immunosuppressive agents, and subjected to FACS-analysis. In addition, H727-cells were infected with patient derived BKPyV, treated with mTOR-inhibitors, and NCCR activity was analysed using qRT-PCR.. While tacrolimus and cyclosporine-A did not affect NCCR-promoter-activity, treatment with mTOR1-inhibitor rapamycin resulted in the reduction of early, but not late-NCCR-promoter-activity. Treatment with dual mTOR1/2 inhibitors (INK128 or pp242) led to significant inhibition of early, however, concomitantly enhanced late-promoter-activity. In BKPyV infected cells both rapamycin and INK128 reduced early expression, however, INK128 resulted in higher late-mRNA levels when compared to rapamycin treatment.. Our results demonstrate that mTOR1-inhibitors are able to reduce early-expression of wildtype and rearranged NCCRs, which might contribute to previously described inhibition of BKPyV-replication. Dual mTOR1/2-inhibitors, however, additionally might shift viral early into late-expression promoting synthesis of viral structural proteins and particle production.

Topics: BK Virus; Cyclosporins; DNA, Viral; Gene Expression Regulation, Viral; HEK293 Cells; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Open Reading Frames; Polyomavirus Infections; RNA, Untranslated; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases; Transplant Recipients; Tumor Virus Infections; Virus Replication

BK polyomavirus (BKPyV) replication causes nephropathy and premature kidney transplant failure. Insufficient BKPyV-specific T cell control is regarded as a key mechanism, but direct effects of immunosuppressive drugs on BKPyV replication might play an additional role. We compared the effects of mammalian target of rapamycin (mTOR)- and calcineurin-inhibitors on BKPyV replication in primary human renal tubular epithelial cells. Sirolimus impaired BKPyV replication with a 90% inhibitory concentration of 4 ng/mL by interfering with mTOR-SP6-kinase activation. Sirolimus inhibition was rapid and effective up to 24 h postinfection during viral early gene expression, but not thereafter, during viral late gene expression. The mTORC-1 kinase inhibitor torin-1 showed a similar inhibition profile, supporting the notion that early steps of BKPyV replication depend on mTOR activity. Cyclosporine A also inhibited BKPyV replication, while tacrolimus activated BKPyV replication and reversed sirolimus inhibition. FK binding protein 12kda (FKBP-12) siRNA knockdown abrogated sirolimus inhibition and increased BKPyV replication similar to adding tacrolimus. Thus, sirolimus and tacrolimus exert opposite effects on BKPyV replication in renal tubular epithelial cells by a mechanism involving FKBP-12 as common target. Immunosuppressive drugs may therefore contribute directly to the risk of BKPyV replication and nephropathy besides suppressing T cell functions. The data provide rationales for clinical trials aiming at reducing the risk of BKPyV replication and disease in kidney transplantation.

Topics: BK Virus; Blotting, Western; Cells, Cultured; Epithelial Cells; Fluorescent Antibody Technique; Humans; Immunosuppressive Agents; Infant; Kidney Tubules; Polyomavirus Infections; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Sirolimus; Tacrolimus; Tacrolimus Binding Protein 1A; Tumor Virus Infections; Virus Replication

Polyomavirus BK (BKV) reactivation causes allograft dysfunction in some kidney transplant recipients. The use of mammalian target of rapamycin (mTOR) inhibitor-based immunotherapy is associated with a lower incidence of polyomavirus-associated nephropathy compared with other immunosuppressants. This retrospective study assessed whether conversion to mTOR inhibitor-based immunotherapy directly reduced urinary BKV load.. A total of 63 kidney recipients were divided into mTOR inhibitor-conversion (21 patients) and nonconversion (42 patients) groups. Urinary BKV loads were determined before and at least 6 months after the conversion.. The results demonstrated that urinary BKV titer was significantly reduced in the conversion group (3.94 ± 0.43 copies (log)/mL to 2.49 ± 0.19 copies (log)/mL) and remained unaltered in the nonconversion group (3.19 ± 0.20 copies (log)/mL to 2.90 ± 0.20 copies (log)/mL). In addition, the percentage of patients with reduced urinary BKV load was significantly higher in the conversion group (76.2% vs. 42.9%). The estimated glomerular filtration rate after 24 months mTOR inhibitor conversion was significantly increased compared with that in the nonconversion group. Conversion to mTOR-inhibitor-based immunotherapy was the only factor associated with an increase in estimated glomerular filtration rate.. This study reveals an association of conversion to mTOR-inhibitor-based immunotherapy with the reduction of urinary BKV load.

Topics: Adult; BK Virus; Creatinine; Everolimus; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Immunotherapy; Kidney Diseases; Kidney Transplantation; Logistic Models; Male; Middle Aged; Polyomavirus Infections; Postoperative Complications; Retrospective Studies; Sirolimus; Taiwan; TOR Serine-Threonine Kinases; Viral Load

BK viral nephropathy is an increasingly recognized cause of early allograft loss in kidney transplantation. This study aimed to determine whether a sirolimus (Sir)-based calcineurin inhibitor-sparing regimen is associated with a lower incidence of BK viremia.. This was a single-center retrospective study. Patients were either on tacrolimus (Tac)-based or on Sir-based immunosuppression. Conversion from Tac to Sir occurred at or after 3 months if patients were <62 years of age, had calculated panel reactive antibodies of <20%, and did not have acute early rejection.. Incidence of clinically significant BK viremia was 17.9% in the Tac group and 4.3% in the Sir group. Cox regression multivariate analysis showed that male gender (hazard ratio [HR] = 2.87) and switch to Sir (HR = 0.333) impacted the incidence of BK viremia. Kaplan-Meier analysis showed a higher BK-free survival in the Sir group. A trend was seen toward shorter time to resolution of BK viremia and lower peak viremia in the Sir group. Patients on Sir had a higher estimated glomerular filtration rate at each time point; 34% of patients discontinued Sir because of side effects.. Conversion to Sir-based maintenance immunosuppression at or about 3 months after kidney transplantation correlates with a lower incidence of BK viremia.

Topics: Adult; Aged; BK Virus; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Polyomavirus Infections; Retrospective Studies; Sirolimus; Tacrolimus; Transplant Recipients; Tumor Virus Infections; Viremia

Topics: Antiviral Agents; Humans; Isoxazoles; Kidney Diseases; Kidney Transplantation; Leflunomide; Polyomavirus Infections; Retrospective Studies; Sirolimus

Reactivation of latent BK polyomavirus (BKV) infection is relatively common following renal transplantation and BKV-associated nephropathy has emerged as a significant complication. JC polyomavirus (JCV) reactivation is less well studied. The aim of the study was to determine reactivation patterns for these polyomaviruses in renal transplant recipients using an in-house quantitative real-time multiplex PCR assay and IgG serological assays using recombinant BK and JC virus-like particles.. Retrospective analysis of urine and plasma samples collected from 30 renal transplant patients from February 2004 to May 2005 at Leeds Teaching Hospitals NHS Trust. Samples were collected at 5 days and thereafter at 1, 3, 6 and 12 months post-transplantation.. Eight patients (26.7%) were positive for BK viruria; three of these patients submitted plasma samples and two had BK viraemia. Five patients (16.7%) were positive for JC viruria. A corresponding rise in BKV and JCV antibody titres was seen in association with high levels of viruria.. Different patterns of reactivation were observed: BK viruria was detected after 3-6 months, and JC viruria was observed as early as 5 days post-transplantation. One patient had biopsy-proven BKV nephropathy. No dual infections were seen. In order to ensure better graft survival, early diagnosis of these polyomaviruses is desirable.

Topics: Adult; Aged; Antibodies, Viral; BK Virus; Female; Humans; Immunosuppressive Agents; JC Virus; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Polymerase Chain Reaction; Polyomavirus Infections; Postoperative Care; Postoperative Complications; Retrospective Studies; Sirolimus; Tacrolimus; Tumor Virus Infections; Viral Load; Virus Activation

Human BK polyomavirus is the causative agent of BK nephropathy which is now the leading cause of early renal graft loss. Although no randomized clinical trials have supported this therapy, reduction of immunosuppressive drugs is the current BK nephropathy treatment. We hypothesized that inhibition of the intracellular protein kinase pathways activated by BK virus may be a more effective therapeutic strategy than reduction of immunosuppression.. Four days after infection of renal epithelial cells lines CCD1103, CCD1105 and human primary tubular epithelial cells with BK virus, we found increased phosphorylation of 3'-phosphoinositide-dependent kinase-1 (PDK-1), the protein kinase Akt (Akt), mammalian target of rapamycin (mTOR), and 70 kDa ribosomal protein S6 kinase (p70S6K). To inhibit this pathway, we used sirolimus, which repressed p70S6K phosphorylation and reduced BK virus large T antigen expression in a dose-dependent manner. We then used the tyrosine kinase inhibitor leflunomide (using the active metabolite A77 1726), which decreased PDK1 and Akt phosphorylation and inhibited BK virus genome replication and early gene expression. The combination of sirolimus and leflunomide inhibited BK virus genome replication, large T antigen expression, PDK1, Akt, mammalian target of rapamycin, and p70S6K phosphorylation.. On the basis of these results, we suggest that inhibition of protein kinase pathways with a combination of sirolimus and leflunomide may be an effective therapy for BK virus reactivation. Because both sirolimus and leflunomide possess immunosuppressive activity, combination therapy may reduce BK pathogenesis while maintaining appropriate transplant immunosuppression.

Topics: Antigens, Viral; Antigens, Viral, Tumor; Antiviral Agents; BK Virus; Cell Line; Drug Therapy, Combination; Epithelial Cells; Humans; Immunosuppressive Agents; Isoxazoles; Kidney Transplantation; Kidney Tubules; Leflunomide; Polymerase Chain Reaction; Polyomavirus Infections; Signal Transduction; Sirolimus; Transplantation Immunology

Because the course of polyoma virus-associated nephropathy (PVAN) has not been evaluated in a large cohort of patients receiving sirolimus (SRL)-based regimens, we have herein presented the incidence, clinical characteristics, and outcomes of 378 renal transplant recipients treated with SRL-based immunosuppression.. This retrospective single center study evaluated 344 kidney alone (KTX) and 34 simultaneous pancreas-kidney (SPK) transplantations performed between June 2000 and December 2004.. At a mean follow-up of 43.3 months, six kidney (1.7%) and three kidney-pancreas (9.0%) transplanted patients displayed biopsy-proven PVAN. The mean time to diagnosis after transplantation was 18.2 months (range: 3.5-31.1 months), with a higher incidence among patients exposed (4.23%) versus not exposed to rabbit antithymocyte globulin (rATG; 0.53%; P=0.019) or SPK (9.0%) versus KTX (1.7%) recipients (odds ratio: 5.43; confidence interval: 1.29-22.8; P=0.038). Despite treatment with cidofovir, reduced immunosuppression and maintenance therapy with no agents other than SRL (C0=10.2+/-2.7 ng/dL) plus modest doses of prednisone (< or =5 mg), five patients (55.5%) experienced renal allograft failure. No rejection episodes were documented during the PVAN treatment and pancreatic function continued to be excellent among the SPK patients.. Patients treated with SRL-based immunosuppression showed an incidence at the lower end of the range described with various other contemporaneous immunosuppressive regimens and with other cohorts not undergoing BK virus polymerase chain reaction surveillance. Exposure to rATG and SPK transplantation represented risk factors for the occurrence of PVAN, which showed a pernicious course despite withdrawal of calcineurin antagonists and/or mycophenolate mofetil.

Topics: Adult; Animals; Antilymphocyte Serum; BK Virus; Cohort Studies; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Incidence; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Pancreas Transplantation; Polyomavirus Infections; Rabbits; Retrospective Studies; Risk Factors; Sirolimus; Transplantation, Homologous; Tumor Virus Infections

BK virus nephritis (BKN) in recipients of renal allografts has reemerged during the past 5 years. Despite increased incidence, therapeutic options remain limited and progression of the disease often leads to allograft failure.. From May 2002 to July 2002, we performed protocol biopsies in 25 recipients of kidney allografts with progressive allograft dysfunction; three patients demonstrated unexpected histopathologic features of BKN. We tested the hypothesis that replacement of their lymphocytotoxic and nephrotoxic immunosuppression (combination of mycophenolate and tacrolimus) with sirolimus- and prednisone-based therapy can lead to disappearance of the virus without increasing the risk of acute rejection.. During the median follow-up of 18 months after sirolimus and prednisone therapy, decoy cells disappeared first, followed by progressive decrease in the median plasma BK virus-DNA load, and undetectable levels at the last follow-up. Patients remained free of acute rejection, and follow-up median estimated creatinine clearance increased to 67 mL/min (range 62-75 mL/min) from 52 mL/min (range 51-54 mL/min) at the time of diagnosis.. Further studies are needed, but at present these preliminary results offer a new direction for therapeutic intervention in recipients of renal allografts with BKN.

Topics: Adult; Biopsy; BK Virus; DNA, Viral; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Polyomavirus Infections; Sirolimus; Transplantation, Homologous; Tumor Virus Infections

Topics: Aged; BK Virus; Creatinine; DNA, Viral; Glomerulonephritis, Membranoproliferative; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Kinetics; Male; Polyomavirus Infections; Prospective Studies; Sirolimus; Viral Load