Adjuvant Low-Dose Cidofovir Therapy for BK Polyomavirus Interstitial Nephritis in Renal Transplant Recipients

BK virus interstitial nephritis (BKVIN) is a serious complication after kidney grafting, necessitating drastic reduction of immunosuppressive therapy in order to enable viral clearance. Despite these measures, progressive graft dysfunction and graft loss occur in the majority of recipients. We diagnosed BKVIN in 21 recipients grafted between 1998 and 2004. Eight of 21 patients were treated with weekly, adjuvant low-dose cidofovir in addition to reduction of immunosuppressive therapy. BKVIN caused irreversible deterioration of graft function in all patients but renal function stabilized after antiviral treatment (creatinine clearance: 51.8-32 mL/min; p=0.001) and no graft loss occurred in cidofovir-treated recipients during 24.8 (8-41) months follow-up. Peak serum cidofovir concentrations were dose-dependent and attained approximately one-tenth of thein vitroEC50 for cidofovir against BK-virus, while pre-treatment with probenecid did not alter peak serum concentrations nor affected the incidence of nephrotoxicity. In fact, no cidofovir-related renal toxicity occurred; few patients had minor transient side effects (nausea, skin rash). In contrast, 9 of 13 patient who received no adjuvant cidofovir therapy lost their graft after median 8 (4-40) months. In this selected group of recipients with BKVIN, the use of adjuvant low-dose cidofovir therapy resulted in prolonged graft survival and stabilized graft function.     

HLA Mismatching Increases the Risk of BK Virus Nephropathy in Renal Transplant Recipients

BK virus (BKV) nephropathy is a serious complication in kidney transplant recipients that may lead to irreversible graft failure. We have analyzed the degree of donor/recipient HLA compatibility and HLA antigen association in 40 kidney transplant patients with BKV nephropathy in comparison with a control group of 404 unaffected transplant recipients who were on tacrolimus-based immunosuppression with no induction. HLA compatibility was assessed by determining the number of HLA-A, -B, -DR-mismatched antigens. BK virus nephropathy was diagnosed histologically and confirmed by immunochemistry. Univariate and multiple logistic regression statistical analyses have shown a significant association between BKV nephropathy and HLA mismatching. This analysis showed also that BKV nephritis is associated with a greater number of rejection episodes and a higher incidence of steroid-resistant rejection requiring antilymphocyte treatment. There was no association between BKV nephropathy and any specific HLA allele. We propose that HLA mismatching promotes the development of BKV nephropathy through rejection-related inflammatory processes and heavy immunosuppression which cause virus reactivation and injury of the tubular epithelium.     

BK Virus Infection in Transplant Recipients: An Overview and Update

BK virus infection after kidney transplantation has been a subject of great interest in the past decade. This article traces the discovery of BK virus and the subsequent development of our knowledge about this emerging pathogen. The pathobiology of the virus is summarized with particular reference to epidemiology, interactions with host cell receptors, cell entry, cytoplasmic trafficking and targeting of the viral genome to the nucleus. This is followed by a discussion of clinical features, laboratory monitoring and therapeutic strategies. Finally, we present potential cellular mechanisms that explain the basis of virus-mediated damage to the human kidney.     

A Prospective Longitudinal Study of BK Virus Infection in 104 Renal Transplant Recipients

BK virus (BKV) infection during the first year after renal transplantation was studied prospectively in 104 unselected consecutive patients. Viral DNA in urine (DNAuria) and plasma (DNAemia) samples was detected and quantified by real-time PCR. The noncoding control region (NCCR) of BKV isolates was sequenced. DNAuria and DNAemia occurred in 57% and 29% of patients, respectively. Three groups were defined, uninfected patients (group 1, n=45), patients with DNAuria (group 2, n=29) and patients with positive DNAemia (group 3, n=30). Active infection started within the first 3 months in 80% of patients. Cold ischemia duration over 24 h and the administration of tacrolimus were identified as significant risks factors for DNAuria, whereas it remains more frequently negative in patients receiving cyclosporine A. The risk for positive DNAemia was higher in patients with DNAuria (notably for viral load (VL)>4 log/mL) or treated with tacrolimus. No relationship was found with genetic variability in the NCCR sequence. Our data highlight the high frequency of active BKV infection after renal transplantation. Although high VL was detected in some patients, none developed a BKV nephropathy. A prospective follow-up of the whole population during the first year post renal transplantation is thus not useful to predict BKV disease.     

Polyomavirus BK-Specific Cellular Immune Response to VP1 and Large T-Antigen in Kidney Transplant Recipients

Polyomavirus BK (BKV) is the primary cause of polyomavirus-associated nephropathy (PVAN) in kidney transplant (KT) recipients. Using ELISpot assays, we compared the frequency of interferon-gamma (IFN-gamma) secreting peripheral blood mononuclear cells (PBMC) after stimulation with overlapping peptide pools covering BKV large T-antigen (LT) and VP1 capsid proteins (VP1). In 10 healthy donors, LT and VP1 responses were low with median 24 (range 15-95) and 25 (7-113) spot-forming units/10(6) PBMC (SFU), respectively. In 42 KT patients with current or recent plasma BKV loads, median LT and VP1 responses of 29 (0-524) and 114 (0-1432) SFU were detected, respectively. In KT patients with decreasing or past plasma BKV loads, significantly higher median BKV-specific IFN-gamma responses were detected compared to KT patients with increasing or persisting BKV loads [LT: 78 (8-524) vs. 22 (0-120) SFU, p=0.003; VP1: 285 (45-1432) vs. 53 (0-423) SFU, p=0.001, respectively]. VP1-specific IFN-gamma responses were higher and more likely to involve CD4(+) T cells, while CD8(+) T cells were more frequently directed against LT. Stimulation with JCV-specific VP1 and LT peptides indicated only low-level cross-recognition. The data suggest that control of BKV replication is correlated with differentiated expansion of BKV-specific cellular immune responses.     

Quantification of BK Viral Load in Asymptomatic Renal Allograft Recipients

Introduction: Polyoma BK virus (BKV) has recently been identified to cause renal allograft dysfunction, which manifests as polyomavirus-associated nephropathy (PVAN). However, the presence and level of BKV DNA in renal allograft patients with good and stable renal function have remained undetermined. Methods: In this prospective study, serum samples were collected from a total of 45 renal allograft recipients with serum creatinine <155 μmol/L. In 17 patients, whose duration of transplantation was under 2 years, samples were collected at 3–4-month intervals for up to 2 years after transplantation. BK viral load was quantified using quantitative polymerase chain reaction (Q-PCR). Results: The BK viral load in asymptomatic renal allograft recipients was independent of the duration of transplantation and did not correlate with allograft function. The mean (± SD) level of viremia was 552.80 ± 1931.00 genome copies/mL, with 92.9% of patients having low levels of viremia corresponding to <1 × 10³ copies/mL. In contrast, patients with proven PVAN had levels in the range of 10⁶ copies/mL. Conclusions: The prevailing BK viral load in asymptomatic renal allograft patients is quantifiably low. Our findings may guide optimal immunosuppressive modulation in PVAN cases, where judicious manipulation of immunosuppression is required without inciting allograft rejection.     

BKV in Simultaneous Pancreas-Kidney Transplant Recipients: A Leading Cause of Renal Graft Loss in First 2 Years Post-Transplant

With the introduction of more potent immunosuppressive agents, rejection has decreased in simultaneous pancreas/kidney transplant (SPK) recipients. However, as a consequence, opportunistic infections have increased. The purpose of this report is to outline the course of SPK patients who developed polyomavirus-associated nephropathy (PVAN). A retrospective review of 146 consecutive SPK recipients from January 1, 1996 to December 31, 2002 was performed. Immunosuppression, rejection and development of PVAN were reviewed. Nine patients were identified. All received induction with either OKT3 or thymoglobulin. Immunosuppression included tacrolimus/cyclosporine, MMF/azathioprine and sirolimus/prednisone. Two patients were treated for kidney rejection prior to the diagnosis of PVAN. Time to diagnosis was an average of 359.3 days post-transplantation. Immunosuppression was decreased but five ultimately lost function. However, none developed pancreatic abnormalities as demonstrated by normal glucose and amylase. Two underwent renal retransplantation after PVAN diagnosis and both have normal kidney function. PVAN was the leading cause of renal loss in SPK patients in the first 2 years after transplantation and is a serious concern for SPK recipients. The pancreas, however, is spared from evidence of infection, and no pancreatic rejection occurred when immunosuppression was decreased.     

环孢素A血药浓度监测的临床意义

目的：探讨环孢素A(CsA)血药谷值浓度监测的临床意义。方法：对269例同种肾移植受者术后4081次CsA血药谷值浓度进行了分析。结果：随着移植肾存活时间的延长,CsA治疗浓度水平呈逐渐下降趋势。排斥反应发生时及排斥反应前两周内,CsA浓度不仅低下,而且有一持续约2周的显著下降过程,平均降幅达31％。术后一周内急性排斥反应的发生与CsA浓度关系不大。过高的CsA浓度则与肾中毒’反应有关。CsA治疗浓度与发生排斥反应时的浓度及肾中毒浓度均有一定程度的重叠。结论：认为术后CsA理想的治疗窗浓度应为：术后第1月内为300-450ng／ml,3月内为250～400ng／ml,半年内为200～350ng／ml,以后CsA浓度最好维持在150～250ng／ml。     

Retransplantation After BK Virus Nephropathy in Prior Kidney Transplant: An OPTN Database Analysis

BK virus (BKV) has emerged as a major complication of kidney transplantation. Since June 30, 2004, the OPTN in the USA collects BKV as a primary or secondary cause of graft loss and also if treatment for BK virus (TBKV) is administered. In this study, we determined characteristics of those recipients of repeat kidney transplants from the OPTN database, where either (a) a graft loss occurred between June 30, 2004 and December 31, 2008 and database recorded prior TBKV in that allograft or (b) a graft loss between June 30, 2004 and December 31, 2008 was attributed primarily or secondarily due to BKV. In the study time period, 823 graft losses have occurred where TBKV or graft failure attributable to BKV was reported in prior transplant; of these, 126 have received a retransplant as of June 5, 2009. Induction and maintenance immunosuppression usage mirrored current trends. As of June 5, 2009, 118/126 grafts are still functioning, one graft failure attributed to BKV. TBKV was reported in 17.5% of the retransplants. In the retransplants performed through December 31, 2007, 1‐year acute rejection rate was 7%, 1‐year and 3‐year Kaplan–Meier graft survival rates and median GFR were 98.5%, 93.6%, 65.5 and 68.4 mL/min, respectively. Retransplantation after BKV appears to be associated with good results.     

Polyomavirus BK Replication Dynamics In Vivo and In Silico to Predict Cytopathology and Viral Clearance in Kidney Transplants

Fast BK virus (BKV) replication in renal tubular epithelial cells drives polyomavirus‐BK‐associated nephropathy (PVAN) to premature kidney transplant (KT) failure. BKV also replicates in urothelial cells, but remains asymptomatic in two‐thirds of affected KT patients. Comparing 518 day‐matched plasma‐urine samples from 223 KT patients, BKV loads were ～3000‐fold higher in urine than in plasma (p < 0.000001). Molecular and quantitative parameters indicated that >95% of urine BKV loads resulted from urothelial replication and <5% from tubular epithelial replication. Fast BKV replication dynamics in plasma and urine with half‐lives of <12 h accounted for daily urothelial and tubular epithelial cell loss of 4×10⁷ and 6×10⁷, respectively. BKV dynamics in both sites were only partly linked, with full and partial discordance in 36% and 32%, respectively. Viral expansion was best explained by models where BKV replication started in the kidney followed by urothelial amplification and tubular epithelial cell cross‐feeding reaching a dynamic equilibrium after ～10 weeks. Curtailing intrarenal replication by 50% was ineffective and >80% was required for clearing viremia within 7 weeks, but viruria persisted for >14 weeks. Reductions >90% cleared viremia and viruria by 3 and 10 weeks, respectively. The model was clinically validated in prospectively monitored KT patients supporting >80% curtailing for optimal interventions.     

Chickenpox in Adult Renal Transplant Recipients

Five of 610 adults developed chickenpox between 35 days and9.2 years after renal transplantation, and only one patientsurvived. All patients received prednisolone and azathioprineduring the incubation period. Corticosteroid therapy was continued,but azathioprine was stopped after diagnosis. Four patientswere treated with acyclovir, but three were given suboptimaldoses. The patient who survived had been taking the lowest doseof azathioprine and was given the recommended dose of acyclovir.All patients who died developed disseminated intravascular coagulation,and at postmortem examination were found to have had cerebralhaemorrhage. None of the patients treated with acyclovir hadevidence of active varicella-zoster virus infection at postmortem examination, but two had disseminated bacterial and fungalinfections. Chickenpox follows a severe and often fatal course in adultswith renal transplants. Prompt acyclovir therapy can be effective,provided an adequate dose is given. Attention should be directedtowards prevention by the identification and immunisation ofat risk patients prior to transplantation.     

肾移植受者BK病毒感染的检测方法及免疫抑制方案对BK病毒活化的影响

目的 探讨肾移植术后受者BK病毒感染的检测方法及免疫抑制方案对BK病毒活化的影响.方法 选择1999年1月至2007年1月问进行肾移植术的200例受者为研究对象,其中100例基础免疫抑制方案为他克莫司(FK506)十霉酚酸酯(MMF)的受者作为密切观察组;另100例基础免疫抑制方案不同、但在年龄和术后是否发生急性排斥反应方面与密切观察组受者相一致(按1:1匹配)的受者作为对照观察组.在肾移植术后平均15.3个月时,分别采集所有受者的血、尿样本,行BK病毒尿沉渣Decoy细胞计数与BK病毒DNA含量的检测.分析和比较尿Decoy细胞计数、尿BK病毒含量及血BK病毒含量之间的关系;比较两组Decoy细胞、BK病毒尿症与BK病毒血症阳性率的差异.结果 200例受者的尿Decoy细胞、BK病毒尿症与病毒血症的阳性率分别为:34.0%、36.0%和16.5%.尿Decoy细胞计数与尿BK病毒含量呈正相关(r=0.714,P＜0.001),但尿液和外周血中BK病毒含量无明显相关性(P＞0.05).密切观察组的尿Decoy细胞、BK病毒尿症与BK病毒血症的阳性率分别为49%、50%和24%,对照观察组上述指标的阳性率分别是19%、22%和9%,两组的差异有统计学意义(P＜0.01).结论 尿沉渣Decoy细胞计数方法简单、易行并敏感,可以做为BK病毒活化的指标;血、尿BK病毒DNA的检测可进一步了解病毒活化情况、筛杳BK病毒相关的移植肾肾病.FK506+MMF的组合免疫抑制方案易发生BK病毒的活化,受者术后需进行密切观察和相关的检测.     

Cytomegalovirus Disease in Renal Transplant Recipients: A Single-Center Experience

Cytomegalovirus (CMV) disease is an important complication and an independent risk factor for acute rejection and recipient morbidity-mortality. The aim of this study was to review the results of CMV disease in renal transplant recipients. Method. We have retrospectively analyzed CMV disease in 120 renal transplant recipients and recorded the demographic features, clinical manifestations, and immunosuppressive regimens. Results. Twenty-nine recipients (24.1%) developed CMV disease after a median interval of 2.8 ± 2,6 months from transplantation. CMV disease developed in 36.3% of recipients who received basiliximab as induction therapy and 21.4% of recipients who were treated with anti-thymocyte globulin (ATG). The most commonly used immunosuppressive regimen was cyclosporine-A (CsA)-based (79.3%). The mean cumulative steroid dose until the diagnosis was 3,600 mg methyl prednisolone per patient. Malaise, fever, and diarrhea were the most common symptoms. Gastritis, pneumonia, and transaminitis were the most commonly seen end-organ involvements. Frequent laboratory findings were leukopenia (34.5%), increased serum creatinine level (34.5%), and leukocytosis (20.7%). We performed renal biopsy to seven patients and detected acute rejection in four patients. In 25 patients, immunosuppressive treatment was modified. Relapsing CMV disease was seen in seven patients. Conclusion. In our study, CMV disease was seen in recipients who were treated with basiliximab, a finding similar to recipients who were treated with ATG.     

A Retrospective Analysis of Ezetimibe Treatment in Renal Transplant Recipients

A retrospective review was conducted to determine the safety and efficacy of ezetimibe as a treatment option for renal transplant recipients. We evaluated the medical records of 34 adult renal transplant recipients receiving ezetimibe as monotherapy or combination therapy. Fasting lipid profiles were obtained at baseline and at 1-6 months post-ezetimibe initiation. Twenty patients received cyclosporine, 12 patients received tacrolimus, 1 patient received either sirolimus or no calcineurin therapy at the time of ezetimibe initiation. Monotherapy was started in 8 patients, who had all previously failed statins, and combination therapy was utilized in 26 patients. Monotherapy or combination therapy resulted in a mean reduction in total cholesterol of 23.3%, triglycerides 40.2%, low-density lipoproteins 16.8% and high-density lipoproteins 4.8% after 3.1 months of therapy. Ezetimibe as combination or monotherapy is a safe and effective treatment option for dyslipidemia in renal transplant recipients without changes in calcineurin inhibitor levels or renal function.