Comparison of the effects of standard vs low-dose prolonged-release tacrolimus with or without ACEi/ARB on the histology and function of renal allografts.

Targeting the renin-angiotensin system and optimizing tacrolimus exposure are both postulated to improve outcomes in renal transplant recipients (RTRs) by preventing interstitial fibrosis/tubular atrophy (IF/TA). In this multicenter, prospective, open-label controlled trial, adult de novo RTRs were randomized in a 2 × 2 design to low- vs standard-dose (LOW vs STD) prolonged-release tacrolimus and to angiotensin-converting enzyme inhibitors/angiotensin II receptor 1 blockers (ACEi/ARBs) vs other antihypertensive therapy (OAHT). There were 2 coprimary endpoints: the prevalence of IF/TA at month 6 and at month 24. IF/TA prevalence was similar for LOW vs STD tacrolimus at month 6 (36.8% vs 39.5%; P = .80) and ACEi/ARBs vs OAHT at month 24 (54.8% vs 58.2%; P = .33). IF/TA progression decreased significantly with LOW vs STD tacrolimus at month 24 (mean [SD] change, +0.42 [1.477] vs +1.10 [1.577]; P = .0039). Across the 4 treatment groups, LOW + ACEi/ARB patients exhibited the lowest mean IF/TA change and, compared with LOW + OAHT patients, experienced significantly delayed time to first T cell-mediated rejection. Renal function was stable from month 1 to month 24 in all treatment groups. No unexpected safety findings were detected. Coupled with LOW tacrolimus dosing, ACEi/ARBs appear to reduce IF/TA progression and delay rejection relative to reduced tacrolimus exposure without renin-angiotensin system blockade. ClinicalTrials.gov identifier: NCT00933231.

Levofloxacin for BK virus prophylaxis following kidney transplantation: a randomized clinical trial.

IMPORTANCE: BK virus infection is a significant complication of modern immunosuppression used in kidney transplantation. Viral reactivation occurs first in the urine (BK viruria) and is associated with a high risk of transplant failure. There are currently no therapies to prevent or treat BK virus infection. Quinolone antibiotics have antiviral properties against BK virus but efficacy at preventing this infection has not been shown in prospective controlled studies. OBJECTIVE: To determine if levofloxacin can prevent BK viruria in kidney transplant recipients. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, placebo-controlled randomized trial involving 154 patients who received a living or deceased donor kidney-only transplant in 7 Canadian transplant centers between December 2011 and June 2013. INTERVENTIONS: Participants were randomly assigned to receive a 3-month course of levofloxacin (500 mg/d; n = 76) or placebo (n = 78) starting within 5 days after transplantation. MAIN OUTCOMES AND MEASURES: The primary outcome was time to occurrence of BK viruria (detected using quantitative real-time polymerase chain reaction) within the first year after transplantation. Secondary outcomes included BK viremia, peak viral load, rejection, and patient and allograft survival. RESULTS: The mean follow-up time was 46.5 weeks in the levofloxacin group and 46.3 weeks in the placebo group (27 patients had follow-up terminated before the end of the planned follow-up period or development of viruria because the trial was stopped early owing to lack of funding). BK viruria occurred in 22 patients (29%) in the levofloxacin group and in 26 patients (33.3%) in the placebo group (hazard ratio, 0.91; 95% CI, 0.51-1.63; P = .58). There was no significant difference between the 2 groups in regard to any of the secondary end points. There was an increased risk of resistant infection among isolates usually sensitive to quinolones in the levofloxacin group vs placebo (14/24 [58.3%] vs 15/45 [33.3%], respectively; risk ratio, 1.75; 95% CI, 1.01-2.98) as well as a nonsignificant increased risk of suspected tendinitis (6/76 [7.9%] vs 1/78 [1.3%]; risk ratio, 6.16; 95% CI, 0.76-49.95). CONCLUSIONS AND RELEVANCE: Among kidney transplant recipients, a 3-month course of levofloxacin initiated early following transplantation did not prevent BK viruria. Levofloxacin was associated with an increased risk of adverse events such as bacterial resistance. These findings do not support the use of levofloxacin to prevent posttransplant BK virus infection. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01353339.

Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno-osseous dysplasia.

Schimke immuno-osseous dysplasia (SIOD, MIM 242900) is an autosomal-recessive pleiotropic disorder with the diagnostic features of spondyloepiphyseal dysplasia, renal dysfunction and T-cell immunodeficiency. Using genome-wide linkage mapping and a positional candidate approach, we determined that mutations in SMARCAL1 (SWI/SNF2-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1), are responsible for SIOD. Through analysis of data from persons with SIOD in 26 unrelated families, we observed that affected individuals from 13 of 23 families with severe disease had two alleles with nonsense, frameshift or splicing mutations, whereas affected individuals from 3 of 3 families with milder disease had a missense mutation on each allele. These observations indicate that some missense mutations allow retention of partial SMARCAL1 function and thus cause milder disease.

Prospective monitoring of BK polyomavirus infection early posttransplantation in nonrenal solid organ transplant recipients.

BACKGROUND: BK virus-associated nephropathy is an important cause of renal dysfunction in renal transplant recipients. Renal dysfunction after nonrenal solid organ transplantation (NRSOT) is common; however, the impact of BK virus remains uncertain. METHODS: Sixty (7 heart, 25 liver, and 28 lung) NRSOT recipients were enrolled in this single center prospective longitudinal study. Urine and plasma were collected for detection of BK viral load using a real-time quantitative polymerase chain reaction assay at transplantation and at 3, 6, and 9 months posttransplantation. Demographic and clinical data including serum creatinine and immunosuppressive therapy were also collected. RESULTS: BK viruria was detected in 16 of 193 (8.3%) samples corresponding to 9 of 60 (15%) subjects. The median BK viral load was 1.12 x 10 (range, 1.1 x 10-2.66 x 10) copies per milliliter. No viremia was detected. In seven of nine, viruria occurred by 3 months posttransplantation. At 9 months of posttransplantation, the median Modification of Diet in Renal Disease-estimated glomerular filtration rate in those with BK viruria on at least one sample was similar to those without viruria (58.0 [IQR 43.1-60.7] mL/min/1.73 m vs. 61.4 [IQR 50.6-74.4] mL/min/1.73 m; P=0.39). CONCLUSIONS: Although BK infection was common in this NRSOT population, BK viremia was not observed and there was no association between BK viruria and renal dysfunction. Our data suggest that routine surveillance for BK virus early posttransplantation in NRSOT may not be warranted but should be further examined in a larger multicenter trial.

Schimke immunoosseous dysplasia: suggestions of genetic diversity.

Schimke immunoosseous dysplasia (SIOD), which is characterized by prominent spondyloepiphyseal dysplasia, T-cell deficiency, and focal segmental glomerulosclerosis, is a panethnic autosomal recessive multisystem disorder with variable expressivity. Biallelic mutations in switch/sucrose nonfermenting (swi/snf) related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1) are the only identified cause of SIOD. However, among 72 patients from different families, we identified only 38 patients with biallelic mutations in the coding exons and splice junctions of the SMARCAL1 gene. This observation, the variable expressivity, and poor genotype-phenotype correlation led us to test several hypotheses including modifying haplotypes, oligogenic inheritance, or locus heterogeneity in SIOD. Haplotypes associated with the two more common mutations, R820H and E848X, did not correlate with phenotype. Also, contrary to monoallelic SMARCAL1 coding mutations indicating oligogenic inheritance, we found that all these patients did not express RNA and/or protein from the other allele and thus have biallelic SMARCAL1 mutations. We hypothesize therefore that the variable expressivity among patients with biallelic SMARCAL1 mutations arises from environmental, genetic, or epigenetic modifiers. Among patients without detectable SMARCAL1 coding mutations, our analyses of cell lines from four of these patients showed that they expressed normal levels of SMARCAL1 mRNA and protein. This is the first evidence for nonallelic heterogeneity in SIOD. From analysis of the postmortem histopathology from two patients and the clinical data from most patients, we propose the existence of endophenotypes of SIOD.

Conversion from calcineurin inhibitors to sirolimus for chronic renal allograft dysfunction: a systematic review of the evidence.

BACKGROUND: Conversion from a calcineurin inhibitor to sirolimus has been used as a strategy to improve deteriorating renal allograft function but the efficacy and safety of this intervention is unknown. METHODS: We performed a systematic review of studies that involved conversion from a calcineurin inhibitor to sirolimus in kidney transplantation. The search yielded five randomized trials (n=1,040 patients) and 25 nonrandomized studies (n=977 patients). RESULTS: In the randomized trials, conversion to sirolimus improved short-term creatinine clearance (weighted mean difference 6.4 mL/min; 95% CI 1.9 to 11.0) compared to controls. In the nonrandomized studies, renal function improved or stabilized in 66% (95% CI 61% to 72%), creatinine clearance improved (weighted mean change 5.7 mL/min; 95% CI 1.4 to 10.1), cholesterol increased (weighted mean change 20.8 mg/dL; 95% CI 11.2 to 30.4) and triglycerides increased (weighted mean change 40.1 mg/dL; 95% CI 18.6 to 61.7). Sirolimus was discontinued by 28% of patients (95% CI 0 to 59%) in the randomized trials and 17% (95% CI 12 to 22%) in the nonrandomized trials. CONCLUSION: Conversion to sirolimus is associated with an improvement in short-term renal function. However, given the discontinuation rate and potential side effects, adequately powered randomized trials with longer follow-up of hard outcomes are needed to determine whether this strategy leads to a lasting benefit in the clinical care of transplant recipients.

National recommendations for donation after cardiocirculatory death in Canada: Donation after cardiocirculatory death in Canada.

These recommendations are the result of a national, multidisciplinary, year-long process to discuss whether and how to proceed with organ donation after cardiocirculatory death (DCD) in Canada. A national forum was held in February 2005 to discuss and develop recommendations on the principles, procedures and practice related to DCD, including ethical and legal considerations. At the forum's conclusion, a strong majority of participants supported proceeding with DCD programs in Canada. The forum also recognized the need to formulate and emphasize core values to guide the development of programs and protocols based on the medical, ethical and legal framework established at this meeting. Although end-of-life care should routinely include the opportunity to donate organs and tissues, the duty of care toward dying patients and their families remains the dominant priority of health care teams. The complexity and profound implications of death are recognized and should be respected, along with differing personal, ethnocultural and religious perspectives on death and donation. Decisions around withdrawal of life-sustaining therapies, management of the dying process and the determination of death by cardiocirculatory criteria should be separate from and independent of donation and transplant processes. The recommendations in this report are intended to guide individual programs, regional health authorities and jurisdictions in the development of DCD protocols. Programs will develop based on local leadership and advance planning that includes education and engagement of stakeholders, mechanisms to assure safety and quality and public information. We recommend that programs begin with controlled DCD within the intensive care unit where (after a consensual decision to withdraw life-sustaining therapy) death is anticipated, but has not yet occurred, and unhurried consent discussions can be held. Uncontrolled donation (where death has occurred after unanticipated cardiac arrest) should only be considered after a controlled DCD program is well established. Although we recommend that programs commence with kidney donation, regional transplant expertise may guide the inclusion of other organs. The impact of DCD, including pre-and post-mortem interventions, on donor family experiences, organ availability, graft function and recipient survival should be carefully documented and studied.

Why take the chance? A qualitative grounded theory study of nocturnal haemodialysis recipients who decline kidney transplantation.

OBJECTIVE: The objective of this study was to examine the factors that influence decision-making to forgo transplantation in favour of remaining on nocturnal haemodialysis (NHD). DESIGN: A grounded theory approach using in-depth telephone interviewing was used. SETTING: Participants were identified from 2 tertiary care renal programmes in Canada. PARTICIPANTS: The study participants were otherwise eligible patients with end-stage renal disease who have opted to remain off of the transplant list. A total of 7 eligible participants were interviewed. 5 were male. The mean age was 46 years. ANALYSIS: A constant comparative method of analysis was used to identify a core category and factors influencing the decision-making process. RESULTS: In this grounded theory study of people receiving NHD who refused kidney transplantation, the core category of 'why take a chance when things are going well?' was identified, along with 4 factors that influenced the decision including 'negative past experience', 'feeling well on NHD', 'gaining autonomy' and 'responsibility'. CONCLUSIONS: This study provides insight into patients' thought processes surrounding an important treatment decision. Such insights might help the renal team to better understand, and thereby respect, patient choice in a patient-centred care paradigm. Findings may also be useful in the development of education programmes addressing the specific concerns of this population of patients.

Efficacy and safety outcomes among de novo renal transplant recipients managed by C2 monitoring of cyclosporine a microemulsion: results of a 12-month, randomized, multicenter study.

BACKGROUND: The clinical benefits of C2 monitoring of cyclosporine microemulsion have been demonstrated, but C2 targets in renal transplant recipients during the first year require validation. METHODS: MO2ART was a prospective, multicenter study of renal transplant recipients managed by C2 monitoring of cyclosporine microemulsion with steroids and mycophenolate mofetil or azathioprine. Patients were randomized on day 3 to two groups, which were managed from month 3 with higher or lower C2 target ranges (months 4-6, 1,000-1,200 ng/mL vs. 800-1,000 ng/mL; months 7-12, 800-1,000 ng/mL vs. 600-800 ng/mL, respectively). The primary endpoint was the glomerular filtration rate (GFR) at month 12. RESULTS: A total of 296 patients were recruited, of whom 250 remained in the study at 3 months (higher-C2, n=131; lower-C2, n=119). GFR at 12 months did not differ between the higher- and lower-C2 groups (65+/-17 mL/min vs. 66+/-14 mL/min). When patients were regrouped according to C2 achieved by months 8 to 12, those with the lowest C2 (<700 ng/mL) showed the lowest GFR at month 3 and the most pronounced increase in GFR between month 3 and month 12 (P=0.04). Five episodes of biopsy-proven acute rejection occurred after month 3 (higher-C2 group, n=2; lower-C2 group, n=3). The overall 12-month Kaplan-Meier incidence of biopsy-proven acute rejection was 13.7%. Patient and graft survival were 93% and 89%, respectively, at 12 months. CONCLUSION: Both C2 target ranges investigated showed excellent and nearly equivalent outcomes at 12 months. The decision to target the higher or lower end of these C2 ranges should be made on an individual basis, taking into account patient and graft characteristics, and co-medication.

Quinolone prophylaxis for the prevention of BK virus infection in kidney transplantation: study protocol for a randomized controlled trial.

BACKGROUND: BK virus infection has emerged as a major complication in kidney transplantation leading to a significant reduction in graft survival. There are currently no proven strategies to prevent or treat BK virus infection. Quinolone antibiotics, such as levofloxacin, have demonstrated activity against BK virus. We hypothesize that administration of a quinolone antibiotic, when given early post-transplantation, will prevent the establishment of BK viral replication in the urine and thus prevent systemic BK virus infection. METHODS/DESIGN: The aim of this pilot trial is to assess the efficacy, safety and feasibility of a 3-month course of levofloxacin in the kidney transplant population. This is a multicenter, randomized, double-blind, placebo-controlled trial with two parallel arms conducted in 11 Canadian kidney transplant centers. A total of 154 patients with end-stage renal disease undergoing kidney transplantation will be randomized to receive a 3-month course of levofloxacin or placebo starting in the early post-transplant period. Levofloxacin will be administered at 500 mg po daily with dose adjustments based on kidney function. The primary outcome will be the time to occurrence of BK viruria within the first year post-transplantation. Secondary outcomes include BK viremia, measures of safety (adverse events, resistant infections,Clostridium difficile-associated diarrhea), measures of feasibility (proportion of transplanted patients recruited into the trial), proportion of patients adherent to the protocol, patient drop-out and loss to follow-up,and use of quinolone antibiotics outside of the trial protocol. DISCUSSION: Results from this pilot study will provide vital information to design and conduct a large, multicenter trial to determine if quinolone therapy decreases clinically meaningful outcomes in kidney transplantation. If levofloxacin significantly reduces BK viruria and urine viral loads in kidney transplantation, it will provide important justification to progress to the larger trial. If the full trial shows that levofloxacin significantly reduces BK infection and improves outcomes, its use in kidney transplantation will be strongly endorsed given the lack of proven therapies for this condition. TRIAL REGISTRATION: This trial was funded by the Canadian Institutes of Health Research (grant number:222493) and is registered at ClinicalTrials.gov (NCT01353339).

Cardiovascular assessment of diabetic end-stage renal disease patients before renal transplantation.

BACKGROUND: Although consensus guidelines for preoperative cardiovascular (CV) assessment exist, diabetic patients with renal insufficiency (DM/RI) undergoing assessment for renal transplantation are a unique high-risk group that remains poorly investigated. METHODS: A consecutive cohort of DM/RI patients being assessed for renal transplantation was studied. We analyzed the ability of clinical characteristics and noninvasive investigation to predict significant coronary artery disease (CAD) and incidence of major adverse CV events. RESULTS: Baseline characteristics (n = 280) are as follows: mean age 48.6 years (± 11.5 standard deviation), 66% men, diabetes duration 22.6 years (mean ± 8.9 standard deviation), 92% hypertension, 46% hypercholesterolemia, 24% family history CAD, and 21% known CAD. Abnormal myocardial perfusion imaging was found in 27.8%, and 56.5% had CAD more than or equal to 50%. Although positive myocardial perfusion imaging was the only independent predictor of CAD (odds ratio 7.18, 95% confidence interval 2.98-17.3), a poor negative predicted value was observed with normal imaging in 50.3% of patients having CAD more than or equal to 50%, 35.4% CAD more than 70%, and 41.8% Duke angiographic score more than or equal to 4. At mean follow up of 4 years (median 3.9), 76 of 280 patients suffered major adverse cardiovascular events including 17% mortality. Angiographic evidence of CAD (≥ 70% odds ratio 1.81, 95% confidence interval 1.02-3.23) was the only independent predictor of major adverse cardiac events. CONCLUSION: DM/RI patients being assessed for renal transplantation have frequent CV risk factors, high likelihood of CAD, and a 28% incidence of major adverse cardiac events after 4 years. Myocardial perfusion imagining is of little clinical utility as a screening tool for CAD in this population. Only angiographic CAD was predictive of subsequent major adverse cardiac events. Further studies of risk stratification and revascularization in this high-risk population are warranted.

The prognostic utility of deceased donor implantation biopsy in determining function and graft survival after kidney transplantation.

BACKGROUND: Uncertainty remains in the prognostic utility of biopsies of deceased donor kidneys in predicting graft outcomes. METHODS: We examined implantation biopsies for 730 kidney transplant recipients from 491 deceased donors from 1990 to 2004. The median follow-up time was 5.1 years. Of the 730 transplants, 633 (86.7%) had implantation biopsies (wedge 89.1%). Of these 633, 541 (85.5%) could be assessed for % glomerulosclerosis (GS), interstitial fibrosis, tubular atrophy, arteriolar hyalinosis, and fibrous intimal thickening. Independent risk factors for delayed graft function include regraft, longer cold ischemia time, and DR mismatch, but not donor age. Independent risk factors for worse function at 6 months include regraft, older donor and recipient, female donor and recipient, and rejection. Independent risk factors of graft failure include regraft, older donor age, male recipient, and rejection. RESULTS: Of the histologic scores, arteriolar hyalinosis was independently associated with delayed graft function and graft loss, whereas fibrous intimal thickening was associated with decreased 6-month renal function. Importantly, the degree of GS was not independently associated with outcomes. CONCLUSIONS: Therefore, although biopsy evidences of vascular pathologic condition, kidney may contribute meaningfully to the assessment of donor quality but the degree of GS does not.

Factors associated with progression of interstitial fibrosis in renal transplant patients receiving tacrolimus and mycophenolate mofetil.

BACKGROUND: We recently reported a randomized study in renal transplant patients (RTP) receiving tacrolimus, mycophenolate mofetil, and prednisone in which patients who had early protocol biopsies (PBx) derived no benefit compared with controls (no PBx) at 6 months, likely due to the low prevalence of subclinical rejection. We report on the follow-up of these patients to 24 months at which time a repeat PBx and tests of renal function were performed. METHODS: Of the 240 RTP randomized, 22 were excluded for a protocol violation. Approximately 75% of the remaining 218 (111 PBx and 107 controls) completed the study. RESULTS: At 24 months, graft function was excellent with a mean creatinine clearance of approximately 74 mL/min and negligible proteinuria; however, the prevalence of interstitial fibrosis and tubular atrophy (IF/TA)-ci + ct more than or equal to 2-increased from approximately 3% at baseline to up to 40% to 50%. By logistic regression analysis, the only independent positive correlate of IF/TA was transplantation with a deceased donor. However, by post hoc analysis, use of angiotensin-II-converting enzyme inhibitors or angiotensin II receptor blockers was negatively correlated with both the prevalence of IF/TA at 24 months and its progression between 6 and 24 months in RTP that had paired biopsies. CONCLUSIONS: A regimen of tacrolimus, mycophenolate mofetil, and prednisone results in excellent renal function at 24 months posttransplant but with a progressive increase in IF/TA. A potential inhibitory effect of angiotensin-II-converting enzyme inhibitor/angiotensin II receptor blockers on IF/TA is suggested that requires confirmation in a randomized study.

Non-melanoma skin cancer incidence and risk factors after kidney transplantation: a Canadian experience.

BACKGROUND: Non-melanoma skin cancer (NMSC) after kidney transplantation is common and can result in significant morbidity and mortality. Incidence and risk factors for NMSC can vary between geographic locations and there is no literature describing the incidence or risk factors for NMSC in Canada. METHODS: The purpose of this retrospective cohort study was to determine the incidence of NMSC, the time of development of NMSC, and risk factors (including sun exposure history) for NMSC in kidney transplant recipients between 1990 and 2003 in our center (n=926). RESULTS: We observed a 9.7% incidence of NMSC lesions after kidney transplant with a median time of development of a first NMSC lesion of 4 years. Risk factors for NMSC (multivariate analysis) include older men (>45 years), a history of posttransplant warts, and longer duration of residence in a northern climate. CONCLUSION: We conclude that NMSC is common after kidney transplantation in a northern climate and these individuals require disease prevention-specific education, more vigilant surveillance and early referral and treatment.

Five-year study of tacrolimus as secondary intervention versus continuation of cyclosporine in renal transplant patients at risk for chronic renal allograft failure.

BACKGROUND: Chronic allograft nephropathy is the most frequent cause of long-term kidney allograft loss. Studies are desperately needed to improve long-term survival. Tacrolimus has been associated with less rejection and better kidney function compared with cyclosporine in clinical trials. This study tested the hypothesis that conversion from cyclosporine to tacrolimus might improve long-term outcomes in patients with chronic allograft damage. METHODS: In this multicenter Canadian clinical trial, cyclosporine-treated patients with biopsy-proven chronic allograft nephropathy and impaired renal function were randomly assigned (2:1) to convert to tacrolimus or continue on cyclosporine therapy. A total of 106 (70 tacrolimus and 36 cyclosporine treated) patients were followed-up for up to 5 years. The primary outcome was graft survival. RESULTS: In an intention to treat analysis, subsequent graft (73% vs. 81%, P=0.2835, log-rank test) and patient survival (91% vs. 92%, P=0.8668, log-rank test) were not different between the tacrolimus and cyclosporine groups, respectively. Changes in Chronic Allograft Damage Index scores on protocol biopsies from baseline to 3 years were not different (+0.4+/-1.8 vs. +1.3+/-3.2, P=0.5910, cyclosporine vs. tacrolimus, respectively). There were no significant differences in biopsy-proven acute rejection (6 [8.6%] vs. 2 [5.6%], tacrolimus vs. cyclosporine, respectively, P=0.5906). CONCLUSIONS: In this study, patients with chronic allograft damage converted from cyclosporine to tacrolimus demonstrated no apparent benefit.

Monitoring of polyomavirus BK virus viruria and viremia in renal allograft recipients by use of a quantitative real-time PCR assay: one-year prospective study.

We have developed a real-time quantitative PCR (rt-QPCR) assay to detect and kinetically monitor BK virus viruria and viremia in renal transplant recipients (RTRs). A total of 607 urine and 223 plasma samples were collected from 203 individuals including those with BK virus-associated nephropathy (BKVAN) (n = 8), those undergoing routine posttransplant surveillance (SV) (n = 155), those with nontransplant chronic kidney disease (NT-CKD) (n = 20), and healthy living kidney donors (LD) (n = 20). The rt-QPCR assay was found to be highly sensitive and specific, with a wide dynamic range (2.4 to 11 log(10) copies/ml) and very good precision (coefficient of variation, approximately 5.9%). There was a significant difference in the prevalences of viruria and viremia between the BKVAN (100% and 100%) and SV (23% and 3.9%) groups (P < 0.001). No viruria or viremia was detected in LD or in NT-CKD patients. The median (range) peak levels of BK virus viruria and viremia, in log(10) copies/ml, were 10.26 (9.04 to 10.83) and 4.83 (3.65 to 5.86) for the BKVAN group versus 0 (0 to 10.83) and 0 (0 to 5.65) for the SV group, respectively (P < 0.001). When the BK virus load in the urine was <7.0 log(10) copies/ml, no BK virus viremia was detected. When the BK virus load in the urine reached 7.0, 8.0, 9.0, and > or =10.0 log(10) copies/ml, the corresponding detection of BK virus viremia increased to 20, 33, 50, and 100%, respectively. We propose monitoring of BK virus viruria in RTRs, with plasma BK virus load testing reserved for those with viruria levels of > or =7.0 log(10) copies/ml.

Proteinuria developing after clinical islet transplantation resolves with sirolimus withdrawal and increased tacrolimus dosing.

Sirolimus is a potent immunosuppressant, which may permit the avoidance of nephrotoxic calcineurin inhibitors (CNI). However, cases of proteinuria associated with sirolimus have been reported following renal transplantation. Here, we report three cases of proteinuria (1, 2 and 7 g/day) developing during therapy with sirolimus plus low-dose tacrolimus following clinical islet transplantation (CIT) in type I diabetic subjects. The proteinuria resolved after discontinuation of sirolimus, substituted by mycophenolate mofetil (MMF) combined with an increased dose of tacrolimus. A renal biopsy in one case indicated only the presence of diabetic glomerulopathy. Five other CIT recipients developed microalbuminuria while on sirolimus which all resolved after switching to tacrolimus and MMF. The resolution of proteinuria from the native kidneys of CIT recipients after the discontinuation sirolimus suggests that, at least in some individuals, sirolimus itself may have adverse renal effects. Sirolimus should be used cautiously with close monitoring for proteinuria or renal dysfunction.