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.

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.

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.

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.

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.

Development of diabetes mellitus following kidney transplantation: a Canadian experience.

The onset of diabetes mellitus following kidney transplantation or post-transplant diabetes mellitus (PTDM) is now recognized as being an increasingly common complication that is associated with poor graft and patient survival. The incidence and clinical correlates of PTDM in a Canadian kidney transplant population has not been examined and may vary based on differences in demographics (i.e. race). Furthermore, little information exists on the association of variables such as cumulative dose of corticosteroids and trough calcineurin inhibitor levels and PTDM. We examined all recipients of a kidney transplant in our center between 1995 and 2001 and found an overall PTDM rate of 9.8%. Five clinical factors were independently associated with PTDM: older recipient age, deceased donor, hepatitis C antibody status, rejection episode and use of tacrolimus (vs. cyclosporine). Furthermore, cumulative corticosteroid dose and calcineurin inhibitor trough level were not associated with PTDM. This study demonstrates that in a Canadian kidney transplant population that there is a significant risk of PTDM following kidney transplantation, and it is therefore advisable to minimize this risk.

The stability of the glomerular filtration rate after renal transplantation is improving.

The 6-mo function and the stability of function posttransplantation in 429 cadaver renal transplants was investigated from 1990 to 2000. The 6-mo creatinine clearance (CrCl) and the rate of change of CrCl beyond 6 mo posttransplantation were calculated. The mean 6-mo CrCl was 64.6 +/- 1.1 ml/min and was stable between 1990 and 2000. The net slope of CrCl was -1.4 +/- 0.5 ml/min per yr. The slope has improved in recent years, such that the mean slopes in the period after 1997 are actually positive (+3.5 ml/min per yr). The slope of CrCl beyond 6 mo was not related to the actual value of the 6 mo CrCl, i.e., there was no accelerated loss of function at low CrCl levels. The 6-mo CrCl was independently determined by donor factors (age, gender), recipient factors (age, gender), and immune factors (rejection episodes, regraft status). The slope of the CrCl correlated independently with the transplant year, recipient gender, rejection episodes, diastolic BP, and the choice of immunosuppressive drugs. Cytomegalovirus infection and mismatch status and lipid levels and treatment were not independently associated with slope or 6-mo CrCl. Thus, the most striking change in the course of renal transplants over the past decade is the new stability of function, correlating with reduced rejection and probably due at least in part to the new immunosuppressive agents. Despite continued calcineurin inhibitor use, late improvement in function now occurs in many cadaver kidney transplants, suggesting a previously unappreciated capacity for functional adaptation.

Donor tissue characteristics influence cadaver kidney transplant function and graft survival but not rejection.

Acute injury and age are characteristics of transplanted tissue that influence many aspects of the course of a renal allograft. The influence of donor tissue characteristics on outcomes can be analyzed by studying pairing, the extent to which two kidneys retrieved from the same cadaver donor manifest similar outcomes. Pairing studies help to define the relative role of donor-related factors (among pairs) versus non-donor factors (within pairs). This study analyzed graft survival for 220 pairs of cadaveric kidneys for the similarity of parameters reflecting function and rejection. It also examined whether the performance of one kidney was predicted by the course of its "mate," the other kidney from that donor. Parameters reflecting function showed sustained pairing posttransplantation, as did graft survival. In contrast, measures of rejection strongly affected survival but showed no pairing. Surprisingly, the survival of a kidney was predicted by the early performance of its mate, an observation we term the "mate effect." Six-month graft survival and renal function were reduced in grafts for which the mate kidney displayed any criteria for functional impairment (dialysis dependency, low urine output [/= 400 micro mol/L), even for kidneys which themselves lacked those criteria. Rejection measures did not demonstrate the mate effect. In conclusion, kidney transplant function is strongly linked to donor-related factors (age, brain death). In contrast, rejection affects survival and function, but it is not primarily determined by the characteristics of the donor tissue. Graft survival reflects both of these influences.

Time dependency of factors affecting renal allograft survival.

The function of renal transplants can deteriorate at any time posttransplant, but the risks and mechanisms may differ at different times posttransplant. Survival of 522 consecutive cadaveric renal transplant recipients followed for at least 6 mo were analyzed, with patient death censored. The overall risk factors in univariate analysis were acute rejection requiring antibody therapy (AR), delayed graft function, elevated serum creatinine at 6 mo, high panel-reactive antibodies, and donor age > or =55 yr, with borderline effects of recipient age and female gender. These risks were studied in each of three intervals posttransplantation: < or =6 mo, 6 mo to 5 yr, and >5 yr. Of the 135 graft failures, 53 occurred < or =6 mo, 61 between 6 mo and 5 yr, and 21 beyond 5 yr. By multivariate analysis. the risks for graft failure in interval < or =6 mo were AR (hazard ratio (HR) = 4.86, P < 0.001); delayed graft function (HR = 1.47, P = 0.06): and high panel-reactive antibodies (HR = 2.04, P = 0.0(3). Between 6 mo and 5 yr, the risks for graft loss were AR (HR = 2.87, P < 0.001) and serum creatinine at 6 mo > or =150 micromol/L (HR = 3.69, P < 0.001). Beyond 5 yr the risk factors were donor age > or =55 yr (HR = 5.87, P = 0.002), with a borderline effect of kidneys from female donors (HR = 2.28, P = 0.07). HLA-A, -B, and -DR matching and presensitization had most of their effect through early AR and impaired function. The results indicate that risks for graft loss are time-dependent: early losses correlate with injury and rejection, but late events correlate with donor age and possibly workload.