Olusegun Famure

Time-dependent variability in tacrolimus trough blood levels is a risk factor for late kidney transplant failure

Wide variations in tacrolimus levels have been identified as a risk factor for inferior kidney allograft survival but past studies have not properly accounted for the dynamic nature of drug exposure over time. Here we evaluated whether time-varying exposure to tacrolimus increases the risk of long-term adverse outcomes in a retrospective cohort study in adult kidney transplant recipients on tacrolimus-based immunosuppression. Time-dependent Cox proportional hazards models were used to examine the association between the standard deviation of tacrolimus levels (TacSD) starting at 1-year post-transplant and the composite end point of late allograft rejection, transplant glomerulopathy, or total graft loss (including death). Among 356 patients, there was a significant 27% increase in the adjusted hazard of the composite end point for every 1-unit increase in TacSD (hazard ratio 1.27 (95% confidence interval 1.03, 1.56)). There was also a graded increase in the relative hazard for the composite end point by TacSD threshold (hazard ratios 1.33, 1.50, 1.84, and 2.56 for TacSD 1.5, 2, 2.5, and 3, respectively). The results were similar for total graft loss and the composite end point excluding death. Thus, increased time-dependent TacSD may be an independent risk factor for adverse kidney transplant outcomes. TacSD may serve as a monitoring tool to identify high-risk patients. Whether interventions to decrease TacSD will improve outcomes requires further study.

Delayed graft function and the risk of acute rejection in the modern era of kidney transplantation

Delayed graft function (DGF) is commonly considered a risk factor for acute rejection, although this finding has not been uniformly observed across all studies. The link between DGF and acute rejection may have changed over time due to advances in immunosuppression and medical management. Here we conducted a cohort study of 645 patients over 12 years to evaluate the association of DGF and biopsy-proven acute rejection (BPAR) in a modern cohort of kidney transplant recipients. DGF was defined as the need for at least one dialysis session in the first week after kidney transplantation. The 1-, 3-, and 5-year cumulative probabilities of BPAR were 16.0, 21.8, and 22.6% in the DGF group, significantly different from the 10.1, 12.4, and 15.7% in the non-DGF group. In multivariable Cox proportional hazards model, the adjusted relative hazard for BPAR in DGF (vs. no DGF) was 1.55 (95% confidence interval (CI): 1.03, 2.32). This association was generally robust to different definitions of DGF. The relative hazard was also similarly elevated for T-cell- or antibody-mediated BPAR (1.52 (0.92, 2.51) and 1.54 (0.85, 2.77), respectively). Finally, the association was consistent across clinically relevant subgroups. Thus DGF remains an important risk factor for BPAR in a contemporary cohort of kidney transplant recipients. Interventions to reduce the risk of DGF and/or its aftereffects remain of paramount importance to improve kidney transplant outcomes.

Increased recipient body mass index is associated with acute rejection and other adverse outcomes after kidney transplantation.

Background Outcomes of kidney transplant recipients with increased body mass index (BMI) remain controversial. We studied the relationship between BMI and clinically relevant outcomes among kidney transplant recipients at a large center. Methods We performed an observational cohort study of all recipients of kidney transplants at our center from January 1, 2000 to December 31, 2010 to determine if increased BMI at transplantation is associated with adverse outcomes, including delayed graft function and biopsy-proven acute rejection (BPAR). Recipient BMI was categorized as <20, 20 to 24.9 (reference), 25 to 29.9, 30 to 34.9, and ≥35 kg/m2. Potential confounders were included in logistic and Cox proportional hazards models. Results A total of 1151 patients were studied. Recipient BMI of 30 to 34.9 and ≥35 kg/m2 were associated with an increased risk of delayed graft function (odds ratio [95% confidence interval [CI], 1.92 [1.16–3.19] and 4.49 [2.24–9.00], respectively). BMI≥35 kg/m2 was also associated with an increased risk of BPAR (hazard ratio [HR; 95% CI], 2.43 [1.48–3.99]), all-cause graft failure (HR [95% CI], 1.97 [1.09–3.56]), and death-censored graft failure (HR [95% CI], 2.43 [1.07–5.51]). Adjustment for acute rejection as a time-varying covariate significantly attenuated the association with graft failure endpoints. There was no significant relation between BMI and death with graft function. Conclusions Increased BMI at kidney transplantation is a predictor of adverse outcomes, including BPAR. The role of pretransplantation weight reduction in improving graft and patient outcomes requires further study.

Hypomagnesemia and the Risk of New-Onset Diabetes Mellitus after Kidney Transplantation

Several studies suggest a link between post-transplant hypomagnesemia and new-onset diabetes after transplantation (NODAT), but this relationship remains controversial. We conducted a retrospective cohort study of 948 nondiabetic kidney transplant recipients from January 1, 2000, to December 31, 2011, to examine the association between serum magnesium level and NODAT. Multivariable Cox proportional hazards models were fitted to evaluate the risk of NODAT as a function of baseline (at 1 month), time-varying (every 3 months), and rolling-average (i.e., mean for 3 months moving at 3-month intervals) serum magnesium levels while adjusting for potential confounders. A total of 182 NODAT events were observed over 2951.2 person-years of follow-up. Multivariable models showed an inverse relationship between baseline serum magnesium level and NODAT (hazard ratio [HR], 1.24 per 0.1 mmol/L decrease; 95% confidence interval [95% CI], 1.05 to 1.46; P=0.01). The association with the risk of NODAT persisted in conventional time-varying (HR, 1.32; 95% CI, 1.14 to 1.52; P<0.001) and rolling-average models (HR, 1.34; 95% CI, 1.13 to 1.57; P=0.001). Hypomagnesemia (serum magnesium <0.74 mmol/L) also significantly associated with increased risk of NODAT in baseline (HR, 1.58; 95% CI, 1.07 to 2.34; P=0.02), time-varying (HR, 1.78; 95% CI, 1.29 to 2.45; P<0.001), and rolling-average models (HR, 1.83; 95% CI, 1.30 to 2.57; P=0.001). Our results suggest that lower post-transplant serum magnesium level is an independent risk factor for NODAT in kidney transplant recipients. Interventions targeting serum magnesium to reduce the risk of NODAT should be evaluated.

Risk factors for late-onset cytomegalovirus infection or disease in kidney transplant recipients.

Background CMV-D+/R− serostatus is the only well-established risk factor for late-onset cytomegalovirus (CMV) infection/disease (i.e., incident CMV infection/disease after cessation of prophylactic antiviral therapy). This study aimed to explore other potential risk factors for late-onset CMV infection/disease in kidney transplant recipients. Methods We conducted a retrospective cohort study of 641 kidney transplant recipients in Toronto, Canada, from January 1, 2003, to December 31, 2010. The cumulative incidence of late-onset CMV infection/disease was assessed using the Kaplan-Meier product–limit method. Potential risk factors for late-onset CMV infection/disease were examined using Cox proportional hazards regression models. Results Cumulative incidence estimates for CMV infection/disease after prophylaxis cessation in D+/R− versus D+/R+ versus D−/R+ patients were 26.2% versus 7.4% versus 3.1% at 6 months and 30.0% versus 7.7% versus 3.7% at 1 year, respectively. D+/R− serostatus (vs. R+ serostatus) and an estimated glomerular filtration rate of less than 45 mL/min (vs. ≥60 mL/min) at prophylaxis cessation were independently associated with late-onset CMV infection/disease (hazard ratio, 4.04 [95% confidence interval, 2.39–6.83]; and hazard ratio, 2.03 [95% confidence interval, 1.07–3.88], respectively). Conclusions Patients with lower estimated glomerular filtration rate at prophylaxis cessation may be at an increased risk of late-onset CMV infection/disease and should be considered for more intensive CMV viral load monitoring, particularly within the first year after prophylaxis cessation.

Health information management for research and quality assurance: The Comprehensive Renal Transplant Research Information System

The Kidney Transplant Program at the Toronto General Hospital uses numerous electronic health record platforms housing patient health information that is often not coded in a systematic manner to facilitate quality assurance and research. To address this, the comprehensive renal transplant research information system was conceived by a multidisciplinary healthcare team. Data analysis from comprehensive renal transplant research information system presented at programmatic retreats, scientific meetings, and peer-reviewed manuscripts contributes to quality improvement and knowledge in kidney transplantation.

Uric Acid and the Risk of Graft Failure in Kidney Transplant Recipients: A Re‐Assessment

The association of hyperuricemia with kidney allograft outcomes remains controversial. We studied this problem in 1170 kidney transplants from January 2000 to December 2010. The primary endpoint was total graft failure (i.e. graft loss or death). Conventional, time‐dependent and marginal structural Cox proportional hazards models were fitted, the latter accounting for kidney function as a time‐varying confounder affected by prior uric acid levels. Uric acid level was associated with an increased risk of total graft failure in time‐fixed and time‐varying models (HR 1.02 [95% CI: 1.003–1.04] and HR 1.02 [95% CI: 1.01–1.03], respectively, for every 10 µmol/L increase in uric acid). In contrast, the marginal structural model showed a modestly protective effect (HR 0.90 [95% CI: 0.85–0.94] for every 10 µmol/L increase in uric acid). Similar results were observed for death‐censored graft failure and death with graft function. In summary, the absence of a deleterious association between elevated uric acid and graft outcome after accounting for graft function as a time‐varying confounder suggests that uric acid is not an independent risk factor for graft failure. The modestly protective effect of uric acid may be an indicator of nutritional status but further study is warranted.

A cross-sectional study examining the functional independence of elderly individuals with a functioning kidney transplant.

Background Cross-sectional studies of patients dependent on dialysis show that they have a high need for help with routine daily activities. In many cases, individuals who undergo kidney transplantation have previously been treated with dialysis for a significant period of time, thus many of the characteristics may be similar. The purpose of this study was to estimate the rate of functional disability in a cross-sectional population of older patients with a functioning kidney transplant. Methods Kidney transplant patients, aged 65 years or more, were approached to participate. Patients were interviewed to ascertain current living situation, employment status, and 1-year fall history. Functional assessments included the Barthel Index, the Lawton-Brody Scale, the Timed Up and Go (TUG) test, and dynamometer handgrip strength. Results Eighty-two patients (71%) agreed to participate. Over half (54%) reported being disabled or requiring assistance for at least one daily-living activity, with housekeeping, grocery shopping, and laundry being the activities most commonly affected. Most patients had markedly impaired TUG and handgrip tests, and 21% recalled having fallen more than once in the past year. Limitations We used a single-center, cross-sectional study design. Conclusions These results demonstrate a high prevalence of functional dependence, unintentional falls, and significant morbidity associated with decreased muscle strength in the older kidney transplant population.

Mental Health and Behavioural Barriers in Access to Kidney Transplantation: A Canadian Cohort Study

Background A history of mental health (MH) disorders or nonadherence (NA) may be barriers to completing the work-up (WU) and/or undergoing kidney transplantation (KT) but this has not been well documented. In this work, we analyzed the relationship between a history of MH disorders or NA and the likelihood of completing the WU or undergoing KT. Methods Patients referred for KT to the Toronto General Hospital from January 1, 2003, to December 31, 2012, and who completed a social work assessment, were included (n = 1769). The association between the history of MH disorders or NA and the time from referral to WU completion or KT were examined using Cox proportional hazards models. Results A history of MH disorders or NA was present in 24% and 18%, respectively. Patients with MH disorders had a 17% lower adjusted hazard of completing the WU within 2 years of referral (HR 0.83; 95% confidence interval [95% CI], 0.71-0.97). Similarly, patients with a history of NA had a 21% lower hazard of completing the WU (hazard ratio [HR], 0.79; 95% CI, 0.66-0.94). The adjusted HR for KT was 0.88 (95% CI, 0.74-1.05) and 0.79 (95% CI, 0.64-0.97) for MH disorders and NA, respectively. Conclusions These findings suggest that a history of MH disorders or NA is a potential barrier to KT. Whether targeted psychosocial support can improve access to KT for these patients requires further study.

CT volumetry is superior to nuclear renography for prediction of residual kidney function in living donors

Living kidney donor evaluation commonly includes nuclear renography to assess split kidney function and computed tomography (CT) scan to evaluate anatomy. To streamline donor workup and minimize exposure to radioisotopes, we sought to assess the feasibility of using proportional kidney volume from CT volumetry in lieu of nuclear renography. We examined the correlation between techniques and assessed their ability to predict residual postoperative kidney function following live donor nephrectomy. In a cohort of 224 live kidney donors, we compared proportional kidney volume derived by CT volumetry with split kidney function derived from nuclear renography and found only modest correlation (left kidney R2=26.2%, right kidney R2=26.7%). In a subset of 88 live kidney donors with serum creatinine measured 6 months postoperatively, we compared observed estimated glomerular filtration rate (eGFR) at 6 months with predicted eGFR from preoperative imaging. Compared to nuclear renography, CT volumetry more closely approximated actual observed postoperative eGFR for Chronic Kidney Disease Epidemiology Collaboration (J‐test: P=.02, Cox–Pesaran test: P=.01) and Mayo formulas (J‐test: P=.004, Cox–Pesaran test: P<.001). These observations support the use of CT volumetry for estimation of split kidney function in healthy individuals with normal kidney function and morphology.