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Tacrolimus is a commonly used immunosuppressant after kidney transplantation. It has a narrow therapeutic range and demonstrates wide interindividual variability in pharmacokinetics, leading to potential underimmunosuppression or toxicity. Genetic polymorphism in CYP3A5 enzyme expression contributes to differences in tacrolimus bioavailability between individuals. Individuals carrying one or more copies of the wild-type allele *1 express CYP3A5, which increases tacrolimus clearance. CYP3A5 expressers require 1.5 to 2-fold higher tacrolimus doses compared to usual dosing to achieve therapeutic blood concentrations. Individuals with homozygous *3/*3 genotype are CYP3A5 nonexpressers. CYP3A5 nonexpression is the most frequent phenotype in most ethnic populations, except blacks. Differences between genotypes in tacrolimus disposition have not translated into differences in clinical outcomes, such as acute rejection and graft survival. Therefore, although genotype-based dosing may improve achievement of therapeutic drug concentrations with empiric dosing, its role in clinical practice is unclear. genotype may predict differences in absorption of extended-release and immediate-release oral formulations of tacrolimus. Two studies found that CYP3A5 expressers require higher doses of tacrolimus in the extended-release formulation compared to immediate release. genotype plays a role in determining the impact of interacting drugs, such as fluconazole, on tacrolimus pharmacokinetics. Evidence conflicts regarding the impact of genotype on risk of nephrotoxicity associated with tacrolimus. Further study is required.

Background Trimethoprim-sulfamethoxazole (TMP-SMX) is the drug of choice for anti- Pneumocystis jirovecii pneumonia (PcP) prophylaxis in kidney transplant recipients (KTR). Post-transplant management balances preventing PcP with managing TMP-SMX-related adverse effects. TMP-SMX dose reduction addresses adverse effects but its implications to incident PcP are unclear. Methods We performed a retrospective review of all patients transplanted between 2011 and 2015 prescribed daily single strength TMP-SMX for twelve months post-transplantation as PcP prophylaxis. Actual TMP-SMX dose and duration, adverse effects, number of dose reductions and reasons, and PcP events were captured. Multivariate logistic regression analyses for risk factors associated with dose reduction were performed. Results Of 438 KTR, 233 (53%) maintained daily TMP-SMX and 205 (47%) sustained ≥1 dose reduction, with the point prevalence of a reduced dose regimen being between 18 and 25%. Median duration for daily TMP-SMX was 8.45/12 months, contributing 4137 patient-months daily TMP-SMX and 1110 patient-months with a reduced dose. PcP did not occur in any patients. There were 84 documented dose reductions for hyperkalemia and 102 for leukopenia, with 12 and 7 patients requiring TMP-SMX cessation. In multivariate analysis, a living donor transplant protected against hyperkalemia (Odds Ratio 0.46, 95% CI 0.26–0.83, p  < 0.01) while acute rejection risked leukopenia (Odds Ratio 3.31, 95% CI 1.39–7.90, p  = 0.006). Conclusions TMP-SMX dose reduction is frequent in the first post-transplant year but PcP does not occur. To limit the need for TMP-SMX dose reduction due to adverse effects, a clinical trial comparing daily to thrice weekly single strength TMP-SMX in de-novo KTR is justified.

Background Cardiovascular disease is a significant cause of morbidity and mortality in patients with end-stage renal disease (ESRD) and kidney transplant (KT) patients. Compared with left ventricular (LV) ejection fraction (LVEF), LV strain has emerged as an important marker of LV function as it is less load dependent. We sought to evaluate changes in LV strain using cardiovascular magnetic resonance imaging (CMR) in ESRD patients who received KT, to determine whether KT may improve LV function. Methods We conducted a prospective multi-centre longitudinal study of 79 ESRD patients (40 on dialysis, 39 underwent KT). CMR was performed at baseline and at 12 months after KT. Results Among 79 participants (mean age 55 years; 30% women), KT patients had significant improvement in global circumferential strain (GCS) ( p  = 0.007) and global radial strain (GRS) ( p  = 0.003), but a decline in global longitudinal strain (GLS) over 12 months ( p  = 0.026), while no significant change in any LV strain was observed in the ongoing dialysis group. For KT patients, the improvement in LV strain paralleled improvement in LVEF (57.4 ± 6.4% at baseline, 60.6% ± 6.9% at 12 months; p  = 0.001). For entire cohort, over 12 months, change in LVEF was significantly correlated with change in GCS (Spearman’s r  = − 0.42, p  < 0.001), GRS (Spearman’s r  = 0.64, p  < 0.001), and GLS (Spearman’s r  = − 0.34, p  = 0.002). Improvements in GCS and GRS over 12 months were significantly correlated with reductions in LV end-diastolic volume index and LV end-systolic volume index (all p  < 0.05), but not with change in blood pressure (all p  > 0.10). Conclusions Compared with continuation of dialysis, KT was associated with significant improvements in LV strain metrics of GCS and GRS after 12 months, which did not correlate with blood pressure change. This supports the notion that KT has favorable effects on LV function beyond volume and blood pessure control. Larger studies with longer follow-up are needed to confirm these findings.

Background: Urinary tract infections (UTI) are common in kidney transplant recipients (KTR). Although risk factors for UTI are well described, predicting symptomatic UTI with positive urine cultures in the first posttransplant year is challenging. Objective: Our clinic routinely monitors serum highly sensitive C-reactive protein (CRP) as part of posttransplant care. We sought to define the role of CRP in identifying symptomatic UTI in KTR. Design: Nested case control study Setting: A large adult single-organ kidney transplant center in Toronto, Canada. Patients: We identified a nested cohort of 78 KTR who experienced a symptomatic UTI with positive urine cultures (cases) and compared them to a cohort of 78 KTR controls matched by time elapsed posttransplant. Measurements: Patient demographics, urine cultures, CRP, and kidney function during the first posttransplant year. Methods: We identified a cohort of KTR transplanted between January 1, 2016, and December 31, 2019. A positive urine culture ordered only for clinical indication in the first posttransplant year identified KTR with a UTI defined >10 5 colony forming units/mL. UTI cases were matched 1:1 to non-UTI controls transplanted immediately preceding or succeeding the UTI case. Bivariate comparisons were performed by t test, Wilcoxon 2-sample test for continuous variables, chi-square, or Fisher’s exact test as appropriate, with clinically significant variables entered into multivariable logistic regression models to determine associations. Results: Older age, female sex, and the presence of a stent were each associated with a UTI. Immediately preceding UTI, eGFR (P = .019), serum albumin (P < .0001), and hemoglobin (P = .002) were lower, while serum CRP (P < .0001) and absolute neutrophils (P = .03) were higher in cases than controls. However, in several multivariable models, only absolute CRP (P = .001), change in CRP (P = .005), female sex (P < .0001), and ureteric stent (P = .008) consistently predicted a UTI. Each 5 mg/dL change between the 2 preceding CRP values predicted a 15% increased likelihood of UTI, while each 1 mg/dL in absolute CRP concentration was associated with a 5% risk. Limitations: Retrospective case-control design, single-center, small sample size. Hospital inpatients and patients with other infections, acute inflammatory conditions, or rejection were excluded. Urine infections may more easily be detected when patients visit the clinic frequently. Conclusions: Routine ambulatory CRP monitoring in the first year may help identify subsequent symptomatic UTI in KTR, allow for the initiation of earlier therapy, and reduce patient morbidity. What was known before? UTI in KTR are common in the first posttransplant year. Antibiotic therapy is typically not initiated until the results of urine cultures become known. What this adds: The routine use of appropriate biomarkers such as CRP as part of a posttransplant monitoring strategy may allow clinicians to order urine cultures, help identify UTI earlier, and start therapy sooner, promoting patient well-being.

Background: Kidney transplant recipients with graft failure (KTR-GF) and those with a failing graft are an increasingly prevalent group of patients. Their clinical management is complex, and outcomes are worse than transplant naïve patients on dialysis. In 2023, the Kidney Disease: Improving Global Outcomes (KDIGO) organization reported findings from a controversies conference and identified several clinical practice priorities for KTR-GF. Objective: As an exercise in needs assessment, we aimed to collate and summarize current practices in adult Canadian kidney transplant programs around these KDIGO-identified clinical practice priorities. Design: Environmental scan followed by content analysis. Setting: Canadian adult kidney transplant programs. Measurements: We categorized the themes of our content analysis around 7 clinical practice priorities: (1) determining prognosis and kidney failure trajectory; (2) immunosuppression management; (3) management of medical complications; (4) preparing for return to dialysis; (5) evaluation and listing for re-transplantation; (6) management of psychological effects; and (7) transition to supportive care. Methods: We solicited documents that identified each program’s current care practices for KTR-GF or patients with a failing graft, including policies, procedures, pathways, and protocols. A content analysis of documents and informal correspondence (email or telephone conversations) was done to extract information surrounding the 7 practice priorities. Results: Of the 18 programs contacted, 12 transplant programs participated in this study and a document from a provincial organization (where 2 non-responding programs are located) was procured and included in this analysis. Overall, practice gaps and discrepancies were noted. Many participants highlighted the lack of evidence or consensus to guide the management of KTR-GF as the key reason. Immunosuppression management was the most frequently addressed priority. Six programs and the provincial document recommended a nuanced approach to immunosuppressant management based on clinical factors and re-transplant candidacy. Two programs used the Kidney Failure Risk Equation and eGFR to determine referral trajectories and prepare patients for return to dialysis. Exact processes outlining medical management during the transition were not found except for nephrectomy indications and in 1 program that has a specific transition clinic for KTR-GF. All programs have a formal or informal policy that KTR-GF should be assessed for re-transplantation. Referrals for psychological support and transition to supportive care were made on a case-by-case basis. Limitations: Our environmental scan was at risk of non-response bias and restricted to transplant programs. Kidney clinics and dialysis units may have relevant policies and procedures that were not examined. Conclusion: The findings from our environmental scan suggest gaps in care and potential areas for quality improvement, including a lack of multidisciplinary care, structured dialysis preparation and psychological support. There is also a need to prioritize research that generates evidence to guide the management of KTR-GF and contributes to the aim of developing clinical practice guidelines.

Background: Some men who donate a kidney have reported testicular pain after donation; however, attribution to donation is not clear as no prior studies included a comparison group of nondonors. Objective: To examine the proportion of male donors who reported testicular pain in the years after nephrectomy compared to male nondonors with similar baseline health characteristics. Design, Participants, and Setting: We enrolled 1042 living kidney donors (351 male) before nephrectomy from 17 transplant centers (12 in Canada and 5 in Australia) from 2004 to 2014. A concurrent sample of 396 nondonors (126 male) was enrolled. Follow-up occurred until November 2021. Measurements: Donors and nondonors completed the same schedule of measurements at baseline (before nephrectomy) and follow-up. During follow-up, participants completed a questionnaire asking whether they had experienced new pain in their eyes, hands, or testicles; those who experienced pain were asked to indicate on which side of the body the pain occurred (left or right). The pain questionnaire was completed by 290 of 351 male donors (83%) and 97 of 126 male nondonors (77%) a median of 3 years after baseline (interquartile range = 2-6). Methods: Inverse probability of treatment weighting on a propensity score was used to balance donors and nondonors on baseline characteristics. After weighting, the nondonor sample increased to a pseudo sample of 295, and most baseline characteristics were similar between donors and nondonors. Results: At baseline, donors (n = 290) were a mean age of 49 years; 83% were employed, and 80% were married; 246 (84.8%) underwent laparoscopic surgery and 44 (15.2%) open surgery; 253 (87.2%) had a left-sided nephrectomy and 37 (12.8%) a right-sided nephrectomy. In the weighted analysis, the risk of testicular pain was significantly greater among donors than nondonors: 51/290 (17.6%) vs 7/295 (2.3%); weighted risk ratio, 7.8 (95% confidence interval [CI] = 2.7 to 22.8). Donors and nondonors did not differ statistically in terms of self-reported eye pain or hand pain. Among donors, the occurrence of testicular pain was most often unilateral (92.2%) and on the same side as the nephrectomy (90.2%). Testicular pain occurred more often in donors who had laparoscopic vs open surgery: 48/246 (19.5%) vs 3/44 (6.8%) but was similar in those who had a left-sided vs right-sided nephrectomy: 44/253 (17.4%) vs 7/37 (18.9%). Limitations: Participants recalled their symptoms several years after baseline, and we did not assess the timing, severity, or duration of pain or any treatments received for the pain. Conclusion: Unilateral testicular pain on the same side of a nephrectomy is a potential complication of living kidney donation that warrants further investigation.

Background: Post-transplant diabetes mellitus (PTDM) encompasses new-onset and previously unrecognized type 2 diabetes. Kidney failure masks type 2 diabetes. Branched-chain amino acids (BCAA) are closely associated with glucose metabolism. Therefore, understanding BCAA metabolism both in kidney failure and after kidney transplantation may inform PTDM mechanisms. Objective: To understand the impact of present or absent kidney function on plasma BCAA concentrations. Design: Cross-sectional study of kidney transplant recipients and kidney transplant candidates. Setting: Large kidney transplant center in Toronto, Canada. Measurements: We measured plasma BCAA and aromatic amino acid (AAA) concentrations in 45 pre-kidney transplant candidates (15 with type 2 diabetes, 30 without type 2 diabetes) and 45 post-kidney transplant recipients (15 PTDM, 30 non-PTDM), along with insulin resistance and sensitivity by 75 g oral glucose loading for those in each group without type 2 diabetes. Methods: Plasma AA concentrations were analyzed using MassChrom AA Analysis and compared between groups. The insulin sensitivity for oral glucose tolerance tests or Matsuda index (a measure of whole-body insulin resistance), Homeostatic Model Assessment for Insulin Resistance (a measure of hepatic insulin resistance), and Insulin Secretion-Sensitivity Index-2 (ISSI-2, a measure of pancreatic β-cell response) was calculated from fasting insulin and glucose concentrations, and compared with BCAA concentrations. Results: Each BCAA concentration was higher in post-transplant subjects than pre-transplant subjects (P < .001 for leucine, isoleucine, valine). In post-transplant subjects, each BCAA concentration was higher in PTDM versus non-PTDM (odds ratio for PTDM 3-4 per 1 SD increase in BCAA concentration, P < .001 for each). Tyrosine concentrations were also higher in post-transplant subjects than pre-transplant subjects, but tyrosine did not differ by PTDM status. By contrast, neither BCAA nor AAA concentrations were different in pre-transplant subjects with or without type 2 diabetes. Whole-body insulin resistance, hepatic insulin resistance, and pancreatic β-cell response did not differ between nondiabetic post-transplant and pre-transplant subjects. Branched-chain amino acid concentrations correlated with the Matsuda index and Homeostatic Model Assessment for Insulin Resistance (P < .05 for each) only in nondiabetic post-transplant subjects—not in nondiabetic pre-transplant subjects. Branched-chain amino acid concentrations did not correlate with ISSI-2 in either pre-transplant or post-transplant subjects. Limitations: The sample size was small, and subjects were not studied prospectively for the development of type 2 diabetes. Conclusions: Plasma BCAA concentrations are higher post-transplant in type 2 diabetic states, but do not differ by diabetes status in the presence of kidney failure. The association of BCAA with measures of hepatic insulin resistance among nondiabetic post-transplant patients is consistent with impaired BCAA metabolism as a characteristic of kidney transplantation.

Background: Increased intrapatient variability (IPV) in tacrolimus levels is associated with graft rejection, de novo donor-specific antibodies, and graft loss. Medication nonadherence may be a significant contributor to high IPV. Objective: The objective of this study is to determine the utility of tacrolimus IPV in detecting nonadherence by examining the relationship between self-reported adherence and tacrolimus coefficient of variability (COV), a measure of IPV. Design: Retrospective cohort study. Setting: St. Michael’s Hospital, Toronto, Ontario. Patients: All patients who were at least 1-year post-kidney transplant as of March 31, 2019, prescribed tacrolimus as an immunosuppressant and had a self-reported adherence status. Patients were excluded from the primary analysis of examining the correlation between COV and self-reported adherence if they lacked a calculatable COV. Measurements: Self-reported adherence, COV, demographic data, transplant, and medication history. Methods: A modified Basel Assessment of Adherence to Immunosuppressive Medications Scale (BAASIS) administered by healthcare professionals to assess self-reported adherence was used. The COV of tacrolimus trough levels was calculated and its correlation to BAASIS response was noted. The median COV was used as a cutoff to examine the characteristics of patients deemed “high COV” and “low COV.” Results: A total of 591 patients fit the initial criteria; however, only 525 had a recent calculatable COV. Overall, 92.38% of the population were adherent by self-report. Primary analysis identified a COV of 25.2% and 29.6% in self-reported adherent and nonadherent patients, respectively, though the result was not significant (P = .2). Secondary analyses showed a significant correlation between younger age at transplant and at the time of adherence self-reporting with nonadherence (P = .01). In addition, there was a strong correlation between those nonadherent with routine post-transplant blood work and younger age (P < .01). Limitations: The limitations included modified nonvalidated BAASIS questionnaire, social desirability bias, BAASIS only administered in English, and patients with graft failure not active in clinic not being captured. Conclusions: The COV should not be used as the sole method for determining medication adherence. However, COV may have some utility in capturing individuals who are not adherent to their blood work or patients who are having a poor response to tacrolimus and should be switched to another medication.

Purpose: Highly sensitized patients (HSPs) with kidney failure have limited access to kidney transplantation and poorer post-transplant outcomes. Prioritizing HSPs in kidney allocation systems and expanding the pool of deceased donors available to them has helped to reduce their wait times for transplant and enhanced post-transplant outcomes. The Canadian HSP Program was established by Canadian Blood Services in collaboration with provincial organ donation and transplantation programs throughout the country to increase transplant opportunities for transplant candidates needing very specific matches from deceased kidney donors. Highly sensitized patients in the Canadian Program are defined by a calculated panel-reactive antibody (cPRA) ≥95%. In this report, we describe the evolution and trajectory of the Canadian HSP Program and evaluate the national impact on the first 1000 kidney transplant cases. Source of Information: To allocate deceased donor kidney organs nationally to HSPs and report on the Canadian HSP Program’s performance, Canadian Blood Services developed a national database registry known as the Canadian Transplant Registry (CTR) and an online reporting tool known as the Canadian HSP Program Data Dashboard. Methods: The CTR, which collects HSPs’ data for the purpose of matching potential donors to HSPs and as part of required national quality, safety, and efficiency performance measurements, was retrospectively reviewed. Due to the nature of using deidentified aggregate registry data, a patient consent form was not required. A Research Ethical Board (REB) application was also waived. Key Findings: In this article, we describe the historical development, initial deployment, and evolution of the Canadian HSP Program with a primary aim to increase the rate of deceased donor kidney transplantation. A secondary aim was to evaluate the national impact of the Canadian HSP Program on the first 1000 kidney transplant cases. Transplant candidates who have participated in the Canadian HSP Program and recipients who received transplants were predominantly females (average age 50 years, female 62%) with blood group O (47% of candidates, 42% of transplants). Seventy percent of all active transplant candidates enrolled in the HSP Program were in the hardest to match group (cPRA ≥99%), and only 22% of the transplant candidates with cPRA of 100% have received a transplant to date through the Program. The average times from first participation in the Canadian HSP Program to transplantation for cPRA ≥99% transplant recipients were significantly longer than for cPRA 95% to 98% recipients averaging 22 months versus 6 months, respectively. By the end of June 2024, the Canadian HSP Program had facilitated 1000 transplants, 613 of which were from interprovincial matches. The average (SD) cold ischemic time (CIT) was 14.5 (5.9) hours, with interprovincial transplants exhibiting significantly longer CITs compared with intraprovincial transplants, averaging an additional 4.7 hours. Limitations: Our study limitations include first that it is a retrospective registry data analysis with no available short- and long-term clinical outcomes data at this point (patient and graft survival). Second, given the nature of registry data, not all relevant data may have been captured and reporting may not be complete for all patients. Implications: Examination of CTR registry data showed the Canadian HSP Program had a meaningful impact in enabling 1000 HSPs to access transplantation opportunities that may otherwise be unavailable to them.

Background: Patients on dialysis have impaired cardiac function, in part due to increased fluid volume and ventricular stress. Restored kidney function through transplantation reduces left ventricular volume in both systole and diastole. We previously reported that the decrease in NT-proB-type natriuretic peptide (NT-proBNP) was associated with a decrease in adiponectin. Paraoxonase 1 (PON1) has been inversely associated with cardiovascular outcomes. We now report the association of changes in PON1 with changes in left ventricular volume and left ventricular mass after kidney transplantation.Design: Patients on dialysis were assessed at baseline and 12 months after kidney transplantation ( n = 38). A comparison group of patients on dialysis who were not expected to receive a transplant in the next 24 months were studied ( n = 43) to determine if the change of PON1 with kidney transplantation achieved a significance greater than that due to biologic variation. Left ventricular volume and mass were determined by cardiac magnetic resonance imaging. PON1 was measured by arylesterase activity and by mass.Results: PON1 mass and activity were not different between the groups at baseline. Both PON1 mass and activity were increased post-kidney transplantation ( p < 0.0001 for change). The change in PON1 mass ( p = 0.0062) and PON1 arylesterase activity ( p = 0.0254) were inversely correlated with the change in NT-proBNP for patients receiving a kidney transplant. However, only the change in the PON1 mass, and not the change in PON1 arylesterase, was inversely correlated with the change in left ventricular volume (ml/m2.7) ( p = 0.0146 and 0.0114 for diastolic and systolic, respectively) and with the change in hemoglobin ( p = 0.0042).Conclusion: Both PON1 mass and arylesterase activity are increased by kidney transplantation. The increase in PON1 mass is consistent with a novel relationship to the increase in hemoglobin and decrease in left ventricular volume and NT-proBNP seen when kidney function is restored.