Evolving trends in immunosuppression use and cytomegalovirus infection risk over the past decade in kidney transplantation.

BACKGROUND: The goal was to determine trends in immunosuppression use and its impact on cytomegalovirus (CMV) outcomes over the past 10 years. METHODS: This was a single-center longitudinal cohort study of adult kidney recipients transplanted between Jan 2012 and June 2021. Baseline and follow-up data were gathered via chart abstraction and analyzed using univariate and multivariate analyses. RESULTS: Of 2392 kidney transplants conducted, 131 patients did not meet inclusion criteria. The mean age was 52 years, 41% were female, 57% were black, and 19% were CMV high-risk. The use of rabbit anti-thymocyte globulin (RATG) induction (odds ratio [OR] 1.6, 1.3-2.1), tacrolimus (FK) level >8 ng/mL (OR 1.1, 1.09-1.11), CMV D+/R- rates (OR 1.06, 1.02-1.10), white blood cell count <3000 (OR 1.22, 1.18-1.26) and valganciclovir prophylaxis (OR 1.7, 1.6-1.9) have significantly increased over the past 10 years.  Rejection rates (OR 0.86, 0.82-0.91) and BK viremia >2000 (OR 0.91, 0.91-0.98) have decreased. RATG induction (adjusted hazard ratio [aHR] 1.35, 1.2-1.5), FK >8 ng/mL (aHR 3.5, 3.2-3.9), Belatacept conversion (aHR 2.5, 2.1-3.1), and rejection (aHR 1.8, 1.6-2.0) were significant risk factors for developing CMV infection, while mycophenolate mofetil <1500 mg (aHR 0.52, 0.47-0.59), mammalian target of rapamycin inhibitor (mTORi) conversion (0.77, 0.56-0.89), cyclosporine-A conversion (aHR 0.68, 0.56-0.84) were associated with lower risk of CMV infection. CONCLUSION: Increasing use of potent immunosuppression coupled with higher CMV D+/R- F rates may be driving higher rates of CMV infection. Cyclosporine and mTORi conversion appears to be protective against CMV.  A more individualized immunosuppression regimen based on infection risk merits consideration.

Impact of CYP3A5 genotype on de-novo LCP tacrolimus dosing and monitoring in kidney transplantation.

OBJECTIVES: LCP tac has a recommended starting dose of 0.14 mg/kg/day in kidney transplant. The goal of this study was to assess the influence of CYP3A5 on perioperative LCP tac dosing and monitoring. METHODS: This was a prospective observational cohort study of adult kidney recipients receiving de-novo LCP tac. CYP3A5 genotype was measured and 90-day pharmacokinetic and clinical were assessed. Patients were classified as CYP3A5 expressors (*1 homozygous or heterozygous) or nonexpressors (LOF *3/*6/*7 allele). RESULTS: In this study, 120 were screened, 90 were contacted and 52 provided consent; 50 had genotype results, and 22 patients expressed CYP3A5*1. African Americans (AA) comprised 37.5% of nonexpressors versus 81.8% of expressors (P = 0.001). Initial LCP tac dose was similar between CYP3A5 groups (0.145 vs. 0.137 mg/kg/day; P = 0.161), whereas steady state dose was higher in expressors (0.150 vs. 0.117 mg/kg/day; P = 0.026). CYP3A5*1 expressors had significantly more tac trough concentrations of less than 6 ng/ml and significantly fewer tac trough concentrations of more than 14 ng/ml. Providers were significantly more likely to under-adjust LCP tac by 10 and 20% in CYP3A5 expressors versus nonexpressors (P < 0.03). In sequential modeling, CYP3A5 genotype status explained the LCP tac dosing requirements significantly more than AA race. CONCLUSION: CYP3A5*1 expressors require higher doses of LCP tac to achieve therapeutic concentrations and are at higher risk of subtherapeutic trough concentrations, persisting for 30-day posttransplant. LCP tac dose changes in CYP3A5 expressors are more likely to be under-adjusted by providers.

Impact of obesity on the conversion of immediate-release tacrolimus to extended-release tacrolimus in kidney transplant recipients.

Outcomes analyzing conversion from IR-tacrolimus (IR) to LCP-tacrolimus (LCP) in obesity are limited. This was a retrospective longitudinal cohort study of patients converted from IR to LCP from June 2019 to October 2020. Primary outcomes were conversion ratios for weight-based dose at a steady-state therapeutic level and identification of appropriate dosing weight. Other outcomes included tacrolimus coefficient of variation (CV), time in therapeutic range (TITR), adverse events, infections, donor specific antibodies (DSAs), and acute rejection. A total of 292 patients were included; 156 and 136 patients with a BMI < 30 and BMI ≥ 30 kg/m2 , respectively. Baseline characteristics were similar, except for pancreas transplant, diabetes, and HLA mismatch. IR to LCP conversion ratio ranged from .73 to .79. Mean LCP dose was similar (.08 vs. .07 mg/kg/day for BMI < 30 and BMI ≥ 30 kg/m2 , respectively); there was a significant difference in IR and LCP mg/kg dosing at steady state with TBW (.11 mg/kg vs.09 mg/kg and .08 mg/kg vs. .06 mg/kg, respectively). The most appropriate dosing weight was adjusted body weight (AdjBW), consistent across IR and LCP steady-state doses, and might yield more accurate steady-state dosing requirements. In multivariable modeling, BMI was a significant predictor of steady state mg/kg dosing at therapeutic goal for total body weight (TBW), but not ideal body weight (IBW) or AdjBW.

Impact of converting adult kidney transplant recipients with high tacrolimus variability from twice daily immediate release tacrolimus to once daily LCP-Tacrolimus.

BACKGROUND: The influence of converting to once daily, extended-release LCP-Tacrolimus (Tac) for those with high tacrolimus variability in kidney transplant recipients (KTRs) is not well-studied. METHODS: Single-center, retrospective cohort study of adult KTRs converted from Tac immediate release to LCP-Tac 1-2 years post-transplant. Primary measures were Tac variability, using the coefficient of variation (CV) and time in therapeutic range (TTR), as well as clinical outcomes (rejection, infections, graft loss, death). RESULTS: A total of 193 KTRs included with a follow-up of 3.2 ± .7 years and 1.3 ± .3 years since LCP-Tac conversion. Mean age was 52 ± 13 years; 70% were African American, 39% were female, 16% living donor and 12% donor after cardiac death (DCD). In the overall cohort, tac CV was 29.5% before conversion, which increased to 33.4% after LCP-Tac (p = .008). In those with Tac CV >30% (n = 86), conversion to LCP-Tac reduced variability (40.6% vs. 35.5%; p = .019) and for those with Tac CV >30% and nonadherence or med errors (n = 16), LCP-Tac conversion substantially reduced Tac CV (43.4% vs. 29.9%; p = .026). TTR significantly improved for those with Tac CV >30% with (52.4% vs. 82.8%; p = .027) or without nonadherence or med errors (64.8% vs. 73.2%; p = .005). CMV, BK, and overall infections were significantly higher prior to LCP-Tac conversion. In the overall cohort, 3% had rejection before conversion and 2% after (p = NS). At end of follow-up, graft and patient survival were 94% and 96%, respectively. CONCLUSIONS: In those with high Tac CV, conversion to LCP-Tac is associated with a significant reduction in variability and improvement in TTR, particularly in those with nonadherence or medication errors.

Diabetes is a significant and independent predictor for tacrolimus immediate release and LCP-tacrolimus conversion ratios.

Diabetes (DM) is a common comorbidity in transplant patients with known effects on gastrointestinal (GI) motility and absorption; however, DM's impact on immediate release (IR) tacrolimus to LCP-tacrolimus (LCP) conversion ratios has not been studied. This multivariable analysis of a retrospective longitudinal cohort study included kidney transplant recipients converted from IR to LCP between 2019 and 2020. The primary outcome was IR to LCP conversion ratio based on DM status. Other outcomes included tacrolimus variability, rejection, graft loss, and death. Of the 292 patients included, 172 patients had DM and 120 did not. The IR:LCP conversion ratio was significantly higher with DM (67.5% ± 21.1% no DM vs. 79.8% ± 28.7% in DM; P < .001). In multivariable modeling, DM was the only variable significantly and independently associated with IR:LCP conversion ratios. No difference was observed in rejection rates. Graft (97.5% no DM vs. 92.4% in DM; P = .062) and patient survival (100% no DM vs. 94.8% in DM; P = .011) were lower with DM. The presence of DM significantly increased the IR:LCP conversion ratio by 13%-14%, compared to patients without DM. On multivariable analysis, DM was the only significant predictor of conversion ratios, potentially related to GI motility or absorption differences.

Impact of metformin on malignancy in solid organ transplantation.

Malignancy after solid organ transplant is a common occurrence that is associated with increased morbidity and mortality. Literature in the general diabetic population has identified possible antineoplastic properties of metformin. This retrospective study aims to determine if metformin results in a malignancy risk reduction in a cohort of diabetic kidney, liver, and heart transplant recipients. The population included transplant recipients without use of metformin at any time point (DMO arm, n = 147) and those with use of metformin (DMM arm, n = 172); the two arms were matched based on organ type and transplant date prior to application of exclusion criteria. Recipients with prior malignancy, malignancy before diabetes diagnosis, and metformin duration <30 days were excluded. The primary endpoint of malignancy first occurrence post-transplant was not found to be statistically significant at 1, 5, 10, and 15 years. In the subgroup of heart transplant recipients, there was a significant reduction in malignancy at 15 years post-transplant. Older age and Caucasian race were identified as significant risk factors for malignancy, while never smoker was a protective factor. Metformin use in this solid organ transplant cohort was not found to significantly reduce malignancy risk compared to use of other anti-diabetic agents.

Tacrolimus Concentration-to-Dose Ratios in Kidney Transplant Recipients and Relationship to Clinical Outcomes.

INTRODUCTION: One factor impacting tacrolimus interpatient variability is the presence of CYP3A5 polymorphisms. Low tacrolimus concentration-to-dose ratios (CDRs), or rapid metabolizers (RMs), have been associated with poor graft function outcomes and higher biopsy-proven acute rejection (BPAR) rates in a predominantly white population. Pretransplant CYP genotyping is not routinely conducted, and therefore only a small number of studies have assessed the use of tacrolimus CDRs as a surrogate for metabolism. We explored differences in outcomes between patients with low tacrolimus CDRs and high tacrolimus CDRs (i.e., nonrapid metabolizers [NRMs]) in a diverse patient population. OBJECTIVE: To determine the relationship between tacrolimus CDRs and graft and patient outcomes in kidney transplant recipients at a large transplant center between 2006 and 2016. METHODS: Inclusion criteria consisted of adult kidney transplant recipients who received rabbit antithymocyte globulin induction followed by a maintenance regimen of tacrolimus, mycophenolate, and prednisone. The primary end point was BPAR at 1 year. Secondary end points included graft survival, patient survival, and toxicities. Determination of clusters was conducted using the two-step cluster analysis with a defined two-cluster distribution. Kaplan-Meier survival curves were created using the log-rank test. RESULTS: The NRM cluster consisted of 322 patients with a mean CDR of 2.91 ng/ml/mg. The RM cluster consisted of 932 patients with a mean CDR of 1.14 ng/ml/mg. The BPAR at 1 year posttransplant was 3.7% in the NRM cluster and 3.6% in the RM cluster (p=0.95). Death at 5 years was higher in the NRM group compared with the RM group for unknown reasons (p=0.03). Differences in the incidence of posttransplant toxicities were not statistically significant at any time point, except for increased rates of cutaneous cancer at 5 years and cardiovascular disease overall in the NRM group. CONCLUSION: Tailoring tacrolimus therapy early posttransplant based on CDR is not supported by the findings in this study.