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Association Between Variants in Calcineurin Inhibitor Pharmacokinetic and Pharmacodynamic Genes and Renal Dysfunction in Adult Heart Transplant Recipients.

ABSTRACT: Background: The goal of the study was to assess the relationship between single nucleotide variants (SNVs) in calcineurin inhibitor (CNI) pharmacokinetic and pharmacodynamic genes and renal dysfunction in adult heart transplant (HTx) recipients. Methods: This retrospective analysis included N = 192 patients receiving a CNI at 1-year post-HTx. Using a candidate gene approach, 93 SNVs in eight pharmacokinetic and 35 pharmacodynamic genes were chosen for investigation. The primary outcome was renal dysfunction 1-year after HTx, defined as an estimated glomerular filtration rate (eGFR) <45 ml/min/1.73m². Results: Renal dysfunction was present in 28.6% of patients 1-year after HTx. Two SNVs [transforming growth factor beta 1 (TGFB1) rs4803455 C > A and phospholipase C beta 1 (PLCB1) rs170549 G > A] were significantly associated with renal dysfunction after accounting for a false discovery rate (FDR) of 20%. In a multiple-SNV adjusted model, variant A allele carriers of TGFB1 rs4803455 had lower odds of renal dysfunction compared to C/C homozygotes [odds ratio (OR) 0.28, 95% CI 0.12-0.62; p = 0.002], whereas PLCB1 rs170549 variant A allele carriers had higher odds of the primary outcome vs. patients with the G/G genotype (OR 2.66, 95% CI 1.21-5.84, p = 0.015). Conclusion: Our data suggest that genetic variation in TGFB1 and PLCB1 may contribute to the occurrence of renal dysfunction in HTx recipients receiving CNIs. Pharmacogenetic markers, such as TGFB1 rs4803455 and PLCB1 rs170549, could help identify patients at increased risk of CNI-associated renal dysfunction following HTx, potentially allowing clinicians to provide more precise and personalized care to this population.

SUBMITTER: Oreschak K

PROVIDER: S-EPMC8047196 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:AimsInvasive haemodynamic profiles at rest and during exercise after heart transplantation (HTx) have never been described in a randomized trial where de novo everolimus (EVR)-based therapy with early calcineurin inhibitor (CNI) withdrawal has been compared with conventional CNI treatment. We report central invasive haemodynamic parameters at rest and exercise during a 3 year follow-up after HTx in a sub-study of the SCandiavian Heart transplant Everolimus De novo stUdy with earLy calcineurin inhibitor avoidancE trial. We hypothesized that the nephroprotective properties, the less development of cardiac allograft vasculopathy (CAV), and the antifibrotic properties of EVR, in comparison with CNI-based immunosuppression, would demonstrate favourable invasive haemodynamic profiles in patients at rest and during exercise.Methods and resultsNinety of 115 HTx recipients randomized to EVR or CNI treatment performed right heart catheterization at rest and 68 performed right heart catheterization at exercise up to 3 years after HTx. Haemodynamic profiles were compared between EVR and CNI treatment groups. Resting haemodynamics improved in both groups from pre-HTx to the first follow-up at 7-11 weeks post-HTx and thereafter remained unchanged up to 3 years of follow-up. During follow-up, cardiac reserve during exercise increased with higher levels of maximum heart rate (118 to 148 b.p.m., P < 0.001), mean arterial pressure (103 to 128 mmHg, P < 0.001), and cardiac output (10.3 to 12.2 l/min, P < 0.001). No significant differences in haemodynamic parameters were observed between the EVR and CNI groups at rest or exercise. Isolated post-capillary pulmonary hypertension (mean pulmonary arterial pressure > 20 mmHg, pulmonary arterial wedge pressure ≥ 15 mmHg, and pulmonary vascular resistance <3) were measured in 11% of the patients at 7-11 weeks, 5% at 12 months, and 6% at 36 months after HTx. The EVR group had significantly better kidney function (76 mL/min/1 vs. 60 mL/min/1, P < 0.001) and reduced CAV (P < 0.01) but an increased rate of early biopsy-proven treated rejections (21.2% vs 5.7%, P < 0.01) compared with the CNI group at any time point. The differences in renal function, CAV, or early biopsy-proven treated acute rejections were not associated with altered haemodynamics.ConclusionsDe novo EVR treatment with early CNI withdrawal compared with conventional CNI therapy did not result in differences in haemodynamics at rest or during exercise up to 3 years after HTx despite significant differences in renal function, reduced CAV, and number of early biopsy-proven treated rejections.

Project description:Calcineurin-inhibitors CI are immunosuppressive agents prescribed to patients after solid organ transplant to prevent rejection. Although these drugs have been transformative for allograft survival, long-term use is complicated by side effects including nephrotoxicity. Given the narrow therapeutic index of CI, therapeutic drug monitoring is used to prevent acute rejection from underdosing and acute toxicity from overdosing, but drug monitoring does not alleviate long-term side effects. Patients on calcineurin-inhibitors for long periods almost universally experience declines in renal function, and a subpopulation of transplant recipients ultimately develop chronic kidney disease that may progress to end stage renal disease attributable to calcineurin inhibitor toxicity (CNIT). Pharmacogenomics has the potential to identify patients who are at high risk for developing advanced chronic kidney disease caused by CNIT and providing them with existing alternate immunosuppressive therapy. In this study we utilized BioVU, Vanderbilt University Medical Center's DNA biorepository linked to de-identified electronic medical records to identify a cohort of 115 heart transplant recipients prescribed calcineurin-inhibitors to identify genetic risk factors for CNIT We identified 37 cases of nephrotoxicity in our cohort, defining nephrotoxicity as a monthly median estimated glomerular filtration rate (eGFR)<30 mL/min/1.73 m2 at least six months post-transplant for at least three consecutive months. All heart transplant patients were genotyped on the Illumina ADME Core Panel, a pharmacogenomic genotyping platform that assays 184 variants across 34 genes. In Cox regression analysis adjusting for age at transplant, pre-transplant chronic kidney disease, pre-transplant diabetes, and the three most significant principal components (PCAs), we did not identify any markers that met our multiple-testing threshold. As a secondary analysis we also modeled post-transplant eGFR directly with linear mixed models adjusted for age at transplant, cyclosporine use, median BMI, and the three most significant principal components. While no SNPs met our threshold for significance, a SNP previously identified in genetic studies of the dosing of tacrolimus CYP34A rs776746, replicated in an adjusted analysis at an uncorrected p-value of 0.02 (coeff(S.E.)=14.60(6.41)). While larger independent studies will be required to further validate this finding, this study underscores the EMRs usefulness as a resource for longitudinal pharmacogenetic study designs.

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Association Between Variants in Calcineurin Inhibitor Pharmacokinetic and Pharmacodynamic Genes and Renal Dysfunction in Adult Heart Transplant Recipients.

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