Donor P-gp Polymorphisms Strongly Influence Renal Function and Graft Loss in a Cohort of Renal Transplant Recipients on Cyclosporine Therapy in a Long-Term Follow-Up

Abstract

Cyclosporin A (CsA) is a substrate for cytochrome P450 3A and the efflux transporter P-glycoprotein (P-gp; ABCB1), both abundantly expressed in the kidney. In a long-term follow-up of a cohort of patients who had received kidney transplants between the years 1990 and 2005, we retrospectively investigated the effect of CYP3A4, CYP3A5, and ABCB1 polymorphisms in kidney graft donors on recipients' renal function and risk of subsequent graft loss. DNA samples from 227 donors and clinical data from the 259 respective recipients were analyzed. Graft loss was significantly associated with the presence of the ABCB1 variant haplotype 1236T/2677T/3435T in the donor (1236T/2677T/3435T vs. other haplotypes: hazard ratio = 9.346; 95% confidence interval (CI) (2.278-38.461); P = 0.0019) and with previous episodes of acute organ rejection (hazard ratio = 3.077; 95% CI (1.213-7.812); P = 0.0178). The variant haplotype was also associated with a greater decrease in renal function (homozygotes for TTT -3.047 mlxmin(-1)/year; heterozygotes for TTT -4.435 mlxmin(-1)/year; others -2.186 mlxmin(-1)/year; P = 0.0240). The study showed that the presence of ABCB1 polymorphisms in donors influences long-term graft outcome adversely with decrease in renal function and graft loss in transplant recipients receiving CsA.

Donor ABCB1 Variant Associates with Increased Risk for Kidney Allograft Failure

“…These studies have shown evidence for an association between donor TT genotype and adverse outcome, 17,18,21 rather than CC genotype as seen in the current study. In the first study of 99 patients, donor TT genotype correlated with the development of acute cyclosporine nephrotoxicity, 17 defined on clinical grounds after a retrospective records review.…”

“…In the first study of 99 patients, donor TT genotype correlated with the development of acute cyclosporine nephrotoxicity, 17 defined on clinical grounds after a retrospective records review. A second study of 259 prevalent transplant recipients with functioning grafts at 12 months post-transplantation suggested that the presence of the homozygous form of a "variant" donor haplotype (which included the TT genotype at ABCB1 C3435T) was associated with increased graft failure rates during a followup of 6 years, 18 with failures due to "clearly identifiable causes" excluded from analysis. Finally, a histology-based study of the same ABCB1 SNP showed an association between donor TT genotype and the development of interstitial fibrosis and tubular atrophy on protocol biopsy specimens taken up to 3 years post-transplantation in patients treated with tacrolimus.…”

“…18 This was therefore examined in the current cohorts. In fact, among donors from the Birmingham cohort, there was evidence of recombination (rather than linkage disequilibrium) between alleles at C3435Tand C1236T (D9, 0.83; 95% CI, 0.79-0.88) and also at C3435T and G2677T/A (D9, 0.83; 95% CI, 0.79-0.88).…”

“…These provide some evidence for an association between genetic variation in donor ABCB1 and acute cyclosporine nephrotoxicity 17 and allograft failure. 18 Both studies focused on the C3435T polymorphism within the ABCB1 gene, an exonic SNP whereby the TT genotype is associated with reduced Pgp expression. 19 The purpose of this study was to assess the relationship of both donor and recipient genotype with kidney allograft survival and recipient mortality.…”

Emerging Role of Pharmacogenetic in Organ Transplantation

“…In the kidney transplant setting there have been relatively few studies looking at the role of polymorphisms in graft donors and their conclusions remains unclear. Woillard et al [34] reported that the presence of ABCB1 polymorphisms in donors influenced long-term graft outcome of renal transplant patients. Nevertheless, Hauser et al [35] reported that in adult renal transplant recipients the incidence of cyclosporine nephrotoxicity was significantly higher when the donor rather than the recipient, had the ABCB1 3435TT genotype.…”