Association of four DNA polymorphisms with acute rejection after kidney transplantation

Abstract

Summary Renal transplant outcomes exhibit large inter‐individual variability, possibly on account of genetic variation in immune‐response mediators and genes influencing the pharmacodynamics/pharmacokinetics of immunosuppressants. We examined 21 polymorphisms from 10 genes in 237 de novo renal transplant recipients participating in an open‐label, multicenter study [Cyclosporine Avoidance Eliminates Serious Adverse Renal‐toxicity (CAESAR)] investigating renal function and biopsy‐proven acute rejection (BPAR) with different cyclosporine A regimens and mycophenolate mofetil. Genes were selected for their immune response and pharmacodynamic/pharmacokinetic relevance and were tested for association with BPAR. Four polymorphisms were significantly associated with BPAR. The ABCB1 2677T allele tripled the odds of developing BPAR (OR: 3.16, 95% CI [1.50–6.67]; P = 0.003), as did the presence of at least one IMPDH2 3757C allele (OR: 3.39, 95% CI [1.42–8.09]; P = 0.006). BPAR was almost fivefold more likely in patients homozygous for IL‐10 ‐592A (OR: 4.71, 95% CI [1.52–14.55]; P = 0.007) and twice as likely in patients with at least one A allele of TNF‐α G‐308A (OR: 2.18, 95% CI [1.08–4.41]; P = 0.029). There were no statistically significant interactions between polymorphisms, or the different treatment regimens. Variation in genes of immune response and pharmacodynamic/pharmacokinetic relevance may be important in understanding acute rejection after renal transplant.

An inosine 5′-monophosphate dehydrogenase 2 single-nucleotide polymorphism impairs the effect of mycophenolic acid

“…Our findings are affirmed by a recent study showing that renal transplant patients carrying the rs11706052 SNP were three times more likely to experience biopsy-proven acute rejection at 3 months, as well as at 12 months after transplantation, under immunosuppressive therapy containing MPA. 21 On the other hand, our results detect no relationship between the IMPDH2 rs11706052 polymorphism and basal IMPDH activity or enzyme activity during treatment with any of the tested concentrations of MPA. IMPDH activity was tested in native, untreated lymphocytes (without Con-A stimulation) because changes in enzyme activity are likely to occur under cell culture conditions over time.…”

Donor ABCB1 Variant Associates with Increased Risk for Kidney Allograft Failure

“…[2][3][4][5][6] Although data are inconsistent, there is evidence that singlenucleotide polymorphisms (SNPs) within these genes are associated with variation in cyclosporine and tacrolimus pharmacokinetics. [7][8][9] Preliminary and unreplicated reports also suggest that recipient genotype for ABCB1 is associated with delayed graft function 10 and acute rejection, 11,12 and recipient CYP3A5 genotype is associated with mortality. 13 However, with the exception of this report by Kreutz and colleagues, 13 no studies have addressed the relationship between recipient genotype and the important "hard" clinical endpoints of renal transplantation (i.e., allograft failure or mortality), with limitations stemming from small sample sizes and short followup.…”

Mechanisms of Resistance to Immunosuppressive Therapy in Patients With Nephrotic Syndrome

“…Продемонстрировано, что эти три аллеля на-ходятся в сильном неравновесном сцеплении друг с другом, поэтому до некоторой степени неясно, ка-кой из них определяет подобные эффекты [25].…”