Multidrug resistance-related protein 2 genotype of the donor affects kidney graft function

Abstract

Kidney graft-specific MRP2 deficiency has mild effects on the renal excretion of some organic solutes under experimental conditions and induces a protein and gene expression pattern indicative of activated antioxidant defense mechanisms. This suggests that MRP2 is a determinant of the redox status in tubular epithelial cells and thus of the susceptibility to renal damage under conditions of treatment with multiple drugs and increased oxygen radical formation.

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

“…Mycophenolic acid-acyl glucuronide pharmacokinetics are similarly altered in healthy volunteers with the C-24T ABCC2 variant (Lévesque et al, 2008). In addition to mediating the disposition of antirejection drugs, Mrp2 may also influence the redox status of graft kidneys (Grisk et al, 2009). In this same study, ABCC2 variants were associated with a delay in clinical graft function (Grisk et al, 2009).…”

Regulatory Pathways for ATP-binding Cassette Transport Proteins in Kidney Proximal Tubules

“…In comparison to MRP2, MRP4 exhibits a higher expression in the kidney and a higher affinity for smaller organic anions (25). Polymorphisms in ABCC2 and ABCC4, leading to diminished MRP2 or MRP4 activity, respectively, are associated with increased sensitivity to nephrotoxicity or delayed graft function after kidney transplantation (26,27). MRP5 (ABCC5) is ubiquitously expressed and located at the basolateral membrane in polarized epithelial cells (as reviewed in (21)).…”

Posttransplant Hypertension: Multipathogenic Disease Process

“…[1][2][3]9,[51][52][53][54][55][56]59,64,71,73,76,86,[88][89][90][91][92][93] As in the recipient, old age, pre-existing hypertension, diabetes mellitus, subclinical kidney disease, and nephron under dosing (innate, female to male donor, old age, and donorrecipient body mass index mismatch) represent potential causes for development or aggravation of hypertension posttransplant. [1][2][3]9,59,64,71,73,[91][92] New evidence is emerging regarding the potential role of the donor genetic makeup in the pathogenesis of posttransplant hypertension.…”

“…93 A particular kidney donor, ABCC2 genotype, is associated with delayed graft function in certain kidney transplant recipients. 51 Similarly, kidney grafts obtained from donors carrying certain polymorphisms of the ABCB1 and CYP 3A5 genes are highly prone to develop cyclosporine nephrotoxicity, 52,53 a major component of the nonimmunologic cause of chronic graft dysfunction. 45,76 Interestingly, these same ABCB1 polymorphisms affecting P-gp expression in the donor are associated with chronic histologic damage, 86 and adversely influence long-term graft outcomes by decreasing renal function and graft loss in calcineurin inhibitor-treated kidney transplant recipients.…”

“…45 Most drug-related adverse effects are mediated by the interaction of 2 distinct genetic profiles of the recipient and the donor with the environment. [46][47][48][49][50][51][52][53][54][55] These gene-gene and gene-environment interactions lead to systemic and nephrotoxic adverse events that predominantly depend upon the recipient and the donor. 47 Evidence is emerging regarding the role of donor age and hence, nephron mass, in the pathogenesis of aortic stiffness in nephrectomized donors 56 and kidney transplant recipients.…”