Donor Age and Renal P-Glycoprotein Expression Associate with Chronic Histological Damage in Renal Allografts

Abstract

The contributions of donor kidney quality (partially determined by donor age), allograft rejection, and calcineurin inhibitor nephrotoxicity on the progression of histologic damage of renal allografts are not completely defined. Moreover, the determinants of individual susceptibility to calcineurin inhibitor nephrotoxicity are not known but may include variability in drug transport and metabolism. In a prospective cohort of 252 adult renal allograft recipients treated with a combination of tacrolimus, mycophenolate mofetil, and corticosteroids, we studied 744 renal allograft biopsies obtained regularly from time of transplantation for 3 yr. We assessed determinants of histologic evolution, including tacrolimus exposure, renal P-glycoprotein (ABCB1) expression, and polymorphisms in the CYP3A4, CYP3A5, and ABCB1 genes. Within the first 3 yr after transplantation, we noted a progressive increase in interstitial fibrosis, tubular atrophy, glomerulosclerosis, and vascular intimal thickening. Older donor age, absence of P-glycoprotein expression at the apical membrane of tubular epithelial cells, and combined donor-recipient homozygosity for the C3435T variant in ABCB1 significantly associated with increased susceptibility to chronic allograft damage independent of graft quality at implantation. Changes in graft function over time reflected these associations with donor age and ABCB1 polymorphisms, but it was acute T cell-mediated and antibody-mediated rejection that determined early graft survival. In conclusion, the effects of older donor age reach beyond the quality of the allograft at implantation and continue to be important for histologic evolution in the posttransplantation period. In addition, ABCB1 genotype and expression of P-glycoprotein in renal tubular epithelial cells determine susceptibility to chronic tubulointerstitial damage of transplanted kidneys.

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.…”

“…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. 21 This donor genotype was not associated with other chronic histologic lesions, such as transplant glomerulopathy 22 or arterial intimal thickening. 23 The discrepancies between these 39 with the relationships denoted by D9 within the relevant box.…”

“…Other histologic studies showing an association between cyclosporine toxicity and reduced tubular P-gp expression predominantly addressed arteriolar hyalinosis and tubular vacuolization as markers of toxicity, 15 although these lesions may actually have limited impact on graft outcome. 24 In addition, the in vivo association between genotype and P-gp expression in biopsy tissue from transplanted kidneys is imperfect 21 and may depend on the tissue studied (i.e., there is some degree of genotype-phenotype disconnect). Even in the nontransplant setting there are conflicting data with regard to the role of ABCB1 genetic variation influencing P-gp expression and function.…”

Posttransplant Hypertension: Multipathogenic Disease Process

“…86 Moreover, kidney transplant recipients who are CYP 3A5*1 expressers are more prone to develop tacrolimus-associated nephrotoxicity, especially in those who continue corticosteroid therapy. 87 Patients with hereditary nephritis may develop recurrent or de novo kidney disease after transplant.…”

“…[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.…”