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

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.Progressive renal allograft dysfunction resulting from cumulative histologic damage to the allograft is the major cause of late renal allograft loss after recipient death with a functioning graft.^1,2 The evolution of renal allograft histology therefore can be regarded as a valuable surrogate marker for long-term graft outcome.³ This evolution has been described in detail by Nankivell et al. using renal allograft biopsies obtained at preset time points after transplantation in kidneys of pristine quality at implantation.⁴ In this study, the kidneys were recovered from a selected group of relatively young donors, and the majority of recipients (kidney–pancreas transplants in all but 1) were treated with a combination of the older formulation of cyclosporine in combination with azathioprine and corticosteroids.⁴However, with the increasing use of kidneys from older or extended criteria donors for transplantation, poor graft quality at implantation emerges as an important determinant of long-term outcome.^5,6 Therefore, the experience of Nankivell et al. may no longer be representative for current clinical practice. In addition, immunosuppressive drug combinations have improved over the past few decades,^7,8 and this has an impact on both histologic and functional evolution of allografts.^9–11 On one hand, although the newer immunosuppressive protocols have reduced the incidence of acute cellular rejection, rejection phenomena continue to play a major role in this histologic evolution. On the other hand, immunosuppressive drugs can elicit direct (e.g., nephrotoxicity of calcineurin inhibitors) and indirect (diabetes mellitus, hyperlipidemia, and hypertension) side effects, which also contribute to renal allograft injury.^12,13The complementary impact of these phenomena (donor kidney quality, allograft rejection, and calcineurin inhibitor nephrotoxicity) on the progression of histologic allograft damage has not been studied in patients treated with the current powerful immunosuppressive protocols nor within the wide range of donor graft quality. Moreover, the determinants of individual susceptibility to calcineurin inhibitor nephrotoxicity are not well known. Previous animal and human studies have suggested a role of decreased P-glycoprotein (ABCB1 or MDR1, the multidrug efflux transporter involved in tacrolimus transport¹⁴) expression^15–17 or activity¹⁸ and genetic polymorphisms in ABCB1^19,20 in the development of calcineurin inhibitor nephrotoxicity.The current study was undertaken to assess the determinants of the histologic evolution of renal allografts in the first years after transplantation in 252 patients treated with a combination of tacrolimus, mycophenolate mofetil, and corticosteroids against a background of varying degrees of pre-existing histologic damage in the donor kidney at implantation.^8,11 In addition, the determinants of individual susceptibility to calcineurin inhibitor nephrotoxicity were evaluated, including extensive tacrolimus exposure data, P-glycoprotein expression, and polymorphisms in ABCB1, CYP3A4, and CYP3A5 of both donor and recipients. Finally, this study examined the features that predict lower MDRD glomerular filtration rate during follow-up and assessed the main determinants of early graft survival.