Donor Age and Renal P-Glycoprotein Expression Associate with Chronic Histological Damage in Renal Allografts
Donor Age and Renal P-Glycoprotein Expression Associate with Chronic Histological Damage in Renal Allografts
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DOI：
10.1681/asn.2009020192
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发表时间：
2009-11-01
影响因子：
13.6
通讯作者：
Kuypers, Dirk R. J.
中科院分区：
文献类型：
--
作者：
Naesens, Maarten;Lerut, Evelyne;Kuypers, Dirk R. J.
供体肾脏质量（部分由供体年龄决定）、同种异体移植物排斥反应和钙调神经磷酸酶抑制剂肾毒性对同种异体肾移植物组织学损伤进展的影响尚未完全确定。此外，个体对钙调神经磷酸酶抑制剂肾毒性的易感性的决定因素尚不清楚，但可能包括药物转运和代谢的变异性。在一项由 252 名成人同种异体肾移植受者组成的前瞻性队列中，接受他克莫司、吗替麦考酚酯和皮质类固醇联合治疗，我们研究了从移植时起 3 年定期采集的 744 份肾同种异体移植物活检样本。我们评估了组织学进化的决定因素，包括他克莫司暴露、肾 P-糖蛋白 (ABCB1) 表达以及 CYP3A4、CYP3A5 和 ABCB1 基因的多态性。在移植后的前 3 年内，我们注意到间质纤维化、肾小管萎缩、肾小球硬化和血管内膜增厚逐渐增加。供体年龄较大、肾小管上皮细胞顶膜缺乏 P-糖蛋白表达以及 ABCB1 中 C3435T 变体的供体-受体联合纯合性与慢性同种异体移植物损伤的易感性增加显着相关，与植入时的移植物质量无关。移植物功能随时间的变化反映了这些与供者年龄和 ABCB1 多态性的关联，但决定早期移植物存活的是急性 T 细胞介导和抗体介导的排斥反应。总之，供体年龄较大的影响超出了植入时同种异体移植物的质量，并且对于移植后的组织学演变仍然很重要。此外，ABCB1基因型和肾小管上皮细胞中P-糖蛋白的表达决定了移植肾对慢性肾小管间质损伤的易感性。
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.