Nankivell Brian J, Borrows Richard J, Fung Caroline L-S, O'Connell Philip J, Allen Richard D M, Chapman Jeremy R
Department of Renal Medicine, University of Sydney, Westmead Hospital, Sydney, NSW, Australia.
N Engl J Med. 2003 Dec 11;349(24):2326-33. doi: 10.1056/NEJMoa020009.
With improved immunosuppression and early allograft survival, chronic allograft nephropathy has become the dominant cause of kidney-transplant failure.
We evaluated the natural history of chronic allograft nephropathy in a prospective study of 120 recipients with type 1 diabetes, all but 1 of whom had received kidney-pancreas transplants. We obtained 961 kidney-transplant-biopsy specimens taken regularly from the time of transplantation to 10 years thereafter.
Two distinctive phases of injury were evident as chronic allograft nephropathy evolved. An initial phase of early tubulointerstitial damage from ischemic injury (P<0.05), prior severe rejection (P<0.01), and subclinical rejection (P<0.01) predicted mild disease by one year, which was present in 94.2 percent of patients. Early subclinical rejection was common (affecting 45.7 percent of biopsy specimens at three months), and the risk was increased by the occurrence of a prior episode of severe rejection and reduced by tacrolimus and mycophenolate therapy (both P<0.05) and gradually abated after one year. Both subclinical rejection and chronic rejection were associated with increased tubulointerstitial damage (P<0.01). Beyond one year, a later phase of chronic allograft nephropathy was characterized by microvascular and glomerular injury. Chronic rejection (defined as persistent subclinical rejection for two years or longer) was uncommon (5.8 percent). Progressive high-grade arteriolar hyalinosis with luminal narrowing, increasing glomerulosclerosis, and additional tubulointerstitial damage was accompanied by the use of calcineurin inhibitors. Nephrotoxicity, implicated in late ongoing injury, was almost universal at 10 years, even in grafts with excellent early histologic findings. By 10 years, severe chronic allograft nephropathy was present in 58.4 percent of patients, with sclerosis in 37.3 percent of glomeruli. Tubulointerstitial and glomerular damage, once established, was irreversible, resulting in declining renal function and graft failure.
Chronic allograft nephropathy represents cumulative and incremental damage to nephrons from time-dependent immunologic and nonimmunologic causes.
随着免疫抑制的改善和移植肾早期存活率的提高，慢性移植肾肾病已成为肾移植失败的主要原因。
我们在一项对120例1型糖尿病患者的前瞻性研究中评估了慢性移植肾肾病的自然病程，这些患者除1例之外均接受了胰肾联合移植。我们获取了961份移植肾活检标本，这些标本从移植时起至此后10年定期采集。
随着慢性移植肾肾病的发展，明显出现了两个不同的损伤阶段。缺血性损伤（P<0.05）、既往严重排斥反应（P<0.01）和亚临床排斥反应（P<0.01）导致的早期肾小管间质损伤的初始阶段预示着1年后病情较轻，94.2%的患者出现这种情况。早期亚临床排斥反应很常见（在3个月时影响45.7%的活检标本），既往严重排斥反应的发生会增加其风险，而他克莫司和霉酚酸酯治疗可降低其风险（均P<0.05），且1年后逐渐减轻。亚临床排斥反应和慢性排斥反应均与肾小管间质损伤增加有关（P<0.01）。1年后，慢性移植肾肾病的后期阶段以微血管和肾小球损伤为特征。慢性排斥反应（定义为持续两年或更长时间的亚临床排斥反应）并不常见（5.8%）。使用钙调神经磷酸酶抑制剂会伴随进行性高级别小动脉玻璃样变伴管腔狭窄、肾小球硬化加重以及额外的肾小管间质损伤。即使在早期组织学表现良好的移植肾中，10年时与晚期持续损伤相关的肾毒性几乎普遍存在。到10年时，58.4%的患者出现严重慢性移植肾肾病，37.3%的肾小球发生硬化。一旦肾小管间质和肾小球损伤形成，就不可逆转，导致肾功能下降和移植肾失败。
慢性移植肾肾病代表了随时间推移由免疫和非免疫原因对肾单位造成的累积性和渐进性损伤。
