Dawidson I, Rooth P
University of Texas, Southwestern Medical Center, Department of Surgery, Dallas 75235-9031.
Am J Med. 1991 May 17;90(5A):37S-41S. doi: 10.1016/0002-9343(91)90484-f.
Although cyclosporin A (CsA) has allowed substantial advances in organ transplantation due to its immunosuppressive properties, its use is complicated by its direct nephrotoxic effects. Initial studies with mice confirmed that CsA caused a dose-related inhibition of the subcapsular microcirculation; subsequent clinical investigations have confirmed this inhibitory effect. Efforts to circumvent CsA-induced nephrotoxicity have focused on calcium antagonists. For example, when the calcium antagonist verapamil was administered before the initiation of CsA, renal blood flow was maintained. Verapamil therapy was also associated with significantly fewer rejection episodes (3 of 22; 14%) within 4 weeks of transplantation than CsA therapy alone (10 of 18; 56%). In a current study, verapamil 10 mg was injected into the renal artery during surgery, followed by 120 mg tid orally for 14 days. This regimen reduced delayed function incidents (the need for dialysis) during the first post-transplant week. Excluding nonfunctioning kidneys and technical failures, there were no graft losses secondary to rejection in patients treated with verapamil. The beneficial effects of verapamil therapy on transplant outcome may be related to its ability to protect cells from ischemia, the selective vasodilation of the efferent arteriole, elevated CsA blood levels, and inherent immunosuppressive properties.
尽管环孢素A（CsA）因其免疫抑制特性在器官移植领域取得了重大进展，但其使用因直接肾毒性作用而变得复杂。对小鼠的初步研究证实，CsA会导致与剂量相关的肾包膜下微循环抑制；随后的临床研究也证实了这种抑制作用。规避CsA诱导的肾毒性的努力主要集中在钙拮抗剂上。例如，在开始使用CsA之前给予钙拮抗剂维拉帕米，肾血流量得以维持。维拉帕米治疗组在移植后4周内的排斥反应发作次数（22例中有3例；14%）也明显少于单独使用CsA治疗组（18例中有10例；56%）。在一项当前研究中，手术期间将10毫克维拉帕米注入肾动脉，随后口服120毫克，每日三次，共14天。该方案减少了移植后第一周内的延迟功能事件（透析需求）。排除无功能肾和技术失败情况，接受维拉帕米治疗的患者中没有因排斥反应导致的移植肾丢失。维拉帕米治疗对移植结果的有益影响可能与其保护细胞免受缺血的能力、出球小动脉的选择性血管舒张、CsA血药浓度升高以及固有的免疫抑制特性有关。
