Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
Transplantation. 2012 Mar 27;93(6):624-31. doi: 10.1097/TP.0b013e3182461288.
Calcineurin inhibitor (CNI)-related acute nephrotoxicity is a common complication of transplantation. Clinical factors and elevated CNI levels are associated with nephrotoxicity; however, they do not fully explain the risk. Genetic factors may also predispose individuals to nephrotoxicity.
We enrolled 945 kidney recipients into a multicenter, prospective study. DNA was genotyped for 2724 single-nucleotide polymorphisms (SNPs) using a customized chip. Cox models, unadjusted and adjusted for clinical factors, examined the association between SNPs and time to early CNI-related acute nephrotoxicity in the first 6 months posttransplant.
Cyclosporine was associated with a 1.49 hazard (95% confidence interval, 1.04-2.14) of acute nephrotoxicity relative to tacrolimus. Acute nephrotoxicity occurred in 22.6% of cyclosporine and 19.8% of tacrolimus recipients. The median (interquartile range) daily dose and trough concentration at time of nephrotoxicity were 400 mg (400-500 mg) and 228 ng/mL (190-272 ng/mL) in the cyclosporine group, and 6 mg (4-8 mg) and 12.6 ng/mL (10.2-15.9 ng/mL) in the tacrolimus group, respectively. In single-SNP adjusted analysis, nine SNPs in the XPC, CYP2C9, PAX4, MTRR, and GAN genes were associated with cyclosporine nephrotoxicity. In a multi-SNP analysis, SNPs from the same genes remained significant after adjusting for the clinical factors, showing that the SNPs are jointly and independently predictive of cyclosporine nephrotoxicity. No SNPs were associated with tacrolimus nephrotoxicity.
We identified SNPs that were potentially associated with early, acute cyclosporine-related nephrotoxicity. Identifying risk SNPs before transplantation provides an opportunity for personalization of immunosuppression by identifying those who may benefit from CNI-avoidance or minimization, or assist in selecting CNI type. These SNPs require independent validation.
钙调磷酸酶抑制剂（CNI）相关的急性肾毒性是移植后的常见并发症。临床因素和 CNI 水平升高与肾毒性相关，但它们并不能完全解释风险。遗传因素也可能使个体易患肾毒性。
我们招募了 945 名肾移植受者参与一项多中心前瞻性研究。使用定制芯片对 2724 个单核苷酸多态性（SNP）进行 DNA 基因分型。Cox 模型，未调整和调整临床因素，研究了 SNP 与移植后前 6 个月内早期 CNI 相关急性肾毒性的时间关系。
与他克莫司相比，环孢素与急性肾毒性的风险增加 1.49（95%置信区间，1.04-2.14）。环孢素组和他克莫司组分别有 22.6%和 19.8%的患者发生急性肾毒性。环孢素组肾毒性发生时的中位（四分位间距）日剂量和谷浓度分别为 400mg（400-500mg）和 228ng/ml（190-272ng/ml），他克莫司组分别为 6mg（4-8mg）和 12.6ng/ml（10.2-15.9ng/ml）。在单 SNP 调整分析中，XPC、CYP2C9、PAX4、MTRR 和 GAN 基因中的 9 个 SNP 与环孢素肾毒性相关。在多 SNP 分析中，调整临床因素后，来自相同基因的 SNP 仍然具有显著性，表明 SNP 共同且独立地预测环孢素肾毒性。没有 SNP 与他克莫司肾毒性相关。
我们发现了一些可能与早期急性环孢素相关肾毒性相关的 SNP。在移植前识别风险 SNP 为避免或最小化 CNI 提供了机会，或有助于选择 CNI 类型，从而实现免疫抑制的个体化。这些 SNP 需要独立验证。
