Sinha A, Sharma A, Mehta A, Gupta R, Gulati A, Hari P, Dinda A K, Bagga A
Department of Pediatrics, Division of Nephrology, All India Institute of Medical Sciences, New Delhi, India.
Indian J Nephrol. 2013 Jan;23(1):41-6. doi: 10.4103/0971-4065.107197.
Prolonged therapy with calcineurin inhibitors (CNI) is effective in patients with difficult nephrotic syndrome. However, information on prevalence and risk factors for nephrotoxicity in children with steroid-resistant nephrotic syndrome is limited. This retrospective observational study was conducted on 40 patients with steroid-resistant nephrotic syndrome treated with cyclosporine (CyA) (n = 28) or tacrolimus (n = 12) for more than 2 years. Nephrotoxicity was defined by the presence of striped fibrosis involving ≥10% of the interstitium or nodular hyalinosis in more than one arteriole. Ten additional parameters were graded semi-quantitatively. Continuous data are presented as median and interquartile range (IQR). The median (IQR) age at onset of nephrotic syndrome and CNI therapy were 30 (21-45) and 49.5 (40-102.5) months. A second renal biopsy, following 30 (26-35) months of CNI therapy, showed histological toxicity in 10 (25%) patients. Toxicity was seen in 7 and 3 patients receiving CyA and tacrolimus, respectively, and 5 patients each with minimal change and focal segmental glomerulosclerosis. Therapy with CNI was associated with significant increases in scores for global glomerulosclerosis, tubular atrophy, interstitial fibrosis, nonnodular arteriolar hyalinosis (P < -0.001 for all), arteriolar smooth-muscle vacuolization (P = -0.02), juxtaglomerular hyperplasia (P = -0.002), and tubular microcalcinosis (P = -0.06). Risk factors for nephrotoxicity were initial resistance (OR 9; 95% CI 1.0-80.1; P = -0.049); dose of CyA (OR 9.2; 95% CI 1.1-74.6; P = -0.037); duration of heavy proteinuria (OR 1.2; 95% CI 1.0-1.4; P = -0.023); and hypertension during therapy (OR 6; 95% CI 1.3-28.3; P = -0.023). Following prolonged CNI therapy, one in four biopsies show features of toxicity. Prolonged duration of heavy proteinuria, hypertension, initial steroid resistance and high CyA dose predict the occurrence of nephrotoxicity.
用钙调神经磷酸酶抑制剂（CNI）进行长期治疗对难治性肾病综合征患者有效。然而，关于激素抵抗性肾病综合征儿童肾毒性的患病率和危险因素的信息有限。本回顾性观察性研究对40例接受环孢素（CyA）（n = 28）或他克莫司（n = 12）治疗超过2年的激素抵抗性肾病综合征患者进行。肾毒性定义为存在累及≥10%间质的条纹状纤维化或多个小动脉中的结节性玻璃样变。另外10个参数进行半定量分级。连续数据以中位数和四分位间距（IQR）表示。肾病综合征和CNI治疗开始时的中位（IQR）年龄分别为30（21 - 45）个月和49.5（40 - 102.5）个月。在CNI治疗30（26 - 35）个月后进行的第二次肾活检显示，10例（25%）患者存在组织学毒性。接受CyA和他克莫司治疗的患者中分别有7例和3例出现毒性，微小病变和局灶节段性肾小球硬化患者各有5例出现毒性。CNI治疗与全球肾小球硬化、肾小管萎缩、间质纤维化、非结节性小动脉玻璃样变（所有P < -0.001）、小动脉平滑肌空泡化（P = -0.02）、球旁增生（P = -0.002）和肾小管微钙化（P = -0.06）的评分显著增加相关。肾毒性的危险因素为初始抵抗（OR 9；95%CI 1.0 - 80.1；P = -0.049）；CyA剂量（OR 9.2；95%CI 1.1 - 74.6；P = -0.037）；大量蛋白尿持续时间（OR 1.2；95%CI 1.0 - 1.4；P = -0.023）；以及治疗期间的高血压（OR 6；95%CI 1.3 - 28.3；P = -0.023）。长期CNI治疗后，四分之一的活检显示有毒性特征。大量蛋白尿持续时间延长、高血压、初始激素抵抗和高CyA剂量可预测肾毒性的发生。
