Tubular Toxicity in Sirolimus- and Cyclosporine-Based Transplant Immunosuppression Strategies: An Ancillary Study From a Randomized Controlled Trial
Tubular Toxicity in Sirolimus- and Cyclosporine-Based Transplant Immunosuppression Strategies: An Ancillary Study From a Randomized Controlled Trial
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DOI：
10.1053/j.ajkd.2009.09.004
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发表时间：
2010-02-01
影响因子：
13.2
通讯作者：
Dickenmann, Michael
中科院分区：
文献类型：
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作者：
Franz, Stefan;Regeniter, Axel;Dickenmann, Michael
背景：西罗莫司已被推广为一种为肾移植受者提供免疫抑制的药物，与钙调神经磷酸酶抑制剂相比，西罗莫司不会对肾脏产生毒性。然而，一些报告观察到西罗莫司治疗的患者出现蛋白尿，范围从低级别到肾病范围。因此，我们在一项比较西罗莫司和环孢素的随机试验的辅助研究中比较了肾小管和肾小球损伤的标志物。研究设计：单中心、开放标签、随机、前瞻性试验。地点和对象：2001年1月至2004年7月在瑞士巴塞尔大学医院接受身体或活体供肾移植的患者。干预：免疫抑制方案包括环孢素、霉酚酸酯、泼尼松和西罗莫司、霉酚酸酯和泼尼松。结果：主要结果是肾功能，用血清肌酐水平进行评估。次要结果包括患者和移植物的存活率、排斥反应的数量和肾损害的证据，通过肾小球和肾小管尿生物标记物水平进行评估。测量：在0、7、30和90天收集尿液和血清。用血肌酐水平评估肾功能。尿液标记物包括α(1)-微球蛋白和视黄醇结合蛋白(管状)、转铁蛋白和白蛋白(肾小球)和半定量评估血糖。结果：63例患者被随机分配到以环孢素为基础的方案中，被随机分配到以西罗莫司为基础的方案中。两组患者的肾功能相似，但与肾小球损伤相关的标志物水平(白蛋白19.5vs8.96 mg/mmol肌酐；P<；0.001；转铁蛋白，13.1vs5.7 mg/mmol肌酐；p<；0.001)和与肾小管损伤相关的标记物水平(α(1)-微球蛋白，11vs7.6 mg/mmol肌酐；P=0.004；视黄醇结合蛋白，19.6vs9.6 mg/mmol肌酐；在随机分配到西罗莫司治疗的患者中，从第7天开始更高(P=0.002)，在第90天有类似的发现。随机分配到30天开始接受西罗莫司治疗的患者血糖尿发生率较高(30天65%对30%；P=0.002；90天51%对22%；P<；0.001)。在组织学检查上，随机分配西罗莫司治疗的患者肾小管病变的总体严重程度显著高于对照组。限制：样本量小，短期随访可能不足以评估钙调神经磷酸酶相关性肾病。结论：与基于环孢素的免疫抑制方案相比，基于西罗莫司的方案与新发的低级别肾小球蛋白尿、肾小管损伤相关标记物的分泌增加以及肾活检中肾小管损伤的证据有关。Am J肾脏Dis 55：335-343。(C)2010年，由国家肾脏基金会公司提供。
Background: Sirolimus has been promoted as an agent to provide immunosuppression for kidney transplant recipients that, in contrast to calcineurin inhibitors, would not be nephrotoxic. However, several reports have observed proteinuria in patients treated with sirolimus, ranging from low grade to nephrotic range. Accordingly, we compared markers of tubular and glomerular damage in an ancillary study of a randomized trial comparing sirolimus and cyclosporine.Study Design: Single-center, open-label, randomized, prospective trial.Setting & Participants: Patients undergoing cadaveric or living donor kidney transplant at the University Hospital in Basel, Switzerland, between January 2001 and July 2004.Intervention: Immunosuppression regimen consisting of cyclosporine, mycophenolate mofetil, and prednisone versus sirolimus, mycophenolate mofetil, and prednisone. Outcomes: The primary outcome was kidney function, assessed using serum creatinine level. Secondary outcomes included patient and graft survival, number of rejections, and evidence of kidney damage, assessed using glomerular and tubular urine biomarker levels.Measurements: Urine and serum were collected at 0, 7, 30, and 90 days. Kidney function was estimated using serum creatinine level. Urinary markers included alpha(1)-microglobulin and retinol-binding protein (tubular), transferrin and albumin (glomerular), and semiquantitative assessment of glucosuria. Protocol kidney biopsies were performed at days 90 and 180.Results: There were 63 patients randomly assigned to cyclosporine-based regimens, and 64, to sirolimus-based regimens. Kidney function was similar in both groups, whereas levels of markers associated with glomerular damage (albumin, 19.5 vs 8.96 mg/mmol creatinine; P < 0.001; transferrin, 13.1 vs 5.7 mg/mmol creatinine; P < 0.001) and those associated with tubular damage (alpha(1)-microglobulin, 11 vs 7.6 mg/mmol creatinine; P = 0.004; retinol-binding protein, 19.6 vs 9.6 mg/mmol creatinine; P = 0.002) were higher beginning at day 7 in patients randomly assigned to sirolimus therapy, with similar findings through day 90. Glucosuria incidence was higher in patients randomly assigned to sirolimus therapy beginning by day 30 (65% vs 30% on day 30; P = 0.002; 51% vs 22% on day 90; P < 0.001). On histologic examination, the overall severity of tubular lesions was significantly higher in patients randomly assigned to sirolimus therapy.Limitations: Small sample size, short-term follow-up likely insufficient to appreciate calcineurin-associated nephropathy.Conclusion: Compared with a cyclosporine-based immunosuppression regimen, a sirolimus-based regimen is associated with de novo low-grade glomerular proteinuria, increased excretion of markers associated with tubular damage, and evidence of tubular damage on kidney biopsy. Am J Kidney Dis 55: 335-343. (C) 2010 by the National Kidney Foundation, Inc.