Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia)
Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia)
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背景：在糖尿病肾病中，血管紧张素转换酶（ACE）抑制剂对蛋白尿和肾小球滤过率（GFR）的进行性下降具有比其他降压药物更大的作用。这种差异是否适用于非糖尿病性蛋白尿肾病的进展尚不清楚。拉米普利在慢性非糖尿病肾病肾病中的疗效研究旨在研究肾小球蛋白运输是否影响肾病进展，以及ACE抑制剂是否优于常规治疗，在相同的血压控制下，在减少蛋白尿、限制GFR下降和预防终末期肾病方面。方法：在这项前瞻性双盲试验中，352例患者根据基线蛋白尿（1:1-3 g/24 h； 2: 1: 0或= 3 g/24 h）进行分类，随机分配雷米普利或安慰剂加常规降压治疗，目标是使舒张压低于90 mm Hg，主要终点是GFR下降率。分析的目的是治疗。在第二次计划的中期分析中，雷米普利组和安慰剂组在第2层GFR下降方面的差异非常显著（p = 0.001）。因此，独立评审小组决定打开随机化代码，并在该层（第1层继续在试验中进行）中进行最终分析。56名雷米普利组患者和61名安慰剂组患者的数据（包括基线在内的至少3项GFR测量）可用。雷米普利组每月GFR下降明显低于安慰剂组（0.53 [0.08]vs 0.88 [0.13] mL/min, p = 0.03）。在指定使用雷米普利的患者中，蛋白尿百分比减少与GFR下降呈负相关（p = 0.035），并预测基线肌酐加倍或终末期肾衰竭的风险降低（雷米普利18 vs安慰剂40，p = 0.04）。在调整收缩压（p = 0.04）和舒张压（p = 0.04）血压变化后，进展风险仍显著降低，但在调整蛋白尿变化后则没有显著降低。两个治疗组的血压控制和心血管事件总数相似。解释：对于每24小时蛋白尿3克或更多的慢性肾病患者，雷米普利可以安全地降低蛋白尿和GFR下降率，其降低程度似乎超过了预期的血压降低程度。
BACKGROUND In diabetic nephropathy, angiotensin-converting-enzyme (ACE) inhibitors have a greater effect than other antihypertensive drugs on proteinuria and the progressive decline in glomerular filtration rate (GFR). Whether this difference applies to progression of nondiabetic proteinuric nephropathies is not clear. The Ramipril Efficacy in Nephropathy study of chronic nondiabetic nephropathies aimed to address whether glomerular protein traffic influences renal-disease progression, and whether an ACE inhibitor was superior to conventional treatment, with the same blood-pressure control, in reducing proteinuria, limiting GFR decline, and preventing endstage renal disease. METHODS In this prospective double-blind trial, 352 patients were classified according to baseline proteinuria (stratum 1: 1-3 g/24 h; stratum 2: > or = 3 g/24 h), and randomly assigned ramipril or placebo plus conventional antihypertensive therapy targeted at achieving diastolic blood pressure under 90 mm Hg. The primary endpoint was the rate of GFR decline. Analysis was by intention to treat. FINDINGS At the second planned interim analysis, the difference in decline in GFR between the ramipril and placebo groups in stratum 2 was highly significant (p = 0.001). The Independent Adjudicating Panel therefore decided to open the randomisation code and do the final analysis in this stratum (stratum 1 continued in the trial). Data (at least three GFR measurements including baseline) were available for 56 ramipril-assigned patients and 61 placebo-assigned patients. The decline in GFR per month was significantly lower in the ramipril group than the placebo group (0.53 [0.08] vs 0.88 [0.13] mL/min, p = 0.03). Among the ramipril-assigned patients, percentage reduction in proteinuria was inversely correlated with decline in GFR (p = 0.035) and predicted the reduction in risk of doubling of baseline creatinine or endstage renal failure (18 ramipril vs 40 placebo, p = 0.04). The risk of progression was still significantly reduced after adjustment for changes in systolic (p = 0.04) and diastolic (p = 0.04) blood pressure, but not after adjustment for changes in proteinuria. Blood-pressure control and the overall number of cardiovascular events were similar in the two treatment groups. INTERPRETATION In chronic nephropathies with proteinuria of 3 g or more per 24 h, ramipril safely reduces proteinuria and the rate of GFR decline to an extent that seems to exceed the reduction expected for the degree of blood-pressure lowering.