Luño José, Barrio Vicente, Goicoechea Maria Angeles, González Cesar, de Vinuesa Soledad García, Gómez Francisco, Bernis Carmen, Espinosa Mario, Ahijado Francisco, Gómez José, Escalada Pedro
Department of Nephrology, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
Kidney Int Suppl. 2002 Dec(82):S47-52. doi: 10.1046/j.1523-1755.62.s82.10.x.
Blockade of the renin-angiotensin system (RAS) with angiotensin converting enzyme (ACE) inhibitors or with angiotensin II type 1 (AT1) receptor blockers has been shown to reduce proteinuria and to slow down the progression of renal disease in diabetic and non-diabetic primary proteinuric nephropathies. Additionally, this beneficial effect is not dependent on blood pressure control.
To assess and compare the effects of lisinopril (up to 40 mg/day), candesartan (up to 32 mg/day) and combination therapy (lisinopril up to 20 mg/day plus candesartan up to 16 mg/day) on urinary protein excretion, 45 patients with primary proteinuric nephropathies (urinary protein/creatinine ratio 3.8+/-2.4 g/g) and normal or slightly reduced renal function (CCr 95+/-33 mL/min) were enrolled in a six month multicenter, prospective, open, randomized, active-controlled and parallel-group trial with 1:1:1 allocation. Blood pressure goal was set at or below 125/75 mm Hg for all patients, with additional antihypertensive medication prescribed if required.
Renal function, estimated by creatinine clearance, remained stable throughout the study. Hyperkalemia (K>5.5 mmol/L) was detected in 3.1% of all measurements in follow-up, and was more frequent in patients treated with lisinopril alone or lisinopril plus candesartan (P<0.001) than in those on candesartan alone. No other relevant adverse event was recorded. The blood pressure goal (<125/75 mm Hg) was achieved by week 4 in all treatment groups (P<0.005 when compared to baseline), and afterwards the mean systolic and diastolic blood pressure remained below these values until the end of the trial with no statistically significant differences between groups. Urinary protein/creatinine ratio (percentage reduction 95% confidence intervals CI) decreased in patients treated with lisinopril alone to -33% (CI -12-56) to -31% (CI 0-68) and to -50% (CI -9-90), in patients treated with candesartan to -28% (CI -12-45), to -41% (CI -30-52) and to -48% (CI -32-63), in patients treated with the combination of both to -60% (CI -44-77) to -54% (CI -38-69) and to -70% (CI -57-83) at two, three, and six months, respectively. All comparisons with baseline achieved statistical significance and treatment with combination therapy was statistically more effective in proteinuria reduction than treatment with candesartan alone at two and six months (P=0.004 and P=0.023, respectively) and than treatment with lisinopril only at two months (P=0.03).
Dual blockade of the renin-angiotensin system with ACE inhibitors and AT1 receptor blockers produces a beneficial antiproteinuric effect that could not be explained only by the systemic blood pressure reduction. All treatments were well tolerated.
血管紧张素转换酶（ACE）抑制剂或血管紧张素II 1型（AT1）受体阻滞剂对肾素-血管紧张素系统（RAS）的阻断已被证明可减少蛋白尿，并减缓糖尿病和非糖尿病原发性蛋白尿性肾病的肾脏疾病进展。此外，这种有益作用并不依赖于血压控制。
为评估和比较赖诺普利（最高40毫克/天）、坎地沙坦（最高32毫克/天）及联合治疗（赖诺普利最高20毫克/天加坎地沙坦最高16毫克/天）对尿蛋白排泄的影响，45例原发性蛋白尿性肾病患者（尿蛋白/肌酐比值3.8±2.4克/克）且肾功能正常或轻度降低（肌酐清除率95±33毫升/分钟）被纳入一项为期6个月的多中心、前瞻性、开放性、随机、活性对照平行组试验，按1:1:1分配。所有患者的血压目标设定为125/75毫米汞柱或以下，必要时加用其他抗高血压药物。
在整个研究过程中，通过肌酐清除率评估的肾功能保持稳定。随访期间所有测量中有3.1%检测到高钾血症（血钾>5.5毫摩尔/升），单独使用赖诺普利或赖诺普利加坎地沙坦治疗的患者比单独使用坎地沙坦治疗的患者更常见（P<0.001）。未记录其他相关不良事件。所有治疗组在第4周时均达到血压目标（<125/75毫米汞柱）（与基线相比P<0.005），此后直至试验结束，平均收缩压和舒张压均保持在这些值以下，组间无统计学显著差异。单独使用赖诺普利治疗的患者尿蛋白/肌酐比值（降低百分比95%置信区间CI）在2个月、3个月和6个月时分别降至-33%（CI -12-56）至-31%（CI 0-68）和-50%（CI -9-90），使用坎地沙坦治疗的患者降至-28%（CI -12-45）、-41%（CI -30-52）和-48%（CI -32-63），联合使用两者治疗的患者降至-60%（CI -44-77）至-54%（CI -38-69）和-70%（CI -57-83）。与基线的所有比较均具有统计学显著性，联合治疗在减少蛋白尿方面在2个月和6个月时比单独使用坎地沙坦治疗在统计学上更有效（分别为P=0.004和P=0.023），在2个月时比仅使用赖诺普利治疗更有效（P=0.03）。
ACE抑制剂和AT1受体阻滞剂对肾素-血管紧张素系统的双重阻断产生有益的抗蛋白尿作用，这不能仅用全身血压降低来解释。所有治疗耐受性良好。
