Berl Tomas
Division of Renal Diseases and Hypertension, University of Colorado at Denver Health Sciences Center, Denver, Colorado 80262, USA.
J Renin Angiotensin Aldosterone Syst. 2009 Mar;10(1):1-8. doi: 10.1177/1470320309102747.
Renin-angiotensin-aldosterone system (RAAS) inhibition exerts a renoprotective effect independent of blood pressure reduction. Many studies using an end-point of proteinuria compared the effects of angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) monotherapy with combination ACE-I/ARB therapy. Despite methodological limitations, most studies suggest that combination therapy provides a greater antiproteinuric effect than monotherapy, perhaps because of more prolonged and complete RAAS inhibition. COOPERATE and ONTARGET used more robust end-points to study renoprotective effects. In COOPERATE, combination therapy resulted in significantly longer times to doubling serum creatinine or developing end-stage renal disease than trandolapril or losartan monotherapy. However, a secondary ONTARGET finding was that combination therapy significantly increased the risk for renal dysfunction compared with ramipril or telmisartan alone. Eventually, the VA NEPHRON-D trial should provide definitive data relating to patients with diabetic nephropathy.
of AVOID suggest the renoprotective benefits of combination therapy extend to the direct renin inhibitors (DRI). In AVOID, combination therapy with aliskiren, a DRI, and losartan resulted in 20% greater protein excretion decrement than losartan monotherapy. Future trials should examine higher RAAS inhibitor doses, facilitate differentiation of renoprotective and antihypertensive effects of RAAS blockade, and use end-points that robustly demonstrate renoprotective effects.
肾素-血管紧张素-醛固酮系统（RAAS）抑制发挥肾脏保护作用，独立于血压降低。许多以蛋白尿为终点的研究比较了血管紧张素转换酶抑制剂（ACE-I）或血管紧张素受体阻滞剂（ARB）单药治疗与ACE-I/ARB联合治疗的效果。尽管存在方法学局限性，但大多数研究表明，联合治疗比单药治疗具有更大的抗蛋白尿作用，这可能是因为RAAS抑制作用更持久、更完全。COOPERATE和ONTARGET研究使用了更可靠的终点来研究肾脏保护作用。在COOPERATE研究中，与群多普利或氯沙坦单药治疗相比，联合治疗使血清肌酐翻倍或发展为终末期肾病的时间显著延长。然而，ONTARGET研究的一个次要发现是，与单独使用雷米普利或替米沙坦相比，联合治疗显著增加了肾功能不全的风险。最终，退伍军人事务部肾病-糖尿病试验（VA NEPHRON-D）应能提供与糖尿病肾病患者相关的确切数据。
AVOID研究表明联合治疗的肾脏保护益处扩展至直接肾素抑制剂（DRI）。在AVOID研究中，直接肾素抑制剂阿利吉仑与氯沙坦联合治疗导致的尿蛋白排泄减少幅度比氯沙坦单药治疗大20%。未来的试验应研究更高剂量的RAAS抑制剂，促进区分RAAS阻断的肾脏保护作用和降压作用，并使用能有力证明肾脏保护作用的终点指标。
