Department of Clinical Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Kidney Int. 2011 Aug;80(3):282-7. doi: 10.1038/ki.2011.79. Epub 2011 Mar 30.
Intervention in the renin-angiotensin-aldosterone-system (RAAS) is associated with slowing the progressive loss of renal function. During initiation of therapy, however, there may be an acute fall in glomerular filtration rate (GFR). We tested whether this initial fall in GFR reflects a renal hemodynamic effect and whether this might result in a slower decline in long-term renal function. We performed a post hoc analysis of the Reduction of Endpoints in Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) trial. Patients assigned to losartan had a significantly greater acute fall in estimated (eGFR) during the first 3 months compared to patients assigned to placebo, but a significantly slower long-term mean decline of eGFR thereafter. A large interindividual difference, however, was noticed in the acute eGFR change. When patients were divided into tertiles of initial fall in eGFR, the long-term eGFR slope calculated from baseline was significantly higher in patients with an initial fall compared to those with an initial rise. When eGFR decline was calculated from 3 months to the final visit, excluding the initial effect, patients with a large initial fall in eGFR had a significant lower long-term eGFR slope compared to those with a moderate fall or rise. This relationship was independent of other risk markers or change in risk markers for progression of renal disease such as blood pressure and albuminuria. Thus, the greater the acute fall in eGFR, during losartan treatment, the slower the rate of long-term eGFR decline. Hence, interpretation of trial results relying on slope-based GFR outcomes should separate the initial drug-induced GFR change from the subsequent long-term effect on GFR.
干预肾素-血管紧张素-醛固酮系统（RAAS）与减缓肾功能的进行性丧失有关。然而，在开始治疗时，肾小球滤过率（GFR）可能会急性下降。我们测试了这种 GFR 的初始下降是否反映了肾脏的血液动力学效应，以及这是否会导致长期肾功能下降速度变慢。我们对血管紧张素 II 拮抗剂氯沙坦减少非胰岛素依赖型糖尿病终点（RENAAL）试验进行了事后分析。与安慰剂组相比，接受氯沙坦治疗的患者在头 3 个月内估算肾小球滤过率（eGFR）的急性下降幅度明显更大，但此后长期 eGFR 的平均下降速度明显较慢。然而，eGFR 急性变化的个体间差异很大。当患者根据 eGFR 初始下降的 tertiles 分组时，从基线计算的长期 eGFR 斜率在初始下降的患者中明显高于初始上升的患者。当从 3 个月到最后一次就诊计算 eGFR 下降时，排除初始效应后，与中度下降或上升的患者相比，eGFR 初始下降较大的患者的长期 eGFR 斜率明显较低。这种关系独立于其他风险标志物或导致肾脏疾病进展的风险标志物（如血压和白蛋白尿）的变化。因此，氯沙坦治疗期间 eGFR 的急性下降幅度越大，长期 eGFR 下降的速度越慢。因此，依赖基于斜率的 GFR 结果的试验结果的解释应将初始药物诱导的 GFR 变化与随后对 GFR 的长期影响分开。
