Abstract

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. 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. Diabetic nephropathy is the most common cause of end-stage kidney disease (ESRD). Agents that block the renin-angiotensin-aldosterone-system (RAAS) can prevent the onset and progression of nephropathy, attenuate deterioration of kidney function, and improve survival in patients with diabetes.1.Brenner B.M. Cooper M.E. de Zeeuw D. et al.Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.N Engl J Med. 2001; 345: 861-869Crossref PubMed Scopus (5795) Google Scholar, 2.Lewis E.J. Hunsicker L.G. Clarke W.R. et al.Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.N Engl J Med. 2001; 345: 851-860Crossref PubMed Scopus (4761) Google Scholar, 3.Parving H.H. Lehnert H. Brochner-Mortensen J. et al.The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes.N Engl J Med. 2001; 345: 870-878Crossref PubMed Scopus (2845) Google Scholar, 4.Ruggenenti P. Fassi A. Ilieva A.P. et al.Preventing microalbuminuria in type 2 diabetes.N Engl J Med. 2004; 351: 1941-1951Crossref PubMed Scopus (870) Google Scholar Data from small-scale studies have suggested that treatment with blood pressure-lowering medication, including angiotensin-converting enzyme (ACE) inhibitors or angiotensin-II receptor blockers (ARBs), is associated with an initial fall in glomerular filtration rate (GFR) or increase in serum creatinine levels, most likely resulting from a reduction in intraglomerular pressure.5.Bjorck S. Mulec H. Johnsen S.A. et al.Renal protective effect of enalapril in diabetic nephropathy.BMJ. 1992; 304: 339-343Crossref PubMed Scopus (402) Google Scholar, 6.Hillege H.L. van Gilst W.H. van Veldhuisen D.J. et al.Accelerated decline and prognostic impact of renal function after myocardial infarction and the benefits of ACE inhibition: the CATS randomized trial.Eur Heart J. 2003; 24: 412-420Crossref PubMed Scopus (133) Google Scholar, 7.Tarnow L. Rossing P. Jensen C. et al.Long-term renoprotective effect of nisoldipine and lisinopril in type 1 diabetic patients with diabetic nephropathy.Diabetes Care. 2000; 23: 1725-1730Crossref PubMed Scopus (62) Google Scholar In daily practice, a rise in serum creatinine may inappropriately raise safety concerns that prevent clinicians from using sufficiently high doses of ACE inhibitors or ARBs or from continuing treatment altogether. A systematic review showed that a rise in serum creatinine of up to 30% of baseline levels is no reason for concern, provided serum electrolytes (principally potassium) remain within normal limits.8.Bakris G.L. Weir M.R. Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: is this a cause for concern?.Arch Intern Med. 2000; 160: 685-693Crossref PubMed Google Scholar A small-scale study in patients with chronic kidney disease even indicates that the magnitude of initial fall in GFR is inversely related to the long-term slope of GFR decline and is reversible after termination of RAAS blockade.9.Apperloo A.J. de Z.D. de Jong P.E. A short-term antihypertensive treatment-induced fall in glomerular filtration rate predicts long-term stability of renal function.Kidney Int. 1997; 51: 793-797Abstract Full Text PDF PubMed Scopus (172) Google Scholar These data do not only show that the initial fall in GFR is hemodynamic rather than structural, but also suggest that the decline can, in fact, serve as an early marker of subsequent slower decline of long-term renal function obtained from RAAS inhibitor treatment. Evidence from large-scale placebo-controlled trials to support this hypothesis is, however, lacking. The Reduction in Endpoints in Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin-II Antagonist Losartan (RENAAL) trial investigated the effects of the ARB losartan versus placebo. The presence of a baseline period without RAAS inhibitor treatment and the availability of serum creatinine values on baseline and every 3 months during therapy allows us to study the associations between treatment-induced short-term responses in estimated GFR (eGFR) on one hand and its long-term renal function decline on the other. The eGFR course during the RENAAL trial is shown in Figure 1. The fall in eGFR at 3 months after the start of treatment was greater in losartan-treated individuals compared with placebo (2.3 (95% confidence interval (CI) 2.7–1.8) vs 1.6 (2.0–1.1) ml/min per 1.73 m2, respectively, P=0.031). The initial fall in eGFR was inversely associated with the long-term eGFR slope, such that the long-term eGFR slope in the losartan group was significantly smaller compared with placebo (−4.2 (95% CI −3.9 to −4.6) vs −5.0 (−4.7 to −5.4) ml/min per 1.73 m2 per year; P30 years old at the time of diagnosis of diabetes, had no history of ketoacidosis, and did not use insulin therapy within 6 month after diagnosis. A serum creatinine between 1.3 and 3.0 mg/dl (1.5–3.0 mg/dl for males >60 kg), UACR from a first morning specimen of at least 300 mg/g, HbA1c <12%, and age between 31 and 70 years were part of the inclusion criteria. After a 6-week screening phase, patients were randomly assigned to either losartan 50 mg (titrated to 100 mg after 4 weeks) or placebo. Additional antihypertensive medications (calcium channel blockers, β-blockers, centrally acting agents, and diuretics, excluding ACE inhibitors or other ARBs) were permitted during follow-up to reach the blood pressure goal of <140/90 mm Hg (systolic/diastolic). The mean follow-up duration was 3.4 year with a range of 2.3 to 4.6 years. The RENAAL trial was conducted according to the Declaration of Helsinki Principles. All patients signed informed consent. The protocol was approved by all relevant ethics committees. Participants were seen at a screening visit, randomization visit, at 1 and 3 months after randomization, and subsequently at 3 months intervals. At each visit, serum creatinine and electrolytes were measured. The MDRD equation was used to estimate GFR.22.Levey A.S. Bosch J.P. Lewis J.B. et al.A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group.Ann Intern Med. 1999; 130: 461-470Crossref PubMed Scopus (12277) Google Scholar The dose of losartan was titrated toward the maximum recommended dose of 100 mg at the first month visit. The acute change in eGFR was assessed from baseline to month 3, 2 months after institution of the maximum recommended dose of losartan.21.Brenner B.M. Cooper M.E. de Zeeuw D. et al.The losartan renal protection study–rationale, study design and baseline characteristics of RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan).J Renin Angiotensin Aldosterone Syst. 2000; 1: 328-335Crossref PubMed Scopus (113) Google Scholar Renal events were defined as a confirmed doubling in serum creatinine from baseline or ESRD, which was defined as chronic dialysis or renal transplantation. All end points were adjudicated by an independent outcome committee. The difference in short-term and long-term eGFR change between placebo and losartan was calculated from baseline to month 3 and from month 3 to month 39. The difference in long-term eGFR slope between both treatment groups was estimated by a linear mixed effects model with random intercepts and random slopes. As an acute fall in eGFR was only observed in individuals assigned to losartan, we investigated which factors predicted an initial fall in eGFR during losartan therapy. A multivariable model was used for this purpose. The following covariates were included in the model: age, gender, body mass index, log-transformed UACR, systolic and diastolic blood pressure, hemoglobin, total cholesterol, diuretic use at baseline, and change from baseline to month 3 in log-transformed UACR, and systolic and diastolic blood pressure. Baseline characteristics that were statistically significantly associated with an acute fall in eGFR were selected for the multivariable regression model. Baseline characteristics not associated with eGFR decline in univariate analyses were step-wise added to the multivariable model to test their inclusion for statistical significance. Subsequently, we questioned whether those individuals with a more pronounced acute fall in eGFR showed a more stable course during long-term follow-up. Therefore, we compared the long-term eGFR slope for losartan-treated individuals within subgroups (tertiles) of acute fall in eGFR. This approach was aimed at identifying subgroups with identical number of patients to increase the power of the analysis while minimizing the risk of bias. The long-term eGFR slope in each tertile of acute fall in eGFR was estimated by a linear mixed effects model with random intercepts and random slopes. To assess whether the long-term slope correlated with the acute eGFR fall independently of other patient characteristics or response parameters, the initial fall in eGFR was controlled for various covariates including baseline eGFR, diastolic blood pressure, hemoglobin, gender, log-transformed UACR, and month 3 change in log-transformed UACR. In a sensitivity analysis eGFR was replaced for serum creatinine. Means and s.d. are provided for continuous variables, whereas number of patients and percentages are provided for class variables. A two-sided P-value ≤0.05 was used to indicate statistical significance. All analyses were conducted with SAS version 9.1 software (SAS Institute, Cary, NC). We acknowledge the supportive role of all RENAAL investigators, support staff, and participating patients.