Shahnaz Shahinfar

Progression of Chronic Kidney Disease: The Role of Blood Pressure Control, Proteinuria, and Angiotensin-Converting Enzyme Inhibition: A Patient-Level Meta-Analysis

Context Guidelines recommend a blood pressure of less than 130/80 mm Hg for patients with chronic kidney disease. Contribution This meta-analysis showed that systolic blood pressure and urinary protein excretion were related to the risk for renal disease progression in patients with nondiabetic kidney disease. Systolic pressures of 110 to 129 mm Hg were associated with the lowest risks. Higher risks with higher pressures were marked in patients with protein excretion greater than 1.0 g/d and were not apparent in those with lower urinary protein excretion. Implications In patients with urinary protein excretion greater than 1.0 g/d, systolic blood pressure of 110 to 129 mm Hg is associated with the lowest risk for progression of renal disease. The Editors Chronic kidney disease is a major public health problem in the United States. The prevalence of kidney failure (recorded as end-stage renal disease) has risen steadily since Medicare assumed funding for the condition in 1973. By 2010, it is estimated that the prevalence will be greater than 650 000 (1). The prevalence of earlier stages of chronic kidney disease is even higher. The Third National Health and Nutrition Examination Survey (NHANES III), conducted from 1988 to 1994, estimates that 5.6 million persons 17 years of age or older had decreased kidney function, as defined by an elevated serum creatinine concentration ( 141 mol/L [ 1.6 mg/dL] in men and 124 mol/L [ 1.4 mg/dL] in women) (2). Hypertension and proteinuria occur in most patients with chronic kidney disease and are risk factors for faster progression of kidney disease. Antihypertensive agents reduce blood pressure and urine protein excretion and slow the progression of kidney disease. The sixth report of the Joint National Committee for the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VI) recommends a lower blood pressure goal for patients with decreased kidney function (<130/85 mm Hg if urine protein excretion is <1 g/d and <125/75 mm Hg if urine protein excretion is >1 g/d) than for patients without target organ damage (<140/90 mm Hg) (3). It is not known whether even lower blood pressure might provide additional benefit. On the other hand, there is concern about excessive lowering of blood pressure because it may be associated with a higher risk for cardiovascular disease (4, 5). Additional lowering of blood pressure might also have a detrimental effect on kidney disease. The recommendations in JNC-VI are based principally on the results of the Modification of Diet in Renal Disease (MDRD) Study (6, 7), a study of nondiabetic kidney disease that did not evaluate the effect of angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers. Since publication of the JNC-VI, other large studies and meta-analyses have shown that antihypertensive regimens containing ACE inhibitors or angiotensin-receptor blockers seem to be more effective than other regimens in slowing the progression of chronic kidney disease (8-17). In some studies, the beneficial effect of these agents seemed to be greater in patients with proteinuria (8-11, 13) and was mediated in part by their effects to lower blood pressure and urine protein excretion (13). Of these studies, only the African American Study of Kidney Disease and Hypertension (AASK) compared two levels of blood pressure in patients treated with an ACE inhibitor (11). In that study of patients with hypertensive nephrosclerosis, a type of kidney disease associated with low levels of proteinuria, a lower blood pressure goal did not reduce the risk for progression of kidney disease when compared with a usual blood pressure goal. However, the AASK does not address the relationships of blood pressure and urine protein excretion with the progression of kidney disease in patients with higher levels of urine protein excretion. We performed a patient-level meta-analysis using data from the ACE Inhibition in Progressive Renal Disease (AIPRD) Study Group database (13) to assess these relationships among patients with nondiabetic kidney disease across a wide range of urine protein excretion values during antihypertensive therapy with and without ACE inhibitors. Methods Study Design The AIPRD Study Group database includes 1860 patients with nondiabetic kidney disease enrolled in 11 randomized, controlled trials of ACE inhibitors to slow the progression of kidney disease. The database contains information on blood pressure, urine protein excretion, serum creatinine concentration, and onset of kidney failure during 22 610 visits. Inclusion and exclusion criteria, search strategies for identifying clinical trials, and details of database formulation have been previously described (13, 18). The AIPRD Study Group was formed in 1997. Briefly, we identified studies by searching the MEDLINE database for English-language reports evaluating the effect of ACE inhibitors or kidney disease in humans between 1977 (when ACE inhibitors were approved for trials in humans) and 1999 (when the database was closed). We included only randomized trials (with a minimum 1-year follow-up) that compared the effects of antihypertensive regimens that included ACE inhibitors with the effects of regimens that did not include ACE inhibitors. Hypertension or decreased kidney function was required for entry into all studies. Exclusion criteria common to all studies were acute kidney failure, treatment with immunosuppressive medications, clinically significant congestive heart failure, obstructive uropathy, renal artery stenosis, active systemic disease, type 1 diabetes mellitus, history of transplantation, history of allergy to ACE inhibitors, and pregnancy. The institutional review board at each participating center approved the study, and all patients gave informed consent. Patients were enrolled between March 1986 and April 1996. All patients were randomly assigned to antihypertensive regimens either with or without ACE inhibitors. The ACE inhibitors included captopril, enalapril, cilazapril, benazepril, and ramipril. Concomitant antihypertensive medications were used in both groups to achieve a target blood pressure less than 140/90 mm Hg in all studies. All patients were followed at least once every 3 months for the first year and at least once every 6 months thereafter. Justification for pooling the 11 clinical trials is based on the similarity of study designs and patient characteristics. Justification for pooling placebo-controlled and active-drugcontrolled trials is based on the presence of preexisting hypertension and the use of antihypertensive agents in most patients in the control groups in each clinical trial. Thus, the pooled analysis addresses the clinically relevant question of the relationship of the level of blood pressure and urine protein excretion with the kidney disease progression during antihypertensive therapy, either with or without ACE inhibitors. Definition and Ascertainment of Blood Pressure and Urine Protein Excretion Clinical trial protocols stipulated measurement of blood pressure more frequently than urine protein excretion. In our database, visit was defined as any contact with patients during which study-related information was recorded or clinical variables were measured. Blood pressure was recorded on the same day as the visit in 94% of the visits and within 3 months before the visit in 99% of the visits. Urine protein excretion was recorded on the same day as the visit in 62% of the visits and within 6 months before the visit in 97% of the visits. Blood pressure and urine protein excretion levels at follow-up visits are defined as the current levels. We used current as well as baseline levels as the variables of interest for these analyses because guidelines for blood pressure target current values (3) and our previous studies have demonstrated that the current level of urine protein excretion is a stronger predictor of kidney disease progression than is the baseline level (19). Blood pressure was measured by using a mercury sphygmomanometer in nine studies (8-10, 20-24; Brenner BM. Personal communication) (93% of visits) and calibrated automatic device in two studies (25, 26). Systolic and diastolic blood pressure were measured after 5 to 10 minutes of rest in the supine position in 10 studies (8-10, 20, 22-26; Brenner BM. Personal communication) and in the sitting position in 1 study (21). Urine protein excretion was reported as total urine protein excretion in a 24-hour urine sample in 10 studies (8-10, 20-22, 24-26; Brenner BM. Personal communication) (95% of visits). One study performed a dipstick assessment in an untimed urine sample and reported quantitative measurement only if the dipstick result was positive (23). For that study, all values of dipstick negative were assigned a value of 0.1 g/d. In all studies, results for urine protein excretion of 0.1 g/d or lower were also assigned a value of 0.1 g/d. Values greater than 0.1 g/d were recorded as the exact values reported in the study and rounded to the nearest 0.1 g/d. Outcomes Serum creatinine concentration was recorded on the same day as the visit in 78% of visits and within 3 months after the visit in 96% of the visits. The primary outcome for the pooled analysis was kidney disease progression, defined as a combined end point of a twofold increase (doubling) in serum creatinine concentration from baseline values or development of kidney failure, defined as the initiation of long-term dialysis therapy. Statistical Analyses We used S-Plus 2000 (Insightful Corp., Seattle, Washington) and SAS software, version 8.2 (SAS Institute, Inc., Cary, North Carolina), software programs for statistical analyses. Cox proportional-hazards regression analysis was performed to detect associations between the covariates and outcomes. Baseline patient characteristics were treatment assignment (ACE inhibitor vs. control, using the intention-to-treat principle), age (logarithmic

Angiotensin-Converting Enzyme Inhibitors and Progression of Nondiabetic Renal Disease: A Meta-Analysis of Patient-Level Data

Chronic renal disease is a major public health problem in the United States. According to the 1999 Annual Data Report of the U.S. Renal Data System, more than 357 000 people have end-stage renal disease (ESRD), and the annual cost of treatment with dialysis and renal transplantation exceeds

Albuminuria, a Therapeutic Target for Cardiovascular Protection in Type 2 Diabetic Patients With Nephropathy

15.6 billion (1). Patients undergoing dialysis have reduced quality of life, a high morbidity rate, and an annual mortality rate of 20% to 25% (1). Identification of therapies to prevent ESRD is an important public health goal. Angiotensin-converting enzyme (ACE) inhibitors are highly effective in slowing the progression of renal disease due to type 1 diabetes (26), and evidence of their efficacy in type 2 diabetes is growing (712). However, although 14 randomized, controlled trials have been completed (1325; Brenner BM; Toto R. Personal communications), no consensus exists on the use of ACE inhibitors in nondiabetic renal disease (2628). In a previous meta-analysis of 11 randomized, controlled trials, we found that therapy with ACE inhibitors slowed the progression of nondiabetic renal disease (29). Since our meta-analysis was performed on group data rather than individual-patient data, we could not fully assess the relationship between the effect of ACE inhibitors and blood pressure, urinary protein excretion, or other patient characteristics (30). Thus, we could not determine whether an equal reduction in blood pressure or urinary protein excretion by using other antihypertensive agents would be as effective in slowing the progression of renal disease. Nor could we determine whether the baseline blood pressure, urinary protein excretion, or other patient characteristics modified the response to treatment. In the current report, we used pooled analysis of individual-patient data to answer these questions. We reasoned that the large number of patients in the pooled analysis would provide sufficient statistical power to detect relationships between patient characteristics and risk for progression of renal disease and interactions of patient characteristics with treatment effect. In principle, strong and consistent results from analysis of this large database would clarify the effects of ACE inhibitors for treatment of nondiabetic renal disease. Methods Study Design We obtained individual-patient data from nine published (1322) and two unpublished (Brenner BM; Toto R. Personal communications) randomized, controlled trials assessing the effects of ACE inhibitors on renal disease progression in predominantly nondiabetic patients. Search strategies used to identify clinical trials have been described elsewhere and are reviewed in Appendix 2. We included 11 randomized trials on progression of renal disease that compared the effects of antihypertensive regimens including ACE inhibitors to the effects of regimens without ACE inhibitors, with a follow-up of at least 1 year. In these studies, the institutional review board at each participating center approved the study, and all patients gave informed consent. Patients underwent randomization between March 1986 and April 1996. Hypertension or decreased renal function was required for entry into all studies. Exclusion criteria common to all studies were acute renal failure, treatment with immunosuppressive medications, clinically significant congestive heart failure, obstructive uropathy, renal artery stenosis, active systemic disease, insulin-dependent diabetes mellitus, history of transplantation, history of allergy to ACE inhibitors, and pregnancy. Table 1 shows characteristics of the patients in each study. Table 1. Study and Patient Characteristics in the Randomized, Controlled Trials Included in the Pooled Analysis Before randomization, patients already taking an ACE inhibitor were switched to alternative medications for at least 3 weeks. After randomization, the ACE inhibitor groups received enalapril in seven studies (1419; Brenner BM; Toto R. Personal communications) and captopril (13), benazepril (20), cilazapril (18), and ramipril (21, 22) in one study each. The control groups received placebo in five studies (1922; Brenner BM; Toto R. Personal communications), a specified medication in five studies (nifedipine in two studies [13, 17] and atenolol or acebutolol in three studies [15, 16, 18]), and no specified medication in one study (14). Other antihypertensive medications were used in both groups to reach the target blood pressure, which was less than 140/90 mm Hg in all studies. All patients were followed at least once every 6 months for the first year and at least once yearly thereafter. Blood pressure and laboratory variables were measured at each visit. Table 1 shows outcomes of each study. We pooled the 11 clinical trials on the basis of similarity of study designs and patient characteristics. In addition, the presence of preexisting hypertension and use of antihypertensive agents in most patients in the control groups in each clinical trial justified pooling data from placebo-controlled and active-controlled trials. Thus, the pooled analysis addresses the clinically relevant question of whether antihypertensive regimens including ACE inhibitors are more effective than anti-hypertensive regimens not including ACE inhibitors in slowing the progression of nondiabetic renal disease. Outcomes Two primary outcomes were defined: ESRD, defined as the initiation of long-term dialysis therapy, and a combined outcome of a twofold increase in serum creatinine concentration from baseline values or ESRD. Because ESRD is a clinically important outcome, we believed that definitive results of analyses using this outcome would be clinically relevant. However, because most chronic renal diseases progress slowly, few patients might reach this outcome during the relatively brief follow-up of these clinical trials, resulting in relatively low statistical power for these analyses. Doubling of baseline serum creatinine is a well-accepted surrogate outcome for progression of renal disease in studies of antihypertensive agents (2, 20) and would be expected to occur more frequently than ESRD, providing higher statistical power for analyses using this outcome. Doubling of baseline serum creatinine concentration was confirmed by repeated evaluation in only one study, which used this variable as the primary outcome. Therefore, we did not require confirmation of doubling for our analysis. Other outcomes included death and a composite outcome of ESRD and death. Withdrawal was defined as discontinuation of follow-up before the occurrence of an outcome or study end. Reasons for withdrawal were 1) nonfatal side effects possibly due to ACE inhibitors, including hyperkalemia, cough, angioedema, acute renal failure, or hypotension; 2) nonfatal cardiovascular disease events, including myo-cardial infarction, congestive heart failure, stroke, transient ischemic attack, or claudication; 3) other nonfatal events, such as malignant disease, pneumonia, cellulitis, headache, or gastrointestinal disturbance; and 4) other reasons, including loss to follow-up, protocol violation, or unknown. Statistical Analysis Five investigators participated in data cleaning. Summary tables were compiled from the individual-patient data from each study and checked against tables in published and unpublished reports. Discrepancies were resolved by contacting investigators at the clinical or data coordinating centers whenever possible. Because the studies followed different protocols, we had to standardize the variable definitions, follow-up intervals, and run-in periods; details of our approach are provided in Appendix 2. S-Plus (MathSoft, Inc., Seattle, Washington) and SAS (SAS Institute, Inc., Cary, North Carolina) software programs were used for all statistical analyses (31, 32). Univariate analysis was performed to detect associations between the covariates and outcomes. Baseline patient characteristics were treatment assignment (ACE inhibitor vs. control), age (logarithmic transformation), sex, ethnicity, systolic blood pressure, diastolic blood pressure, mean arterial pressure, serum creatinine concentration (reciprocal transformation), and urinary protein excretion. Study characteristics were blinding, type of antihypertensive regimen in the control group, planned duration of follow-up, whether dietary protein or sodium was restricted, and year of publication. Baseline patient characteristics and study characteristics were introduced as fixed covariates. Since renal biopsy was not performed in most cases and since criteria for classification of cause of renal disease were not defined, the cause of renal disease was not included as a variable in the analysis. Follow-up patient characteristics (blood pressure and urinary protein excretion) were adjusted as time-dependent covariates; the value recorded at the beginning of each time segment was used for that segment. This convention was used so that each outcome would be determined only by previous exposure. The intention-to-treat principle was followed for comparison of randomized groups. Cox proportional-hazards regression models were used to determine the effect of assignment to ACE inhibitors (treatment effect) and other covariates on risk for ESRD and the combined outcome (33, 34). Multivariable models were built by using candidate predictors that were associated with the outcome (P<0.2) in the univariate analysis. Each model was adjusted for study, but since some studies had no events, we could not include a dummy variable for each study. Rather, we adjusted models for studies that differed significantly from the rest (studies 2 [14], 5 [15], 10 [20], and 11 [21, 22]). We also performed tests for interactions between all covariates and treatment effect. All P values were based on two-sided tests, and significance was set at a P value less than 0.05. Results are expressed as relative risks with 95% CIs. Residual diagnostics were performed on these final models (33, 34)

Albuminuria Is a Target for Renoprotective Therapy Independent from Blood Pressure in Patients with Type 2 Diabetic Nephropathy: Post Hoc Analysis from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) Trial

Background—Albuminuria is an established risk marker for both cardiovascular and renal outcomes. Albuminuria can be reduced with drugs that block the renin-angiotensin system (RAS). We questioned whether the short-term drug-induced change in albuminuria would predict the long-term cardioprotective efficacy of RAS intervention. Methods and Results—We analyzed data from Reduction in Endpoints in Non–insulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL), a double-blind, randomized trial in 1513 type 2 diabetic patients with nephropathy, focusing on the relationship between the prespecified cardiovascular end point (composite) or hospitalization for heart failure and baseline or reduction in albuminuria. Patients with high baseline albuminuria (≥3 g/g creatinine) had a 1.92-fold (95% CI, 1.54 to 2.38) higher risk for the cardiovascular end point and a 2.70-fold (95% CI, 1.94 to 3.75) higher risk for heart failure compared with patients with low albuminuria (<1.5 g/g). Among all available baseline risk markers, albuminuria was the strongest predictor of cardiovascular outcome. The association between albuminuria and cardiovascular outcome was driven by those patients who also had a renal event. Modeling of the initial 6-month change in risk parameters showed that albuminuria reduction was the only predictor for cardiovascular outcome: 18% reduction in cardiovascular risk for every 50% reduction in albuminuria and a 27% reduction in heart failure risk for every 50% reduction in albuminuria. Conclusions—Albuminuria is an important factor predicting cardiovascular risk in patients with type 2 diabetic nephropathy. Reducing albuminuria in the first 6 months appears to afford cardiovascular protection in these patients.

Retinal Neovascularization Is Prevented by Blockade of the Renin-Angiotensin System

Albuminuria reduction could be renoprotective in hypertensive patients with diabetic nephropathy. However, the current use of renin-angiotensin-system intervention is targeted to BP only. Therefore, this study investigated the adequacy of this approach in 1428 patients with hypertension and diabetic nephropathy from the placebo-controlled Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. Investigated were the extent of discordance in treatment effects on systolic BP (SBP) and albuminuria and its association with renal outcome in a multivariate Cox model. Among patients with a reduced SBP during treatment, a lack of albuminuria reduction was observed in 37, 26, and 51% (total, losartan, and placebo, respectively) at month 6. SBP or albuminuria reduction was associated with a lower risk for ESRD, whereas combined SBP and albuminuria reduction was associated with the lowest risk for events. Across all categories of SBP change, a progressively lower ESRD hazard ratio was observed with a larger albuminuria reduction. A lower residual level of albuminuria was also associated with lower ESRD risk. In conclusion, changes in albuminuria are not concordant in a substantial proportion of patients when titrated for BP. Meanwhile, the ESRD risk showed a clear dependence on albuminuria reduction. The ESRD risk also showed dependence on the residual level of albuminuria, even in patients who reached the current SBP target. Antihypertensive treatment that is aimed at improving renal outcomes in patients with diabetic nephropathy may therefore require a dual strategy, targeting both SBP and albuminuria reduction.

Salt-dependent renal effects of an angiotensin II antagonist in healthy subjects.

Both angiotensin II and vascular endothelial growth factor are angiogenic agents that have recently been implicated in the pathogenesis of proliferative diabetic retinopathy. In this study, retinal neovascularization was examined in a model of retinopathy of prematurity with the use of neonatal transgenic (mRen-2)27 rats, which overexpress renin in tissues, and Sprague-Dawley rats. Blockers of the renin-angiotensin system were administered during the neovascularization period. The ACE inhibitor lisinopril and the angiotensin type 1 receptor antagonist losartan both increased retinal renin levels and prevented inner retinal blood vessel growth. Quantitative in situ hybridization revealed that the expression of vascular endothelial growth factor and its type 2 receptor in the inner retina and proliferating blood vessels were increased in rats with retinopathy of prematurity. Lisinopril reduced both retinal vascular endothelial growth factor and its type 2 receptor mRNA in retinopathy of prematurity rats, whereas losartan had no effect. It is predicted that agents that interrupt the renin-angiotensin system may play an important role as retinoprotective agents in various forms of proliferative retinopathy.

An acute fall in estimated glomerular filtration rate during treatment with losartan predicts a slower decrease in long-term renal function

This study was designed to evaluate in healthy volunteers the renal hemodynamic and tubular effects of the orally active angiotensin II receptor antagonist losartan (DuP 753 or MK 954). Losartan or a placebo was administered to 23 subjects maintained on a high-sodium (200 mmol/d) or a low-sodium (50 mmol/d) diet in a randomized, double-blind, crossover study. The two 6-day diet periods were separated by a 5-day washout period. On day 6, the subjects were water loaded, and blood pressure, renal hemodynamics, and urinary electrolyte excretion were measured for 6 hours after a single 100-mg oral dose of losartan (n = 16) or placebo (n = 7). Losartan induced no significant changes in blood pressure, glomerular filtration rate, or renal blood flow in these water-loaded subjects, whatever the sodium diet. In subjects on a low-salt diet, losartan markedly increased urinary sodium excretion from 115 +/- 9 to 207 +/- 21 mumol/min (P < .05). The fractional excretion of endogenous lithium was unchanged, suggesting no effect of losartan on the early proximal tubule in our experimental conditions. Losartan also increased urine flow rate (from 10.5 +/- 0.4 to 13.1 +/- 0.6 mL/min, P < .05); urinary potassium excretion (from 117 +/- 6.9 to 155 +/- 11 mumol/min); and the excretion of chloride, magnesium, calcium, and phosphate. In subjects on a high-salt diet, similar effects of losartan were observed, but the changes induced by the angiotensin II antagonist did not reach statistical significance. In addition, losartan demonstrated significant uricosuric properties with both sodium diets.(ABSTRACT TRUNCATED AT 250 WORDS)

Risk Scores for Predicting Outcomes in Patients with Type 2 Diabetes and Nephropathy: The RENAAL Study

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.

Effect of a Reduction in Uric Acid on Renal Outcomes During Losartan Treatment A Post Hoc Analysis of the Reduction of Endpoints in Non-Insulin-Dependent Diabetes Mellitus With the Angiotensin II Antagonist Losartan Trial

Diabetic nephropathy is the most important cause of ESRD. The aim of this study was to develop a risk score from risk predictors for ESRD, with and without death, in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study and to compare ability of the ESRD risk score and its components to predict ESRD. The risk score was developed from coefficients of independent risk factors from multivariate analysis of baseline variables and equals (1.96 x log [urinary albumin:creatinine ratio]) - (0.78 serum albumin [g/dl]) + (1.28 x serum creatinine [mg/dl]) - (0.11 x hemoglobin [g/dl]). It was robust with respect to severity of nephropathy, gender, race, and treatment group. The risk score for ESRD or death was comparable. The four risk predictors for progression of kidney disease were independent of therapy. For combined treatment groups, the hazard ratio between the fourth and first quartiles of the ESRD risk score was 49.0, as compared with the corresponding hazard ratios for each component: 14.7 for urinary albumin:creatinine ratio, 9.2 for serum creatinine, 5.5 for hemoglobin, and 10.2 for serum albumin. The RENAAL risk scores for ESRD with or without death emphasize the importance of identification of level of albuminuria, serum albumin, serum creatinine, and hemoglobin to predict development of ESRD in patients with type 2 diabetes and nephropathy. Although albuminuria is a strong risk factor for ESRD, the contribution of serum albumin, serum creatinine, and hemoglobin level further enhances prediction of ESRD. Future trials with a similar patient population and outcomes measures should consider adjusting analyses for baseline risk factors.

The losartan renal protection study — rationale, study design and baseline characteristics of RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan)

Emerging data show that increased serum uric acid (SUA) concentration is an independent risk factor for end-stage renal disease. Treatment with the antihypertensive drug losartan lowers SUA. Whether reductions in SUA during losartan therapy are associated with renoprotection is unclear. We therefore tested this hypothesis. In a post hoc analysis of 1342 patients with type 2 diabetes mellitus and nephropathy participating in the Reduction of Endpoints in Non-Insulin-Dependent Diabetes Mellitus With the Angiotensin II Antagonist Losartan Trial, we determined the relationship between month 6 change in SUA and renal endpoints, defined as a doubling of serum creatinine or end-stage renal disease. Baseline SUA was 6.7 mg/dL in placebo and losartan-treated subjects. During the first 6 months, losartan lowered SUA by −0.16 mg/dL (95% CI: −0.30 to −0.01; P=0.031) as compared with placebo. The risk of renal events was decreased by 6% (95% CI: 10% to 3%) per 0.5-mg/dL decrement in SUA during the first 6 months. This effect was independent of other risk markers, including estimate glomerular filtration rate and albuminuria. Adjustment of the overall treatment effects for SUA attenuated losartans renoprotective effect from 22% (95% CI: 6% to 35%) to 17% (95% CI: 1% to 31%), suggesting that approximately one fifth of losartans renoprotective effect could be attributed to its effect on SUA. Losartan lowers SUA levels compared with placebo treatment in patients with type 2 diabetes mellitus and nephropathy. The degree of reduction in SUA is subsequently associated with the degree in long-term renal risk reduction and explains part of losartans renoprotective effect. These findings support the view that SUA may be a modifiable risk factor for renal disease.