Renoprotection by enzyme replacement therapy.
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Enzyme Therapy↗
Biomedical subjects
Barry M Brenner
Publications and source records attributed to Barry M Brenner.
Continuum of renoprotection with losartan at all stages of type 2 diabetic nephropathy: a post hoc analysis of the RENAAL trial results.
Renin angiotensin system inhibitor therapy is seldom offered to individuals who have diabetes and advanced chronic kidney disease because of safety concerns. In this post hoc, secondary analysis of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial, angiotensin antagonism risk/benefit profile was assessed in 1513 individuals with type 2 diabetes and overt nephropathy. Incidence of ESRD, hospitalizations for heart failure, withdrawals for adverse events, and proteinuria during losartan or conventional treatment were compared within three tertiles of baseline serum creatinine concentration (highest, 2.1 to 3.6 mg/dl; middle, 1.6 to 2.0 mg/dl; lowest, 0.9 to 1.6 mg/dl). Losartan decreased the risk of ESRD by 24.6, 26.3, and 35.3% in highest, middle, and lowest tertiles, respectively. For every 100 patients with serum creatinine >2.0, 1.6 to 2.0, or <1.6 mg/dl, respectively, 4 yr of losartan therapy was estimated to save 18.9, 8.4, and 2.9 ESRD events and US$1,502,855, US$1,021,770, and US$528,591 costs for renal replacement therapy. Losartan also decreased the hospitalizations for heart failure by 50.2 and 45.1, in the highest and middle tertile, respectively. Withdrawals for adverse events other than heart failure were comparable between tertiles and treatment groups. Proteinuria decreased more on losartan than on placebo in all tertiles (highest, 24 versus -8%; middle, 16 versus -8%; lowest, 15 versus -10%). In proteinuric individuals with type 2 diabetes, losartan therapy reduced ESRD and hospitalizations for heart failure and was well tolerated at all levels of renal function. Angiotensin II antagonism is a suitable and well-tolerated treatment for individuals with type 2 diabetes even with GFR levels approaching renal replacement therapy.
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Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL.
BACKGROUND: Proteinuria or albuminuria is an established risk marker for progressive renal function loss. Albuminuria can be effectively lowered with antihypertensive drugs that interrupt the renin-angiotensin system (RAS). We investigated whether albuminuria could not only serve as a marker of renal disease, but also function as a monitor of the renoprotective efficacy of RAS intervention by the angiotensin II (Ang II) antagonist, losartan, in patients with diabetic nephropathy. METHODS: The data from the RENAAL (Reduction in End Points in Noninsulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan) study, a double-blind, randomized trial, were used to examine the effects of losartan on the renal outcome [i.e., the primary composite end point of doubling of serum creatinine, end-stage renal disease (ESRD) or death] in 1513 type 2 diabetic patients with nephropathy. We examined the effect of the degree of albuminuria at baseline, initial antiproteinuric response to therapy, and the degree of remaining (residual) albuminuria on renal outcome (either the primary composite end point of RENAAL or ESRD). We also evaluated the contribution to renal protection of the antiproteinuric effect of losartan independently of changes in blood pressure. RESULTS: Baseline albuminuria is almost linearly related to renal outcome, and is the strongest predictor among all measured well-known baseline risk parameters. After adjusting for baseline risk markers of age, gender, race, weight, smoking, sitting diastolic blood pressure, sitting systolic blood pressure, total cholesterol, serum creatinine, albuminuria, hemoglobin, and hemoglobin A(1c) (HbA(1c)) patients with high baseline albuminuria (> or =3.0 g/g creatinine) showed a 5.2-fold (95% CI 4.3-6.3) increased risk for reaching a renal end point, and a 8.1-fold (95% CI 6.1-10.8) increased risk for progressing to ESRD, compared to the low albuminuria group (<1.5 g/g). The changes in albuminuria in the first 6 months of therapy are roughly linearly related to the degree of long-term renal protection: every 50% reduction in albuminuria in the first 6 months was associated with a reduction in risk of 36% for renal end point and 45% for ESRD during later follow-up. Albuminuria at month 6, designated residual albuminuria, showed a linear relationship with renal outcome, almost identical to the relationship between baseline albuminuria and renal risk. Losartan reduced albuminuria by 28% (95% CI -25% to -36%), while placebo increased albuminuria by 4% (95% CI +8% to -1%) in the first 6 months of therapy. The specific (beyond blood pressure lowering) renoprotective effect of the Ang II antagonist, losartan, in this study is for the major part explained by its antialbuminuric effect (approximately 100% for the renal end point, and 50% for ESRD end point). CONCLUSION: Albuminuria is the predominant renal risk marker in patients with type 2 diabetic nephropathy on conventional treatment; the higher the albuminuria, the greater the renal risk. Reduction in albuminuria is associated with a proportional effect on renal protection, the greater the reduction the greater the renal protection. The residual albuminuria on therapy (month 6) is as strong a marker of renal outcome as is baseline albuminuria. The antiproteinuric effect of losartan explains a major component of its specific renoprotective effect. In conclusion, albuminuria should be considered a risk marker for progressive loss of renal function in type 2 diabetes with nephropathy, as well as a target for therapy. Reduction of residual albuminuria to the lowest achievable level should be viewed as a goal for future renoprotective treatments.
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Anemia and end-stage renal disease in patients with type 2 diabetes and nephropathy.
BACKGROUND: Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD). Anemia is common in diabetics with nephropathy; however, the impact of anemia on progression to ESRD has not been carefully examined. METHODS: We studied the relationship between baseline hemoglobin concentration (Hb) and progression of diabetic nephropathy to ESRD in 1513 participants enrolled in Reduction in Endpoints in NIDDM with the Angiotensin II Antagonist Losartan study and followed for an average of 3.4 years. Multivariate Cox proportional hazards models were used to analyze the relationship between Hb and ESRD, after adjusting for predictors for ESRD. Analyses were performed with Hb stratified by quartile: first quartile <11.3 g/dL, second quartile 11.3 to 12.5 g/dL, third quartile 12.6 to 13.8 g/dL, and fourth quartile >/=13.8 g/dL (reference) and as a continuous variable. RESULTS: Baseline hemoglobin concentration was correlated with subsequent development of ESRD. After adjustment for predictors of ESRD, the hazard ratios for the first, second, and third Hb quartiles were 1.99 (95% CI, 1.34-2.95), 1.61 (95% CI 1.08-2.41), and 1.87 (95% CI 1.25-2.80). With hemoglobin as a continuous variable, the adjusted hazard ratio was 0.90 (95% CI 0.84-0.96, P= 0.0013). The average increase in adjusted relative risk was 11% for each 1 g/dL decrease in hemoglobin concentration. CONCLUSION: Our data suggest that even mild anemia, Hb <13.8 g/dL increases risk for progression to ESRD. Hemoglobin is an independent risk factor for progression of nephropathy to ESRD in type 2 diabetes.
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Why is proteinuria an ominous biomarker of progressive kidney disease?
Progressive tubule injury and interstitial fibrosis frequently accompany glomerulopathies associated with proteinuria. Clinical experience indicates that higher levels of proteinuria prior to, as well as after initiation of treatment predict more rapid decline in renal function and more pronounced tubulointerstitial injury. It has been proposed that filtration of potentially tubulotoxic plasma proteins is responsible for the observed correlations between proteinuria and progression (i.e., proteinuria is a cause and not only a consequence of progressive renal injury). Numerous attempts have been made to identify the species of putative tubulotoxic proteins in this progressive injury process, but much uncertainty persists. These uncertainties stem from nonphysiologic exposure of apical cell surfaces to proteins in vitro, the extremely high concentrations of various proteins tested in vitro, and the nonuniformity of end points measured. Furthermore, there is often a lack of correlation between in vitro and in vivo findings, and a lack of uniformity of results even for seemingly similar in vitro experiments. Less controversy is evident in the potential pathways whereby injured tubules evoke a tubulointerstitial inflammatory and fibrotic response, with many in vivo models serving to incriminate excessive cytokine and chemokine production, infiltration of various inflammatory cells, and the balance between apoptosis and cell proliferation. Despite many years of concerted efforts, we believe it is still unclear whether proteinuria is a cause (and if so, which species of protein), or only a consequence of progressive renal injury. Nevertheless, pending the resolution of these uncertainties by more decisive and unambiguous experimentation, the strongly predictive inverse relationship between level of proteinuria and long-term renal survival currently justifies aggressive antiproteinuric treatment strategies, with a goal of reducing protein excretion rate to the lowest level possible without the induction of symptoms or undue risk.
Biomarkers↗
From secondary to primary prevention of progressive renal disease: the case for screening for albuminuria.
Many subjects nowadays present with end-stage renal failure and its attendant cardiovascular complications without known prior renal damage. In this report we review the evidence available to strongly suggest that the present practice of secondary prevention in those with known prior renal disease should be extended to primary prevention for those subjects in the general population who are at risk for progressive renal failure, but who had never suffered from a primary renal disease. We show that such subjects can be detected by screening for albuminuria. Elevated urinary albumin loss is an indicator not only of poor renal, but also of poor cardiovascular prognosis. In addition to diabetic subjects who are at risk for albuminuria, we also show that hypertensive, obese, and smoking subjects are more susceptible. We suggest that therapies that have been shown to lower albumin excretion, such as ACE inhibitors, angiotensin II receptor antagonists, and statins be started early in such patients to prevent them from developing clinical renal disease and its attendant cardiovascular complications.
Albuminuria↗
Renin angiotensin aldosterone system blockade and renal disease in patients with type 2 diabetes. An Asian perspective from the RENAAL Study.
OBJECTIVE: Asia is predicted to have the largest population of patients with diabetes who are at high risk for renal disease. In the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study, approximately 17% of patients were Asians. In this subgroup analysis, we examined the characteristics, response, and adherence to treatment of the Asian population, as well as their baseline predictors of risk of renal end points. RESEARCH DESIGN AND METHODS: A total of 252 Asian patients were enrolled in the RENAAL study, which compared losartan (50 mg titrated to 100 mg) to placebo in addition to conventional antihypertensive medications in type 2 diabetic patients with nephropathy. Mean follow-up was 3.2 years. The effect of losartan therapy on renal and cardiovascular outcomes was examined, and baseline predictors of risk were determined using a Cox proportional hazards model with prespecified baseline covariates. RESULTS: Losartan reduced the risk of the primary composite end point composed of a doubling of serum creatinine, end-stage renal disease, or all-cause mortality in Asian patients by 35% (P = 0.02). No difference between losartan and placebo was observed for the cardiovascular composite outcomes. Losartan reduced the level of proteinuria by 47% (P < 0.001) and rate of decrease in renal function by 31% (0.0074). Discontinuations were lower in the losartan-treated patients. The strongest baseline predictors of risk of renal end points were proteinuria (hazard ratio 1.42, P < 0.0001) and low Hb (0.81, P < 0.0001). CONCLUSIONS: In this subgroup analysis of the RENAAL study, losartan conferred significant renal benefits and was well tolerated in Asian patients with type 2 diabetes and clinical nephropathy. Baseline proteinuria and low Hb were strong predictors of risk of renal outcomes.
Antihypertensive Agents↗
Regarding: "Management of glomerular proteinuria: a commentary".
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Angiotensin-Converting Enzyme Inhibitors↗
Effects of blood pressure level on progression of diabetic nephropathy: results from the RENAAL study.
BACKGROUND: Clinical trials of nephropathy in people with type 2 diabetes mellitus have not examined the effects of systolic blood pressure (SBP) or pulse pressure (PP) on the time to end-stage renal disease (ESRD) or death. OBJECTIVES: To evaluate the impact of baseline and treated SBP, diastolic blood pressure (DBP), and PP on composite and individual outcomes including doubling of serum creatinine, ESRD, or death in participants of the Reduction of Endpoints in NIDDM (non-insulin-dependent diabetes mellitus) With the Angiotensin II Antagonist Losartan (RENAAL) Study; to assess the specific effect of the angiotensin receptor blocker losartan potassium on composite and renal outcomes; and to explore the implications of dihydropyridine calcium channel blockers as concurrent therapy on composite and renal outcomes. DESIGN: A Cox proportional hazards regression model was used to assess the hazard risk profile of baseline SBP (categories: <130, 130-139, 140-159, 160-179, and > or =180 mm Hg), DBP (categories: <70, 70-79, 80-89, 90-99, and > or =100 mm Hg), and PP (categories: <60, 60-69, 70-79, 80-89, and > or =90 mm Hg) on renal outcomes. PARTICIPANTS: The study comprised 1513 participants with established nephropathy and hypertension associated with type 2 diabetes. INTERVENTIONS: The RENAAL study was a randomized, placebo-controlled study of losartan vs placebo, with other agents added to achieve the goal of a trough BP (ie, BP immediately prior to the next dosing) below 140/90 mm Hg, and had a mean follow-up of 3.4 years. MAIN OUTCOME MEASURES: The primary analysis was time to composite end point of doubling of serum creatinine, ESRD, or death. RESULTS: A baseline SBP range of 140 to 159 mm Hg increased risk for ESRD or death by 38% (P =.05) compared with those below 130 mm Hg. In a multivariate model, every 10-mm Hg rise in baseline SBP increased the risk for ESRD or death by 6.7% (P =.007); the same rise in DBP decreased the risk by 10.9% (P =.01) when adjusting for urinary albumin-creatinine ratio, serum creatinine, serum albumin, hemoglobin, and hemoglobin A1c. Those randomized to the losartan group with a baseline PP above 90 mm Hg had a 53.5% risk reduction for ESRD alone (P =.003) and a 35.5% risk reduction for ESRD or death (P =.02) compared with the placebo group. CONCLUSIONS: Baseline SBP is a stronger predictor than DBP of renal outcomes in those with nephropathy resulting from type 2 diabetes. Those with the highest baseline PP have the highest risk for nephropathy progression but also garner the greatest risk reduction with SBP lowered to less than 140 mm Hg.
Antihypertensive Agents↗
AMGEN International Prize: the history and future of renoprotection.
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Animals↗
The risk of developing end-stage renal disease in patients with type 2 diabetes and nephropathy: the RENAAL study.
BACKGROUND: Diabetic nephropathy has become the single most important cause of end-stage renal disease (ESRD) worldwide. Strategies to slow the rate of loss of renal function in these patients have been developed. We examined the risk factors that predict loss of kidney function (doubling of serum creatinine) or ESRD (dialysis or transplantation) in patients with type 2 diabetes in whom blood pressure was controlled. METHODS: We evaluated risk factors for doubling of serum creatinine or the development of ESRD in the Reduction of End Points in NIDDM with the Angiotensin II Receptor Antagonist Losartan (RENAAL) study, which included 1513 patients with type 2 diabetes and nephropathy. RESULTS: Univariate analyses demonstrated a group of 23 risk factors that significantly predicted doubling of serum creatinine or ESRD. From these univariate analyses, a multivariate model was developed that demonstrated four independent risk factors: proteinuria, serum creatinine, serum albumin, and hemoglobin level. Proteinuria was the strongest and most consistent risk factor. The multivariate risk model was derived from only the placebo group and was similar to that derived for the total population, suggesting that the risk predictors for progression of kidney disease were independent of therapy. CONCLUSION: After control of blood pressure in type 2 diabetic patients with nephropathy, proteinuria, degree of renal failure, serum albumin, and hemoglobin level are independent risk factors that predict renal outcomes. The level of proteinuria proved to be the most important risk for progressive kidney injury in these diabetic patients.
Aged↗
Dialysis delayed is death prevented: a clinical perspective on the RENAAL study.
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Developing Countries↗
Retarding the progression of renal disease.
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Adult↗
Clinical renoprotection trials involving angiotensin II-receptor antagonists and angiotensin-converting-enzyme inhibitors.
The leading cause of end-stage renal disease (ESRD) is diabetic nephropathy. Interventions that prevent or palliate renal disease have a positive impact by improving patient care and diminishing healthcare costs. The following review summarizes clinical trals that evaluated treatment in various patient populations including Type 2 diabetic patients with microalbuminuria, subjects with proteinuric non-diabetic nephropathies, and Type 1 and Type 2 diabetic patients with overt nephropathy. These clinical trials have demonstrated that agents directly affecting the renin-angiotensin-aldosterone system provide renal protection beyond that attributable to blood pressure control.
Angiotensin II Type 2 Receptor Blockers↗
Losartan reduces the costs associated with diabetic end-stage renal disease: the RENAAL study economic evaluation.
OBJECTIVE: To evaluate the within-trial effect of losartan and conventional antihypertensive therapy (CT) compared with placebo and CT on the economic cost associated with end-stage renal disease (ESRD). RESEARCH DESIGN AND METHODS: The Reduction of End Points in Type 2 Diabetes With the Angiotensin II Antagonist Losartan (RENAAL) study was a multinational double-blind randomized placebo-controlled clinical trial designed to evaluate the renal protective effects of losartan on a background of CT (excluding ACE inhibitors and angiotensin II receptor agonists [AIIAs]) in patients with type 2 diabetes and nephropathy. The primary composite end point was doubling of serum creatinine, ESRD, or death. Data on the duration of ESRD were used to estimate the economic benefits of slowing the progression of nephropathy. The cost associated with ESRD was estimated by combining the days each patient experienced ESRD with the cost of ESRD over time. The cost of ESRD for individuals with diabetes was estimated using data from the U.S. Renal Data System. Total cost was estimated as the sum of the cost associated with ESRD and the cost of study therapy. RESULTS-We estimated that losartan and CT compared with placebo and CT reduced the number of days with ESRD by 33.6 per patient over 3.5 years (P = 0.004, 95% CI 10.9-56.3). This reduction in ESRD days resulted in a decrease in cost associated with ESRD of 5144 US dollars per patient (P = 0.003, 95% CI 1701 to 8587 US dollars). After accounting for the cost of losartan, the reduction in ESRD days resulted in a net savings of 3522 US dollars per patient over 3.5 years (P = 0.041, 143 to 6900 US dollars). CONCLUSIONS: Treatment with losartan in patients with type 2 diabetes and nephropathy not only reduced the incidence of ESRD, but also resulted in substantial cost savings.
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Analysis of metabolic parameters as predictors of risk in the RENAAL study.
OBJECTIVE: Metabolic factors such as glycemic control, hyperlipidemia, and hyperkalemia are important considerations in the treatment of patients with type 2 diabetes and nephropathy. In the RENAAL (Reduction of End Points in Type 2 Diabetes With the Angiotensin II Antagonist Losartan) study, losartan reduced renal outcomes in the patient population. This post hoc analysis of the RENAAL study reports the effects of losartan on selected metabolic parameters and assesses the relationship between baseline values of metabolic parameters and the primary composite end point or end-stage renal disease (ESRD). RESEARCH DESIGN AND METHODS: Glycemic control (HbA(1c)) and serum lipid, uric acid, and potassium levels were compared between the losartan and placebo groups over time, and baseline levels were correlated with the risk of reaching the primary composite end point (doubling of serum creatinine, ESRD, or death) or ESRD alone. RESULTS: Losartan did not adversely affect glycemic control or serum lipid levels. Losartan-treated patients had lower total (227.4 vs. 195.4 mg/dl) and LDL (142.2 vs. 111.7 mg/dl) cholesterol. Losartan was associated with a mean increase of up to 0.3 mEq/l in serum potassium levels; however, the rate of hyperkalemia-related discontinuation was similar between the placebo and losartan groups. Univariate analysis revealed that baseline total and LDL cholesterol and triglyceride levels were associated with increased risk of developing the primary composite end point. Similarly, total and LDL cholesterol were also associated with increased risk of developing ESRD. CONCLUSIONS: Overall, losartan was well tolerated by patients with type 2 diabetes and nephropathy and was associated with a favorable effect on the metabolic profile of this population.
Cholesterol↗
Losartan in patients with type 2 diabetes and proteinuria: observations from the RENAAL Study.
BACKGROUND: Recently, the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) Study demonstrated the benefit of losartan in reducing renal outcomes in patients with type 2 diabetes and proteinuria. Additional questions concerning the reduction of proteinuria and its relationship to end-stage renal disease (ESRD) as well as cardio-renal outcomes and the safety and tolerability of losartan remain to be addressed. METHODS: Three analyses were performed: (a) the impact of losartan on the relationship between the reduction of proteinuria and ESRD; (b) a time-to-event analysis of the cardio-renal composite endpoint of ESRD, myocardial infarction, stroke or all-cause death; and (c) additional analyses of adverse events, particularly in patients with serum creatinine >or=2.0 mg/dL. RESULTS: After adjusting the values for proteinuria over the entire study, the reduction of proteinuria accounted for approximately half of the treatment effect of losartan on the risk reduction for ESRD. In addition, losartan was associated with a 21% risk reduction for the composite cardio-renal outcome (P=0.003). The addition of losartan to a conventional antihypertensive regimen did not increase the overall incidence of adverse events, regardless of severity of renal impairment. CONCLUSIONS: Losartan significantly reduced the risk of cardiorenal outcomes and was well tolerated by patients, including those with serum creatinine levels >or=2.0 g/dL. In addition, although this study shows that the reduction of proteinuria does not completely explain the impact of intervention on outcomes such as ESRD, reduction of proteinuria must remain an important consideration when treating patients with type 2 diabetes and nephropathy. However, the reduction of outcomes such as ESRD should remain the goal of therapy when evaluating renal protection in this patient population.
Adult↗
Combination ACEI and ARB therapy: additional benefit in renoprotection?
PURPOSE OF REVIEW: The fact that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers antagonize the renin-angiotensin system at different levels suggests that these agents, already each of confirmed clinical benefit in retarding the progression of chronic renal disease, may have additive effects that result in even greater renoprotection when used in combination. In the light of the persisting need for treatments that afford more effective renoprotection, this Special Commentary examines available experimental and clinical evidence in support of this hypothesis. RECENT FINDINGS: Experimental studies to date have failed to distinguish clearly between the additive antihypertensive effects of combination therapy and additive intrinsic renoprotective effects. Clinical studies, albeit with relatively small patient numbers and short follow-up periods, have shown that combination therapy results in greater antihypertensive and antiproteinuric effects than monotherapy in diabetic nephropathy and non-diabetic forms of chronic renal disease. SUMMARY: At present we recommend the addition of angiotensin receptor blocker therapy in patients with continued hypertension or proteinuria despite angiotensin-converting enzyme inhibition. Further long-term studies are required to evaluate more fully the renoprotective potential of this combination.
Angiotensin Receptor Antagonists↗