PubMed Health⌕ Search

Biomedical subjects

Barry M Brenner

Publications and source records attributed to Barry M Brenner.

At least 19 recordsLinked to original sources
PubMed2006

Adult hypertension and kidney disease: the role of fetal programming.

Hypertension (HTN) and chronic kidney disease are highly prevalent diseases that tend to occur more frequently among disadvantaged populations, in whom prenatal care also tends to be poor. More and more evidence is emerging highlighting the important role of fetal programming in the development of adult disease, suggesting a possible common pathophysiologic denominator in the development of these disorders. Epidemiologic evidence accumulated over the past 2 decades has demonstrated an association between low birth weight and subsequent adult HTN, diabetes, and cardiovascular disease. More recently, a similar association has been found with chronic kidney disease. Animal studies and indirect evidence from human studies support the hypothesis that low birth weight, as a marker of adverse intrauterine circumstances, is associated with a congenital deficit in nephron number. The precise mechanism of the reduction in nephron number has not been established, but several hypotheses have been put forward, including changes in DNA methylation, increased apoptosis in the developing kidney, alterations in renal renin-angiotensin system activity, and increased fetal glucocorticoid exposure. A reduction in nephron number is associated with compensatory glomerular hypertrophy and an increased susceptibility to renal disease progression. HTN in low birth weight individuals also appears to be mediated in part through a reduction in nephron number. Increased awareness of the implications of low birth weight and inadequate prenatal care should lead to public health policies that may have long-term benefits in curbing the epidemics of HTN, diabetes, and kidney disease in generations to come.

Animals↗
PubMed2006

Losartan: lessons learned from the RENAAL study.

Renal and cardiovascular diseases associated with Type 2 diabetes are increasing at rapid rates, and are significant burdens to patients and healthcare systems. The RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan) study was conducted from 1996 to 2001. This landmark clinical trial provided the opportunity to study renal and cardiovascular outcomes, as well as risk predictors, in a relatively large number of patients with Type 2 diabetes and nephropathy. The RENAAL study also provided information that will be valuable to those designing future clinical trials in this patient population. This review highlights key findings from the RENAAL study.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2006

The impact of losartan on the lifetime incidence of end-stage renal disease and costs in patients with type 2 diabetes and nephropathy.

INTRODUCTION: The RENAAL (Reduction of Endpoints in Non-insulin dependent diabetes with the Angiotensin II Antagonist Losartan) study demonstrated that, in hypertensive patients with type 2 diabetes mellitus and nephropathy, treatment with losartan plus conventional antihypertensive therapy (CT) reduced the relative risk of end-stage renal disease (ESRD) by 29% versus placebo over the time span of the study (mean patient follow-up of 3.4 years). The objective of this study was to project the effect of losartan compared with placebo on the lifetime incidence of ESRD and associated costs (from a US healthcare system perspective). METHODS: To estimate lifetime incidence of ESRD, we used a competing risks method to account for the risk of death without ESRD. We estimated the cost (US dollars, year 2002 values) associated with ESRD by combining the cumulative incidence of ESRD with the lifetime cost associated with ESRD. Total cost was estimated as the sum of the cost associated with ESRD, the cost of losartan study therapy and other costs (non-ESRD/non-losartan) expected for patients with type 2 diabetes. Survival was estimated by weighting the life expectancies with and without ESRD by the cumulative risk of ESRD. Costs and outcomes were discounted by 3% per annum. RESULTS: We projected a lower lifetime incidence of ESRD for losartan patients (66%) compared with placebo patients (83%). This reduction in ESRD resulted in a decrease in cost associated with ESRD of US dollars 31,803 per patient and a gain of 0.99 life-years per patient (0.70 discounted). After accounting for the cost of losartan and the additional cost associated with greater survival, we projected that treatment with losartan would result in a lifetime net saving of US dollars 24,632 per patient. CONCLUSION: Treatment with losartan plus CT in patients with type 2 diabetes and nephropathy reduced the within-trial incidence of ESRD and is projected to result in lifetime reductions in ESRD and associated costs, and increased survival, versus placebo.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2006

Efficacy and safety of angiotensin II receptor blockade in elderly patients with diabetes.

OBJECTIVE: While national guidelines recommend ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB) therapy in patients with diabetes and nephropathy, guidelines concerning elderly patients with diabetes have not endorsed these drugs. We sought to assess the nephroprotective efficacy and safety of ARB therapy in elderly patients by conducting age-specific subgroup analyses using data from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. RESEARCH DESIGN AND METHODS: We studied 1,513 patients with type 2 diabetes and nephropathy who randomly received either losartan or placebo. We tested for effect modification by age of the effect of losartan on the incidence of the predefined end points (doubling of serum creatinine, end-stage renal disease [ESRD], or death) and the risk of adverse events. RESULTS: Of 1,513 participants, 421 (27.8%) were aged >65 years (maximum age 74 years). Age did not modify the efficacy of losartan in reducing the risk of the primary outcome, a composite of doubling of serum creatinine, ESRD, or death (P(interaction) = 0.66) or its individual components (all P(interaction) > 0.44). In patients aged >65 years, losartan reduced the risk of ESRD by 50% (95% CI 30-81, P = 0.005). We found no evidence that older patients were more likely to experience adverse events from losartan such as a rise in serum creatinine or hyperkalemia than younger patients. CONCLUSIONS: Elderly patients had the same level of benefits and risks as younger patients from treatment with losartan. Underuse of ACEI and ARB therapy in elderly patients because of the perceived lack of efficacy or a greater risk of adverse events appears unjustified.

Aged↗
PubMed2005

Hospitalizations for new heart failure among subjects with diabetes mellitus in the RENAAL and LIFE studies.

We sought to study the risk factors for heart failure (HF) and the relation between antihypertensive treatment with losartan and the first hospitalization for HF in patients with diabetes mellitus in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) and Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) studies. We evaluated 1,195 patients with hypertension, left ventricular hypertrophy, and diabetes from the LIFE study and 1,513 patients with type 2 diabetes and nephropathy from the RENAAL study. The comparative treatments were atenolol in the LIFE study and placebo in the RENAAL study. Patients with a history of HF were excluded from this analysis. Losartan significantly reduced the incidence of first hospitalizations for HF versus placebo in the RENAAL study (hazard ratio 0.74, p=0.037) and versus atenolol in the LIFE study (hazard ratio 0.57, p=0.019). Patients enrolled in the RENAAL study were at a higher risk of developing HF (hazard ratio for RENAAL vs LIFE diabetics 3.0, p<0.0001). The significant, independent baseline risk factors for the development of HF in the RENAAL study were urinary albumin/creatinine ratio, age, peripheral vascular disease, the Cornell product, body mass index, and previous angina; in the LIFE study they were the Cornell product, previous myocardial infarction, peripheral vascular disease, baseline atrial fibrillation, alcohol use (inverse relation), and urinary albumin/creatinine ratio. The beneficial effect of losartan on the reduction of risk for hospitalization for new HF was demonstrated in patients who were at high renal and/or high cardiovascular risk.

Adrenergic beta-Antagonists↗
PubMed2005

Importance of baseline distribution of proteinuria in renal outcomes trials: lessons from the reduction of endpoints in NIDDM with the angiotensin II antagonist losartan (RENAAL) study.

A key issue in the analysis of outcome trials is the adjustment for baseline covariates that influence the primary outcome. Imbalance of an important covariate between treatment groups at baseline is of considerable concern if one treatment group is favored over another with respect to the hypothesis testing outcome. With the use of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study database as an example, the influence of baseline proteinuria on the primary composite endpoint, ESRD, and ESRD or death after adjusting for baseline proteinuria as a continuous covariate was examined. Increasing baseline proteinuria was associated with increased risk for renal events, confirming that proteinuria is an important covariate for renal outcomes. When the randomization was stratified according proteinuria <2000 mg/g or >/=2000 mg/g, within the higher proteinuria stratum (>/=2000 mg/g), patients in the losartan group had a higher baseline mean proteinuria value. When the imbalance was adjusted, an increase in the magnitude and the significance of the risk reduction with losartan for each outcome was observed. No apparent interaction between treatment effect and baseline proteinuria was found, and there was no heterogeneity in the treatment response in patients with different baseline proteinuria levels. After proteinuria was adjusted as a continuous variable, greater treatment effects were observed in the RENAAL study. This effect was due solely to the imbalance in baseline proteinuria. Considering the importance of proteinuria as a risk factor, adjustment for baseline proteinuria as a continuous covariate should be prespecified in the design and analysis of clinical trials involving renal outcomes, even when patients are stratified on the basis of level of proteinuria.

Adult↗
PubMed2005

Losartan and end-organ protection--lessons from the RENAAL study.

BACKGROUND: The Reduction in ENdpoints with the Angiotensin Antagonist Losartan (RENAAL) study reported that losartan delayed the progression of renal disease in patients with type 2 diabetes and nephropathy. Diabetic or renally impaired patients are at high cardiovascular risk, a risk potentially increased in patients with both conditions. HYPOTHESIS: This post hoc analysis examined whether baseline proteinuria was predictive of cardiovascular outcomes, and whether losartan modifies the risk of cardiovascular outcomes in these patients given its renal-protective effects. METHODS: The RENAAL study compared losartan with placebo (in addition to conventional antihypertensive medications) in type 2 diabetic patients with proteinuria. Morbidity and mortality due to cardiovascular causes were ascertained, and the relationship between baseline proteinuria and cardiovascular outcome was determined. The effect of treatment with losartan was examined using three time-to-event analyses of composite cardiorenal outcomes as described below. RESULTS: Increasing baseline proteinuria was associated with significantly increased risk of myocardial infarction (MI) and all-cause or cardiovascular death, but not stroke. Losartan significantly reduced the risk for the combined endpoint of end-stage renal disease (ESRD), MI, stroke, or death by 21% (p < or = 0.005), irrespective of whether all-cause or cardiovascular death was included in the analysis. In addition, losartan reduced the risk for the composite of ESRD or cardiovascular death by 19.2% (p < 0.05). CONCLUSION: In patients with type 2 diabetes and nephropathy, there is an increased risk of MI and cardiovascular or all-cause mortality. Treatment with losartan is associated with a reduction in proteinuria, a delay in the onset of ESRD, and no increased risk of cardiovascular events in this pre-ESRD population.

Adult↗
PubMed2005

Strategies to retard the progression of chronic kidney disease.

Chronic kidney disease (CKD) is a common and, in advanced cases, highly morbid disorder. The most severe form of CKD is end-stage renal disease (ESRD), in which the patient requires some form of renal replacement therapy to survive. The increasing incidence, prevalence, and costs of ESRD are major national health care concerns; interventions that may prevent or slow the progression of CKD towards ESRD are extremely important and the focus of this article.

Anemia↗
PubMed2005

Primary and secondary prevention of chronic kidney disease.

The incidence and prevalence of chronic kidney disease (CKD) is on the rise worldwide. End-stage renal disease (ESRD) is the most advanced form of CKD, requiring some form of renal replacement therapy to ensure survival. Interventions to prevent or slow the progression of CKD, irrespective of the original cause, are thus of significant importance. The most effective of these interventions is based on the inhibition of the renin-angiotensin system (RAS) and is the main focus of this review.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2005

Low birth weight, nephron number, and kidney disease.

More and more evidence is emerging that highlights the far-reaching consequences of prenatal (intrauterine) programming on organ function and adult disease. In humans, low birth weight (LBW) occurs more frequently in disadvantaged communities among whom there is often a disproportionately high incidence of adult cardiovascular disease, hypertension, diabetes mellitus, and kidney disease. Indeed, many epidemiologic studies have found an inverse association between LBW and higher blood pressures in infancy and childhood, and overt hypertension in adulthood. Multiple animal models have demonstrated the association of LBW with later hypertension, mediated, at least in part, by an associated congenital nephron deficit. Although no direct correlation has been shown between nephron number and birth weight in humans with hypertension, nephron numbers were found to be lower in adults with essential hypertension, and glomeruli tend to be larger in humans of lower birth weight. An increase in glomerular size is consistent with hyperfiltration necessitated by a reduction in total filtration surface area, which suggests a congenital nephron deficit. Hyperfiltration manifests clinically as microalbuminuria and accelerated loss of renal function, the prevalence of which are higher among adults who had been of LBW. A kidney with a reduced nephron number has less renal reserve to adapt to dietary excesses or to compensate for renal injury, as is highlighted in the setting of renal transplantation, where smaller kidney to recipient body-weight ratios are associated with poorer outcomes, independent of immunologic factors. Both hypertension and diabetes are leading causes of end-stage renal disease worldwide, and their incidences are increasing, especially in underdeveloped communities. Perinatal programming of these 2 diseases, as well as of nephron number, may therefore have a synergistic impact on the development of hypertension and kidney disease in later life. Existing evidence suggests that birth weight should be used as a surrogate marker for future risk of adult disease. Although the ideal solution to minimize morbidity would be to eradicate LBW, until this panacea is realized, it is imperative to raise awareness of its prognostic implications and to focus special attention toward early modification of risk factors for cardiovascular and renal disease in individuals of LBW.

Adult↗
PubMed2004

Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy.

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 (> or =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.

Aged↗
PubMed2004

The renoprotective effects of structured care in a clinical trial setting in type 2 diabetic patients with nephropathy.

BACKGROUND: The RENAAL Study has confirmed the renoprotective effects of Losartan in type 2 diabetes. In this subgroup analysis from the RENAAL Study, we hypothesized that the intensive care received by patients in a clinical trial setting also reduced the rate of decline in renal function through optimization of all risk factors. METHODS: We compared the rate of deterioration in renal function, expressed as the regression coefficient of the monthly serum creatinine (SeCr) reciprocal (beta-1/Cr) in 55 Chinese type 2 diabetic patients before and after entry into the RENAAL Study. RESULTS: Of the 55 patients, 44 had at least three out-patient SeCr measurements both before (2.9+/-2.4 years) and after (3.3+/-0.8 years) entry into the study for evaluation. In the Losartan group (n = 24), the median beta-1/Cr fell from -11.4 x 10(-5) l micro mol(-1) month(-1) before entry into the trial to -4.7 x 10(-5) l micro mol(-1) month(-1) following entry (P = 0.001). The respective figures were -9.1 x 10(-5) and -5.0 x 10(-5) l micro mol(-1) month(-1) (P = 0.01) in the placebo group (n = 20). A decrease in beta-1/Cr was observed in 21 (87.5%) and 14 (70.0%) patients in the Losartan and placebo groups, respectively. Spot urinary albumin-to-creatinine ratio was reduced by 56% (P = 0.001) in the Losartan group but the change was not significant in the placebo group. At the end of the study, patients in both groups had lower blood pressure and better lipid control. The frequency of patient visits to doctors and nurses were doubled. CONCLUSIONS: The rate of renal function decline was significantly reduced in the majority of patients allocated to either Losartan or placebo following entry into the RENAAL study. These results suggest that in patients with diabetic nephropathy, implementation of a structured care protocol in a clinical trial setting facilities intensive treatment of risk factors confering renoprotective effects in addition to those resulting from Losartan treatment.

Aged↗
PubMed2004

Impact of renin angiotensin system blockade on renal function in health and disease: an end or a beginning?

Substantial reduction of functioning nephrons from any origin is followed by a relentless progression to chronic renal failure. This progression continues long after the acute nephropathy and its initiating events have subsided. Glomerular hypertension and hyperfiltration are the major contributors to this progressive nephron loss. Studies on the adverse effects of hemodynamic changes and attempts to define the modalities that slow the rate of progression of renal disease have been among the dominant trends in modern nephrology. Numerous animal studies as well as recent clinical trials indicate that blockade of the renin angiotensin system effectively retards progression of nephropathy from diverse origins.

Humans↗
PubMed2004

Impact of the supplementation of kidney mass on blood pressure and progression of kidney disease.

BACKGROUND: To test the hypothesis that nephron mass is an independent determinant of arterial pressure, the effects of augmenting renal mass by isograft transplantation were studied in the model of secondary hypertension. METHODS: The effects of isograft transplantation or sham operation on blood pressure, proteinuria, remnant kidney mass, glomerular filtration rate and glomerulosclerosis were assessed in 5/6 nephrectomized (5/6 NPX) rats. RESULTS: Systolic blood pressure was lowered on average by approximately 35 mmHg and glomerular hyperfiltration was attenuated in the remnant kidneys of transplant recipients. Markedly lower urinary protein excretion rates and glomerulosclerosis scores in the remnant kidney accompanied these supplemental transplants to values roughly one-third of those from sham-operated rats. CONCLUSIONS: The data show that reduced renal mass per se is the major factor in the development and maintenance of arterial hypertension and glomerular injury in 5/6 NPX rats and these changes can be reversed by supplementing renal mass. The data provide strong support for the notion that renal mass is a significant, independent determinant of arterial pressure.

Animals↗