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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. [ABSTRACT FROM AUTHOR]

Screening takes on new meaning when percentage of kidney function, not creatinine clearance, is used for assessment. Treatment is boosted by new data supporting the efficacy of angiotensin receptor blockers, which are challenging the first-line status of ACE inhibitors. [ABSTRACT FROM AUTHOR]

New knowledge about markers for renal injury can help you detect kidney disease before significant loss of function occurs. Guidelines for detection and management of chronic renal disease are changing to reflect these and other findings from recent clinical trials. [ABSTRACT FROM AUTHOR]

The effect of famotidine, a new histamine H2-receptor antagonist, on renal tubular creatinine secretion was evaluated in twelve patients with reduced renal function (creatinine clearance 10-60 ml min-1). Creatinine and inulin clearances were determined at baseline and for 4 h after a 10 mg intravenous dose of famotidine. Famotidine renal clearance exceeded inulin clearance by an average of 152%, indicating that renal tubular secretion of famotidine occurred. No significant changes in the clearances of creatinine or inulin, or the fractional clearance of creatinine were observed after famotidine administration. These data suggest that famotidine, unlike cimetidine, does not inhibit renal tubular secretion of creatinine. Thus, famotidine does not affect creatinine-dependent measurements of renal function and is unlikely to alter the renal elimination of basic drugs. [ABSTRACT FROM AUTHOR]

Background: Diabetic nephropathy is the leading cause of end-stage renal disease. Interruption of the renin-angiotensin system slows the progression of renal disease in patients with type 1 diabetes, but similar data are not available for patients with type 2, the most common form of diabetes. We assessed the role of the angiotensin-II-receptor antagonist losartan in patients with type 2 diabetes and nephropathy.Methods: A total of 1513 patients were enrolled in this randomized, double-blind study comparing losartan (50 to 100 mg once daily) with placebo, both taken in addition to conventional antihypertensive treatment (calcium-channel antagonists, diuretics, alpha-blockers, beta-blockers, and centrally acting agents), for a mean of 3.4 years. The primary outcome was the composite of a doubling of the base-line serum creatinine concentration, end-stage renal disease, or death. Secondary end points included a composite of morbidity and mortality from cardiovascular causes, proteinuria, and the rate of progression of renal disease.Results: A total of 327 patients in the losartan group reached the primary end point, as compared with 359 in the placebo group (risk reduction, 16 percent; P=0.02). Losartan reduced the incidence of a doubling of the serum creatinine concentration (risk reduction, 25 percent; P=0.006) and end-stage renal disease (risk reduction, 28 percent; P=0.002) but had no effect on the rate of death. The benefit exceeded that attributable to changes in blood pressure. The composite of morbidity and mortality from cardiovascular causes was similar in the two groups, although the rate of first hospitalization for heart failure was significantly lower with losartan (risk reduction, 32 percent; P=0.005). The level of proteinuria declined by 35 percent with losartan (P<0.001 for the comparison with placebo).Conclusions: Losartan conferred significant renal benefits in patients with type 2 diabetes and nephropathy, and it was generally well tolerated. [ABSTRACT FROM AUTHOR]

Background: Long-chain omega-3 fatty acid concentrate pharmaceuticals are used in the United States for treatment of severe hypertriglyceridemia (≥500 mg/dL) and are under investigation as adjuncts to statins for lowering cardiovascular risk in patients with high triglycerides (TGs; 200-499 mg/dL)., Objective: To evaluate MAT9001, an investigational prescription-only omega-3 fatty acid agent containing predominantly eicosapentaenoic acid (EPA) and docosapentaenoic acid, in 42 men and women with fasting TG 200 to 400 mg/dL., Methods: In this open-label, crossover trial, subjects received MAT9001 and EPA ethyl esters (EPA-EE) in random order. They were housed in a clinical research unit for 2 14-day treatment periods, separated by a ≥35-day washout. Lipoprotein lipids, apolipoproteins (Apos) and proprotein convertase subtilisin kexin type 9 levels were measured before and at the end of each treatment period., Results: MAT9001, compared with EPA-EE, resulted in significantly (P < .05) larger reductions from pretreatment levels for TG (-33.2% vs -10.5%), total cholesterol (-9.0% vs -6.2%), non-high-density lipoprotein cholesterol (-8.8% vs -4.6%), very low-density lipoprotein cholesterol (-32.5% vs -8.1%), Apo C3 (-25.5% vs -5.0%), and proprotein convertase subtilisin kexin type 9 (-12.3% vs +8.8%). MAT9001 also produced a significantly (P = .003) larger reduction in Apo A1 (-15.3% vs -10.2%), but responses for high-density lipoprotein cholesterol (-11.3% vs -11.1%), low-density lipoprotein cholesterol (-2.4% vs -4.3%), and Apo B (-3.8% vs -0.7%), respectively, were not significantly different relative to EPA-EE., Conclusions: MAT9001 produced significantly larger reductions than EPA-EE in several lipoprotein-related variables that would be expected to favorably alter cardiovascular disease risk in men and women with hypertriglyceridemia., (Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Cardiovascular disease is increased in patients with chronic kidney disease (CKD) and is the principle cause of morbidity and mortality in these patients. In patients with stage 5 CKD, structural changes in the myocardium have been implicated as the principle cardiovascular processes leading to this increase in morbidity and mortality, while atherosclerotic events including acute myocardial infarction and strokes are responsible for approximately 10-15% of cardiovascular deaths. Dyslipidemia is common in CKD patients and is usually not characterized by elevated cholesterol levels, except in patients with marked proteinuria. Increased triglyceride levels in conjunction with decreased high-density lipoprotein levels are the commonest qualitative abnormality. Characteristically, abnormalities in the metabolism of apolipoprotein (apo) B-containing lipoproteins have been described, including both gut derived (apoB-48) as well as those produced by hepatic synthesis (apoB-100). A decrease in enzymatic delipidation as well as reduced receptor removal of these lipoproteins both contribute to the increased levels of these apo-B-containing particles and their remnants (which are believed to be highly atherogenic). Abnormalities in the metabolism of apoA-containing lipoproteins are also present and these changes contribute to the lower levels of HDL seen. Qualitative abnormalities of these HDL particles may be associated with cellular oxidative injury and contribute to a pro-inflammatory, pro-thrombotic milieu that is frequently present in CKD patients.

Cardiovascular disease is increased in patients with chronic kidney disease (CKD) and is the principle cause of morbidity and mortality in these patients. Dyslipidemia, while common in these patients, is usually not characterized by elevated cholesterol, except in those patients with massive proteinuria. Qualitatively, increased triglycerides and reduced high-density lipoproteins (HDL) are most frequently described. Extensive abnormalities in the metabolism of apolipoprotein (apo) B-containing lipoproteins have been demonstrated, including those derived from the gut (apoB-48) as well as those derived from hepatic synthesis (apoB-100). Decreased enzymatic delipidation, in addition to reduced receptor removal of these lipoproteins, results in increased concentrations of these apoB-containing moieties, and in particular, their atherogenic remnants. Abnormalities in apoA-containing lipoproteins are also present and these changes may contribute not only to the lower levels of HDL seen, but also to the proinflammatory state that is frequently present in CKD patients. As a result, therapeutic strategies designed to modify atherosclerotic-caused outcomes in CKD may require multiple approaches., (Copyright © 2011 S. Karger AG, Basel.)

Renal pathology and dyslipidemia commonly coexist. Treatments that lower albuminuria/proteinuria may lower lipids, but it is not known whether lipid lowering independent of lessening albuminuria/proteinuria slows progression of kidney disease. We examined the association between LDL cholesterol levels and treatment with losartan on end-stage renal disease (ESRD). Lipid levels and albuminuria measurements were obtained at baseline and at year 1 in a post hoc analysis from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study, which compared the effects of losartan- versus placebo-based antihypertensive therapy in patients with type 2 diabetes and nephropathy. LDL cholesterol lowering was associated with a lower risk of ESRD; however, this seemed to be largely an association with the reduction in albuminuria.

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.

Background: The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study has previously shown losartan to confer significant benefits to patients with type 2 diabetes and nephropathy. The original study of 1513 patients included 96 Japanese patients; the present study is a post-hoc analysis of the effects of losartan in this Japanese subpopulation., Methods: This double-blind, randomized study compared losartan (50 to 100 mg once daily) with placebo. The study medication was taken in addition to conventional antihypertensive treatment, and the mean follow-up period for the Japanese patients was 2.8 years. The primary endpoint was the composite of doubling of serum creatinine, endstage renal disease, or death. Secondary endpoints included changes in proteinuria levels. Safety was also evaluated., Results: The primary composite endpoint was reached in fewer Japanese patients receiving losartan than placebo (50.0% versus 65.4%, respectively). The treatment effects of losartan were more robust when data were corrected for differences in proteinuria at baseline--a significant relative risk reduction of 45% with losartan (P=0.0397) was apparent. Treatment benefit exceeded that attributable to blood pressure changes alone. Levels of proteinuria were reduced with losartan compared with placebo, with an overall losartan treatment effect of 37.8% (P<0.001). Overall, losartan was similarly well tolerated in both the Japanese patients and the total population., Conclusions: In Japanese patients with type 2 diabetes and nephropathy, losartan offers renal protection and is generally well tolerated.

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.

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.

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.

Cardiovascular complications are common inpatients with kidney disease. Regulating the lipid levels in these patients is important so that the risks of kidney and cardiovascular complications can be minimized. Lipid regulation decreases the incidence of coronary vascular events and other vascular complications in patients with kidney disease; however, whether lipid regulation slows progression of kidney disease is not yet known. Additional studies of the implications of dyslipidemia in patients with kidney disease are needed.

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.

Background: The Kidney Early Evaluation Program (KEEP 2.0) cross-sectional, community-based study, targeted individuals at increased risk for kidney disease and measured blood glucose, creatinine, and hemoglobin., Methods: KEEP 2.0 screening data were used to determine the prevalence of anemia by level of kidney function and diabetes status. Estimated glomerular filtration rate (EGFR) was calculated using serum creatinine values, and categorized as > or =90, 60-89, 30-59 and <30 mL/min/1.73 m(2). Anemia was defined as hemoglobin <12 g/dL in men and in women aged >50 years, and <11 g/dL in women < or =50 years. Diabetes was defined as participant-reported diagnosis, fasting glucose >125 mg/dL, or nonfasting glucose >200 mg/dL., Results: Data were available on 5380 participants screened from August 2000 through December 2001. Diabetes was present in 26.9% of participants, and anemia in 7.7%; 15.9% of participants had at least moderately reduced kidney function (EGFR <60 mL/min/1.73 m(2)). In participants with diabetes, anemia prevalence at the 4 levels of descending EGFR were 8.7%, 7.5%, 22.2%, and 52.4%, compared with 6.9%, 5.0%, 7.9%, and 50.0% in persons without diabetes. In a multivariable model, participants of non-white race/ethnicity, those with diabetes and those with EGFR <30 or 30-59 mL/min/1.73 m(2) had significantly increased odds of anemia. In addition, a significant sex-diabetes interaction was identified; odds of anemia were 4-fold greater in men than women with diabetes relative to sex-matched participants without diabetes., Conclusion: Diabetes was independently correlated with anemia, more so in men than women, and may be linked to premature expression of anemia in persons with moderate reductions in kidney function.

Background: Type 2 diabetes is the leading cause of end-stage renal disease (ESRD). The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study provided the opportunity to estimate costs associated with ESRD by baseline albuminuria from a United States perspective., Methods: Costs for ESRD in patients with diabetes were estimated by baseline albuminuria using the U.S. Renal Data System by using the number of days each patient experienced ESRD and the daily estimated U.S. cost of ESRD., Results: The losartan-based antihypertensive therapy group experienced a 28.6% (P=0.002) reduction in the risk of the development of ESRD compared with placebo-based conventional antihypertensive therapy. The previously estimated annual ESRD-related cost saving in the losartan group was 5,144 dollars (95% CI 1,701-8,586 dollars, P=0.003) at 3.5 years. With the cost of losartan, the net savings in the losartan group was estimated at 3,522 dollars (143-6,900 dollars, P=0.041) by 3.5 years. More ESRD-free days were observed and reduced ESRD costs estimated with losartan-based treatment over all levels of baseline albuminuria., Conclusion: Treatment with losartan in patients with type 2 diabetes and nephropathy in the RENAAL study not only reduces the incidence of ESRD, but is also estimated from a U.S. perspective to result in substantial cost savings over the 3.5-year duration of the trial across all levels of baseline albuminuria.

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.

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.

Background: Early identification of persons at risk for kidney disease provides an opportunity to prevent or delay its progression and decrease morbidity and mortality. Our hypothesis was that implementation of a targeted screening program in communities with high-risk populations would detect previously unidentified persons with or at high risk for chronic kidney disease (CKD) with a prevalence that exceeds that predicted for CKD in the general population., Methods: Persons with hypertension or diabetes or a first-order relative with hypertension, diabetes, or kidney disease were screened for kidney disease risk factors. Blood pressure, blood glucose level, serum creatinine level, hemoglobin level, microalbuminuria, hematuria, pyuria, body mass index, and estimated glomerular filtration rate (EGFR) were evaluated., Results: Six thousand seventy-one eligible persons were screened from August 2000 through December 2001: of these persons, 68% were women, 43% were African American, 36% were white, 10% were Hispanic, and 5% were Native American. Most reported high-school education or more (84%) and health insurance coverage (86%). Twenty-seven percent met the screening definitions for diabetes; 64%, for hypertension; 29%, for microalbuminuria; 8%, for anemia; 18%, for hematuria; 13%, for pyuria; 5%, for elevated serum creatinine level; 16%, for reduced EGFR; and 44%, for obesity. Among participants without a reported history of specified conditions, screening identified 82 participants (2%) with diabetes, 1,014 participants (35%) with hypertension, 277 participants (5%) with elevated serum creatinine levels, 839 participants (14%) with reduced EGFRs, and 1,712 participants (29%) with microalbuminuria. Thirty-five percent of participants with a history of diabetes had elevated serum glucose levels at screening (> or =180 mg/dL [10 mmol/L]), and 64% with a history of hypertension did not have blood pressure controlled to less than 140/90 mm Hg. Only 18% of participants with a history of diabetes and 31% with a reduced EGFR had blood pressure controlled to less than 130/80 mm Hg and less than 135/85 mm Hg, respectively., Conclusion: Targeted screening is effective in identifying persons with previously unidentified or poorly controlled kidney disease risk factors, as well as persons with a moderately decreased EGFR.

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.

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 recently have been developed. The renin-angiotensin-aldosterone system has proven to be an important target for intervention., Methods: The Reduction of Endpoints in NIDDM with the Angiotensin II Receptor Antagonist Losartan (RENAAL) study was a randomized, double-blind, multinational, clinical trial that studied 1,513 patients with type 2 diabetes and nephropathy for a mean of 3.4 years. Patients were administered either losartan or placebo, each in addition to conventional antihypertensive therapy, with dosage adjustments as necessary to achieve a target blood pressure of less than 140/less than 90 mm Hg., Results: The study showed a significant benefit of losartan, beyond the effects of lowering blood pressure, on the primary composite end point of doubling serum creatinine level, ESRD, or death (-16%; P = 0.02). Losartan reduced the incidence of serum creatinine level doubling (-25%; P = 0.006) and ESRD (-28%; P = 0.002), but had no effect on rate of death. The composite end point of cardiovascular morbidity and mortality was similar in the two groups. The rate of first hospitalization for heart failure was reduced in the losartan group (-32%; P = 0.005), as was proteinuria (-35%; P < 0.001). The RENAAL study also provided the opportunity to evaluate risk factors that predict ESRD in patients with type 2 diabetes in whom blood pressure was aggressively treated. In our multivariate model, four independent risk factors, proteinuria (most important), serum creatinine level, hypoalbuminemia, and anemia, were identified that predicted the development of ESRD., Conclusion: Proteinuria is the single most powerful predictor of ESRD in patients with type 2 diabetes and nephropathy. Thus, it is imperative that it be assessed in all patients with type 2 diabetes to identify those at risk for progressive renal disease. The routine availability of the urinary albumin-creatinine ratio as a diagnostic test provides an important opportunity to further improve the prognosis of individuals with type 2 diabetes and nephropathy.

Background: More than 340,000 individuals were receiving renal replacement therapy in the United States at the end of 1999; this number is projected to double by the year 2010. Almost half had a primary diagnosis of diabetes mellitus particularly type 2, and more than one quarter a primary diagnosis of hypertension. Studies have demonstrated effective maneuvers to prevent or delay the rate of progression of kidney disease, and decrease morbidity and mortality. The objective of early diagnosis is early detection of asymptomatic disease at a time when intervention has a reasonable potential to have a positive impact on outcome., Methods: In 1997, the National Kidney Foundation launched KEEP trade mark (Kidney Early Evaluation Program), a free community-based screening that targets first order relatives of persons with hypertension, diabetes or kidney disease, and those with a personal history of diabetes or hypertension., Results: Of the 889 individuals screened in the pilot study, 71.4% had at least one abnormality. The program includes an educational component and referral to a physician for follow-up of abnormal values., Conclusions: Targeted screenings are an effective means of identifying persons at risk for kidney disease, and can identify individuals at risk early enough in the course of their disease to allow for effective intervention.

Background: The pathophysiologic and potential therapeutic role of selectins in renal ischemia-reperfusion injury (IRI) is not fully understood, due in part to redundancy in the roles of individual selectins. We hypothesized that blockade of ligands for all three selectins using a novel small molecule (TBC-1269) would improve the course of renal IRI by overcoming redundancy issues. This was investigated in a rat model of renal IRI., Methods: Rats were treated with TBC-1269 either during or post-IRI. The effects of TBC-1269 were investigated in two models of renal IRI: moderate IRI (30 minutes bilateral renal artery clamping) and severe IRI (45 minutes clamping). The combination of anti-E- and anti-P-selectin antibodies also was investigated in rats subjected to moderate IRI. Renal function, histological injury and mortality were assessed., Results: Rats treated with TBC-1269 during moderate IRI showed significantly reduced serum creatinine (SCr) and tubular necrosis post-ischemia compared to control animals. By contrast, delayed treatment (post-IRI) did not show a reduction in SCr. In rats with severe IRI, TBC-1269 treatment during IRI significantly reduced mortality at 48 hours post-ischemia. Rats with moderate IRI and treated with the combination of anti-E- and anti-P-selectin antibodies showed significantly reduced SCr compared to control rats at 24 hours post-ischemia., Conclusions: Small molecule selectin ligand inhibition provides a novel and effective approach to attenuate ischemic acute renal failure. Timing of treatment is crucial to success.

Clinical data have established microalbuminuria/proteinuria as an independent risk factor for the development and progression of renal disease in patients with either diabetes or essential hypertension. Decreased kidney function is associated with increased cardiovascular risk, even at modest reductions in estimated creatinine clearance (to approximately 60 mL/min/1.73 m(2)) or modest elevations in serum creatinine (>1.4 mg/dL). Treatment with angiotensin-converting enzyme inhibitors has been shown in clinical trials to delay or stabilize the rate of progression of renal disease. Reduction in cardiovascular events, such as stroke and myocardial infarction, also has been shown in these high-risk individuals. These effects are dependent and independent of blood pressure control, suggesting a nonhemodynamic effect in blockade of the renin-angiotensin system. In conjunction with other therapeutic interventions, such as dietary modification and control of serum lipids, it appears that for at least a subgroup of patients it is possible to delay or prevent progression of kidney failure. There frequently is a clustering of risk factors in these individuals, including insulin resistance, salt sensitivity, hypertension, and dyslipidemia. The mechanism of the relationship between albuminuria and cardiovascular disease is unclear but may be related to endothelial cell dysfunction. Nonetheless, the presence of microalbuminuria/proteinuria as a marker for cardiovascular disease has important implications for the identification and treatment of individuals at risk.

Introduction: Diabetic nephropathy is the leading cause of end-stage renal disease. Interruption of the renin-angiotensin system slows the progression of renal disease in type 1 diabetic patients, but similar data are not available for type 2, the most common form of diabetes. We assessed the role of the angiotensin II receptor antagonist, losartan, in type 2 diabetic patients with nephropathy., Material and Methods: One thousand five hundred and thirteen patients were enrolled in this randomised, placebo-controlled study of losartan (50 to 100 mg, once daily) or placebo, in addition to conventional antihypertensive treatment (calcium antagonists, diuretics, alpha- and beta-blockers, centrally acting agents) for a mean of 3.4 years. The primary outcome was the composite of doubling of baseline serum creatinine, end-stage renal disease, or death. Secondary end points included a composite of cardiovascular morbidity and mortality, proteinuria, and the progression rate of renal disease., Results: Baseline demographics in the two groups were similar. Three hundred and twenty-seven patients receiving losartan reached the primary end point, as compared with 359 on placebo (risk reduction = 16 per cent, p = 0.02). Losartan reduced the incidence of doubling of serum creatinine (risk reduction = 25 per cent, p = 0.006) and end-stage renal disease (risk reduction = 28 per cent, p = 0.002), but had no effect on death. Benefits exceeded that attributable to changes in blood pressure. The composite of cardiovascular morbidity and mortality was similar in the two groups, except hospitalisation for heart failure, which was reduced with losartan (risk reduction = 32 per cent, p = 0.005). Proteinuria declined by 35 per cent with losartan (p < 0.001)., Discussion: Losartan conferred significant renal benefits in type 2 diabetic patients with nephropathy and was generally well tolerated.

Microalbuminuria, one of the earliest indicators of kidney injury, could be a harbinger of progressive kidney failure. Similarly, it can also be one of the early signs that a patient at risk for cardiovascular disease is in fact developing the disease. If so, the patient's therapy is failing. Discussion of specific appropriate interventions are beyond the scope of this article. However, publications referred to in this work have recently discussed such interventions in substantial practical detail. Ample evidence shows that factors that are kidney-protective are also cardiovascular-protective.

In the last few decades, clinical and experimental data have established microalbuminuria/proteinuria as an independent risk factor for renal disease and for progression of renal disease in patients with diabetes and in those with essential hypertension. Reduction of proteinuria with the use of angiotensin-converting enzyme inhibitors has been shown in clinical trials to delay or stabilize the rate of progression of renal disease. This effect appears to be independent of any effect on blood pressure control. In conjunction with other therapeutic interventions such as dietary modification and control of serum lipids, it appears that for at least a subgroup of patients, it is possible to delay or prevent progression of kidney failure. More recently, evidence has accumulated that establishes microalbuminuria/proteinuria as an independent risk factor for cardiovascular morbidity and mortality even in those without other clinical evidence of kidney disease. There is frequently a clustering of risk factors in these individuals that includes insulin resistance, salt-sensitivity, hypertension, and dyslipidemia. The mechanism of this relationship of proteinuria and cardiovascular disease is unclear, but the presence of proteinuria as a marker for cardiovascular disease has important implications for the identification and treatment of individuals at risk.

The alarming increase in the incidence and mortality rate of end-stage renal disease (ESRD) over the past several years has prompted concerned physicians to ask why--and to ponder what can be done to ameliorate the situation. This article, the first in a seven-part series coordinated by the National Kidney Foundation, examines the factors surrounding the epidemic of chronic kidney disease and introduces readers to the organization's new clinical practice guidelines developed through its Kidney Disease Outcomes Quality Initiative. These recommendations emphasize early detection and treatment and offer a new avenue of communication between primary care physicians and nephrologists.

IL-18 binding protein (IL-18BP) is a circulating antagonist of the proinflammatory Th1 cytokine IL-18. It effectively blocks IL-18 by forming a 1:1 high affinity (Kd=400 pM) complex, exhibiting a very low dissociation rate. We have developed a sandwich ELISA for IL-18BPa and determined its limit of detection (62 pg/ml). Interference by IL-18 and related cytokines, as well as cross reactivity with other IL-18BP isoforms (b, c, and d) were determined. Using this ELISA, we measured serum IL-18BPa in large cohorts of healthy individuals and in septic patients. Serum IL-18BPa in healthy individuals was 2.15+/-0.15 ng/ml (range 0.5-7 ng/ml). In sepsis, the level rose to 21.9+/-1.44 ng/ml (range 4-132 ng/ml). Total IL-18 was measured in the same sera by an electrochemiluminescence assay and free IL-18 was calculated based on the mass action law. Total IL-18 was low in healthy individuals (64+/-17 pg/ml) and most of it ( approximately 85%) was in its free form. Total IL-18 and IL-18BPa were both elevated in sepsis patients upon admission (1.5+/-0.4 ng/ml and 28.6+/-4.5 ng/ml, respectively). At these levels, most of the IL-18 is bound to IL-18BPa, however the remaining free IL-18 is still higher than in healthy individuals. We conclude that IL-18BPa considerably inhibits circulating IL-18 in sepsis. Yet, exogenous administration of IL-18BPa may further reduce circulating IL-18 activity., (Copyright 2001 Academic Press.)

Background: The anemia associated with acute renal failure (ARF) is currently treated with blood transfusions, while the anemia of chronic renal failure is treated with recombinant erythropoietin (EPO). We hypothesized that EPO treatment during ARF could rapidly improve hemoglobin levels and be a useful therapeutic approach. In addition, as tubular epithelial cells have EPO receptors that can mediate proliferation, enhanced recovery of renal function may occur with EPO use., Methods: An established rat model of ischemic ARF was studied, using either moderate or severe ischemia. EPO was administered in a dose of 500 or 3000 U/kg starting at time of ischemia. Hematocrit (Hct), serum creatinine, reticulocyte count, and mortality rate were measured., Results: EPO treatment led to a rapid and significant increase in Hct at 48 and 72 hours after moderate ischemic renal reperfusion injury (IRI) in EPO (500 U/kg)-treated rats compared with control (saline treated) rats (mean +/- SE; 45.6 +/- 0.3% vs. 42.0 +/- 1.0%, P < 0.01) and (46.6 +/- 0.3 vs. 41.0 +/- 1.0, P < 0.01, N = 3 per group). In severe renal IRI, EPO treatment also led to significantly increased Hct at 48 (40.0 +/- 4.4% vs. 36.8 +/- 0.3%, P < 0.01, N = 3 per group) and 72 hours (43.5 +/- 1.5% vs. 34.7 +/- 2.3%, P < 0.01, N = 3 per group). Higher dose (3000 U/kg) EPO led to a more pronounced Hct increase after severe IRI at 48 hours compared with the 500 U/kg dose (43.5 +/- 0.3 vs. 40.3 +/- 0.3, P < 0.01, N = 3 per group). EPO treatment during moderate or severe renal IRI did not change the course of the renal dysfunction. EPO treatment (N = 19) had a significant protective effect on mortality during severe IRI. In addition, loss of body weight during ARF was not affected by EPO therapy., Conclusions: Recombinant EPO can rapidly increase Hct and improve mortality during ARF. Human studies are warranted to evaluate the clinical applicability of this important finding.

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin)-mediated lowering of serum cholesterol has been associated with a significant reduction in cardiovascular morbidity and mortality. Recent studies suggest that additional non-lipid lowering effects (eg, endothelial stabilization, anti-inflammatory, antithrombogenic) may be important in modulating their effectiveness. Dyslipidemia is common in end-stage renal disease (ESRD), and hemodialysis patients have increased cardiovascular morbidity and mortality. Cerivastatin, a new statin with powerful low-density lipoprotein-cholesterol (LDL-C) lowering capabilities, possesses some unique non-LDL-C-mediated properties that may contribute to a reduction of coronary events in the patient with ESRD. The primary objective of this multicenter multinational study of 1,054 hemodialysis patients is to compare 2 years of treatment with cerivastatin (0.4 mg/d) versus placebo on the composite clinical event rate of myocardial infarction, sudden cardiac death, ischemic stroke, and the need for coronary arterial bypass graft (CABG) or percutaneous transluminal coronary angioplasty (PTCA) procedures in these patients. Changes in lipids, inflammatory proteins including heat stable C-reactive protein (hsCRP), interleukin-6 (IL-6), oncostatin-M, intracellular adhesion molecule-1 (ICAM-1) and monocyte-chemoattractant protein-1 (MCP-1), as well as markers of cardiac muscle pathology, such as troponin I and troponin T, will be assessed in a subset of patients. This study is the first of its kind to assess the effect of a statin on the reduction of cardiovascular morbidity and mortality in an incident hemodialysis population. It will determine whether treatment with cerivastatin can effectively reduce the significant cardiovascular morbidity and mortality.

The RENAAL Study is a double-blind, placebo-controlled trial to evaluate the renal protective effects of losartan in Type 2 diabetic patients with nephropathy. The study has enrolled 1513 patients and is expected to continue for 3.5 years after the last patient has been entered. Eligible patients must have a urinary albumin:creatinine ratio of at least 300 mg/g and serum creatinine between 1.3 to 3.0 mg/dL. Eligible hypertensive or normotensive patients are randomised to receive either losartan or placebo, in addition to their existing antihypertensive therapy. Medications that block angiotensin production or action, are excluded. The primary endpoint is a composite of the time to first event of doubling of serum creatinine, end-stage renal disease, or death; secondary endpoints include cardiovascular events, progression of renal disease, and changes in proteinuria; tertiary endpoints include quality of life, healthcare resource utilisation, and amputations. Patients include Caucasians (48.6%), Blacks (15.2%), Asians (16.7%), and Hispanics (18.2%). Baseline urinary albumin:creatinine ratio and serum creatinine levels average 1867 mg/g and 1.9 mg/dL, respectively. Mean systolic and diastolic blood pressures are 153 and 82 mmHg, respectively. RENAAL will document whether blockade of the AII receptor with losartan produces clinical benefits in patients with Type 2 diabetes and nephropathy.

Background: Losartan is a selective angiotensin AT1 receptor antagonist currently employed in the management of essential hypertension. This compound is in common use in populations with renal failure and end-stage renal disease (ESRD)., Objective: To investigate the pharmacokinetics and pharmacodynamics of losartan in patients with ESRD in order to establish administration guidelines., Methods: Patients were administered losartan 100 mg/day for 7 days, and after the seventh and final dose pharmacokinetic parameters were determined for both losartan and its active metabolite E-3174. During the study, the haemodialytic clearances of losartan and E-3174 were measured during a standard 4-hour dialysis session. Neurohumoral and biochemical changes were assessed during losartan administration., Results: The pharmacokinetics of losartan and E-3174 in haemodialysis patients did not alter to a clinically significant level. Losartan administration was accompanied by a decline in plasma aldosterone level as well as by an increase in plasma renin activity. Losartan administration resulted in a decline in plasma uric acid level, despite the fact that the study participants had no residual renal function. Losartan and E-3174 were not dialysable., Conclusions: The pharmacokinetics of losartan and E-3174 are minimally altered in ESRD; thus, dosage adjustment is not required in the presence of advanced dialysis-dependent renal failure. In addition, postdialysis supplementation is not required for losartan because of the negligible dialysability of losartan and E-3174.