Effects of MAT9001 containing eicosapentaenoic acid and docosapentaenoic acid, compared to eicosapentaenoic acid ethyl esters, on triglycerides, lipoprotein cholesterol, and related variables.

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.

Lipid abnormalities in patients with chronic kidney disease: implications for the pathophysiology of atherosclerosis.

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.

Lipid abnormalities in patients with chronic kidney disease.

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.

Effect of LDL cholesterol and treatment with losartan on end-stage renal disease in the RENAAL study.

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 is a target for renoprotective therapy independent from blood pressure in patients with type 2 diabetic nephropathy: post hoc analysis from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial.

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.

Renal function and risk for cardiovascular events in type 2 diabetic patients with hypertension: the RENAAL and LIFE studies.

OBJECTIVE: To investigate whether a threshold exists for cardiovascular risk in type 2 diabetic patients with hypertension, the association between renal function and cardiovascular risk was examined across the entire physiological range of serum creatinine. DESIGN AND METHODS: The RENAAL and LIFE studies enrolled 1513 and 1195 patients with type 2 diabetes and hypertension, respectively. The relationship between baseline serum creatinine and the risk for a composite outcome of myocardial infarction, stroke or cardiovascular death was examined using Cox regression models. To adjust for heterogeneity between studies and treatment groups, these factors were included as strata when applicable. The analyses were conducted with adjustment for age, gender, smoking, alcohol use, blood pressure, heart rate, total and high-density lipoprotein (HDL) cholesterol, hemoglobin, albuminuria and prior cardiovascular disease. RESULTS: The hazard ratios across the baseline serum creatinine categories < 0.9 mg/dl, 0.9-1.2 mg/dl, 1.2-1.6 mg/dl, 1.6-2.8 mg/dl and >or= 2.8 mg/dl were 0.51 (95% confidence interval 0.34, 0.74), 0.74 (0.55, 1.00), 1.00 (reference), 1.24 (0.96, 1.59) and 1.67 (1.17, 2.91), respectively. Baseline serum creatinine (per mg/dl) strongly predicted the composite cardiovascular endpoint in LIFE [2.82(1.74,4.56), P < 0.001], RENAAL [1.41(1.12,1.79), P < 0.001], as well as the combined studies [1.51(1.21,1.87), P < 0.001]. CONCLUSION: A progressively higher risk for the composite cardiovascular endpoint was observed with incremental baseline serum creatinine in type 2 diabetic patients with hypertension, even within the normal range. Thus, there appears to be no serum creatinine threshold level for an increased cardiovascular risk. Baseline serum creatinine was a major independent risk factor for cardiovascular disease (www.ClinicalTrials.gov number NCT00308347).

Renin angiotensin aldosterone system blockade and renal disease in patients with type 2 diabetes: a subanalysis of Japanese patients from the RENAAL study.

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.

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.

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.

Risk scores for predicting outcomes in patients with type 2 diabetes and nephropathy: the RENAAL study.

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.

Kidney disease and cardiovascular disease: implications of dyslipidemia.

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.

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.

Higher prevalence of anemia with diabetes mellitus in moderate kidney insufficiency: The Kidney Early Evaluation Program.

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.

Losartan and the United States costs of end-stage renal disease by baseline albuminuria in patients with type 2 diabetes and nephropathy.

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.

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.

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.

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.

Identification of persons at high risk for kidney disease via targeted screening: the NKF Kidney Early Evaluation Program.

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.