Climate change and its influence in nephron mass.

PURPOSE OF REVIEW: The consequences of climate change, including heat and extreme weather events impact kidney function in adults and children. The impacts of climate change on kidney development during gestation and thereby on kidney function later in life have been poorly described. Clinical evidence is summarized to highlight possible associations between climate change and nephron mass. RECENT FINDINGS: Pregnant women are vulnerable to the effects of climate change, being less able to thermoregulate, more sensitive to the effects of dehydration, and more susceptible to infections. Exposure to heat, wildfire smoke, drought, floods and climate-related infections are associated with low birth weight, preterm birth and preeclampsia. These factors are associated with reduced nephron numbers, kidney dysfunction and higher blood pressures in offspring in later life. Exposure to air pollution is associated with higher blood pressures in children and has variable effects on estimated glomerular filtration rate. SUMMARY: Climate change has important impacts on pregnant women and their unborn children. Being born too small or too soon is associated with life-time risk of kidney disease. Climate change may therefore have a dual effect of impacting fetal kidney development and contributing to cumulative postnatal kidney injury. The impact on population kidney health of future generations may be significant.

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy.

BACKGROUND: Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium-glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS: In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin-angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS: The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P = 0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P = 0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P = 0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS: In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years. (Funded by Janssen Research and Development; CREDENCE ClinicalTrials.gov number, NCT02065791.).

Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups.

BACKGROUND: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention). METHODS: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. RESULTS: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67-0.95]; P=0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49-0.94]) and secondary (HR, 0.85 [95% CI, 0.69-1.06]) prevention groups (P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61-1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59-1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56-1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction >0.5 for each outcome). CONCLUSIONS: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02065791.

N-terminal pro-brain natriuretic peptide (NT-proBNP) predicts the cardio-renal response to aliskiren in patients with type 2 diabetes at high renal and cardiovascular risk.

Sodium retention and volume overload are the main determinants of poor response to renin-angiotensin-aldosterone system (RAAS) inhibition in patients with diabetes. As volume excess can exist without symptoms, biomarkers are needed to identify a priori which patients are volume overloaded and may experience less benefit from RAAS inhibition. N-terminal pro-brain natriuretic peptide (NT-proBNP) is released in the setting of increased cardiac wall stress and volume overload. We conducted a post hoc analysis among 5081 patients with type 2 diabetes mellitus participating in the ALTITUDE trial to investigate whether NTproBNP can predict the effects of additional therapy with aliskiren on cardio-renal endpoints. Aliskiren compared to placebo reduced the risk of the primary cardio-renal endpoint events by 20% (95% confidence interval [CI] 16 to 61) and 2% (95% CI -42 to 30) in the two lowest NT-proBNP tertiles, and it increased the risk by 25% (95% CI -4 to 96) in the highest NT-proBNP tertile (P value for trend = 0.009). Similar trends were observed for the cardiovascular and end-stage renal disease endpoints. Effects of aliskiren compared to placebo on safety outcomes (hyperkalaemia and hospitalization for acute kidney injury) were independent of NT-proBNP. In conclusion, baseline NT-proBNP may be used as a marker to predict the response to aliskiren with regard to cardio-renal outcomes when added to standard therapy with RAAS inhibition.

The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) Study Rationale, Design, and Baseline Characteristics.

BACKGROUND: People with diabetes and kidney disease have a high risk of cardiovascular events and progression of kidney disease. Sodium glucose co-transporter 2 inhibitors lower plasma glucose by reducing the uptake of filtered glucose in the kidney tubule, leading to increased urinary glucose excretion. They have been repeatedly shown to induce modest natriuresis and reduce HbA1c, blood pressure, weight, and albuminuria in patients with type 2 diabetes. However, the effects of these agents on kidney and cardiovascular events have not been extensively studied in patients with type 2 diabetes and established kidney disease. METHODS: The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial aims to compare the efficacy and safety of canagliflozin -versus placebo at preventing clinically important kidney and cardiovascular outcomes in patients with diabetes and established kidney disease. CREDENCE is a randomized, double-blind, event-driven, placebo-controlled trial set in in 34 countries with a projected duration of ∼5.5 years and enrolling 4,401 adults with type 2 diabetes, estimated glomerular filtration rate ≥30 to <90 mL/min/1.73 m2, and albuminuria (urinary albumin:creatinine ratio >300 to ≤5,000 mg/g). The study has 90% power to detect a 20% reduction in the risk of the primary outcome (α = 0.05), the composite of end-stage kidney disease, doubling of serum creatinine, and renal or cardiovascular death. CONCLUSION: CREDENCE will provide definitive evidence about the effects of canagliflozin on renal (and cardiovascular) outcomes in patients with type 2 diabetes and established kidney disease. TRIAL REGISTRATION: EudraCT number: 2013-004494-28; ClinicalTrials.gov identifier: NCT02065791.

Cardiorenal end points in a trial of aliskiren for type 2 diabetes.

BACKGROUND: This study was undertaken to determine whether use of the direct renin inhibitor aliskiren would reduce cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. METHODS: In a double-blind fashion, we randomly assigned 8561 patients to aliskiren (300 mg daily) or placebo as an adjunct to an angiotensin-converting-enzyme inhibitor or an angiotensin-receptor blocker. The primary end point was a composite of the time to cardiovascular death or a first occurrence of cardiac arrest with resuscitation; nonfatal myocardial infarction; nonfatal stroke; unplanned hospitalization for heart failure; end-stage renal disease, death attributable to kidney failure, or the need for renal-replacement therapy with no dialysis or transplantation available or initiated; or doubling of the baseline serum creatinine level. RESULTS: The trial was stopped prematurely after the second interim efficacy analysis. After a median follow-up of 32.9 months, the primary end point had occurred in 783 patients (18.3%) assigned to aliskiren as compared with 732 (17.1%) assigned to placebo (hazard ratio, 1.08; 95% confidence interval [CI], 0.98 to 1.20; P=0.12). Effects on secondary renal end points were similar. Systolic and diastolic blood pressures were lower with aliskiren (between-group differences, 1.3 and 0.6 mm Hg, respectively) and the mean reduction in the urinary albumin-to-creatinine ratio was greater (between-group difference, 14 percentage points; 95% CI, 11 to 17). The proportion of patients with hyperkalemia (serum potassium level, ≥6 mmol per liter) was significantly higher in the aliskiren group than in the placebo group (11.2% vs. 7.2%), as was the proportion with reported hypotension (12.1% vs. 8.3%) (P<0.001 for both comparisons). CONCLUSIONS: The addition of aliskiren to standard therapy with renin-angiotensin system blockade in patients with type 2 diabetes who are at high risk for cardiovascular and renal events is not supported by these data and may even be harmful. (Funded by Novartis; ALTITUDE ClinicalTrials.gov number, NCT00549757.).

Effect of fetal and child health on kidney development and long-term risk of hypertension and kidney disease.

Developmental programming of non-communicable diseases is now an established paradigm. With respect to hypertension and chronic kidney disease, adverse events experienced in utero can affect development of the fetal kidney and reduce final nephron number. Low birthweight and prematurity are the most consistent clinical surrogates for a low nephron number and are associated with increased risk of hypertension, proteinuria, and kidney disease in later life. Rapid weight gain in childhood or adolescence further compounds these risks. Low birthweight, prematurity, and rapid childhood weight gain should alert clinicians to an individual's lifelong risk of hypertension and kidney disease, prompting education to minimise additional risk factors and ensuring follow-up. Birthweight and prematurity are affected substantially by maternal nutrition and health during pregnancy. Optimisation of maternal health and early childhood nutrition could, therefore, attenuate this programming cycle and reduce the global burden of hypertension and kidney disease in the future.

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

Intervention in the renin-angiotensin-aldosterone-system (RAAS) is associated with slowing the progressive loss of renal function. During initiation of therapy, however, there may be an acute fall in glomerular filtration rate (GFR). We tested whether this initial fall in GFR reflects a renal hemodynamic effect and whether this might result in a slower decline in long-term renal function. We performed a post hoc analysis of the Reduction of Endpoints in Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) trial. Patients assigned to losartan had a significantly greater acute fall in estimated (eGFR) during the first 3 months compared to patients assigned to placebo, but a significantly slower long-term mean decline of eGFR thereafter. A large interindividual difference, however, was noticed in the acute eGFR change. When patients were divided into tertiles of initial fall in eGFR, the long-term eGFR slope calculated from baseline was significantly higher in patients with an initial fall compared to those with an initial rise. When eGFR decline was calculated from 3 months to the final visit, excluding the initial effect, patients with a large initial fall in eGFR had a significant lower long-term eGFR slope compared to those with a moderate fall or rise. This relationship was independent of other risk markers or change in risk markers for progression of renal disease such as blood pressure and albuminuria. Thus, the greater the acute fall in eGFR, during losartan treatment, the slower the rate of long-term eGFR decline. Hence, interpretation of trial results relying on slope-based GFR outcomes should separate the initial drug-induced GFR change from the subsequent long-term effect on GFR.

The clinical importance of nephron mass.

Abundant evidence supports the association between low birth weight (LBW) and renal dysfunction in humans. Anatomic measurements of infants, children, and adults show significant inverse correlation between LBW and nephron number. Nephron numbers are also lower in individuals with hypertension compared with normotension among white and Australian Aboriginal populations. The relationship between nephron number and hypertension among black individuals is still unclear, although the high incidence of LBW predicts low nephron number in this population as well. LBW, a surrogate for low nephron number, also associates with increasing BP from childhood to adulthood and increasing risk for chronic kidney disease in later life. Because nephron numbers can be counted only postmortem, surrogate markers such as birth weight, prematurity, adult height, reduced renal size, and glomerulomegaly are potentially useful for risk stratification, for example, during living-donor assessment. Because early postnatal growth also affects subsequent risk for higher BP or reduced renal function, postnatal nutrition, a potentially modifiable factor, in addition to intrauterine effects, has significant influence on long-term cardiovascular and renal health.

Comparison of different measures of urinary protein excretion for prediction of renal events.

There are many methods to screen for abnormal amounts of proteinuria to identify patients at risk for progression of renal disease, but which method best predicts renal risk is unknown. Here, we analyzed a subset of 701 patients with type 2 diabetes and nephropathy participating in the Reduction of Endpoints in Non Insulin Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) trial to compare the ability of urinary protein excretion (UPE) and urinary albumin excretion (UAE) from a 24-hour urine collection and urinary albumin concentration (UAC) and the albumin:creatinine ratio (ACR) from a first-morning void in predicting renal events. The primary outcome measure was the time to a doubling of serum creatinine or end-stage renal disease. During follow-up, 202 events occurred. The hazard ratios for the risk of a renal outcome (95% CIs) associated with 1-SD increment in the log-transformed measures were 3.16 (2.60 to 3.86) for UAE, 3.02 (2.53 to 3.62) for UPE, 3.23 (2.67 to 3.91) for UAC, and 4.36 (3.50 to 5.45) for ACR. The area under the ROC curve was significantly higher for ACR compared with the other measures. In conclusion, measurement of the albumin:creatinine ratio in a first-morning void is the superior method to predict renal events in patients with type 2 diabetes and nephropathy.

Clinical consequences of developmental programming of low nephron number.

Nephron number in humans varies up to 13-fold, likely reflecting the impact of multiple factors on kidney development, including inherited body size and ethnicity, as well as maternal health and nutrition, fetal exposure to gestational diabetes or preeclampsia and other environmental factors, which may potentially be modifiable. Such conditions predispose to low or high offspring birth weight, growth restriction or preterm birth, which have all been associated with increased risks of higher blood pressures and/or kidney dysfunction in later life. Low birth weight, preterm birth, and intrauterine growth restriction are associated with reduced nephron numbers. Humans with hypertension and chronic kidney disease tend to have fewer nephrons than their counterparts with normal blood pressures or kidney function. A developmentally programmed reduction in nephron number therefore enhances an individual's susceptibility to hypertension and kidney disease in later life. A low nephron number at birth may not lead to kidney dysfunction alone except when severe, but in the face of superimposed acute or chronic kidney injury, a kidney endowed with fewer nephrons may be less able to adapt, and overt kidney disease may develop. Given that millions of babies are born either too small, too big or too soon each year, the population impact of altered renal programming is likely to be significant. Many gestational exposures are modifiable, therefore urgent attention is required to implement public health measures to optimize maternal, fetal, and child health, to prevent or mitigate the consequences of developmental programming, to improve the health future generations.

Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE): rationale and study design.

BACKGROUND: Patients with type 2 diabetes are at increased risk of macro- and microvascular disease, and the presence of albuminuria and/or reduced kidney function further enhances macrovascular risk. Angiotensin-converting-enzyme inhibitors reduce both macro- and microvascular events, yet the residual renal and cardiovascular risk still remains high. Aliskiren a novel oral direct renin inhibitor that unlike ACEi and ARBs, lowers plasma renin activity, angiotensin I and angiotensin II levels, may thereby provide greater benefit compared to ACEi or ARB alone. METHODS: The primary objective of the ALTITUDE trial is to determine whether aliskiren 300 mg once daily, reduces cardiovascular and renal morbidity and mortality compared with placebo when added to conventional treatment (including ACEi or ARB). ALTITUDE is an international, randomized, double-blind, placebo-controlled, parallel-group study, which will include three categories of high-risk patients with type 2 diabetes (aged > or =35 years): those with either urinary albumin/creatinine ratio (UACR) > or =200 mg/g; microalbuminuria (UACR) > or =20 <200 mg/g and eGFR > or =30 <60 mL/min/1.73 m2; and thirdly, those with a history of cardiovascular disease and eGFR > or =30 <60 mL/min/1.73 m2 with or without microalbuminuria. ALTITUDE is an event driven trial that aims to randomize 8600 patients with a planned follow-up time of 48 months. The primary outcome measure is time to first event for the composite endpoint of cardiovascular death, resuscitated death, myocardial infarction, stroke, unplanned hospitalization for heart failure, onset of end-stage renal disease or doubling of baseline serum creatinine concentration. Secondary endpoints include a composite CV endpoint and a composite renal endpoint. CONCLUSION: ALTITUDE will determine whether dual RAAS blockade with the direct renin inhibitor aliskiren in combination with an ACEi or ARB will reduce major morbidity and mortality in a broad range of high-risk patients with type 2 diabetes.

ACE gene polymorphism and losartan treatment in type 2 diabetic patients with nephropathy.

Losartan treatment reduced renal outcomes in proteinuric patients with type 2 diabetes in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. It is unknown whether an insertion (I)/deletion (D) polymorphism in the angiotensin I-converting enzyme (ACE) gene predicts renal outcomes and death and influences the effect of losartan in these patients. Pharmacogenetic analyses were performed comparing losartan with placebo administered with conventional blood pressure-lowering therapy in 1435 (95%) of the 1513 RENAAL study patients. The primary endpoint was the composite of doubling of baseline serum creatinine concentration, end-stage renal disease (ESRD) or death. Cox regression models were stratified on baseline proteinuria and included treatment, geographic region, ACE/ID genotype, and treatment x genotype interaction. Within the placebo group, subjects with the ID or DD genotype were more likely than those with the II genotype to reach the composite endpoint (by 17.5% and 38.1%, respectively, P = 0.029) or its individual components. Within the losartan group, genotype did not correlate with reaching the composite endpoint. Compared with placebo, however, losartan reduced the risk of reaching the composite endpoint by 5.8% (95% confidence interval, -23.3, 28.0), 17.6% (3.8, 29.4), and 27.9% (7.0, 44.1) among those with the II, ID, and DD genotypes, respectively. Similar trends were demonstrated for the individual endpoints. In conclusion, proteinuric type 2 diabetic patients with the D allele of the ACE gene have an unfavorable renal prognosis, which can be mitigated and even improved by losartan.

Recommendations and guidelines for the diagnosis and treatment of Fabry nephropathy in adults.

Progressive loss of kidney function complicates Fabry disease, an X-linked lysosomal storage disorder that arises from deficiency of alpha-galactosidase activity. Heterozygous females with Fabry disease can be as severely affected as hemizygous males, who have the classic form of the disease. Enzyme-replacement therapy with recombinant human alpha-galactosidase clears the glycosphingolipid globotriaosylceramide from kidney cells, and can stabilize renal function in adults with mild to moderate Fabry nephropathy. However, adults with more advanced nephropathy and overt proteinuria do not respond as well. For these patients, antiproteinuric therapy given in conjunction with enzyme-replacement therapy might prevent further decline in kidney function. In this Review, we propose guidelines and recommendations for the diagnosis and management of Fabry nephropathy in adults, based on published data and on the consensus of opinion of participants in the 7(th) International Fabry Nephropathy Roundtable in 2007. These organ-specific guidelines could be easier to implement than general guidelines, provided they are used in the context of an overall multisystem care approach.

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).

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.

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.

Renal outcomes with aliskiren in patients with type 2 diabetes: a prespecified secondary analysis of the ALTITUDE randomised controlled trial.

BACKGROUND: The primary results of the ALTITUDE trial showed no benefit of aliskiren on renal outcomes (doubling of serum creatinine and end-stage renal disease) when used as an adjunct to angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in patients with type 2 diabetes and chronic kidney disease or cardiovascular disease. We did a prespecified analysis of the ALTITUDE trial to analyse the effects of aliskiren on surrogate renal outcomes in all patients and on primary renal outcomes in subgroups of patients. METHODS: In the double-blind, randomised, controlled ALTITUDE trial, 8561 patients with type 2 diabetes and chronic kidney disease or cardiovascular disease were randomly assigned (1:1) to receive aliskiren 300 mg per day or placebo as an adjunct to ACE inhibitors or ARBs. Randomisation was stratified on the basis of baseline urinary albumin-to-creatinine ratio and presence of cardiovascular disease history, and treatment assignments were masked to all patients and study staff. Patients were followed up for a median of 2·6 years (IQR 2·0-3·2). In our secondary analysis, we investigated prespecified intermediate renal outcomes of transitions in albuminuria stages (ie, transitions between normoalbuminuria, microalbuminuria, and macroalbuminuria) and rate of change of estimated glomerular filtration rate (eGFR). We investigated all outcomes in the intention-to-treat population. The primary composite renal outcome of ALTITUDE was defined as a sustained doubling of serum creatinine, end-stage renal disease, or renal death. The ALTITUDE trial is registered with ClinicalTrials.gov, number NCT00549757. FINDINGS: Aliskiren significantly decreased progression (hazard ratio [HR] 0·83, 95% CI 0·75-0·93) and increased regression (HR 1·29, 95% CI 1·19-1·39) of transitions in albuminuria classes. The annual rate of change of eGFR was -3·1 mL/min/1·73 m(2) per year (95% CI -2·9 to -3·3) in the aliskiren group and -3·0 mL/min/1·73 m(2) per year (-2·8 to -3·2) in the placebo group (p=0·52). eGFR change during the first 6 months was significantly larger with aliskiren than with placebo (-2·5 mL/min/1·73 m(2), 95% CI -2·9 to -2·2 vs -1·4 mL/min/1·73 m(2), 95% CI -1·7 to -1·0; p<0·0001). Subsequent eGFR change did not differ significantly between groups (-2·8 mL/min/1·73 m(2) per year, 95% CI -3·0 to -2·6 with aliskiren vs -3·1 mL/min/1·73 m(2) per year, 95% CI -3·3 to -2·8 with placebo; p=0·068). The absence of a benefit of aliskiren on the primary composite renal endpoint in the overall population was also seen in various subgroups. INTERPRETATION: Aliskiren showed no beneficial effect on hard renal outcomes in the overall population or in various subgroups, but delayed progression to microalbuminuria and macroalbuminuria, and improved regression to microalbuminuria and normoalbuminuria. Whether the chosen intermediates are poor surrogates for clinical outcomes or whether off-target effects disrupt the association between the surrogate and clinical outcomes requires further study. FUNDING: Novartis.