Venglustat, a Novel Glucosylceramide Synthase Inhibitor, in Patients at Risk of Rapidly Progressing ADPKD: Primary Results of a Double-Blind, Placebo-Controlled, Phase 2/3 Randomized Clinical Trial.

RATIONALE & OBJECTIVE: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of multiple kidney cysts that leads to growth in total kidney volume (TKV) and progression to kidney failure. Venglustat is a glucosylceramide synthase inhibitor that has been shown to inhibit cyst growth and reduce kidney failure in preclinical models of ADPKD. STUDY DESIGN: STAGED-PKD was a 2-stage, multicenter, double-blind, randomized, placebo-controlled phase 2/3 study in adults with ADPKD at risk of rapidly progressive disease, who were selected based on Mayo Clinic imaging classification of ADPKD class 1C, 1D, or 1E and an estimated glomerular filtration rate (eGFR) of 30-89.9mL/min/1.73m2. SETTING & PARTICIPANTS: Enrollment included 236 and 242 patients in stages 1 and 2, respectively. INTERVENTIONS: In trial stage 1, the patients were randomized 1:1:1 to venglustat, 8mg; venglustat, 15mg; or placebo. In stage 2, the patients were randomized 1:1 to venglustat, 15mg (highest dose identified as safe and well tolerated in stage 1), or placebo. OUTCOMES: Primary end points were rate of change in TKV over 18 months in stage 1 and eGFR slope over 24 months in stage 2. Secondary end points were eGFR slope over 18 months (stage 1), rate of change in TKV (stage 2), and safety/tolerability, pain, and fatigue (stages 1 and 2). RESULTS: A prespecified interim futility analysis showed that venglustat treatment had no effect on the annualized rate of change in TKV over 18 months (stage 1) and had a faster rate of decline in eGFR slope over 24 months (stage 2). Due to this lack of efficacy, the study was terminated early. LIMITATIONS: The short follow-up period after the end of treatment and limited generalizability of the findings. CONCLUSIONS: In patients with rapidly progressing ADPKD, treatment with venglustat at either 8mg or 15mg showed no change in the rate of change in TKV and a faster rate of eGFR decline in STAGED-PKD despite a dose-dependent decrease in plasma glucosylceramide levels. FUNDING: This study was funded by Sanofi. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT03523728.

Multiple Prior Live Births Are Associated With Cardiac Remodeling and Heart Failure Risk in Women.

OBJECTIVE: Greater parity has been associated with cardiovascular disease risk. We sought to find whether the effects on cardiac remodeling and heart failure risk are clear. METHODS: We examined the association of number of live births with echocardiographic measures of cardiac structure and function in participants of the Framingham Heart Study (FHS) using multivariable linear regression. We next examined the association of parity with incident heart failure with preserved (HFpEF) or reduced (HFrEF) ejection fraction using a Fine-Gray subdistribution hazards model in a pooled analysis of n = 12,635 participants in the FHS, the Cardiovascular Health Study, the Multi-Ethnic Study of Atherosclerosis, and Prevention of Renal and Vascular Endstage Disease. Secondary analyses included major cardiovascular disease, myocardia infarction and stroke. RESULTS: Among n = 3931 FHS participants (mean age 48 ± 13 years), higher numbers of live births were associated with worse left ventricular fractional shortening (multivariable ß -1.11 (0.31); P = 0.0005 in ≥ 5 live births vs nulliparous women) and worse cardiac mechanics, including global circumferential strain and longitudinal and radial dyssynchrony (P < 0.01 for all comparing ≥ 5 live births vs nulliparity). When examining HF subtypes, women with ≥ 5 live births were at higher risk of developing future HFrEF compared with nulliparous women (HR 1.93, 95% CI 1.19-3.12; P = 0.008); by contrast, a lower risk of HFpEF was observed (HR 0.58, 95% CI 0.37-0.91; P = 0.02). CONCLUSIONS: Greater numbers of live births are associated with worse cardiac structure and function. There was no association with overall HF, but a higher number of live births was associated with greater risk for incident HFrEF.

Serum bicarbonate is associated with kidney outcomes in autosomal dominant polycystic kidney disease.

BACKGROUND: Metabolic acidosis accelerates progression of chronic kidney disease, but whether this is also true for autosomal dominant polycystic kidney disease (ADPKD) is unknown. METHODS: Patients with ADPKD from the DIPAK (Developing Interventions to halt Progression of ADPKD) trial were included [n = 296, estimated glomerular filtration rate (eGFR) 50 ± 11 mL/min/1.73 m2, 2.5 years follow-up]. Outcomes were worsening kidney function (30% decrease in eGFR or kidney failure), annual eGFR change and height-adjusted total kidney and liver volumes (htTKV and htTLV). Cox and linear regressions were adjusted for prognostic markers for ADPKD [Mayo image class and predicting renal outcomes in ADPKD (PROPKD) scores] and acid-base parameters (urinary ammonium excretion). RESULTS: Patients in the lowest tertile of baseline serum bicarbonate (23.1 ± 1.6 mmol/L) had a significantly greater risk of worsening kidney function [hazard ratio = 2.95, 95% confidence interval (CI) 1.21-7.19] compared with patients in the highest tertile (serum bicarbonate 29.0 ± 1.3 mmol/L). Each mmol/L decrease in serum bicarbonate increased the risk of worsening kidney function by 21% in the fully adjusted model (hazard ratio = 1.21, 95% CI 1.06-1.37). Each mmol/L decrease of serum bicarbonate was also associated with further eGFR decline (-0.12 mL/min/1.73 m2/year, 95% CI -0.20 to -0.03). Serum bicarbonate was not associated with changes in htTKV or htTLV growth. CONCLUSIONS: In patients with ADPKD, a lower serum bicarbonate within the normal range predicts worse kidney outcomes independent of established prognostic factors for ADPKD and independent of urine ammonium excretion. Serum bicarbonate may add to prognostic models and should be explored as a treatment target in ADPKD.

Serum Calcification Propensity and the Risk of Cardiovascular and All-Cause Mortality in the General Population: The PREVEND Study.

OBJECTIVE: Vascular calcification contributes to the cause of cardiovascular disease. The calciprotein particle maturation time (T50) in serum, a measure of calcification propensity, has been linked with adverse outcomes in patients with chronic kidney disease, but its role in the general population is unclear. We investigated whether serum T50 is associated with cardiovascular mortality in a large general population-based cohort. Approach and Results: The relationship between serum T50 and cardiovascular mortality was studied in 6231 participants of the PREVEND (Prevention of Renal and Vascular End-Stage Disease) cohort. All-cause mortality was the secondary outcome. Mean (±SD) age was 53±12 years, 50% were male, and mean serum T50 was 329±58 minutes. A shorter serum T50 is indicative of a higher calcification propensity. Serum T50 was inversely associated with circulating phosphate, age, estimated glomerular filtration rate, and alcohol consumption, whereas plasma magnesium was positively associated with serum T50 (P<0.001, total multivariable model R2=0.281). During median (interquartile range) follow-up for 8.3 (7.8-8.9) years, 364 patients died (5.8%), of whom 95 (26.1%) died from a cardiovascular cause. In multivariable Cox proportional hazard models, each 60 minutes decrease in serum T50 was independently associated with a higher risk of cardiovascular mortality (fully adjusted hazard ratio [95% CI], 1.22 [1.04-1.36], P=0.021). This association was modified by diabetes mellitus; stratified analysis indicated a more pronounced association in individuals with diabetes mellitus. CONCLUSIONS: Serum T50 is independently associated with an increased risk of cardiovascular mortality in the general population and thus may be an early and potentially modifiable risk marker for cardiovascular mortality.

Cardiovascular outcome trials in patients with chronic kidney disease: challenges associated with selection of patients and endpoints.

Although cardiovascular disease is a major health burden for patients with chronic kidney disease, most cardiovascular outcome trials have excluded patients with advanced chronic kidney disease. Moreover, the major cardiovascular outcome trials that have been conducted in patients with end-stage renal disease have not demonstrated a treatment benefit. Thus, clinicians have limited evidence to guide the management of cardiovascular disease in patients with chronic kidney disease, particularly those on dialysis. Several factors contribute to both the paucity of trials and the apparent lack of observed treatment effect in completed studies. Challenges associated with conducting trials in this population include patient heterogeneity, complexity of renal pathophysiology and its interaction with cardiovascular disease, and competing risks for death. The Investigator Network Initiative Cardiovascular and Renal Clinical Trialists (INI-CRCT), an international organization of academic cardiovascular and renal clinical trialists, held a meeting of regulators and experts in nephrology, cardiology, and clinical trial methodology. The group identified several research priorities, summarized in this paper, that should be pursued to advance the field towards achieving improved cardiovascular outcomes for these patients. Cardiovascular and renal clinical trialists must partner to address the uncertainties in the field through collaborative research and design clinical trials that reflect the specific needs of the chronic and end-stage kidney disease populations, with the shared goal of generating robust evidence to guide the management of cardiovascular disease in patients with kidney disease.

Compositional Features of HDL Particles Interact with Albuminuria to Modulate Cardiovascular Disease Risk.

Lipoproteins containing apolipoprotein B modify associations of elevated urinary albumin excretion (UAE) with cardiovascular disease (CVD). Additionally, it is known that elevated UAE alters high-density lipoprotein functionality. Accordingly, we examined whether HDL features might also modify UAE-associated CVD. Multivariable Cox proportional-hazards modeling was performed on participants of the PREVEND (Prevention of Renal and Vascular Endstage Disease) study at the baseline screening with standard lipid/lipoprotein analyses and, three-to-four years later (second screen), with nuclear magnetic resonance lipoprotein analyses focusing on HDL parameters including HDL particle (HDL-P) and apolipoprotein A-I concentrations. These were used with UAE and derived measures of HDL apoA-I content (apoA-I/HDL-C and apoA-I/HDL-P) in risk models adjusted for gender, age, apoB, diabetes, past CVD history, CRP and GFR. Interaction analysis was also performed. Baseline screening revealed significant associations inverse for HDL-C and apoA-I and direct for apoA-I/HDL-C. The second screening demonstrated associations inverse for HDL-P, large HDL-P, medium HDL-P, HDL size, and apoA-I/HDL-P. Significant interactions with UAE included apoA-I/HDL-C at the baseline screening, and apoA-I/HDL-P and medium HDL-P but not apoA-I/HDL-C at the second screening. We conclude that features of HDL particles including apoA-I/HDL-P, indicative of HDL apoA-I content, and medium HDL-P modify associations of elevated UAE with CVD risk.

Urinary renin-angiotensin markers in polycystic kidney disease.

In autosomal dominant polycystic kidney disease (ADPKD), activation of the renin-angiotensin aldosterone system (RAAS) may contribute to hypertension and disease progression. Although previous studies have focused on circulating RAAS components, preliminary evidence suggests that APDKD may increase urinary RAAS components. Therefore, our aim was to analyze circulating and urinary RAAS components in ADPKD. We cross-sectionally compared 60 patients with ADPKD with 57 patients with non-ADPKD chronic kidney disease (CKD). The two groups were matched by sex, estimated glomerular filtration rate (eGFR), blood pressure, and RAAS inhibitor use. Despite similar plasma levels of angiotensinogen and renin, urinary angiotensinogen and renin excretion were five- to sixfold higher in ADPKD (P < 0.001). These differences persisted when adjusting for group differences and were present regardless of RAAS inhibitor use. In multivariable analyses, ADPKD, albuminuria, and the respective plasma concentrations were independent predictors for urinary angiotensinogen and renin excretion. In ADPKD, both plasma and urinary renin correlated negatively with eGFR. Total kidney volume correlated with plasma renin and albuminuria but not with urinary renin or angiotensinogen excretions. Albuminuria correlated positively with urinary angiotensinogen and renin excretions in ADPKD and CKD. In three ADPKD patients who underwent nephrectomy, the concentrations of albumin and angiotensinogen were highest in plasma, followed by cyst fluid and urine; urinary renin concentrations were higher than cyst fluid. In conclusion, this study shows that, despite similar circulating RAAS component levels, higher urinary excretions of angiotensinogen and renin are a unique feature of ADPKD. Future studies should address the underlying mechanism and whether this may contribute to hypertension or disease progression in ADPKD.

Circulating total bilirubin and risk of incident cardiovascular disease in the general population.

OBJECTIVE: To assess the association of circulating total bilirubin and cardiovascular disease (CVD) risk in a new prospective study and to determine whether adding information on total bilirubin values to established cardiovascular risk factors is associated with improvement in prediction of CVD risk. APPROACH AND RESULTS: Circulating total bilirubin levels were measured at baseline in the PREVEND (Prevention of Renal and Vascular End-stage Disease) prospective study of 7222 participants and 773 incident CVD events. Total bilirubin was log-linearly associated with CVD risk. Age- and sex-adjusted hazard ratio (95% confidence interval) for CVD per 1-SD increase in loge total bilirubin was 0.82 (0.76 to 0.88; P<0.001), which was minimally attenuated to 0.89 (0.82 to 0.96; P=0.003) after further adjustment for established risk factors. In a meta-analysis of 12 population-based prospective studies involving 9378 incident CVD cases, the pooled multivariate-adjusted relative risk (95% confidence interval) for CVD was 0.93 (0.90 to 0.97; P<0.001) per 1-SD increase in total bilirubin levels. The corresponding pooled risks for coronary heart disease and stroke were 0.95 (0.92 to 0.99; P=0.018) and 0.93 (0.88 to 0.98; P=0.006), respectively. Addition of information on total bilirubin to a CVD risk prediction model containing established risk factors was associated with a C-index change of 0.0013 (-0.0004 to 0.0029; P=0.13). CONCLUSIONS: There is a log-linear inverse association between circulating total bilirubin level and CVD risk, which is independent of established risk factors. Nonetheless, inclusion of total bilirubin in the standard established risk factors panel provides no significant improvement in CVD risk prediction.

Screening for chronic kidney disease can be of help to prevent atherosclerotic end-organ damage.

Atherosclerotic damage to the kidney is one of the most prevalent causes of chronic kidney disease and ultimately kidney failure. It frequently coincides with atherosclerotic damage to the heart, the brain and the lower extremities. In fact, the severity of the damage in the various end organs runs in parallel. As damage to the kidney is easy to measure by monitoring albuminuria and eGFR, and as the early phases of kidney damage frequently precede the alarming symptomatology in the heart, brain and peripheral vasculature, we argue that the nephrologist should consider taking the lead in better organizing early detection and management of CKD. The nephrologist can guide the general practitioner and general health care workers to offer better preventive care to the subjects at risk of progressive atherosclerotic end-organ damage.

Do albuminuria and hs-CRP add to the International Diabetes Federation definition of the metabolic syndrome in predicting outcome?

BACKGROUND: To investigate the added value of elevated urinary albumin excretion (UAE) and high high-sensitive C-reactive protein (hs-CRP) in predicting new-onset type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD) and chronic kidney disease (CKD) in addition to the present metabolic syndrome (MetS) defining criteria. METHODS: The PREVEND Study is a prospective population-based cohort study in the Netherlands, including 8592 participants. The MetS was defined according to the 2004 International Diabetes Federation criteria, elevated UAE as albuminuria ≥ 30 mg/24 h and high hs-CRP as ≥ 3 mg/L. RESULTS: At follow-up, subjects without MetS when compared to subjects with MetS had a lower incidence of T2DM, CVD as well as CKD (2.5 versus 15.5; 4.1 versus 10.3 and 5.8 versus 11.2%, all P < 0.001). In subjects with MetS, the incidence of all three outcomes was higher among subjects with elevated albuminuria versus subjects with normoalbuminuria (all P < 0.01). The incidence of all outcomes was also higher among subjects with high hs-CRP versus subjects without elevated hs-CRP but only significant for CKD (P = 0.002). Multivariate analysis including elevated UAE, hs-CRP and the variables defining the MetS showed that elevated albuminuria was independently associated with the risk for new-onset T2DM, CVD and CKD, whereas high hs-CRP was only independently associated with new-onset CVD and CKD. CONCLUSION: Our data show that elevated UAE has added value to the present MetS defining variables in predicting new-onset T2DM, CVD and CKD, whereas hs-CRP adds to predicting new-onset CVD and CKD, but not T2DM.

The STAGED-PKD 2-Stage Adaptive Study With a Patient Enrichment Strategy and Treatment Effect Modeling for Improved Study Design Efficiency in Patients With ADPKD.

Rationale & Objective: Venglustat, a glucosylceramide synthase inhibitor, inhibits cyst growth and reduces kidney failure in mouse models of autosomal dominant polycystic kidney disease (ADPKD). STAGED-PKD aims to determine the safety and efficacy of venglustat and was designed using patient enrichment for progression to end-stage kidney disease and modeling from prior ADPKD trials. Study Design: STAGED-PKD is a 2-stage, international, double-blind, randomized, placebo-controlled trial in adults with ADPKD (Mayo Class 1C-1E) and estimated glomerular filtration rate (eGFR) 45-<90 mL/min/1.73 m2 at risk of rapidly progressive disease. Enrichment for rapidly progressing patients was identified based on retrospective analysis of total kidney volume (TKV) and eGFR slope from the combined Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease and HALT Progression of Polycystic Kidney Disease A studies. Setting & Participants: Target enrollment in stages 1 and 2 was 240 and 320 patients, respectively. Interventions: Stage 1 randomizes patients 1:1:1 to venglustat 8 mg or 15 mg once daily or placebo. Stage 2 randomizes patients 1:1 to placebo or venglustat, with the preferred dose based on stage 1 safety data. Outcomes: Primary endpoints are TKV growth rate over 18 months in stage 1 and eGFR slope over 24 months in stage 2. Secondary endpoints include: annualized rate of change in eGFR from baseline to 18 months (stage 1); annualized rate of change in TKV based on magnetic resonance imaging from baseline to 18 months (stage 2); and safety, tolerability, pain, and fatigue (stages 1 and 2). Limitations: If stage 1 is unsuccessful, patients enrolled in the trial may develop drug-related adverse events that can have long-lasting effects. Conclusions: Modeling allows the design and powering of a 2-stage combined study to assess venglustat's impact on TKV growth and eGFR slope. Stage 1 TKV assessment via a nested approach allows early evaluation of efficacy and increased efficiency of the trial design by reducing patient numbers and trial duration. Funding: This study was funded by Sanofi. Trial registration: STAGED-PKD has been registered at ClinicalTrials.gov with study number NCT03523728.

Comparison of the yield of different screening approaches to detect chronic kidney disease.

BACKGROUND: Screening for chronic kidney disease (CKD) has been advised in high-risk populations. The present study aims to compare the yields of four approaches to select high-risk subjects for CKD screening, which are defined as follows: Approach 1, history of cardiovascular (CV) disease, diabetes mellitus or hypertension (=high CV risk); Approach 2, high CV risk or age >55 years; Approach 3, urinary albumin concentration (UAC) ≥20 mg/L; or Approach 4, UAC ≥10 mg/L at pre-screening. METHODS: The study population is a sample of the general population of Groningen, the Netherlands (n = 3398). UAC was measured (nephelometry) in a first morning void urine sample collected at home and sent to a laboratory by post. Information on demographics and the presence of CV risk factors was obtained by a questionnaire. The presence of CKD was determined during examination at an outpatient clinic. RESULTS: At baseline, 12% of the subjects met the criteria of Approach 1, 33% of Approach 2, 8% of Approach 3 and 25% of Approach 4. CKD was diagnosed in 370 subjects (11%). Approach 2 detected the most CKD patients (sensitivity 65%), while Approach 3 resulted in the lowest number needed to screen (1.9). During a follow-up of 7 years, only the UAC pre-screening approaches detected CKD patients who had both significantly accelerated renal function loss and increased CV risk compared to subjects without CKD. Only 28% of CKD patients detected by the UAC approaches used antihypertensive/angiotensin-converting enzyme inhibitor treatment prior to screening. CONCLUSIONS: This study suggests that pre-screening based on UAC should be favoured in comparison to screening based on CKD risk factors to detect CKD patients at high renal and CV risk.

Selection on albuminuria enhances the efficacy of screening for cardiovascular risk factors.

BACKGROUND: As many subjects with a cardiovascular (CV) risk factor are undiagnosed, guidelines to prevent cardiovascular disease argue for case finding on those risk factors. Such an approach is, however, labour and cost intensive. An elevated urinary albumin loss is an early marker of vascular damage and is associated with an increased CV risk. As albuminuria is easy to measure, we tested whether a screening approach in which detailed risk factor measurement is done only after selection of subjects with an elevated albuminuria results in a higher yield of subjects at risk. METHODS: A random sample of the general population as investigated in the Prevention of Renal and Vascular End-Stage Disease study was used. Plasma glucose, blood pressure, serum cholesterol and renal function were measured in an overall random sample of the population, in subgroups according to their urinary albumin concentration (UAC) of one first morning urine void and in subgroups in whom the elevated albuminuria level was confirmed with two 24 h urine collections for measurement of urinary albumin excretion (UAE). RESULTS: In the overall population, the number of subjects with any newly found CV risk factor was higher than the number of subjects already known with any CV risk factor (n = 1331 versus 370; 39.2 versus 10.9%). The prevalence of subjects with any newly diagnosed CV risk factor was higher in the group of 267 subjects with a first morning UAC of ≥ 20 mg/L (61.0%; P < 0.05) compared to the overall population (39.2%). Although the sensitivity of a UAC ≥ 20 mg/L to detect a subject with at least one CV risk factor was relatively low (12%), the specificity was very high (96%). The positive predictive value was 70%. When the elevated UAC could be confirmed in two subsequent 24-h urine collections, the diagnostic yield still further improved. CONCLUSION: The prevalence of undiagnosed CV risk factors in the general population is much higher than the prevalence of known risk factors. After a selection of subjects with an elevated albuminuria, the relative prevalence of subjects with newly diagnosed CV risk factors increases while the number of subjects to test for presence of CV risk factors is smaller. Such an approach facilitates a more effective and simple strategy for risk factor screening.

Changes in renal risk factors versus renal function outcome during follow-up in a population-based cohort study.

BACKGROUND: Chronic kidney disease is a growing public health problem worldwide. Previous studies have identified several predictors for renal function decline. However, these studies used a single measurement of these risk factors. Therefore, the aim of this study was to investigate whether besides the baseline values of these risk factors, changes in risk factors are associated with subsequent rate of renal function loss. METHODS: Five thousand, six hundred and fifty-one participants in the Prevention of Renal and Vascular ENd-stage Disease (PREVEND) Study, a prospective, community-based cohort study, completed three screening visits during a follow-up of 6.5 years for detailed clinical and biochemical measurements. Change in renal function between the second and third screening rounds was chosen as the study parameter of interest. Changes in risk factors between the first and second screening rounds were incorporated as potential predictors for renal function loss in multivariable linear regression analyses. Based on the results of a previous study, gender-specific analyses were performed. RESULTS: In males, an increase in urinary albumin excretion (UAE), systolic blood pressure (SBP) and cholesterol was associated with a subsequent higher rate of renal function loss, whereas in females, increases in glucose levels were associated with an increase in renal function. For males, the analyses showed that both the baseline values and the change in UAE and cholesterol were significant predictors for increased rate of renal function loss during subsequent follow-up. With respect to SBP, when taking also the change in this variable into account, the baseline value was no longer a significant predictor for renal function loss. CONCLUSIONS: The results of the present study show the value of screening programs including repeated measurements of risk factors. Furthermore, these data indicate that, besides baseline values of risk factors, the changes over time in these factors should also be taken into account when developing 'Renal Risk Scores' to identify subjects in the general population who are at risk for accelerated renal function deterioration.

High protein intake associates with cardiovascular events but not with loss of renal function.

The long-term effects of higher dietary protein intake on cardiovascular and renal outcomes in the general population are not clear. We analyzed data from 8461 individuals who did not have renal disease and participated in two or three subsequent screenings (6.4-yr follow-up) in a prospective, community-based cohort study (Prevention of Renal and Vascular ENd-stage Disease [PREVEND]). We calculated daily protein intake from 24-h urinary urea excretion (Maroni formula) and used Cox proportional hazard models to analyze the associations between protein intake, cardiovascular events, and mortality. We used mixed-effects models to investigate the association between protein intake and change in renal function over time. The mean +/- SD daily protein intake was 1.20 +/- 0.27 g/kg. Protein intake was significantly associated with cardiovascular events during follow-up. The associations seemed U-shaped; compared with intermediate protein intake, individuals with either higher or lower protein intake had higher event rates. All-cause mortality and noncardiovascular mortality also were significantly associated with protein intake; individuals with low protein intake had the highest event rates. We found no association between baseline protein intake and rate of renal function decline during follow-up. In summary, in the general population, high protein intake does not promote accelerated decline of renal function but does associate with an increased risk for cardiovascular events.

Screening for albuminuria identifies individuals at increased renal risk.

It is unknown whether screening for albuminuria in the general population identifies individuals at increased risk for renal replacement therapy (RRT) or accelerated loss of renal function. Here, in a general population-based cohort of 40,854 individuals aged 28 to 75 yr, we collected a first morning void for measurement of urinary albumin. In a subset of 6879 individuals, we measured 24-h urinary albumin excretion and estimated GFR at baseline and during 6 yr of follow-up. Linkage with the national RRT registry identified 45 individuals who started RRT during 9 yr of follow-up. The quantity of albuminuria was associated with increased renal risk: the higher the level of albuminuria, the higher the risk of need for renal replacement therapy and the more rapid renal function decline. A urinary albumin concentration of > or =20 mg/L identified individuals who started RRT during follow-up with 58% sensitivity and 92% specificity. Of the identified individuals, 39% were previously unknown to have impaired renal function, and 50% were not being medically treated. Restricting screening to high-risk groups (e.g., known hypertension, diabetes, cardiovascular disease [CVD], older age) reduced the sensitivity of the test only marginally but failed to identify 45% of individuals with micro- and macroalbuminuria. In conclusion, individuals with elevated levels of urinary albumin are at increased risk for RRT and accelerated loss of renal function. Screening for albuminuria identifies patients at increased risk for progressive renal disease, 40 to 50% of whom were previously undiagnosed or untreated.

Extended prognostic value of urinary albumin excretion for cardiovascular events.

Because urinary albumin excretion (UAE) is a marker of cardiovascular (CV) risk, some have proposed screening the general population; however, it is unknown how the predictive power of a single screening value changes over time. In this study, data of 8496 individuals in a community-based, prospective cohort were used to evaluate this question. For each doubling of baseline UAE, the hazard ratio (HR) for a CV event was 1.36 (95% confidence interval [CI] 1.31 to 1.42). Baseline UAE similarly predicted events occurring >5 yr after baseline, suggesting that it remains a good predictor during at least the first 5 yr after measurement. Approximately 4 yr after baseline, UAE was measured again in 6800 individuals. Once again, high UAE (>75th percentile) predicted subsequent CV events, whether defined using the baseline UAE or follow-up UAE (HR 3.39 [95% CI 2.58 to 4.45] and HR 2.50 [95% CI] 1.90 to 3.29, respectively; P = 0.3 for difference). Finally, compared with individuals with consistently low UAE, individuals who progressed from low to high UAE during follow-up had a significantly higher risk for CV events (HR 3.68; 95% CI 2.45 to 5.53). In conclusion, UAE remains a good predictor of CV events during the first 5 yr after measurement, but repeating the measurement several years later also detects progression of UAE, which is also associated with increased CV risk. Future studies are required to determine the optimal interval of repeat testing and its cost-effectiveness.

Gender differences in predictors of the decline of renal function in the general population.

We sought to identify predictors of the decline in renal function, especially those that are modifiable, in the 5488 participants of the prospective, community-based cohort study PREVEND who completed three visits during a mean follow-up of 6.5 years. The change in renal function was used as the outcome and this was calculated as the linear regression of three estimated GFR measurements obtained during follow-up. Risk factors, known to influence renal outcome in patients with primary renal diseases, were used as potential predictors in multivariate regression analyses. High systolic blood pressure and plasma glucose were found to be independent predictors for an accelerated decline in function for both genders. In males, albuminuria was the strongest independent predictor for renal function decline, whereas in females albuminuria was univariately associated only after adjustment for age. The direction of the association between cholesterol/HDL ratio and decline of renal function differed by gender. Surprisingly, in males, waist circumference was an independent predictor and positively associated with renal function outcome. These studies show that there are gender differences in the standard predictors of the decline in renal function.

Cardiovascular and renal outcome in subjects with K/DOQI stage 1-3 chronic kidney disease: the importance of urinary albumin excretion.

BACKGROUND: The Kidney Disease Outcomes Quality Initiative guidelines aim to define chronic kidney disease (CKD) and classify its stages. Stage 3 CKD generally receives more attention than stage 1 or 2, because the more impaired glomerular filtration rate (GFR) in stage 3 suggests a higher cardiovascular and renal risk. In this study we evaluated cardiovascular and renal outcome in subjects with stage 1 and 2 CKD. For comparison, we also studied these outcomes in stage 3 CKD. METHODS: We used data of 8495 subjects of the PREVEND study, a prospective community-based cohort study, with data on urinary albumin excretion (UAE) and serum creatinine available. As measure of cardiovascular outcome, combined cardiovascular morbidity and mortality was used. As renal outcome, mean annual change of estimated GFR (eGFR) was used. RESULTS: 6905 subjects had no CKD; 243, 856 and 491 subjects had stage 1, 2 and 3 CKD, respectively. During a median follow-up of 7.5 years 565 cardiovascular events occurred. Incidence rates of cardiovascular events were higher (P < 0.001 for all groups) in subjects with stage 1-3 CKD (17.2, 22.2 and 20.9 events/1000 person-years, respectively) than in subjects without CKD (7.0 events/1000 person-years). Using subjects without CKD as reference, age- and sex-adjusted hazard ratios [HR (95% CI)] were 2.2 (1.5-3.3), 1.6 (1.3-2.0) and 1.3 (1.0-1.7), respectively. Compared to subjects without CKD but similar baseline eGFR, subjects with stage 1 or 2 CKD showed a larger decline in eGFR (-1.1 versus -1.5 and -0.2 versus -0.6 ml/min/1.73 m(2)/year, respectively, both P < 0.01). When subjects with stage 3 CKD were stratified according to the absence or presence of a UAE >30 mg/24 h, age- and sex-adjusted HRs for CVD were 1.0 (0.7-1.4) and 1.6 (1.1-2.3) and the change in eGFR was 0.2 versus -0.3 ml/min/1.73 m(2)/year, respectively. CONCLUSION: Subjects with stage 1 or 2 CKD have an increased risk for adverse cardiovascular and renal outcome and should receive equal attention as subjects with stage 3 CKD. Subdividing stage 3 CKD according to the presence or absence of a UAE >30 mg/24 h improves risk stratification within this stage.

Better understanding of ADPKD results in potential new treatment options: ready for the cure?

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common hereditary disorders. It accounts for 6% of the incidence of end-stage renal disease in Europe. Over the last decade, knowledge of the pathology underlying this disease has increased rapidly. Attributing important roles to tubular cell ciliary functioning, cell proliferation and fluid secretion, subsequent alterations in levels of intracellular calcium, adenosine 3',5'-cyclic monophosphate (cAMP) and activation of a variety of cellular kinases, including mammalian target of rapamycin (mTOR), has laid out the foundations for development of potentially effective treatments. In this editorial, the possible therapeutic roles for vasopressin antagonists, rapamycin, somatostatin and roscovitine are discussed. Clinical trials have been started to investigate the efficacy and safety of these agents for treating ADPKD in humans.