Insulin resistance, kidney outcomes and effects of the endothelin receptor antagonist atrasentan in patients with type 2 diabetes and chronic kidney disease.

BACKGROUND: Insulin resistance (IR) is a pathophysiologic hallmark of type 2 diabetes and associated with the presence of chronic kidney disease (CKD). Experimental studies suggest that endothelin-1 increases IR. We assessed the association between IR and cardio-renal outcomes and the effect of the selective endothelin receptor antagonist atrasentan on IR in patients with type 2 diabetes and CKD. METHODS: We used data from the RADAR and SONAR trials that recruited participants with type 2 diabetes and CKD [eGFR 25-75 mL/min/1.73 m², urine albumin-to-creatinine ratio of 300-5000 mg/g]. IR was calculated using the homeostatic model assessment (HOMA-IR). The association between HOMA-IR and the pre-specified cardio-renal outcomes was assessed using multivariable Cox proportional hazards regression, and effects of atrasentan on HOMA-IR by a linear mixed effect model. RESULTS: In the SONAR trial, each log-unit increase in HOMA-IR was associated with an increased risk of the composite cardio-renal outcome [hazard ratio 1.32 (95%CI 1.09,1.60; p = 0.004)], kidney outcome [hazard ratio 1.30 (95%CI 1.00,1.68; p-value = 0.048)], and the kidney or all-cause mortality outcome [hazard ratio 1.25 (95%CI 1.01,1.55; p-value = 0.037)]. After 12 weeks treatment in the RADAR trial (N = 123), atrasentan 0.75 mg/day and 1.25 mg/day compared to placebo reduced HOMA-IR by 19.1 (95%CI -17.4, 44.3) and 26.7% (95%CI -6.4, 49.5), respectively. In the SONAR trial (N = 1914), atrasentan 0.75 mg/day compared to placebo reduced HOMA-IR by 9.6% (95%CI 0.6, 17.9). CONCLUSIONS: More severe IR is associated with increased risk of cardio-renal outcomes. The endothelin receptor antagonist atrasentan reduced IR. TRIAL REGISTRATION: RADAR trial (Reducing Residual Albuminuria in Subjects With Diabetes and Nephropathy With AtRasentan): NCT01356849. SONAR trial (The Study Of Diabetic Nephropathy With AtRasentan) NCT01858532.

Epidemiology of the diabetes-cardio-renal spectrum: a cross-sectional report of 1.4 million adults.

BACKGROUND: Type-2 diabetes (T2D), chronic kidney disease, and heart failure (HF) share epidemiological and pathophysiological features. Although their prevalence was described, there is limited contemporary, high-resolution, epidemiological data regarding the overlap among them. We aimed to describe the epidemiological intersections between T2D, HF, and kidney dysfunction in an entire database, overall and by age and sex. METHODS: This is a cross-sectional analysis of adults ≥ 25 years, registered in 2019 at Maccabi Healthcare Services, a large healthcare maintenance organization in Israel. Collected data included sex, age, presence of T2D or HF, and last estimated glomerular filtration rate (eGFR) in the past two years. Subjects with T2D, HF, or eGFR < 60 mL/min/1.73 m2 were defined as within the diabetes-cardio-renal (DCR) spectrum. RESULTS: Overall, 1,389,604 subjects (52.2% females) were included; 445,477 (32.1%) were 25- < 40 years, 468,273 (33.7%) were 40- < 55 years, and 475,854 (34.2%) were ≥ 55 years old. eGFR measurements were available in 74.7% of the participants and in over 97% of those with T2D or HF. eGFR availability increased in older age groups. There were 140,636 (10.1%) patients with T2D, 54,187 (3.9%) with eGFR < 60 mL/min/1.73m2, and 11,605 (0.84%) with HF. Overall, 12.6% had at least one condition within the DCR spectrum, 2.0% had at least two, and 0.23% had all three. Cardiorenal syndrome (both HF and eGFR < 60 mL/min/1.73m2) was prevalent in 0.40% of the entire population and in 2.3% of those with T2D. In patients with both HF and T2D, 55.2% had eGFR < 60 mL/min/1.73m2 and 15.8% had eGFR < 30 mL/min/1.73m2. Amongst those within the DCR spectrum, T2D was prominent in younger participants, but was gradually replaced by HF and eGFR < 60 mL/min/1.73m2 with increasing age. The congruence between all three conditions increased with age. CONCLUSIONS: This large, broad-based study provides a contemporary, high-resolution prevalence of the DCR spectrum and its components. The results highlight differences in dominance and degree of congruence between T2D, HF, and kidney dysfunction across ages.

Effects of Vitamin D Receptor Activation and Dietary Sodium Restriction on Residual Albuminuria in CKD: The ViRTUE-CKD Trial.

Reduction of residual albuminuria during single-agent renin-angiotensin-aldosterone blockade is accompanied by improved cardiorenal outcomes in CKD. We studied the individual and combined effects of the vitamin D receptor activator paricalcitol (PARI) and dietary sodium restriction on residual albuminuria in CKD. In a multicenter, randomized, placebo (PLAC)-controlled, crossover trial, 45 patients with nondiabetic CKD stages 1-3 and albuminuria >300 mg/24 h despite ramipril at 10 mg/d and BP<140/90 mmHg were treated for four 8-week periods with PARI (2 µg/d) or PLAC, each combined with a low-sodium (LS) or regular sodium (RS) diet. We analyzed the treatment effect by linear mixed effect models for repeated measurements. In the intention-to-treat analysis, albuminuria (geometric mean) was 1060 (95% confidence interval, 778 to 1443) mg/24 h during RS + PLAC and 990 (95% confidence interval, 755 to 1299) mg/24 h during RS + PARI (P=0.20 versus RS + PLAC). LS + PLAC reduced albuminuria to 717 (95% confidence interval, 512 to 1005) mg/24 h (P<0.001 versus RS + PLAC), and LS + PARI reduced albuminuria to 683 (95% confidence interval, 502 to 929) mg/24 h (P<0.001 versus RS + PLAC). The reduction by PARI beyond the effect of LS was nonsignificant (P=0.60). In the per-protocol analysis restricted to participants with ≥95% compliance with study medication, PARI did provide further albuminuria reduction (P=0.04 LS + PARI versus LS + PLAC). Dietary adherence was good as reflected by urinary excretion of 174±64 mmol Na+ per day in the combined RS groups and 108±61 mmol Na+ per day in the LS groups (P<0.001). In conclusion, moderate dietary sodium restriction substantially reduced residual albuminuria during fixed dose angiotensin-converting enzyme inhibition. The additional effect of PARI was small and nonsignificant.

Association of Skin Autofluorescence Levels With Kidney Function Decline in Patients With Peripheral Artery Disease.

OBJECTIVE: Skin autofluorescence (SAF), a measure of advanced glycation end product accumulation, is associated with kidney function. We investigated the association of SAF with rate of kidney function decline in a cohort of patients with peripheral artery disease. APPROACH AND RESULTS: We performed a post hoc analysis of an observational longitudinal cohort study. We included 471 patients with peripheral artery disease, and SAF was measured at baseline. Primary end point was rate of estimated glomerular filtration rate (eGFR) decline. Secondary end points were incidence of eGFR <60 and <45 mL/min/1.73 m(2) and rapid eGFR decline, defined as a decrease in eGFR of >5 mL/min/1.73 m(2)/y. During a median follow-up of 3 years, the mean change in eGFR per year was -1.8±4.4 mL/min/1.73 m(2)/y. No significant difference in rate of eGFR decline was observed per 1 arbitrary unit increase in SAF (-0.1 mL/min/1.73 m(2)/y; 95% confidence interval, -0.7 to 0.5; P=0.8). Analyses of the secondary end points showed that there was an association of SAF with incidence of eGFR <60 and <45 mL/min/1.73 m(2) (hazard ratio, 1.54; 95% confidence interval, 1.13-2.10; P=0.006 and hazard ratio, 1.76; 95% confidence interval, 1.20-2.59; P=0.004, respectively), but after adjustment for age and sex, significance was lost. There was no association of SAF with rapid eGFR decline. CONCLUSIONS: In conclusion, in this cohort of patients with peripheral artery disease, elevated SAF was associated with lower baseline eGFR. Although SAF has previously been established as a predictor for cardiovascular disease and mortality, it did not predict the rate of kidney function decline during follow-up in this study.

Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease.

BACKGROUND: Although inhibitors of the renin-angiotensin-aldosterone system can slow the progression of diabetic kidney disease, the residual risk is high. Whether nuclear 1 factor (erythroid-derived 2)-related factor 2 activators further reduce this risk is unknown. METHODS: We randomly assigned 2185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease (estimated glomerular filtration rate [GFR], 15 to <30 ml per minute per 1.73 m(2) of body-surface area) to bardoxolone methyl, at a daily dose of 20 mg, or placebo. The primary composite outcome was end-stage renal disease (ESRD) or death from cardiovascular causes. RESULTS: The sponsor and the steering committee terminated the trial on the recommendation of the independent data and safety monitoring committee; the median follow-up was 9 months. A total of 69 of 1088 patients (6%) randomly assigned to bardoxolone methyl and 69 of 1097 (6%) randomly assigned to placebo had a primary composite outcome (hazard ratio in the bardoxolone methyl group vs. the placebo group, 0.98; 95% confidence interval [CI], 0.70 to 1.37; P=0.92). In the bardoxolone methyl group, ESRD developed in 43 patients, and 27 patients died from cardiovascular causes; in the placebo group, ESRD developed in 51 patients, and 19 patients died from cardiovascular causes. A total of 96 patients in the bardoxolone methyl group were hospitalized for heart failure or died from heart failure, as compared with 55 in the placebo group (hazard ratio, 1.83; 95% CI, 1.32 to 2.55; P<0.001). Estimated GFR, blood pressure, and the urinary albumin-to-creatinine ratio increased significantly and body weight decreased significantly in the bardoxolone methyl group, as compared with the placebo group. CONCLUSIONS: Among patients with type 2 diabetes mellitus and stage 4 chronic kidney disease, bardoxolone methyl did not reduce the risk of ESRD or death from cardiovascular causes. A higher rate of cardiovascular events with bardoxolone methyl than with placebo prompted termination of the trial. (Funded by Reata Pharmaceuticals; BEACON ClinicalTrials.gov number, NCT01351675.).

Urine Albumin-Creatinine Ratio Versus Albumin Excretion for Albuminuria Staging: A Prospective Longitudinal Cohort Study.

BACKGROUND: New guidelines advocate the use of albumin-creatinine ratio (ACR) in a urine sample instead of 24-hour urinary albumin excretion (UAE) for staging albuminuria. Concern has been expressed that this may result in misclassification for reasons including interindividual differences in urinary creatinine excretion. STUDY DESIGN: Prospective longitudinal cohort study. SETTING & PARTICIPANTS: We examined 7,623 participants of the PREVEND and RENAAL studies for reclassified when using ACR instead of 24-hour UAE, the characteristics of reclassified participants, and their outcomes. Albuminuria was categorized into 3 ACR and UAE categories: <30, 30 to 300, and >300mg/g or mg/24 h, respectively. PREDICTORS: Baseline ACR and 24-hour UAE. OUTCOMES: Cardiovascular (CV) morbidity and mortality and all-cause mortality. RESULTS: When using ACR in the early morning void instead of 24-hour UAE, 88% of participants were classified in corresponding albuminuria categories. 307 (4.0%) participants were reclassified to a higher, and 603 (7.9%), to a lower category. Participants who were reclassified to a higher ACR category in general had a worse CV risk profile compared with nonreclassified participants, whereas the reverse was true for participants reclassified to a lower ACR category. Similarly, Cox proportional hazards regression analyses showed that reclassification to a higher ACR category was associated with a tendency for increased risk for CV morbidity and mortality and all-cause mortality, whereas reclassification to a lower ACR category was associated with a tendency for lower risk. Net reclassification improvement, adjusted for age, sex, and duration of follow-up, was 0.107 (P=0.002) for CV events and 0.089 (P<0.001) for all-cause mortality. LIMITATIONS: Early morning void urine collection instead of spot urine collection. CONCLUSIONS: Our results indicate that there is high agreement between early morning void ACR and 24-hour UAE categories. Reclassification is therefore limited, but when present, is generally indicative of the presence of CV risk factors and prognosis.

High urinary sulfate concentration is associated with reduced risk of renal disease progression in type 2 diabetes.

Diabetes is associated with a high incidence of microvascular disease, including nephropathy. Diabetic nephropathy is the most common cause of chronic kidney disease in the Western world. Sulfate in the urine is the metabolic end product of hydrogen sulfide (H2S), a recent discovered gaseous signaling molecule. Urinary sulfate has earlier shown beneficial predictive properties in renal transplant recipients. Based on the protective role of exogenous H2S in experimental models of diabetic nephropathy, we aimed to cross-sectionally investigate the association of sulfate with renal risk markers, and to prospectively investigate its predictive value for renal events in patients with diabetic nephropathy. Post-hoc analysis on data of the sulodexide macroalbuminuria (Sun-MACRO) trial and the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study was performed. A total of 1004 patients with type 2 diabetes were included. Urinary sulfate concentration was measured and cross-sectionally associated to renal risk markers by linear regression. Multivariable Cox regression analysis was performed to assess the prospective association of sulfate with renal events, which was defined as end stage renal disease or a doubling of baseline serum creatinine. Mean age was 63 ± 9 years, median sulfate concentration was 8.0 (IQR 5.8-11.4) mmol/L. Urinary sulfate positively associated with male gender, hemoglobin, and negatively associated with albuminuria at baseline. During follow-up for 12 (IQR 6-18) months, 38 renal events occurred. Each doubling of urinary sulfate was associated with a 19% (95%CI 1%-34%) lower risk of renal events, independent of adjustment for potential confounders, including age, estimated glomerular filtration rate (eGFR), and albuminuria. To conclude, higher urinary sulfate concentration is associated with a more beneficial profile of renal risk markers, and is independently associated with a reduced risk for renal events in type 2 diabetes patients with nephropathy.

Vitamin D receptor activator and dietary sodium restriction to reduce residual urinary albumin excretion in chronic kidney disease (ViRTUE study): rationale and study protocol.

UNLABELLED: Optimal albuminuria reduction is considered essential to halting chronic kidney disease (CKD) progression. Both vitamin D receptor activator (VDRA) treatment and dietary sodium restriction potentiate the efficacy of renin-angiotensin-aldosterone-system (RAAS) blockade to reduce albuminuria. The ViRTUE study addresses whether a VDRA in combination with dietary sodium restriction provides further albuminuria reduction in non-diabetic CKD patients on top of RAAS blockade. The ViRTUE study is an investigator-initiated, prospective, multi-centre, randomized, double-blind (paricalcitol versus placebo), placebo-controlled trial targeting stage 1-3 CKD patients with residual albuminuria of >300 mg/day due to non-diabetic glomerular disease, despite angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use. During run-in, all subjects switched to standardized RAAS blockade (ramipril 10 mg/day) and blood pressure titrated to <140/90 mmHg according to a standardized protocol. Eligible patients are subsequently enrolled and undergo four consecutive study periods in random order of 8 weeks each: (i) paricalcitol (2 µg/day) combined with a liberal sodium diet (∼200 mmol Na(+)/day, i.e. mean sodium intake in the general population), (ii) paricalcitol (2 µg/day) combined with dietary sodium restriction (target: 50 mmol Na(+)/day), (iii) placebo combined with a liberal sodium diet and (iv) placebo combined with dietary sodium restriction. Data are collected at the end of each study period. The primary outcome is 24-h urinary albumin excretion. Secondary study outcomes are blood pressure, renal function (estimated glomerular filtration rate), plasma renin activity and, in a sub-population (N = 9), renal haemodynamics (measured glomerular filtration rate and effective renal plasma flow). A sample size of 50 patients provides 90% power to detect a 23% reduction in albuminuria, assuming a 25% dropout rate. Further reduction of residual albuminuria by combination of VDRA treatment and sodium restriction during single-agent RAAS-blockade will justify long-term studies on cardiorenal outcomes and safety. CLINICAL TRIAL REGISTRATION: NTR2898 (Dutch trial register).

Assessing the Validity of Surrogate Outcomes for ESRD: A Meta-Analysis.

Validation of current and promising surrogate outcomes for ESRD in randomized controlled trials (RCTs) has been limited. We conducted a systematic review and meta-analysis of RCTs to further inform the ability of surrogate outcomes for ESRD to predict the efficacy of various interventions on ESRD. MEDLINE, EMBASE, and CENTRAL (from inception through September 2013) were searched. All RCTs in adults with proteinuria, diabetes, or CKD stages 1-4 or renal transplant recipients reporting ≥10 ESRD events and a surrogate outcome (change in proteinuria or doubling of serum creatinine [DSCR]) for ESRD during a ≥1-year follow-up were included. Two reviewers abstracted trial characteristics and outcome data independently. To assess the correlation between the surrogate outcomes and ESRD, we determined the treatment effect ratio (TER), defined as the ratio of the treatment effects on ESRD and the effects on the change in surrogate outcomes. TERs close to 1 indicate greater agreement between ESRD and the surrogate, and these ratios were pooled across interventions. We identified 27 trials (97,458 participants; 4187 participants with ESRD). Seven trials reported the effects on change in proteinuria and showed consistent effects for proteinuria and ESRD (TER, 0.82; 95% confidence interval, 0.59 to 1.16), with minimal heterogeneity. Twenty trials reported on DSCR. Treatment effects on DSCR were consistent with the effects on ESRD (TER, 0.98; 95% confidence interval, 0.85 to 1.14), with moderate heterogeneity. In conclusion, DSCR is generally a good surrogate for ESRD, whereas data on proteinuria were limited. Further assessment of the surrogacy of proteinuria using prospective RCTs is warranted.

Sodium excretion and risk of developing coronary heart disease.

BACKGROUND: Despite compelling evidence for sodium's adverse effects on blood pressure, it remains uncertain whether excess sodium intake is a risk factor for coronary heart disease (CHD) in the overall population and in potentially more susceptible subgroups. METHODS AND RESULTS: We prospectively followed 7543 adults aged 28 to 75 years and free of cardiovascular and kidney disease in 1997/1998 of the Prevention of Renal and Vascular End-stage Disease (PREVEND) study. Sodium excretion was measured in two 24-hour urine collections at baseline. Potential susceptibility factors were blood pressure and plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP). Median 24-hour sodium excretion was 137 mmol (Q1-Q3, 106-171 mmol). During a median follow-up of 10.5 (Q1-Q3: 9.9-10.8) years, 452 CHD events occurred. In the entire cohort, there was no association between each 1-g/d (43 mmol/24 h) increment in sodium excretion and CHD risk (adjusted hazard ratio, 1.07; 95% confidence interval, 0.98-1.18; P=0.15). However, the association of sodium excretion with CHD risk tended to be modified by mean arterial pressure (Pinteraction=0.08) and was modified by NT-proBNP (Pinteraction=0.002). When stratified, each 1-g/d increment in sodium excretion was associated with an increased risk for CHD in subjects with hypertension (adjusted hazard ratio, 1.14; 95% confidence interval, 1.01-1.28; n=2363) and in subjects with NT-proBNP concentrations above the sex-specific median (adjusted hazard ratio, 1.16; 95% confidence interval, 1.03-1.30; n=3771). CONCLUSIONS: Overall, there was no association between sodium excretion and risk of CHD. The association between sodium excretion and CHD risk was modified by NT-proBNP. Higher sodium excretion was associated with an increased CHD risk among subjects with increased NT-proBNP concentrations or with hypertension.

Surrogate endpoints in clinical trials of chronic kidney disease progression: moving from single to multiple risk marker response scores.

PURPOSE OF REVIEW: There is increased interest in developing surrogate endpoints for clinical trials of chronic kidney disease progression, as the established clinically meaningful endpoint end-stage renal disease requires large and lengthy trials to assess drug efficacy. We describe recent developments in the search for novel surrogate endpoints. RECENT FINDINGS: Declines in estimated glomerular filtration rate (eGFR) of 30% or 40% and albuminuria have been proposed as surrogates for end-stage renal disease. However, changes in eGFR or albuminuria may not be valid under all circumstances as drugs always have effects on multiple renal risk markers. Changes in each of these other 'off-target' risk markers can alter renal risk (either beneficially or adversely), and can thereby confound the relationship between surrogates that are based on single risk markers and renal outcome. Risk algorithms that integrate the short-term drug effects on multiple risk markers to predict drug effects on hard renal outcomes may therefore be more accurate. The validity of these risk algorithms is currently investigated. SUMMARY: Given that drugs affect multiple renal risk markers, risk scores that integrate these effects are a promising alternative to using eGFR decline or albuminuria. Proper validation is required before these risk scores can be implemented.

Fibroblast growth factor 23 and the antiproteinuric response to dietary sodium restriction during renin-angiotensin-aldosterone system blockade.

BACKGROUND: Residual proteinuria during renin-angiotensin-aldosterone system (RAAS) blockade is a major renal and cardiovascular risk factor in chronic kidney disease. Dietary sodium restriction potentiates the antiproteinuric effect of RAAS blockade, but residual proteinuria remains in many patients. Previous studies linked high fibroblast growth factor 23 (FGF-23) levels with volume overload; others linked higher serum phosphate levels with impaired RAAS-blockade efficacy. We hypothesized that FGF-23 reduces the capacity of dietary sodium restriction to potentiate RAAS blockade, impairing the antiproteinuric effect. STUDY DESIGN: Post hoc analysis of cohort data from a randomized crossover trial with two 6-week study periods comparing proteinuria after a regular-sodium diet with proteinuria after a low-sodium diet, both during background angiotensin-converting enzyme inhibition. SETTING & PARTICIPANTS: 47 nondiabetic patients with CKD with residual proteinuria (median protein excretion, 1.9 [IQR, 0.8-3.1] g/d; mean age, 50±13 [SD] years; creatinine clearance, 69 [IQR, 50-110] mL/min). PREDICTOR: Plasma carboxy-terminal FGF-23 levels. OUTCOMES: Difference in residual proteinuria at the end of the regular-sodium versus low-sodium study period. Residual proteinuria during the low-sodium diet period adjusted for proteinuria during the regular-sodium diet period. RESULTS: Higher baseline FGF-23 level was associated with reduced antiproteinuric response to dietary sodium restriction (standardized ß=-0.46; P=0.001; model R(2)=0.71). For every 100-RU/mL increase in FGF-23 level, the antiproteinuric response to dietary sodium restriction was reduced by 10.6%. Higher baseline FGF-23 level was a determinant of more residual proteinuria during the low-sodium diet (standardized ß=0.27; P=0.003) in linear regression analysis adjusted for baseline proteinuria (model R(2)=0.71). There was no interaction with creatinine clearance (P interaction=0.5). Baseline FGF-23 level did not predict changes in systolic or diastolic blood pressure upon intensified antiproteinuric treatment. LIMITATIONS: Observational study, limited sample size. CONCLUSIONS: FGF-23 levels are associated independently with impaired antiproteinuric response to sodium restriction in addition to RAAS blockade. Future studies should address whether FGF-23-lowering strategies may further optimize proteinuria reduction by RAAS blockade combined with dietary sodium restriction.

Serum Bicarbonate and Kidney Disease Progression and Cardiovascular Outcome in Patients With Diabetic Nephropathy: A Post Hoc Analysis of the RENAAL (Reduction of End Points in Non-Insulin-Dependent Diabetes With the Angiotensin II Antagonist Losartan) Study and IDNT (Irbesartan Diabetic Nephropathy Trial).

BACKGROUND: Low serum bicarbonate level has been reported to be an independent predictor of kidney function decline and mortality in patients with chronic kidney disease. Mechanisms underlying low serum bicarbonate levels may differ in patients with and without diabetes. We aimed to specifically investigate the association of serum bicarbonate level with kidney disease progression and cardiovascular outcome in a cohort of patients with type 2 diabetes and nephropathy. STUDY DESIGN: Post hoc analysis of 2 multicenter randomized controlled trials. SETTING & PARTICIPANTS: 2,628 adults with type 2 diabetes and nephropathy. FACTOR: Serum bicarbonate level. OUTCOMES: Incidence of: (1) end-stage renal disease (ESRD), (2) ESRD or doubling of serum creatinine level, (3) all-cause mortality, (4) cardiovascular events (fatal/nonfatal stroke/myocardial infarction), and (5) heart failure. MEASUREMENTS: Serum bicarbonate was measured at baseline as total carbon dioxide. Associations of baseline serum bicarbonate level with end points were investigated using Cox regression models. Serum bicarbonate levels were studied as a continuous variable and stratified in quartiles. Follow-up was 2.8±1.0 (SD) years. RESULTS: Cox regression analyses showed that serum bicarbonate level had inverse associations with incident ESRD (HR, 0.91; 95% CI, 0.89-0.93; P<0.001) and incidence of the combined end point of ESRD or serum creatinine doubling (HR, 0.94; 95% CI, 0.92-0.96; P<0.001). These associations were independent of age, sex, and cardiovascular risk factors, but disappeared after adjustment for baseline estimated glomerular filtration rate (all P>0.05). Analysis of bicarbonate quartiles showed similar results for the quartile with the lowest bicarbonate (≤21 mEq/L) versus the quartile with normal bicarbonate levels (24-26 mEq/L). There was no association of bicarbonate level with cardiovascular events and heart failure. LIMITATIONS: Post hoc analysis and single measurement of serum bicarbonate. CONCLUSIONS: In this cohort of patients with type 2 diabetes with nephropathy, serum bicarbonate level associations with kidney disease end points were not retained after adjustment for estimated glomerular filtration rate, which is in contrast to results of earlier studies in nondiabetic populations.

Drugs meeting the molecular basis of diabetic kidney disease: bridging from molecular mechanism to personalized medicine.

Diabetic kidney disease (DKD) is a complex, multifactorial disease and is associated with a high risk of renal and cardiovascular morbidity and mortality. Clinical practice guidelines for diabetes recommend essentially identical treatments for all patients without taking into account how the individual responds to the instituted therapy. Yet, individuals vary widely in how they respond to medications and therefore optimal therapy differs between individuals. Understanding the underlying molecular mechanisms of variability in drug response will help tailor optimal therapy. Polymorphisms in genes related to drug pharmacokinetics have been used to explore mechanisms of response variability in DKD, but with limited success. The complex interaction between genetic make-up and environmental factors on the abundance of proteins and metabolites renders pharmacogenomics alone insufficient to fully capture response variability. A complementary approach is to attribute drug response variability to individual variability in underlying molecular mechanisms involved in the progression of disease. The interplay of different processes (e.g. inflammation, fibrosis, angiogenesis, oxidative stress) appears to drive disease progression, but the individual contribution of each process varies. Drugs at the other hand address specific targets and thereby interfere in certain disease-associated processes. At this level, biomarkers may help to gain insight into which specific pathophysiological processes are involved in an individual followed by a rational assessment whether a specific drug's mode of action indeed targets the relevant process at hand. This article describes the conceptual background and data-driven workflow developed by the SysKid consortium aimed at improving characterization of the molecular mechanisms underlying DKD at the interference of the molecular impact of individual drugs in order to tailor optimal therapy to individual patients.

Will the future lie in multitude? A critical appraisal of biomarker panel studies on prediction of diabetic kidney disease progression.

Diabetic kidney disease is diagnosed and staged by albuminuria and estimated glomerular filtration rate. Although albuminuria has strong predictive power for renal function decline, there is still variability in the rate of renal disease progression across individuals that are not fully captured by the level of albuminuria. Therefore, research focuses on discovering and validating additional biomarkers that improve risk stratification for future renal function decline and end-stage renal disease in patients with diabetes, on top of established biomarkers. Most studies address the value of single biomarkers to predict progressive renal disease and aim to understand the mechanisms that underlie accelerated renal function decline. Since diabetic kidney disease is a disease encompassing several pathophysiological processes, a combination of biomarkers may be more likely to improve risk prediction than a single biomarker. In this review, we provide an overview of studies on the use of multiple biomarkers and biomarker panels, appraise their study design, discuss methodological pitfalls and make recommendations for future biomarker panel studies.

Prognostic clinical and molecular biomarkers of renal disease in type 2 diabetes.

Diabetic kidney disease occurs in ∼ 25-40% of patients with type 2 diabetes. Given the high risk of progressive renal function loss and end-stage renal disease, early identification of patients with a renal risk is important. Novel biomarkers may aid in improving renal risk stratification. In this review, we first focus on the classical panel of albuminuria and estimated glomerular filtration rate as the primary clinical predictors of renal disease and then move our attention to novel biomarkers, primarily concentrating on assay-based multiple/panel biomarkers, proteomics biomarkers and metabolomics biomarkers. We focus on multiple biomarker panels since the molecular processes of renal disease progression in type 2 diabetes are heterogeneous, rendering it unlikely that a single biomarker significantly adds to clinical risk prediction. A limited number of prospective studies of multiple biomarkers address the predictive performance of novel biomarker panels in addition to the classical panel in type 2 diabetes. However, the prospective studies conducted so far have small sample sizes, are insufficiently powered and lack external validation. Adequately sized validation studies of multiple biomarker panels are thus required. There is also a paucity of studies that assess the effect of treatments on novel biomarker panels and determine whether initial treatment-induced changes in novel biomarkers predict changes in long-term renal outcomes. Such studies can not only improve our healthcare but also our understanding of the mechanisms of actions of existing and novel drugs and may yield biomarkers that can be used to monitor drug response. We conclude that this will be an area to focus research on in the future.

The blood pressure lowering potential of sulodexide--a systematic review and meta-analysis.

AIMS: Sulodexide is a highly purified mixture of glycosaminoglycans that has been studied for its anti-albuminuric potential. Considering the effects of glycosaminoglycans on endothelial function and sodium homeostasis, we hypothesized that sulodexide may lower blood pressure (BP). In this meta-analysis, we therefore investigated the antihypertensive effects of sulodexide treatment. METHODS: We selected randomized controlled trials that investigated sulodexide treatment of at least 4 weeks and measured BP at baseline and after treatment. Two reviewers independently extracted data on study design, risk of bias, population characteristics and outcome measures. In addition, we contacted authors and pharmaceutical companies to provide missing data. RESULTS: Eight studies, totalling 3019 subjects (mean follow-up 4.4 months) were included. Mean age was 61 years and mean baseline BP was 135/75 mmHg. Compared with control treatment, sulodexide resulted in a significant systolic (2.2 mmHg [95% CI 0.3, 4.1], P = 0.02) and diastolic BP reduction (1.7 mmHg [95% CI 0.6, 2.9], P = 0.004). Hypertensive patients displayed the largest systolic BP and diastolic BP reductions (10.2/5.4 mmHg, P < 0.001). Higher baseline systolic and diastolic BP were significantly associated with larger systolic (r(2)=0.83, P < 0.001) and diastolic BP (r(2)=0.41, P = 0.02) reductions after sulodexide treatment. In addition, systolic (r(2)=0.41, P = 0.03) and diastolic BP reductions (r(2)=0.60, P = 0.005) were significantly associated with albuminuria reduction. CONCLUSION: Our data suggest that sulodexide treatment results in a significant BP reduction, especially in hypertensive subjects. This indicates that endothelial glycosaminoglycans might be an independent therapy target in cardiovascular disease. Future studies should further address the BP lowering potential of sulodexide.

The endothelin antagonist atrasentan lowers residual albuminuria in patients with type 2 diabetic nephropathy.

Despite optimal treatment, including renin-angiotensin system (RAS) inhibitors, patients with type 2 diabetic nephropathy have high cardiorenal morbidity and mortality related to residual albuminuria. We evaluated whether or not atrasentan, a selective endothelin A receptor antagonist, further reduces albuminuria when administered concomitantly with maximum tolerated labeled doses of RAS inhibitors. We enrolled 211 patients with type 2 diabetes, urine albumin/creatinine ratios of 300-3500 mg/g, and eGFRs of 30-75 ml/min per 1.73 m(2) in two identically designed, parallel, multinational, double-blind studies. Participants were randomized to placebo (n=50) or to 0.75 mg/d (n=78) or 1.25 mg/d (n=83) atrasentan for 12 weeks. Compared with placebo, 0.75 mg and 1.25 mg atrasentan reduced urine albumin/creatinine ratios by an average of 35% and 38% (95% confidence intervals of 24 to 45 and 28 to 47, respectively) and reduced albuminuria≥30% in 51% and 55% of participants, respectively. eGFR and office BP measurements did not change, whereas 24-hour systolic and diastolic BP, LDL cholesterol, and triglyceride levels decreased significantly in both treatment groups. Use of atrasentan was associated with a significant increase in weight and a reduction in hemoglobin, but rates of peripheral edema, heart failure, or other side effects did not differ between groups. However, more patients treated with 1.25 mg/d atrasentan discontinued due to adverse events. After stopping atrasentan for 30 days, measured parameters returned to pretreatment levels. In conclusion, atrasentan reduced albuminuria and improved BP and lipid spectrum with manageable fluid overload-related adverse events in patients with type 2 diabetic nephropathy receiving RAS inhibitors.

Microalbuminuria: target for renoprotective therapy PRO.

Drug efficacy is ascertained using clinically meaningful outcomes that directly affect the well-being of patients. However, in studies of chronic kidney disease progression, clinically meaningful outcomes like end-stage renal disease take a long time to occur. The use of surrogate end points/markers as replacement for clinical outcomes is tempting as it may reduce sample size requirements, shorten follow-up time, facilitate trial conduct, and allow the performance of intervention trials in earlier stages of kidney disease to be carried out. We here reviewed recent data supporting the use of microalbuminuria as a valid surrogate end point in clinical trials of chronic kidney disease. We provide data that albuminuria is associated with worse renal prognosis and that pharmacological treatment aimed to reduce albuminuria levels delays the progression of renal disease and the occurrence of clinical outcomes. Furthermore, we review new studies showing that albumin is not only an inert molecule but also directly affects the function of several cell types in the kidney and may have a pathogenic role in renal disease. Accepting microalbuminuria as a surrogate marker for renal outcomes will lead to less resource-consuming hard outcome trials, will accelerate the development of drugs for chronic kidney disease, and enable earlier access of these drugs to individual patients.

Estimated albumin excretion rate versus urine albumin-creatinine ratio for the assessment of albuminuria: a diagnostic test study from the Prevention of Renal and Vascular Endstage Disease (PREVEND) Study.

BACKGROUND: Albumin-creatinine ratio (ACR) in spot urine samples is recommended for albuminuria screening instead of measured albumin excretion rate (mAER) in 24-hour urine collections. In patients with extremes of muscle mass, differences in spot urine creatinine values may lead to under- or overestimation of mAER by ACR. We hypothesized that calculating estimated AER (eAER) using spot ACR and estimated creatinine excretion rate (eCER) may improve albuminuria assessment. STUDY DESIGN: Diagnostic test study. SETTING & PARTICIPANTS: 2,711 community-living individuals from the general population of the Netherlands participating in the PREVEND (Prevention of Renal and Vascular Endstage Disease) Study. INDEX TEST: eAER was computed as the product of ACR and eCER. eCER was computed using 3 previously validated methods (Ix, Ellam, and Walser). REFERENCE TEST: mAER, based on two 24-hour urine collections. Accuracy of the eAER and ACR were defined as the percentage of participants falling within 30% (P30) of mAER. RESULTS: Mean age was 49 years, 46% were men, mean estimated glomerular filtration rate was 84 ± 15 mL/min/1.73 m(2), and median mAER was 7.2 (IQR, 5.4-11.0) mg/d. Mean measured CER was 1,381 mg/d, and median ACR was 4.9 mg/g. Using the Ix equation, median eAER was 6.4 mg/d. In the full cohort, eAER was more accurate and less biased compared to ACR (P30, 48.9% vs 33.6%; bias, -34.2% vs -14.1%, respectively). In subgroup analysis, improvement was most notable in the middle and highest weight tertiles and in men. Using the other methods for eCER produced similar results. LIMITATIONS: Little ethnic heterogeneity and a generally healthy cohort make extension of findings to other races and the chronically ill uncertain. CONCLUSIONS: In a large community-dwelling cohort, eAER was more accurate than ACR in assessing albuminuria.