Renal Risk Markers Research Articles

856-P: Cardiovascular (CV) and Kidney Outcomes with Canagliflozin (CANA) According to Type 2 Diabetes (T2D) Treatment Targets at Baseline (BL) : Data from the CANVAS Program and CREDENCE

In T2D, treatment targets include maintaining HbA1c ≤7.0%, LDL-C <2 mmol/L (<77 mg/dL) , and BP <130/80 mmHg. It is also recommended to improve urinary albumin:creatinine ratio (UACR) , a marker of renal damage and CV risk. We examined effects of CANA vs. placebo on CV and kidney outcomes in patients with T2D and high CV risk and/or chronic kidney disease according to BL treatment targets and risk factors. Pooled data from the CANVAS Program (N=10,142) and the CREDENCE trial (N=4401) were analyzed according to treatment target achievement and by number of targets achieved at BL. Hazard ratios and 95% CIs were estimated using Cox regression models. Of 14,432 participants at BL, 3683 (26%) had achieved 0, 5851 (41%) had achieved 1, 3680 (25%) had achieved 2, and 1218 (8%) had achieved either 3 or 4 targets. At BL, 8415 (58%) participants had UACR >2 mg/mmol. CANA consistently reduced risk of MACE, HHF/CV death, and ESKD or doubling of serum creatinine vs. placebo, regardless of whether BL targets were met or if UACR was elevated (Figure) . The number of uncontrolled targets at BL did not impact the beneficial effect of CANA on CV and kidney outcomes (all P interaction >0.17) . In conclusion, CANA demonstrated consistent CV and renal benefits in patients with T2D, regardless of risk factor control. Disclosure V.C.Woo: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly, Novo Nordisk, Speaker's Bureau; Janssen Pharmaceuticals, Inc. M.Tsoukas: Speaker's Bureau; AstraZeneca, Bausch Health, Canada, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Johnson & Johnson, Novo Nordisk Canada Inc. S.Tobe: Other Relationship; Bayer AG, Speaker's Bureau; AstraZeneca, Otsuka Pharmaceutical Co., Ltd. A.Slee: Consultant; Alydia Health, Elixir Medical , IHP Therapeutics , iLumen Scientific, Intuitive Surgical, Janssen Global Services, LLC, Laborie, Providence Medical, Pulse Biosciences, SonoMotion. W.Rapattoni: Employee; Janssen Pharmaceuticals, Inc. F.Ang: Employee; Bristol-Myers Squibb Company, Janssen Pharmaceuticals, Inc. J.Seufert: Advisory Panel; Abbott, Sanofi-Aventis Deutschland GmbH, Research Support; Boehringer Ingelheim International GmbH, Speaker's Bureau; Abbott Diabetes, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Lilly, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. D.C.Wheeler: Advisory Panel; Bayer AG, Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., GlaxoSmithKline plc., Janssen Global Services, LLC, Merck Sharp & Dohme Corp., Mundipharma, Tricida, Inc., Vifor Pharma Management Ltd., Consultant; AstraZeneca, Speaker's Bureau; Amgen Inc., Astellas Pharma Inc. Funding Janssen Inc., Toronto, ON, Canada

MO208ASSOCIATION OF SERUM BETA-2 MICROGLOBULIN LEVEL WITH DIFFERENT CARDIAC AND METABOLIC RISK FACTORS IN CKD PATIENTS

Abstract Background and Aims Serum β M is a middle molecule uremic toxin that accumulates in serum and deposits at various tissues in chronic kidney disease (CKD), especially more in dialysis patients. The βâ M is generally considered as a predictor of cardiovascular morbidity and mortality and this is more investigated in dialysis group. However its relationship with several cardiac and metabolic risk factors in all stages of CKD is still under evaluation. This study was undertaken to evaluate the association of plasma βâ M level in different stages of chronic kidney disease patients with different cardiac, renal and metabolic risk factors that can predict future cardiovascular events Method This cross-sectional study was conducted by selecting consecutive 132 CKD subjects of stages 1-5D including both patients not requiring dialysis and those on maintenance hemodialysis. Their demographic, clinical and laboratory data were recorded in a data sheet. Fasting blood samples in dialysis non requiring subjects and predialysis samples in hemodialysis group (G5D) were taken for testin in laboratory for CBC, serum βâ M, hCRP, iPTH, lipid profile, creatinine, uric acid and serum albumin as cardiac, renal and metabolic risk markers. Urine sample was taken from predialysis patients for chemical test and ACR. The CKD staging were done by MDRD criteria. Additional 25 no CKD subject was taken as healthy referents. Results Primarily Beta-2 microglobulin was higher in CKD patients than in healthy group (13.53 ± 14.74 vs. 1.81 ± 0.47, mg/l; p<.001). The levels were gradually rising with the advancing stages of CKD (G1&2-3.46 ± 2.39, G3-3.66 ± 1.08, G4-6.51 ± 2.20, G5-11.43 ± 2.98 and G5D-41.79 ± 8.58, mg/l). A Beta-2 microglobulin cut-off of >7.7 vs. < 7.7 mg/l showed significantly increased Systolic BP (136 ±22 vs. 123 ± 22, mmHg), diastolic BP (80 ± 12 vs. 75 ± 8.96, mmHg),( p<0.01); CRP (6.83 ± 6.03 vs. 4.39 ± 5.35, mg/l)( p<0.007); serum phosphate (4.84 ± 1.79 vs. 3.85 ±.92,mg/dl)( p<0.001); uric acid (5.89 ± 1.41 vs. 5.01 ± 1.57,mg/dl)( p<0.01); TG (189± 103 vs. 155 ± 88, mg/dl),( p<0.04); and PTH (239.83 ± 186.50 vs. 90.52 ± 81.77, pg/ml), ( p<0.001) indicating higher cardio metabolic risks in higher group. Similarly renal parameters were also more altered in high Beta-2 microalbumin group for serum creatinine (6.89 ± 3.54 vs. 1.58 ± .81, mg/dl) (p<0.001) and ACR (824 ± 917 vs. 320 ± 753, mg/g),( p<0.001). B-2 microglobulin also positively correlated with systolic blood pressure (r=.295, p<.001), serum creatinine (r=.879, p<.001), serum phosphate (r=.175, p =.047), serum iPTH (r=.403, p<.001) , hCRP ( r=.193, p =.050) , Triglycerides (r=.196, p =.023) and urine ACR in CKD patients. Conclusion Beta-2 microglobulin level was significantly higher in CKD with an increasing pattern towards advancing stages. The higher levels positively correlated with cardio renal and metabolic risk factors. Hence measuring Beta-2 microglobulin regularly can help to take preventive measures early to manage patients at risk.

Exposure-response relationships for the sodium-glucose co-transporter-2 inhibitor dapagliflozin with regard to renal risk markers.

AimsTo quantitate the consistency of an individual's plasma exposure to dapagliflozin upon re‐exposure, and to investigate whether the individual's systemic exposure to dapagliflozin explains inter‐individual variation in response to dapagliflozin with regard to multiple renal risk markers.MethodsData were used from a crossover randomized clinical trial that assessed the albuminuria‐lowering effect of dapagliflozin in 33 people with type 2 diabetes and elevated albuminuria. Fifteen participants were exposed twice to dapagliflozin. Trough plasma concentrations of dapagliflozin were measured for each participant at steady state. Dapagliflozin plasma concentrations were measured by liquid chromatography tandem mass spectrometry, and pharmacokinetic characteristics were simulated based on a population pharmacokinetic model. Linear mixed‐effects models were used to quantify the exposure–response relationships.ResultsThe median plasma concentration after first and second exposure to dapagliflozin was 5.3 ng/mL vs 4.6 ng/mL, respectively (P = 0.78). Lin's concordance correlation coefficient between occasions was 0.73 (P < 0.0021). Every 100 ng.h/mL increment in area under the dapagliflozin plasma concentration curve was associated with a decrease in log‐transformed urinary albumin:creatinine ratio (β = −5.9, P < 0.01), body weight (β = −0.3, P < 0.01) and estimated glomerular filtration rate (β = −0.7, P = 0.01) and an increase in urinary glucose excretion (β = 17.0, P < 0.001).ConclusionAn individual's exposure to dapagliflozin is consistent upon re‐exposure and correlates with pharmacodynamic response in renal risk markers.

Baseline characteristics and enrichment results from the SONAR trial.

AimThe SONAR trial uses an enrichment design based on the individual response to the selective endothelin receptor antagonist atrasentan on efficacy (the degree of the individual response in the urinary albumin‐to‐creatinine ratio [UACR]) and safety/tolerability (signs of sodium retention and acute increases in serum creatinine) to assess the effects of this agent on major renal outcomes. The patient population and enrichment results are described here.MethodsPatients with type 2 diabetes with an estimated glomerular filtration rate (eGFR) within 25 to 75 mL/min/1.73 m2 and UACR between 300 and 5000 mg/g were enrolled. After a run‐in period, eligible patients received 0.75 mg/d of atrasentan for 6 weeks. A total of 2648 responder patients in whom UACR decreased by ≥30% compared to baseline were enrolled, as were 1020 non‐responders with a UACR decrease of <30%. Patients who experienced a weight gain of >3 kg and in whom brain natriuretic peptide exceeded ≥300 pg/mL, or who experienced an increase in serum creatinine >20% (0.5 mg/dL), were not randomized.ResultsBaseline characteristics were similar for atrasentan responders and non‐responders. Upon entry to the study, median UACR was 802 mg/g in responders and 920 mg/g in non‐responders. After 6 weeks of treatment with atrasentan, the UACR change in responders was −48.8% (95% CI, −49.8% to −47.9%) and in non‐responders was −1.2% (95% CI, −6.4% to 3.9%). Changes in other renal risk markers were similar between responders and non‐responders except for a marginally greater reduction in systolic blood pressure and eGFR in responders.ConclusionsThe enrichment period has successfully identified a population with a profound UACR reduction without clinical signs of sodium retention in whom a large atrasentan effect on clinically important renal outcomes is possible. The SONAR trial aims to establish whether atrasentan confers renal protection.

Effects of an energy-restricted low-carbohydrate, high unsaturated fat/low saturated fat diet versus a high-carbohydrate, low-fat diet in type 2 diabetes: A 2-year randomized clinical trial.

To examine whether a low-carbohydrate, high-unsaturated/low-saturated fat diet (LC) improves glycaemic control and cardiovascular disease (CVD) risk factors in overweight and obese patients with type 2 diabetes (T2D). A total of 115 adults with T2D (mean [SD]; BMI, 34.6 [4.3] kg/m2 ; age, 58 [7] years; HbA1c, 7.3 [1.1]%) were randomized to 1 of 2 planned energy-matched, hypocaloric diets combined with aerobic/resistance exercise (1 hour, 3 days/week) for 2 years: LC: 14% energy as carbohydrate, 28% as protein, 58% as fat (<10% saturated fat); or low-fat, high-carbohydrate, low-glycaemic index diet (HC): 53% as CHO, 17% as protein, 30% as fat (<10% saturated fat). HbA1c, glycaemic variability (GV), anti-glycaemic medication effect score (MES, calculated based on the potency and dosage of diabetes medication), weight, body composition, CVD and renal risk markers were assessed before and after intervention. A total of 61 (LC = 33, HC = 28) participants completed the study (trial registration: http://www.anzctr.org.au/, ANZCTR No. ACTRN12612000369820). Reductions in weight (estimated marginal mean [95% CI]; LC, -6.8 [-8.8,-4.7], HC, -6.6 [-8.8, -4.5] kg), body fat (LC, -4.3 [-6.2, -2.4], HC, -4.6 [-6.6, -2.7] kg), blood pressure (LC, -2.0 [-5.9, 1.8]/ -1.2 [-3.6, 1.2], HC, -3.2 [-7.3, 0.9]/ -2.0 [-4.5, 0.5] mmHg), HbA1c (LC, -0.6 [-0.9, -0.3], HC, -0.9 [-1.2, -0.5] %) and fasting glucose (LC, 0.3 [-0.4, 1.0], HC, -0.4 [-1.1, 0.4] mmol/L) were similar between groups (P ≥ 0.09). Compared to HC, the LC achieved greater reductions in diabetes medication use (MES; LC, -0.5 [-0.6, -0.3], HC, -0.2 [-0.4, -0.02] units; P = 0.03), GV (Continuous Overall Net Glycemic Action calculated every 1 hour (LC, -0.4 [-0.6, -0.3], HC, -0.1 [-0.1, 0.2] mmol/L; P = 0.001), and 4 hours (LC, -0.9 [-1.3, -0.6], HC, -0.2 [-0.6, 0.1] mmol/L; P = 0.02)); triglycerides (LC, -0.1 [-0.3, 0.2], HC, 0.1 [-0.2, 0.3] mmol/L; P = 0.001), and maintained HDL-C levels (LC, 0.02 [-0.05, 0.1], HC, -0.1 [-0.1, 0.01] mmol/L; P = 0.004), but had similar changes in LDL-C (LC, 0.2 [-0.1, 0.5], HC, 0.1 [-0.2, 0.4] mmol/L; P = 0.85), brachial artery flow mediated dilatation (LC, -0.5 [-1.5, 0.5], HC, -0.4 [-1.4, 0.7] %; P = 0.73), eGFR and albuminuria. Both diets achieved comparable weight loss and HbA1c reductions. The LC sustained greater reductions in diabetes medication requirements, and in improvements in diurnal blood glucose stability and blood lipid profile, with no adverse renal effects, suggesting greater optimization of T2D management.

Renal outcomes in patients with AL amyloidosis: Prognostic factors, renal response and the impact of therapy.

A staging system for patients with renal AL amyloidosis, based on eGFR (<50 ml/min/1.73 m2 ) and proteinuria (≥5 g/day) at diagnosis, as well as criteria for renal progression (≥25% eGFR reduction) and response (≥30% reduction of proteinuria without renal progression) were recently proposed. We validated these criteria in a cohort of 125 patients with renal AL amyloidosis, mostly treated with bortezomib or lenalidomide. We confirmed the prognostic value of the renal staging system but also identified the limitations of renal progression criteria which are based only on eGFR reduction. We identified the ratio of 24h proteinuria to eGFR as a sensitive marker of renal risk which also accounts for changes in both proteinuria and eGFR: 24h proteinuria/eGFR ratio <30 (in mg/ml/min/1.73 m2 ) was associated with a 2-year progression to dialysis rate of 0% compared to 9% for a ratio of 31-99 and 35% for a ratio ≥100 (P < .001). In landmark analysis, patients who achieved a reduction of this ratio by at least 25% or ≤100 (if initially >100) at 3 months had a 2-year progression to dialysis of 0% vs 24% for patients who either did not reduce to or still had a ratio >100 (P = .001); similar results were obtained by applying the same criteria at 6 months; thus, the evaluation of treatment effect on renal function may be identified early. Furthermore, primary bortezomib-based therapy was more effective than lenalidomide-based therapy, in terms of renal outcomes, especially in patients at intermediate renal risk, but without affecting overall survival.

Hyperuricemia: From the Evolution of Species to Cardiovascular Risk

In this review we analyze the cardiorenal effects of hyperuricemia and try to answer the eternal question of whether it is or is not to be considered a true risk factor in addition to a well-established marker of cardiovascular, cerebrovascular and renal risk.

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.

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

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. 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. 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.

Plasma proteomics classifiers improve risk prediction for renal disease in patients with hypertension or type 2 diabetes.

Micro and macroalbuminuria are strong risk factors for progression of nephropathy in patients with hypertension or type 2 diabetes. Early detection of progression to micro and macroalbuminuria may facilitate prevention and treatment of renal diseases. We aimed to develop plasma proteomics classifiers to predict the development of micro or macroalbuminuria in hypertension or type 2 diabetes. Patients with hypertension (n = 125) and type 2 diabetes (n = 82) were selected for this case-control study from the Prevention of REnal and Vascular ENd-stage Disease cohort and the Steno Diabetes Center. Cases transitioned from normo to microalbuminuria, or from micro to macroalbuminuria. Controls, matched for age, sex, and baseline albuminuria stage, did not transition. Follow-up was 3.0 ± 0.9 years. Plasma proteomics profiles were measured by liquid chromatography-electrospray-trap mass-spectrometry. Classifiers were developed and cross-validated for prediction of transition in albuminuria stage. Improvement in risk prediction was tested on top of a reference model of baseline albuminuria, estimated glomerular filtration rate, and renin-angiotensin-aldosterone system intervention. In hypertensive patients, the classifier improved risk prediction for transition in albuminuria stage on top of the reference model (C-index from 0.69 to 0.78; P < 0.01). In type 2 diabetes, the classifier improved risk prediction for transition from micro to macroalbuminuria (C-index from 0.73 to 0.80; P = 0.04). In both diseases, the identified peptides were linked to pathways recognized to contribute to nephropathy, including fibrosis, inflammation, angiogenesis, and mineral metabolism. Plasma proteomics predict the transition in albuminuria stage beyond established renal risk markers in hypertension or type 2 diabetes. External validation is needed to assess reproducibility.

Urine and plasma metabolites predict the development of diabetic nephropathy in individuals with Type 2 diabetes mellitus

Early detection of individuals with Type 2 diabetes mellitus or hypertension at risk for micro- or macroalbuminuria may facilitate prevention and treatment of renal disease. We aimed to discover plasma and urine metabolites that predict the development of micro- or macroalbuminuria. Patients with Type 2 diabetes (n = 90) and hypertension (n = 150) were selected from the community-cohort 'Prevention of REnal and Vascular End-stage Disease' (PREVEND) and the Steno Diabetes Center for this case-control study. Cases transitioned in albuminuria stage (from normo- to microalbuminuria or micro- to macroalbuminuria). Controls, matched for age, gender, and baseline albuminuria stage, remained in normo- or microalbuminuria stage during follow-up. Median follow-up was 2.9 years. Metabolomics were performed on plasma and urine. The predictive performance of a metabolite for albuminuria transition was assessed by the integrated discrimination index. In patients with Type 2 diabetes with normoalbuminuria, no metabolites discriminated cases from controls. In patients with Type 2 diabetes with microalbuminuria, plasma histidine was lower (fold change = 0.87, P = 0.02) and butenoylcarnitine was higher (fold change = 1.17, P = 0.007) in cases vs. controls. In urine, hexose, glutamine and tyrosine were lower in cases vs. controls (fold change = 0.20, P < 0.001; 0.32, P < 0.001; 0.51, P = 0.006, respectively). Adding the metabolites to a model of baseline albuminuria and estimated glomerular filtration rate metabolites improved risk prediction for macroalbuminuria transition (plasma integrated discrimination index = 0.28, P < 0.001; urine integrated discrimination index = 0.43, P < 0.001). These metabolites did not differ between hypertensive cases and controls without Type 2 diabetes. Type 2 diabetes-specific plasma and urine metabolites were discovered that predict the development of macroalbuminuria beyond established renal risk markers. These results should be confirmed in a large, prospective cohort.

Statin use and the presence of microalbuminuria. Results from the ERICABEL trial: a non-interventional epidemiological cohort study.

BackgroundMicroalbuminuria (MAU) is considered as a predictor or marker of cardiovascular and renal events. Statins are widely prescribed to reduce cardiovascular risk and to slow down progression of kidney disease. But statins may also generate tubular MAU. The current observational study evaluated the impact of statin use on the interpretation of MAU as a predictor or marker of cardiovascular or renal disease.Methodology/Principal FindingsWe used cross-sectional data of ERICABEL, a cohort with 1,076 hypertensive patients. MAU was defined as albuminuria ≥20 mg/l. A propensity score was created to correct for “bias by indication” to receive a statin. As expected, subjects using statins vs. no statins had more cardiovascular risk factors, pointing to bias by indication. Statin users were more likely to have MAU (OR: 2.01, 95%CI: 1.34–3.01). The association between statin use and MAU remained significant after adjusting for the propensity to receive a statin based on cardiovascular risk factors (OR: 1.82, 95%CI: 1.14–2.91). Next to statin use, only diabetes (OR: 1.92, 95%CI: 1.00–3.66) and smoking (OR: 1.49, 95%CI: 0.99–2.26) were associated with MAU.ConclusionsUse of statins is independently associated with MAU, even after adjusting for bias by indication to receive a statin. In the hypothesis that this MAU is of tubular origin, statin use can result in incorrect labeling of subjects as having a predictor or marker of cardiovascular or renal risk. In addition, statin use affected the association of established cardiovascular risk factors with MAU, blurring the interpretation of multivariable analyses.

Knowledge translation for nephrologists: strategies for improving the identification of patients with proteinuria

For health scientists, knowledge translation refers to the process of facilitating uptake of knowledge into clinical practice or decision making. Since high-quality clinical research that is not applied cannot improve outcomes, knowledge translation is critical for realizing the value and potential for all types of health research. Knowledge translation is particularly relevant for areas within health care where gaps in care are known to exist, which is the case for some areas of management for people with chronic kidney disease (CKD), including assessment of proteinuria. Given that proteinuria is a key marker of cardiovascular and renal risk, forthcoming international practice guidelines will recommend including proteinuria within staging systems for CKD. While this revised staging system will facilitate identification of patients at higher risk for progression of CKD and mortality who benefit from intervention, strategies to ensure its appropriate uptake will be particularly important. This article describes key elements of effective knowledge translation strategies based on the knowledge-to-action cycle framework and describes options for effective knowledge translation interventions related to the new CKD guidelines, focusing on recommendations related to assessment for proteinuria specifically. The article also presents findings from a multidisciplinary meeting aimed at developing knowledge translation intervention strategies, with input from key stakeholders (researchers, knowledge users, decision makers and collaborators), to facilitate implementation of this guideline. These considerations are relevant for dissemination and implementation of guidelines on other topics and in other clinical settings.

High serum potassium levels after losartan can reflect more severe renal disease. Reply to Gonçalves AR, El Nahas AM [letter

High serum potassium levels after losartan can reflect more severe renal disease. Reply to Gonçalves AR, El Nahas AM [letter

Debate: PRO Position. Should Microalbuminuria Ever Be Considered as a Renal Endpoint in Any Clinical Trial

from cardiovascular trials. Such trials are not specifically designed for renal outcomes, and may consequently not lend themselves to firm conclusions on the topic of the current debate [1, 2]. Indeed, the number of patients with microalbuminuria in these studies makes up such a small proportion of the total (approximately 25%) that one cannot answer any questions of changes in albuminuria and outcome by analyzing the total group. We will have to await analysis in the microalbuminuria subgroups which are underway. The most compelling argument to refute the results of these cardiovascular trials is the fact that other parameters could have changed and negatively influenced renal outcomes. As mentioned in our commentary, diuretics are illustrative for such a phenomenon. They lower blood pressure, but if they induce hypokalemia, they appear not to be cardioprotective, despite their blood pressure lowering ability. This has never been a reason to question the suitability of blood pressure as a surrogate for cardiovascular outcome; neither should it be a reason to abandon microalbuminuria as a surrogate for renal outcomes. Having made these comments, we do agree with our opponent that there is indeed a need for more clinical trials to provide us with data that strengthen the fact that the lowering of albuminuria, independent of other renal or cardiovascular risk markers, is associated with renal protection. Our opponent states that microalbuminuria should not be used as a renal endpoint. His arguments are based on two major points: in absence of microalbuminuria, one may observe progression of renal function loss, and decrease in microalbuminuria is not always associated with renal protection. We disagree with our opponent that studies showing the development of renal disease in the absence of microalbuminuria form a sound reason to discard microalbuminuria as a valid renal endpoint. As already stated in our commentary, these studies only indicate that other factors than increased albuminuria can also promote progressive renal function loss (note: in the absence of hypertension, renal progression occurs; this does not disqualify high blood pressure as a renal surrogate). The question is whether the presence of microalbuminuria predicts renal outcomes. The answer to this question is undoubtedly yes! We agree that only a limited number of trials have properly evaluated the effect of interventions on the change in albuminuria and the relationship with renal outcomes. However, the few clinical trials that tested the effect of intervention on progression of renal disease unquestionably show associations between the change in albuminuria and renal outcomes. Our opponent quotes the ACCOMPLISH trial in which this relation is not observed and similar findings were reported in the ONTARGET trial. However, these are secondary analyses Published online: April 22, 2010 Nephrology American Journal of

Abdominal obesity is associated with microalbuminuria and an elevated cardiovascular risk profile in patients with hypertension

Overweight and obesity are frequently associated with preventable death and have emerged as a major challenge to public health. There is an ongoing debate on the role of abdominal obesity and its value in predicting cardiovascular and renal outcomes. The present analysis evaluates the prevalence of microalbuminuria (MAU) and conventional cardiovascular risk factors in relation to measures of general and abdominal obesity. In this multinational, observational study, 20828 hypertensive out-patients from 26 countries including Europe, North and Latin America, Middle East, and Asia were analyzed. Urinary dipstick screening for MAU was performed as well as data on patient demographics, anthropometric measures, cardiovascular risk factors, comorbid conditions, and cardiovascular drug therapy collected. MAU prevalence was determined by a stepwise logistic regression analysis with cardiovascular risk factors as univariate. In the univariate analysis, MAU prevalence systematically increased with body mass index (BMI) from 54.4% (1st tertial) to 62.1% (3rd tertial) (p < 0.0001), an increase which was also observed for waist circumference (WC). At any level of BMI, MAU increased with WC from 53.5%, 54.8%, and 55.0% (1st tertial of WC in all three BMI tertials) to 61.4%, 62.1%, and 64.0% (3rd tertial of WC in all BMI tertials) (p < 0.0001). In the multivariate analysis, WC, but not BMI was independently associated with MAU. Furthermore, overweight/obesity were associated with the presence of modifiable and nonmodifiable risk factors. An abnormal WC, but not BMI appears to be independently associated with MAU, an early marker of cardiovascular and renal risk. Increasing WC confers an incremental risk for MAU at any level of BMI, underlining the prognostic importance of abdominal fat accumulation beyond general obesity.

Renal risk scores: Progress and prospects

Worldwide adoption of the Kidney Disease Outcomes Quality Initiative classification for chronic kidney disease (CKD) and widespread use of the estimated glomerular filtration rate to assess renal function have identified large numbers of patients with previously undiagnosed CKD. It is clear, however, that this is a heterogeneous group and that only a small minority of such patients ever progress to end-stage renal disease. There is thus an urgent need for a simple method of risk assessment that can be applied to all patients with CKD to identify those few at greatest risk. The magnitude of baseline proteinuria has long been recognized as an important predictor of renal prognosis. Furthermore, several studies have found that change in proteinuria after initiation of antihypertensive treatment as well as achieved level of proteinuria correlate with prognosis. Thus, proteinuria has emerged as the single most important marker of renal risk. Many other factors have been identified as risk factors for CKD progression. Several attempts have been made to combine a relatively small number of risk factors into a risk score to predict renal outcomes in specific groups of patients. Validation of these risk scores as well as further studies are now required to develop a renal risk score applicable to a more general population of patients with CKD. Similar methodology could be applied to assess the important issue of the cardiovascular risk associated with CKD.

Microalbuminuria and urinary albumin excretion: French guidelines

Measurement of urinary albumin excretion (UAE) may be done on a morning urinary sample or on a 24 hour-urine sample. Values defining microalbuminuria are: - 24-hour urine sample: 30-300 mg/24 hours - Morning urine sample: 20-200 mg/mL or 30-300 mg/g creatinine or 2.5-25 mg/mmol creatinine (men) or 3.5-35 mg/mol (women). - Timed urine sample: 20-200 mug/min. The optimal use of semi-quantitative urine test-strip is not clearly defined. It is generally believed that microalbuminuria reflects a generalized impairment of the endothelium; however, no definite proof has been shown in humans. In diabetic subjects, microalbuminuria is a marker of increased risk of cardiovascular (CV) and renal morbidity and mortality in type 1 and type 2 diabetic subjects. The increase in UAE during follow-up is also a marker of CV and renal risk in type 1 and type 2 diabetic subjects; its decrease during follow-up is associated with lower risks. In non-diabetic subjects, microalbuminuria is a marker of increased risk for diabetes mellitus, deterioration of the renal function, CV morbidity and all-cause mortality. It is a marker of increased risk for the development of hypertension in normotensive subjects, and is associated with unfavorable outcome in patients with cancer and lymphoma. Persistence or elevation of UAE overtime is associated with deleterious outcome in some hypertensive subjects. Measurement of UAE may be recommended in hypertensive subjects with 1 or 2 CV risk factors in whom CV risk remains difficult to assess, and in those with refractory hypertension: microalbuminuria indicates a high CV risk and must lead to strict control of arterial pressure. Studies focused on microalbuminuria in non-diabetic, non-hypertensive subjects are limited; most of them suggest that microalbuminuria predicts CV complications and deleterious outcome as it is in diabetic or hypertensive subjects. Subjects with a history of CV or cerebrovascular disease have an even greater CV risk if microalbuminuria is present than if it is not; however, in all cases, therapeutic intervention must be aggressive regardless of whether microalbuminuria is present or not. It is not recommended to measure UAE in non-diabetic non-hypertensive subjects in the absence of history of renal disease. Monitoring of renal function (UAE, serum creatinine and estimation of GFR) is annually recommended in all subjects with microalbuminuria. in patients with microalbuminuria, weight reduction, sodium restriction (< 6 g/day), smoking cessation, strict glucose control in diabetic subjects, strict arterial pressure control are necessary; in diabetic subjects: use of maximal doses of ACEI or ARB are recommended; ACEI/ARB and thiazides have synergistic actions on arterial pressure and reduction of UAE; in non-diabetic subjects, any of the five classes of anti-hypertensive medications (ACEI, ARB, thiazides, calcium channel blockers or beta-blockers) can be used.

Microalbuminurie et excrétion urinaire d'albumine : recommandations pour la pratique clinique

Measurement of urinary albumin excretion (UAE) may be done on a morning urinary sample or on a 24 hours-urine sample. Values defining microalbuminuria are: 24 hour-urine sample: 30–300 mg/24 hours; morning urine sample: 20–200 mg/ml or 30–300 mg/g creatinine or 2.5–25 mg/mmol creatinine (men) or 3.5–35 mg/mol (women). Timed urine sample: 20–200 μg/min. The optimal use of semi-quantitative urine test-strip is not clearly defined. It is generally believed that microalbuminuria reflects a generalized impairment of the endothelium; however, no definite proof has been shown in humans. In diabetic subjects Microalbuminuria is a marker of increased risk of cardiovascular (CV) and renal morbidity and mortality in type 1 and type 2 diabetic subjects. The increase in UAE during follow-up is also a marker of CV and renal risk in type 1 and type 2 diabetic subjects; its decrease during follow-up is associated with lower risks. In no diabetic subjects Microalbuminuria is a marker of increased risk for diabetes mellitus, deterioration of the renal function, CV morbidity and all-cause mortality. It is a marker of increased risk for the development of hypertension in normotensive subjects, and is associated with unfavorable outcome in patients with cancer and lymphoma. Persistence or elevation of UAE overtime is associated with deleterious outcome in some hypertensive subjects. Measurement of UAE may be recommended in hypertensive subjects with one or two CV risk factors in whom CV risk remains difficult to assess, and in those with refractory hypertension: microalbuminuria indicates a high CV risk and must lead to strict control of arterial pressure. Studies focused on microalbuminuria in non-diabetic non-hypertensive subjects are limited; most of them suggest that microalbuminuria predicts CV complications and deleterious outcome as it is in diabetic or hypertensive subjects. Subjects with a history of CV or cerebrovascular disease have an even greater CV risk if microalbuminuria is present than if it is not; however, in all cases, therapeutic intervention must be aggressive regardless of whether microalbuminuria is present or not. It is not recommended to measure UAE in non-diabetic non-hypertensive subjects in the absence of history of renal disease. Monitoring of renal function (UAE, serum creatinine and estimation of GFR) is annually recommended in all subjects with microalbuminuria. Management In patients with microalbuminuria, weight reduction, sodium restriction (< 6 g/day), smoking cessation, strict glucose control in diabetic subjects, strict arterial pressure control are necessary; in diabetic subjects: use of maximal doses of ACEI or ARB are recommended; ACEI/ARB and thiazides have synergistic actions on arterial pressure and reduction of UAE; in non diabetic subjects, any of the five classes of antihypertensive medications (ACEI, ARB, thiazides, calcium channel blockers or betablockers) can be used.

The kidney and cardiovascular risk – Implications for management: A consensus statement from the European Society of Hypertension

Cardiovascular and renal diseases share many of the same risk factors. In fact, renal failure is usually accompanied by an increased global cardiovascular risk. Thus, preservation of kidney function might simultaneously protect the heart and the brain and, conversely, addressing cardiovascular risk factors might safeguard the kidney. This review considers the evidence supporting this approach, focusing on the protective effect of blood‐pressure lowering and the ancillary actions of antihypertensive agents on renal protection. We review recent evidence on renal protection in individuals with and without diabetes, and the importance of offering a high standard of care also to those with the metabolic syndrome or prediabetes in order to prevent initial forms of renal, and as a consequence, cardiovascular damage. Intervention may be appropriate even in individuals with high‐normal blood pressure, if they already have early renal and/or cardiovascular risk markers. As a consequence of these insights, thresholds for starting antihypertensive therapy are gradually falling, whereas awareness of the need for an early intervention in patients at high risk of developing renal damage and simultaneously cardiovascular disease is growing.