The Experts below are selected from a list of 25383 Experts worldwide ranked by ideXlab platform
Dick De Zeeuw - One of the best experts on this subject based on the ideXlab platform.
-
effect of canagliflozin on renal and cardiovascular outcomes across different levels of Albuminuria data from the canvas program
2019Co-Authors: Brendon L Neuen, Hiddo J.l. Heerspink, Toshiaki Ohkuma, Bruce Neal, David R Matthews, Dick De Zeeuw, Kenneth W Mahaffey, Greg Fulcher, Meg Jardine, Vlado PerkovicAbstract:BACKGROUND If SGLT2 inhibitors protect the kidneys by reducing Albuminuria as hypothesized, people with type 2 diabetes mellitus (T2DM) with higher Albuminuria should benefit more. METHODS We conducted a post-hoc analysis of data from the CANagliflozin cardioVascular Assessment Study (CANVAS) Program, which randomized 10,142 participants with T2DM and high cardiovascular risk to canagliflozin or placebo. We assessed effects of canagliflozin on renal, cardiovascular, and safety outcomes by baseline Albuminuria. The trial included 2266 participants (22.3%) with moderately increased Albuminuria (urinary albumin/creatinine ratio [UACR] 30-300 mg/g) and 760 (7.5%) with severely increased Albuminuria (UACR >300 mg/g) at baseline. RESULTS Canagliflozin lowered Albuminuria with greater proportional reductions in those with moderately and severely increased Albuminuria (P heterogeneity<0.001). After week 13, canagliflozin slowed the annual loss of kidney function across Albuminuria subgroups, with greater absolute reductions in participants with severely increased Albuminuria (placebo-subtracted difference 3.01 ml/min per 1.73 m2 per year; P heterogeneity<0.001). Heterogeneity for the renal composite outcome of 40% reduction in eGFR, ESKD, or renal-related death was driven by lesser effects in participants with moderately increased Albuminuria (P heterogeneity=0.03), but no effect modification was observed when Albuminuria was fitted as a continuous variable (P heterogeneity=0.94). Cardiovascular and safety outcomes were mostly consistent across Albuminuria levels including increased risks for amputation across Albuminuria subgroups (P heterogeneity=0.66). Greater absolute risk reductions in the renal composite outcome were observed in participants with severely increased Albuminuria (P heterogeneity=0.004). CONCLUSIONS The proportional effects of canagliflozin on renal and cardiovascular outcomes are mostly consistent across patients with different levels of Albuminuria, but absolute benefits are greatest among those with severely increased Albuminuria.
-
the glycocalyx linking Albuminuria with renal and cardiovascular disease
2015Co-Authors: Ton J Rabelink, Dick De ZeeuwAbstract:Albuminuria is commonly used as a marker of kidney disease progression, but some evidence suggests that Albuminuria also contributes to disease progression by inducing renal injury in specific disease conditions. Studies have confirmed that in patients with cardiovascular risk factors, such as diabetes and hypertension, endothelial damage drives progression of kidney disease and cardiovascular disease. A key mechanism that contributes to this process is the loss of the glycocalyx-a polysaccharide gel that lines the luminal endothelial surface and that normally acts as a barrier against albumin filtration. Degradation of the glycocalyx in response to endothelial activation can lead to Albuminuria and subsequent renal and vascular inflammation, thus providing a pathophysiological framework for the clinical association of Albuminuria with renal and cardiovascular disease progression. In this Review, we examine the likely mechanisms by which glycocalyx dysfunction contributes to kidney injury and explains the link between cardiovascular disease and Albuminuria. Evidence suggests that glycocalyx dysfunction is reversible, suggesting that these mechanisms could be considered as therapeutic targets to prevent the progression of renal and cardiovascular disease. This possibility enables the use of existing drugs in new ways, provides an opportunity to develop novel therapies, and indicates that Albuminuria should be reconsidered as an end point in clinical trials.
-
drug induced reduction in Albuminuria is associated with subsequent renoprotection a meta analysis
2015Co-Authors: Hiddo J.l. Heerspink, Tobias F Kropelin, Jarno Hoekman, Dick De ZeeuwAbstract:Albuminuria has been proposed as a surrogate end point in randomized clinical trials of renal disease progression. Most evidence comes from observational analyses showing that treatment-induced short-term changes in Albuminuria correlate with risk change for ESRD. However, such studies are prone to selection bias and residual confounding. To minimize this bias, we performed a meta-analysis of clinical trials to correlate the placebo-corrected drug effect on Albuminuria and ESRD to more reliably delineate the association between changes in Albuminuria and ESRD. MEDLINE and EMBASE were searched for clinical trials reported between 1950 and April 2014. Included trials had a mean follow-up of ≥1000 patient-years, reported ESRD outcomes, and measured Albuminuria at baseline and during follow-up. Twenty-one clinical trials involving 78,342 patients and 4183 ESRD events were included. Median time to first Albuminuria measurement was 6 months. Fourteen trials tested the effect of renin-angiotensin-aldosterone-system inhibitors and seven trials tested other interventions. We observed variability across trials in the treatment effect on Albuminuria (range, −1.3% to −32.1%) and ESRD (range, −55% to +35% risk change). Meta-regression analysis revealed that the placebo-adjusted treatment effect on Albuminuria significantly correlated with the treatment effect on ESRD: for each 30% reduction in Albuminuria, the risk of ESRD decreased by 23.7% (95% confidence interval, 11.4% to 34.2%; P =0.001). The association was consistent regardless of drug class ( P =0.73) or other patient or trial characteristics. These findings suggest Albuminuria may be a valid substitute for ESRD in many circumstances, even taking into account possible other drug-specific effects that may alter renal outcomes.
-
Albuminuria estimated gfr traditional risk factors and incident cardiovascular disease the prevend prevention of renal and vascular endstage disease study
2012Co-Authors: Paul A Smink, Hiddo J.l. Heerspink, Ron T. Gansevoort, Hans L Hillege, Paul E De Jong, Stephan J L Bakker, Dick De ZeeuwAbstract:Background Abnormal levels of both Albuminuria and estimated glomerular filtration rate (eGFR) have been reported separately to be associated with cardiovascular risk. This study assessed the contribution of each separately in correctly identifying individuals at cardiovascular risk in the general population beyond traditional risk markers. Study Design Prospective community-based cohort study. Setting & Participants 8,507 individuals from the city of Groningen in the Netherlands followed up for 10.5 years for cardiovascular morbidity and mortality. Predictor or Factor The contribution of Albuminuria and eGFR separately on top of the traditional Framingham risk factors was assessed. Outcomes The composite of first occurrence of myocardial infarction, stroke, ischemic heart disease, revascularization procedure, and all-cause mortality. Measurements At the baseline visit, Albuminuria was measured in 2 consecutive 24-hour urine samples. eGFR was calculated using the serum creatinine–based CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation. Results In multivariable Cox regression models, Albuminuria, but not eGFR, was associated independently with the primary study outcome (HR, 1.08 [95% CI, 1.04-1.12] per doubling of Albuminuria). When added to the risk model consisting of Framingham risk factors, Albuminuria significantly contributed to better risk stratification, shown by an increase in net reclassification index of 7.2% (95% CI, 3.3%-11.0%; P Limitations The cohort includes mainly individuals of European ancestry. Therefore, results should not be extrapolated to other ethnicities. Conclusion In a general population cohort, Albuminuria, but not eGFR, significantly adds to traditional cardiovascular risk factors in identifying individuals at risk of cardiovascular morbidity and all-cause mortality.
-
Albuminuria and blood pressure independent targets for cardioprotective therapy in patients with diabetes and nephropathy a post hoc analysis of the combined renaal and idnt trials
2011Co-Authors: Frank A Holtkamp, Julia B. Lewis, Giuseppe Remuzzi, Hanshenrik Parving, Dick De Zeeuw, Pieter A De Graeff, Gozewijn D Laverman, Tom Berl, David K PackhamAbstract:Aims The long-term cardioprotective effect of angiotensin receptor blockers (ARBs) is associated with the short-term lowering of its primary target blood pressure, but also with the lowering of Albuminuria. Since the individual blood pressure and Albuminuria response to an ARB varies between and within an individual, we tested whether the variability and discordance in systolic blood pressure (SBP) and Albuminuria response to ARB therapy are associated with its long-term effect on cardiovascular outcomes. Methods and results The combined data of the RENAAL and IDNT trials were used. We first investigated the extent of variability and discordance in SBP and Albuminuria response (baseline to 6 months). Subsequently, we assessed the combined impact of residual Month 6 SBP and Albuminuria level with cardiovascular outcome. In ARB-treated patients, 421 patients (34.5%) either had a reduction in SBP but no reduction in Albuminuria, or vice versa, indicating substantial discordance in response in these parameters. The initial reduction in SBP and Albuminuria independently correlated with cardiovascular protection: HR per 5 mmHg SBP reduction 0.97 (95% CI 0.94–0.99) and HR per decrement log Albuminuria 0.87 (95% CI 0.76–0.99). Across all SBP categories at Month 6, a progressively lower cardiovascular risk was observed with a lower Albuminuria level. This was particularly evident in patients who reached the guideline recommended SBP target of ≤130 mmHg. Conclusion The SBP and Albuminuria response to ARB therapy is variable and discordant. Therapies intervening in the renin–angiotensin–aldosterone system with the aim of improving cardiovascular outcomes may therefore require a dual approach targeting both blood pressure and Albuminuria.
Hiddo J.l. Heerspink - One of the best experts on this subject based on the ideXlab platform.
-
effect of canagliflozin on renal and cardiovascular outcomes across different levels of Albuminuria data from the canvas program
2019Co-Authors: Brendon L Neuen, Hiddo J.l. Heerspink, Toshiaki Ohkuma, Bruce Neal, David R Matthews, Dick De Zeeuw, Kenneth W Mahaffey, Greg Fulcher, Meg Jardine, Vlado PerkovicAbstract:BACKGROUND If SGLT2 inhibitors protect the kidneys by reducing Albuminuria as hypothesized, people with type 2 diabetes mellitus (T2DM) with higher Albuminuria should benefit more. METHODS We conducted a post-hoc analysis of data from the CANagliflozin cardioVascular Assessment Study (CANVAS) Program, which randomized 10,142 participants with T2DM and high cardiovascular risk to canagliflozin or placebo. We assessed effects of canagliflozin on renal, cardiovascular, and safety outcomes by baseline Albuminuria. The trial included 2266 participants (22.3%) with moderately increased Albuminuria (urinary albumin/creatinine ratio [UACR] 30-300 mg/g) and 760 (7.5%) with severely increased Albuminuria (UACR >300 mg/g) at baseline. RESULTS Canagliflozin lowered Albuminuria with greater proportional reductions in those with moderately and severely increased Albuminuria (P heterogeneity<0.001). After week 13, canagliflozin slowed the annual loss of kidney function across Albuminuria subgroups, with greater absolute reductions in participants with severely increased Albuminuria (placebo-subtracted difference 3.01 ml/min per 1.73 m2 per year; P heterogeneity<0.001). Heterogeneity for the renal composite outcome of 40% reduction in eGFR, ESKD, or renal-related death was driven by lesser effects in participants with moderately increased Albuminuria (P heterogeneity=0.03), but no effect modification was observed when Albuminuria was fitted as a continuous variable (P heterogeneity=0.94). Cardiovascular and safety outcomes were mostly consistent across Albuminuria levels including increased risks for amputation across Albuminuria subgroups (P heterogeneity=0.66). Greater absolute risk reductions in the renal composite outcome were observed in participants with severely increased Albuminuria (P heterogeneity=0.004). CONCLUSIONS The proportional effects of canagliflozin on renal and cardiovascular outcomes are mostly consistent across patients with different levels of Albuminuria, but absolute benefits are greatest among those with severely increased Albuminuria.
-
comparison of exposure response relationship of atrasentan between north american and asian populations
2017Co-Authors: Hiddo J.l. Heerspink, Dennis L Andress, John J. Brennan, Justin W Davis, Ken Idler, Blai Coll, Donald E. Kohan, Ricardo Correarotter, Hirofumi Makino, Vlado PerkovicAbstract:AIMS: The selective endothelin (ET) A receptor antagonist atrasentan has been shown to lower Albuminuria in North American and Asian patients with type 2 diabetes and nephropathy. As drug responses to many drugs may differ between North American and Asian populations, we assessed the influence of geographical region on the Albuminuria and fluid retention response to atrasentan. MATERIALS AND METHODS: Two 12-week double-blind randomised controlled trials were performed with atrasentan 0.75 or 1.25 mg/d vs placebo in patients with type 2 diabetes and nephropathy. The efficacy endpoint was the percentage change in Albuminuria. Bodyweight change, a proxy of fluid retention, was used as a safety endpoint. Pharmacodynamics were determined in Asians (N = 77) and North Americans (N = 134). Atrasentan plasma concentration was measured in 161 atrasentan-treated patients. RESULTS: Mean Albuminuria reduction in Asian, compared to North American, patients was, respectively, -34.4% vs -26.3% for 0.75 mg/d ( P = .44) and -48.0% vs -28.9% for 1.25 mg/d ( P = .035). Bodyweight gain did not differ between North American and Asian populations. Atrasentan plasma concentrations were higher in Asians compared to North Americans and correlated with Albuminuria response (7.2% Albuminuria reduction per doubling atrasentan concentration; P = .024). Body surface area (β = -1.09 per m2 ; P < .001) and bilirubin, as a marker of hepatic organic anion transporter activity, (β = 0.69 per mg/dL increment; P = .010) were independent determinants of atrasentan plasma concentration; correction by body surface area and bilirubin left no significant difference in plasma concentration between Asian and North American populations. CONCLUSION: The higher exposure and Albuminuria reduction of atrasentan in Asian patients is not associated with more fluid retention, suggesting that Asian patients are less sensitive to atrasentan-induced sodium retention.
-
dapagliflozin reduces Albuminuria in patients with diabetes and hypertension receiving renin angiotensin blockers
2016Co-Authors: Hiddo J.l. Heerspink, E Johnsson, Ingrid Gausenilsson, Valerie A Cain, C D SjostromAbstract:Aims To characterize the effect of dapagliflozin on Albuminuria and estimated glomerular filtration rate (eGFR) and to determine whether effects on Albuminuria were mediated through changes in glycated haemoblogin (HbA1c), systolic blood pressure (SBP), body weight or eGFR. Methods We conducted a post hoc analysis of data pooled from two phase III clinical trials in hypertensive patients with type 2 diabetes (T2DM) on stable angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, randomly assigned to dapagliflozin 10 mg/day or matched placebo. This analysis included only patients with microAlbuminuria or macroAlbuminuria at baseline. Results Patients were randomized to receive dapagliflozin 10 mg (n = 167) or placebo (n = 189). Dapagliflozin resulted in greater 12-week reductions in Albuminuria compared with placebo: −33.2% [95% confidence interval (CI) −45.4, −18.2]. The reduction in Albuminuria was also present after adjusting for age, sex and changes in HbA1c, SBP, body weight and eGFR: −23.5% (95% CI −37.6, −6.3). There was a decrease in eGFR with dapagliflozin versus placebo that was readily reversed 1 week after last dose. No serious renal-related adverse events were observed in any group. Conclusions Dapagliflozin was effective in lowering Albuminuria in patients with T2DM and hypertension using renin-angiotensin system blockade therapy. Reductions in Albuminuria were still present after adjusting for changes in HbA1c, SBP, body weight and eGFR. Dapagliflozin-induced improvements in glycaemic control and reductions in SBP, coupled with other potentially beneficial renal effects, may lead to a reduced long-term renal and cardiovascular risk.
-
is a reduction in Albuminuria associated with renal and cardiovascular protection a post hoc analysis of the altitude trial
2016Co-Authors: Hiddo J.l. Heerspink, Toshiharu Ninomiya, Frederik Persson, Barry M Brenner, Patrick Brunel, Nish Chaturvedi, Akshay S Desai, S M Haffner, John J V Mcmurray, Scott D SolomonAbstract:Aims: In the ALTITUDE trial, direct renin inhibition with aliskiren on top of ACEi_or_ARB therapy decreased Albuminuria by 14% while this did not lead to cardiorenal protection. Prior studies have demonstrated that the renoprotective effect of single RAAS blockade is associated with approximately 30% Albuminuria reduction. . We therefore firstly investigated whether the degree of Albuminuria reduction is associated with renal and cardiovascular protection, and secondly, whether the reduction in Albuminuria in ALTITUDE was too small to afford clinical benefit. Methods: In a post-hoc analysis of the ALTITUDE trial in 8561 patients with type 2 diabetes and chronic kidney disease or cardiovascular disease we examined the effect of month-6 Albuminuria changes on renal and cardiovascular outcomes by Cox proportional_hazard_regression. Results: The median change in Albuminuria in the first 6 months in the aliskiren group was -12%( 25th to 75th Percentile: -48.7_to_+41.9%) and 0.0[-40.2_to_55%] in the placebo arm. Changes in Albuminuria in the first 6 months were linearly associated with renal and cardiovascular endpoints: >30% reduction in Albuminuria in the first 6 months was associated with 62% renal and 25% cardiovascular risk reduction compared to an increase in Albuminuria. The association between month-6 changes in Albuminuria and renal or cardiovascular endpoints was similar in both treatment groups (p for interaction >0.1 for both endpoints). Conclusions: Addition of aliskiren to ACEi/ARB therapy shows Albuminuria changes that are associated with renal and cardiovascular risk changes. This did not translate into renal or cardiovascular protection since the overall Albuminuria reduction in the aliskiren arm was too small and nearly similar to placebo.
-
predictors of atrasentan associated fluid retention and change in Albuminuria in patients with diabetic nephropathy
2015Co-Authors: Donald E. Kohan, Dennis L Andress, John J. Brennan, Blai Coll, Vlado Perkovic, Dalane W. Kitzman, Ricardo Correarotter, Hiddo J.l. Heerspink, Hirofumi Makino, Giuseppe RemuzziAbstract:BACKGROUND AND OBJECTIVES: Endothelin A receptor antagonists (ERAs) decrease residual Albuminuria in patients with diabetic kidney disease; however, their clinical utility may be limited by fluid retention. Consequently, the primary objective of this study was to identify predictors for ERA-induced fluid retention among patients with type 2 diabetes and CKD. A secondary objective was to determine if the degree of fluid retention necessarily correlated with the magnitude of Albuminuria reduction in those patients receiving ERAs. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A post hoc analysis was conducted of the phase IIb atrasentan trials assessing Albuminuria reduction in 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) who were randomly assigned to receive placebo (n=50) or atrasentan 0.75 mg/d (n=78) or 1.25 mg/d (n=83) for 12 weeks. Changes in body weight and hemoglobin (Hb) after 2 weeks of treatment were used as surrogate markers of fluid retention. RESULTS: Baseline predictors of weight gain after 2 weeks of atrasentan treatment were higher atrasentan dose, lower eGFR, higher glycated hemoglobin, higher systolic BP, and lower homeostatic metabolic assessment product. Higher atrasentan dose and lower eGFR also predicted decreases in Hb. There were no changes in B-type natriuretic peptide. There was no correlation between reduction in Albuminuria after 2 weeks of atrasentan treatment and changes in body weight or Hb. CONCLUSIONS: In the Reducing Residual Albuminuria in Subjects With Diabetes and Nephropathy With Atrasentan/JAPAN trials, atrasentan-associated fluid retention was more likely in patients with diabetes and nephropathy who had lower eGFR or received a higher dose of atrasentan. Finding that Albuminuria reduction was not associated with changes in body weight and Hb suggests that the Albuminuria-reducing efficacy of atrasentan is not impaired by fluid retention.
Hanshenrik Parving - One of the best experts on this subject based on the ideXlab platform.
-
Albuminuria and blood pressure independent targets for cardioprotective therapy in patients with diabetes and nephropathy a post hoc analysis of the combined renaal and idnt trials
2011Co-Authors: Frank A Holtkamp, Julia B. Lewis, Giuseppe Remuzzi, Hanshenrik Parving, Dick De Zeeuw, Pieter A De Graeff, Gozewijn D Laverman, Tom Berl, David K PackhamAbstract:Aims The long-term cardioprotective effect of angiotensin receptor blockers (ARBs) is associated with the short-term lowering of its primary target blood pressure, but also with the lowering of Albuminuria. Since the individual blood pressure and Albuminuria response to an ARB varies between and within an individual, we tested whether the variability and discordance in systolic blood pressure (SBP) and Albuminuria response to ARB therapy are associated with its long-term effect on cardiovascular outcomes. Methods and results The combined data of the RENAAL and IDNT trials were used. We first investigated the extent of variability and discordance in SBP and Albuminuria response (baseline to 6 months). Subsequently, we assessed the combined impact of residual Month 6 SBP and Albuminuria level with cardiovascular outcome. In ARB-treated patients, 421 patients (34.5%) either had a reduction in SBP but no reduction in Albuminuria, or vice versa, indicating substantial discordance in response in these parameters. The initial reduction in SBP and Albuminuria independently correlated with cardiovascular protection: HR per 5 mmHg SBP reduction 0.97 (95% CI 0.94–0.99) and HR per decrement log Albuminuria 0.87 (95% CI 0.76–0.99). Across all SBP categories at Month 6, a progressively lower cardiovascular risk was observed with a lower Albuminuria level. This was particularly evident in patients who reached the guideline recommended SBP target of ≤130 mmHg. Conclusion The SBP and Albuminuria response to ARB therapy is variable and discordant. Therapies intervening in the renin–angiotensin–aldosterone system with the aim of improving cardiovascular outcomes may therefore require a dual approach targeting both blood pressure and Albuminuria.
-
Albuminuria is a target for renoprotective therapy independent from blood pressure in patients with type 2 diabetic nephropathy post hoc analysis from the reduction of endpoints in niddm with the angiotensin ii antagonist losartan renaal trial
2007Co-Authors: Wouter B A Eijkelkamp, Giuseppe Remuzzi, Shahnaz Shahinfar, Zhongxin Zhang, William F. Keane, Gilbert W. Gleim, Mark E. Cooper, Hanshenrik Parving, Matthew R WeirAbstract:Albuminuria reduction could be renoprotective in hypertensive patients with diabetic nephropathy. However, the current use of renin-angiotensin-system intervention is targeted to BP only. Therefore, this study investigated the adequacy of this approach in 1428 patients with hypertension and diabetic nephropathy from the placebo-controlled Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. Investigated were the extent of discordance in treatment effects on systolic BP (SBP) and Albuminuria and its association with renal outcome in a multivariate Cox model. Among patients with a reduced SBP during treatment, a lack of Albuminuria reduction was observed in 37, 26, and 51% (total, losartan, and placebo, respectively) at month 6. SBP or Albuminuria reduction was associated with a lower risk for ESRD, whereas combined SBP and Albuminuria reduction was associated with the lowest risk for events. Across all categories of SBP change, a progressively lower ESRD hazard ratio was observed with a larger Albuminuria reduction. A lower residual level of Albuminuria was also associated with lower ESRD risk. In conclusion, changes in Albuminuria are not concordant in a substantial proportion of patients when titrated for BP. Meanwhile, the ESRD risk showed a clear dependence on Albuminuria reduction. The ESRD risk also showed dependence on the residual level of Albuminuria, even in patients who reached the current SBP target. Antihypertensive treatment that is aimed at improving renal outcomes in patients with diabetic nephropathy may therefore require a dual strategy, targeting both SBP and Albuminuria reduction.
-
Albuminuria a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy
2004Co-Authors: Dick De Zeeuw, Giuseppe Remuzzi, Shahnaz Shahinfar, Zhongxin Zhang, William F. Keane, Mark E. Cooper, Hanshenrik Parving, Steve Snapinn, William E Mitch, Barry M BrennerAbstract:Background— Albuminuria is an established risk marker for both cardiovascular and renal outcomes. Albuminuria can be reduced with drugs that block the renin-angiotensin system (RAS). We questioned whether the short-term drug-induced change in Albuminuria would predict the long-term cardioprotective efficacy of RAS intervention. Methods and Results— We analyzed data from Reduction in Endpoints in Non-insulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL), a double-blind, randomized trial in 1513 type 2 diabetic patients with nephropathy, focusing on the relationship between the prespecified cardiovascular end point (composite) or hospitalization for heart failure and baseline or reduction in Albuminuria. Patients with high baseline Albuminuria (≥3 g/g creatinine) had a 1.92-fold (95% CI, 1.54 to 2.38) higher risk for the cardiovascular end point and a 2.70-fold (95% CI, 1.94 to 3.75) higher risk for heart failure compared with patients with low Albuminuria (<1.5 g/g). Amon...
-
proteinuria a target for renoprotection in patients with type 2 diabetic nephropathy lessons from renaal
2004Co-Authors: Dick De Zeeuw, Giuseppe Remuzzi, Shahnaz Shahinfar, Zhongxin Zhang, William F. Keane, Mark E. Cooper, Hanshenrik Parving, Steve Snapinn, William E Mitch, Barry M BrennerAbstract:Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: Lessons from RENAAL. Background Proteinuria or Albuminuria is an established risk marker for progressive renal function loss. Albuminuria can be effectively lowered with antihypertensive drugs that interrupt the renin-angiotensin system (RAS). We investigated whether Albuminuria could not only serve as a marker of renal disease, but also function as a monitor of the renoprotective efficacy of RAS intervention by the angiotensin II (Ang II) antagonist, losartan, in patients with diabetic nephropathy. Methods The data from the RENAAL (Reduction in End Points in Noninsulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan) study, a double-blind, randomized trial, were used to examine the effects of losartan on the renal outcome [i.e., the primary composite end point of doubling of serum creatinine, end-stage renal disease (ESRD) or death] in 1513 type 2 diabetic patients with nephropathy. We examined the effect of the degree of Albuminuria at baseline, initial antiproteinuric response to therapy, and the degree of remaining (residual) Albuminuria on renal outcome (either the primary composite end point of RENAAL or ESRD). We also evaluated the contribution to renal protection of the antiproteinuric effect of losartan independently of changes in blood pressure. Results Baseline Albuminuria is almost linearly related to renal outcome, and is the strongest predictor among all measured well-known baseline risk parameters. After adjusting for baseline risk markers of age, gender, race, weight, smoking, sitting diastolic blood pressure, sitting systolic blood pressure, total cholesterol, serum creatinine, Albuminuria, hemoglobin, and hemoglobin A 1c (HbA 1c ) patients with high baseline Albuminuria (≥3.0g/g creatinine) showed a 5.2-fold (95% CI 4.3–6.3) increased risk for reaching a renal end point, and a 8.1-fold (95% CI 6.1–10.8) increased risk for progressing to ESRD, compared to the low Albuminuria group ( Conclusion Albuminuria is the predominant renal risk marker in patients with type 2 diabetic nephropathy on conventional treatment; the higher the Albuminuria, the greater the renal risk. Reduction in Albuminuria is associated with a proportional effect on renal protection, the greater the reduction the greater the renal protection. The residual Albuminuria on therapy (month 6) is as strong a marker of renal outcome as is baseline Albuminuria. The antiproteinuric effect of losartan explains a major component of its specific renoprotective effect. In conclusion, Albuminuria should be considered a risk marker for progressive loss of renal function in type 2 diabetes with nephropathy, as well as a target for therapy. Reduction of residual Albuminuria to the lowest achievable level should be viewed as a goal for future renoprotective treatments.
Ron T. Gansevoort - One of the best experts on this subject based on the ideXlab platform.
-
change in Albuminuria as a surrogate endpoint for progression of kidney disease a meta analysis of treatment effects in randomised clinical trials
2019Co-Authors: Hiddo Lambers J Heerspink, Andrew L Simon, Fan Fan Hou, Tak Mao Chan, Ron T. Gansevoort, Tom Greene, Hocine Tighiouart, Josef Coresh, Julia B. LewisAbstract:Summary Background Change in Albuminuria has strong biological plausibility as a surrogate endpoint for progression of chronic kidney disease, but empirical evidence to support its validity is lacking. We aimed to determine the association between treatment effects on early changes in Albuminuria and treatment effects on clinical endpoints and surrograte endpoints, to inform the use of Albuminuria as a surrogate endpoint in future randomised controlled trials. Methods In this meta-analysis, we searched PubMed for publications in English from Jan 1, 1946, to Dec 15, 2016, using search terms including "chronic kidney disease", "chronic renal insufficiency", "Albuminuria", "proteinuria", and "randomized controlled trial"; key inclusion criteria were quantifiable measurements of Albuminuria or proteinuria at baseline and within 12 months of follow-up and information on the incidence of end-stage kidney disease. We requested use of individual patient data from the authors of eligible studies. For all studies that the authors agreed to participate and that had sufficient data, we estimated treatment effects on 6-month change in Albuminuria and the composite clinical endpoint of treated end-stage kidney disease, estimated glomerular filtration rate of less than 15 mL/min per 1·73 m2, or doubling of serum creatinine. We used a Bayesian mixed-effects meta-regression analysis to relate the treatment effects on Albuminuria to those on the clinical endpoint across studies and developed a prediction model for the treatment effect on the clinical endpoint on the basis of the treatment effect on Albuminuria. Findings We identified 41 eligible treatment comparisons from randomised trials (referred to as studies) that provided sufficient patient-level data on 29 979 participants (21 206 [71%] with diabetes). Over a median follow-up of 3·4 years (IQR 2·3–4·2), 3935 (13%) participants reached the composite clinical endpoint. Across all studies, with a meta-regression slope of 0·89 (95% Bayesian credible interval [BCI] 0·13–1·70), each 30% decrease in geometric mean Albuminuria by the treatment relative to the control was associated with an average 27% lower hazard for the clinical endpoint (95% BCI 5–45%; median R2 0·47, 95% BCI 0·02–0·96). The association strengthened after restricting analyses to patients with baseline Albuminuria of more than 30 mg/g (ie, 3·4 mg/mmol; R2 0·72, 0·05–0·99]). For future trials, the model predicts that treatments that decrease the geometric mean Albuminuria to 0·7 (ie, 30% decrease in Albuminuria) relative to the control will provide an average hazard ratio (HR) for the clinical endpoint of 0·68, and 95% of sufficiently large studies would have HRs between 0·47 and 0·95. Interpretation Our results support a role for change in Albuminuria as a surrogate endpoint for the progression of chronic kidney disease, particularly in patients with high baseline Albuminuria; for patients with low baseline levels of Albuminuria this association is less certain. Funding US National Kidney Foundation.
-
Albuminuria and tolvaptan in autosomal dominant polycystic kidney disease results of the tempo 3 4 trial
2016Co-Authors: Ron T. Gansevoort, Esther Meijer, Arlene B Chapman, Frank S Czerwiec, Olivier Devuyst, Jared J Grantham, Eiji Higashihara, Holly B Krasa, John OuyangAbstract:The TEMPO 3:4 Trial results suggested that tolvaptan had no effect compared with placebo on Albuminuria in autosomal-dominant polycystic kidney disease (ADPKD) patients. However, the use of categorical 'Albuminuria events' may have resulted in a loss of sensitivity to detect changes. The aim of this study is to investigate the effects of tolvaptan on Albuminuria as a continuous variable. Post hoc analysis of a 3-year prospective, blinded randomized controlled trial, including 1375 ADPKD patients. Albuminuria was measured in a spot morning urine sample prior to tolvaptan dosing and expressed as albumin-to-creatinine ratio (ACR). Baseline median (interquartile range) ACR was 3.2 (1.7-7.1) mg/mmol. Of note, 47.9% of ADPKD patients had normal, 48.7% moderately increased and 3.4% severely increased ACR. Subjects with higher baseline ACR had higher blood pressure and total kidney volume (TKV) and lower estimated glomerular filtration rate (eGFR). During follow-up, higher baseline ACR was associated with more rapid eGFR loss (P <0.0001 for trend), but not with rate of growth in TKV. During the 3-year trial, ACR rose in placebo- and decreased in tolvaptan-treated patients (+0.23 versus -0.40 mg/mmol). The difference ACR increased over time, reaching a maximum of 24% at Month 36 (P <0.001). At that time only a minor difference in blood pressure was observed (mean arterial pressure -1.9 mmHg for tolvaptan). The decrease in ACR was similar in all subgroups investigated, and remained after withdrawal of study drug. The beneficial effect of tolvaptan on TKV growth and eGFR loss was stronger in patients with higher baseline ACR. In ADPKD, higher baseline Albuminuria was associated with more eGFR loss. Tolvaptan decreased Albuminuria compared with placebo, independent of blood pressure. Treatment efficacy of tolvaptan on changes in TKV and eGFR was more readily detected in patients with higher Albuminuria.
-
the association of Albuminuria and high sensitivity c reactive protein with the efficacy of hmg coenzyme a reductase inhibitors for cardiovascular event prevention
2016Co-Authors: Akin Ozyilmaz, Maarten J Postma, Paul E De Jong, Cornelis Boersma, Sipke T Visser, Lolkje T W De Jongvan Den Berg, Hiddo J Lambersheerspink, Ron T. GansevoortAbstract:Background: It is not clear which hypercholesterolemic patients benefit most from beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitors with respect to the prevention of cardiovascular events. Early signs of atherosclerotic vascular damage may identify high-risk patients. Design: We studied whether subjects with hypercholesterolemia will benefit more from starting statin treatment in the case of high Albuminuria and/or high-sensitivity C-reactive protein (hsCRP). Methods: Included were subjects who had hypercholesterolemia at baseline, a negative cardiovascular disease history and who were not treated with statins. In total, 2011 subjects were analysed, of whom 695 started with a statin during a follow-up of 7.0 +/- 1.7 years. Adjusted hazard ratios (HRs) for cardiovascular events were calculated in subjects who started versus those who did not start a statin stratified for Albuminuria less than or >= 15mg/day and/or hsCRP less than or >= 3mg/L. Results: The start of a statin was associated with a beneficial effect on cardiovascular risk in subjects with high Albuminuria (HR 0.38 (0.23-0.60)), while the effect of starting a statin was non-significant in subjects with low Albuminuria (HR 0.74 (0.44-1.24), P for interaction Conclusions: The start of statin treatment is associated with a significantly lower absolute as well as relative risk of cardiovascular events in subjects with hypercholesterolemia and elevated Albuminuria, whereas these drugs had less effect in subjects with normal Albuminuria.
-
Albuminuria is an appropriate therapeutic target in patients with ckd the pro view
2015Co-Authors: Hiddo J.l. Heerspink, Ron T. GansevoortAbstract:The presence of elevated levels of Albuminuria is associated with an increased risk of progressive renal function loss over time. This association is found in various pathophysiological conditions, including diabetic nephropathy, hypertensive nephropathy, and various primary renal diseases, but also, the general, otherwise healthy population. Emerging data report that elevated Albuminuria causes tubulointerstitial damage through activation of proinflammatory mediators, which ultimately leads to a progressive decline in renal function. Nowadays, various drugs are available that decrease the rate of GFR loss in patients with kidney disease. Well known are renin-angiotensin-aldosterone system inhibitors, but there are also other drugs and interventions, like intensive glucose control, anti-inflammatory agents (pentoxifylline), or a low-protein diet. These interventions have an additional effect beyond their original target, namely lowering Albuminuria. Analyses from clinical trials show that the reduction in Albuminuria observed during the first months of treatment with these drugs correlates with the degree of long-term renal protection: the larger the initial reduction in Albuminuria, the lower the risk of ESRD during treatment. In addition, in treated patients, residual Albuminuria is again the strongest risk marker for renal disease progression. These observations combined provide a strong argument that Albuminuria is an appropriate therapeutic target in patients with CKD.
-
Albuminuria estimated gfr traditional risk factors and incident cardiovascular disease the prevend prevention of renal and vascular endstage disease study
2012Co-Authors: Paul A Smink, Hiddo J.l. Heerspink, Ron T. Gansevoort, Hans L Hillege, Paul E De Jong, Stephan J L Bakker, Dick De ZeeuwAbstract:Background Abnormal levels of both Albuminuria and estimated glomerular filtration rate (eGFR) have been reported separately to be associated with cardiovascular risk. This study assessed the contribution of each separately in correctly identifying individuals at cardiovascular risk in the general population beyond traditional risk markers. Study Design Prospective community-based cohort study. Setting & Participants 8,507 individuals from the city of Groningen in the Netherlands followed up for 10.5 years for cardiovascular morbidity and mortality. Predictor or Factor The contribution of Albuminuria and eGFR separately on top of the traditional Framingham risk factors was assessed. Outcomes The composite of first occurrence of myocardial infarction, stroke, ischemic heart disease, revascularization procedure, and all-cause mortality. Measurements At the baseline visit, Albuminuria was measured in 2 consecutive 24-hour urine samples. eGFR was calculated using the serum creatinine–based CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation. Results In multivariable Cox regression models, Albuminuria, but not eGFR, was associated independently with the primary study outcome (HR, 1.08 [95% CI, 1.04-1.12] per doubling of Albuminuria). When added to the risk model consisting of Framingham risk factors, Albuminuria significantly contributed to better risk stratification, shown by an increase in net reclassification index of 7.2% (95% CI, 3.3%-11.0%; P Limitations The cohort includes mainly individuals of European ancestry. Therefore, results should not be extrapolated to other ethnicities. Conclusion In a general population cohort, Albuminuria, but not eGFR, significantly adds to traditional cardiovascular risk factors in identifying individuals at risk of cardiovascular morbidity and all-cause mortality.
Josef Coresh - One of the best experts on this subject based on the ideXlab platform.
-
change in Albuminuria as a surrogate endpoint for progression of kidney disease a meta analysis of treatment effects in randomised clinical trials
2019Co-Authors: Hiddo Lambers J Heerspink, Andrew L Simon, Fan Fan Hou, Tak Mao Chan, Ron T. Gansevoort, Tom Greene, Hocine Tighiouart, Josef Coresh, Julia B. LewisAbstract:Summary Background Change in Albuminuria has strong biological plausibility as a surrogate endpoint for progression of chronic kidney disease, but empirical evidence to support its validity is lacking. We aimed to determine the association between treatment effects on early changes in Albuminuria and treatment effects on clinical endpoints and surrograte endpoints, to inform the use of Albuminuria as a surrogate endpoint in future randomised controlled trials. Methods In this meta-analysis, we searched PubMed for publications in English from Jan 1, 1946, to Dec 15, 2016, using search terms including "chronic kidney disease", "chronic renal insufficiency", "Albuminuria", "proteinuria", and "randomized controlled trial"; key inclusion criteria were quantifiable measurements of Albuminuria or proteinuria at baseline and within 12 months of follow-up and information on the incidence of end-stage kidney disease. We requested use of individual patient data from the authors of eligible studies. For all studies that the authors agreed to participate and that had sufficient data, we estimated treatment effects on 6-month change in Albuminuria and the composite clinical endpoint of treated end-stage kidney disease, estimated glomerular filtration rate of less than 15 mL/min per 1·73 m2, or doubling of serum creatinine. We used a Bayesian mixed-effects meta-regression analysis to relate the treatment effects on Albuminuria to those on the clinical endpoint across studies and developed a prediction model for the treatment effect on the clinical endpoint on the basis of the treatment effect on Albuminuria. Findings We identified 41 eligible treatment comparisons from randomised trials (referred to as studies) that provided sufficient patient-level data on 29 979 participants (21 206 [71%] with diabetes). Over a median follow-up of 3·4 years (IQR 2·3–4·2), 3935 (13%) participants reached the composite clinical endpoint. Across all studies, with a meta-regression slope of 0·89 (95% Bayesian credible interval [BCI] 0·13–1·70), each 30% decrease in geometric mean Albuminuria by the treatment relative to the control was associated with an average 27% lower hazard for the clinical endpoint (95% BCI 5–45%; median R2 0·47, 95% BCI 0·02–0·96). The association strengthened after restricting analyses to patients with baseline Albuminuria of more than 30 mg/g (ie, 3·4 mg/mmol; R2 0·72, 0·05–0·99]). For future trials, the model predicts that treatments that decrease the geometric mean Albuminuria to 0·7 (ie, 30% decrease in Albuminuria) relative to the control will provide an average hazard ratio (HR) for the clinical endpoint of 0·68, and 95% of sufficiently large studies would have HRs between 0·47 and 0·95. Interpretation Our results support a role for change in Albuminuria as a surrogate endpoint for the progression of chronic kidney disease, particularly in patients with high baseline Albuminuria; for patients with low baseline levels of Albuminuria this association is less certain. Funding US National Kidney Foundation.
-
glomerular filtration rate Albuminuria and risk of cardiovascular and all cause mortality in the us population
2008Co-Authors: Brad C Astor, Stein Hallan, Edgar R Miller, Edwina H Yeung, Josef CoreshAbstract:Decreased glomerular filtration rate (GFR) and Albuminuria are used in combination to define chronic kidney disease, but their separate and combined effects on cardiovascular and all-cause mortality have not been studied 15 in the general population. The linked mortality file of the Third National Health and Nutrition Examination Survey includes data from 13 years of follow-up (1988–2000) for 14,586 US adults. The authors estimated GFR from standardized serum creatinine levels. Albuminuria was defined by the urinary albumin:creatinine ratio. Incidence rate ratios (IRRs) were adjusted for major cardiovascular disease risk factors and C-reactive protein. Lower estimated GFR was associated with higher risks of cardiovascular and all-cause mortality overall and within every 20 Albuminuria category. Likewise, increasing Albuminuria was associated with higher risk of estimated GFR overall and within every category. When estimated GFR and Albuminuria were examined simultaneously, a 10-ml/minute/ 1.73 m 2 lower estimated GFR (among persons with estimated GFR <60 ml/minute/1.73 m 2 ) was associated with an IRR of 1.29 (95% confidence interval: 1.06, 1.55) for cardiovascular mortality and a doubling of Albuminuria was associated with an IRR of 1.06 (95% confidence interval: 1.04, 1.08) for cardiovascular mortality. The authors 25 conclude that moderately decreased estimated GFR and Albuminuria independently predict cardiovascular and allcause mortality in the general population. These data support recent recommendations defining chronic kidney disease and stratifying subsequent risks based on both decreased GFR and Albuminuria. Albuminuria; glomerular filtration rate; kidney diseases; mortality
-
glomerular filtration rate Albuminuria and risk of cardiovascular and all cause mortality in the us population
2008Co-Authors: Brad C Astor, Stein Hallan, Edgar R Miller, Edwina H Yeung, Josef CoreshAbstract:Decreased glomerular filtration rate (GFR) and Albuminuria are used in combination to define chronic kidney disease, but their separate and combined effects on cardiovascular and all-cause mortality have not been studied in the general population. The linked mortality file of the Third National Health and Nutrition Examination Survey includes data from 13 years of follow-up (1988-2000) for 14,586 US adults. The authors estimated GFR from standardized serum creatinine levels. Albuminuria was defined by the urinary albumin:creatinine ratio. Incidence rate ratios (IRRs) were adjusted for major cardiovascular disease risk factors and C-reactive protein. Lower estimated GFR was associated with higher risks of cardiovascular and all-cause mortality overall and within every Albuminuria category. Likewise, increasing Albuminuria was associated with higher risk of estimated GFR overall and within every category. When estimated GFR and Albuminuria were examined simultaneously, a 10-ml/minute/1.73 m(2) lower estimated GFR (among persons with estimated GFR <60 ml/minute/1.73 m(2)) was associated with an IRR of 1.29 (95% confidence interval: 1.06, 1.55) for cardiovascular mortality and a doubling of Albuminuria was associated with an IRR of 1.06 (95% confidence interval: 1.04, 1.08) for cardiovascular mortality. The authors conclude that moderately decreased estimated GFR and Albuminuria independently predict cardiovascular and all-cause mortality in the general population. These data support recent recommendations defining chronic kidney disease and stratifying subsequent risks based on both decreased GFR and Albuminuria.