Change in albuminuria and subsequent risk of end-stage kidney disease: an individual participant-level consortium meta-analysis of observational studies

Coresh, Josef; Heerspink, Hiddo J.L.; Sang, Yingying; Matsushita, Kunihiro; Ärnlöv, Johan; Astor, Brad C.; Black, Corri; Brunskill, Nigel J.; Carrero, Juan-Jesús; Feldman, Harold I.; Fox, Caroline S.; Inker, Lesley A.; Ishani, Areef; Ito, Sadayoshi; Jassal, Simerjot K; Konta, Tsuneo; Polkinghorne, Kevan R.; Romundstad, Solfrid; Solbu, Marit Dahl; Stempniewicz, Nikita; Stengel, Bénédicte; Tonelli, Marcello; Umesawa, Mitsumasa; Waikar, Sushrut S.; Wen, Chi‐Pang; Wetzels, Jack F.M.; Woodward, Mark; Kövesdy, Csaba P.; Levey, Andrew S.; Gansevoort, Ron T.; Appel, Lawrence J.; Greene, Tom; Chen, Teresa K.; Chalmers, John; Arima, Hisatomi; Perkovic, Vlado; Levin, Adeera; Djurdjev, Ognjenka; Tang, Mila; Nally, Joseph V.; Navaneethan, Sankar D.; Schold, Jesse D.; Weldegiorgis, Misghina; Herrington, William G.; Smith, Margaret; Hsu, Chi‐yuan; Hwang, Shih‐Jen; Chang, Alex R.; Kirchner, H. Lester; Green, Jamie A.; Ho, Kevin; Marks, Angharad; Prescott, Gordon; Clark, Laura; Fluck, Nick; Shalev, Varda; Chodick, Gabriel; Blankestijn, Peter J.; Zuilen, Arjan van; Brand, Jan Ajg van den; Sarnak, Mark J.; Böttinger, Erwin; Nadkarni, Girish N.; Ellis, Stephen G.; Nadukuru, Rajiv; Metzger, Marie; Flamant, Martin; Houillier, Pascal; Haymann, Jean‐Philippe; Froissart, Marc; Kenealy, Timothy; Elley, Raina; Collins, John; Drury, Paul; Cuddeback, John K.; Ciemins, Elizabeth L.; Stempniewicz, Rich; Nelson, Robert G.; Knowler, William C.; Bakker, Stephen J. L.; Major, Rupert; Mu, James; Shepherd, David; Barrett‐Connor, Elizabeth; Bergstrom, Jaclyn; Ix, Joachim H.; Molnar, Miklos Z.; Sumida, Keiichi; Zeeuw, Dick de; Brenner, Barry M.; Qureshi, Abdul Rashid; Elinder, Carl‐Gustaf; Runesson, Björn; Evans, Marie; Segelmark, Mårten; Stendahl, Maria; Schön, Staffan; Naimark, David; Tangri, Navdeep; Sud, Maneesh; Hirayama, Atsushi; Ichikawa, Kazunobu; Bilo, Henk J. G.; Landman, Gijs W. D.; Hateren, Kornelis Jj van; Kleefstra, Nanne; Hallan, Stein; Ballew, Shoshana H.; Chen, Jingsha; Kwak, Lucia; Surapaneni, Aditya; Parving, Hans‐Henrik; Rodby, Roger A.; Rohde, Richard D.; Lewis, Julia B.; Lewis, Edmund J.; Perrone, Ronald D.; Abebe, Kaleab Z.; Hou, Fan Fan; Xie, Di; Hunsicker, Lawrence G.; Imai, Enyu; Kobayashi, Fumiaki; Makino, Hírofumi; Remuzzi, Giuseppe; Ruggenenti, Piero; Eckardt, Kai‐Uwe; Guðmundsdóttir, Hrefna; Mačiulaitis, Romaldas; Manley, Tom; Smith, Kimberly A.; Stockbridge, Norman; Thompson, Aliza; Vetter, Thorsten; Willis, Kerry; Zhang, Luxia

doi:10.1016/s2213-8587(18)30313-9

Cited by 238 publications

(151 citation statements)

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“…The remission of albuminuria has the potential to improve patient outcomes by reducing the risk of kidney and cardiovascular events and preserving kidney function in patients with type 2 diabetes mellitus (6,22,23). Although various limitations have been raised in the literature regarding microalbuminuria changes alone as a surrogate end point of diabetic kidney disease (24), two recent metaanalysis studies report that a .30% reduction in albuminuria confers substantial risk reduction for ESKD (25,26). In this study, significant remission rates were achieved with esaxerenone 2.5 and 5 mg/d.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Esaxerenone (CS-3150) for the Treatment of Type 2 Diabetes with Microalbuminuria

Ito

Shikata

Nangaku

et al. 2019

CJASN

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Background and objectives The progression of kidney disease in some patients with type 2 diabetes mellitus may not be adequately suppressed by renin-angiotensin system inhibitors. Esaxerenone (CS-3150) is a nonsteroidal mineralocorticoid receptor blocker that has shown kidney protective effects in preclinical studies, and it is a potential add-on therapy to treat diabetic kidney disease. This phase 2 study evaluated the efficacy and safety of esaxerenone in Japanese patients with type 2 diabetes mellitus and microalbuminuria.Design, setting, participants, & measurements This multicenter, randomized, double-blind, placebo-controlled trial enrolled 365 hypertensive or normotensive patients with type 2 diabetes mellitus and microalbuminuria (urinary albumin-to-creatinine ratio $45 to ,300 mg/g creatinine) treated with renin-angiotensin system inhibitor who had eGFR$30 ml/min per 1.73 m 2 . Participants were randomized to receive 0.625, 1.25, 2.5, or 5 mg/d esaxerenone or placebo for 12 weeks. The primary end point was the change in urinary albumin-tocreatinine ratio from baseline to week 12 (with last observation carried forward).Results Esaxerenone treatment at 1.25, 2.5, and 5 mg/d significantly reduced urinary albumin-to-creatinine ratio by the end of treatment (38%, 50%, and 56%, respectively) compared with placebo (7%; all P,0.001). The urinary albumin-to-creatinine ratio remission rate (defined as urinary albumin-to-creatinine ratio ,30 mg/g creatinine at the end of treatment and $30% decrease from baseline) was 21% in the 2.5-and 5-mg/d groups versus 3% for placebo (both P,0.05). Adverse events occurred slightly more frequently with esaxerenone versus placebo, but the frequencies of drug-related adverse events and discontinuation rates were similar in the placebo and the 0.625-, 1.25-, and 2.5-mg/d groups. Drug-related adverse events and treatment discontinuations were marginally higher in the 5-mg/d group. The most common drug-related adverse event was hyperkalemia, which was dose proportional.Conclusions Adding esaxerenone at 1.25, 2.5, and 5 mg/d for 12 weeks to an ongoing renin-angiotensin system inhibitor significantly reduces urinary albumin-to-creatinine ratio in patients with type 2 diabetes mellitus and microalbuminuria.

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Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Esaxerenone (CS-3150) for the Treatment of Type 2 Diabetes with Microalbuminuria

Ito

Shikata

Nangaku

et al. 2019

CJASN

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“…Albuminuria is reported to be a strong prognostic factor [31][32][33]. A reduction in the UACR in patients with diabetic nephropathy is correlated with a reduction in the occurrence of adverse renal events (end-stage renal disease).…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of dosage-escalation of low-dosage esaxerenone added to a RAS inhibitor in hypertensive patients with type 2 diabetes and albuminuria: a single-arm, open-label study

et al. 2019

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The stimulation of mineralocorticoid receptors is linked to the development of hypertension and cardiovascular or renal damage in patients with diabetes, and the blockade of these receptors may be an effective treatment option. This open-label study with a 12-week treatment period assessed the antihypertensive (primary) and antialbuminuric (secondary) efficacy and safety of esaxerenone as an add-on therapy to a renin-angiotensin system inhibitor in hypertensive patients with type 2 diabetes and albuminuria (urinary albumin-creatinine ratio 30 to <1000 mg/g•Cr). Esaxerenone was administered over 12 weeks at a starting dosage of 1.25 mg/day, which was gradually titrated to 2.5 mg/day and 5 mg/day at weeks 4, 6, or 8 according to the dosage-escalation criteria based on serum K + levels, the estimated glomerular filtration rate, and the likelihood/occurrence of hypotension. Of the 51 patients enrolled, 44 (86.3%) reached an esaxerenone dosage of 2.5 or 5 mg/ day. The changes from the baseline in sitting systolic and diastolic blood pressures were −13.7 mmHg (p < 0.05) and −6.2 mmHg (p < 0.05), respectively. Significant decreases in blood pressure occurred regardless of age, baseline systolic blood pressure, glycated hemoglobin level, and estimated glomerular filtration rate. The urinary albumin-creatinine ratio decreased by 32.4% from the baseline (p < 0.05). Two consecutive serum K + measurements ≥ 5.5 mEq/L occurred in one patient but resolved after dosage reduction. Esaxerenone showed antihypertensive and antialbuminuric effects and a low risk of hyperkalemia with dosage titration from 1.25 mg in Japanese hypertensive patients with type 2 diabetes and albuminuria receiving a renin-angiotensin system inhibitor.

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“…The aim of the present study was to use the sparse data collected in the phase IIb ARTS-DN and ARTS-DN Japan studies and characterize pharmacokinetic variability, investigate covariate effects, and discern the pharmacokinetic/pharmacodynamic (PK/ PD) relationship to relevant safety (serum potassium and estimated glomerular filtration rate [eGFR]) and efficacy parameters (UACR) in adult patients with T2D and CKD. Increasing albuminuria as measured by UACR is a robust predictor of renal and cardiovascular risk, and retrospective and observational studies have demonstrated a strong association between changes in albuminuria and risk of end-stage renal disease (ESRD) and mortality [12][13][14][15]. A population pharmacokinetic (popPK) model utilized data from all subjects of the phase IIb ARTS-DN and ARTS-DN Japan studies simultaneously to characterize the concentration-time course of the drug for both the study population and individual subjects [16].…”

Section: Introductionmentioning

confidence: 99%

Population Pharmacokinetic and Exposure–Response Analysis of Finerenone: Insights Based on Phase IIb Data and Simulations to Support Dose Selection for Pivotal Trials in Type 2 Diabetes with Chronic Kidney Disease

Snelder¹,

Heinig

Drenth³

et al. 2019

Clin Pharmacokinet

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Background Finerenone (BAY 94-8862) is a potent non-steroidal, selective mineralocorticoid receptor antagonist being developed for the treatment of patients with type 2 diabetes and chronic kidney disease. Methods We present the population pharmacokinetics and pharmacodynamics (PD) analysis for efficacy and safety markers based on data from two clinical phase IIb studies: ARTS-DN (NCT01874431) and ARTS-DN Japan (NCT01968668). Results The pharmacokinetics of finerenone were adequately characterized, with estimated glomerular filtration rate (eGFR) and body weight as influencing covariates. The area under the plasma concentration-time curve in Japanese patients did not differ from that in the global population, and the investigated pharmacokinetics were dose-and time-linear. In addition, the pharmacokinetic model provided robust individual exposure estimates to study exposure-response. The concentration-effect relationship over time for the efficacy marker urinary albumin:creatinine ratio (UACR) was well-characterized by a maximum effect model indicating saturation at high exposures. For the safety markers, a log-linear model and a power model were identified for serum potassium concentration and eGFR, respectively, indicating attenuation of effect gains at high exposures. There was no apparent ethnic effect on the investigated pharmacokinetic-pharmacodynamic relationships. The model-predicted times to reach the full (99%) steady-state drug effect on UACR, serum potassium, and eGFR were 138, 20, and 85 days, respectively, while the pharmacokinetic half-life was 2-3 h and steady state was achieved after 2 days, indicating timescale separation. Conclusion Our dose-exposure-response modeling and simulation indicates effects were largely saturated at finerenone 20 mg and doses of both 10 and 20 mg once daily appear safe and efficacious at reducing albuminuria.

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Change in albuminuria and subsequent risk of end-stage kidney disease: an individual participant-level consortium meta-analysis of observational studies

Cited by 238 publications

References 38 publications

Efficacy and Safety of Esaxerenone (CS-3150) for the Treatment of Type 2 Diabetes with Microalbuminuria

Efficacy and Safety of Esaxerenone (CS-3150) for the Treatment of Type 2 Diabetes with Microalbuminuria

Efficacy and safety of dosage-escalation of low-dosage esaxerenone added to a RAS inhibitor in hypertensive patients with type 2 diabetes and albuminuria: a single-arm, open-label study

Population Pharmacokinetic and Exposure–Response Analysis of Finerenone: Insights Based on Phase IIb Data and Simulations to Support Dose Selection for Pivotal Trials in Type 2 Diabetes with Chronic Kidney Disease

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