Change in albuminuria as a surrogate endpoint for progression of kidney disease: a meta-analysis of treatment effects in randomised clinical trials

Heerspink, Hiddo J.L.; Greene, Tom; Tighiouart, Hocine; Gansevoort, Ron T.; Coresh, Josef; Simon, Andrew; Chan, Tak Mao; Hou, Fan Fan; Lewis, Julia B.; Locatelli, Francesco; Praga, Manuel; Schena, Francesco Paolo; Levey, Andrew S.; Inker, Lesley A.; Sevillano, Ángel; Kamper, Anne-Lise; Zuilen, Arjan D. van; Brenner, Barry M.; Maes, Bart; Ihle, Benno U.; Barret, Brendan; Cb, Leung; Szeto, Christopher; Fitzner, Christina; Wanner, Christoph; Pozzi, Claudio; Montagnino, Claudio Ponticelli; Xie, Di; Zeeuw, Dick de; Lewis, Edmund J.; Verde, Eduardo; Gutiérrez, Eduardo; Imai, Enyu; Caravaca, Fernando; Fervenza, Fernando C.; Kobayashi, Fumiaki; Moroni, Gabriella; Becker, Gavin J.; Beck, Gerald J.; Appel, Gerald B.; Frisch, Gershon; Essen, GG van; Maschio, Giuseppe; Remuzzi, Giuseppe; Montogrino, Giuseppe; Parving, Hans‐Henrik; Makino, Hírofumi; Jehan, Imitiaz; Wetzels, Jack F.M.; Donadío, James V.; Dwyer, Jamie P.; Brand, Jan van den; Kusek, John W.; Lachin, John M.; Luño, José; Floege, Jürgen; Abebe, Kaleab Z.; Chow, Kai‐Ming; Hunsicker, Lawrence G.; Vecchio, Lucia Del; Manno, Carlo; Goicoechea, Marián; Eynatten, Maximilian von; Poulter, Neil; Chaturvedi, Nish; Passerini, Patrizia; Jong, Paul E. de; Blankestijn, Peter J.; Li, Hui; Ruggenenti, Piero; Zucchelli, P; Kincaid‐Smith, Priscilla; Hilgers, Ralf‐Dieter; Estacio, Raymond O.; Rohde, Richard D.; Katafuchi, Ritsuko; Toto, Robert D.; Schrier, Robert W.; Rodby, Roger A.; Perrone, Ronald D.; Ito, Sadayoshi; Klahr, Saulo; Andrulli, Simeone; Strandgaard, Svend; Hannedouche, Thierry; Rauen, Thomas; Verdalles, Úrsula; Perkovic, Vlado; Keane, William F.

doi:10.1016/s2213-8587(18)30314-0

Cited by 257 publications

(163 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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“…In patients with nondiabetic CKD, lower levels of proteinuria are associated with a lower incidence of glomerular disease, 4 and in diabetic CKD, excess urinary protein (albumin) excretion is a risk factor for kidney disease progression and is associated with a more rapid decline in GFR and progression to end-stage renal disease. [5][6][7][8] Although several interventional trials employing individual inhibitors of the renin-angiotensin-aldosterone system, including Reduction of Endpoints in Non-Insulin-dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan and Irbesartan Diabetic Nephropathy Trial, have shown that the reduction of proteinuria was associated with delayed progression of diabetic and nondiabetic CKD, [9][10][11][12] the relation between changes in proteinuria and outcomes in other more complex trials is less clear. [13][14][15][16][17][18] Through activation of nuclear factor erythroid-derived 2-related factor 2 and inhibition of nuclear factor kappa-lightchain-enhancer of activated B-cells, bardoxolone methyl and related semisynthetic triterpenoids upregulate the antioxidant response and suppress proinflammatory signaling to reduce inflammation and improve mitochondrial function.…”

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confidence: 99%

Effect of bardoxolone methyl on the urine albumin-to-creatinine ratio in patients with type 2 diabetes and stage 4 chronic kidney disease

Rossing

Block

Chin

et al. 2019

Kidney International

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Bardoxolone methyl attenuates inflammation by inducing nuclear factor erythroid-derived 2-related factor 2 and suppressing nuclear factor kB. The Bardoxolone Methyl Evaluation in Patients With Chronic Kidney Disease and Type 2 Diabetes (BEACON) trial was a phase 3 placebocontrolled, randomized, double-blind, parallel-group, international, multicenter trial in 2185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease. BEACON was terminated because of safety concerns, largely related to a significant increase in early heart failure events in patients randomized to bardoxolone methyl. Bardoxolone methyl resulted in increased estimated glomerular filtration rate (eGFR) and urine albumin-tocreatinine ratio. Herein, we present post hoc analyses characterizing the relation between the urine albumin-tocreatinine ratio and eGFR. The urine albumin-to-creatinine ratio and eGFR were assessed every four weeks through Week 12, followed by assessments every eight weeks thereafter, and 4 weeks after the last dose of bardoxolone methyl was administered. The initial increases in urine albumin-to-creatinine ratio observed in patients randomized to bardoxolone methyl were attenuated after six months. Multivariable regression analysis identified baseline eGFR and eGFR over time as the dominant factors associated with change in the urine albumin-to-creatinine ratio. Relative to placebo, bardoxolone methyl resulted in a significant decrease in albuminuria when indexed to eGFR (least-squared means: L0.035 [95% confidence interval L0.031 to L0.039]). Thus, among patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl, changes in albuminuria are directly related to changes in eGFR, challenging the conventional construct that increases in albuminuria universally reflect kidney injury and denote harm.

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Change in albuminuria as a surrogate endpoint for progression of kidney disease: a meta-analysis of treatment effects in randomised clinical trials

Cited by 257 publications

References 56 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

Effect of bardoxolone methyl on the urine albumin-to-creatinine ratio in patients with type 2 diabetes and stage 4 chronic kidney disease

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