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Risk factors for progression of chronic kidney disease in the EPPIC trials and the effect of AST-120.

ABSTRACT: Two randomized, double-blind, placebo-controlled trials (EPPIC-1 and EPPIC-2) investigated the efficacy and safety of AST-120, an oral spherical carbon adsorbent, in adults with chronic kidney disease (CKD). While the benefit of adding AST-120 to standard therapy was not supported by these trials, we performed a post hoc analysis to focus on CKD progression and to determine the risk factors for the primary endpoint in the EPPIC trial population.In the EPPIC trials, patients were randomly assigned 1:1 to treatment with AST-120 or placebo. The primary endpoint was a composite of dialysis initiation, kidney transplantation, or doubling of serum creatinine. The EPPIC trial pooled population was evaluated with the same statistical methods used for analysis of the primary and secondary efficacy endpoints. The trials were registered on ClinicalTrials.gov (NCT00500682 [EPPIC-1] and NCT00501046 [EPPIC-2]).An analysis of the placebo population suggested baseline urinary protein to urinary creatinine ratio (UP/UCr) ?1.0 and hematuria were independent risk factors for event occurrence and eGFR lowering. Analysis of the high risk patients revealed a difference in the primary endpoint occurrence between treatment groups, if angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers were administered (hazard ratio 0.74, 95% confidence interval 0.56-0.96). Also, the eGFR changes from baseline in the AST-120 group were smaller than that in the placebo group (P = 0.035).CKD progression may have an association with baseline UP/UCr and hematuria. Treatment with AST-120 may delay the time to the primary endpoint in patients with progressive CKD receiving standard therapy, thus warranting further investigation.

SUBMITTER: Schulman G

PROVIDER: S-EPMC5838144 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Risk factors for progression of chronic kidney disease in the EPPIC trials and the effect of AST-120.

Schulman Gerald G Berl Tomas T Beck Gerald J GJ Remuzzi Giuseppe G Ritz Eberhard E Shimizu Miho M Kikuchi Mami M Shobu Yuko Y

Clinical and experimental nephrology 20170724 2

<h4>Background</h4>Two randomized, double-blind, placebo-controlled trials (EPPIC-1 and EPPIC-2) investigated the efficacy and safety of AST-120, an oral spherical carbon adsorbent, in adults with chronic kidney disease (CKD). While the benefit of adding AST-120 to standard therapy was not supported by these trials, we performed a post hoc analysis to focus on CKD progression and to determine the risk factors for the primary endpoint in the EPPIC trial population.<h4>Methods</h4>In the EPPIC tri ...[more]

PMID: 28741050

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Project description:BackgroundThe prevalence of sarcopenia is increased with declining renal function. Elevated serum indoxyl sulfate levels are associated with poor skeletal muscle conditions. We aimed to determine the effects of AST-120, the oral adsorbent of indoxyl sulfate, on sarcopenia and sarcopenia-associated factors in chronic kidney disease patients.MethodsThis was a 48 week, randomized controlled, parallel group, open-label, multicentre trial (n = 150). The participants were randomly assigned in a 1:1 ratio to the control (CON) and AST-120 (Renamezin®, REN) groups. Outcome measurements were performed at baseline and every 24 weeks for 48 weeks. The primary outcome was gait speed difference ≥0.1 m/s between the two groups, and secondary outcomes included hand grip strength, muscle mass, and health-related quality of life.ResultsA difference of gait speed ≥0.1 m/s was not observed during the study period. The mean dynamic-start gait speed in the REN group increased from baseline to 48 weeks (1.04 ± 0.31 to 1.08 ± 0.32 m/s, P = 0.019). The static-start gait speed changed by -0.024 and 0.04 m/s (P = 0.049) in the CON and REN groups over 48 weeks, respectively. Hand grip strength decreased during the first 24 weeks and did not significantly change over the next 24 weeks in either group. The proportion of low muscle mass or sarcopenia at baseline was larger in the REN group than in the CON group, but the difference attenuated over the study period [low muscle mass and sarcopenia in the CON and REN groups at baseline, 4.0% vs. 18.9% (P = 0.004) and 2.7% vs. 13.5% (P = 0.017); at 24 weeks, 2.9% vs. 13.6% (P = 0.021) and 1.4% vs. 10.5% (P = 0.029); and at 48 weeks, 7.6% vs. 12.9% (P = 0.319) and 4.5% vs. 8.1% (P = 0.482), respectively]. Bodily pain, vitality, symptoms/problems, and cognitive function in the REN group improved, while the quality of social interactions and the kidney disease effects in the CON group aggravated from baseline to 48 weeks. Interaction between time and group was evident only in symptoms/problems, cognitive function, and kidney disease effects.ConclusionsThe addition of AST-120 to standard treatment in chronic kidney disease patients did not make a significant difference in gait speed, although AST-120 modestly had beneficial effects on gait speed change and quality of life and showed the potential to improve sarcopenia. (clinicaltrials.gov: NCT03788252).

Project description:The risk factors influencing the natural course of chronic kidney disease (CKD) are complex and heterogeneous, and few systematic reviews to date have focused on this issue. The aim of the study is to identify the risk factors for disease development and progression in each stage of CKD. We conducted electronic literature searches of PubMed, MEDLINE, Scopus, and the Cochrane Library up to October 15, 2012, for observational studies evaluating the risk factors on the development or progression of CKD. Eligible studies should have collected repeated information that could evaluate changes in renal function. Extracted information from all the included studies was synthesized narratively. Quality assessments were performed using the Newcastle-Ottawa Scale. An exploratory random-effects meta-analysis was performed where feasible to pool effect sizes across studies for a specific risk factor in a specific outcome. We identified 38 cohort studies and 2 case-control studies from 40 articles, with a total of 318,898 participants from 14 countries. The follow-up duration ranged from 1.5 to 16 years. The majority of the included studies were of high quality. The baseline CKD stages of the included studies ranged from normal to later stages, and only 19 studies could be classified into a specific range of CKD stages during follow-up. Three risk factors from studies of the same baseline and follow-up CKD stages were eligible for the exploratory meta-analysis, including male sex, substantial proteinuria, and diabetes. The hazard ratios for the progression from CKD stages 3-5 to end-stage renal disease (ESRD) were 1.37 (95% confidence interval 1.17-1.62), 1.64 (1.01-2.66), and 1.16 (0.98-1.38) for male sex, substantial proteinuria, and diabetes, respectively. In conclusion, our analyses comprehensively summarize the initiating and perpetuating factors for CKD. Male sex and substantial proteinuria are significant perpetuating factors for the progression from late stage CKD to ESRD, and diabetes may play a minor role for the outcome of ESRD among patients with later stages of CKD.

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Risk factors for progression of chronic kidney disease in the EPPIC trials and the effect of AST-120.

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Risk factors for progression of chronic kidney disease in the EPPIC trials and the effect of AST-120.

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