Ketoanalogue supplements reduce mortality in patients with pre-dialysis advanced diabetic kidney disease: A nationwide population-based study

Abstract

Background & aims: Metabolism dysregulation and protein energy wasting occur in patients with chronic kidney disease (CKD) and are associated with poor survival, especially in patients prior to starting dialysis. Accumulating evidence indicates that dietary supplementation with ketoanalogues (KAs, a mixture of branched-chain amino acids) exerts a variety of beneficial effects for patients with CKD. However, the role of KAs in diabetic kidney disease (DKD), one of the major causes of CKD, is still controversial. The aim of this study was to explore the impact of KA supplements on survival in patients with stage 5 DKD who have not yet started dialysis (DKD-5-ND). Methods: We analyzed a nationwide cohort retrieved from the National Health Insurance Research Database in Taiwan to study the long-term impact of KA supplements in patients with DKD-5-ND. We enrolled 15,782 incident pre-dialysis DKD patients between January 1, 2004 and December 31, 2007. Landmark analysis was used to eliminate immortal bias, and overlap weighting was used to balance differences between the KA users and nonusers in the beginning. The primary study endpoint was allcause mortality, and the occurrence of permanent dialysis (presenting the end-stage renal disease, ESRD) and major adverse cardiovascular events (MACEs) was also evaluated. All patients were followed for five years or until death. Results: The prevalence of KA usage in the DKD-5-ND patients was 6.3%. The 5-year all-cause mortality rate in the KA users was lower than that in the nonusers (34.7% vs 42.7%). After adjusting for known covariates, the KA users still had a lower risk of mortality (adjusted hazard ratio [aHR]: 0.73, 95% confidence interval [CI]: 0.66e0.82). In addition, the incidence of ESRD was also slightly lower among the KA users (90.9% for users vs 91.2% for nonusers, adjusted cause-specific hazard ratio [aCSHR]: 0.65, 95% CI: 0.61e0.69), and the occurrence of MACEs was lower (adjusted incidence rate ratios [aIRR]: 0.76, 95% CI: 0.67e0.86). Although the all-cause mortality was higher among patientsolder than 70 years (60.5% for KA users vs 46.5% for nonusers) the risk reduction seemed prominent among older patients (aHR: 0.65, 95% CI: 0.56e0.76 for patients aged !70 years; aHR: 0.82, 95% CI: 0.71e0.96 for patients aged < 70 years). The reduction in risks of mortality was consistent in subgroup analysis and sensitivity tests. Conclusions: The use of KA supplements seemed to be beneficial for patients with DKD-5-ND; further indepth analysis of using KA for these patients is warranted.

Effects of Low Protein Diet on Modulating Gut Microbiota in Patients with Chronic Kidney Disease: A Systematic Review and Meta-analysis of International Studies

“…Low protein diet (LPD), defined as daily intake < 0.8 g/Kg body weight, can decrease sodium loading, regulate sympathetic and angiotensin pathway, ameliorate urea and nitrogenous wastes and improve intraglomerular pressure resulting in reduced proteinuria and uremia [5][6][7][8]. Clinical studies have indicated that the use of very low protein diet (VLPD, 0.4-0.6 g/Kg body weight/day) supplemented with ketoanalogues amino acids can further retard renal progression and reduce mortality [5,[9][10][11]. Although associations between dietary protein restriction and preservation of renal function have been reported; however, the results remain ambiguous from diverse studies [12][13][14].…”

How to Overcome Anabolic Resistance in Dialysis-Treated Patients?

“…Even less information on the anabolic effect for ONS containing AA and KA is available in the HD or PD setting. Currently, AA and KAs containing supplements are associated to low protein diets (LPDs) or very-low protein diets (VLPDs) in patients with CKD4-5 ( 162 , 163 ); these supplements have phosphate-chelating properties, are likely anabolic, can substantially postpone time to renal replacement therapy and decrease uremic toxicity ( 162 ); very recently, they have also been shown to protect patients with diabetic CKD from CV mortality ( 164 ).…”

Ketoanalogue Supplementation in Patients with Non-Dialysis Diabetic Kidney Disease: A Systematic Review and Meta-Analysis

“…A manual review of references cited in the studies yielded 2 additional citations, resulting in a total of 27 articles that were formally assessed for eligibility. Eleven of these studies were identified for the systematic review (Table 2) [2,8,12,[23][24][25][26][27][28][29][30]. Agreement between 2 researchers was high.…”

“…Agreement between 2 researchers was high. Of the 11 studies, 2 included patients with CKD stages 3 or 4 [12,23], 1 with CKD stage 4 [28], 2 with CKD stages 3-5 [2,8], 1 with CKD stages 4 or 5 [27], 2 with CKD stage 5 [26,29], and 3 did not report CKD stages, including patients with nephropathy [24,25,30]. The study periods spanned from 12 weeks to approximately 9 years.…”