Feasibility, safety and tolerability of intradialytic creatine supplementation in hemodialysis: A double-blind, randomized, placebo-controlled pilot study.

Patients receiving hemodialysis are at risk of creatine deficiency due to impaired endogenous synthesis and losses during dialysis. Creatine deficiency is associated with lower health-related quality of life and higher mortality. We investigated the feasibility, tolerability and safety of intradialytic creatine supplementation during hemodialysis. In this double-blind, randomized, placebo-controlled pilot study (ClinicalTrials.gov ID: NCT05148208), 16 hemodialysis patients were included into four sequentially initiated groups, with each group receiving a fixed creatine concentration in the dialysate (0.5 mmol/L, 1.0 mmol/L, 1.5 mmol/L and 2.0 mmol/L, respectively), with block randomization in a 3:1 ratio (creatine:placebo) per group. Dropouts were replaced. Intra-dialytic creatine was administered during a 6-week period. Primary outcomes were changes in pre-dialytic intra-erythrocytic and plasma creatine concentrations, which were analyzed with linear mixed models. 16 hemodialysis patients (aged 27-78 years, 9 female) completed the study. Creatine supplementation was generally well tolerated. One patient receiving 1.5 mmol/L creatine dropped out due to a potential side effect. No serious adverse events occurred. The median (minimum-maximum) baseline pre-dialytic intra-erythrocytic and plasma creatine concentrations were 963 (407-1822) and 35 (13-287) µmol/L, respectively. At 6 weeks, the changes in pre-dialytic intra-erythrocytic creatine concentration compared to placebo (95% CI) were +399 (-269, 1066), + 685 (+17, + 1352), + 1146 (+431, + 1766) and +1098 (+431, + 1766) µmol/L for the increasing dosage treatment groups respectively (overall treatment effect p < 0.001). The changes in pre-dialytic plasma creatine concentration compared to placebo were -16 (-301, + 270), + 21 (-264, + 307), + 119 (-264, + 307) and +163 (-122, + 449) µmol/L for the increasing dosage treatment groups respectively (overall treatment effect p = 0.002). Intra-dialytic creatine supplementation is a feasible, safe, well-tolerated method to increase circulating creatine concentrations in patients treated with hemodialysis. These findings support the rationale for a larger randomized controlled trial to investigate its potential to improve health-related quality of life and reduce mortality risk in this population. Trial Registration: ClinicalTrials.gov ID NCT05148208, date of first registration 08/12/2021.