Patients treated with hemodialysis are at increased risk of creatine deficiency because endogenous synthesis is impaired and creatine is lost during dialysis. The kidney houses the rate-limiting enzyme (AGAT/GATM) required for production of the creatine precursor, and kidney failure reduces endogenous synthesis. In addition, creatine is removed directly into the dialysate through the dialysis filter and creatine is lost when creatine converts non-enzymatically to creatinine and is eliminated. These combined factors, together with often low dietary intake, create a heightened risk of depleted creatine pools in this population.
Creatine is central to cellular energy metabolism and is predominantly located in muscle and nervous tissue. Observationally, lower creatine concentrations in dialysis patients have been associated with reduced health-related quality of life (HRQoL) and increased mortality. The investigators hypothesized that replenishing creatine during dialysis might be a viable strategy to correct deficiency and potentially improve clinical outcomes, and therefore tested the feasibility, tolerability and safety of delivering creatine via the dialysate.
This study was a double-blind, randomized, placebo-controlled pilot trial (ClinicalTrials.gov ID: NCT05148208). Sixteen adult patients receiving hemodialysis were enrolled across four sequentially initiated groups. Each group corresponded to a fixed dialysate creatine concentration: 0.5 mmol/L, 1.0 mmol/L, 1.5 mmol/L and 2.0 mmol/L. Within each dose group participants were randomized in blocks at a 3:1 ratio to receive creatine-containing dialysate or placebo. Dropouts were replaced to maintain intended group size.
Participants’ ages ranged from 27 to 78 years, with nine female participants in the cohort. The intradialytic intervention was provided during a six-week treatment period.
Creatine was administered by adding a fixed concentration of creatine to the dialysate during routine hemodialysis sessions. Four ascending concentrations were tested sequentially: 0.5 mmol/L, 1.0 mmol/L, 1.5 mmol/L and 2.0 mmol/L. The placebo arms within each block received standard dialysate without added creatine. The protocol and final study plan were reviewed and approved by the funder prior to study initiation, though the funder did not take part in conduct or analysis.
Primary outcomes were the changes from baseline in pre-dialytic intra-erythrocytic creatine concentrations and plasma creatine concentrations after six weeks of intradialytic creatine exposure. These outcomes were analyzed using linear mixed models. Baseline medians were reported for both compartments: intra-erythrocytic creatine median 963 µmol/L (range 407–1822) and plasma creatine median 35 µmol/L (range 13–287).
Tolerability and safety were prospectively monitored during the six-week intervention. Overall the supplementation was described as generally well tolerated. One participant allocated to the 1.5 mmol/L creatine group discontinued participation due to a potential side effect; the study reports no serious adverse events across the trial population.
At six weeks, intradialytic creatine produced dose-related increases in pre-dialytic intra-erythrocytic creatine compared with placebo. The estimated changes versus placebo (95% CI) in intra-erythrocytic creatine were:
The overall treatment effect for intra-erythrocytic creatine was statistically significant (p < 0.001).
Changes in pre-dialytic plasma creatine compared with placebo were smaller but demonstrated an overall effect (p = 0.002). The changes versus placebo were:
These findings show that intradialytic delivery of creatine increases intracellular erythrocyte stores and raises circulating concentrations in a dose-related manner.
The pilot provides proof-of-concept that intradialytic creatine supplementation is a feasible method to augment creatine concentrations in hemodialysis patients and is generally safe and tolerable over six weeks in this small cohort. The authors note the study’s pilot nature and limited sample size; while biochemical endpoints changed, the trial was not designed or powered to assess clinical outcomes such as HRQoL or mortality.
On the basis of these biochemical and safety data, the investigators recommend that a larger randomized controlled trial is warranted to evaluate whether restoring creatine status via intradialytic supplementation can improve health-related quality of life and reduce mortality risk in patients on hemodialysis.
The trial is registered as NCT05148208. The study received financial support from Crearene AG, Switzerland; the funder reviewed and approved the final protocol but did not participate in conduct, data collection, analysis, interpretation, or manuscript preparation. One author is a member of the funder’s advisory board; other authors declared no conflicts. Pseudonymized data can be made available on reasonable request to the study coordinator, but are not publicly posted because of re-identification risk in a small dialysis population.