Plasma creatine, estimated intramuscular creatine and risk of mortality in stable kidney transplant recipients: Results from the TransplantLines biobank and cohort study

Background
Kidney transplant recipients (KTR) have reduced survival rates compared to the general population. Creatine is an endogenous nitrogenous organic acid, essential for energy metabolism. This study investigates sex stratified plasma creatine and estimated intramuscular creatine concentrations, and their transmembrane cellular gradient in relation to mortality in KTR.

Methods
We included 700 adult KTR with a functioning graft for at least one year post transplantation (TransplantLines Biobank and Cohort Study (NCT03272841)). Plasma creatine was measured using nuclear magnetic resonance spectroscopy. Intramuscular creatine was estimated using 24-h urinary creatinine excretion divided by muscle mass, measured with bioelectrical impedance analysis. Transmembrane cellular gradient was defined as intramuscular creatine/plasma creatine. Cox proportional hazard models were used to assess associations with all-cause mortality.

Results
The mean age of participants was 56 ± 13 years, mean eGFRcysc + creat was 55 ± 19 ml/min/1.73 m2 and 39 % were female. Plasma creatine and estimated intramuscular creatine were higher in females than males (36 [24; 49] vs 24 [18; 32] μmol/L; and 29.5 ± 6.6 vs 26.2 ± 6.5 mmol/kg, respectively, both P < 0.001), while the transmembrane cellular gradient was lower in females (810 [591; 1189] vs 1062 [781; 1506] L/kg, P < 0.001). During a median of 6.1 [5.0; 7.1] years of follow-up, a total of 148 KTR died. When adjusting for potential confounders, higher plasma creatine was associated with increased mortality in males (HR per doubling: 1.42 [1.10; 1.84], P = 0.007), but not in females (HR: 1.03 [0.70; 1.51]; P = 0.88). Higher estimated intramuscular creatine was associated with lower mortality in both sexes (HR: 0.28 [0.07; 0.46], P < 0.001 in females; HR: 0.52 [0.29; 0.91], P = 0.022 in males). A higher transmembrane cellular gradient was linked to lower mortality in males (HR: 0.63 [0.50; 0.81], P < 0.001), while there was a non-significant trend in females (0.71 [0.48; 1.06]; P = 0.09).

Conclusion
Creatine homeostasis markers are associated with mortality in a sex-specific manner in KTR, suggesting a potential role for creatine metabolism in patient prognosis. Future studies should explore underlying mechanisms and the potential of creatine-based interventions.