What is Creatine
Creatine is a naturally occurring compound synthesized endogenously in the kidney and liver from arginine and glycine, and obtained exogenously through dietary consumption of skeletal and cardiac muscle (primarily meat), serving as a precursor to phosphocreatine in the ATP-CP energy system for rapid cellular energy production. 1, 2
Biochemical Properties and Metabolism
Creatine combines with phosphate in muscle tissue to form phosphocreatine (also called creatine phosphate), which serves as a high-energy phosphagen in the ATP-CP energy system critical for rapid energy production during short-duration, high-intensity activities 1, 3
Approximately 95% of the body's total creatine stores (roughly 120 grams in a 70 kg male) reside in skeletal muscle, existing as 40% free creatine and 60% phosphocreatine 1, 2
Creatine undergoes irreversible degradation to creatinine at a relatively constant rate, with creatinine production approximately proportional to skeletal muscle mass in metabolically stable adults 4
The creatinine index (creatinine synthesis rate) is determined primarily by skeletal muscle mass and dietary intake of creatine/creatinine from meat consumption 4
Physiological Functions
Creatine prevents ATP depletion during periods of high energy demand, allowing cells to better handle rapidly changing energy requirements 1, 5
Supplemental creatine stimulates protein synthesis, reduces protein degradation, and stabilizes biological membranes 1
The compound is actively absorbed from the gastrointestinal tract through mechanisms similar to amino acid and peptide transport 5
Distribution throughout the body depends on the presence of creatine transporters, which serve both to distribute creatine and act as a clearance mechanism through "trapping" by skeletal muscle 5
Clinical Implications for Kidney and Liver Disease
Kidney Disease Considerations
Individuals with pre-existing chronic kidney disease (GFR <45 mL/min/1.73m²) or those with a solitary kidney should avoid creatine supplementation entirely due to the critical need to preserve remaining renal function 6
Creatine supplementation increases serum creatinine by 0.2-0.3 mg/dL through non-pathologic conversion to creatinine, which falsely suggests kidney injury when using creatinine-based eGFR calculations 6
The National Kidney Foundation explicitly discourages dietary supplement use, including creatine, in kidney donors and patients with compromised renal function 6
In dialysis patients, predialysis serum creatinine below 10 mg/dL mandates nutritional evaluation, as low creatinine reflects protein-energy malnutrition and correlates with increased mortality risk independent of cause of death 7, 8
Short-term (5 days to 2 weeks) high-dose creatine supplementation (20-30 g/day) stimulates production of methylamine and formaldehyde (potential cytotoxic metabolites), though definite clinical evidence of adverse kidney effects remains lacking in individuals without underlying kidney disease 9
Liver Disease Considerations
Severe liver disease reduces creatine synthesis capacity, as the liver is one of two primary organs (along with kidney) responsible for endogenous creatine production from arginine and glycine 1, 2
Low serum creatinine in advanced liver disease reflects both reduced hepatic creatine synthesis and decreased muscle mass from protein-energy malnutrition, carrying significant mortality risk when creatinine falls below 9-11 mg/dL 7
Cases of liver complications have been reported when creatine is combined with other supplements or taken at higher than recommended doses for several months, though creatine alone appears relatively safe in individuals without pre-existing hepatic dysfunction 3, 9
Diagnostic Pitfalls in Disease States
Serum creatinine alone should never be used to assess kidney function in patients consuming creatine (either through supplementation or high meat intake), as it reflects both endogenous muscle production and exogenous dietary intake 6
eGFR formulas incorporating serum creatinine are unreliable in patients with abnormal muscle mass (either low from wasting or high from supplementation/bodybuilding), requiring alternative assessment with cystatin C, which is unaffected by muscle mass or creatine metabolism 7, 6
Dietary creatine/creatinine from meat consumption causes transient serum creatinine elevations without indicating kidney damage, necessitating fasting from meat for 12-24 hours before creatinine testing for accurate kidney function assessment 6
In kidney disease patients, low creatinine index indicates protein-energy malnutrition and muscle wasting, requiring prompt nutritional intervention as it correlates with mortality independently of cause of death 7, 8
Safety Profile in Healthy Individuals
Short-term and long-term creatine supplementation (5 days to 5 years) with doses ranging from 5-30 g/day demonstrates no significant adverse effects on kidney function indices including glomerular filtration rate in healthy athletes without underlying kidney disease 9
The most common adverse effect is transient water retention in early supplementation stages due to the osmotic effect of increased intramuscular total creatine 3, 2
Creatine supplementation up to 8 weeks with high doses has not been associated with major health risks in healthy individuals; low-dose supplementation for up to 5 years shows no adverse effects 2