Creatinine

Creatinine is a nitrogenous organic compound formed as a breakdown product of phosphocreatine in skeletal muscle. Its production occurs at a relatively constant rate in proportion to an individual’s muscle mass, making it a valuable biochemical indicator of renal function. As it is freely filtered by the glomeruli and largely not reabsorbed, serum and urine creatinine measurements hold central importance in the clinical assessment of kidney performance.
Creatinine originates from creatine and phosphocreatine metabolism, processes that serve vital roles in cellular energy storage and rapid energy release. Because the compound is excreted unchanged by the kidneys, altered creatinine concentrations in blood and urine provide insight into both muscular activity and renal health. Its interpretation requires consideration of factors such as age, sex, muscle mass, metabolic activity, and pharmacological influences.

Biological Formation and Metabolism

Creatinine is produced via the conversion of creatine and phosphocreatine, compounds crucial to intracellular energy buffering. Creatine is synthesised primarily in the liver through methylation of guanidinoacetate, itself formed in the kidney from arginine and glycine. Once synthesised, creatine circulates to skeletal muscle and the brain, where creatine kinase catalyses its phosphorylation to phosphocreatine, a high-energy reservoir used during intense metabolic demand.
A spontaneous, non-enzymatic cyclisation converts a proportion of phosphocreatine to creatinine. The rate of formation remains broadly stable, correlating with muscle mass. Factors such as increased muscular turnover, high-intensity physical activity, and dietary creatine intake can increase creatinine production.
Creatinine is eliminated predominantly through glomerular filtration, with a smaller contribution from proximal tubular secretion. Reabsorption is negligible. In health, daily creatinine excretion reflects its constant generation. Men generally excrete larger quantities per kilogram of body weight, reflecting greater average muscle mass, while women demonstrate distinct patterns of muscle protein turnover across the lifespan that may influence creatinine production.

Renal Handling and Clinical Significance

The plasma creatinine concentration is a central marker of renal function. When filtration is impaired, serum creatinine rises because excretion decreases. Creatinine clearance (CrCl) can be calculated from serum and urine measurements to approximate the glomerular filtration rate (GFR). Estimated GFR (eGFR), derived from serum creatinine and demographic variables, is widely used for clinical screening and staging of kidney disease.
In severe renal dysfunction, CrCl may overestimate true GFR because tubular secretion comprises a more significant proportion of creatinine elimination. Certain substances—such as ketoacids, cimetidine, and trimethoprim—reduce tubular secretion, improving the accuracy of GFR estimations in advanced renal impairment. In the absence of secretion, creatinine behaves similarly to inulin, a gold-standard filtration marker.
The blood urea nitrogen-to-creatinine ratio may also be interpreted to distinguish intrinsic renal disease from prerenal states such as dehydration or reduced effective circulating volume, in which urea rises disproportionately.

Diagnostic Applications and Influencing Factors

Serum creatinine is the most widely used routine indicator of renal function. Its reference interval in adults typically ranges from approximately 0.61–1.3 mg/dL (53–115 μmol/L), though interpretation must account for muscle mass and metabolic variables. Rising serum creatinine is generally a late finding, as substantial nephron loss may occur before measurable changes appear.
High creatinine readings may arise from increased production rather than decreased renal clearance. These include ingestion of cooked meat (which contains heat-converted creatinine), high protein intake, creatine supplementation, and strenuous exercise. Fever or inflammatory dehydration may transiently elevate serum creatinine without true decline in kidney function.
Assay interference is another important consideration. Various medications and endogenous chromogens may alter measured values. Agents that block tubular secretion can raise serum concentrations without worsening filtration.
The widespread adoption of isotope dilution mass spectrometry (IDMS) has increased accuracy and standardisation of creatinine assays. However, the method yields slightly lower measured values at low concentrations, potentially leading to overestimation of GFR and affecting drug-dosing algorithms. Some dosing guidelines for medicines such as carboplatin have been adjusted to mitigate toxicity risks associated with such discrepancies.

Antibacterial and Potential Immunological Properties

Evidence suggests that creatinine exhibits antibacterial activity against both Gram-positive and Gram-negative organisms, including antimicrobial-resistant strains. Although the underlying mechanism is not well understood, its selective lack of effect on fungi and yeasts permits its use in isolating slow-growing fungal species from mixed environmental samples. Some studies propose possible immunosuppressive properties, though these remain incompletely characterised.

Urinary Excretion and Diagnostic Use in Drug Testing

Under normal physiological conditions, creatinine excretion matches its production. Daily urinary output averages 150–200 μmol/kg in men and 100–150 μmol/kg in women. Urinary creatinine measurements are used to assess sample validity in drug testing. Very low concentrations may indicate dilution or attempted manipulation, leading to test invalidation.

Interpretation and Reference Ranges

Creatinine is reported in mg/dL in many countries, whereas μmol/L is the preferred unit in the United Kingdom and several Commonwealth nations. One mg/dL equals 88.4 μmol/L. Typical reference ranges for adults are approximately 45–90 μmol/L for women and 60–110 μmol/L for men. Individual values must always be interpreted in the context of muscle mass and overall health.
Trend analysis is more clinically meaningful than isolated measurements. Gradual increases may reflect progressive renal disease. When angiotensin-converting enzyme inhibitors are prescribed for heart failure or chronic kidney disease, an increase in creatinine of up to 30 per cent is expected and should not prompt discontinuation unless hyperkalaemia or further deterioration occurs.