Serum creatinine (a blood measurement) is an important indicator of kidney health, because it is an easily measured byproduct of muscle metabolism that is excreted unchanged by the kidneys. Creatinine itself is produced via a biological system involving creatine, phosphocreatine (also known as creatine phosphate), and adenosine triphosphate (ATP, the body's immediate energy supply).
Creatine is synthesized primarily in the liver from the methylation of glycocyamine (guanidino acetate, synthesized in the kidney from the amino acids arginine and glycine) by S-adenosyl methionine. It is then transported through blood to the other organs, muscle, and brain, where, through phosphorylation, it becomes the high-energy compound phosphocreatine. Creatine conversion to phosphocreatine is catalyzed by creatine kinase; spontaneous formation of creatinine occurs during the reaction.
Creatinine is removed from the blood chiefly by the kidneys, primarily by glomerular filtration, but also by proximal tubular secretion. Little or no tubular reabsorption of creatinine occurs. If the filtration in the kidney is deficient, blood creatinine concentrations rise. Therefore, creatinine concentrations in blood and urine may be used to calculate the creatinine clearance (CrCl), which correlates approximately with the glomerular filtration rate (GFR). Blood creatinine concentrations may also be used alone to calculate the estimated GFR (eGFR).
The GFR is clinically important as a measurement of kidney function. In cases of severe kidney dysfunction, though, the CrCl rate will overestimate the GFR because hypersecretion of creatinine by the proximal tubules will account for a larger fraction of the total creatinine cleared. Ketoacids, cimetidine, and trimethoprim reduce creatinine tubular secretion and, therefore, increase the accuracy of the GFR estimate, in particular in severe kidney dysfunction. (In the absence of secretion, creatinine behaves like inulin).
An alternative estimation of kidney function can be made when interpreting the blood plasma concentration of creatinine along with that of urea. BUN-to-creatinine ratio (the ratio of blood urea nitrogen to creatinine) can indicate other problems besides those intrinsic to the kidney; for example, a urea concentration raised out of proportion to the creatinine may indicate a prerenal problem such as volume depletion.
Counterintuitively, supporting the observation of higher creatinine production in women compared to men, and putting into question the algorithms for GFR that do not distinguish for sex accordingly, women have higher muscle protein synthesis and higher muscle protein turnover across the life span. As HDL supports muscle anabolism, higher muscle protein turnover links increased creatine to the generally higher serum HDL in women as compared to serum HDL in men and the HDL associated benefits like reduced incidence of cardiovascular complications and reduced COVID-19 severity.