For decades, serum creatinine has held a central position in blood panels. General practitioners, nephrologists, and sports medicine physicians all rely on it to estimate glomerular filtration rate (GFR, the speed at which the kidneys filter blood) and screen for potential kidney dysfunction. It is an entrenched clinical reflex. It is also, in a substantial number of cases, a source of systematic misinterpretation.
For a sedentary individual with average body composition, creatinine works reasonably well. For a competitive athlete, a strength-training practitioner, or anyone with elevated muscle mass, it loses much of its informational value. The reason is biochemical, direct, and well-documented.
Creatinine: a muscle derivative, not a neutral marker
Creatinine is the degradation product of phosphocreatine, a molecule stored in muscle fibers and used for rapid ATP regeneration during intense exercise. The process is continuous and non-enzymatic: a fraction of phosphocreatine spontaneously converts into creatinine (without any enzyme involved), which enters the bloodstream and is filtered by the renal glomeruli (the kidney's microscopic filtering units).
This mechanism has an immediate implication: the higher the muscle mass, the greater the baseline production of creatinine. This relationship is linear. It does not reflect the functional state of the kidney; it reflects the quantity of muscle tissue in the individual.
Standard GFR estimation equations (CKD-EPI, MDRD, mathematical formulas used by laboratories) do incorporate age, sex, and race to partially correct for this bias. But they were developed and validated on general population cohorts, not on athletic populations. As soon as an individual's morphology deviates from the statistical average of those cohorts, the precision of the equations collapses (PubMed).
A 75 kg marathon runner with 12% body fat and a sedentary 75 kg man with 28% body fat will, according to the model, have the same creatinine if their kidneys filter identically. In reality, the athlete produces more creatinine simply because he has more active muscle tissue. His creatinine will be higher. And the equations will, incorrectly, place him in a renal caution zone.
False positives: a documented reality, not an anecdote
The data are unambiguous. In individuals with above-average muscle mass, creatinine-estimated GFR (eGFRcr) systematically tends to underestimate actual kidney function (PubMed). This is the inverse of the bias observed in low muscle mass individuals (elderly patients, those with sarcopenia), where eGFRcr overestimates kidney function.
A study published in Occupational and Environmental Medicine measured the magnitude of these discrepancies in 458 sugarcane cutters from Central America, a population struck by an epidemic of nephropathy. The mean absolute difference between eGFRcr (creatinine-estimated GFR) and eGFRcys (cystatin C-estimated GFR) reached 22 mL/min/1.73 m² in Nicaragua and 13 in El Salvador, the creatinine-based estimate being the higher of the two (PubMed). The study includes no measured GFR: it does not say which of the two estimates is the more accurate, it shows that one and the same kidney receives two verdicts depending on the marker retained. This is a clinically significant gap, sufficient to shift an individual from "normal" to "renal caution" status.
Creatine supplementation compounds the problem further. Millions of athletes consume creatine monohydrate, whose metabolism produces creatinine directly. A recent meta-analysis published in BMC Nephrology, which retained twenty-one studies, concludes that serum creatinine rises modestly and transiently, an increase attributed to metabolic turnover rather than to renal impairment, with no significant change in glomerular filtration rate (PubMed). In other words: creatinine rises, the kidney filters normally. But a standard blood panel cannot distinguish between the two situations. The molecule's full dossier, doses and limits included, is the subject of our dedicated decoding.
Cystatin C: a marker produced at a constant rate, independent of muscle
Cystatin C is a small protein belonging to the family of cysteine protease inhibitors (enzymes that break down proteins). Its key property: it is produced at a constant, stable rate by all nucleated cells in the body, independent of muscle mass (PubMed). It is then freely filtered by the glomeruli, completely reabsorbed and broken down by the proximal tubules (the part of the kidney that reclaims useful substances after filtration) — and is not secreted by the renal tubule in any significant quantity.
Its plasma concentration therefore depends almost exclusively on the glomerular filtration rate. Not on muscle tissue volume. Not on diet. Not on creatine supplementation.
A study published in the American Journal of Kidney Diseases demonstrated that cystatin C detects alterations in glomerular filtration with a sensitivity of 93.4%, compared to 86.8% for creatinine — and that it begins rising when GFR falls below 88 mL/min/1.73 m², versus 75 mL/min/1.73 m² for creatinine (PubMed). Not only is it more reliable in situations of atypical muscle mass; it also provides earlier detection of nascent functional impairment.
Cystatin C begins rising when GFR falls below 88 mL/min/1.73 m², versus 75 mL/min/1.73 m² for creatinine. It detects glomerular impairment earlier.
The new CKD-EPI equations: toward combining both markers
The nephrology community has acknowledged these limitations. In 2021, the New England Journal of Medicine published new CKD-EPI equations incorporating cystatin C, alone or combined with creatinine (PubMed). These race-free equations have been the reference equations of international guidelines ever since. The European position is more nuanced. The EFLM, the European Federation of Clinical Chemistry and Laboratory Medicine, recommends the EKFC equation (European Kidney Function Consortium) to laboratories on the continent. It considers that equation better suited to European populations than CKD-EPI 2021 (PubMed).
The combined equation (eGFRcr-cys) is now considered the most accurate for populations presenting non-standard creatinine determinants, which is precisely the description of athletic profiles. It compensates for the muscular bias of creatinine with the stability of cystatin C. And when creatinine is reliable, the combination introduces no additional bias.
But this combination is only possible if both markers are actually measured. In standard clinical practice and in the vast majority of commercial blood panels, cystatin C is not measured by default. It remains a second-line test, ordered only when creatinine appears discordant. For an athlete with "moderately elevated" creatinine, no alarm is triggered: the result is noted, sometimes monitored, and cystatin C is never requested.
What the creatinine-to-cystatin C gap actually reveals
When creatinine indicates a reduced eGFR and cystatin C indicates a normal eGFR, the conclusion is not that the two markers "contradict" each other. The conclusion is that creatinine is confounded, and that cystatin C provides the more representative measure of actual filtration.
The inverse is equally informative. When both markers converge on a reduced eGFR, the probability of genuine glomerular dysfunction increases. This is precisely the logic behind combined equations: reducing biases specific to either marker, without cancelling all uncertainty or automatically establishing etiology.
In athletes, discordance between the two markers is the rule, not the exception. Interpreting a kidney panel without cystatin C in this context means deliberately accepting a high error rate in the assessment.
The question of renal filtration in athletic populations is not settled by creatinine alone. It opens onto a broader challenge: how to design reference ranges that account for the biological reality of each individual, rather than the statistical average of a sedentary population. That challenge remains largely unresolved in standard clinical practice.
And these markers gain their full meaning over time. A single cystatin C measurement, however reliable, remains a snapshot. Panels spaced a few months apart can provide a pragmatic framework, provided the same method and comparable conditions are preserved. Several results can document stability or change; that change must be assessed against repeatability and, when available, a reference change limit suited to the assay. An eGFRcys moving from 105 to 92 mL/min/1.73 m² over nine months therefore warrants clinical interpretation, but the difference is not conclusive without its uncertainty and context.
For athletic profiles, this longitudinal tracking is especially relevant because muscle mass fluctuates with training seasons. Creatinine may follow those body-composition changes; cystatin C is less dependent on muscle, but it retains its own determinants and measurement uncertainty. Repeated discordance is compatible with a muscular effect on creatinine: by itself, it neither confirms that origin nor excludes silent renal progression.
Frequently asked questions
References
- Stehlé T et al. Development and validation of a new equation based on plasma creatinine and muscle mass assessed by CT scan to estimate glomerular filtration rate. Clin Kidney J. 2023;16(8):1265-1277 (PubMed).
- Horio M. Development of evaluation of kidney function and classification of chronic kidney disease — including CKD clinical practice guide 2012. Rinsho Byori. 2013;61(7):616-21 (PubMed).
- Andersson A et al. Large difference but high correlation between creatinine and cystatin C estimated glomerular filtration rate in Mesoamerican sugarcane cutters. Occup Environ Med. 2022;79(7):497-502 (PubMed).
- Kabiri Naeini E et al. Effect of creatine supplementation on kidney function: a systematic review and meta-analysis. BMC Nephrol. 2025;26(1):622 (PubMed).
- Onopiuk A, Tokarzewicz A, Gorodkiewicz E. Cystatin C: a kidney function biomarker. Adv Clin Chem. 2015;68:57-69 (PubMed).
- Coll E et al. Serum cystatin C as a new marker for noninvasive estimation of glomerular filtration rate and as a marker for early renal impairment. Am J Kidney Dis. 2000;36(1):29-34 (PubMed).
- Inker LA et al. New Creatinine- and Cystatin C-Based Equations to Estimate GFR without Race. N Engl J Med. 2021;385(19):1737-1749 (PubMed).
- Cavalier E et al. Recommendations for European laboratories based on the KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Clin Chem Lab Med. 2024;63(3):525-534 (PubMed).
