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 quantified the magnitude of these discrepancies in a population of healthy physical workers. The absolute difference between eGFRcr (creatinine-estimated GFR) and eGFRcys (cystatin C-estimated GFR) regularly exceeded 13 to 22 mL/min/1.73 m² (PubMed). This is a clinically significant gap — sufficient to shift an individual from "normal" to "renal caution" status on the sole basis of a biological artefact.
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 confirmed that creatine supplementation produces a statistically significant rise in serum creatinine with no measurable impact on actual glomerular filtration (PubMed). In other words: creatinine rises, the kidney functions perfectly. But a standard blood panel cannot distinguish between the two situations.
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 sex, age, or 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 represent the current standard for GFR estimation.
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 substantially. This is precisely the logic behind combined equations: using redundancy to cancel out noise.
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. Longitudinal monitoring with panels spaced three to six months apart distinguishes a transient fluctuation from a trend. A stable eGFRcys at 105 mL/min/1.73 m² across three consecutive measurements tells a reassuring story. The same eGFRcys declining from 105 to 92 over nine months warrants closer attention, even though each individual value remains within the normal range.
For athletic profiles, this longitudinal tracking is especially relevant because muscle mass fluctuates with training seasons. Creatinine will follow those body composition changes. Cystatin C will only shift if glomerular filtration genuinely changes. Tracking both markers over time confirms that the discordance is muscular in origin, rather than the sign of silent renal progression.
Frequently asked questions
References
- 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).
- 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).
- 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).
- 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).
- 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).
