Cystatin C in Athletes: Why the Standard Kidney Test Misses the Mark
Table of Contents
Key takeaways: Cystatin C in Athletes
- Creatinine is usually the first-line kidney marker in clinical practice, but in athletes it can be misleading when interpreted without context.
- High muscle mass, recent intense exercise, creatine supplementation, high meat intake, hydration status, and exertional muscle damage can all influence creatinine and creatinine-based eGFR.
- Cystatin C is less dependent on skeletal muscle mass than creatinine, which makes it useful when creatinine-based eGFR does not fit the clinical picture.
- Cystatin C should not be seen as a routine replacement for creatinine in every athlete’s blood panel. Its main value is as a confirmatory marker in selected situations.
- In suspected rhabdomyolysis or major exertional muscle damage, creatinine can reflect both kidney stress and muscle breakdown. It should be interpreted alongside the broader clinical picture, including CK, myoglobin when available, potassium, hydration status, symptoms, and urine findings.
- Cystatin C is not perfect. Inflammation, thyroid disease, corticosteroid use, adiposity, and other non-GFR factors can affect its interpretation.
- When creatinine and cystatin C point in different directions, one of the markers may be affected by non-GFR factors. In athletes, creatinine interference from muscle mass, training, diet, or supplementation should be considered.
- When creatinine-based and cystatin C–based estimates are broadly aligned, there is more confidence that the result reflects the kidney-function picture.
- The combined creatinine–cystatin C eGFR equation is often the most useful approach when creatinine alone may be less accurate and the result matters clinically.
- The practical question in athlete blood work is not just whether a value is outside the reference range, but whether the result makes physiological and clinical sense for that athlete.
Introduction: Cystatin C in Athletes
In clinical practice, creatinine is usually the first-line test used to assess kidney function. It is widely available, inexpensive, and often included automatically in standard blood panels. Cystatin C, by contrast, is less commonly ordered and less familiar outside more specialized settings. In my clinical experience, it tends to appear more often when kidney function needs clarification beyond the standard creatinine-based estimate — for example in nephrology-led assessment, or when there is a reasonable concern that creatinine may be misleading because of high muscle mass, recent training, diet, or creatine supplementation.
This becomes especially relevant in athletes. Athletes with high muscle mass, high training loads, recent intense exercise, high meat intake, or creatine supplementation may sometimes receive creatinine-based blood test results that appear borderline despite normal kidney function. When this happens, the problem is often not the kidneys — it is what the equation is being fed.
Cystatin C in athletes offers a different way to assess kidney function, because it is less influenced by muscle mass, exercise-related muscle damage, and dietary protein than creatinine. It is not that creatinine becomes useless, but rather that its interpretation can become more complicated when the person being tested does not resemble the average reference population. When I see a physically fit or muscular patient with a borderline creatinine-based eGFR, I try to avoid jumping directly to the conclusion that the kidneys are impaired. The more useful question is whether the test result fits the whole clinical picture — and in selected cases, cystatin C can help answer that question.
This article explains what cystatin C in athletes means, why it matters specifically in athletic populations, what happens to cystatin C during and after intense exercise, and how it should be interpreted in the context of a comprehensive blood panel.
Why Cystatin C in Athletes Is More Accurate Than Creatinine
Serum creatinine is the most widely used marker of kidney function in clinical medicine. It is inexpensive, routinely included in basic metabolic panels, and well understood at the population level. The problem is that creatinine is a metabolic byproduct of creatine phosphate in skeletal muscle — and creatinine-based estimates are affected by non-GFR factors including muscle mass, physical activity, nutritional status, protein intake, age, and sex [3].
For athletes, this creates a systematic problem. A competitive strength athlete or a high-volume endurance runner will typically carry more skeletal muscle than the reference population used to build creatinine-based eGFR equations. More muscle means more creatinine production, which means higher serum creatinine and an artificially lowered eGFR. The kidney has not changed. The equation is simply being fed a non-representative input.
The consequence is predictable: in individuals with increased muscle mass, such as bodybuilders, elite athletes, and others who vigorously exercise, as well as those with high dietary red meat consumption or who take creatine supplements, serum creatinine-based eGFR calculations may underestimate the true GFR, potentially leading to the diagnosis of kidney disease in individuals with normal kidney function [2]. Conversely, in malnourished individuals or those with cachexia or amputation, the same equations may overestimate GFR.
A multinational expert meeting held in April 2002 in Marburg, Germany concluded that cys-C is at least equal if not superior to serum creatinine as a marker of GFR, and that the independence from height, gender, age, and muscle mass is advantageous [1].
This pattern overlaps with several other blood markers that behave atypically in athletic populations. For an overview of how dilutional effects alter standard blood panels in endurance athletes, see our guide to sports anemia and blood volume expansion.
In day-to-day clinical work, cystatin C is still much less familiar to many clinicians than creatinine, at least in Finland. Its interpretation is not usually part of routine practice in the same way that creatinine-based eGFR is. More often, cystatin C is measured in specific situations, or in clinical settings where kidney function is being assessed in more detail. It may also simply be less available: in some laboratory panels, occupational health contracts, or routine health check packages, cystatin C is not automatically included or may not be available at all. This practical limitation is one reason its use remains much less common than creatinine.
That does not mean clinicians interpret creatinine blindly. In practice, an elevated creatinine result is usually assessed together with the clinical context and the patient’s characteristics. When I see a higher creatinine value, the next question is not only “what is the eGFR?” but also “does this result make sense for this person?” A muscular build, recent strenuous training, high meat intake, creatine supplementation, hydration status, and the timing of the blood test can all become relevant. Many clinicians are already used to making this kind of contextual judgment, and in some cases that clinical interpretation may be enough without immediately ordering cystatin C.
This is why cystatin C should not be presented as a replacement for clinical reasoning. Its value is more specific: it can be useful when the creatinine-based estimate does not fit the patient in front of you, or when the consequences of misclassifying kidney function would matter. In athletes, that distinction is important. The goal is not to order more tests for every borderline creatinine result, but to recognize when the standard creatinine-based equation may be giving a misleading impression.
What Is Cystatin C? Understanding the Marker in Athletic Blood Work
Cystatin C (cys-C) is a low molecular weight protein of approximately 13 kDa, produced at a constant rate by all nucleated cells in the body [3]. Unlike creatinine, it is encoded by a housekeeping gene and is much less dependent on skeletal muscle mass.
After being produced, cystatin C is freely filtered at the glomerulus, then almost completely reabsorbed and metabolized by proximal tubular cells without returning to circulation [3]. This makes it, in principle, an ideal endogenous marker of glomerular filtration: if the kidneys filter less, cystatin C accumulates in proportion.
Serum cystatin C levels started to increase to greater than normal values when GFR was 88 mL/min/1.73 m², whereas serum creatinine level began to increase when GFR was 75 mL/min/1.73 m² [4]. This suggests cystatin C may detect some mild reductions in GFR earlier than serum creatinine.
Cystatin C is usually not ordered as casually as creatinine. In many clinical settings, especially in primary care or routine occupational health testing, it tends to appear more in selected situations rather than as part of everyday screening. It is more familiar in nephrology-led assessment or when kidney function needs to be clarified because creatinine may not be a reliable reflection of true filtration.
That distinction matters in athletes. In my view, athletic status alone is not usually a reason to replace creatinine with cystatin C in routine blood work. The clinical context still comes first. If there is a genuine concern about kidney dysfunction, that concern should be evaluated whether the person is an athlete or not. Athletic status can then become part of the interpretation: it may help explain why creatinine is borderline or why a creatinine-based eGFR does not fit the rest of the clinical picture.
In practice, cystatin C becomes most useful when the question is not simply “what is the creatinine?” but “is creatinine giving us the right impression of kidney function in this particular person?” For a muscular athlete, someone tested soon after heavy training, or someone using creatine, that question can be clinically relevant. But cystatin C should be seen as a confirmatory tool used in selected situations, not as a routine replacement for creatinine in every athlete’s periodic lab check.
Cystatin C in Athletes During and After Exercise
This is where the clinical picture becomes genuinely interesting — and where the potential advantage of measuring cystatin C in athletes alongside creatinine becomes clinically relevant.
Approximately 40% of marathon runners experience a transient rise in serum creatinine that meets criteria of acute kidney injury (AKI) with a parallel elevation of cystatin C, and supportive elevations of neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 in the urine — and all biomarker elevations resolved by 24 h [5].
A critical observation from marathon research clarifies the picture: serum cystatin C and creatinine concentrations were elevated after marathon running in 26% and 46% of the 70 recreational male runners, respectively, and the mean cystatin C increase was twice as low as compared to creatinine (21% and 41%, respectively), suggesting that cystatin C is indeed less biased by muscle damage [6]. A post-race creatinine rise may partly reflect exercise-related muscle damage and should not be interpreted as reduced filtration without considering timing, cystatin C, hydration status, and clinical context.
This was examined directly in an ultramarathon study of 24 finishers completing a 120 km trail race. Depending on the methodology used to calculate GFR, the prevalence of AKI was observed from 0 to 12.5%; eGFR CKD-EPI cystatin C increased significantly from the beginning to the end of the race by about 4.5 ml/min/1.73 m², whereas creatinine-based eGFR showed a different pattern. The study concluded that there was very low prevalence of AKI and no evidence that ultra-endurance running can cause important kidney damage in properly hydrated subjects with no use of NSAIDs [7].
The clinical implication is clear: creatinine-based eGFR measured immediately after a race should be interpreted cautiously; if results are abnormal, repeat testing after adequate recovery and, where available, cystatin C can help distinguish reduced filtration from creatinine-related confounding.
One situation where I become particularly cautious with creatinine interpretation is suspected rhabdomyolysis. In that setting, creatinine can be difficult to read because the clinical problem itself involves muscle breakdown. The same process that raises concern for kidney stress can also increase the amount of creatinine entering the bloodstream from damaged muscle. So when I see a high creatinine value after severe exertion, I do not automatically read it as a clean measure of filtration.
In practice, I would not assess possible rhabdomyolysis through creatinine alone. I would want to look at the full clinical picture: symptoms, urine findings, creatine kinase, myoglobin when available, potassium, hydration status, and the overall trend in renal markers. This matters especially after major exertional muscle damage, such as a marathon, an ultramarathon, or an unusually intense training session. In those situations, a high creatinine value may reflect both kidney stress and the biochemical spillover from injured muscle.
This is where cystatin C can become clinically useful for me. I would not use it as a stand-alone test for rhabdomyolysis, and it does not replace the broader assessment. But if I specifically want to understand the filtration side of the picture, cystatin C may help separate the kidney-function question from the muscle-damage signal. In my view, that is the real practical value: not diagnosing the whole condition, but helping avoid an overconfident conclusion from creatinine alone.
For a broader discussion of how endurance exercise can affect blood markers beyond kidney function, it is worth looking at the full post-race blood picture. Creatinine and eGFR is only one example of a marker that can become harder to interpret after prolonged or intense exercise. Muscle damage, plasma volume expansion, red cell turnover, platelet changes, and footstrike-related hemolysis can all influence standard lab results in athletes. I discuss these patterns in more detail in my guides to endurance athlete blood ranges, elevated creatine kinase after exercise, myoglobin in athletes, footstrike hemolysis in distance runners, platelet count in runners, reticulocyte count in athletes, sports anemia, and post-marathon blood work.
Non-GFR Confounders of Cystatin C in Athletes: What Can Interfere
Cystatin C in athletes is not a perfect marker. Whilst its reduced dependence on muscle mass is its key clinical advantage, it does have non-GFR determinants that clinicians must be aware of. Systemic inflammation, adiposity, thyroid disease, and steroid use have been reported as non-GFR determinants of cystatin C [3].
In practice, the most clinically relevant confounders for athletes are:
Thyroid dysfunction. Thyroid dysfunction is a reported non-GFR determinant of cystatin C, so thyroid status should be considered when cystatin C and creatinine-based estimates diverge without another obvious explanation [3].
Corticosteroids. Steroid use has been reported as a non-GFR determinant of cystatin C [3]. Athletes using therapeutic corticosteroids should have their cystatin C results interpreted with this in mind.
Inflammation. Systemic inflammation has been reported as a non-GFR determinant of cystatin C [3]. In athletes with clinical or biochemical evidence of systemic inflammation, this potential confounder should be considered when interpreting results.
One reason cystatin C can be useful in athletes is that exercise itself does not appear to influence it in the same direct way that it can influence creatinine. Creatinine is closely tied to skeletal muscle metabolism and muscle damage, whereas cystatin C is much less dependent on muscle mass. From a clinical perspective, that difference is the whole reason cystatin C becomes interesting when an athlete’s creatinine-based eGFR looks questionable.
That said, I would still avoid saying that exercise has no effect on cystatin C at all. Hard training can influence inflammatory markers, hydration status, and the overall physiological state of the athlete, and cystatin C has recognized non-GFR determinants, including inflammation. In practice, however, the effect is usually not treated as being as direct or as problematic as the muscle-related effect on creatinine. This is why, when I am trying to separate true kidney filtration from the noise created by muscle mass or recent training, cystatin C can be a helpful additional marker.
The Combined eGFR Equation: Best Practice for Cystatin C in Athletes
Given the complementary limitations of both markers, current evidence and KDIGO 2024 guidance support using the combined CKD-EPI creatinine–cystatin C equation when both markers are available and eGFRcr alone may be less accurate [8][10].
The 2012 CKD-EPI combined equation was developed using cross-sectional analyses in diverse populations totaling 5,352 participants from 13 studies, and validated in 1,119 participants from 5 different studies in which GFR had been measured [8]. The combined creatinine–cystatin C equation performed better than equations based on either marker alone [8].
The 2024 KDIGO (Kidney Disease: Improving Global Outcomes) guideline recommends using eGFRcr-cys in clinical situations when eGFRcr is less accurate and GFR affects clinical decision-making (Recommendation 1.2.2.1, evidence grade 1C) [9]. The guideline also notes that interpretation of serum creatinine level requires consideration of dietary intake (Practice Point 1.2.2.4), and recommends considering the use of cystatin C–based eGFR in specific circumstances where creatinine-based estimates are less reliable (Practice Point 1.2.2.6) [9].
In practice, this is often how kidney function is clarified clinically. If there is a real concern about impaired renal function, cystatin C is usually not interpreted completely on its own. It is commonly assessed alongside creatinine, and the relationship between the two results can be informative.
When creatinine and cystatin C point in different directions, it raises the possibility that one of the markers is being influenced by non-GFR factors. In an athlete, that may mean creatinine is being affected by muscle mass, recent training, diet, creatine supplementation, or muscle injury. On the other hand, if creatinine-based and cystatin C–based estimates are broadly aligned, that makes creatinine interference less likely and gives more confidence that the result reflects the kidney-function picture more accurately.
This is also how I usually think about it clinically. Cystatin C is rarely the first test I would expect to see in a basic screening panel. In most cases, the process begins with creatinine because it is widely available and routinely measured. If creatinine is unexpected, borderline, or inconsistent with the person in front of me, then combining it with cystatin C can help clarify whether the creatinine result is truly reflecting reduced filtration or whether it is being distorted by athlete-specific factors.
Conclusion: Cystatin C in Athletes as a Confirmatory Tool for Kidney Function Assessment
Creatinine remains the practical first-line marker for assessing kidney function, but in athletes it sometimes needs more clinical context than the number alone can provide. High muscle mass, recent intense training, creatine supplementation, dietary factors, and exertional muscle damage can all make creatinine-based eGFR look more concerning than the true filtration picture may be. In my clinical view, this is where cystatin C has its most useful role: not as a routine replacement for creatinine in every athletic blood panel, but as a confirmatory marker when creatinine does not seem to fit the person in front of you.
Cystatin C is less dependent on skeletal muscle mass and muscle breakdown, which makes it particularly helpful when the clinical question is whether a borderline or abnormal creatinine result reflects kidney dysfunction or athlete-related confounding. It is still not a perfect marker, and inflammation, thyroid disease, corticosteroid use, and other non-GFR factors can affect interpretation. That is why the most reliable approach is usually not to look at cystatin C or creatinine in isolation, but to interpret them together with the clinical picture, training context, hydration status, timing of blood sampling, and other relevant laboratory markers.
For athletes with unexplained low creatinine-based eGFR, chronically elevated creatinine, recent competition, suspected exertional muscle damage, or a mismatch between lab results and clinical status, cystatin C can help clarify whether kidney filtration is truly reduced. The goal is not to create unnecessary testing, but to avoid unnecessary anxiety and misclassification. In athlete blood work, the better question is often not simply “is this value outside the reference range?” but “does this result make physiological and clinical sense for this athlete?”
References
[1] https://pubmed.ncbi.nlm.nih.gov/15607309/
[2] https://www.asn-online.org/policy/webdocs/2022-04-12_cystatinCreimbursement_NGSInc.pdf
[3] https://doi.org/10.34067/KID.0003202022
[4] https://pubmed.ncbi.nlm.nih.gov/10873868/
[5] https://pubmed.ncbi.nlm.nih.gov/21272132/
[6] https://pubmed.ncbi.nlm.nih.gov/19544228/
[7] https://doi.org/10.3389/fspor.2019.00071
