Cystatin C and Kidney Function: When Creatinine-Based eGFR Can Be Misleading
Kidney function is one of the most common things we evaluate on routine blood work.
Most laboratory panels report a serum creatinine and an estimated glomerular filtration rate, or eGFR. For most patients, this works well.
But there are situations where creatinine can give us a misleading picture of kidney function.
One increasingly common example is the physically active patient taking creatine monohydrate.
A patient may begin creatine, repeat laboratory testing a few months later, and suddenly notice that their creatinine has increased and their calculated eGFR has fallen.
The immediate concern is often:
“Did creatine damage my kidneys?”
Not necessarily.
Creatinine is influenced by more than kidney filtration. Muscle mass, diet, exercise, medications, and creatine supplementation can all affect the number.
This is where another blood test called cystatin C can be useful.
What does eGFR actually measure?
The kidneys contain millions of microscopic filtration units called glomeruli.
Glomerular filtration rate, or GFR, describes how much blood the kidneys are filtering.
Measuring GFR directly is possible, but it requires specialized testing using substances that are filtered by the kidneys and then measured over time. Because that is cumbersome, physicians usually estimate GFR instead.
That is where eGFR comes from.
The most common calculation uses:
Serum creatinine
Age
Sex
Current U.S. equations no longer use race.
The important word is estimated.
An eGFR of 72 does not mean your kidneys are filtering at precisely 72 mL/min/1.73 m². It is an estimate derived from a blood marker that itself can be influenced by factors unrelated to kidney function. NIDDK
What is creatinine?
Creatinine is a breakdown product related to creatine metabolism in skeletal muscle.
Your kidneys normally remove creatinine from the bloodstream.
If kidney filtration declines, serum creatinine usually rises.
That makes creatinine a useful and inexpensive kidney marker.
But creatinine production also depends partly on how much muscle and creatine you have in your body.
A small older adult with very little muscle may have a relatively low creatinine even when kidney function is impaired.
A muscular athlete may have a higher creatinine despite having completely normal kidneys.
This is one of the fundamental limitations of creatinine-based eGFR. NIDDK specifically notes that muscle mass can affect serum creatinine and therefore the accuracy of creatinine-based kidney estimates. NIDDK
Where does creatine supplementation fit in?
Creatine monohydrate increases the body's creatine stores.
A portion of creatine naturally converts into creatinine.
Therefore, taking supplemental creatine can sometimes increase serum creatinine even when kidney filtration has not changed.
A recent systematic review and meta-analysis found that creatine supplementation was associated with a modest increase in serum creatinine but no significant decline in measured or estimated GFR overall. The authors concluded that the rise in creatinine was more consistent with creatine metabolism than kidney injury. PubMed Central (PMC)
Controlled studies have similarly found that recommended doses of creatine do not appear to impair kidney function in healthy individuals, although evidence is more limited in people with pre-existing kidney disease. PubMed Central (PMC)
This creates an important clinical problem:
Creatine may make the kidney marker look worse without actually making the kidneys worse.
A common example
Imagine a healthy, muscular 35-year-old who begins taking 5 grams of creatine monohydrate per day.
Before supplementation:
Creatinine: 1.0 mg/dL
eGFR: 100
Several months later:
Creatinine: 1.25 mg/dL
eGFR: 75
If we look only at those numbers, it might appear that kidney function has declined substantially.
But the patient:
Feels well
Has normal blood pressure
Has no albumin in the urine
Has no kidney disease history
Exercises regularly
Has significant muscle mass
Recently started creatine
That is exactly the type of situation where I would question whether creatinine is accurately reflecting filtration.
Rather than immediately diagnosing chronic kidney disease or stopping a useful supplement, we may need another way to estimate GFR.
What is cystatin C?
Cystatin C is a small protein produced by most nucleated cells in the body.
It circulates in the bloodstream and is filtered by the kidneys.
Unlike creatinine, cystatin C is much less dependent on skeletal muscle mass or creatine metabolism.
That makes it particularly useful when creatinine may be unreliable.
Kidney function can therefore be estimated in three major ways:
eGFRcr
Based primarily on creatinine.
eGFRcys
Based primarily on cystatin C.
eGFRcr-cys
Combines both creatinine and cystatin C.
For many patients in whom additional precision is needed, the combined creatinine-cystatin C equation is the most accurate approach. NIDDK notes that the combined equation generally has greater accuracy and less bias than creatinine alone. NIDDK
When should cystatin C be checked?
I do not think cystatin C needs to be ordered routinely on every healthy patient.
Creatinine-based eGFR remains an appropriate first-line kidney test for most people.
KDIGO's 2024 chronic kidney disease guideline recommends beginning with creatinine-based eGFR and adding creatinine plus cystatin C when creatinine is less accurate and knowing the true GFR would affect a clinical decision. KDIGO
There are several situations where this becomes particularly useful.
1. Someone taking creatine with an unexpectedly elevated creatinine
This is becoming one of the most practical uses in active adults.
If someone begins creatine and subsequently develops:
Higher serum creatinine
Lower creatinine-based eGFR
No albuminuria
No other evidence of kidney disease
cystatin C can help determine whether the apparent decline is real.
Research specifically evaluating creatine users has found that cystatin C and other kidney markers can remain normal despite changes in creatinine. In one randomized controlled trial, three months of relatively high-dose creatine did not worsen cystatin C–based kidney function. PubMed
This does not mean that every elevated creatinine in someone taking creatine should be ignored.
It means the result deserves interpretation.
2. Very muscular patients
Bodybuilders, strength athletes, and people carrying substantially more muscle than average may naturally generate more creatinine.
KDIGO specifically lists extreme exercise and bodybuilding as situations where creatinine can be influenced by factors other than GFR and where cystatin C may be appropriate. KDIGO
A muscular athlete with a creatinine of 1.3 mg/dL may have very different kidney function than a sedentary older adult with the same laboratory value.
Context matters.
3. Very low muscle mass
The opposite problem also occurs.
Patients who are frail, sarcopenic, have amputations, spinal cord injury, neuromuscular disease, eating disorders, or severe chronic illness may generate very little creatinine.
Their creatinine may appear reassuringly low.
As a result, creatinine-based eGFR can sometimes overestimate kidney function.
Cystatin C can be especially valuable in these situations because it is less dependent on muscle mass. KDIGO specifically identifies several of these conditions as situations where cystatin C–based assessment may improve GFR estimation. KDIGO
4. When two kidney estimates do not make sense clinically
Sometimes the laboratory result simply does not fit the patient.
For example:
eGFR suddenly falls despite otherwise stable health
A highly muscular person appears to have mild CKD
A frail older adult has an unexpectedly normal eGFR
Kidney function appears to change dramatically after weight loss
Creatinine changes after a medication is started
These are situations where using another filtration marker can provide additional context.
5. When medication dosing depends on kidney function
Some medications require dose adjustments at specific kidney-function thresholds.
If someone's creatinine-based eGFR is sitting near one of those cutoffs, greater precision may matter.
NIDDK specifically recommends considering the combined creatinine-cystatin C equation when eGFR is close to an important drug-dosing decision point, particularly for medications with narrow therapeutic windows. NIDDK
This is much more clinically important than simply trying to obtain the “best-looking” eGFR.
6. Certain medications can artificially increase creatinine
Some medications interfere with the kidney's tubular secretion of creatinine.
Examples include drugs such as:
Trimethoprim
Cimetidine
Certain other medications affecting creatinine handling
Serum creatinine can therefore increase even though true filtration has not materially changed.
KDIGO identifies medications that alter creatinine secretion as another situation in which cystatin C may be useful. KDIGO
7. Significant changes in body composition
Large weight loss can also complicate creatinine interpretation.
For example, a patient undergoing:
Major weight loss
Cancer treatment
Severe chronic illness
Prolonged hospitalization
Muscle wasting
may lose substantial skeletal muscle.
Their creatinine can fall, making eGFR appear to improve even though kidney filtration has not changed to the same degree.
A cystatin C measurement may provide a more complete picture.
What if creatinine and cystatin C disagree?
This happens.
You might see:
Creatinine eGFR: 68
but:
Cystatin C eGFR: 96
That discordance itself is informative.
The next step is not necessarily choosing whichever number looks better.
Instead, physicians should ask:
Which marker is more likely to be biased in this particular patient?
For a muscular person taking creatine with otherwise normal health, creatinine may be the less reliable marker.
For someone with significant inflammation, obesity, thyroid dysfunction, or corticosteroid use, cystatin C may also be affected.
That is one reason the combined eGFRcr-cys equation is generally useful.
The biases of the two biomarkers can partially offset each other.
Cystatin C is not perfect either
It is important not to turn cystatin C into another “optimal biomarker” that is assumed to be infallible.
Cystatin C can also be influenced by factors unrelated to kidney filtration.
Potential influences include:
Corticosteroid use
Thyroid dysfunction
Higher adiposity
Systemic inflammation
Smoking
Certain chronic illnesses
NIDDK specifically notes steroid use, thyroid dysfunction, adiposity, and inflammation as non-GFR factors that can alter cystatin C. NIDDK
So cystatin C is not automatically superior to creatinine in every patient.
The strength comes from understanding the limitations of both.
Why the combined equation is often useful
When both markers are available, laboratories can calculate:
eGFRcr-cys
This incorporates both serum creatinine and cystatin C.
Current kidney guidance increasingly favors this combined approach when more accurate assessment is clinically important.
KDIGO recommends eGFRcr-cys specifically in circumstances where creatinine is less accurate and the GFR estimate will influence clinical decision-making. KDIGO
NIDDK similarly states that the combined equation generally provides greater accuracy than creatinine alone. NIDDK
Don't forget the urine
Another mistake is trying to assess kidney health using eGFR alone.
Kidney evaluation should also consider whether the kidneys are leaking albumin.
This is typically measured using a:
Urine albumin-to-creatinine ratio, or UACR
A patient with:
Stable cystatin C
Normal or reassuring eGFR
Normal UACR
Normal blood pressure
Stable laboratory trends
has a very different risk profile from someone with persistent albuminuria.
KDIGO recommends urine ACR as the preferred initial quantitative assessment for albuminuria. KDIGO
For someone taking creatine whose serum creatinine rises unexpectedly, I am usually more interested in the entire kidney picture than one isolated number.
Does creatine damage the kidneys?
For healthy adults taking standard amounts of creatine monohydrate, the current evidence is generally reassuring.
A 2025 systematic review and meta-analysis found a modest increase in serum creatinine but no significant reduction in GFR associated with creatine supplementation. PubMed Central (PMC)
A broader review of controlled trials similarly concluded that recommended creatine supplementation has not been shown to cause kidney dysfunction in healthy individuals. PubMed Central (PMC)
However, this does not mean creatine should automatically be considered safe in every patient with significant kidney disease.
People with known CKD, rapidly changing kidney function, nephrotoxic medication exposure, or complex medical disease require individualized assessment.
Should everyone taking creatine get cystatin C?
No.
If someone is healthy, taking a typical dose of creatine, and has stable kidney markers, there may be little reason to repeatedly order cystatin C.
I would consider it when:
Creatinine increases after starting creatine
Creatinine-based eGFR becomes unexpectedly low
The patient has unusually high muscle mass
The result would lead someone to diagnose CKD
Medication dosing depends on the GFR
There is significant discordance between the laboratory result and the clinical picture
We need additional reassurance before continuing therapy
Testing should answer a question.
It should not simply create another number to track.
A practical approach for patients taking creatine
When a patient's creatinine appears elevated while taking creatine monohydrate, I generally think through the following:
1. Look at prior values
Is the creatinine actually new, or has it always been slightly elevated?
2. Ask about creatine use
Dose, duration, formulation, and timing matter.
3. Consider muscle mass and recent exercise
Hard resistance training can also influence laboratory results.
4. Review medications and hydration
Both can affect interpretation.
5. Check urine albumin when appropriate
Kidney disease is about more than serum creatinine.
6. Consider cystatin C
Especially when creatinine-based eGFR does not fit the clinical picture.
7. Use the combined eGFRcr-cys when appropriate
This frequently provides the best overall estimate.
8. Investigate true abnormalities
Persistent albuminuria, hematuria, progressive eGFR decline, hypertension, electrolyte abnormalities, or other concerning findings should not be dismissed simply because someone uses creatine.
When even cystatin C is not enough
There are situations where both creatinine and cystatin C may be unreliable.
When knowing kidney filtration precisely will change an important treatment decision, kidney specialists can measure GFR directly using an external filtration marker.
KDIGO recommends measured GFR when greater accuracy is needed for important clinical decisions and estimated methods remain uncertain. KDIGO
For routine preventive care, this is rarely necessary.
But it is useful to remember:
Every eGFR is still an estimate.
My practical take
Creatinine is an excellent screening tool, but it needs context.
The growing popularity of creatine monohydrate provides a perfect example.
Creatine is one of the better-studied supplements for strength and exercise performance. But because creatine metabolism contributes to serum creatinine, supplementation can make creatinine-based kidney function look somewhat worse without necessarily indicating kidney damage.
Rather than automatically stopping creatine or labeling a healthy athletic patient as having kidney disease, I would first ask whether creatinine is the right filtration marker for that individual.
Sometimes cystatin C provides the missing piece.
And when greater accuracy matters, combining cystatin C with creatinine often gives us a better estimate than either marker alone.
Bottom line
Creatinine-based eGFR remains an appropriate first-line kidney test for most people.
But serum creatinine can be influenced by muscle mass, exercise, diet, medications, and creatine supplementation.
If someone taking creatine develops an unexpected increase in creatinine or decline in eGFR, that does not automatically mean the supplement has damaged their kidneys.
In the right patient, checking cystatin C — and preferably calculating a combined creatinine-cystatin C eGFR — can help distinguish an altered creatinine level from a true reduction in kidney filtration.
The goal is not to order more biomarkers.
It is to use the right biomarker when the usual one may be misleading.