Understanding your kidney function: eGFR, creatinine, and cystatin C.

What eGFR actually tells you

GFR — glomerular filtration rate — is the gold standard measure of kidney function. It represents the volume of blood filtered by the kidneys' glomeruli per minute, expressed as mL/min/1.73m2 (normalized to body surface area). A normal GFR is above 90. Below 60 sustained for three months or more is the threshold for chronic kidney disease (CKD)[1].

True GFR is measured by injecting a tracer substance (iohexol or inulin) and measuring its clearance — a procedure that is accurate but impractical for routine use. So in clinical practice, GFR is estimated (hence "eGFR") from blood markers, primarily creatinine. The estimation equation takes your creatinine level, age, and sex and produces an eGFR number. That number appears on virtually every routine blood panel.

The problem is that the estimation is only as good as the input — and creatinine has significant limitations as an input.

Creatinine: useful but misleading

Creatinine is a waste product of creatine phosphate metabolism in skeletal muscle. It is produced at a relatively constant rate (proportional to muscle mass), filtered freely by the glomeruli, and not significantly reabsorbed. In theory, this makes it a reasonable filtration marker. In practice, several factors confound it[2]:

• Muscle mass: A muscular 30-year-old who lifts weights will have a creatinine of 1.2-1.4 mg/dL with perfectly healthy kidneys. The eGFR equation interprets this as reduced kidney function. Conversely, a frail 80-year-old with genuine kidney disease may have a creatinine of only 1.0 mg/dL because low muscle mass produces less creatinine.
• Diet: High-protein diets (especially red meat) increase creatinine production. A steak dinner the night before a blood test can raise serum creatinine by 10-30%[3].
• Creatine supplements: Creatine is metabolized to creatinine. Supplementation with creatine monohydrate raises serum creatinine without any effect on actual kidney function.
• Intense exercise: Heavy exercise in the 24-48 hours before testing can transiently elevate creatinine due to both muscle breakdown and temporary shifts in renal hemodynamics.
• Hydration: Dehydration concentrates the blood and raises creatinine. This is a measurement artifact, not kidney damage.
• Tubular secretion: Some creatinine is actively secreted by the renal tubules (not just filtered by glomeruli). This means creatinine clearance slightly overestimates true GFR, especially at lower GFR levels. Certain medications (trimethoprim, cimetidine) block this secretion and raise creatinine without affecting actual filtration[2].

The CKD-EPI 2021 equation

The equation used to calculate eGFR from creatinine has evolved over time. The most significant recent change was the CKD-EPI 2021 equation, which removed the race coefficient that had been included in previous versions (CKD-EPI 2009 and MDRD)[4].

The previous equations included a race multiplier (1.159 for Black individuals) based on the observation that Black Americans had higher average creatinine levels, attributed to greater average muscle mass. This was controversial for multiple reasons: it overestimated eGFR in Black patients, potentially delaying referral to nephrology and access to transplant waitlists. The 2021 equation eliminates the race variable entirely, using only creatinine, age, and sex. This is now the recommended equation by KDIGO (Kidney Disease: Improving Global Outcomes) and most major nephrology organizations[5].

Cystatin C: the better kidney marker

Cystatin C is a small protein (13 kDa) produced by all nucleated cells at a relatively constant rate. Unlike creatinine, its production is not significantly affected by muscle mass, diet, sex, or age (beyond the kidney aging effect itself). It is freely filtered by the glomeruli and almost completely reabsorbed and catabolized by the proximal tubules[6].

This makes cystatin C a more accurate filtration marker than creatinine in several populations:

• Muscular individuals: No false reduction in eGFR from high muscle mass
• Elderly or sarcopenic patients: No false reassurance from low creatinine due to low muscle mass
• Vegetarians and vegans: No dietary creatinine confound
• Creatine supplement users: No interference
• People at extremes of body composition: Amputees, bodybuilders, cachexic patients

KDIGO guidelines now recommend that when creatinine-based eGFR is between 45-90 mL/min and you need better accuracy, confirm with cystatin C-based eGFR or a combined creatinine-cystatin C equation[5]. The combined equation (using both creatinine and cystatin C) is the most accurate estimation method available, approaching the accuracy of measured GFR.

Cystatin C limitations

Cystatin C is not perfect. A few factors can influence it independently of kidney function:

• Thyroid disease: Hyperthyroidism increases cystatin C production; hypothyroidism decreases it[6]
• High-dose corticosteroids: Can increase cystatin C levels
• Obesity and inflammation: Some evidence of mildly increased cystatin C in states of significant systemic inflammation
• Cost and availability: Cystatin C is more expensive than creatinine and not yet universally available on standard panels

Urine albumin: the early warning signal

eGFR tells you how well the kidneys are filtering. Urine albumin tells you whether the kidney's filtration barrier is intact. These are complementary and both are needed for a complete picture[1].

Healthy glomeruli filter virtually no albumin (a large protein). Even small amounts of albumin leaking into urine indicate glomerular damage. The urine albumin-to-creatinine ratio (uACR) is the standard test:

Microalbuminuria (uACR 30-300) is the earliest detectable sign of diabetic nephropathy and a powerful independent predictor of cardiovascular events — even in people without diabetes[7]. It should be checked annually in anyone with diabetes, hypertension, or other CKD risk factors.

The stages of chronic kidney disease

Important nuance: an eGFR of 75 in a 25-year-old is very different from an eGFR of 75 in a 65-year-old. GFR naturally declines with age — approximately 1 mL/min/year after age 30-40[8]. An eGFR of 70 in a healthy 70-year-old may represent normal aging, while the same eGFR in a 30-year-old would be concerning. Context matters.

When to worry (and when not to)

Reasons for a low eGFR that are NOT kidney disease

• High muscle mass: Elevated creatinine from muscle, not kidney dysfunction. Confirm with cystatin C.
• Creatine supplementation: Increases serum creatinine directly. Confirm with cystatin C.
• Recent heavy exercise: Transient creatinine elevation. Retest after 48-72 hours of rest.
• Dehydration: Concentrated blood artificially raises creatinine. Retest when well-hydrated.
• High-protein meal: Steak or large protein load before the test. Fast or eat normally next time.
• Medications: Trimethoprim, cimetidine, and others block creatinine secretion without affecting GFR[2].

Reasons to take a low eGFR seriously

• Persistently low eGFR (confirmed on repeat testing 3 months apart)
• Declining eGFR trend over time (even within the "normal" range)
• Low eGFR confirmed by cystatin C-based equation
• Elevated urine albumin alongside low eGFR
• Presence of risk factors: diabetes, hypertension, family history of kidney disease, chronic NSAID use[1]

Hydration, protein, and practical confounders

Acute dehydration reduces renal blood flow and concentrates the blood, both of which raise creatinine and lower eGFR temporarily. This is pre-renal — the kidneys are fine, they just are not receiving as much blood to filter. If your eGFR comes back borderline on a day you were dehydrated, sick, or fasting for an extended period, retest when well-hydrated[8].

High-protein diets increase GFR (the kidneys filter more to clear the extra nitrogen load). This is called hyperfiltration. In people with healthy kidneys, current evidence does not show that this causes kidney disease[9]. However, in people with existing CKD, high protein intake accelerates decline, and protein restriction (0.6-0.8 g/kg/day) is a standard part of CKD management.

Medications that affect kidney markers

Several common medications can affect creatinine or eGFR without damaging the kidneys:

• ACE inhibitors / ARBs: Can raise creatinine by 10-20% when started (by reducing intraglomerular pressure). This is expected and usually protective. Concern arises if creatinine rises by more than 30%[1].
• NSAIDs: Reduce renal blood flow and can cause genuine kidney injury with chronic use. Periodic monitoring is warranted in regular NSAID users.
• SGLT2 inhibitors: Cause an initial eGFR dip (5-10 mL/min) that stabilizes and is ultimately renoprotective. The "dip and recover" pattern is well-characterized[10].
• Metformin: Does not damage kidneys but is dose-adjusted based on eGFR. Current guidelines allow metformin use at eGFR above 30.

Who should get cystatin C?

The short answer: anyone whose creatinine-based eGFR might be inaccurate. Specific situations where cystatin C adds real value:

• Muscular individuals or athletes with eGFR 60-90 on creatinine alone
• Elderly or frail patients where creatinine may underestimate kidney disease
• Creatine supplement users
• Vegetarians/vegans (lower dietary creatinine intake)
• Amputees or people with neuromuscular diseases
• Anyone with a borderline creatinine-based eGFR (45-90) where the clinical decision depends on the accuracy of the number[5]

The combined creatinine-cystatin C eGFR equation is the most accurate non-invasive kidney function estimate available[4]. If kidney function is an important clinical question — guiding medication dosing, surgical clearance, or CKD staging — both markers together give the best answer.