Kidney Health Basics: Creatinine, eGFR, Cystatin C, and BUN

Your kidneys are among the most metabolically active organs in the body. Every 24 hours, they filter roughly 180 litres of blood, reclaim nutrients, regulate electrolytes, manage blood pressure, and excrete waste through approximately one million nephron units — per kidney. Despite this workload, chronic kidney disease (CKD) is estimated to affect more than 10% of adults globally, and nearly 90% of those affected are unaware of their condition. The reason is straightforward: kidneys lose function silently. By the time symptoms emerge, a substantial proportion of filtration capacity may already be gone.

This is why biomarkers exist. Four measurements sit at the centre of kidney function assessment in modern laboratory medicine: serum creatinine, estimated glomerular filtration rate (eGFR), cystatin C, and blood urea nitrogen (BUN). Each reflects a different aspect of renal physiology. Each carries its own confounders and blind spots. And read together, they offer a substantially more complete picture than any single marker alone.

1. The Glomerular Filtration Rate: Why It Is the Central Metric

Kidney function is ultimately expressed as glomerular filtration rate (GFR) — the volume of blood plasma filtered through the glomeruli per unit time, measured in millilitres per minute per 1.73 m² of body surface area. The glomeruli are dense networks of specialised capillaries embedded within each nephron. They act as the primary filtration interface, retaining proteins and blood cells while allowing water, electrolytes, and small waste molecules to pass into the tubular system.

Direct GFR measurement, using exogenous markers such as inulin or iohexol, is accurate but logistically demanding — requiring intravenous infusion, timed collections, and specialised laboratory analysis. In routine clinical and biomarker practice, GFR is estimated from endogenous filtration markers: principally creatinine and cystatin C. These estimates are powerful tools for population-level screening and longitudinal tracking, but both introduce assumptions that are important to understand.

The clinical staging framework used worldwide is established by the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, which define five stages of kidney function based on eGFR:

• G1: eGFR ≥ 90 mL/min/1.73 m² — normal or high function
  
• G2: eGFR 60–89 — mildly decreased
  
• G3a/3b: eGFR 30–59 — moderately decreased
  
• G4: eGFR 15–29 — severely decreased
  
• G5: eGFR <15 — kidney failure

An eGFR above 90 mL/min/1.73 m² is generally considered within normal range in adults. It is important to note that eGFR naturally declines with age — the average decline from midlife onward is approximately 0.75–1 mL/min/1.73 m² per year in healthy individuals — which means the interpretation of a result at age 35 differs from that at age 70.

2. Creatinine: The Standard Marker and Its Limitations

Serum creatinine has been the cornerstone of kidney function assessment for decades. Creatinine is a metabolic waste product formed through the non-enzymatic breakdown of phosphocreatine in muscle tissue. It is released into the bloodstream at a relatively constant rate, freely filtered by the glomeruli, and excreted primarily in urine. When filtration declines, creatinine accumulates in the blood — which is the basis of its utility as a kidney biomarker.

However, creatinine is not produced uniformly across individuals. Its generation rate is directly proportional to muscle mass. A professional athlete with high skeletal muscle volume will naturally have higher baseline serum creatinine than a sedentary elderly person — not because of kidney dysfunction, but because of body composition. This creates two important clinical blind spots:

• False elevation: individuals with high muscle mass (athletes, bodybuilders) may show elevated creatinine despite normal kidney function, leading to unnecessary concern or investigation.
   
• False reassurance: individuals with low muscle mass (older adults, those with sarcopenia, prolonged illness, or low protein intake) may maintain serum creatinine within reference range even as filtration capacity meaningfully declines. Research suggests creatinine may not rise until approximately 50% of kidney function is already lost in low-muscle-mass populations.

Diet also introduces variability. A high-protein meal or creatine supplementation can transiently elevate serum creatinine independent of renal function. Studies confirm that creatine supplementation is associated with small but statistically significant increases in serum creatinine without corresponding changes in GFR — meaning the elevation is metabolic in origin rather than a sign of kidney impairment.

Despite these limitations, creatinine remains the standard first-line marker due to its cost-effectiveness, widespread availability, and the depth of clinical validation data behind it. It is measured via colorimetric (Jaffe) or enzymatic assays in serum or plasma, and is included as part of the Biostarks Metabolic Health panel.

3. eGFR: Translating Creatinine into Filtration Rate

Because serum creatinine alone is a concentration measurement rather than a rate, it is mathematically transformed into an estimated GFR using validated equations that incorporate additional demographic variables. The current guideline-recommended approach in most countries is the 2021 CKD-EPI creatinine equation, developed by the Chronic Kidney Disease Epidemiology Collaboration. Importantly, the 2021 revision removed the race coefficient that had been included in earlier versions — a modification driven by growing recognition that race is a social rather than biological construct, and that the earlier coefficient contributed to systematic inequities in clinical care.

The 2021 CKD-EPI equation incorporates age, sex, and serum creatinine to produce an eGFR estimate. Its accuracy is considered adequate for most clinical and screening contexts, though it inherits the muscle-mass sensitivity of creatinine itself. An important practical point: eGFR shows intra-individual day-to-day variability driven by hydration status, recent exercise, dietary protein intake, and sample handling. A single eGFR result should be interpreted in context, and a diagnosis of CKD requires confirmation at least 90 days apart by KDIGO criteria.

For longitudinal biomarker tracking — monitoring trajectory rather than diagnosing disease — eGFR derived from creatinine is a practical and informative metric. It is calculated automatically as part of the Biostarks Metabolic Health panel from the serum creatinine measurement, using the 2021 CKD-EPI formula.

4. Cystatin C: The Muscle-Independent Alternative

Cystatin C is a small (approximately 13 kDa) cysteine protease inhibitor produced at a constant rate by all nucleated cells in the body. Unlike creatinine, its production is not dependent on muscle mass. It is freely filtered at the glomerulus, completely reabsorbed and catabolised in the proximal tubule, and — crucially — not secreted back into the tubular lumen or into the bloodstream. This makes it a highly specific indicator of glomerular filtration.

The case for cystatin C as a superior or complementary filtration marker rests on several lines of evidence. A landmark meta-analysis published in the New England Journal of Medicine, encompassing over 90,000 participants across 16 cohorts, demonstrated that cystatin C-based eGFR reclassified CKD prevalence from 9.7% (creatinine-based) to 13.7% — identifying a substantially larger group at meaningful risk. Reclassification to lower eGFR using cystatin C was associated with significantly increased mortality, cardiovascular risk, and end-stage renal disease rates. This suggests that creatinine systematically underestimates kidney functional decline in lower-muscle-mass populations.

Cystatin C also detects acute filtration decline more rapidly than creatinine. In clinical studies of acute kidney injury, cystatin C levels peaked significantly earlier than creatinine following an injury event — providing a shorter diagnostic window and earlier opportunity for intervention.

The 2024 KDIGO Clinical Practice Guideline on CKD now explicitly endorses the combined use of both creatinine and cystatin C for the most accurate kidney function assessment, particularly in ambiguous cases. The combined CKD-EPI creatinine–cystatin C equation achieves greater accuracy than either marker alone. Current clinical guidance from the National Kidney Foundation and the American Society of Nephrology also recommends cystatin C, particularly as a confirmatory test when creatinine-based eGFR falls in the 45–60 mL/min/1.73 m² range without other markers of kidney damage.

Cystatin C is not entirely free of non-GFR determinants. Thyroid dysfunction, systemic corticosteroids, obesity, and some inflammatory states may influence levels. These confounders are generally less impactful on clinical interpretation than the muscle-mass dependency of creatinine, but they are relevant context when interpreting results in specific populations.

Cystatin C also carries relevance in the longevity and biological ageing context. Studies show that cystatin C levels rise progressively with age even in healthy individuals without clinical risk factors, and that lower baseline cystatin C — reflecting preserved filtration capacity — is associated with substantially better long-term survival trajectories. The discordance between cystatin C-based and creatinine-based eGFR in older adults (where cystatin C eGFR is lower) has been linked to increased risk of falls, hospitalisation, and all-cause mortality independent of kidney function staging — suggesting it may partially capture information about frailty and sarcopenia beyond filtration alone.

Cystatin C is currently in pipeline at Biostarks and is expected to be available for testing in late 2026.

5. Blood Urea Nitrogen (BUN): Protein Metabolism and Renal Clearance

BUN measures the nitrogen component of urea in blood. Urea is the primary end-product of protein catabolism: amino acids are deaminated in the liver, generating ammonia, which is rapidly converted to urea through the urea cycle. Urea is then released into the bloodstream and filtered by the kidneys for excretion in urine.

A normal adult BUN typically falls between 7 and 20 mg/dL, though reference ranges vary by laboratory and shift with age. BUN is not a direct measure of filtration rate, which is why it is rarely used in isolation. Multiple extra-renal factors elevate BUN independently of kidney function:

• High dietary protein intake
  
• Gastrointestinal bleeding (blood proteins are catabolised, increasing urea load)
  
• Catabolic states: fever, infection, corticosteroid use
  
• Dehydration (reduced renal perfusion with increased tubular urea reabsorption)
  
• Heart failure (reduced kidney perfusion)

Conversely, BUN may fall with low protein intake, liver disease (impaired urea synthesis), overhydration, or pregnancy.

Despite these confounders, BUN retains clinical utility — particularly when interpreted alongside creatinine through the BUN:creatinine ratio. A ratio above 20:1 is classically associated with pre-renal causes of kidney stress (dehydration, reduced cardiac output, hypovolemia), where urea disproportionately accumulates due to increased tubular reabsorption. A lower ratio suggests intrinsic kidney pathology or low urea production states. Importantly, prospective cohort data indicate that higher BUN levels in patients with stage 3–5 CKD are independently associated with worse renal outcomes even after adjusting for eGFR — suggesting BUN may carry prognostic signal beyond its role as a simple filtration surrogate.

BUN is measured via enzymatic urease-based assays in clinical chemistry settings and is typically reported as part of a comprehensive metabolic panel. It should be interpreted alongside creatinine and eGFR, not as a standalone kidney function metric.

6. Reading the Four Biomarkers Together: Interpretation Principles

The real clinical and biomarker value of this quartet emerges when the markers are read as a system rather than as individual data points. Several interpretive patterns are worth understanding:

• Creatinine high, eGFR low, BUN elevated, cystatin C high: consistent pattern across all markers suggesting reduced filtration. Warrants clinical evaluation.
  
• Creatinine high in isolation, eGFR borderline, BUN and cystatin C normal: may reflect high muscle mass rather than kidney impairment. Context — age, physical build, diet — is essential.
  
• Creatinine normal but cystatin C elevated: may indicate early filtration decline masked by low muscle mass, particularly relevant in older adults, individuals with sarcopenia, or those with prolonged illness. This discordance pattern is associated with elevated mortality risk in cohort data. 
• BUN:creatinine ratio >20 with mildly elevated creatinine: may suggest a pre-renal contributor (dehydration, high protein intake) rather than intrinsic kidney disease. Rehydration and repeat testing are appropriate first steps.
  
• Elevated BUN with normal or near-normal creatinine and eGFR: consider dietary protein load, gastrointestinal bleeding, or liver function as explanatory factors before attributing to kidney dysfunction.

Importantly, a single measurement is rarely sufficient. Kidney function biomarkers carry intra-individual variability. KDIGO guidelines require at least two eGFR measurements more than 90 days apart — both below 60 mL/min/1.73 m² — to diagnose CKD. Longitudinal tracking is therefore more informative than any single result. Rate of change over time — a declining trajectory even within the "normal" range — may be more clinically meaningful than a single absolute value.

7. Biomarker Mapping

The following table maps kidney health concepts to their primary biomarkers and measurement methods, in alignment with the Biostarks biomarker framework:

• Glomerular filtration capacity → eGFR (creatinine-based, 2021 CKD-EPI) → calculated from serum creatinine by enzymatic or Jaffe colorimetric assay
  
• Muscle-independent filtration assessment → Cystatin C → immunonephelometry or immunoturbidimetry; eGFR calculated via CKD-EPI Cys or combined creatinine–cystatin C equation
  
• Nitrogen waste clearance / protein catabolism → BUN → enzymatic urease assay (colorimetric)
  
• Pre-renal vs. renal differentiation → BUN:creatinine ratio → derived from BUN and serum creatinine
  
• Contextual interpretation: methylation and cardiovascular risk → Homocysteine — creatinine and kidney function markers are explicitly recommended as interpretation context for homocysteine results, since impaired renal clearance independently elevates homocysteine
  
• Contextual interpretation: inflammation and iron metabolism → Ferritin — CKD is a recognised context in which ferritin rises as an acute-phase reactant, and where iron deficiency thresholds require recalibration

Primary biomarkers: serum creatinine, eGFR, cystatin C, BUN
Secondary contextual biomarkers: BUN:creatinine ratio, homocysteine (clearance context), ferritin (inflammation and iron context in CKD), albumin (nutritional and proteinuria context)

8. How Biostarks Can Help

Creatinine and eGFR are currently included in the Biostarks Metabolic Health panel, providing a baseline window into filtration capacity as part of a broader metabolic biomarker picture that includes glucose metabolism, lipids, and hormones. Tracking these markers longitudinally — every three to six months under active optimisation, or annually for baseline maintenance — allows early detection of downward filtration trends before they reach clinical thresholds.

Cystatin C is currently in development and expected to be available within the Biostarks testing menu in late 2026. Its addition will enable the full combined creatinine–cystatin C eGFR equation, addressing the muscle-mass limitation inherent in creatinine-only estimation and providing greater accuracy in populations where this matters most: older adults, athletes, and individuals with body composition shifts.

Kidney function biomarkers do not exist in isolation. They interact with metabolic context — blood glucose and insulin resistance influence renal haemodynamics; inflammation elevates ferritin and confounds cystatin C; impaired filtration raises homocysteine independently of nutritional status. A panel-based approach to biomarker measurement is more informative than any single marker, and longitudinal data transforms individual results into actionable biological trajectories.

References

• Creatinine Clearance — StatPearls, NIH — Shahbaz H, Rout P, Gupta M — (2024) — Source
  
• New Creatinine- and Cystatin C–Based Equations to Estimate GFR without Race — New England Journal of Medicine — Inker LA et al. — (2021) — Source
  
• Cystatin C versus Creatinine in Determining Risk Based on Kidney Function — New England Journal of Medicine — Shlipak MG et al. — (2013) — Source
  
• Cystatin C as a Biomarker of Chronic Kidney Disease: Latest Developments — PMC — McMahon GM, Waikar SS — (2020) — Source
  
• Which is the Best Glomerular Filtration Marker: Creatinine, Cystatin C or Both? — European Journal of Clinical Investigation — Stehlé T et al. — (2024) — Source
  
• Biomarkers in Chronic Kidney Disease, from Kidney Function to Kidney Damage — PMC — Endre ZH et al. — (2015) — Source
  
• Large Discordance Between Creatinine-Based and Cystatin C-Based Estimated GFR in Older Adults — JASN — Shlipak MG et al. — (2024) — Source
  
• Blood Urea Nitrogen is Independently Associated with Renal Outcomes in Japanese Patients with Stage 3–5 CKD — PubMed — Kawakami et al. — (2019) — Source
  
• The Meaning of the BUN/Creatinine Ratio in Acute Kidney Injury — PMC — Beier K et al. — (2011) — Source
  
• Estimated GFR With Cystatin C and Creatinine in Clinical Practice — Kidney Medicine — Strohbehn IA et al. — (2023) — Source
  
• Estimated Glomerular Filtration Rate in Observational and Interventional Studies in CKD — PMC — (2024) — Source
  
• Effect of Creatine Supplementation on Kidney Function: Systematic Review and Meta-Analysis — PMC — (2025) — Source