In adults with suspected early chronic kidney disease where serum creatinine‑based estimated glomerular filtration rate (eGFR) is unreliable (e.g., elderly, low or abnormal muscle mass, obesity, rapid renal function change, pregnancy), what is the clinical significance of measuring cystatin C for kidney function assessment?

Clinical Significance of Cystatin C in Suspected Early Kidney Disease

Cystatin C measurement is clinically significant for confirming or excluding chronic kidney disease (CKD) in adults with borderline creatinine-based eGFR (45-59 mL/min/1.73 m²) who lack other markers of kidney damage, as it prevents misclassification in approximately 42% of these patients. 1

Primary Clinical Algorithm for Cystatin C Use

The KDIGO guidelines establish a stepwise approach that prioritizes selective, not universal, cystatin C testing 2:

• Start with creatinine-based eGFR (eGFRcr) as the initial assessment for all patients 1
• Add cystatin C measurement when eGFRcr is suspected to be inaccurate or when clinical decisions require greater accuracy 2, 3
• Calculate the combined creatinine-cystatin C equation (eGFRcr-cys) as it consistently outperforms either marker alone 1, 2

Confirmatory Testing in Borderline CKD (Grade 2C Recommendation)

Measure cystatin C in adults with eGFRcr 45-59 mL/min/1.73 m² who do not have markers of kidney damage (such as albuminuria) if confirmation of CKD is required 1:

• If eGFRcys or eGFRcr-cys is ≥60 mL/min/1.73 m², the diagnosis of CKD is not confirmed 1
• If eGFRcys or eGFRcr-cys is <60 mL/min/1.73 m², CKD diagnosis is confirmed 1
• This approach is critical because 42% of patients with eGFRcr 45-59 mL/min/1.73 m² have eGFRcys ≥60 mL/min/1.73 m², indicating normal kidney function 1

Specific Clinical Situations Where Cystatin C is Essential

Cystatin C should be measured when creatinine-based estimates are unreliable due to non-GFR determinants 2, 3:

Muscle Mass Extremes

• Reduced muscle mass: elderly patients, malnutrition, muscle wasting diseases, amputees, paralysis 2, 3
• Increased muscle mass: bodybuilders, athletes 2

Dietary Factors Affecting Creatinine

• Low-protein diets, ketogenic diets, vegetarian diets 2, 3
• High-protein diets, creatine supplements 2

Chronic Illness States

• Cirrhosis and other conditions where both creatinine and cystatin C non-GFR determinants are affected 2

Critical Clinical Decisions

• CKD diagnosis and staging 2, 3
• Medication dosing decisions 2, 3
• Timing of dialysis initiation 2
• Preemptive kidney transplant listing 1, 2

Superiority of the Combined Equation (eGFRcr-cys)

The combined creatinine-cystatin C equation demonstrates the highest accuracy across all patient populations 1, 2, 3:

• Improved precision compared to either marker alone 2, 3
• Better risk stratification for mortality and cardiovascular events 1, 2
• More accurate medication dosing decisions 2, 3
• Correct GFR classification rates of 62% compared to 38% for eGFRcr alone and 45% for eGFRcys alone 3

Key Advantages of Cystatin C Over Creatinine Alone

Cystatin C has superior diagnostic characteristics for early kidney disease 2, 3, 4:

• Independent of muscle mass, age, sex, and diet 2, 3
• Diagnostic accuracy of 90% for discriminating normal from reduced GFR, compared to 77% for creatinine 2, 3
• Detects early kidney dysfunction earlier than creatinine, particularly in patients with diabetes 3, 5
• Fewer non-GFR determinants than creatinine 2, 3

Important Limitations and Caveats

Be aware of situations where cystatin C may be inaccurate 2, 3:

• Very low muscle mass (use eGFRcys alone in otherwise healthy individuals) 2
• Very high levels of inflammation 2, 3
• High catabolic states 2, 3
• Exogenous steroid use 2, 3
• Thyroid dysfunction: hypothyroidism increases cystatin C levels; hyperthyroidism decreases them 3

Clinical Decision Algorithm for Limitations

• Use eGFRcys alone in otherwise healthy individuals with isolated reduction or increase in muscle mass 2
• Use eGFRcr-cys when comorbid illnesses are present or most accurate assessment is needed 2

Laboratory Reporting Standards (Grade 1B Recommendation)

Clinical laboratories that measure cystatin C must 1:

• Measure serum cystatin C using an assay with calibration traceable to international standard reference material 1
• Report serum cystatin C concentration rounded to the nearest 0.01 mg/L 1, 2
• Report eGFRcys and eGFRcr-cys rounded to the nearest whole number in mL/min/1.73 m² 1, 2
• Report eGFRcys and eGFRcr-cys levels <60 mL/min/1.73 m² as "decreased" 1
• Use a GFR estimating equation to derive GFR from serum cystatin C rather than relying on the serum cystatin C concentration alone 1

Practical Implementation Considerations

Laboratory Availability

Many laboratories in the United States do not routinely perform cystatin C assays on-site and must send specimens to reference laboratories, which can take several days to over a week for results 6. This requires advance planning when ordering the test 6.

Cost-Effectiveness Context

While the Canadian Society of Nephrology noted in 2015 that widespread cystatin C use lacked cost-effectiveness data and effectiveness had yet to be demonstrated 1, the KDIGO 2024 guidelines now strongly recommend its use in specific clinical situations where accuracy impacts outcomes 2, 3. The key is selective, not universal, application in populations where creatinine-based estimates are known to be unreliable 2.

When NOT to Use Cystatin C Routinely

The Canadian Society of Nephrology explicitly stated: "We do not recommend the widespread use of cystatin C in clinical practice" 1. This reflects the importance of targeted use in specific clinical scenarios rather than routine screening 1.

Risk Stratification and Prognostic Value

Beyond diagnosis, cystatin C provides superior risk stratification 1, 2:

• Cystatin C markedly strengthens the association between eGFR and cardiovascular events, kidney failure, and death 1
• Lower eGFR and higher albuminuria are both strongly associated with risks of cardiovascular events, kidney failure, and mortality 1
• The combined assessment of eGFR (using cystatin C) and albuminuria is critical for effective risk stratification 1

Common Pitfalls to Avoid

Pitfall 1: Relying on Cystatin C Concentration Alone

Always use a GFR estimating equation to derive GFR from serum cystatin C rather than interpreting the concentration alone 1. The raw cystatin C value without calculation into eGFR has limited clinical utility 1.

Pitfall 2: Ignoring Discordance Between eGFRcr and eGFRcys

When eGFRcys is higher than eGFRcr, the creatinine-based estimate is typically underestimating true kidney function, often due to reduced muscle mass 3. Always use the combined eGFRcr-cys equation in cases of discordance 3.

Pitfall 3: Using Creatinine-Based eGFR for Medication Dosing in High-Risk Populations

In patients with altered muscle mass or other conditions affecting creatinine, using eGFRcr for medication dosing may lead to inappropriate dose adjustments 3. Use eGFRcr-cys for all medication dosing decisions in these populations 3.

Pitfall 4: Failing to Confirm CKD Diagnosis

CKD diagnosis requires persistence of reduced eGFR for ≥3 months 3. Repeat both creatinine and cystatin C in 3 months to confirm stability and recalculate eGFRcr-cys 3.

Clinical Significance Summary

The clinical significance of cystatin C determination in suspected early kidney disease is substantial and evidence-based 1, 2, 3:

1. Prevents misdiagnosis: Identifies 42% of patients with borderline eGFRcr who actually have normal kidney function 1
2. Improves accuracy: Provides 90% diagnostic accuracy versus 77% for creatinine alone 2, 3
3. Guides treatment decisions: More accurate GFR estimates lead to appropriate medication dosing, timing of interventions, and risk stratification 2, 3
4. Detects disease earlier: Identifies kidney dysfunction at earlier stages than creatinine, particularly in diabetes 3, 5
5. Reduces health disparities: Offers GFR estimates that do not require race coefficients 1