What does an elevated cystatin C level indicate and how is it managed?

Elevated Cystatin C: Clinical Significance and Management

An elevated cystatin C level indicates reduced kidney function (glomerular filtration rate) and should prompt calculation of eGFRcys and eGFRcreat-cys, assessment for chronic kidney disease, evaluation of cardiovascular risk, and investigation of potential non-renal causes including thyroid dysfunction. 1, 2, 3

What Elevated Cystatin C Indicates

Primary Indication: Reduced Kidney Function

• Cystatin C is a superior early marker of kidney dysfunction compared to creatinine alone, detecting GFR decline when it falls below 88 mL/min/1.73 m², whereas creatinine only rises when GFR drops below 75 mL/min/1.73 m² 4, 5
• Cystatin C is produced at a constant rate by all nucleated cells, freely filtered at the glomerulus, and catabolized in tubules without returning to the bloodstream, making it an ideal GFR marker 2, 4
• Unlike creatinine, cystatin C is independent of age, sex, and muscle mass, providing more reliable assessment in populations where creatinine is unreliable 1, 2

Prognostic Significance Beyond Kidney Function

• Elevated cystatin C strongly predicts cardiovascular mortality, heart failure, stroke, myocardial infarction, and all-cause death, even in patients without chronic kidney disease by creatinine-based criteria 6
• Each standard deviation increase in cystatin C (0.18 mg/L) confers a 33% increased risk of death, 42% increased risk of cardiovascular death, and 28% increased risk of heart failure 6
• Cystatin C >1.0 mg/L in patients without CKD by creatinine criteria indicates a 4-fold increased risk of progressing to CKD within 4 years 6

How to Calculate and Interpret eGFR

Step 1: Calculate eGFRcys Using the 2012 CKD-EPI Cystatin C Equation

• Use the 2012 CKD-EPI cystatin C equation to calculate eGFRcys from the measured cystatin C level 1, 2, 3
• Ensure the cystatin C assay is traceable to international standard reference materials 1

Step 2: Calculate Combined eGFRcreat-cys for Maximum Accuracy

• The combined creatinine-cystatin C equation (eGFRcreat-cys) provides the most accurate GFR estimation, achieving 89-95% of estimates within 30% of measured GFR 2, 7
• This combined approach is superior to either marker alone and should be used when both values are available 1, 2

Step 3: Interpret Results for CKD Diagnosis

• If eGFRcys or eGFRcreat-cys is <60 mL/min/1.73 m², CKD is confirmed (assuming duration >3 months) 1, 2, 3
• If eGFRcys/eGFRcreat-cys is ≥60 mL/min/1.73 m² in a patient with eGFRcreat 45-59 mL/min/1.73 m² and no albuminuria, CKD diagnosis is not confirmed 1, 2

Investigating Non-Renal Causes of Elevated Cystatin C

Critical Non-Renal Factors to Evaluate

Check thyroid function (TSH) as hypothyroidism increases cystatin C independent of GFR 3, 7

Assess smoking status as active smoking elevates cystatin C through non-GFR mechanisms 2, 3, 7

Review corticosteroid use as high-dose corticosteroids can affect cystatin C levels independent of kidney function 3, 7

Consider obesity and inflammation as class III obesity and inflammatory states can elevate cystatin C through non-renal pathways 2

Management Algorithm for Elevated Cystatin C

Immediate Assessment

• Obtain spot urine albumin-to-creatinine ratio (ACR) on first morning void to assess for albuminuria and kidney damage 3
• Perform urinalysis with microscopy to evaluate for intrinsic kidney disease 7
• Calculate both eGFRcys and eGFRcreat-cys using validated equations 2, 3

Risk Stratification and Cardiovascular Protection

• Initiate or optimize blood pressure control targeting <130/80 mmHg for cardiovascular risk reduction, as elevated cystatin C independently predicts cardiovascular events 3, 7
• Recognize that elevated cystatin C identifies patients at high cardiovascular risk who require aggressive risk factor modification 6

Monitoring Strategy

• Monitor kidney function every 3-6 months if eGFR is 30-45 mL/min/1.73 m² (Stage 3b CKD) 7
• Do not use cystatin C for routine CKD monitoring after diagnosis is established, as creatinine-based monitoring is sufficient and more cost-effective 2

When to Refer to Nephrology

• Consider nephrology referral for eGFR <30 mL/min/1.73 m², rapidly declining kidney function, or significant albuminuria (>300 mg/g) 7
• Refer for advanced CKD management and potential renal replacement therapy planning if eGFR approaches <20 mL/min/1.73 m² 7

Common Pitfalls and How to Avoid Them

Do Not Rely on Creatinine Alone in High-Risk Populations

• Creatinine significantly underestimates kidney dysfunction in patients with low muscle mass (elderly, malnutrition, neuromuscular disease, amputees) 2, 7
• In these populations, cystatin C detects kidney dysfunction that creatinine misses entirely 2

Recognize Limitations of Cystatin C

• Cystatin C can be elevated by thyroid dysfunction, smoking, high-dose corticosteroids, and certain malignancies independent of GFR 2, 3
• Always investigate these potential confounders before attributing elevated cystatin C solely to kidney dysfunction 3, 7

Avoid Overuse of Cystatin C

• The Canadian Society of Nephrology does not recommend widespread cystatin C use due to lack of evidence for improved outcomes and cost-effectiveness 2
• Reserve cystatin C for confirmatory testing when creatinine-based eGFR is unreliable or when accurate GFR assessment is critical for treatment decisions 1, 2

Understand When Combined Equations Are Less Accurate

• In patients with malnutrition, chronic illness, or high cell turnover cancers, both creatinine and cystatin C are affected, reducing accuracy of combined equations 2
• In these situations, consider measured GFR using exogenous filtration markers for treatment decisions 1, 2