What does an elevated cystatin C level indicate?

Interpreting Cystatin C Levels

Elevated cystatin C levels primarily indicate decreased glomerular filtration rate (GFR) and are a more sensitive marker for early kidney dysfunction than serum creatinine, especially when GFR is mildly to moderately reduced. 1, 2, 3

Key Points About Cystatin C

• Production and Filtration

  • Low-molecular-weight protein (13 kDa) produced at a constant rate by all nucleated cells
  • Freely filtered by renal glomeruli and primarily catabolized in the tubules
  • Not secreted or reabsorbed as an intact molecule 1, 3

• Advantages Over Creatinine

  • Less influenced by age, sex, muscle mass, and diabetes than serum creatinine
  • More sensitive for detecting early kidney dysfunction
  • Can detect renal impairment when creatinine is still within normal range 2, 3

• Diagnostic Value

  • Begins to increase when GFR falls below approximately 88 mL/min/1.73m², whereas creatinine typically increases when GFR falls below 75 mL/min/1.73m² 3
  • Higher sensitivity (93.4%) than serum creatinine (86.8%) for detecting impaired renal function 3
  • Particularly useful in detecting mild reductions in GFR and early renal insufficiency 3

Clinical Applications

• GFR Estimation

  • Can be used alone or in combination with creatinine in equations to estimate GFR
  • The 2012 CKD-EPI cystatin C equation: 133 × min(SCysC/0.8,1)^-0.499 × max(SCysC/0.8,1)^-1.328 × 0.996^Age [×0.932 if female] 1
  • Combined creatinine-cystatin C equations have the least bias in GFR estimation in cirrhosis 1

• Early Detection of Kidney Disease

  • Identifies "preclinical" states of kidney dysfunction not detected by creatinine or estimated GFR 4
  • Useful in populations where creatinine may be misleading (elderly, reduced muscle mass, women) 2

• Prognostic Value

  • Strong predictor of cardiovascular events, heart failure, stroke, and mortality, even in patients without established chronic kidney disease 4
  • Elevated levels (≥1.0 mg/L) in patients without CKD indicate 4-fold increased risk for progressing to CKD after 4 years 4

Special Clinical Scenarios

• Liver Disease

  • In patients with chronic liver disease, cystatin C remains a reliable marker of kidney function rather than liver impairment 5
  • At a cutoff of 1.65 mg/L, shows 100% accuracy in discriminating between those with and without renal impairment in hepatic patients 5

• Obstructive Sleep Apnea

  • Higher levels observed in patients with OSA compared to controls
  • Positively correlated with T90 SpO2 and negatively correlated with mean SpO2 levels during sleep 1

Limitations and Pitfalls

• Non-Renal Influences

  • May be elevated in patients with malignant disease independent of renal function 6
  • Lower specificity in renal transplant patients with little discrimination between normal and pathological creatinine clearance levels 6

• Confirmatory Testing

  • When elevated, should be confirmed with repeat testing in 2-4 weeks 2
  • Consider additional markers such as albumin-to-creatinine ratio to assess for albuminuria 2

• KDIGO Strategy Limitations

  • The KDIGO strategy of using cystatin C only when eGFR-creatinine is between 45-60 mL/min may miss early kidney dysfunction in those with higher eGFR values 1
  • May not show added value in kidney transplant recipients compared to strategies based on serum creatinine alone 1

Clinical Decision Points

• Consider nephrology referral if:

  • Persistent elevation of cystatin C
  • Evidence of albuminuria
  • Rapid decline in kidney function (>5 mL/min/1.73m²/year)
  • eGFR <45 mL/min/1.73m² 2

• Medication dosing should be adjusted and more frequent monitoring of renal function implemented in patients with elevated cystatin C indicating reduced renal function 2