What is the cystatin C effect?

Understanding the Cystatin C Effect in Kidney Function Assessment

Cystatin C is a superior biomarker for estimating glomerular filtration rate (GFR) that provides more accurate kidney function assessment than creatinine alone, particularly for early detection of kidney dysfunction and improved risk stratification for cardiovascular and mortality outcomes. 1

What is Cystatin C?

• Cystatin C is a non-glycosylated basic protein produced at a constant rate by all nucleated cells, freely filtered by the renal glomeruli, and primarily catabolized in the tubules without being secreted or reabsorbed as an intact molecule 2, 3
• Unlike creatinine, cystatin C production is largely independent of age, sex, muscle mass, and other non-renal factors that affect creatinine levels 4, 3
• It belongs to the cysteine proteinase inhibitor superfamily with a molecular mass of approximately 13 kDa 5

Clinical Advantages of Cystatin C

Enhanced GFR Estimation

• Cystatin C provides more accurate GFR estimation than creatinine alone, especially for detecting mild reductions in kidney function 2, 3
• It can detect kidney dysfunction at earlier stages (when GFR is around 88 mL/min/1.73m²) compared to creatinine (which detects at around 75 mL/min/1.73m²) 2
• The 2021 KDIGO conference strongly recommended using creatinine and cystatin C in parallel for more accurate CKD diagnosis and staging with less misclassification 1

Improved Risk Stratification

• Cystatin C markedly strengthens the association between estimated GFR and cardiovascular events, kidney failure, and mortality 1
• Higher levels of cystatin C are predictive of incident or recurrent cardiovascular events and adverse outcomes 6
• It serves as an independent biomarker associated with renal resistive index in CKD patients, indicating its relationship with vascular dysfunction 7

Clinical Applications

CKD Diagnosis and Confirmation

• KDIGO guidelines recommend measuring cystatin C in adults with eGFRcreat 45-59 mL/min/1.73m² who don't have markers of kidney damage to confirm CKD diagnosis 1, 4
• The "triple marker" panel (serum creatinine, serum cystatin C, and urine albumin-to-creatinine ratio) is recommended for comprehensive CKD assessment 1

Special Populations

• Particularly valuable in populations where creatinine may be unreliable, such as:
  • Elderly patients 1, 4
  • Individuals with low muscle mass 4
  • Cancer patients receiving nephrotoxic medications 1
  • Liver transplant recipients 1, 4

Practical Implementation

GFR Estimation Equations

• Three main equations are recommended by KDIGO 4:
  • eGFRcys (using cystatin C alone)
  • eGFRcreat (using creatinine alone)
  • eGFRcreat-cys (combined equation using both markers)
• The combined equation (eGFRcreat-cys) provides the most accurate GFR estimation 1, 4

Reclassification Effect

• In a meta-analysis of 90,750 participants, 23% of persons with eGFRcreat 60-74 mL/min/1.73m² had eGFRcys <60 mL/min/1.73m² 1
• Conversely, 42% of persons with eGFRcreat 45-59 mL/min/1.73m² had eGFRcys ≥60 mL/min/1.73m² 1
• This reclassification has important implications for CKD diagnosis and management

Limitations and Controversies

• The added value of cystatin C for CKD detection in kidney transplant recipients has been questioned, with some studies showing no advantage over creatinine-based strategies 1
• Cystatin C levels can be affected by thyroid dysfunction, smoking, and certain types of cancer 4
• Limited availability and higher cost compared to creatinine testing in many healthcare settings 1, 4
• The higher prognostic value of cystatin C compared to creatinine remains controversial in some populations 1

Future Directions

• National efforts to facilitate increased, routine, and timely use of cystatin C are recommended, especially to confirm eGFR in adults at risk for or with CKD 4
• Standardization of cystatin C assays with calibration traceable to international reference materials is essential for reliable results 4