PATHCHAT Edition No. 49
September 2018
Please contact your local Ampath pathologist for more information.
Author: Dr. Marita du Plessis
Introduction
✅ Chronic Kidney Disease (CKD) is increasing globally.
- Diagnosis relies on estimated glomerular filtration rate (eGFR), urine sediment analysis, and protein excretion assessment.
- GFR estimation is essential for staging CKD and adjusting dosages of medications with narrow therapeutic windows (e.g., cytotoxic drugs).
- Early detection allows interventions (e.g., ACE inhibitors) to slow disease progression.
📌 CKD is defined as either a GFR < 60 mL/min/1.73m² or kidney damage markers (e.g., albuminuria) for at least three months.
GFR Estimation & Creatinine Limitations
✅ Gold Standard GFR Measurement:
- Inulin clearance is the most accurate method but is expensive and impractical for routine use.
✅ Routine GFR Estimation Methods:
- Creatinine Clearance (Requires 24-hour urine collection).
- Serum Creatinine-Based eGFR Equations (e.g., CKD-EPI, MDRD).
🔹 Limitations of Creatinine-Based GFR Estimation:
- Creatinine is affected by muscle mass, diet, and tubular secretion.
- Delays in creatinine elevation make it an unreliable early marker of acute kidney injury (AKI).
- Tubular secretion increases as GFR declines, overestimating renal function.
📌 Creatinine overestimates true GFR by 10–20%, particularly in advanced CKD.
Cystatin C: A Superior Alternative to Creatinine
✅ What is Cystatin C?
- A low molecular weight (13,250 kDa) cysteine proteinase inhibitor produced by all nucleated cells at a constant rate.
- Freely filtered by glomeruli and completely reabsorbed and metabolized by proximal tubules.
- Not secreted or excreted in urine, making it a more accurate GFR marker than creatinine.
✅ Advantages of Cystatin C Over Creatinine:
- Unaffected by muscle mass, diet, or ethnicity.
- More sensitive in detecting early kidney dysfunction.
- More accurate for acute kidney injury (AKI) due to faster equilibration.
- More reliable in elderly, children, and patients with low muscle mass (e.g., cirrhosis, cachexia).
📌 Cystatin C-based eGFR (eGFRcys) provides a more precise renal function estimate in patients with chronic illness or low muscle mass.
Factors Affecting Cystatin C Levels
✅ Increased Cystatin C Levels (Independent of GFR):
- Hyperthyroidism.
- Obesity (increased BMI or fat mass).
- Diabetes (8.5% higher than non-diabetics).
- Inflammation (correlated with CRP, WBC count).
- Cigarette smoking.
- Corticosteroid or immunosuppressant use.
✅ Decreased Cystatin C Levels:
- Hypothyroidism.
- Advancing age (4.3% lower per 20 years of age).
- Female sex (requires sex-specific reference ranges).
📌 Corticosteroids and immunosuppressants increase Cystatin C, limiting its use in oncology and transplant patients.
Current Recommendations for GFR Estimation
✅ Key Guidelines for eGFR Testing (KDIGO 2013 & UpToDate 2018):
✔ 1. Use a GFR Estimating Equation:
- eGFRcreat (creatinine-based) or eGFRcys (Cystatin C-based) is preferred over single serum markers.
✔ 2. Combined Creatinine + Cystatin C Equation (eGFRcreat-cys) Is More Accurate:
- Improves precision and accuracy over creatinine or cystatin C alone.
✔ 3. Clinical Situations Where eGFRcys or eGFRcreat-cys is Preferred:
- Adults with eGFRcreat 45–59 mL/min/1.73m² and no markers of kidney damage (for CKD confirmation).
- Patients with factors affecting creatinine measurement:
- High/low muscle mass (children, elderly, cirrhosis, amputees, neuromuscular disease).
- Dietary extremes (high-protein, vegetarian, creatine supplements).
- Kidney donor evaluation.
✔ 4. Drug Dosing & eGFR Correction for Body Size:
- Most eGFR equations are standardized to a body surface area of 1.73 m².
- For accurate drug dosing in very small or large patients, body surface area (BSA) correction is required.
- If corrected eGFR is needed, provide the patient’s height and weight and request ‘Creatinine eGFR corrected’ (mnemonic CRC).
📌 For paediatric patients, the updated Schwartz formula is used to calculate eGFR.
Conclusion
✅ Cystatin C is a superior renal function biomarker, especially in patients with altered muscle mass.
✅ Cystatin C-based eGFR (eGFRcys) is more accurate for CKD and acute kidney injury than creatinine.
✅ Combining creatinine and cystatin C (eGFRcreat-cys) improves precision.
✅ Cystatin C should be considered in select patient populations (elderly, transplant recipients, cirrhotics, amputees, cachectic patients).
✅ Drug dosing should consider BSA-corrected eGFR in non-average-sized patients.
📌 Cystatin C testing provides a valuable alternative for estimating renal function, particularly when creatinine is unreliable.