What are alternative methods to assess renal function beyond creatinine levels?

Alternative Methods to Assess Renal Function Beyond Creatinine

Use cystatin C-based equations (CKD-EPI-CystC or CKD-EPI-Cr-CystC) as the primary alternative to creatinine for confirmatory testing, or measure GFR directly using exogenous filtration markers like iohexol when accurate GFR determination will impact treatment decisions. 1

Cystatin C-Based Assessment

Cystatin C provides superior renal function assessment compared to creatinine alone, particularly in populations where creatinine-based estimates are unreliable. 1

• Cystatin C is a low molecular weight protein produced at a constant rate by all nucleated cells and is less influenced by muscle mass, gender, age, and nutritional status compared to creatinine. 1
• Among liver transplant recipients, cystatin C-based equations demonstrated superior performance (r²=0.78-0.83) compared to creatinine-based equations (r²=0.76-0.77) in estimating measured GFR. 1
• The combination of creatinine and cystatin C (CKD-EPI-Cr-CystC equation) provides the most precise estimate of measured GFR and improves risk stratification. 1
• KDIGO guidelines recommend using cystatin C for confirmatory testing in specific circumstances when eGFR based on creatinine is less accurate, particularly in patients with eGFR 45-59 mL/min/1.73 m² without albuminuria. 1

Limitations of Cystatin C

• Cystatin C still underestimates measured GFR by approximately 12%, particularly in low GFR groups. 1
• It is more expensive than creatinine testing and has its own non-GFR determinants that can affect accuracy. 1

Direct Measurement of GFR Using Exogenous Markers

Direct GFR measurement represents the gold standard and should be used when accurate ascertainment will impact treatment decisions. 1

Iohexol Plasma Clearance

• Iohexol is the preferred exogenous marker, with recent consensus standardization protocols published by the European Kidney Function Consortium in 2024. 1
• Iohexol is filtered without secretion or reabsorption by renal tubules and is exclusively eliminated by the kidneys unbound to proteins. 1
• The 2024 KDIGO guidelines specifically recommend harmonizing and standardizing mGFR protocols to improve accuracy and comparability. 1

Other Exogenous Markers

• Inulin clearance was the original gold standard but is laborious and requires IV infusion with reliable urine collection. 1
• Iothalamate (including ¹²⁵I-iothalamate) can be used for urinary or plasma clearance measurements. 1
• Tagged radioisotopes (such as ⁵¹Cr-EDTA) can estimate GFR through filtration and clearance measurements. 1

When Direct Measurement is Necessary

Direct GFR measurement should be performed in the following clinical scenarios: 1, 2

• Extremes of age and body size
• Severe malnutrition or obesity
• Diseases of skeletal muscle
• Paraplegia or quadriplegia
• Vegetarian diet
• Rapidly changing kidney function
• Calculation of doses for potentially toxic drugs that are renally excreted

Alternative Creatinine-Based Approaches for Specific Situations

For Unstable Kidney Function (ICU/Acute Settings)

• The Jelliffe equation for unstable kidney function calculates GFR based on volume of distribution and creatinine kinetics rather than steady-state parameters. 1
• Kinetic eGFR estimates GFR based on creatinine kinetics and has shown promise but requires validation in hospitalized patients with native kidneys. 1
• Standard eGFR equations (MDRD, CKD-EPI) cannot be used in ICU settings because they require serum creatinine to be in steady-state. 1

Short Timed Urine Creatinine Clearance

• Short timed urine creatinine clearance can be used as an alternative to estimate GFR in acute settings. 1
• However, creatinine clearance overestimates true GFR because creatinine is both filtered and secreted by the kidneys, especially in patients with AKI. 1, 2

Common Pitfalls and Caveats

Never use serum creatinine concentration alone to assess kidney function. 1, 2

• GFR must decline to approximately half the normal level before serum creatinine rises above the upper limit of normal. 1
• In elderly patients, serum creatinine does not reflect age-related GFR decline due to concomitant decline in muscle mass. 1

24-hour urine creatinine clearance does not provide more accurate estimates than prediction equations and is fraught with collection errors. 1, 3

Be aware of laboratory method differences: 2, 4

• The Jaffe method overestimates serum creatinine by 5-15% compared to enzymatic methods
• When using enzymatic methods, consider adding 0.2 mg/dL to avoid underdosing medications

Recognize that all creatinine-based equations have significant limitations in certain populations: 1, 2

• Not validated in diabetic kidney disease
• Less accurate in patients with serious comorbid conditions
• Should be avoided in normal persons or GFR >60 mL/min/1.73 m²
• Unreliable in persons older than 70 years