What is the best indicator of kidney function, creatinine or Glomerular Filtration Rate (GFR), in patients with known or suspected kidney disease?

GFR is the Best Indicator of Kidney Function

GFR (glomerular filtration rate) is unequivocally the best indicator of kidney function and should be used instead of serum creatinine alone for assessing kidney function in patients with known or suspected kidney disease. 1

Why GFR is Superior to Creatinine Alone

The Fundamental Problem with Creatinine

Serum creatinine alone is fundamentally inadequate for assessing kidney function because it:

• Fails to detect early kidney disease: GFR must decline to approximately half the normal level before serum creatinine rises above the upper limit of normal, meaning patients can have significantly impaired kidney function (GFR 30-60 mL/min/1.73 m²) while maintaining a "normal" creatinine of 1.3 mg/dL. 1

• Is influenced by non-renal factors: Creatinine levels are affected by muscle mass, age, sex, race, body size, dietary protein intake, and medications—all independent of actual kidney function. 1

• Grossly overestimates kidney function: Research demonstrates that relying on serum creatinine alone results in "gross and unpredictable overestimates of kidney function," with approximately 60% of patients showing abnormal renal function by eGFR but only 5% by serum creatinine alone. 1, 2

• Particularly misleading in elderly patients: Age-related decline in muscle mass reduces creatinine generation, masking the concurrent age-related decline in GFR, making creatinine especially unreliable in older adults. 1

Why GFR is the Gold Standard

GFR was specifically chosen by K/DOQI guidelines to classify chronic kidney disease severity because it represents the best overall measure of kidney function in both health and disease. 1

The advantages of GFR include:

• Direct measure of kidney filtration capacity: GFR quantifies the actual volume of plasma filtered by the kidneys per unit time, providing a true functional assessment. 1

• Standardized classification system: GFR enables consistent staging of CKD across all patients regardless of underlying diagnosis, facilitating communication among providers and with patients. 1, 3

• Earlier disease detection: GFR-based assessment identifies kidney dysfunction at earlier stages when interventions are most effective. 1

How to Assess GFR in Clinical Practice

Initial Assessment Algorithm

Start with estimated GFR using serum creatinine (eGFRcr) for all patients as the initial screening tool. 1, 2

• Use validated equations such as the 2021 race-free CKD-EPI equation that incorporate creatinine, age, and sex. 1, 2

• Clinical laboratories should automatically report eGFR alongside creatinine measurements. 1

• This approach is inexpensive, widely available, and easily repeatable. 2

When eGFRcr is Insufficient

Use combined creatinine-cystatin C equation (eGFRcr-cys) when eGFRcr is expected to be inaccurate and GFR affects clinical decision-making (KDIGO Grade 1C recommendation). 1, 2

Clinical situations requiring eGFRcr-cys include:

• Extremes of muscle mass: Very low muscle mass (malnutrition, amputation, muscle wasting) or very high muscle mass (bodybuilders). 1, 2

• Severe obesity: BMI >40 kg/m² reduces eGFRcr accuracy. 2

• Advanced cirrhosis or cancer: High catabolism and inflammation compromise creatinine-based estimates. 2

• Medications affecting creatinine: Trimethoprim, cimetidine, anabolic steroids alter creatinine secretion independent of GFR. 2

• Critical drug dosing decisions: Chemotherapy or other nephrotoxic medications requiring precise GFR. 2

• Dietary extremes: Vegetarian diet or creatine supplementation. 4

When to Measure GFR Directly

Measure GFR using plasma or urinary clearance of exogenous filtration markers (such as iothalamate or iohexol) when accurate GFR determination will impact treatment decisions and estimated GFR is thought to be inaccurate. 1, 2

Specific indications include:

• Extremes of age (very young or very old). 1
• Paraplegia or quadriplegia. 1
• Rapidly changing kidney function. 1
• Calculation of doses for potentially toxic drugs excreted by kidneys. 1
• When both eGFRcr and eGFRcr-cys are expected to be unreliable. 2

Critical Pitfalls to Avoid

Never Use Creatinine Alone

Clinicians should not use serum creatinine concentration as the sole means to assess kidney function (K/DOQI Level A recommendation). 1

This is a critical error that leads to:

• Missed diagnoses of significant kidney disease. 1, 2
• Inappropriate medication dosing. 1
• Delayed referral to nephrology. 1

Avoid Routine 24-Hour Creatinine Clearance

Measurement of creatinine clearance using timed urine collections does not provide more accurate estimates of GFR than prediction equations (Level A recommendation). 1, 4

The MDRD study demonstrated that predicted GFR is actually more accurate than measured creatinine clearance when compared to the gold standard (urinary clearance of ¹²⁵I-iothalamate). 1

Timed urine collections are:

• Inconvenient and frequently inaccurate due to collection errors. 1
• Only useful in exceptional circumstances (extremes of dietary intake, assessment of nutritional status). 4
• Should be considered only when measured GFR is unavailable and eGFRcr-cys is thought inaccurate. 1

Ensure Laboratory Standardization

Autoanalyzer manufacturers and clinical laboratories must calibrate serum creatinine assays using international reference standards (Level A recommendation). 1

• Differences in calibration can cause errors in GFR estimates as high as 20%, particularly problematic in patients with near-normal creatinine. 1
• The Jaffe method overestimates serum creatinine by 5-15% compared to enzymatic methods. 2
• Enzymatic assays are preferred, especially in children where non-creatinine chromogens have greater relative contribution. 1

Establishing CKD Diagnosis

CKD is diagnosed when GFR <60 mL/min/1.73 m² persists for ≥3 months, with or without other markers of kidney damage. 3

The diagnostic criteria require either:

• Kidney damage (pathological abnormalities, elevated albumin-to-creatinine ratio, abnormal imaging) present for ≥3 months with or without decreased GFR. 3
• GFR <60 mL/min/1.73 m² for ≥3 months regardless of whether other damage markers are present. 3

GFR-based staging classifies CKD severity into five stages, with stages 1-2 requiring evidence of kidney damage, while stages 3-5 are defined by GFR alone. 3