What causes a discrepancy between estimated Glomerular Filtration Rate (eGFR) measured by creatinine and eGFR measured by cystatin C in patients?

Discrepancies Between Creatinine-Based and Cystatin C-Based eGFR

Discrepancies between eGFRcr and eGFRcys occur because creatinine and cystatin C are influenced by different non-GFR determinants—creatinine is primarily affected by muscle mass and diet, while cystatin C is influenced by inflammation, thyroid dysfunction, obesity, and steroid use. 1

Primary Mechanisms of Discrepancy

When eGFRcr is Higher Than eGFRcys (Most Common Pattern)

This pattern occurs in 25% of patients and indicates that creatinine-based estimates are overestimating true kidney function. 2

Key contributing factors include:

• Inflammation and comorbidities: Higher inflammatory states (elevated C-reactive protein), chronic illness burden (higher Elixhauser Comorbidity index), and systemic inflammation elevate cystatin C independent of GFR, lowering eGFRcys. 3, 4 This discrepancy is most pronounced in hospitalized patients (median delta 18 mL/min/1.73 m²) compared to outpatients (median delta 4 mL/min/1.73 m²). 3

• Obesity and metabolic factors: Higher body mass index, increased waist circumference, higher body fat percentage, diabetes, and elevated triglycerides are strongly associated with lower eGFRcys relative to eGFRcr along non-GFR pathways. 4, 2

• Thyroid dysfunction: Hypothyroidism increases cystatin C levels, while hyperthyroidism decreases them, creating discrepancies independent of kidney function. 2

• Steroid use: Exogenous corticosteroids elevate cystatin C levels, lowering eGFRcys. 1, 2

• Demographic factors: Older age, female sex, and non-Black race are independent predictors of having eGFRcys 30% lower than eGFRcr. 5, 2

When eGFRcr is Lower Than eGFRcys (Less Common Pattern)

This pattern occurs in 5% of patients and indicates that creatinine-based estimates are underestimating true kidney function. 2

Key contributing factors include:

• Reduced muscle mass: Conditions causing decreased creatinine generation include malnutrition, muscle wasting diseases, amputations, paralysis, advanced cirrhosis, cancer cachexia, and elderly frail patients. 1 These patients generate less creatinine independent of kidney function, artificially lowering eGFRcr. 1

• Dietary factors: Low-protein diets, ketogenic diets, and vegetarian diets reduce creatinine generation, while high-protein diets and creatine supplements increase it. 1

• Medications affecting creatinine secretion: Trimethoprim, cimetidine, and other drugs that block tubular secretion of creatinine increase serum creatinine without affecting GFR. 1

• Increased muscle mass: Bodybuilders and athletes generate more creatinine, potentially elevating eGFRcr above eGFRcys. 1

Clinical Significance of Discrepancies

Large positive discrepancies (eGFRcr >> eGFRcys) carry prognostic significance beyond kidney function alone. 6, 5

• Patients with eGFRcys 30% lower than eGFRcr have 2.12-fold higher risk of major adverse cardiovascular events (hazard ratio 2.12,95% CI 1.28-3.51) compared to those with concordant values. 6

• These patients demonstrate more coronary artery calcification (OR 1.38,95% CI 1.03-1.86) and accelerated calcification progression (≥50 Agatston units/year). 6

• Higher risk of mortality, kidney failure, AKI, and heart failure occurs in those with large discrepancies. 5

• More severe anemia, higher uric acid, elevated fibroblast growth factor 23, and higher phosphate levels are observed. 5

Recommended Clinical Approach

Use the combined creatinine-cystatin C equation (eGFRcr-cys) when discrepancies exist, as it consistently outperforms either marker alone and reduces the impact of non-GFR determinants. 1

Algorithmic Decision-Making:

1. Initial assessment: Start with eGFRcr for all patients. 1

2. Identify high-risk situations requiring cystatin C measurement: 1

   • Extremes of muscle mass (very low or very high)
   • Obesity class III (BMI >40 kg/m²)
   • Chronic inflammatory conditions
   • Malnutrition or muscle wasting diseases
   • Cirrhosis, cancer, heart failure
   • Steroid use
   • Dietary extremes (vegetarian, ketogenic, high-protein)
   • Medications affecting creatinine secretion

3. Measure cystatin C and calculate eGFRcr-cys in these situations. 1

4. Use eGFRcr-cys for all clinical decisions including CKD staging, medication dosing, and risk stratification when discrepancies exist. 1

Critical Pitfalls to Avoid

• Never rely on eGFRcr alone in hospitalized patients, as inflammation and comorbidities create large discrepancies with median differences of 18 mL/min/1.73 m². 3

• Do not assume eGFRcys is always more accurate—in patients with isolated muscle mass abnormalities without comorbid illness, eGFRcys alone may be appropriate, but when comorbidities exist, eGFRcr-cys is superior. 1

• Recognize that cystatin C has its own limitations: very high inflammation, high catabolic states, thyroid dysfunction, and exogenous steroids can render even eGFRcr-cys inaccurate. 1 In these extreme situations, measured GFR using exogenous filtration markers is needed. 1

• Understand that discrepancies provide clinical information: the direction and magnitude of eGFR differences are informative about underlying pathophysiology and prognosis, not just measurement error. 1