What are the reasons for a discrepancy between an estimated Glomerular Filtration Rate (eGFR) with creatinine and an eGFR adjusted with creatinine?

Reasons for Discrepancy Between eGFR with Creatinine and eGFR Adjusted with Creatinine

Discrepancies between creatinine-based eGFR (eGFRcr) and combined creatinine-cystatin C-based eGFR (eGFRcr-cys) are primarily due to non-GFR determinants of creatinine that affect its generation, secretion, or elimination independent of actual kidney function. 1

Common Factors Causing eGFRcr to Differ from eGFRcr-cys

Muscle Mass and Creatinine Generation

• Decreased muscle mass: Leads to lower creatinine generation, causing eGFRcr to be higher than eGFRcr-cys
  • Seen in elderly patients, malnutrition, muscle wasting diseases
  • Can result in overestimation of true GFR by eGFRcr 1
• Increased muscle mass: Athletes, bodybuilders, or those with high muscle mass
  • Results in higher creatinine generation and lower eGFRcr than eGFRcr-cys 1

Dietary Factors

• Low-protein diet: Reduces creatinine generation
• Vegetarian diet: Lower creatinine generation due to reduced meat intake
• High-protein diets and creatine supplements: Increase creatinine levels
• Keto diets: Can affect creatinine levels independent of kidney function 1

Medications

• Drugs affecting tubular secretion of creatinine: Trimethoprim, cimetidine, dolutegravir
  • Decrease creatinine secretion, leading to higher serum creatinine without actual GFR change
• Steroids (anabolic, hormone): Affect non-GFR determinants of creatinine 1
• Broad-spectrum antibiotics: Can decrease extrarenal elimination of creatinine 1

Chronic Illness

• Malnutrition, cancer, heart failure, cirrhosis: These conditions affect both creatinine and cystatin C generation
• Catabolic states: Tuberculosis, AIDS, hematologic malignancies
• Inflammation: Can affect cystatin C levels more than creatinine 1

Clinical Significance of Discrepancies

Impact on Patient Outcomes

• Patients with eGFRcys significantly lower than eGFRcr (negative eGFRdiff) have:
  • Higher risk of acute kidney injury (2.6 times higher)
  • Increased risk of kidney failure requiring replacement therapy (1.4 times higher)
  • Higher cardiovascular disease risk (1.4 times higher)
  • Increased mortality (2.6 times higher) 2

Medication-Related Adverse Events

• Patients with eGFRcys >30% lower than eGFRcr have higher rates of:
  • Supratherapeutic vancomycin levels (24% vs 10%)
  • Trimethoprim-sulfamethoxazole-related hyperkalemia (24% vs 12%)
  • Baclofen-induced neurotoxicity
  • Supratherapeutic digoxin levels 3

Recommended Approach to Discrepancies

When to Use Combined eGFRcr-cys

• When eGFRcr and eGFRcys are discordant, eGFRcr-cys provides the most accurate estimate of true GFR 4, 5
• KDIGO recommends using eGFRcr-cys in clinical situations when:
  • eGFRcr is less accurate
  • GFR affects clinical decision-making 1

Algorithm for GFR Assessment

1. Start with eGFRcr (standard initial assessment)
2. Consider potential sources of error in eGFRcr
3. If eGFRcr is thought to be inaccurate, measure cystatin C
4. Calculate eGFRcr-cys
5. If even more accurate assessment is needed, consider measured GFR 1

Important Caveats and Pitfalls

• Magnitude of discrepancy matters: Larger discrepancies (>15 mL/min/1.73m²) between eGFRcr and eGFRcys indicate higher likelihood of inaccuracy in one or both markers 5
• Combined equation is most reliable: When discrepancies exist, eGFRcr-cys is more accurate than either equation alone 4
• Avoid relying solely on serum filtration markers: Always use validated estimating equations rather than raw creatinine or cystatin C values 1
• Consider measured GFR: In cases where even eGFRcr-cys may be inaccurate (e.g., advanced cirrhosis, cancer with high cell turnover) or when precise GFR is needed for critical clinical decisions (e.g., kidney-cleared chemotherapeutic agents) 1

Understanding these discrepancies is crucial for accurate clinical decision-making, particularly for medication dosing, CKD staging, and risk assessment.