Concordance of Chronic Kidney Disease Stage and Metformin Management Using CKD-EPI 2021 Race-Free Equation vs CKD-EPI 2009 Equation to Estimate Glomerular Filtration Rate Free

To the Editor:

Metformin is a first-line agent for the treatment of hyperglycemia in type 2 diabetes. However, the risk of lactic acidosis necessitates close monitoring of renal function (1). The Kidney Disease: Improving Global Outcomes (KDIGO) organization clinical practice guidelines recommend using an estimation of glomerular filtration rate (eGFR) to assess renal function, categorize chronic kidney disease (CKD) stage, and guide metformin management (2). Multiple professional organizations have recommended implementation of the new CKD Epidemiology Collaboration (CKD-EPI) 2021 race-free eGFR equation, calculated from creatinine (eGFR_cr), that does not disproportionately affect any one group of individuals (35). In order to assess the potential impact of implementation, a retrospective analysis was performed to determine concordance of CKD stage and metformin management categories using the CKD-EPI 2021 vs CKD-EPI 2009 eGFR_cr equations.

Creatinine concentration (first result used if multiple measurements available), age, hemoglobin A_1c (HbA_1c), and race from patients 18 years old with an active metformin medication between April 1, 2021, and July 1, 2021, were retrieved from the electronic health record. eGFR_cr was calculated from reported serum creatinine (mg/dL) using both the CKD-EPI 2021 and CKD-EPI 2009 equations. Concordance, defined as the number (percentage) of eGFR_cr values that fell into the same CKD stage and metformin management categories using each equation, was evaluated in both self-reported Black and non-Black patients. Patients whose race was listed as unknown in the medical record were excluded. Metformin management recommendation categories were defined according to the KDIGO Clinical Practice Guidelines for the Evaluation and Management of Chronic Kidney Disease. KDIGO recommends continuing metformin use in patients with an eGFR_cr 45 mL/min/1.73 m² (CKD-1 to -3a), reviewing use for potential dosage adjustments with an eGFR_cr 30 to 44 (CKD-3b), and discontinuing use when eGFR_cr is 30 (CKD-4 to -5).

A total of 6757 unique individuals were identified with an active metformin prescription and creatinine measurement during the 3-month interval (IRB-22-0205). Patient demographics in the sample cohort were self-reported Black (n 2076; 30.7) or non-Black (n 4681; 69.3) individuals. The cohort was 53.6 female and 46.4 male ranging in age from 18 to 99 years old (mean 61.9 13.5 years). The mean and SD of serum creatinine for all individuals was 0.95 (84 umol/L) and 0.48 mg/dL (42 umol/L) with a range of 0.20 (17 umol/L) to 15.52 mg/dL (1372 umol/L).

Concordance of CKD stage was 79.6 (n 1652/2076) and 86.4 (n 4043/4681) for self-reported Black and non-Black individuals, respectively, with an overall concordance of 84.3 (n 5695/6757) using the CKD-EPI 2021 eGFR_cr vs CKD-EPI 2009 eGFR_cr equations (Table 1). The remaining 15.7 (n 1062/6757) of patients were reclassified to a different CKD stage using the CKD-EPI 2021 equation. As anticipated, eGFR_cr was lower for self-reported Black individuals while higher for non-Black individuals using the CKD-EPI 2021 race-free eGFR_cr equation.

KIDGO metformin management category changed for 69 (3.3) Black individuals with an active metformin prescription (bold text, Table 1). For Black individuals previously in CKD-3a (Recommendation: continue metformin use), 27.8 (n 55/198) were reclassified to CKD-3b (Recommendation: review metformin use) and 13.0 (n 14/108) previously in CKD-3b were reclassified to CKD-4 (Recommendation: discontinue metformin use). Metformin management category changed for 90 (1.9) non-Black individuals with an active metformin prescription. For non-Black individuals previously in CKD-3b, 24.7 (n 73/296) moved to CKD-3a, and 30.4 (n 17/56) of individuals previously in CKD-4 moved to CKD-3b. Sex, age, or HbA_1c did not demonstrate any significant impact on CKD stage reclassification or changes in metformin management category.

Implementation of the CKD-EPI 2021 eGFR_cr equation will change CKD categorization and metformin management in some patients with moderate to severe renal dysfunction. Risk reassessment, frequency of monitoring, dose adjustment, or discontinuation of metformin may be warranted for select Black patients currently in CKD-3a and 3b based on CKD-EPI 2009 eGFR_cr, whereas non-Black patients currently in CKD-3b and CKD-4 may benefit from initiation of a metformin therapy or dose adjustment. A similar percentage of Black and non-Black patients (1.5 and 1.3, respectively) in CKD-4 and 5 had active metformin prescriptions, suggesting physician-assessed drug benefit outweighed risk of lactic acidosis for some individuals irrespective of race.

Limitations of the study include the assumption that medications listed in the electronic health record were accurate and up-to-date. The influence of race in metformin prescribing practices has been reported previously before and after Food and Drug Administration updates to metformin label warnings (6). New provider education of expected changes in CKD stage, as it relates to drug dosing and prescribing practices, may be necessary during implementation of the CKD-EPI 2021 eGFR_cr equation.

Nonstandard Abbreviations

KIDGO, Kidney Disease: Improving Global Outcomes; eGFR, glomerular filtration rate; CKD, chronic kidney disease; CKD-EPI, CKD Epidemiology Collaboration; eGFR_cr, race-free eGFR equation, calculated from creatinine; HbA_1c, hemoglobin A_1c.

Author Contributions

The corresponding author takes full responsibility that all authors on this publication have met the following required criteria of eligibility for authorship: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved. Nobody who qualifies for authorship has been omitted from the list.

Authors Disclosures or Potential Conflicts of Interest

Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest:

Employment or Leadership

N. Korpi-Steiner, AACC Nominating Committee Member, AACC CPOCT Past-Chair, CDC CLIAC CoW and PPMP Working Group Member; S.W. Cotten, ASCP Chemistry Scientific Interest Group.

Consultant or Advisory Role

N. Korpi-Steiner, Werfen Point of Care Advisory Council; S.W. Cotten, Siemens Medical Consensus Advisory Council.

Stock Ownership

None declared.

Honoraria

S.W. Cotten, BioRad.

Research Funding

S.W. Cotten, NIH 1U24CA268153-01.

Expert Testimony

None declared.

Patents

None declared.

Other Remuneration

R.D. Maynard, Society for Young Clinical Laboratorians Travel Grant for the 2022 AACC Annual Scientific Meeting and Clinical Lab Expo; S.W. Cotten, support for attending meetings and/or travel from AACC.

References

Author notes