Abstract
Elevated erythropoietin (EPO) levels have been reported to predict poor survival in various populations including diabetic patients. However, data regarding its impact on renal outcomes are scarce. We conducted a single-center, prospective cohort study of 339 type 2 diabetic patients with anemia. The primary outcome was the estimated glomerular filtration rate (eGFR) slope for two years. We performed multiple linear regression and restricted cubic spline analyses to assess the association of serum EPO levels with the renal outcome. Chronic kidney disease (CKD) was defined as eGFR <60 mL/min/1.73 m2 or urine albumin-to-creatinine ratio >30 mg/g creatinine. Median baseline EPO and eGFR level were 14.4 IU/L and 53 mL/min/1.73 m2, respectively. Inappropriately low EPO levels were observed in 73% of anemic patients and 59% of anemic patients even without CKD, suggesting that EPO deficiency precedes the onset of CKD in diabetes mellitus. Multivariable analysis revealed that iron status and hemoglobin levels were major determinants of EPO levels. Median eGFR slope was −1.3 mL/min/1.73 m2/year. We found that low EPO levels, but not low hemoglobin levels, were associated with a faster decline in eGFR, independent of clinically relevant factors. The eGFR decline was steeper, particularly when the EPO level was below the upper limit of normal. Lower EPO concentrations were associated with rapid eGFR decline, especially in patients with iron deficiency (P for interaction = 0.01). Relative EPO deficiency should be considered as a culprit in anemia of unknown etiology in diabetic patients, even those without CKD. Low EPO levels, especially when accompanied by poor iron status, are predictive of rapid loss of renal function.
Highlights
Diabetes mellitus is the leading cause of end-stage kidney disease (ESKD) and a risk factor for cardiovascular disease (CVD) and mortality1
The results showed that low EPO levels, below the level of the upper normal limit (23.7 IU/L), predict rapid estimated glomerular filtration rate (eGFR) decline independently of established prognostic factors including eGFR, urine albumin-to-creatinine ratio (UACR), and Hgb
Several mechanisms have been proposed for the low EPO levels in diabetic patients, including abnormal anemia-sensing mechanisms owing to diabetic autonomic neuropathy, impaired production of EPO due to tubulointerstitial damage, and dysfunction of hypoxia inducible factor (HIF)5
Summary
Multivariable linear regression analyses with robust variances were performed to assess clinical and biochemical associations with log-transformed EPO levels as a dependent variable. We employed linear regression analyses with robust variances to evaluate the association of baseline log-transformed EPO levels with eGFR slope. We hierarchically adjusted for the following confounders: age, sex, eGFR, urine albumin-to-creatinine ratio (UACR), and Hgb (model 1); model 1 plus diabetic retinopathy, systolic blood pressure (SBP), and hemoglobin A1c (HbA1c) (model 2); model 2 plus usage of angiotensin-converting enzyme inhibitor (ACEI) and/or angiotensin II receptor blocker (ARB) and statins (model 3); model 3 plus FGF23 and 25D (model 4); and model 4 plus u-LFABP (model 5). As the association between EPO level and the eGFR slope may be non-linear, we applied restricted cubic spline models with three knots. Interactions between age, sex, eGFR, C-reactive protein (CRP), Hgb, and ID and EPO level were examined, and stratified analyses were performed only when the interaction was significant. All statistical analyses were performed using Stata/SE 15 (Stata Corp., College Station, TX)
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