Anemia Mysteries in Diabetic Kidneys - The Role of SGLT2 inhibitors on EPOR Antibodies

Written by: Priti Meena, MD

Infographic by: Corina Teodosiu, MD

AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.

Anemia, in individuals with type 2 diabetes (T2D) and chronic kidney disease (CKD) is a complex phenomenon with multifactorial origins; often attributed to deficiencies in iron and erythropoietin (EPO), as well as hyporesponsiveness to EPO. Surprisingly, previous investigations into EPO hyporesponsive anemia have uncovered the presence of autoantibodies targeting the EPO receptor (EPOR). This discovery suggested a potential underexplored cause of anemia (with erythroid hypoplasia) in the subgroup of patients with type 2 diabetes (T2D) and CKD. diabetic patients with CKD. Recent revelations linking anti-EPOR antibodies to  kidney function decline in systemic lupus erythematosus have prompted exploratory studies into their clinical and pathological implications in T2D patients with CKD. The EPOR (figure 1) , which forms a homodimer on erythroid progenitor cells, plays a pivotal role in erythrocyte differentiation. Interestingly, EPOR also exists on organ-specific cells such as cardiomyocytes and renal cells, forming a complex with the β common chain. Studies have indicated that IgG fractions containing anti-EPOR antibodies inhibit the anti-inflammatory effect of EPO in kidney tubular epithelial cells. Inflammatory infiltrates, including EPOR-expressing T lymphocytes and macrophages, may be modulated by EPO administration, highlighting the potential involvement of anti-EPOR antibodies in disease progression. Furthermore, these antibodies have been implicated in the pathogenesis of cardiac dysfunction in patients with CKD. Studies have shown that anti-EPOR antibody positivity is associated with left ventricular dysfunction in patients undergoing hemodialysis. Identifying these autoantibodies could serve as a valuable serologic marker for renal prognosis in high-risk T2D patients with CKD, enabling physicians to offer more targeted and intensive care to prevent end-stage kidney disease (ESKD). Despite their potential clinical significance, previous studies on anti-EPOR antibodies were limited in scope, lacking ethnic diversity, and detailed information on cardiovascular (CV) and mortality endpoints.

Treatment of patients with SGLT2 inhibitors has demonstrated a notable increase in hemoglobin and hematocrit levels, effectively preventing anemia when compared to a placebo, most notably the CREDENCE trial. Interestingly, the CREDENCE trial findings emphasized a robust correlation between changes in hemoglobin due to SGLT2 inhibition and the protection of CV and kidney health. With the emergence of sodium-glucose cotransporter 2 (SGLT2) inhibitors as key players in reducing CKD progression and cardiovascular events, understanding the interplay between anti-EPOR antibodies and the impact of these inhibitors on anemia becomes imperative for optimizing treatment strategies. Here we discuss a post-hoc analysis of the CREDENCE trial that assesses the prevalence of anti-EPOR antibodies and their association with clinical outcomes in this population. 

Study design 

Post hoc analysis of the CREDENCE trial 

Outcome assessment 

• The association of anti-EPOR antibodies with composite kidney and CV events, and mortality in patients with T2DM and CKD.

• The effects of canagliflozin on hemoglobin, hematocrit, and incident anemia 

Anti-EPOR antibody measurement 

Serum anti-EPOR antibodies were measured at baseline and week 52 using an indirect enzyme-linked immunosorbent assay. Hemoglobin concentration and hematocrit level were measured at baseline and every 52 weeks.

Baseline characteristics (Table1) 

The characteristics of these 2600 individuals were generally comparable to the overall CREDENCE population. At baseline, the mean age was 63.3 (SD = 9.1) years, 33.7% of participants were female, 51.5% had a history of CV disease, 34.7% had anemia, and the mean hemoglobin was 132.7 (SD =17.1)g/l .

Table 1.

Of the participants, 191 (6.9% in canagliflozin group and 7.8% in placebo group) were positive (≥2 EU) for anti-EPOR antibodies. Patients with anti-EPOR antibodies, compared to those without, were older and more likely to have a history of CV disease. 

Outcome results

The event rate for the primary outcome was higher in patients with anti-EPOR antibodies compared to those without anti-EPOR antibodies (63.0 vs. 50.1 per 1000 patient-years). After adjusting for age, sex, race, and randomized treatment, anti-EPOR antibodies (as a continuous variable) were significantly associated with the primary outcome. Anti-EPOR antibodies remained significant after adjusting for kidney disease parameters alone or for both kidney and CV parameters (glomerular filtration rate (eGFR), log-transformed urine albumin-creatinine ratio (uACR), history of CV disease and systolic blood pressure). 

Event rates for CV and all-cause death were higher in patients with versus without anti-EPOR antibodies. The associations of anti-EPOR antibodies with the primary outcome and all-cause death were consistent across eGFR and UACR categories. The following table shows the associations of anti-erythropoietin receptor antibodies at baseline with primary composite outcomes, renal specific composite outcomes, and mortality outcomes.

Table 2.

Effect of Canagliflozin on Anemia in the presence of Anti-EPOR Antibodies

Hemoglobin and hematocrit increased in the canagliflozin group from baseline to week 52. The mean difference during follow-up between the canagliflozin group and the placebo group was 7.0 g/l (95% CI = 6.2–7.9) for hemoglobin and 2.4% (95% CI = 2.2–2.7) for hematocrit, respectively. These effects of canagliflozin on hemoglobin and hematocrit were consistent across patients with and without anti-EPOR antibodies. 

Figure 2.

Discussion

The post hoc analysis of the CREDENCE trial sheds light on the presence of anti-EPOR antibodies in a subset of patients with T2DM and CKD. The study reveals that 7.3% of patients in this population exhibited these antibodies. Interestingly, higher levels of anti-EPOR antibodies were found to be associated with adverse clinical outcomes, specifically the primary composite outcome comprising CV death and all-cause mortality. Notably, the beneficial effect of canagliflozin on anemia was consistent across patients, irrespective of anti-EPOR antibody status. A key strength of this study lies in its multinational representation of patients, enhancing the generalizability of the findings. Furthermore, the rigorously adjudicated clinical outcomes in the CREDENCE trial provide a robust foundation for the analysis. However, the study has its limitations, and caution must be exercised in interpreting the results. The association between anti-EPOR antibodies and the primary outcome, while significant, was relatively small, highlighting the need for further validation studies. The post hoc study design also introduces the possibility of chance findings. The adjustment for multiple confounders in the analysis is a commendable effort, but the potential for remaining confounding factors cannot be entirely ruled out. The subgroup of patients with anti-EPOR antibodies (≥2 EU) was relatively small, limiting statistical power for certain analyses. Moreover, the unavailability of EPO concentration data in the current study poses a challenge in understanding the dynamics of EPO production in patients with anti-EPOR antibodies. The hypothesis that EPO production might be stimulated in these patients could not be tested, emphasizing the need for further research in this area. Despite these limitations, the study brings attention to a novel aspect of T2D and CKD, suggesting that anti-EPOR antibodies may serve as potential indicators of increased mortality risk. The finding that the effects of canagliflozin on hemoglobin and hematocrit were consistent across patients with and without anti-EPOR antibodies needs further explanation. In conclusion, the study provides valuable insights into the association between anti-EPOR antibodies and adverse clinical outcomes in patients with T2D and CKD. Further research is imperative to validate these findings, elucidate the underlying pathophysiology of anti-EPOR antibodies, and explore their potential application in clinical practice.

AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.