#2934 SGLT2 inhibitors awaken the norns: unraveling novel erythropoietic mechanisms in diabetic nephropathy

Abstract Background and Aims Interstitial fibroblast-like cells that produce erythropoietin, recently identified as "Norn cells," significantly advance our understanding of renal physiology. Our study examines how sodium-glucose cotransporter-2 inhibitors (SGLT2i) influence erythropoiesis in patients with diabetic nephropathy. While SGLT2 inhibitors are established nephroprotective agents, their ability to increase hemoglobin levels remains an underappreciated effect that warrants further investigation. This hemoglobin-raising effect starkly contrasts other nephroprotective agents, particularly renin-angiotensin-aldosterone system inhibitors (RAASi), which typically reduce hemoglobin levels. Specifically, we analyze changes in hemoglobin levels and explore the mechanistic interactions between SGLT2 inhibition and these specialized interstitial cells in diabetic kidney disease. We aim to elucidate the currently unclear mechanisms underlying this unique therapeutic effect. Method In this retrospective, three-center observational study, we analyzed 371 patients with chronic kidney disease (CKD). The cohort had a mean age of 65 years and consisted predominantly of male (65%) and Caucasian (98%) individuals. Clinical and laboratory parameters were evaluated at baseline and following 7 months of treatment with SGLT2 inhibitors. Additionally, we performed histological analysis of renal biopsies from 15 SGLT2i-treated patients and 15 matched controls who had not received gliflozins. The control group was matched for age, eGFR, proteinuria and blood pressure to ensure comparable baseline characteristics. Results Hemoglobin levels showed a statistically significant median increase of 0.40 g/dL (P-value 2.63 x 10⁻¹¹). Renal biopsy analysis revealed a significant reduction in proximal tubular cell thickness and interstitial cell number, with no changes in endothelial cell count or capillary cross-sectional area. Notably, interstitial cell count correlated with creatinine levels. The observed hemoglobin increase suggests potential interactions with Norn cells, including reduced tubular metabolic stress and restored erythropoietin production. Conclusion The study reveals the multifaceted effects of SGLT2 inhibitors on erythropoiesis in patients with chronic kidney disease. Beyond their established glycosuric and nephroprotective properties, these agents can improve hemoglobin levels through mechanisms independent of traditional erythropoietic pathways. Our findings suggest that SGLT2 inhibition may modulate tubular function and potentially enhance the activity of erythropoietin-producing Norn cells in the renal interstitium. However, the precise molecular mechanisms require further investigation. This beneficial effect on hemoglobin levels is particularly noteworthy as it contrasts with the anemic tendencies often observed with other nephroprotective medications. These observations expand our understanding of SGLT2 inhibitors' pleiotropic effects and suggest new therapeutic possibilities for managing the complex interplay between chronic kidney disease and hematological dysfunction. The ability to simultaneously address renal protection and anemia represents a significant advancement in CKD management, potentially reducing the need for exogenous erythropoiesis-stimulating agents in some patients.