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      Competing Effects of Renin Angiotensin System Blockade and Sodium-Glucose Cotransporter-2 Inhibitors on Erythropoietin Secretion in Diabetes

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          Background: Anaemia is a common finding in diabetes, particularly in those patients with albuminuria or renal dysfunction and is associated with impaired erythropoietin (EPO) secretion. This review focuses on mechanisms involved in the regulation of erythropoiesis in diabetic patients in an effort to elucidate the competing effects of the renin angiotensin system (RAS) blockade and sodium-glucose cotransporter-2 (SGLT2) inhibitors on haemoglobin concentration and hematocrit values. Summary: The RAS shows significant activation in diabetic subjects. Angiotensin II, its active octapeptide, causes renal tubulointerstitial hypoxia, which stimulates hypoxia-inducible factors (HIF) and increases EPO secretion and erythropoiesis. As expected, drugs that inactivate RAS, such as angiotensin converting enzyme inhibitors or angiotensin receptor blockers (ACEi/ARB) are associated with a significant hematocrit-lowering effect and/or anaemia in various clinical conditions, including diabetes. Dual blockade by a combination of ACEi and ARB in diabetic patients achieves a better RAS inhibition, but at the same time a worse drop of haemoglobin concentration. Increased glucose reabsorption by SGLTs in diabetic subjects generates a high-glucose environment in renal tubulointerstitium, which may impair HIF-1, damage renal erythropoietin-producing cells (REPs) and decrease EPO secretion and erythropoiesis. SGLT2 inhibitors, which inhibit glucose reabsorption, may attenuate glucotoxicity in renal tubulointerstitium, allowing REPs to resume their function and increase EPO secretion. Indeed, EPO levels increase within a few weeks after initiation of therapy with all known SGLT2 inhibitors, followed by increased reticulocyte count and a gradual elevation of haemoglobin concentration and hematocrit level, which reach zenith values after 2–3 months. Key Messages: The competing effects of RAS blockade and SGLT2 inhibitors on erythropoiesis may have important clinical implications. The rise of hematocrit values by SGLT2 inhibitors given on top of RAS blockade in recent outcome trials may significantly contribute to the cardiorenal protection attained. The relative contribution of each system to erythropoiesis and outcome remains to be revealed in future studies.

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          Author and article information

          Am J Nephrol
          American Journal of Nephrology
          S. Karger AG
          May 2020
          02 April 2020
          : 51
          : 5
          : 349-356
          aOnassis Cardiac Surgery Center, Athens, Greece
          b2nd Department of Internal Medicine-Propaedeutic, Research Institute and Diabetes Centre, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece
          cDepartment of Pulmonary and Critical Care Services, Evangelismos Hospital, Athens, Greece
          Author notes
          *Demetrios V. Vlahakos, MD, 2nd Department of Internal Medicine-Propaedeutic, Research Institute and Diabetes Centre, National and Kapodistrian University of Athens Medical School, Attikon University Hospital, 1 Rimini Street, Haidari, GR–12462 Athens (Greece), E-Mail
          507272 Am J Nephrol 2020;51:349–356
          © 2020 S. Karger AG, Basel

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          Page count
          Figures: 1, Tables: 2, Pages: 8
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