New Approaches to Diabetic Nephropathy from Bed to Bench

Abstract

Diabetic nephropathy (DN) is the main cause of end-stage kidney disease (ESKD). DN-related ESKD has the worst prognosis for survival compared with other causes. Due to the complex mechanisms of DN and the heterogeneous presentations, unmet needs exist for the renal outcome of diabetes mellitus. Clinical evidence for treating DN is rather solid. For example, the first Kidney Disease: Improving Global Outcomes (KDIGO) guideline was published in October 2020: KDIGO Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. In December of 2020, the International Society of Nephrology published 60 (+1) breakthrough discoveries in nephrology. Among these breakthroughs, four important ones after 1980 were recognized, including glomerular hyperfiltration theory, renal protection by renin-angiotensin system inhibition, hypoxia-inducible factor, and sodium-glucose cotransporter 2 inhibitors. Here, we present a review on the pivotal and new mechanisms of DN from the implications of clinical studies and medications.

Keywords: anemia; chronic kidney disease; diabetic nephropathy; glomerular hyperfiltration; hypoxia; hypoxia-inducible factor (HIF).

Figure 1

Pivotal mechanisms and potential treatments of DM related CKD. Sugar control is beneficial for DN control. Glomerular hyperfiltration (due to afferent arteriolar vasodilatation or efferent arteriolar vasoconstriction) and energy imbalance are both associated with DN. Low salt diet, low animal protein diet, controlled BP, SGLT2i and GLP1-RA are associated with afferent arteriole. On the contrary, RASi and ET-1RA are associated with efferent arteriole. The energy imbalance is due to energy wasting or too little energy production. The energy wasting can be due to excessive sodium reabsorption, and it can be stopped by SGLT2i and GLP1-RA. Low energy production can be due to anemia, mitochondrial dysfunction, and hypoxia. Renal anemia is both due to EPO deficiency and iron dysregulation. Renal anemia can be ameliorated by HIF stabilizers or SGLT2is. Abbreviations: DM, diabetes mellitus; CKD, chronic kidney disease; BP, blood pressure; SGLT2i, sodium-glucose cotransporter 2 inhibitor; GLP1-RA, GLP-1 receptor agonist; TGF, tubuloglomerular feedback; RASi, renin-angiotensin system inhibitor; ET-1RA, endothelin-1 receptor antagonist; EPO, erythropoietin; HIF, hypoxia-inducible factor. (↑: increased; ↓: decreased).

Figure 2

Overview for mechanisms of anemia in DM-related CKD. Patients with anemia due to either blood loss (bleeding or hemolysis) or too little RBC production (insufficient iron, folate, vitamin B12, or bone marrow disease). In addition, impaired O2 sensing can also cause renal anemia, associated with HIF-1α, renal efferent denervation, ROS, and ACEi/ARB. Moreover, reduced EPO production, increased urinary loss of EPO or poor response to EPO can also cause renal anemia. Abbreviations: EPO, erythropoietin; AngII, angiotensin II; ACEi/ARB, angiotensin converting enzyme inhibitor/angiotensinⅡreceptor blocker; ROS, reactive oxidative stress; CKD, chronic kidney disease; AGE, advanced glycation end product; RBC, red blood cell; HIF, hypoxia-inducible factor.

Figure 3

Increased HIF-1α and reduced HIF-2α in DM related CKD. Renal injury due to increased HIF-1α and reduced HIF-2α. Increased HIF-1α can be due to increased tubular ROS and increased cortical oxygen consumption. The overproduction of HIF-1α caused epithelial-mesenchymal transition and renal fibrosis. Compared to HIF-1α, HIF-2α is associated with EPO production. Abbreviations: ROS, reactive oxidative stress; HIF, hypoxia-inducible factor; EPO, erythropoietin.