exceeds 300 mg/g (Figure 1) (14). These renal changes are usually associated with progressive increase in blood pressure. Keen et al. (15) first described increased UAE in the early sixties of the twentieth century. Twenty years later, the term “microalbuminuria” became popular after the results of a 14-year longitudinal study showed microalbuminuria as a predictor of renal disease and mortality in T1DM (16). Similar results were also reported in T2DM (17). These observations led to the use of renin-angiotensin system (RAS) blockers in patients with incipient nephropathy (18, 19). However, the predictive significance of microalbuminuria was not confirmed by later studies (20, 21). Furthermore, progression of microalbuminuria to overt proteinuria was not observed in one-third of patients with T1DM that develop advanced renal disease (22). These observations then led to the reluctance to use RAS blockers in incipient nephropathy and to restrict their use to patients with overt nephropathy (23). The Endothelium The role of the endothelium as a regulator of the local vascular tone was first highlighted in 1980 (24). Endothelial dysfunction is an eminent feature in diabetes patients and in patients suffering from obesity or metabolic syndrome. Decreased synthesis of nitric oxide (NO), also known as endothelial derived relaxing factor (EDRF), is the salient feature of endothelial dysfunction. By decreasing insulin access to target cells, decreased NO underlies insulin resistance (25). Insulin also crosses the endothelial cells to reach the target cells (26, 27). Hyperglycemia leads to increased production of reactive oxygen species (ROS) in many cells including endothelium (28). Increased endothelial ROS is associated with increased breakdown of NO (29). Endothelial dysfunction is associated with development and progression of nephropathy (30) (Figure 2). In two separate studies, endothelial nitric-oxide synthase (eNOS) deficient mice consistently developed diabetic nephropathy (31, 32). Sodium Hydrogen Exchangers The sodium hydrogen exchangers (NHE) are responsible for intracellular pH regulation. NHE exist in nine isoforms (33, 34). NHE1 is encountered on the surface of endothelial cells, vascular smooth muscle cells (VSMCs), cardiomyocytes, and platelets, whereas NHE3 is encountered on renal tubular and intestinal epithelium. Activation of the NHE1 within endothelium, VSMCs, and cardiomyocytes may underlie microvascular and macrovascular complications of diabetes. It can also have a role in insulin resistance and systemic hypertension. These exchangers cause increased sodium influx that stimulates sodium-calcium Main Points • This review was written to emphasize the importance of use of SGLT2 inhibitors, DPP4 inhibitors and GLP1 receptor agonist to prevent the development of diabetic nephropathy in both type 1 and type 2 diabetes mellitus. • The patients of both types of diabetes that are prone to develop diabetic nephropathy can be suspected using serum mannose binding lectin, serum adiponectin and serum fibrinogen levels as very early predictors. • The patients suspected to develop diabetic nephropathy according to these tests should start using SGLTIs. In order to get the maximum benefit, at least a small dose of either an ACEI or ARB should be added. • In patients of type 2 diabetes not well controlled by Metformin and the maximum dose of SGLT2I, sequential addition of DPP4I and GLP1RA would improve glycemic control and reinforce the preventive action of SGLT2I-RAS blocker combination. Figure 1. Stages of diabetic nephropathy. Stage 2 is characterized by the progressive increase in mesangial deposits on light microscopy without corresponding clinical or laboratory findings; ESRD: end stage renal disease when eGFR≤15 mL/min./1.73 m2 . Stage 1 Hyperfiltration Renal hypertrophy Stage 2 Clinical quiescence Stage 3 Incipient nephropathy Stage 4 Overt nephropathy Stage 5 ESRD Sharaf El Din et al. Diabetic Nephropathy Prevention Turk J Nephrol 2020; 29(2): 161-73 162 exchanger with consequent increase of intracellular calcium. Within endothelium, increased cytoplasmic calcium inhibits eNOS and thus decreases NO synthesis (Figure 3, 4). Increased intracellular calcium is also associated with increased intracellular and mitochondrial activity of calpain, the cysteine protease that can damage the inner mitochondrial membrane, a process that ends with cell apoptosis (35). Inhibition of endothelial NHE1 using cariporide increased eNOS activity and NO release. Enhancement of eNOS activity simultaneously inhibited ROS production, nuclear factor- κB (NF-κB) activation, and tumor necrosis factor-α and intercellular adhesion molecule-1 production (36). Within the myocardium, increased cellular calcium induced by NHE1 leads to cardiac hypertrophy. Peripheral coronary ischemia consequent to endothelial dysfunction can further activate cardiac NHE1. Increased intracellular calcium stimulates calpain enzyme activity within cardiomyocytes leading to degeneration, apoptosis, and fibrosis of myocardium (5) (Figure 4). Proximal convoluted tubular (PCT) and ascending loop of Henle have NHE3. When NHE3 is activated, excess sodium retention occurs and contributes to systemic hypertension in diabetes patients (5, 37) (Figure 5). NHE1 plays a significant role in platelet