Ferri, C.; Rodríguez-Rodríguez, A.E.; Mora-Fernández, C.; Navarro-González, J.F. Inflammatory targets in diabetic nephropathy. J. Clin. Med. 2020, 9, 458. [CrossRef] [PubMed] 2. Lavoz, C.; Rayego-Mateos, S.; Orejudo, M.; Opazo-Ríos, L.; Marchant, V.; Marquez-Exposito, L.; Tejera-Muñoz, A.; Navarro-González, J.F.; Droguett, A.; Ortiz, A.; et al. Could IL-17A be a novel therapeutic target in diabetic nephropathy? J. Clin. Med. 2020, 9, 272. [CrossRef] [PubMed] 3. Caro-Ordieres, T.; Marín-Royo, G.; Opazo-Ríos, L.; Jiménez-Castilla, L.; Moreno, J.A.; Gómez-Guerrero, C.; Egido, J. The coming age of flavonoids in the treatment of diabetic complications. J. Clin. Med. 2020, 9, 346. [CrossRef] [PubMed] 4. Garcia-F Time to Prevent the Development of Diabetic Nephropathy Usama A. Sharaf El Din1 , Mona M. Salem2 , Dina O. Abdulazim3 1 Division of Nephrology, Department of Internal Medicine, Cairo University School of Medicine, Cairo, Egypt 2 Division of Endocrinology, Department of Internal Medicine, Cairo University School of Medicine, Cairo, Egypt 3 Department of Rheumatology and Rehabilitation, Cairo University School of Medicine, Cairo, Egypt Corresponding Author: Usama A. Sharaf El Din * usamaaas@gmail.com Received: 21.11.2019 Accepted: 24.01.2020 Review 161 Abstract The consistent increase in the incidence of diabetes and its complications represents an obsession of health care providers worldwide. Diabetic nephropathy is responsible for nearly half of the chronic kidney diseases. The morbidity and mortality rates of diabetes patients admitted to dialysis is much higher than non-diabetic cases. These facts are behind the tremendous efforts undertaken to understand the pathogenesis and therapeutic modalities of this disease. Over the last four years, a plethora of data has evolved to revive the hope not only to slow the rate of progression of this disease but possibly to prevent its evolution. In this review, we are going to discuss the most relevant and novel pathogenic mechanisms of diabetic nephropathy and the most suitable approach to prevent its development. Keywords: Type 1 diabetes, type 2 diabetes, diabetic nephropathy, novel markers, DPP4 inhibitors, SGLT2 inhibitors, GLP1Ras, nrf2 agonists Cite this article as: Sharaf El Din UA, Salem MM, Abdulazim DO. Time to Prevent the Development of Diabetic Nephropathy. Turk J Nephrol 2020; 29(2): 161-73. This work is licensed under a Creative Commons Attribution 4.0 International License. INTRODUCTION In 2014, diabetes mellitus was diagnosed in 430 million people worldwide, compared with 108 million in 1980 (1). The most common cause of end-stage renal disease (ESRD) is diabetes. One-third of patients with type 1 diabetes mellitus (T1DM) develop ESRD, whereas only 10%-20% with type 2 diabetes mellitus (T2DM) progress to ESRD (2, 3). The evolution of diabetic nephropathy (DN) is responsible for a six-fold increase in the overall 10-year mortality among diabetes patients compared with healthy age matched non-diabetic individuals (4). Endothelial dysfunction is a common underlying pathogenic mechanism of diabetic complications (5). Endothelial dysfunction is a sequel to many metabolic changes encountered in patients with hyperglycemia. These metabolic changes include increased oxidative stress (6), hyperuricemia (7), stimulation of sodium hydrogen exchangers (NHE) (5), and stimulation of renal sodium glucose transporters (SGLT) (8). During the last 16 years, three novel hypoglycemic groups were introduced to improve glycemic control in patients with T2DM, namely glucagon-like peptide-1 receptor agonists (GLP-1RA), dipeptidyl peptidase 4 inhibitors (DPP4Is), and sodium glucose co-transporter-2 inhibitors (SGLT2Is). These three groups carry unique features, namely a minimal chance to develop significant hypoglycemia and a neutral effect on body weight in case of DPP4Is and body weight reduction in case of GLP-1RA and SGLT2Is (9, 10). Compared to older hypoglycemic agents, these newer groups carry potential favorable protective effects on endothelium and can significantly reduce adverse cardiovascular events and are renoprotective. SGLT2Is may also prevent or hamper diabetic retinal complications (11). Few months ago, DECLARE-TIMI 58 trial has shown that treatment with the SGLT2I dapagliflozin for median duration of 4.2 years was associated with significant reduction in the chance to develop renal end points even among patients with normal glomerular filtration rate (GFR) and normal urine protein excretion (12). In this review of literature, we are going to demonstrate how it is feasible to abort the development of DN. Evolution of Diabetic Nephropathy Renal hyperfunction and hypertrophy represents the earliest stage of DN (13). Persistent increase in urine albumin excretion (UAE) develops a few years later when UAE becomes more than 30 mg/day, more than 20 μg/minute, or albumin-creatinine ratio (ACR) more than 30 mg/g of creatinine. When patients develop these features, they are considered to be in stage 3 DN that is also called the stage of incipient nephropathy. Initially, persistent increase in UAE is associated with increased GFR. Later on, GFR consistently declines and becomes pronounced with the continuous increase of UAE above 300 mg/day, 200 μg/ minute, or when ACR