Diabetic Kidney Disease Challenges, Progress, and Possibilities Radica Z. Alicic,*† Michele T. Rooney,* and Katherine R. Tuttle*†‡§| Abstract Diabetic kidney disease develops in approximately 40% of patients who are diabetic and is the leading cause of CKD worldwide. Although ESRD may be the most recognizable consequence of diabetic kidney disease, the majority of patients actually die from cardiovascular diseases and infections before needing kidney replacement therapy. The natural history of diabetic kidney disease includes glomerular hyperfiltration, progressive albuminuria, declining GFR, and ultimately, ESRD. Metabolic changes associated with diabetes lead to glomerular hypertrophy, glomerulosclerosis, and tubulointerstitial inflammation and fibrosis. Despite current therapies, there is large residual risk of diabetic kidney disease onset and progression. Therefore, widespread innovation is urgently needed to improve health outcomes for patients with diabetic kidney disease. Achieving this goal will require characterization of new biomarkers, designing clinical trials that evaluate clinically pertinent end points, and development of therapeutic agents targeting kidney-specific disease mechanisms (e.g., glomerular hyperfiltration, inflammation, and fibrosis). Additionally, greater attention to dissemination and implementation of best practices is needed in both clinical and community settings.Introduction Clin J Am Soc Nephrol 12: 2032–2045, 2017. doi: https://doi.org/10.2215/CJN.11491116 It took more than three millennia from the first description of diabetes in 1552 BC to the recognition of an association between diabetes and kidney disease, but it took only several decades for diabetic kidney disease (DKD) to become the leading cause of ESRD in the United States (1,2). This microvascular complication develops in approximately 30% of patients with type 1 diabetes mellitus (DM1) and approximately 40% of patients with type 2 diabetes mellitus (DM2) (2,3). The increasing prevalence of DKD parallels the dramatic worldwide rise in prevalence of diabetes (4,5). In the United States, the prevalence of diabetes among adultsincreased from 9.8%in the 1988–1994 time period to 12.3% in the 2011–2012 time period (6). Worldwide, in the year 2015, 415 million people were estimated to have diabetes; by 2040, prevalence is projected to increase to 642 million, with disproportionate growth in low- to middle-income countries (7). The driving force behind the escalating prevalence of diabetes is the global pandemic of obesity (4). Between the years 1980 and 2000, the overall prevalence of obesity in adults snowballed from 15% to 31% in the United States (8). By 2013–2014, the adjusted prevalence of obesity was up to 35% among men and 40% among women (9). Kidney disease attributed to diabetes is a major but under-recognized contributor to the global burden of disease. Between 1990 and 2012, the number of deaths attributed to DKD rose by 94% (10). This dramatic rise is one of the highest observed for all reported chronic diseases (11). Notably, most of the excess risk of allcause and cardiovascular disease (CVD) mortality for patients with diabetes is related to the presence of DKD (12). Risk Factors DKD risk factors can conceptually be classified as susceptibility factors (e.g., age, sex, race/ethnicity, and family history), initiation factors (e.g., hyperglycemia and AKI), and progression factors (e.g., hypertension, dietary factors, and obesity) (Table 1) (13). Two of the most prominent established risk factors are hyperglycemia and hypertension. Hyperglycemia In normoalbuminuric patients with DM1, poor glycemic control is an independent predictor of progression to development of proteinuria (albuminuria) and/or ESRD (14). Two landmark trials conducted with patients with early-stage DM1 or DM2 showed that intensive blood glucose control early in the course of disease exhibits a long-lasting favorable effect on the risk of DKD development (15,16). This “legacy effect,” also named “metabolic memory,” suggests that early intensive glycemic control can prevent irreversible damage, such as epigenetic alterations, associated with hyperglycemia (17). In patients with DM1, an intensive glucose control intervention targeting a hemoglobin A1C (HbA1C) level #7% reduced the 9-year risks of developing microalbuminuria and macroalbuminuria by 34% and 56%, respectively, compared with standard care (18). After a median follow-up of 22 years, the intensive therapy group had approximately 50% *Providence Health Care, Spokane, Washington; † University of Washington School of Medicine, Seattle, Washington; ‡ Division of Nephrology, University of Washington School of Medicine, Seattle, Washington; § Institute of Translational Health Sciences, Seattle, Washington; and | Kidney Research Institute, Seattle, Washington Correspondence: Dr. Radica Z. Alicic, 104 West 8th Avenue, 6050, Spokane, WA 99204. Email: radica. alicic@providence. org 2032 Copyright © 2017 by the American Society of Nephrology www.cjasn.org Vol 12 December, 2017 lower risk of a low eGFR (,60 ml/min per 1.73 m2), and the