average rate of eGFR loss was significantly reduced from 1.56 ml/min per 1.73 m2 per year with standard therapy to 1.27 ml/min per 1.73 m2 per year with intensive therapy (19). Similarly, in patients with newly diagnosed DM2, 10 years of an intensive glycemic control intervention targeting an HbA1C of 7% produced a 24% reduction in development of microvascular complications, including DKD, compared with conventional therapy (20,21). After 12 years, intensive glycemic control resulted in a 33% reduction in the risk of development of microproteinuria or “clinical grade” proteinuria and a significant reduction in the proportion of patients with a doubling of the blood creatinine level (0.9% versus 3.5%) relative to the conventional therapy group (20,21). Hypertension In patients with newly diagnosed DM2, treating to a target BP of ,150/85 mmHg over a median of 15 years resulted in a significant 37% risk reduction of microvascular complications compared with that in patients treated to a target of ,180/105 mmHg. Each 10-mmHg increase in mean systolic BP was associated with a 15% increase in the hazard ratio for development of both micro- and macroalbuminuria and impaired kidney function defined as eGFR,60 ml/min per 1.73 m2 or doubling of the blood creatinine level (22). Broadly, a baseline systolic BP .140 mmHg in patients with DM2 has been associated with higher risk of ESRD and death (23,24). Structural Changes Development of DKD is associated with many alterations in the structure of multiple kidney compartments. The earliest consistent change is thickening of glomerular basement membrane, which is apparent within 1.5–2 years of DM1 diagnosis. It is paralleled by capillary and tubular basement membrane thickening (14,25,26) (Figure 1). Other glomerular changes include loss of endothelial fenestrations, mesangial matrix expansion, and loss of podocytes with effacement of foot processes (Figure 2). Mesangial volume expansion is detectable within 5–7 years after DM1 diagnosis (14,25,27,28). Segmental mesangiolysis is observed with progression of diabetes and thought to be associated with development of Kimmelstiel–Wilson nodules and microaneurysms, which often present together (29,30) (Figure 3). The exudative lesions result from subendothelial deposits of plasma proteins, which form periodic acid–Schiff-positive and electron-dense deposits and accumulate in small arterial branches, arterioles, and glomerular capillaries as well as microaneurysms. These deposits can result in luminal compromise (e.g., hyaline arteriosclerosis). Similar subepithelial deposits are seen in Bowman’s capsule (capsular drop lesion) and proximal renal tubules. In later stages of diabetes, interstitial changes and glomerulopathy coalesce into segmental and global sclerosis (31). In patients with DM1, GFR, albuminuria, and hypertension are strongly correlated with mesangial expansion and somewhat less strongly associated with glomerular basement membrane width (31) (Figure 4). Renal structure changes in patients with DM2 are similar to those seen in DM1, but they are more heterogeneous and less predictably associated with clinical presentations (32). Early renal pathology studies described a high prevalence of nondiabetic glomerular disease in the patients with DM2 population, probably because of selection bias: patients who were diabetic and underwent biopsies tended to have atypical presentations of DKD. Conclusions from more recent biopsy studies are more conservative, estimating ,10% prevalence of non-DKD in patients with diabetes and albuminuria (24). Factors underlying the different presentation of DKD in DM2 may include the unreliable timing of DM2 onset compared with DM1, with potentially longer exposure to Table 1. Risk factors for diabetic kidney disease Risk Factor Susceptibility Initiation Progression Demographic Older age 1 Sex (men) 1 Race/ethnicity (black, American Indian, Hispanic, Asian/Pacific Islanders) 1 1 Hereditary Family history of DKD 1 Genetic kidney disease 1 Systemic conditions Hyperglycemia 1 11 Obesity 1 11 Hypertension 1 1 Kidney injuries AKI 1 1 Toxins 1 1 Smoking 1 1 Dietary factors 1 1 High protein intake 1 1 DKD, diabetic kidney disease. Clin J Am Soc Nephrol 12: 2032–2045, December, 2017 Diabetic Kidney Disease, Alicic et al. 2033 hyperglycemia before diagnosis; an older patient population; and a higher burden of atherosclerosis. Additionally, many patients with DM2 are treated with renin-angiotensin system inhibitors before diagnosis of diabetes. An international consensus working group has provided a pathologic classification system to address the heterogeneity of DKD presentation, which includes scoring of glomerular, interstitial, and vascular lesions (Tables 2 and 3) (33). Natural History The paradigm of the natural history of DKD continues to evolve. In many patients, DKD clearly does not follow the Figure 1. | Electron microscope images of structural changes in diabetic kidney disease. Structural changes in diabetic glomerulopathy found with electron microscopy. A indicates marked expansion of the mesangium. B indicates marked diffuse thickening of capillary basement membranes (to three times the normal thickness in this case). C indicates segmental effacement of the visceral epithelial foot processes.