Original magnification, 33500. Figure 2. | Normal kidney morphology and structural changes in diabetes mellitus. Diabetic kidney disease induces structural changes, including thickening of the glomerular basement membrane, fusion of foot processes, loss of podocytes with denuding of the glomerular basement membrane, and mesangial matrix expansion. 2034 Clinical Journal of the American Society of Nephrology classic pattern of glomerular hyperfiltration progressing to persistent albuminuria associated with hypertension and declining GFR (34) (Figure 5). The United Kingdom Prospective Diabetes Study (UKPDS) offered a unique opportunity to observe the natural history of DKD in patients with DM2 from early in the course of diabetes. Of enrolled patients, approximately 2% per year progressed from normo- to microalbuminuria and from micro- to macroalbuminuria. At a median of 15 years after diagnosis, 40% of participants developed albuminuria, and 30% developed eGFR,60 ml/min per 1.73 m2 or doubling of the blood creatinine level (22,35). It is noteworthy that 60% of those developing kidney functional impairment did not have preceding albuminuria, and 40% never developed albuminuria during the study (22). This finding underscores the fact that albuminuria is a dynamic, fluctuating condition rather than a linearly progressive process. For example, in the Multifactorial Intervention for Patients with Type 2 Diabetes Study, 31% of participants with microalbuminuria progressed to macroalbuminuria, whereas 31% regressed to normoalbuminuria during 7.8 years of follow-up. Another 38% remained microalbuminuric during this time period (36). Recent clinical data from over 20,000 patients with DM1 show lower frequencies of low eGFR (,60 ml/min per 1.73 m2) and albuminuria in this population; 19613 years after diagnosis, frequencies of low eGFR and albuminuria were 8% and 19%, respectively (37). In step with the changing paradigm of the natural history of DKD, emerging evidence suggests that the clinical presentation of DKD is altering. A comparison of DKD presentation in adults with diabetes during the time periods between 1988 and 1994 and between 2009 and 2014 shows that the prevalence of albuminuria as a manifestation of DKD decreased from 21% to 16%, that low eGFR (,60 ml/min per 1.73 m2) increased from 9% to 14%, and that severely reduced eGFR (,30 ml/min per 1.73 m2) increased from 1% to 3% (38). Furthermore, lack of albuminuria or low eGFR may not necessarily preclude structural DKD. A recent autopsy study found a considerably higher prevalence of DKD diagnosed histologically compared with that indicated by clinical laboratory testing. Of 168 patients with DM1 or DM2, 106 exhibited histopathologic changes characteristic of DKD. Albuminuria or low eGFR was absent in 20% (20 of 106) of patients throughout life. Moreover, structural changes were highly variable and encompassed almost all histopathologic classes of DKD (39). In later stages of DKD, as GFR declines, both kidney- and nonkidney-related DKD complications develop. Anemia and bone and mineral metabolism disorders often develop earlier in DKD than in other types of CKD. Predominant tubulointerstitial disease is associated with damage to the peritubular interstitial cells that produce erythropoietin. As a result, patients with diabetes may be prone to erythropoietin deficiency and are nearly twice as likely to have anemia compared with patients with nondiabetic CKD and comparable eGFR (40). Insulin is a cofactor for parathyroid hormone release; therefore, insulin deficiency and/or resistance may be associated with lower parathyroid hormone levels than in other types of CKD (41), which may predispose patients with DKD to adynamic bone disease. Deaths due to CVDs and infections are highly prevalent and compete with progression to ESRD. In the UKPDS, the overall death rate after onset of DKD in those with blood creatinine levels .2 mg/dl or those receiving kidney replacement therapy was nearly 20% per year (35). Figure 3. | Diabetic glomerulopathy.Changesin glomerular histologyin diabetic glomerulopathy(A)Normal glomerulus.(B)Diffusemesangial expansion with mesangial cell proliferation. (C) Prominent mesangial expansion with early nodularity and mesangiolysis. (D) Accumulation of mesangial matrix forming Kimmelstiel–Wilson nodules. (E) Dilation of capillaries forming microaneurysms, with subintimal hyaline (plasmatic insudation). (F) Obsolescent glomerulus. A–D and F were stained with period acid–Schiff stain, and E was stained with Jones stain. Original magnification, 3400. Clin J Am Soc Nephrol 12: 2032–2045, December, 2017 Diabetic Kidney Disease, Alicic et al. 2035 Follow-up data from 2003 showed crude 1-year mortality of patients on dialysis ranging from 6.6% in Japan to 21.5% in the United States (42). Patients on dialysis over age 75 years old are 3.9 times more likely to die than their counterparts in the general population (43). Pathophysiology of DKD Critical metabolic changes that alter kidney hemodynamics and promote inflammation and fibrosis in early diabetes include hyperaminoacidemia, a promoter of glomerular hyperfiltration and hyperperfusion, and hyperglycemia Figure 4. | Tubulointerstitial changes and arteriolar hyalinosis in