Glomerulomegaly, vascular lesions, IFTA, and tubular resorption droplets are all commonly seen. The pathogenesis of diabetic nephropathy involves metabolic, hemodynamic, growth, and inflammatory and fibrotic factors. The relative contributions of these factors vary among patients, over time, and even in different compartments of the kidney, and genetic and environmental factors can modify the appearance of the kidney lesions. AKI plays an important role in the progression of kidney disease in patients with diabetes. MR activation, particularly in the myeloid cells, may be important in mediating inflammation and fibrosis in CKD and after AKI in individuals with type 2 diabetes, and MR antagonist therapy may be protective. See references starting on p. 34. Dr. Agarwal is a professor of medicine in the Division of Nephrology, Department of Medicine, at the Indiana University School of Medicine and a staff physician at Richard L. Roudebush Veterans Administration Medical Center, in Indianapolis, IN 8 CHRONIC KIDNEY DISEASE AND TYPE 2 DIABETES Risk Factors, Symptoms, Biomarkers, and Stages of Chronic Kidney Disease Peter Rossing, MD, DMSc Whereas the symptoms of chronic kidney disease (CKD) in diabetes are few, there are many risk factors and biomarkers that can be used to identify individuals at high risk for development of this complication, and many of these are targets for intervention to prevent or delay the disease. This article describes the risk factors and other markers of CKD and the various stages of the disease. Risk Factors for CKD in Diabetes Many factors are associated with CKD in diabetes (Figure 1). Associations may be with both albuminuria and glomerular filtration rate (GFR) or with one variable only. Some factors influence initial development of kidney disease and others progression of the disease. Duration of diabetes is one of the strongest risk factors for diabetic nephropathy, but because type 2 diabetes is often silent, CKD may be present at diagnosis of diabetes. Hyperglycemia Several studies demonstrate the importance of hyperglycemia in the development and progression of CKD in diabetes (or diabetic kidney disease [DKD]) (43,44). The UK Prospective Diabetes Study documented a progressive beneficial effect of intensive metabolic control on the development of microalbuminuria and overt proteinuria (45), and a 10-year post-study follow-up demonstrated long-lasting benefit, which was termed a “legacy effect” (46). Greater variability in A1C is associated independently with albuminuria and diabetic nephropathy (47,48). The beneficial effect of improved glycemic control was confirmed in the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial, in which 11,140 patients with type 2 diabetes were followed and a 21% reduction (95% CI 7–34%) in development of nephropathy was seen in patients randomly assigned to strict glycemic control (49). Even end-stage renal disease (ESRD) was reduced in the ADVANCE trial, although it was a very rare event (50). Overall, it has been difficult to demonstrate the benefit of improving glycemic control on established CKD in type 2 diabetes, in contrast to the benefit on development of CKD. Recent studies with glucose-lowering agents such as glucagon-like peptide 1 receptor agonists found reduced progression of albuminuria and loss of kidney function (51,52). Sodium–glucose cotransporter 2 (SGLT2) inhibitors in particular have demonstrated benefit on progression of albuminuria, decline in kidney function, and development of kidney failure; but, although the mechanisms are not clear, the reduction in glucose is probably of minor importance (8,53). Thus, SGLT2 inhibitors are even beneficial in people with CKD who do not have diabetes (53). Blood Pressure Blood pressure is crucial to the development and progression of CKD in diabetes (44,54,55). The excess prevalence of hypertension in type 1 diabetes is confined to patients with nephropathy (56). Once severely increased albuminuria is present, frank hypertension is present in 80% of individuals and is almost universal in those with ESRD. In type 2 diabetes, the link between hypertension and kidney disease is less striking because hypertension is so common. Almost all patients with moderately elevated or worse albuminuria have hypertension. In people with diabetic nephropathy, variability in systolic blood pressure is independently associated with the development of ESRD (57). Treatment of blood pressure, particularly with inhibitors of the renin angiotensin system (RAS), has been a standard of care for both prevention and treatment of CKD in diabetes based on studies with angiotensin II receptor blockers in moderately elevated albuminuria (microalbuminuria) and type 2 diabetes (58), as well as in established proteinuria in type 2 diabetes (3,4). Even prevention of CKD has been suggested, at least in hypertensive type 2 diabetes, when treated with RAS-blocking agents (59). Renin-Angiotensin-Aldosterone System Several components of the renin-angiotensin-aldosterone system (RAAS) are elevated and considered to contribute to the progression of diabetic nephropathy. Accordingly, blocking the RAAS has been demonstrated to be kidney protective. FIGURE 1 Putative promoters of CKD progression in diabetes. Protein