disease progression in type 2 diabetes. The results of newer clinical trials are another important area for discussion, as well as trials that are planned or are currently underway. The newer clinical trials have been conducted in patients who are already on optimal medical therapy, including improved blood pressure control, highest tolerated doses of renin-angiotensin system blockers, and lipid-lowering therapy. Ultimately, we need more precision in guiding pharmacotherapy given the many new therapeutic options available. This compendium will provide an updated opportunity to gauge our progress in the efforts underway to improve longer-term outcomes for patients who have diabetes and CKD. See references starting on p. 34. Dr. Weir is a professor and chief of nephrology in the Division of Nephrology, Department of Medicine, at the University of Maryland School of Medicine in Baltimore. 2 CHRONIC KIDNEY DISEASE AND TYPE 2 DIABETES Pathogenesis of Diabetic Nephropathy Rajiv Agarwal, MD, MS Our understanding of the natural history of diabetic nephropathy has emerged largely from patients with type 1 diabetes. However, histological manifestations among those with type 2 diabetes are similar (10). Both the clinical manifestations and the histological appearances of kidney disease associated with diabetes have been well characterized. The pathogenesis, however, is less well understood, and there are gaps in our understanding of how various causal factors relate to the histological manifestations of diabetes; in part, this is because of a paucity of kidney biopsies and longitudinal data. Here, we will focus on the pathogenesis, summarizing our current understanding of the histological and clinical correlates and pointing out remaining controversies in the context of pathogenesis. The pathogenesis of diabetic nephropathy is initiated and maintained by four causal factors, which can be classified broadly into metabolic, hemodynamic, growth, and proinflammatory or profibrotic factors (Figure 1). Although there is both a substantial overlap among these factors and variability in their relative contribution among individuals and over time, for ease of discussion, we will describe the pathogenesis as if each factor played an isolated role. These pathogenetic factors produce lesions in various kidney compartments: glomeruli, tubuli, interstitium, and vasculature. A complex series of molecules, receptors, enzymes, and transcription factors participate in the process that drives the earliest stages of kidney disease to an enlarged kidney with hypertrophy, expanded extracellular matrix (ECM), glomerulosclerosis, vascular hyalinosis, interstitial fibrosis and tubular atrophy, and loss of function culminating in end-stage renal disease (ESRD). Metabolic Factors The earliest changes are triggered by metabolic factors, namely hyperglycemia. Damage resulting from hyperglycemia can occur by alteration of tissues or can be induced by products of glucose metabolism (11). An overview of the deranged metabolic pathways that mediate the pathogenesis of nephropathy in people with diabetes is shown in Figure 2. Glycation of Tissues Hyperglycemia through a nonenzymatic mechanism can lead to production of advanced glycation end products (AGEs), which by glycation of various tissue constituents such as proteins, collagen, lipids, and ECM can provoke organ dysfunction. This process is likened to that of accelerated aging through browning of tissues or the Maillard reaction (11). Glycation of molecules provokes downstream injury by several mechanisms that can be broadly classified into receptor-mediated and non–receptor-mediated categories (12). Glycation leads to activation of receptors on cells—the best characterized of which is the receptor of advanced glycation end products (RAGE)—that trigger the synthesis and release of nuclear FIGURE 1 Overview of pathogenic factors in diabetic nephropathy. The key drivers of diabetic nephropathy can be broadly classified as metabolic, hemodynamic, growth, and proinflammatory or profibrotic factors. Hemodynamic factors Systemic hypertension Intraglomerular hypertension AGEs Receptor-mediated Polyol pathway Endothelial cell activation Non–receptor-mediated Hexosamine pathway Tissue injury PKC pathway MR overactivation MBL H-ficolin Myeloid MR Others TLR NOD VEGF Macrophage activation Metabolic factors Growth factors Proinflammatory and profibrotic factors Glucose metabolism byproducts Angiopoietins Recurrent AKI Innate immunity Complement activation CHRONIC KIDNEY DISEASE AND TYPE 2 DIABETES 3 factor κB (NFκB) and the generation of reactive oxygen species (ROS). These molecules, although transcription factors, initiate and maintain kidney damage by several processes (12), including cell growth and hypertrophy, inflammation, angiogenesis, endothelial dysfunction, and ECM production. Within the cells, AGEs can produce cellular dysfunction without binding to a receptor. For example, glycation of cytosolic proteins can reduce nitric oxide (NO) bioavailability and provoke oxidative stress (12). Similarly, outside the cells, AGEs can provoke tissue dysfunction without binding to a receptor. For example, glycation of connective tissue constituents such as collagen can crosslink molecules in the ECM and cause dysfunction (12).