intake Obesity Smoking Albuminuria Genetics Glycemic control Fibrosis Inflammation Dyslipidemia Oxidative stress RAAS Systemic and intraglomerular blood pressure Metabolic syndrome CHRONIC KIDNEY DISEASE AND TYPE 2 DIABETES 9 Experimental studies have suggested that succinate, formed by the tricarboxylic acid cycle, provides a direct link between high glucose and renin release in the kidney (60). Focus was initially on the damaging effect of angiotensin II. As discussed for blood pressure, RAS-blocking agents have been a standard of care in CKD in 20 years. Aldosterone represents another component of the RAAS that should be considered important in the pathophysiology of diabetic nephropathy. Aldosterone is a hormone that, in addition to regulating electrolyte and fluid homeostasis, has widespread actions through genomic and nongenomic effects in both the kidney and tissues not originally considered targets for aldosterone such as the vasculature, central nervous system, and heart (61). Obesity Obesity is an increasing problem in the general population and among people with diabetes. Several studies have indicated that severe obesity (BMI >40 kg/m2 ) enhances ESRD risk sevenfold (62). Even a BMI >25 kg/m2 was found to increase ESRD risk (62). This effect is independent of the effects of hypertension and diabetes, the prevalence of which are increased in individuals with obesity. An effect of obesity on renal hemodynamics leading to increased glomerular pressure and hyperfiltration has been suggested as the mechanism (63), and adiponectin was suggested to link obesity to podocyte damage (64). Weight reduction from bariatric surgery (65) or pharmacological treatment (66) has been associated with improved renal outcomes, although large weight reductions will improve estimated GFR (eGFR) and not true GFR because of loss of muscle mass and then decline in serum creatinine (67). Other Metabolic Factors Blood lipids, including triglycerides (68,69), contribute to the development and progression of CKD, although the lipid phenotype alters as kidney disease progresses (70–72). Insulin resistance increases the risk of albuminuria in type 2 diabetes (73). Individuals with type 1 or type 2 diabetes and CKD are more likely to have the metabolic syndrome (74–76). Multifactorial intervention targeting lifestyle, glucose, blood pressure, and lipids has a beneficial impact on both cardiovascular and kidney outcomes (77). Genetic Factors Genetic factors influence susceptibility to CKD in both type 1 and type 2 diabetes (78,79). If one sibling with type 1 diabetes has nephropathy, the risk to a second sibling is increased four- to eightfold compared to sibling sets in which neither has nephropathy (80). Similar familial clustering has been described in type 2 diabetes (81). Despite these findings, strong and clinically useful genes for CKD in diabetes are still lacking. The clustering of conventional cardiovascular risk factors and cardiovascular disease (CVD) in people with diabetes and CKD also occurs in their parents (82,83). This finding suggests that the genetic susceptibility to nephropathy also influences the associated CVD. Multiple genes, either protective or deleterious, are involved. Different loci may influence albuminuria and GFR separately (84). Epigenetic modification may also be important (85). Ethnicity Albuminuria and CKD stages 4 and 5 are more common in U.K. Afro-Caribbean and South Asian individuals than White European people (86,87). The prevalence of early CKD (defined as moderately elevated or greater albuminuria and eGFR30% (HR 4.81, 95% CI 1.92–12.01). Applying urinary proteomic analysis with capillary electrophoresis coupled to mass spectrometry, Good et al. (115) described a high-dimensional urinary biomarker pattern composed of 273 peptides associated with overt kidney disease: CKD273. The original studies included people with CKD on a mixed background compared to healthy control subjects. The components of CKD273 include collagen fragments and are assumed to relate to early fibrosis in the kidney. In retrospective studies, this proteomic classifier identified subjects at risk for CKD and progression in albuminuria class earlier than the indices currently used in clinical practice (116). In a prospective study including people with type 2 diabetes and normoalbuminuria, it was also demonstrated that CKD273 was associated with development of microalbuminuria and impaired kidney function (117). Inflammation Multiple markers have been investigated related to inflammation. These include fibrinogen, interleukin 6, and tumor necrosis factor-α (TNF-α), which were found to be associated with risk of CKD progression (118). Some of the most widely studied markers have been tumor necrosis factor receptors (TNFRs) 1 and 2. Recently, a Kidney Risk Inflammatory Signature was developed with 17 inflammatory markers, including TNFR superfamily members (119). The signature was tested in two cohorts as a marker of ESRD in both type 1 and type 2 diabetes. All components of the signature had a systemic, non-kidney source and may guide therapy to new targets. Interestingly, the signature was improved with the anti-inflammatory agent baricitinib, but not with RAS blockade (119). FIGURE 2 Stages and prognosis of CKD based on albuminuria and GFR from the KDIGO (Kidney