Immunity and inflammation in diabetic kidney disease: translating mechanisms to biomarkers and treatment targets

Abstract

Increasing incidences of obesity and diabetes have made diabetic kidney disease (DKD) the leading cause of chronic kidney disease and end-stage renal disease worldwide. Despite current pharmacological treatments, including strategies for optimizing glycemic control and inhibitors of the renin-angiotensin system, DKD still makes up almost one-half of all cases of end-stage renal disease in the United States. Compelling and mounting evidence has clearly demonstrated that immunity and inflammation play a paramount role in the pathogenesis of DKD. This article reviews the involvement of the immune system in DKD and identifies important roles of key immune and inflammatory mediators. One of the most recently identified biomarkers is serum amyloid A, which appears to be relatively specific for DKD. Novel and evolving treatment approaches target protein kinases, transcription factors, chemokines, adhesion molecules, growth factors, advanced glycation end-products, and other inflammatory molecules. This is the beginning of a new era in the understanding and treatment of DKD, and we may have finally reached a tipping point in our fight against the growing burden of DKD.

Keywords: diabetes; diabetic kidney disease; inflammation; treatment.

Fig. 1.

Global distribution of diabetes and prevalence of diabetes projected from the years 2014 to 2035. Projected growth rates from 2014 to 2035 of global numbers of people living with diabetes as estimated by the International Diabetes Federation are shown. The number of people with diabetes will increase by 55% by 2035. Please also note that three-fourths of people with diabetes live in middle- and low-income countries.

Fig. 2.

Advanced glycation end-products (AGE), receptor for AGE (RAGE), and serum amyloid A (SAA) as inflammatory mediators of diabetic kidney disease. Diabetes has been shown to increase serum levels of SAA, but has also been demonstrated to increase SAA expression in renal cells, including podocytes, mesangial cells, and tubular epithelial cells. Some of these effects are mediated through RAGE, protein kinase C, Janus kinase, and NF-κB signaling pathways. Cultured podocytes also significantly increased endogenous SAA expression when exposed to exogenous SAA, suggesting a possibly self-perpetuating autocrine amplification loop.