Pathogenesis, Clinical Manifestations, and Natural History of Diabetic Kidney Disease

Diabetic kidney disease (DKD) occurs in 30% to 40% of patients with type 1 or 2 diabetes, suggesting a potential polygenic influence. Hyperfiltration is an early feature that could be prevented by inhibiting the sodium-glucose cotransporter 2 (SGLT2) in the proximal tubule. Substrates of diabetes, such as high glucose, advanced glycation end products and their carbonyl intermediates, stimulate intrarenal inflammatory and subsequently fibrogenic processes leading to mesangial expansion, thickening of the glomerular basement membrane, and tubulopathic changes via modulation of a number of intracellular signaling pathways, including the AMPK, PKC, and polyol pathways, and activation of innate immunity and mitochondrial dysfunction. Clinical trials have demonstrated the beneficial effects of glycemic and blood pressure control in slowing the progression of DKD, but targets need to be individualized. The impact of SGLT2 inhibitors have dramatically changed the outlook for patients with diabetic nephropathy. Although albuminuria is a hallmark, a growing population of normoalbuminuric patients with progressive DKD has been recognized. Lipotoxicity, epigenetics and epigenomics and gut microbiota dysbiosis are increasingly recognized as pathogenetic contributors. A key challenge will be to personalize treatment for patients with diabetic nephropathy at different clinical stages of disease.