Osmotic polyuria: an overlooked mechanism in diabetic nephropathy

Abstract

Tubulo-interstitial pathology in diabetic nephropathy is thought to be caused by cell injury that is induced by high ambient glucose levels and increased proportions of glycated proteins. Other mechanistic hypotheses engage glomerular ultrafiltration of proteins and bioactive growth factors and their effects on tubular cells. Some scholars promote tubular ischaemia due to reduced peritubular blood flow as a response to glomerular injury. All of these mechanisms contribute to renal tubulo-interstitial injury in diabetic nephropathy. However, they do not well explain observations that have been made in studies of experimental animals and evaluations of human biopsies showing dilated collecting ducts in early diabetic nephropathy. Dilatation of distal nephron segments is routinely seen in human biopsies or in histological sections from experimental diabetic nephropathy and is reminiscent of similar findings in obstructive nephropathy. Moreover, it is these dilated tubules that are the primary source for pro-inflammatory and pro-fibrogenic cytokines and regulators. Based on this large body of observations from this laboratory and the published literature this narrative develops a novel hypothesis where hyperglycaemic, osmotic polyuria play important contributory roles in the initiation and progression of tubulo-interstitial injury in diabetic nephropathy.