Proteinuria and Tubulotoxicity

Chronic proteinuric renal diseases, independent from the type of the insult, have in common the loss of selectivity of the glomerular barrier to protein filtration. The glomerular ultrafiltration of excessive amount of plasma proteins and protein-associated factors, as present in diabetic nephropathy, incites tubulointerstitial damage and further promotes the effect of glomerular disease on the tubular compartment. The noxious substances in the proteinuric ultrafiltrate may set off tubular epithelial injury with tubular apoptosis, secondary generation of inflammatory mediators, and peritubular inflammation. Thus, the mechanisms whereby increased urinary protein concentration leads to nephrotoxic injury are multifactorial and involve complex interaction between numerous pathways of cellular damage. This chapter focuses on factors and tubular intracellular pathways leading to cell apoptosis upon exposure of excessive protein load contributing to tubular atrophy and tubuloglomerular disconnection. It also highlights the vasoactive, inflammatory, and fibrogenic mediators that characterize the protein-overload-induced phenotypic changes of the tubular cells and anticipate the development of the immune interstitial response and eventually interstitial fibrosis. These events contribute to the multifaceted process of kidney scarring and progressive function loss.