New insights into mechanisms of glomerular permselectivity

Proteinuria has emerged as a key predictor of progression from renal insufficiency to end-stage renal disease, and clearly plays a pathogenic role in loss of renal function. Control of proteinuria is seen as critical to delaying disease progression, and myriad treatments which appear to reduce proteinuria have been reported and have entered clinical practice. Despite the increasing emphasis on control of proteinuria, the precise mechanism by which the kidney retains proteins in the blood remains a subject of dispute in the literature. In the past decade, mechanisms for protein retention by the kidney which transcend simple molecular sieve heuristics have been proposed. This renewed interest in renal physiology is exciting, as new insights may drive forward mechanism-based treatments for renal disease. In this review article, four schools of thought on renal protein retention are described, including three from other groups and our own hypothesis. Arguments and data supporting and refuting each paradigm are discussed without the intent or effect of supporting one to the exclusion of others.