Albuminuria and renal injury—beware of proteins bearing gifts

Over the last two decades a shift in paradigm has taken place regarding the role of proteinuria in the progression of renal disease. Across a wide spectrum of glomerular and non‐glomerular diseases (especially those characterized by tubulointerstitial fibrosis), the degree of proteinuria has been shown to correlate with the risk of progression to end‐stage renal disease [1]. Initially, proteinuria was thought simply to be a marker of the severity of glomerular injury. Recent evidence, however, suggests that proteinuria, and particularly albuminuria, may itself promote tubular injury, with interstitial inflammation and eventual fibrosis [2,3]. While several mechanisms have been put forward to explain how albuminuria can produce renal injury, a direct causal relationship, even in animal models, has yet to be established. To complicate matters further, recent in vitro data indicate that albumin can inhibit apoptosis and promote the survival of primary cultures of mouse proximal tubular epithelial (MPT) cells and macrophages [4–6]. These results present a seeming paradox: how can albumin act as a potent survival factor for tubular epithelial cells in culture and yet at the same time mediate their injury in vivo? We will attempt, in this brief review, to reconcile these seemingly contradictory findings.