Metabolic processing of proteins during renal passage

The underlying mechanism of albuminuria has generally been attributed to a loss of glomerular permselectivity, involving a loss of charge selectivity and/or the formation of large pores in the glomerular capillary wall (GCW). Contrary to this, studies have shown that the GCW is not significantly charge or conformation selective, and that the mechanisms of albuminuria are centred at the post-filtration processing events. Despite this body of evidence highlighting the importance of post- filtration processing of albumin, there are ongoing controversies in the literature regarding the mechanisms of albuminuria. This thesis aims to address these controversies and re-examines the renal processing of proteins, in particular albumin, and low molecular weight proteins (LMWP). Although studies have shown the contrary, albuminuria, or increased fractional clearance (FC) of albumin, in nephrotic states is still being attributed to glomerular permeability dysfunction. A portion of this thesis re-examines this issue and presents studies confirming that charge selectivity does not govern the FC of albumin, and that large pores in the GCW do not account for albuminuria. In the same manner, hypoalbuminemia, or increased albumin loss from the plasma, is thought to be controlled by mechanisms centred at the GCW. A large portion of this thesis focuses on the plasma elimination of albumin and re-evaluates the issue of glomerular permselectivity. The studies presented demonstrate that increased plasma clearance of albumin, with accompanying increase in urinary excretion, is not due to increased glomerular permeability, but rather, is associated with post-filtration processing events. The majority of studies on renal function and proteinuria have been performed on albumin. There are no similar studies on LMWP. The LMWP have not been examined since the very early studies performed more than 30 years ago using ex- vivo techniques. A section of this thesis examines the renal processing of LMWP in- vivo, in comparison studies with albumin. Although it has generally been assumed that all proteins are processed by the same mechanism in the kidney, this thesis demonstrates differential renal processing of albumin as compared to LMWP. This finding has great impact on the interpretation of proteinuria and its underlying mechanisms, and provides plausible explanation why low molecular weight proteinuria and albuminuria are entirely separate processes. Finally, this thesis discusses the findings that highlight the important and under- estimated role of post-filtration processing events in the mechanisms of albuminuria and hypoalbuminemia. This has great clinical implication, as it is important for clinicians to distinguish albuminuria that gives rise to clinically significant hypoalbuminemia, from albuminuria with no associated hypoalbuminemia.