1. Proteinuria is consequence of two mechanisms: the abnormal transglomerular
passage of proteins due to increased permeability of glomerular capillary wall and
their subsequent impaired reabsorption by the epithelial cells of the proximal tubuli.
In the various glomerular diseases, the severity of disruption of the structural
integrity of the glomerular capillary wall correlates with the area of the glomerular
barrier being permeated by "large" pores, permitting the passage in the tubular
lumen of high-molecular-weight (HMW) proteins, to which the barrier is normally
impermeable. The increased load of such proteins in the tubular lumen leads to the
saturation of the reabsorptive mechanism by the tubular cells, and, in the most
severe or chronic conditions, to their toxic damage, that favors the increased urinary
excretion of all proteins, including low-molecular-weight (LMW) proteins, which are
completely reabsorbed in physiologic conditions. Recent clinical studies showed that
in patients with glomerular diseases the urinary excretion of some HMW proteins
[immunoglobulins G and M (IgG and IgM)] and of some LMW proteins, alpha1-
microglobulin, beta2-microglobulin, correlates with the severity of the histologic
lesions, and may predict, better than the quantity of proteinuria, the natural course,
the outcome, and the response to treatment. It is suggested that some patients have
already, at the time of clinical presentation, a structural damage of the glomerular
capillary wall (injury of podocytes) and of the tubulointerstitium, the severity and
scarce reversibility of which are reliably indicated by an elevated urinary excretion of
HMW and LMW proteins.

2. The filtration of albumin and nonalbumin proteins across the abnormal glomerular
capillary wall (GCW) exposes mesangial and tubular cells to these proteins. Albumin
and nonalbumin proteins are normally reabsorbed from the glomerular filtrate in the
proximal convoluted tubule (PCT).
Heavy proteinuria may exceed the capacity of lysosomes in the PCT cells to
metabolize reabsorbed protein, and toxic enzymes may leak into the cells and the
surrounding renal interstitium[1] as a consequence of lysosomal degranulation.
Whether the nephrotoxic protein is albumin, nonalbumin protein, or both remains
unclear.
Other proteins, such as transferrin, complement components, and low-density
lipoproteins (LDLs), also appear to be directly toxic to tubular cells. In addition,
lipoproteins appear to be toxic to mesangial cells and may contribute to the
development of glomerular sclerosis.
A consequence of protein-mediated cytotoxicity is the production of chemokines and
cytokines that initiate an inflammatory response and ultimately lead to sclerosis and
fibrosis.