Proteinuria: pathophysiology, diagnostic and therapeutic approach

Normal urine contains minute amounts of protein. The normal glomerular basement membrane imposes a barrier to large plasma proteins. This effect depends mainly on basement membrane pore size and electrostatic charge. However, a relevant role is also played by podocytes. Smaller proteins are filtered freely. Most of the proteins normally entering the urine are catabolized by the proximal tubules. The most frequent cause of major proteinuria is the functional failure of the glomerular barrier (glomerular proteinuria). In tubular proteinuria functional disturbances of the tubules result in a lack of catabolization of smaller proteins that can readily cross the glomerular barrier. The overflow proteinuria is caused by the glomerular filtration of compounds that are present in the plasma at higher concentrations in certain diseases; for example: light chain of immunoglobulins in multiple myeloma. Proteinuria may occur as a consequence of resistance to venous outflow, as in orthostatic proteinuria. This is asymptomatic and occurs mainly in young, slim and tall males, and it is generally benign. Proteinuria should be monitored regularly in any disease that is potentially related to glomerular damage, such as diabetes mellitus, autoimmune disorders, and hypertension. The correct diagnosis in a patient with proteinuria can only be obtained by renal biopsy. The presence of proteinuria is a well-known major independent risk factor for progressive renal damage, and for cardiovascular morbidity and mortality. The interaction of albumin with proximal tubules leads to renal damage through an increased expression of a variety of inflammatory and fibrogenic cytokines. This progression seems to be largely independent of the initial insult, and it is the final common pathway for chronic, proteinuric nephropathies in animals and humans. Both interstitial inflammation and progression of disease can be controlled by drugs that interfer with the renin angiotensin system, such as the angiotensin-converting enzyme inhibitors (ACEI), the angiotensin receptor blockers (ARB), and the aldosterone receptor blockers. These agents strengthen the glomerular permeability barrier to protein, limit proteinuria and filtered protein-dependent inflammatory indicators.