Pathogenesis and progression of proteinuria.

Progressive albuminuria is the sine qua non of diabetic nephropathy. It is not only a marker of renal damage but also significantly contributes to its development and progression. However, the precise mechanisms by which escalating amounts of albumin leave the blood stream, cross the endothelial glycocalyx, the glomerular basement membrane and the slit pores between the foot processes of the podocytes, transit through Bowman's space, bypass the resorptive mechanisms of the nephron and ultimately pass into the urineremain hotly debated. Certainly, diabetes is associated with significant dysfunction at each of these levels, and will be discussed in detail in this review. Moreover, dilation of the afferent and constriction of the efferent arterioles triggered by defective autoregulation and subsequently by loss of peritubular capillaries also act to increase the glomerular transcapillary hydrostatic pressure and facilitate a far greater transit of albumin into the urine. Importantly, none of these mechanisms exists in isolation. Indeed, the most likely reason for progression of albuminuria is the fact that dysfunction initiated by compromise of one component will inevitably modify other parts, and ultimately affect the whole nephron function. From this 'holonephric' view of albuminuria, the best treatment will be a combination that can promote regression and restore the integrity of the entire pathway, as while fixing one part may slow the process, because of the integrated nature of renal function, it will not completely prevent nephropathy.