Proteinuria and interstitial injury.

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Abstract
It has long been recognized that patients with high-grade proteinuria due to chronic glomerular disease are more likely to develop chronic renal failure than a matched group of patients with low-grade or no proteinuria [1,2]. Although this association may seem intuitively obvious, suggesting correlation with the severity of glomerular damage, two important observations promote an alternative compelling hypothesis. First is the fact that renal functional outcome for patients with chronic glomerulopathy is best predicted histologically by the severity of chronic extraglomerular damage—peritubular capillary loss, tubular atrophy and interstitial fibrosis. Second is research evidence that urinary proteins themselves may elicit pro-inflammatory and pro-fibrotic effects that directly contribute to chronic tubulointerstitial damage. For example, rodents injected daily with large doses of albumin develop ‘overload proteinuria’ that consists of both the exogenous albumin as well as several endogenous plasma proteins [3,4]. Although there does not appear to be an immunological response to the albumin, shortly after the onset of proteinuria, interstitial inflammation develops and fibrosis ensues. While this exact scenario would be unusual in humans, analogous cases have been reported including two children with hemolytic uremic syndrome, severe hyperproteineamia and proteinuria associated with aggressive plasma-infusion therapy [5]. The existence of a direct proteinuria–interstitial inflammation–fibrosis connection has important clinical implications including avoidance of unnecessary albumin and plasma infusions and the use of therapies that reduce protein excretion rates, both immunosuppressive therapy for the primary disease and angiotensin II blockade, especially for hypertensive patients.

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