Emerging Concepts Regarding Albumin Handling By The Kidney

A new understanding of the role of proximal tubular cells in the degradation of filtered proteins including albumin has been reached in the last 5 years. Studies by Comper's group and ourselves have shown that albumin is normally degraded in the kidney and that albumin-derived fragments are not detectable by standard immunological methods [89]. The normal renal handling of albumin involves its degradation through lysosomal uptake from the tubular fluid and subsequent exocytosis of the peptide products back into the urine [28, 90]. Our recent studies of 3H-albumin handling in patients with type 1 diabetes have shown that albuminuria is also directly linked to changes in lysosomal mediated degradation of proteins [29]. These albumin-derived degradation products are found exclusively in the urine and not in blood. The above studies have shown that filtered albumin is fragmented to small peptides of <10-15 kD in size within minutes and that these albumin-derived fragments constitute >90-95% of urinary albumin compared with <5-10% of albumin that is in an intact form [91]. In general, the proportion of intact albumin increases as renal disease progresses from normo- to micro- to macroalbuminuria and may reflect renal tubular dysfunction.

In experimental and human diabetes, an increase in total albuminuria may reflect both an increase in the intact to fragment ratio of urinary albumin as well as alterations in the activity of a trans-tubular transport pathway [92]. By contrast, in experimental hypertension, increases in total albuminuria appear to be explained purely on the basis of a change in the intact:fragment ratio of urinary albumin [89]. The complexity of albumin-derived components in urine has recently been highlighted as intact albumin appears to be excreted in two forms, i.e. immuno-reactive and immuno-unreactive. Preliminary results have demonstrated a high prevalence of immuno-unreactive intact albumin, as measured by HPLC, in the early stages of diabetic renal disease. The exact nature and significance of immuno-unreactive intact urinary albumin is not known but elevated levels may possibly prove to be a useful early marker of renal disease that precedes an increase in immuno-reactive urinary albumin.

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