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REVIEW

Disease-dependent mechanisms of albuminuria

¹Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia; ²CVK Research, New York, New York; ³Department of Nephrology and Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia; and ⁴Center for Systems Biology, Program in Membrane Biology, and Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts

Submitted 16 March 2008 ; accepted in final form 18 June 2008

ABSTRACT

The mechanism of albuminuria is perhaps one of the most complex yet important questions in renal physiology today. Recent studies have directly demonstrated that the normal glomerulus filters substantial amounts of albumin and that charge selectivity plays little or no role in preventing this process. This filtered albumin is then processed by proximal tubular cells by two distinct pathways; dysfunction in either one of these pathways gives rise to discrete forms of albuminuria. Most of the filtered albumin is returned to the peritubular blood supply by a retrieval pathway. Albuminuria in the nephrotic range would arise from retrieval pathway dysfunction. The small quantities of filtered albumin that are not retrieved undergo obligatory lysosomal degradation before urinary excretion as small peptide fragments. This degradation pathway is sensitive to metabolic factors responsible for hypertrophy and fibrosis, particularly molecules such as angiotensin II and transforming growth factor-β1, whose production is stimulated by hyperglycemic and hypertensive environments. Dysfunction in this degradation pathway leads to albuminuria below the nephrotic range. These new insights into albumin filtration and processing argue for a reassessment of the role of podocytes and the slit diaphragm as major direct determinants governing albuminuria, provide information on how glomerular morphology and "tubular" albuminuria may be interrelated, and offer a new rationale for drug development.

proximal tubular cell; albumin retrieval; albumin degradation

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