Under physiologic conditions, significant amounts of plasma protein pass the renal filter and are reabsorbed by proximal tubular cells, but it is not clear whether the endocytosed protein, particularly albumin, is degraded in lysosomes or returned to the circulatory system intact. To resolve this question, a transgenic mouse with podocyte-specific expression of doxycycline-inducible tagged murine albumin was developed. To assess potential glomerular backfiltration, two types of albumin with different charges were expressed. On administration of doxycycline, podocytes expressed either of the two types of transgenic albumin, which were secreted into the primary filtrate and reabsorbed by proximal tubular cells, resulting in serum accumulation. Renal transplantation experiments confirmed that extrarenal transcription of transgenic albumin was unlikely to account for these results. Genetic deletion of the neonatal Fc receptor (FcRn), which rescues albumin and IgG from lysosomal degradation, abolished transcytosis of both types of transgenic albumin and IgG in proximal tubular cells. In summary, we provide evidence of a transcytosis within the kidney tubular system that protects albumin and IgG from lysosomal degradation, allowing these proteins to be recycled intact. 24: 196624: -198024: , 201324: . doi: 10.1681 The main function of the kidney is to filter plasma, while at the same time, retain the majority of plasma proteins. However, a certain fraction of plasma proteins inevitably passes the glomerular filtration barrier. The most abundant and most studied plasma protein, albumin, is produced at a rate of about 15 g per day in humans. 1 In the renal glomerulus, the albumin sieving coefficient (i.e., the transport rate of albumin across the glomerular filter in relation to water) has been estimated to be below 0.001. [2][3][4] In more recent studies using intravital microscopy, the albumin sieving coefficient has been estimated to be significantly higher, although this result is still controversial. 5-7 Thus, even when assuming a tight renal filtration barrier, significant amounts of albumin pass the glomerular filterroughly in the range of 1 g per day in healthy humans, J Am Soc Nephrol

Human kidneys produce more than 4 million litres of virtually protein-free primary urine in a lifetime. In healthy individuals, the sieving process is accomplished by the glomerular filter without the smallest sign of clogging, even in old age. How nature accomplishes this extraordinary task is a mystery, but unravelling the functioning of the glomerular filter is important. The basic principles that govern glomerular filtration are probably also true for peripheral filtering by fenestrated capillaries. In addition, understanding the sieving process is a prerequisite to understanding the pathogenesis of proteinuria (that is, the leakage of plasma proteins into the urine). Proteinuria is the hallmark of glomerular disease and a major risk factor for systemic cardiovascular complications, a fact that emphasizes the relationship between the glomerular and peripheral filtering capillaries. In this Review, we briefly summarize the major models that have been proposed for the mechanisms of glomerular filtration and discuss their strengths and limitations. A special emphasis is placed on the 'electrokinetic model' that we have proposed, a model that could potentially resolve many of the seemingly strange characteristics of the glomerular filtration barrier.

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