The clearance (top; left to right) of IgG (white) from mouse kidney filters is slowed in the absence of FcRn (bottom).

SHAW/NAS

Filters in the mammalian kidney must be unclogged by a transport receptor, say Shreeram Akilesh, Andrey Shaw (Washington University, St. Louis, MO), and colleagues. The receptor moves obstructing proteins into the urine, where they can later be returned to the bloodstream.

The kidney filters the blood through a bed of capillaries known as the glomerulus. Large and highly charged proteins are mostly kept out of the urine filtrate first by a basement membrane and then by finger-like projections of epithelial cells called podocytes. Shaw's group wondered why the gaps between podocyte projections do not get clogged by the proteins they prevent from passing.

The two dominant large proteins in the blood—those mostly likely to cause a clog—are albumin and IgG. Using microarray analyses, the team found that a receptor for these proteins, called FcRn, was expressed in podocytes. FcRn was first identified for its role in bringing IgG antibodies from breast milk across the surface of an infant's gastrointestinal tract. The new findings suggest it similarly transports IgG and albumin across the podocyte surface into the urinary fluid.

In mice lacking FcRn, IgG clearance was slowed, and the antibody accumulated in the kidney filter. Clogged kidneys meant greater susceptibility to agents that would otherwise be quickly cleared; a normally harmless dose of a kidney-targeting antibody was toxic to mice whose kidneys were overloaded with IgG.

An overloaded filter might also explain why kidney failure is often the downfall of patients with lupus. “The autoantibodies in lupus patients aren't so uncommon,” says Shaw. “But with clogging from all the excess antibodies, the kidneys probably cannot get cleared of them in time.”

Because IgG and albumin are not normally found in urinary waste, the authors imagine that they are reabsorbed into the bloodstream in kidney tubules, where sugars and amino acids are also reclaimed. The expression of FcRn in tubules supports this idea. To prove their theory, the authors hope to put FcRn back into podocytes but not tubules of the knockout mice, to see whether IgG is sent out with the urine.

Reference:

Akilesh, S., et al.
2008
.
Proc. Natl. Acad. Sci. USA.
105
:
967
–972.