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Proteinuria

Educational resources for renal medicine

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In preparation ...

Diagram

The glomerular filter is quite porous, in that it's only when you get up to molecular weights of 60,000 or so that the barrier is nearly complete. Below 20,000 there is free filtration, so many short peptides, including many hormones such as insulin and other small proteins, are normally filtered. Between 20 and 60,000 there is a gradient of progressively less filtration. These filtered proteins are normally taken up from the filtrate in the proximal tubule and metabolised in proximal tubular cells. The small amount of protein normally found in urine is most Tamm Horsfall protein which is secreted further down the tubule.

Tubular diseases that upset the mechanism for the reabsorption of protein can lead to tubular proteinuria, when low molecular weight proteins appear in the urine, but this does not normally amount to more than a maximum of a couple of grams of protein per day. Beta-2 microglobulin appearing in the urine would be a sign of this. Immunoglobulin light chains are mentioned here because if free light chains are overproduced, as happens in some B lymphocyte disorders, they will be freely filtered, and some of these chains may precipitate and/or be toxic to tubules, causing myeloma kidney for example.

Albumin is a very useful marker, because there are huge quantities of it in plasma, and the tiny quantities that get filtered at a normal glomerulus (it has a molecular weight of 67,000) are easily reabsorbed by the usual tubular mechanism. However this mechanism can be quickly overloaded if there is a glomerular protein leak.

Barrier - Wartiovaara

Let's take a closer look at the glomerular filtration barrier by electron microscopy. A shows an enlarged view of a segment of a glomerular capillary wall, with the capillary lumen below. E is for endothelial cell, which has pores known as fenestrae in it, and FP are the cut-across, complex foot processes of podocytes. C shows the gap between two adjacent foot processes at higher magnification to show the

slit diaphragm

You can see a faint structure in the middle which is magnified further in D. Pores between these strands are almost exactly the size of an albumin molecule. The strands are made up nephrin, and when this protein is mutated or absent, there is a catastrophically severe protein leak, a condition known as Finnish congenital nephrotic syndrome. It is so severe that affected babies sometimes have nephrectomies to control it, meaning of cause that they have to be dialysed from infancy.

EM from

Here, the lower panel shows a normal rat glomerular capillary, endothelial side below, urinary side above. The upper panel shows a similar view a few hours after injection of a monoclonal antibody that disrupts the slit diaphragm. The animal develops proteinuria within minutes, and this is associated with the loss of morphology of the foot processes.

This and other pieces of evidence suggest that the slit diaphragm is the site of the glomerular barrier to protein, and not the GBM itself, which is a more open network like a big sponge.

Glomerular proteinuria

So to summarize, Albumin is the hallmark of glomerular proteinuria

There are some circumstances in which it is a transient phenomenon, but if persistent it implies significant glomerular disease.

Microalbuminuria

Using very specific and sensitive assays, albumin can be detected in urine before it reaches levels that increase total urinary protein. This provides early warning of glomerular disease, and has proved very useful for instance in early diabetic nephropathy. However microalbuminuria is also found in patients with extensive vascular disease, as in atherosclerosis. The mechanism is not clear, but it is important because there is a strong association between even these very low levels of albuminuria and increased cardiac risk, even if GFR is normal.

Proteinuria: quantitative

Quantitation of proteinuria is the other useful differentiating feature. Although traditionally done by measuring protein in a 24 hour collection, it is best done by measuring protein/creatinine ratio in single samples. 100mg/mmol is approximately equivalent to a daily protein excretion of 1 gram.

 
Page last modified 04.03.2012, 23:10 by Neil Turner. edrep and edren are produced by the Renal Unit at the Royal Infirmary of Edinburgh and Univ. Edinburgh. CAUTIONS and Contact us. Note that the information published here is primarily intended for education, not for clinical care.