Glomerular proteinuria

The glomerular basement membrane through which blood is filtered does not usually allow passage of albumin and large proteins, and proteinuria is most often due to abnormally ‘leaky’ glomeruli. The extent of this ‘leakiness’ varies enormously. At its most extreme, the glomerulus allows large quantities of protein to escape. When this happens, the ability of the body to replace the lost protein is exceeded, and the protein concentration in the patient’s blood falls. Protein is measured in blood either as total protein or albumin. When patients become hypoproteinaemic and hypoalbuminaemic due to excessive proteinuria, the normal balance of osmotic and hydrostatic forces at capillary level is disturbed, leading to loss of fluid into the interstitial space (oedema). This is known as the nephrotic syndrome (defined in terms of protein excretion – more than 3 g daily).

Tubular proteinuria

Some proteins are so small that, unlike albumin and other larger proteins, they pass through the glomerulus freely. The best-known examples are beta-2-microglobulin and alpha-1-microglobulin. Others include retinol-binding protein and N-acetyl-glucosaminidase. If these proteins are detected in excess in the urine, this reflects tubular rather than glomerular dysfunction, i.e. an inability of the renal tubules to reabsorb them. However, tubular function is normally investigated in other ways, and the measurement of these proteins in urine is normally confined to the screening and detection of chronic asymptomatic tubular dysfunction, or a small number of specific clinical scenarios, e.g. toxicity due to aminoglycosides, lithium, or mercury.

Overflow proteinuria

Overflow proteinuria occurs when the ability of the glomeruli to hold back proteins is overwhelmed by the sheer quantity of protein. The best-characterized example of overflow proteinuria is multiple myeloma. This condition involves malignant proliferation of a clone of plasma cells (a special kind of lymphocyte, the function of which is to produce immunoglobulins). This results in the production of vast amounts of the immunoglobulin produced by the malignant clone. In this kind of proteinuria, the glomeruli are normal (at least initially). Bence-Jones proteins are light chain fragments of the immunoglobulin that can be detected in the urine.

Tamm–Horsfall proteinuria

This glycoprotein gets its name from the authors of a 1952 paper describing its purification. It is one of the most abundant proteins in urine. Its significance lies in the fact that, unlike the other proteins mentioned above, it is not derived from the blood, but rather is produced and secreted into the filtrate by the thick ascending limb of the loop of Henle. It forms large aggregates that, when concentrated, can in turn form urinary casts (gel-like cylindrical structures that reflect the shape of the renal tubules and that get dislodged and pass into the urine).

Dipstick urinalysis

The procedure for dipstick urine testing is shown in Figure 16.2 on page 32. Dipsticks are commercially available disposable strips, impregnated with coloured reagent blocks, which are immersed in urine. The reagents in each block react with a specific component of urine in such a way that the block changes colour if the component is present. Protein is just one of several components tested for; others include glucose, blood and bilirubin.

Dipstick testing is the most widely used method of screening for proteinuria. It is convenient for both patient and clinician, and provides a near-instant result at the point of care. However, it gives only a rough indication of the presence or absence of pathological proteinuria, and cannot be used alone to diagnose or exclude proteinuria. It must be used in conjunction with more reliable methods.

Protein/creatinine ratio

Quantitative measurement of protein in urine provides a much more reliable evaluation of proteinuria. Accuracy is further improved by measuring the urinary creatinine concentration as well and expressing the result as the protein/creatinine ratio; this corrects for variation in urine concentration. Dipstick urine testing and protein/creatinine ratio (PCR) both require a spot urine sample and so are equally convenient from a patient perspective. An early morning sample is preferred (because it correlates best with 24-hour protein excretion) but random samples are acceptable.

Urine protein excretion

A 24-hour timed urine collection for protein excretion is still widely used as the reference method for comparing other ways of assessing urine (e.g. dipstick testing and PCR above). However, timed urine collections are inconvenient and not always completely accurate. It has been suggested that daily protein excretion (in mg/24 hours) can be ‘guesstimated’ by multiplying the PCR (in mg/mmol) by a factor of 10 (i.e. assuming average daily creatinine excretion of 10 mmol/day).

Albumin/creatinine ratio and ‘microalbuminuria’

Methods for measuring albumin in urine are more accurate than methods for measuring protein in urine, especially at low concentrations. However, these immunoassay methods are more expensive than those used to measure urine total protein. ‘Microalbuminuria’ refers to the excretion of albumin in urine in amounts that are abnormal but not detectable by standard urine dipstick testing. (The term is misleading – the albumin excreted in microalbuminuria is exactly the same as in other proteinuric conditions.) If detected in a diabetic patient, microalbuminuria signifies early diabetic nephropathy and therefore allows treatment with e.g. angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) that may help reduce the progression of kidney damage.