The kidney handles three major types of protein: albumin, small molecular weight proteins such as peptide proteins and amino acids, and occasionally light chains derived from immunoglobulins. Albumin is the major protein in plasma and is important in maintaining Starling forces which regulate the circulating plasma volume. The healthy kidney has a number of mechanisms by which it conserves albumin. Blood enters the glomerulus through the afferent arteriole and is filtered across the glomerular capillary wall and the glomerular basement membrane. The glomerular basement membrane (GBM) is the primary barrier to filtration of protein. The GBM is negatively charged and repels the negatively charged proteins including albumin. In addition to this charge barrier, the GBM also acts as a size barrier, preventing albumin and larger protein molecules from passing into the tubules. As a result, only a small percentage of the total albumin that enters the glomerulus is filtered into the renal tubules. Furthermore, 90% of the albumin that reaches the tubules is reabsorbed so that an even smaller amount is eventually excreted in the urine (<150 mg/24 h in a nonpregnant woman and <300 mg/24 h in a pregnant woman).

There are three mechanisms which lead to proteinuria. Glomerular proteinuria results from the filtration of macromolecules, namely albumin, across the glomerular basement membrane. Defects in the GBM may lead to an alteration in the charge barrier, the size barrier or both. Glomerular proteinuria is a marker of glomerular disease that may result from primary renal disease or from systemic disease that affects the kidney. Tubular proteinuria is due to tubular or interstitial injury which impairs resorption of protein, resulting in increased excretion of small molecular weight proteins and small amounts of albumin. Overflow proteinuria is less common and is due to an excess production of small molecular weight protein which overwhelms the resorptive capacity of the tubules. The classic example of overflow proteinuria is the overproduction of light chains from immunoglobulins in multiple myeloma.

A number of methods are available to measure urine protein. The urine dipstick is the most common screening test. This tests measures only albumin and will miss tubular or overflow proteinuria. The urine dipstick is a poor measure of the severity of proteinuria. It measures albumin concentration and since concentration is dependent on volume, results may vary according to the patient’s volume status. The 24- hour urine collection is the gold standard for quantifying urine. It measures all types of protein. Its primary disadvantage is a high degree of collection error such as missed samples or timing errors. For this reason, the National Kidney Foundation has recommended that, in the nonpregnant patient, a urine/protein creatinine ratio be the preferred method for measuring proteinuria [2]. When the urinary protein and the urinary creatinine are expressed in mg/dL, the ratio provides a correlation with the 24-hour urine that is easy to interpret. For example, a urine protein/creatinine ratio of 0.1 represents 100 mg of protein in a 24-hour urine; 0.2 would represent 200 mg, etc. A number of studies show significant correlation between the 24-hour urine collection and the urine protein/creatinine ratio in pregnancy [3,4]. However, there is no clear consensus on the best cut-off value to distinguish normal from abnormal levels of proteinuria. Still, other studies conclude that the urine protein/creatinine ratio is a poor predictor of significant proteinuria in women with suspected pre-eclampsia [5,6]. More studies are needed to clarify the role of the urine protein/creatinine ratio in pregnancy but in the absence of pre-eclampsia, it is reasonable to use this test to initiate the investigation of unexplained proteinuria.

Proteinuria may be divided into two broad categories: benign and disease related. There are only two benign cause of proteinuria, while there are many disease-related causes (Box 41.1). Benign causes include transient and orthostatic proteinuria and are usually associated with low-range proteinuria, that is less than 1 g. The urinalysis and creatinine are normal in both of these conditions. Transient proteinuria occurs in 7% of women on a single exam [7]. It is most often triggered by some type of physiologic stress such as fever, heavy exercise, cold exposure or stress. The diagnosis is confirmed if a repeat urine dipstick is negative for protein once the physiologic stress is resolved. Orthostatic proteinuria is primarily a disease of children but it occurs in 2–5% of adolescents and can be seen in women in their 20s [8]. Orthostatic proteinuria is rare in women over the age of 30 years. In this condition, the patient excretes an abnormal amount of urine while in the upright position, but normal levels of protein while supine.

Disease-related proteinuria has many causes, both primary renal and systemic disease (see Box 41.1) There are a number of classification systems causing much confusion. A classification system based on clinical presentation seems to be the most clinically useful approach to the evaluation of disease-related proteinuria and will be presented here.