Proteinuria 

Plasma proteins are essential components of any living being. The kidneys play a major role in the retention of plasma proteins, and this is accomplished by the renal tubules through their reabsorption of such proteins as they pass through the glomerular filtration barrier. Normal urine protein excretion is up to 150 mg/d. Therefore, the detection of abnormal quantities or types of protein in the urine is considered an early sign of significant renal or systemic disease.

The detection of various types of proteins excreted in the urine has been extensively used in the assessment of renal diseases. The detection of low levels of albumin excretion (termed microalbuminuria) has been linked to the identification of the early stages of diabetic kidney disease.

Normally, the concentration of albumin in the urine is less than 5 mg/L. When expressed as an excretion rate (ie, urine albumin excretion rate [UAER]), this concentration averages 2.6-12.6 µg/min in males and 1.1-21.9 µg/min in females. Microalbuminuria is referred to as excretion of 30-300 mg/d or 20-200 µg/min of albumin, which, by routine dipstick screening methods, is too small to be detected.

To date, numerous assays have been developed to detect this range of concentration of albumin in the urine. However, most of these assays are limited by intraindividual variations, such as physical activity level, acute illnesses or fevers, menstruation, pregnancy, vaginal discharge, diet, blood pressure, volume status, degree of glycemic control, and urine collection method (eg, 24 h, overnight or timed, short-term). On average, albumin excretion is 25% higher during the day than overnight, with a day-to-day variation of 40%. Therefore, before a patient is classified as having microalbuminuria, at least 3 urine samples over a 6-month period that satisfy the above range criterion are recommended.

Recent studies

In a study of 225 proteinuric patients with diabetes mellitus type 2, Chiu et al investigated whether vascular calcification, which can be particularly severe in nondialyzed patients with coexisting proteinuria and diabetes, is a prognostic indicator in early stage type 2 diabetic nephropathy. Eighty-six percent of the study's patients were found to have coronary artery calcification, the degree of which, the authors determined, was associated with older age, white ethnicity, and being male. (Fifty-four patients died during the follow-up period, which averaged 39 months.) Univariate and multivariate analyses indicated that the degree of coronary artery calcification was, in relation to the calcification's severity, an independent predictor of all-cause mortality in the study's patients, with a 2.5-fold greater mortality risk found in subjects with a calcification score in the highest quartile.^[1]

The presence of abnormal amounts or types of protein in the urine reflects the following:

• Systemic diseases that result in an inability of the kidneys to normally reabsorb the proteins through the renal tubules
• Overproduction of plasma proteins that are capable of passing through the normal glomerular basement membrane (GBM), as they enter the tubular fluid in amounts that exceed the capacity of the normal proximal tubule to reabsorb them
• A defective glomerular barrier that allows abnormal amounts of proteins of intermediate molecular weight to enter the Bowman space

Frequency

United States

Approximately 4% of males and 7% of females have proteinuria detected by a single routine dipstick test. The vast majority of these cases are due to transient proteinuria, which resolves spontaneously and does not represent significant underlying renal disease. Proteinuria is found upon repeat testing in 21% of males and 7% of females.

Mortality/Morbidity

• Filtration of albumin and nonalbumin proteins across the abnormal glomerular capillary wall (GCW) exposes mesangial cells and tubular cells to these proteins. Albumin and nonalbumin proteins are normally reabsorbed from the glomerular filtrate in the proximal convoluted tubule (PCT).
• Heavy proteinuria may exceed the capacity of lysosomes in the PCT cells to metabolize reabsorbed protein, and toxic enzymes may leak into the cells and the surrounding renal interstitium^[2] as a consequence of lysosomal degranulation. Whether the nephrotoxic protein is albumin, nonalbumin protein, or both remains unclear. Other proteins, such as transferrin, complement components, and low-density lipoproteins, also appear to be directly toxic to tubular cells. Lipoproteins also appear to be toxic to mesangial cells and may contribute to the development of glomerular sclerosis. A consequence of protein-mediated cytotoxicity is the production of chemokines and cytokines that initiate an inflammatory response and ultimately lead to sclerosis and fibrosis.
• In addition to being a predictor of outcome in patients with renal disease, microalbuminuria also is a predictor of morbidity and mortality in patients who do not have evidence of significant renal disease. In patients with hypertension, the presence of microalbuminuria is correlated to the presence of left ventricular hypertrophy. In hypertensive patients and normotensive patients, the presence of microalbuminuria predicts an increased risk of cardiovascular morbidity and mortality.
• In a study of 2310 patients, Jackson et al examined the prognostic value of spot urinary-to-creatinine ratios (UACRs) in persons with heart failure.^[3] The authors determined that compared with patients with normoalbuminuria, individuals with an increased UACR tended to be older, had higher rates of cardiovascular comorbidity and diabetes mellitus, and suffered from worse renal function. However, even after adjustment for variables such as renal function and diabetes, it was determined that an increased UACR was associated with a greater mortality risk. The authors concluded that elevated UACR has significant value as a prognostic indicator for patients with heart failure.

Race

Many causes of proteinuria are more common in African Americans and other groups.

• Diabetic nephropathy is more common in American Indians, African Americans, and Hispanics.
• The primary glomerular disorder, focal segmental glomerulosclerosis, also is more common in African Americans.
• In general, African Americans have a higher incidence and tend to have more rapid progression of glomerular diseases and, hence, proteinuria.
• In a study by Friedman et al, nondiabetic chronic kidney disease was found to occur in more than 3 million African Americans who have genetic variants in both copies of APOL1, increasing their risk for hypertension-attributable end-stage renal disease and focal segmental glomerulosclerosis. However, African Americans without the risk genotype appear to have a similar risk for developing nondiabetic chronic kidney disease as European Americans.^[4]

Sex

Most primary glomerular diseases associated with proteinuria (eg, membranous glomerulonephritis) and secondary renal diseases (eg, diabetic nephropathy) are more common in males than in females. As a result, persistent proteinuria is at least twice as common in males as in females.

Age

The incidence of hypertension and diabetes increases with age, and, as a consequence, the incidence of persistent proteinuria (and microalbuminuria) also increases with age.