The loss of 150 mg or less of protein (Tamm-Horsfall, albumin, immunoglobulins, transferrin, and hormones) per day via the urine is considered normal. Mild and transient elevations greater than 150 mg/day can be seen with exercise, cold exposure, fever, heat injury congestive heart failure, inflammation, and with orthostatic proteinuria (a benign condition in which proteinuria occurs when the patient is upright but not supine). Orthostatic proteinuria should be suspected when the level of proteinuria is less than 1 g/24 h and occurs in children or young adults without underlying disease. Collection of an early morning urine sample (after the patient has been supine all night while sleeping) for protein will aid in making the diagnosis. Persistent elevations greater than 150 mg/day of protein constitutes proteinuria that may be associated with an underlying disease process. It is of note that proteinuria itself is an independent risk factor for progression of renal disease secondary to direct tubulointerstitial injury from the urinary proteins. The rate of renal decline is dependent on the amount of proteinuria with a more rapid decline noted with higher levels of proteinuria.
Proteinuria is often first detected on routine screening via the dipstick method. In this test the indicator (usually tetrabromophenol blue with a buffer to maintain the pH at 3.0) changes color upon contact with protein secondary to their negative charge. This test is useful as a screening tool; however, it does not accurately quantify the amount of protein, is subject to interpretation, and is subject to both false-positive and false-negative results. False-negative results occur when the urine is dilute, contaminated with radiocontrast agents, or when the underlying etiology is light chain proteinuria (such as in multiple myeloma). When light chain proteinuria is suspected, the sulfosalicylic acid test or urine immunoelectrophoresis are more sensitive at detecting Bence-Jones proteinuria. False-positive results on urinalysis testing occur when the urine is concentrated, alkaline, or contaminated with radiocontrast agents, or when there is hematuria. One other limitation of the urine dipstick method is its lack of sensitivity when screening patients with diabetes mellitus for microalbuminuria. If a diabetic patient is urine dipstick negative for protein, they should be subjected to further testing for urinary microalbuminuria, and if they are found to be positive, treatment with an ACE inhibitor or ARB should be initiated.
Three types of proteinuria exist depending on the site of entry into the urine and include: glomerular, tubular, and overflow. Normally, the small size of the glomerular basement membranes pores in relation to protein size and the electrostatic repulsion of proteins by the negatively charged glomerular basement membrane prevents significant proteinuria. Glomerular proteinuria results when the glomerulus suffers an impaired ability to prevent the migration of protein into the urine or when intraglomerular pressures become elevated. Proteins that do enter the urine are then either reabsorbed or catabolized by the proximal tubular cells. When the tubular cells are damaged they can no longer reabsorb or catabolize urinary protein and the end result is tubular proteinuria. When an underlying disease process causes a significant overproduction of low molecular weight proteins (usually Bence-Jones proteins associated with multiple myeloma) such that the reabsorptive ability of renal tubular cells is overwhelmed, the result is overflow proteinuria.
Once diagnosed, the next step in the workup is to determine the quantity of proteinuria from a 24-hour urine sample for protein or from a spot sample for determination of the protein to creatinine ratio which correlates with the 24-hour urine protein level. If the level is greater than 3.5 g/24 h, a workup for the nephrotic syndrome and its possible etiologies should be initiated.
If the proteinuria is below the nephrotic range, the next step in the work-up is to assess renal function with determination of the serum BUN and creatinine and the glomerular filtration rate (GFR). If renal function is impaired, ultrasonography of the kidneys should be performed to assess size and as preparation for possible renal biopsy. Consultation with a nephrologist is indicated if no clear etiology (diabetes mellitus, viral hepatitis , HIV, etc.) has been determined.
If renal function is within normal limits and their is no history or evidence of underlying disease, further workup is indicated. A complete history should include questions about a family history of renal disease (IgA nephropathy, Alport syndrome, cystic kidney disease), medication use (NSAIDs, gold, penicillamine, lithium, norepinephrine infusion), and possible contact with heavy metals or drug use (heroin). Further testing should include a diabetes workup, serum ANA (systemic lupus erythematosus), syphilis serology, viral hepatitis serologies, serum and urine immunoelectrophoresis (multiple myeloma), and HIV testing. If there is concomitant hematuria, then the morphology of the urinary red blood cells may help localize the site of damage (dysmorphic RBCs and RBC casts indicate a glomerular source). If the source is glomerular, determination of the serum complement level will help narrow the differential diagnosis. Poststreptococcal glomerulonephritis, membranoproliferative glomerulonephritis, systemic lupus erythematosus, and cryoglobulinemia are all associated with a low complement level. If this work-up is unrewarding, consultation with a nephrologist for possible biopsy may be indicated.
As stated, proteinuria may accelerate the progression of renal decline separate from the underlying etiology. Therefore, treatment should be instituted to preserve renal function for as long as possible. The most effective therapy is cure or control (euglycemia in diabetics, normotension in hypertensives) of the underlying etiology if possible. Aggressive blood pressure control should be instituted using ACE inhibitors or ARB's. If ACE inhibitors or ARB's alone are ineffective, other antihypertensives should be added until blood pressure is adequately controlled, especially spironolactone. Restriction of dietary protein intake may be helpful in decreasing the amount of proteinuria and in slowing progression of renal decline.