Proteinuria usually reflects an increase in glomerular permeability for normally non-filtered plasma macromolecules such as albumin. A 24-hour urine collection containing more than 150 mg of protein is abnormal. Significant proteinuria is suspected when a dipstick test of the urine is persistently positive for protein. In such a situation the daily protein excretion will usually exceed 300-500 mg per day. Since the dipstick method can detect urine protein concentration of as little as 30 mg/dL, a very concentrated urine specimen might test positive for protein even though the quantitative amount of proteinuria is less than 150 mg/day.

The dipstick method for detection of proteinuria relies on a color change of the indicator dye—a reaction primarily dependent on the amount of albumin in the urine. The sulfosalicylic acid (SSA) method of protein detection may be useful in certain situations, but is generally not readily available in most clinical situations. The SSA method detects proteinuria by acid precipitation and detects any type of proteins in the urine. The SSA test is carried out by mixing 1 part urine supernatant (eg, 2.5 mL) with 3 parts 3% sulfosalicylic acid and grading the resultant turbidity
(Table 1).

Four important qualifications to the foregoing definitions are needed: 1.) Both dipstick and SSA will record false positive results for protein in the presence of radiocontrast agents.² 2.) Since the dipstick method is most sensitive for detection of albumin, disease states in which the proteinuria is mainly composed of heavier plasma proteins such as immunoglobulins or their light-chains (multiple myeloma or plasma cell dyscrasias) may be associated with a negative or weakly positive dipstick reaction for protein. The SSA method will give a strongly positive reaction and subsequent analysis of the urine for immunoglobulins or light-chains will verify that the proteinuria is due to proteins other than albumin.³ 3.) Dipstick and SSA will both detect urinary lysozymes that are increased in production and excretion in some patients with acute monocytic leukemia.⁴ 4.) In early diabetic nephropathy, persistent excretion of increased amounts of albumin in the range of 30-300 mg daily is called microalbuminuria. Standard dipstick methodology might fail to detect such small but clinically important amounts of albuminuria. Hence using a specific assay for urinary albumin is the more sensitive and recommended technique.

Microalbuminuria is defined by the presence of >30 and <300 mg of albuminuria daily. Since 24-hour urine collections are difficult to obtain, the measurement of the albumin to creatinine concentration in an untimed random urine specimen is used. The albumin to creatinine concentration of >30 mg per gram of creatinine correlates very well with a 24-hour urine albumin measurement. Its detection in Type I diabetes mellitus is the earliest clinical evidence of diabetic nephropathy. Transient increases in urinary albumin excretion may be seen in short-term hyperglycemia, exercise, urinary tract infections, marked hypertension, heart failure, and acute febrile illnesses. There is also diurnal variation in urinary albumin excretion. Confirmation of microalbuminuria requires verification on 2 or 3 collections over 3 to 6 months (Table 2).⁵

Transient and clinically insignificant dipstick proteinuria might occur in a variety of clinical states including febrile illnesses, following vigorous exercise, in congestive heart failure, and exposure to cold. Transient proteinuria might be seen in 4% of men and 7% of women on a single examination. In screening studies of asymptomatic healthy individuals, dipstick proteinuria on 2 consecutive occasions has been reported in from 0.5-5%.⁵ In the same studies, the positive predictive value of proteinuria identifying serious urogenital disease was 0-11%. Orthostatic proteinuria occurs primarily in older adolescents and is characterized by increased protein excretion in the upright position and normal protein excretion in the supine position (ie, as found in a urine sample taken early in the morning after the subject has been lying down). Orthostatic proteinuria is a benign condition.⁶ Persistent proteinuria, especially in clinical illnesses, or when accompanied by other urinary abnormalities, such as hematuria, proteinuria, or bacteruria, deserves further investigation.⁷ In one study of adults, IgA nephritis, membranous nephropathy, and focal and segmental glomerulosclerosis were the most common histologic diagnoses in patients with asymptomatic proteinuria and/or hematuria.⁸

There are 3 basic types of proteinuria—glomerular, tubular, and overflow.

Glomerular Proteinuria
The glomerular filtration barrier is composed of the endothelial cell, the basement membrane, and the epithelial cell foot processes. Proteinuria occurring in glomerular disease is due to increased filtration of albumin and other macromolecules across the glomerular basement membrane. This occurs because of an alteration in both the charge selectivity and size selectivity of the glomerular barrier.

Normally the basement membrane and endothelial cells possess a negative charge. Plasma albumin, which also possesses a negative charge, is repelled by the normal negative charge on the basement membrane and the intact endothelial cells. Circulating IgG has a neutral or positive charge and is not restricted by a negative charge on the basement membrane. Rather, immunoglobulins are restricted by the size selective barrier of the membrane and the epithelial slit diaphragm located across the spaces between the epithelial foot processes.

In glomerular disease, the injury to the glomerular basement membrane causes proteinuria due to a loss in negative charge as well as from an increase in the number of larger non-selective pores. Glomerular diseases are also accompanied by disruption and loss of the epithelial foot process covering of the basement membrane. It appears that the increased protein leakage occurs especially at the sites of this epithelial alteration.

Tubular Proteinuria
Low molecular weight molecules such as B2 microglobulin, amino acids, and immunoglobulin light chains have a molecular weight of about 25000 (albumin is 69000). These smaller proteins are easily filtered across the basement membrane and then completely reabsorbed by the proximal tubular cells. A variety of diseases that produce tubular and interstitial injury impair the tubular reabsorption of these molecules. Some glomerular diseases are also accompanied by tubular injury and tubular proteinuria. Standard dipstick methods will not detect these proteins. Specific urinary measurements of B2 microglobulin are quite sensitive for any tubular injury, but they are not specific for any disease.⁹

Overflow Proteinuria
Increased excretion of low molecular weight proteins might be seen in states where there is significant increased production of these proteins, as in multiple myeloma. The proteinuria results from the fact that the amount of these proteins filtered exceeds the reabsorptive capacity of the proximal tubule.

Most patients with proteinuria have no signs or symptoms from the proteinuria. In states of heavy (nephrotic range) proteinuria exceeding 3 g daily, the patient might report foamy urine and might demonstrate edema. The foamy urine is due to increased lipid in the urine, which alters the surface tension of the urine. Lipiduria is caused by the filtration of lipoproteins across the damaged glomerular barrier. On urine microscopy lipiduria might appear as free fat, or as fat droplets in tubular cells or casts where they are referred to as oval fat bodies or fatty casts respectively. Edema, which frequently accompanies nephrotic range proteinuria, is caused by reduction of plasma oncotic pressure due to reduced plasma albumin. Hypoalbuminemia is the result of increased glomerular losses and defective synthesis of albumin. At times the hypoalbuminemia and loss in plasma oncotic pressure produce true intravascular volume depletion resulting in hypotension and pre-renal acute renal failure. The loss of albumin stimulates the liver synthetic activity, which also contributes to increased lipoprotein production and hyperlipidemia.

The clinical assessment of the cause for persistent dipstick proteinuria requires a thorough history and physical examination looking for clues for the presence of systemic diseases such as diabetes, prior history of renal disease, congestive heart failure, and collagen vascular disorders, which could be associated with proteinuria. The National Kidney Foundation¹⁰ has published guidelines for the assessment of proteinuria. In the absence of a systemic disease that might explain the proteinuria, a primary renal disorder should be sought. Further evaluation for the specific renal disease causing the proteinuria should include urine microscopy, quantification of urinary protein excretion (either by 24-hour collection of urine for protein or single random urine for protein:creatinine ratio), and determination of renal excretory function with serum creatinine. Patients with dipstick proteinuria who have urinary microhematuria, urinary casts, elevated quantitative protein excretion and/or azotemia should be referred to a nephrologist for more detailed evaluation.

Urine Microscopy (Figure 1)
In addition, a careful microscopic exam of recently voided centrifuged urine should be performed. The presence of bacteria and leukocytes will suggest urinary infection. The presence of leukocytes and leukocyte casts in the absence of bacteruria suggests interstitial nephritis. The presence of dysmorphic erythrocytes and erythrocyte casts suggests a nephritic syndrome such as an acute or subacute glomerulonephritis, IgA nephropathy, or membranoproliferative glomerulonephritis. The presence of fatty casts or oval fat bodies suggests that the patient has a glomerular disease associated with nephrotic syndrome or nephrotic range proteinuria. In patients with a benign urine sediment, acute renal failure and slightly positive dipstick for proteinuria, one should perform a sulfosalicylic acid (SSA) test of the urine. A strongly positive SSA and weakly positive dipstick proteinuria should lead one to suspect light chains in the urine and a diagnosis of some type of plasma cell dyscrasia.

Quantification of Proteinuria
Quantification of protein excretion may be performed on a complete 24-hour urine specimen or by determining the protein:creatinine ratio in a random urine specimen. The protein:creatinine ratio has been validated and shown to compare favorably with complete 24-hour collection.¹¹ Thus, a protein:creatinine ratio of less than 1 and greater than 3 is consistent with 24-hour protein excretions of less than one gram and greater than 3.5 g respectively. This method is also easier and likely to be more accurate since it does not require a 24-hour collection of urine.

Quantification of protein excretion allows one to begin to differentiate among the various renal disorders causing proteinuria. Diseases may be grouped into those with less than 1-2 grams/day, and greater than 3.5 grams daily (Table 3). Patients with less than 1-2 grams of proteinuria usually have tubulointerstitial disease, nephrosclerosis, polycystic kidney disease, orthostatic proteinuria, or benign glomerular disease such as IgA nephritis. Proteinuria of greater than 3.5 g per day is due to glomerular diseases.

The therapy of the various diseases causing persistent proteinuria is based upon the individual disease and its prognosis. These disease-specific therapies will not be discussed here. However, there is significant data from multiple clinical trials showing that progression of renal diseases is proportional to the degree of proteinuria—proteinuria of greater than 1 gram daily associated with more rapid progression.¹² It is assumed that the greater the proteinuria, the more damaging the renal injury and hence the more likely the disease to progress. However, there is also some evidence to suggest that the proteinuria itself might be part of the injurious process. Whatever the role of proteinuria, treatments associated with reducing proteinuria have been shown to slow disease progression. Two specific interventions—treatment of hypertension and use of angiotensin enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) slow the rate of progression of renal disease in both diabetic and non-diabetic renal disorders.^13-15 In the African-American Kidney Disease Study (AASK) of hypertensive renal disease, ramipril treated patients had a 38% reduced risk of the clinical end-points (reduction of glomerular filtration rate [GFR] of more than 50%, end-stage renal disease, or death), a 36% slower decline in GFR at 3 months, and less proteinuria than those patients treated with amlodipine.¹⁶

1. Larson T. Concise review for primary-care physicians: evaluation of proteinuria. Mayo Clin Proceed. 1994;69:1154-1158.
   
   
2. Morcos SK, El-Nahas AM, Brown P, Haylor J. Effect of iodinated water-soluble contrast media on urinary protein assays. BMJ. 1992;305:29.
   
   
3. American Diabetes Association. Position Statement: Diabetic Nephropathy. Diabetes Care.
   2001;24(Suppl 1).
   
   
4. Mok CC, Tam SC, Kwong YL. Pseudonephrotic syndrome caused by lysozymuria [letter]. Ann Intern Med. 1994;121:818.
   
   
5. Levitt JI. The prognostic significance of proteinuria in young college students. Ann Intern Med. 1967;66:685.
   
   
6. Springberg PD, Garrett LE Jr, Thompson AL, et al. Fixed and reproducible orthostatic proteinuria: results of a 20-year follow-up study. Ann Intern Med. 1982;97:516-519.
   
   
7. Robinson RR. Isolated proteinuria in asymptomatic patients. Kidney Int.1980;18:395-406.
   
   
8. Yamagata K, Yamagata Y, Kobayashi M, Koyama A. A long-term follow-up study of asymptomatic hematuria and/or proteinuria in adults. Clin Nephrol. 1996; 45:281-288.
   
   
9. Sumpio BE, Hayslett JPH. Renal handling of proteins in normal and diseased states. Q J Med. 1985;57:611-635.
   
   
10. NKF/DOQI Clinical Practice Guidelines: Assessment of Proteinuria. Am J Kid Disease. 2002;39:S93-S102.
    
    
11. Schwab SJ, Christensen RL, Dougherty K, Klahr S. Quantitation of proteinuria by the use of protein-to-creatinine ratio in single urine samples. Arch Intern Med. 1987;147:943-944.
    
    
12. Jafar T, Schmid CH, Landa M, et al. Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease: A meta-analysis of patient-level data. Ann Intern Med. 2001;135:73-87.
    
    
13. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. NEJM. 2001;345:851-860.
    
    
14. Brenner BM, Cooper ME, deZeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. NEJM. 2001;345:861-869.
    
    
15. Parving HH, Lehnert H, Brochner-Mortensen J, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. NEJM. 2001;345:870-878.
    
    
16. Agodoa LY, Appel L, Bakris GL, et al. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA. 2001;285:2719-2728.

This information is provided for general medical education purposes only and is not meant to substitute for the independent medical judgment of a physician relative to diagnostic and treatment options of a specific patient's medical condition.

In no event will The Cleveland Clinic Foundation be liable for any decision made or action taken in reliance upon the information provided through this web site.