Jean Wu
Edward S. Kraus
Normally, 60% of urinary protein is plasma protein that has been filtered by glomeruli and only partially reabsorbed by renal tubules. The remaining 40% is synthesized and secreted into the urine by the renal tubules and by the more distal portions of the urogenital tract. The main plasma protein is albumin, which usually makes up 20% of normal urinary protein excretion.
Proteinuria has been defined traditionally as the urinary excretion of greater than 150 mg per 24 hours. Proteinuria in that range is a common finding in the general population; the prevalence of dipstick-positive proteinuria in adults is approximately 10% (1). It is usually a transient finding without any long-term clinical sequelae. However, persistent proteinuria (see Significance of Proteinuria section) may be a marker of renal disease and merits more aggressive workup and treatment. Additionally, much interest has been focused on low levels of urinary albumin excretion (microalbuminuria), defined as the urinary albumin excretion of 30 to 300 mg/day or as it is commonly reported, 30 to 300 mg of albumin per g creatinine. Microalbuminuria has been well established as a strong predictor of the development of atherosclerotic disease as well as of progressive kidney disease. Also, regardless of the cause, patients with persistent proteinuria have an increase in overall and cardiovascular mortality compared to those without proteinuria. It is therefore important to screen for proteinuria in selected populations at high risk for kidney disease and evaluate and treat the finding of proteinuria in all populations (see Significance of Proteinuria). This chapter discusses the methods of detection of proteinuria, the significance of proteinuria, and an approach to its evaluation and management.
Methods for Detecting Proteinuria
Urinary Dipstick
A dipstick measures protein concentration through a colorimetric change that occurs when protein binds to a pH indicator dye, which ranges from yellow (no protein) to increasing shades of green, representing increasing protein concentration. This test is simple, inexpensive, widely available and highly specific. However, this technique is not very sensitive, as it cannot detect protein excretion of less than 30 mg/dL. Also, as the dipstick is specific for albumin, it may miss positively charged proteins like globulins or parts of globulins (e.g., heavy or light chains and Bence-Jones protein). False-positive results can occur if the urine is alkaline (pH greater than 7.5) and in the presence of leukocytes, gross hematuria, mucus, or semen.
Sulfosalicylic Acid and Limitations of Testing
Other tests are available to detect other urinary proteins. The most commonly used one is the sulfosalicylic acid (SSA) test, which detects the presence of both large and
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small protein molecules. In this test, a 3% to 10% solution of SSA is added to urine. The results range from “clear” to “flocculent precipitate” suggesting protein levels of 0 to greater than 500 mg/dL respectively. Since this is a turbidimetric test, false positive test results can occur if the urine is already turbid. Also, the SSA test detects proteins of prostatic and vaginal origin. These contaminants can be avoided by not palpating the prostate before collecting urine from men and by obtaining a clean voided urine specimen from women. False-positive results can occur also in the presence of a number of medications, most notably high doses of cephalosporins and penicillins. Additionally, radiocontrast agents can lead to false positive results with both dipstick and SSA testing.
Quantitation of Proteinuria
Quantitation of proteinuria is important to help define the etiology of proteinuria and to follow response to therapy. The “standard criterion” for quantitation has been the measurement of protein in a 24-hour urine collection. However, it has been shown that spot measurement of urinary protein and creatinine is an excellent approximation to the 24-hour collection and is now the preferred method for quantifying urinary protein, as it is simpler, faster, and more readily obtained.
Protein/Creatinine Ratio
There is an excellent correlation between the 24-hour urinary protein excretion and the protein/creatinine concentration ratio (mg/dL of protein divided by mg/dL of creatinine), as determined in a random sample of urine obtained during normal daytime activity (2). The accuracy of this ratio is related to the fortuitous occurrence that daily creatinine excretion is around 1 g/day. Thus, the ratio approximates daily protein excretion. For example, a ratio of 3.5 represents daily protein excretion of around 3.5 g/day and represents nephrotic-range proteinuria. A spot albumin to creatinine ratio is also the preferred method for quantifying albumin excretion.
24-Hour Urine Collection for Protein
Although the spot protein to creatinine ratio is the preferred method for quantifying proteinuria, the ratio may overestimate 24-hour urinary protein excretion in certain circumstances, most notably when urine is collected after strenuous exercise, from patients with diabetes mellitus, or from patients whose daily urinary creatinine excretion is considerably less than 1 g (e.g., frail adults). Conversely, determination of this ratio from a first morning urine specimen may underestimate daily urinary protein losses (see Orthostatic Proteinuria). The first morning urine specimen should therefore not be used for the spot urine protein to creatinine ratio and the spot urine should therefore not be collected after strenuous exercise.
A 24-hour measurement for proteinuria may be required for patients with diabetes mellitus or for frail adults. In this test, a clean container without preservatives, usually a gallon jug, is given to the patient with instructions about the collection process. The 24-hour collection is best done on a day when the patient will be using a single toilet, and it is helpful for the patient to place a note on the toilet on the day of collection, as a reminder to collect all required specimens. On the day of collection, the first voided morning specimen is discarded, and then all urine voided during the next 24 hours, including the next morning's first voided specimen, is collected in the container. Once the urine is collected, it is not critical when protein determination is done. If there is excessive delay, however, bacterial growth can falsely raise protein concentrations. Therefore, it is advisable to refrigerate the urine specimen until it is brought to the laboratory, if it is not brought in on the day the collection is completed. Simultaneous measurement of urinary creatinine and urinary volume is helpful as an index of the adequacy of collection. Most patients who are of average body mass excrete between 800 and 1,500 mg of creatinine per day (21 to 26 mg/kg/day in adult men, 16 to 22 mg/kg/day in adult women).
Assessment of Patients with Proteinuria
Mechanism of Proteinuria
The most common reason for proteinuria is glomerular dysfunction, leading to the presence of increased urinary albumin. Albuminuria (either micro or macro) is thus a potent marker of glomerular disease. However, albuminuria can also occur in states of systemic illness that may lead to changes in renal hemodynamics. In tubulointerstitial disease, tubular reabsorption of proteins is abnormal. This usually leads to the presence of proteins other than albumin in the urine, such as β2 microglobulins. The other major cause of proteinuria is increased systemic generation of filterable proteins associated with plasma cell dyscrasias.
Approach to Patients with Proteinuria
It is important to determine if proteinuria is transient, intermittent, or persistent (see below). In an otherwise healthy person without any other signs of renal or systemic disease, a positive test for urinary protein should be repeated before pursuing additional workup as the proteinuria is likely to be an inconsequential finding. Transient proteinuria also can occur in a number of circumstances that alter renal hemodynamics such as fever, strenuous
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exercise, and exposure to cold. Acute illnesses like decompensated congestive heart failure and seizures, and some chronic illnesses like obstructive sleep apnea are also associated with proteinuria. If the proteinuria is a response to the acute event, it usually resolves within several days and is not associated with any other renal abnormalities and may not reflect progressive renal disease. However, testing should be repeated to ensure that persistent proteinuria is not present.
Further laboratory studies to evaluate proteinuria should include microscopic urinalysis to look for other abnormalities that may suggest renal disease. Also, serum creatinine concentration or creatinine clearance should be measured to identify whether renal function is impaired (see Chapter 52). Finally, the amount of protein excreted should be quantitated. Excretion in excess of 3.5 g per 24 hours (protein/creatinine ratio greater than 3.5) defines nephrotic proteinuria.
Nonnephrotic Proteinuria
Nonnephrotic range proteinuria can be a benign finding or be a marker of underlying renal disease. A variety of primary renal and systemic diseases including hypertensive nephrosclerosis may be associated with nonnephrotic range proteinuria. Also, most patients with nephrotic range proteinuria have had nonnephrotic range protein excretion at some time in the past. Evaluation is best defined by considering patients who have normal physical examinations and laboratory profiles (so called “isolated proteinuria”) separately from patients who have other abnormalities in their urinalysis or who have hypertension, diabetes, or signs of systemic illness like rash or arthritis.
Isolated Proteinuria in Apparently Healthy Patients
If the initial evaluation is negative except for the presence of isolated proteinuria, the proteinuria may be further classified as persistent(25% to 30% of patients) or intermittent (70% to 75% of patients) (3). Making the distinction between these two entities may have some value in that the prognosis of patients with intermittent proteinuria is generally better than the prognosis of patients with persistent proteinuria. However, making this distinction in practice may be challenging because it requires the practitioner to obtain five or six specimens for semiquantitative analysis over several months. The 24-hour urine protein excretion is almost always less than 1 g in patients with isolated proteinuria. If the total protein excretion is greater than 2 g/24 hours, the chance of significant kidney disease is high, and further investigation for nonisolated proteinuria should be considered.
Intermittent Proteinuria
A study of patients with intermittent isolated proteinuria (protein in fewer than 80% of repeat urine dipstick testing) revealed definite abnormalities by light microscopy in the renal tissue of approximately 60% of patients; the remainder had normal or almost normal biopsy findings (4). However, a retrospective study evaluating the prognostic significance of proteinuria in male college students did not find an increased risk of renal disease in this group (5). Although intermittent proteinuria is generally considered to be benign, the prognosis of patients with this finding has not been extensively studied. Thus, it would be prudent to monitor patients with intermittent proteinuria with yearly measurements of urine protein excretion, a urinalysis, and determination of serum creatinine. Should deterioration in renal function, significant increase in protein excretion, or new abnormalities occur, reassessment and possibly a renal biopsy would become necessary.
Persistent Proteinuria
Patients with protein in more than 80% of urine specimens are defined as having persistent proteinuria. The disorder may be further classified by evaluating the effect of posture. Orthostatic persistent proteinuria is present when the patient is in the upright position only.Constant persistent proteinuria is not influenced by the position of the patient.
Orthostatic Proteinuria
A simple method of determining the presence of this phenomenon is to have the patient collect two urine specimens. The patient rests quietly for 2 hours and then voids just before retiring in the evening to ensure an empty bladder on assuming the recumbent posture. The patient then does not get out of bed for 8 hours. On arising, he or she voids completely into a container labeled recumbent urine (specimen 1). The patient then remains upright but is not vigorously active and collects all subsequent urine over the next 8 hours. This specimen is labeled ambulatory urine (specimen 2). The protein concentrations in the two urine specimens are compared. In patients with orthostatic proteinuria, the recumbent protein excretion is negligible but proteinuria is found when the patient assumes the upright posture.
A renal biopsy is not necessary in the evaluation of a patient with orthostatic proteinuria. When biopsies have been done as part of a research protocol, minor abnormalities have been defined in approximately one half of those patients with orthostatic proteinuria; the others have had a biopsy that appeared normal on light microscopy (3). However, it would be prudent to monitor the patient by measuring urinary protein excretion and serum creatinine on a yearly basis.
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Patients with orthostatic proteinuria have an excellent prognosis. Military recruits with this problem have been monitored for 20 years; none developed renal failure, and in approximately 80% proteinuria resolved (6). Not all patients who were free of protein in the urine at 10-year followup remained protein-free after 20 years, but none showed significant deterioration in renal function. A 35-year followup of these same patients did suggest that some developed a decline of renal function greater than expected for normal aging (7).
Constant Isolated Proteinuria
In most patients with constant isolated proteinuria, diverse morphologic changes are identified in kidney biopsy specimens. Few long-term studies of these patients have been made, but the course is likely to be indolent. Renal failure develops very rarely, although most patients develop abnormal urine sediment and 50% develop hypertension (8). It is not necessary to perform a renal biopsy if there are no other findings, but yearly re-evaluation is appropriate and should include blood pressure measurement, urinalysis, and determination of 24-hour protein excretion and serum creatinine and creatinine clearance. If proteinuria exceeds 2 g/day, additional evaluations (such as a renal sonogram or collagen vascular screens, see Proteinuria Nephrotic section) should be pursued.
Nonisolated Proteinuria
Proteinuria associated with impaired renal function, hypertension, or other abnormalities in the urinalysis requires a more aggressive workup. Additionally, the earliest manifestation of diabetic nephropathy is microalbuminuria. Additional workup should follow that outlined for nephrotic proteinuria as discussed below.
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TABLE 48.1 Causes of Nephrotic Syndrome in Adultsa |
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Nephrotic Proteinuria
There are many causes of nephrotic syndrome, but few conditions are seen with significant frequency in general medical practice (Table 48.1). Clinical and laboratory assessments for systemic illness should be performed first in an effort to establish the etiology of the nephrotic syndrome (e.g., detection of Bence Jones proteinuria, collagen vascular screens for SLE). Table 48.2 lists some of the laboratory evaluations that may be helpful in determining
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the cause of renal disease. If nephrotic-range proteinuria develops in a patient who has been diabetic for longer than 10 years, the renal lesion is almost always diabetic glomerulosclerosis, particularly if the patient also has diabetic microaneurysms in the retina. In this setting, a renal biopsy usually is unnecessary. On the other hand, a biopsy usually is necessary to diagnose a specific primary renal disease if a diagnosis cannot be made by other tests or it may be needed to guide therapy and to help determine prognosis.
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TABLE 48.2 Selected Investigations That May Be Appropriate in the Diagnosis of Proteinuria That Is Not Isolated or Is Nephrotic |
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Renal Biopsy
Patient Experience
Generally, in patients without renal failure and normal hemostasis, percutaneous biopsy is performed under local anesthesia with computed tomographic or sonographic guidance. This technique permits the nephrologist to sample the lower portion of the kidney, avoiding the hilar vessels and the renal collecting system. With percutaneous biopsy, the patient usually experiences minimal discomfort and is able to be out of bed in 6 to 12 hours.
The biopsy core is approximately 1 mm in diameter and 10 to 20 mm in length. Usually two such tissue cores are obtained. The risk associated with percutaneous renal biopsy is small if it is performed by an experienced physician.
Microscopic hematuria after the procedure is almost inevitable, and usually there is a small hematoma at the biopsy site on the surface of the kidney. However, it usually is of no clinical consequence. Gross hematuria occurs in 5% to 10% of patients, but less than 5% of this group require a transfusion to replace blood loss. Fewer than 1 in 1,000 patients require nephrectomy because of continued massive bleeding, and death from biopsy is rare. A renal arteriovenous fistula may develop after biopsy, but it usually closes spontaneously. Rarely, this complication may require treatment if bleeding continues or if hypertension develops (see Stiles et al., athttp://www.hopkinsbayview.org/PAMreferences). Even more rarely, there may be perforation of another viscus.
When percutaneous biopsy is not feasible (e.g., obesity, ectopic location, small size of kidney), open transjugular or laparoscopic biopsy can be obtained; some surgeons perform this procedure under local anesthesia in selected patients (see Stiles et al., athttp://www.hopkinsbayview.org/PAMreferences).
Regardless of the technique of obtaining the biopsy, the evaluation of tissue by a pathologist experienced in preparation and interpretation of renal biopsy material includes light, immunofluorescent, and electron microscopy.
The practitioner who has referred to a nephrologist a patient for whom a renal biopsy has been performed should expect communication of the following: the probable diagnosis based on all aspects of the microscopic assessment; whether specific therapy for the condition is indicated; and what prognostic judgment can be made.
Significance of Proteinuria
It has been well established that the amount or presence of proteinuria is directly correlated with adverse outcomes and with progression of kidney disease, regardless of its underlying etiology. Among diabetic patients, even microalbuminuria is associated with an increased likelihood (up to nine times greater incidence than diabetic patients without microalbuminuria) of developing diabetic nephropathy (9). A recent study also suggests that microalbuminuria may predict future development of renal disease in otherwise healthy patients (10).
Besides its association with adverse renal outcomes, the presence of microalbuminuria is also a powerful predictor of cardiovascular events. In the Framingham study population, overall and cardiovascular mortality rates in men with microalbuminuria were slightly but significantly increased (approximately threefold) compared to the rates of men even with intermittent proteinuria (11). It has also been well established that microalbuminuria is a predictor of cardiovascular risk in diabetic patients (12). The African American Study of Kidney Disease and Hypertension (AASK) trial showed that this relationship is present only in patients with hypertension and that any increase in urinary albumin, even at the current normal range, was associated with adverse cardiovascular outcomes (13). A continuous and graded relationship between urinary albumin excretion and cardiovascular risk has been demonstrated in the general population (14).
Thus, there is strong evidence that even small increases in urinary albumin excretion are associated with increased risks of developing cardiovascular and renal disease. One possible explanation for this relationship is that urinary albumin leakage is a reflection of generalized endothelial dysfunction, which may play a pathophysiological role in accelerated atherosclerosis. Reduction of albuminuria has also been associated with renal protection in both nondiabetic and diabetic renal diseases. Therefore, measuring and reducing urinary protein excretion is key to preventing progression of renal disease and reducing the high cardiovascular mortality in this population.
Currently, screening for proteinuria is not recommended for the general population. In diabetics, clinical practice recommendations (see American Diabetes Association, 2001, at http://www.hopkinsbayview.org/PAMreferences) recommend that patients with insulin-dependent diabetes for at least 5 years and all non–insulin-dependent diabetic patients be screened annually for the presence of microalbuminuria. The National Kidney Foundation guidelines recommend using a quantitative measurement of microalbuminuria in all patients at risk for kidney
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disease, particularly patients with hypertension or diabetes mellitus, although the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) 7 considers testing for proteinuria optional (see NKF/DOQI and JNC 7 guidelines, athttp://www.hopkinsbayview.org/PAMreferences).
Treatment of Patients with Proteinuria
Patient care is directed at diagnosis, education, surveillance, and treatment of any underlying disease (renal biopsy findings may help target specific interventions). If proteinuria is believed to be caused by a drug, the agent should be discontinued. Proteinuria from drugs may take several months to resolve, and occasionally it is permanent.
Regardless of the cause though, therapy in patients with proteinuria should be directed at reducing urinary protein excretion rate and at modification of cardiovascular risk factors, given the association of proteinuria with both progression of renal disease and cardiovascular mortality.
The mainstay of antiproteinuric therapy is blood pressure control, always including the use of angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers (ARBs). Based on multiple treatment studies, it is clear that lower blood pressure is associated with improved renal outcomes (15). However, the optimal blood pressure target is somewhat controversial. JNC 7 guidelines suggest that the target blood pressure should be 130/80 mm Hg or less while the National Kidney Foundation guidelines recommend decreasing blood pressure to less than 120/75 mm Hg (see NKF/DOQI and JNC 7 guidelines, athttp://www.hopkinsbayview.org/PAMreferences).
In addition, it has now been clearly shown that ACE inhibitors and ARBs can reduce proteinuria and stabilize renal function in both diabetic and nondiabetic renal disease (16, 17, 18, 19, 20, 21, 22, 23). Thus, these classes of antihypertensives should be the first line choice in patients with proteinuria and hypertension. Several short-term and few long-term comparative studies have shown these two classes of drugs of have comparative efficacy in slowing progression of renal disease (see Venkat, at http://www.hopkinsbayview.org/PAMreferences). Thus, it is likely that both have equivalent renoprotective effects and other considerations such as costs and side effects should drive choice of agent.
The goal of treatment is stabilization or fall of at least 30% to 50% in urinary albumin excretion over 3 to 6 months. It has also been advocated that even if blood pressure is at goal, these agents should be titrated until protein excretion is less than 0.5 g/day. Patients should be monitored for a rise in serum creatinine or for the development of hyperkalemia during the first few weeks after initiation of ACE inhibitor or ARB therapy and with each dose increase. Serum creatinine often increases slightly as a result of ACE inhibitor or ARB therapy (usually to less than 15% to 20% above the patient's baseline concentration) and then reaches a plateau. If serum creatinine increases to a more significant extent, the drug usually should be discontinued or the dose decreased to one that was previously well-tolerated. Multiple other therapies such as use of statins, smoking cessation, and weight loss have also been associated with reduction in proteinuria although the data for these therapies are not as strong (see Wilmer et al., at http://www.hopkinsbayview.org/PAMreferences).
If either edema or hypoalbuminemia is present, special therapy may be indicated. In the absence of renal failure, albumin synthesis is either increased or normal in patients with the nephrotic syndrome. Whereas a high-protein diet was previously recommended to patients with proteinuria, mild to moderate protein restriction is now advised, because it is believed that high protein intake may lead to progressive renal dysfunction by producing hyperfiltration (24). Appropriate standards for protein intake and pharmacologic intervention in this setting remain controversial and are a subject of intense research.
In the presence of edema, salt restriction to a tolerable level, such as a no-added-salt diet (approximately 2 to 3 g/day of sodium; seeChapter 67) is appropriate. If the edema is more severe and is unresponsive to sodium chloride restriction, cautious use of a loop diuretic (furosemide, torsemide, or bumetanide) may be necessary. No attempt should be made to rid the patient entirely of edema, which could risk contraction of the circulating volume, with serious consequences. Potassium-sparing diuretics (spironolactone, triamterene, or amiloride) may be added if renal failure is absent. Metolazone or thiazides may be added if loop diuretics have not been entirely adequate. Monitoring of serum potassium is important for selection and adjustment of the diuretic regimen, especially if ACE inhibitors or ARBs are used in this setting. In many instances, the patient can establish the correct diuretic dosage schedule by keeping a diary of weights and drug intake. If acceptable control is still not achieved, consultation with a nephrologist is appropriate.
Numerous extrarenal complications are associated with nephrotic syndrome. These include alterations in cellular immunity leading to increased infections, hyperlipidemia, and changes in calcium and bone metabolism. Nephrotic syndrome can be associated with a hypercoagulable state with thrombosis of the renal veins as well as other vessels. Clues to the development of renal vein thrombosis include pulmonary embolism, sudden deterioration in renal function, significant increase in the level of proteinuria, back or flank pain, or the development of hematuria. Suspicion of this complication requires hospitalization of the patient for urgent evaluation. Patients with nephrotic syndrome should be counseled about risk factors for deep venous
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thrombosis, such as long periods of immobilization. This is especially true for patients with membranous glomerulonephritis, although renal vein thrombosis has been reported in all types of glomerulonephritis.
Prediction of the course and selection of specific therapy in patients with nephrotic-range proteinuria depend on the pathologic pattern that is identified in the biopsy. Patients with nephrotic-range proteinuria need regularly scheduled office visits at 1- to 4-month intervals. Usually this followup is done by the primary care provider and the patient sees the nephrologist only once a year. The office visit provides an opportunity to review the patient's symptoms and to perform a physical examination (which, at a minimum, should include weight, volume assessment, and blood pressure) as well as to evaluate the 24-hour urine protein excretion or a protein/creatinine ratio, renal function (creatinine or creatinine clearance), and the serum electrolytes if diuretics are being used. Less often, an assessment of the serum albumin concentration may be necessary.
Specific References*
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.