Lawrence J. D'Angelo
Lawrence S. Neinstein
Asymptomatic proteinuria, defined as proteinuria not associated with hematuria, hypertension, other symptoms or renal insufficiency, is a common finding on a screening urinalysis in adolescent patients. For most of these teens, no significant renal disease is present and the long-term prognosis is excellent. Therefore, except for patients at high risk, screening for proteinuria is not felt to be cost-effective (Boulware et al., 2003). Unfortunately, because testing the urine for protein is so common, many patients with no provable renal disease are identified as having proteinuria. Even in the absence of significant renal disease, proteinuria can cause problems for adolescents by interfering with employment, insurance, or the armed service or by causing anxiety or concerns about long-term prognosis. The objective in evaluating these adolescents is to establish the significance of the proteinuria, search noninvasively for underlying treatable conditions, and select those few patients who need referral for more extensive evaluation, including renal biopsy. Most adolescents can be reassured that they are healthy and that their proteinuria is of no clinical consequence.
Up to 10% to 19% of healthy adolescents have protein in their urine on a dipstick test of a random urine sample. This prevalence falls with repeated testing, and a diagnosis of persistent proteinuria should be based on three separate urine tests. The prevalence peaks at approximately 16 years of age.
Small amounts of protein in the urine are normal, and most individuals excrete 30 to 130 mg of protein/day. Although the maximum “normal” amount for adolescents and adults is 150 mg/day, completely healthy adolescents may excrete up to 300 mg/day of protein without any evidence of clinical or histopathological renal disease. Nonetheless, “isolated asymptomatic proteinuria” refers to protein excretion of >150 mg/day by a person without clinical signs or symptoms. The leading causes of this condition are “benign persistent proteinuria” and orthostatic proteinuria. Orthostatic (postural) proteinuria, which is proteinuria while upright but not while recumbent, is common in adolescents. The etiology is unclear, although exaggerated hemodynamic response to the upright position and functional compromise of the left renal vein have been postulated as two possible causes (Shintaku et al., 1990). The condition is characterized by the following:
The presence of hypertension, edema, hypoalbuminemia, or hyperlipidemia suggests more significant renal abnormalities.
The qualitative dipstick test for protein will detect protein levels as low as 10 to 30 mg/dL. An initial positive test result should be confirmed on two more tests, because many individuals have transient proteinuria and then have negative findings on subsequent evaluation. False-positive test results should be considered (Table 27.1). If proteinuria is confirmed, then a more thorough history, physical examination, and laboratory evaluation are indicated to rule out significant disease. Currently, the most practical method of estimating total urinary protein excretion is a spot urine protein/creatinine ratio. A random urine sample is analyzed for protein and creatinine. When both are expressed in milligram amounts, a ratio of <0.2 is normal and a ratio >1.0 signifies nephroticrange proteinuria. This test is also useful for monitoring the course of proteinuria without performing the more burdensome timed urine collections.
Inquire about the following:
Check for the following:
Include the following in the evaluation:
blood cell (RBC) casts suggest glomerulonephritis; white blood cell casts suggest pyelonephritis or interstitial nephritis.
Follow-up should be done every 6 to 12 months to monitor for increasing proteinuria, a rising serum creatinine concentration, or the development of hematuria or hypertension. Although it is unusual, significant glomerulopathies can begin with orthostatic proteinuria that later becomes persistent.
With a careful history, physical examination, urinalysis, and 24-hour urinary protein test, one should be able to identify those adolescents with significant proteinuria and thereby determine which teenagers need follow-up only and which need referral for more expert monitoring or renal biopsy.
Prognosis and Follow-Up
In general, the prognosis for asymptomatic orthostatic or persistent proteinuria (excretion of <500 mg protein in 24 hours) is good. A study of the 1937 Yale University class revealed a prevalence of proteinuria of 13.8% (Baskin et al., 1972). On 30-year follow-up, the group with proteinuria had a mortality rate similar to that of the rest of the class. Another study of patients observed
for 20 years showed only 17% with persistent proteinuria, with the decrease being progressive over time (Springberg et al., 1982). Table 27.2 addresses the risk of chronic renal disease based on the pattern of proteinuria and suggests recommendations for follow-up.
The prognosis depends on the underlying cause of the proteinuria and is rarely dictated by the level of the proteinuria. The exception to this is proteinuria seen as a part of diabetic nephropathy—the ultimate prognosis is worse as the level of protein excretion rises.
There is some evidence that abnormal urinary microalbumin excretion may be a marker for renal disease in “healthy” children and adolescents. It has been documented to be a risk factor for renal complications in those with hypertension and diabetes mellitus. Assaid (2005) found that in those children and adolescents with hematuria, the presence of microalbuminuria (microalbumin/creatinine [MA/Cr] µg/mg ratio >30) had a 91% prevalence of abnormal renal biopsies. This may be a useful screen in those individuals with microscopic hematuria to evaluate for higher risk categories.
Hematuria is defined as the excretion of abnormal quantities of RBCs in the urine. Most authorities accept 2 to 4 erythrocytes per high-power field (HPF) on a resuspended centrifuged urine sediment specimen as normal. The orthotoluidine-impregnated paper strips give a positive result with a urine specimen that contains as few as 2 to 5 RBCs/HPF. Hematuria must be differentiated from pigmenturia caused by myoglobinuria, hemoglobinuria, porphyrinuria, or exogenous pigments.
Fewer than 3% of healthy individuals excrete > 3 RBCs/HPF. Several studies have examined the prevalence of hematuria in school-aged children and young adults and these have ranged from 0.5% to 5.6% (Vehaskari et al., 1979; Dodge et al., 1976; Froom et al., 1984).
Like proteinuria, hematuria in adolescents is usually asymptomatic. When present, however, the symptoms often suggest a cause. Lower urinary tract infections cause dysuria and frequency, whereas upper tract infections are accompanied by fever and flank pain. Renal stones are often heralded by colicky flank pain, whereas “loin-pain hematuria” is characterized by episodic unilateral or bilateral loin pain. Rash and joint pain often accompany SLE, whereas abdominal pain and “palpable purpura” are seen with Henoch-Schönlein disease. Intrinsic renal disease may be accompanied by edema, hypertension, and symptoms of uremia. Decreased hearing or vision may indicate the presence of familial nephritis.
Although the differential diagnosis of hematuria is extensive, the common conditions in adolescents are much fewer and are listed and discussed here separately. In addition, use of a systematic evaluation will narrow the diagnostic possibilities. The causes of hematuria can be divided into renal parenchymal, urinary tract, and systemic coagulation disturbances. False hematuria must also be considered.
Renal Parenchymal Diseases
Urinary Tract Disease
Rarely, hematuria is caused by coagulopathy without structural abnormalities in the genitourinary tract and without the use of instruments such as Foley catheters. Such causes include:
False hematuria can be caused by vaginal bleeding, factitious hematuria, or pigmenturia, including endogenous (porphyrinuria, hemoglobinuria, myoglobinuria) and exogenous (foods and drugs) forms of pigmenturia.
The most common causes of microscopic hematuria in adolescents are acute lower or upper tract urinary infections, trauma, over exercise, hypercalciuria and renal
stones, benign recurrent hematuria, and hereditary nephritis. The most common causes of gross hematuria are IgA nephropathy, trauma, hypercalciuria, and cystitis.
The health care practitioner must first differentiate between true hematuria and false hematuria.
As with proteinuria, the occurrence of true hematuria is determined with repeated examinations. Therefore, significant hematuria should be confirmed on repeated urinalyses before an extensive evaluation is undertaken. Urine should be examined to determine the presence or absence of RBC casts and proteinuria. RBC casts and >10% dysmorphic RBCs suggest a renal parenchymal origin, usually either glomerulonephritis or interstitial nephritis, and the need for further evaluation. Significant associated proteinuria would also suggest a glomerular cause and the need for further evaluation. Although blood in the urine can cause some proteinuria, even heavy bleeding usually results in <1 g/24 hour. If there are no RBC casts or a qualitative proteinuria (>1+), the evaluation will depend on the history and the physical examination findings. Because idiopathic hypercalciuria is now recognized as an important cause of microscopic hematuria, it is useful to obtain a calcium/creatinine ratio on a spot, random urine sample. A ratio of <0.2 is normal. If the ratio is greater, hypercalciuria is overwhelmingly likely to be the cause of the hematuria and no further evaluation is required.
If, after evaluation, the diagnosis is unclear and hematuria is persistent or recurrent, then one should obtain a renal sonogram to look for structural causes of hematuria such as cysts or hydronephrosis. If the diagnosis is still unclear and the patient has lower tract symptoms of dysuria or urgency and the RBC morphological features are normal, the next step is cystoscopy. In the presence of RBC casts and significant proteinuria a renal biopsy is indicated, as is done if hypertension accompanies either of these two symptoms. Without such a history, almost all individuals will have either normal biopsy findings or changes not indicative of significant pathological changes. If gross hematuria persists without an obvious cause, renal angiography can be considered while looking for vascular causes of the hematuria.
Marathon Runner's (Athlete's) Hematuria
Gross or microscopic hematuria is associated with many forms of exercise, including baseball, track, football, hockey, boxing, cross-country skiing, swimming, crew, lacrosse, rugby, and military training (Hoover and Cromie, 1981). The typical history is one of normal urine before exercise, with hematuria on the first specimen voided after exercise, lasting up to 24 to 48 hours, possibly in association with dysuria and suprapubic discomfort. The cause is unclear, but the condition seems unrelated to the duration of sustained activity. It may be caused by a decrease in renal plasma flow, local trauma to the bladder, or leakage of blood from spiral vessels in the adventitia of minor calyces. It is less of a problem in children than in older adolescents and adults. The prognosis is excellent unless another renal problem is the underlying cause.
Loin-Pain Hematuria Syndrome
This is a cause of hematuria found mainly in young females receiving oral contraceptives (Burke and Hardie, 1996). The condition occurs with recurrent bouts of gross or microscopic hematuria with or without dysuria but almost always with unilateral or bilateral loin pain. The blood pressure and renal function are normal. Protein excretion is usually <1 g/day. The renal biopsy shows C3 deposits in arterioles by fluorescence microscopy. Treatment has not been satisfactory, although nonsteroidal anti-inflammatory agents and calcium channel blockers may be of some use. The use of birth control pills should be discontinued.
IgA Nephropathy (Berger Disease)
IgA nephropathy is a relatively common cause of gross hematuria in young adults. It is associated with IgA and IgG deposits in the mesangium. Eighty percent of patients are between 16 and 35 years of age. The male to female ratio is 6:1. Symptoms include recurrent bouts of hematuria (usually gross) after upper respiratory tract infections. The disease may be associated with dysuria and flank pain. The urinary protein excretion is usually >1 g/day. Renal function is usually normal, but a substantial proportion of individuals (40%) may progress to renal insufficiency over the long term. Poor prognostic signs include hypertension, renal insufficiency, and persistent proteinuria (protein excretion >1 g/day). Serum IgA levels are elevated in 50% of patients. The diagnosis is made by characteristic history or renal biopsy. No treatment is available. Henoch-Schönlein purpura can cause similar renal lesions, but it is associated with nonthrombocytopenic vasculitic purpura, arthralgias, and abdominal pain. These two conditions may represent different parts of the spectrum of a similar pathogenic process.
Hereditary Nephritis (Alport Syndrome) and Polycystic Kidney Disease
The adult form of polycystic kidney disease usually manifests in the second or third decade of life with hematuria and hypertension. It is an autosomal dominant disease. Familial nephritis in males often causes an early onset of renal insufficiency. The renal disease is often accompanied by abnormalities of the lens and retina and high-frequency hearing loss.
Benign Familial Hematuria
This is a condition characterized by glomerular hematuria (RBC casts), nonprogressive renal disease, and normal renal function in many affected family members. It is often associated with thinning of the glomerular basement membrane. The inheritance is autosomal dominant. The diagnosis is suggested by (a) the presence of hemoglobin or RBC casts in the urine of the adolescent and in that of a parent or sibling, (b) absence of renal insufficiency in the patient, and (c) no history of renal failure or auditory abnormalities in the affected family members. The disease is more common in females.
For Teenagers and Parents
http://kidney.niddk.nih.gov/kudiseases/pubs/proteinuria/index.htm. National Institutes of Health (NIH) site on proteinuria.
http://www.kidney.org/news/newsroom/fsitem.cfm?id=9. National Kidney Foundation site on proteinuria.
For Health Professionals
http://www.aafp.org/afp/981001ap/loghman.html. American Academy of Family Physicians (AAFP) article on proteinuria in children.
http://www.aafp.org/afp/20000915/1333.html. AAFP article on proteinuria in adults.
For Teenagers and Parents
http://kidney.niddk.nih.gov/kudiseases/pubs/hematuria/index.htm. NIH Education site on hematuria.
http://www.urologychannel.com/Hematuria/. Information site on hematuria.
http://www.keepkidshealthy.com/welcome/commonproblems/hematuria.html. Information site for parents on hematuria in children.
For Health Professionals
http://www.duj.com/hematuria.html. Digital Urology Journal on hematuria.
http://www.aafp.org/afp/20010315/1145.html. AAFP article on work-up of microscopic hematuria.
References and Additional Readings
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