Adolescent Health Care: A Practical Guide
Asymptomatic Proteinuria and Hematuria
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.
- Increased glomerular permeability, as in primary or secondary glomerulopathies (e.g., minimal change disease, systemic lupus erythematosus [SLE], membranous nephropathy)
- Increased production of abnormal proteins (e.g., mono-clonal gammopathies)
- Decreased tubular reabsorption of proteins, as in tubular disease (e.g., Fanconi syndrome, aminoglycoside nephrotoxicity) or chronic interstitial nephritis
- Miscellaneous—functional proteinuria (e.g., fever, exercise, congestive heart failure) and orthostatic proteinuria
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:
- An asymptomatic state
- Age at onset: 10 to 20 years
- Dipstick urine findings:
- In the p.m.: 1 to 3+
- In the a.m.: Negative finding
- Urine sediment: Negative finding
- Quantitative protein excretion
- Supine: A protein/creatinine ratio of <0.2 on a spot urine sample (<75 mg in 12 hours)
- Upright: A spot urine value of 0.3 to 2.0 (150–1,000 mg in 12 hours)
- Renal function: Normal
The presence of hypertension, edema, hypoalbuminemia, or hyperlipidemia suggests more significant renal abnormalities.
- Mild asymptomatic proteinuria (expected excretion of protein: <500 mg/m2in 24 hours)
- Benign persistent proteinuria
- Orthostatic or postural proteinuria (proved with split 24-hour urine collection)
- Pyelonephritis (usually with fever and pyuria)
- Renal tubular disorders
- Chronic interstitial nephritis
- Congenital dysplastic lesions
- Other: Exercise, trauma (with hematuria), fever, congestive heart failure (severe)
- Moderate proteinuria (expected excretion of protein: 500–2,000 mg/m2in 24 hours)
- Acute poststreptococcal glomerulonephritis (PSGN)
- Primary glomerulonephritis
- Hereditary chronic nephritis (Alport syndrome)
- Systemic diseases: SLE
- Severe proteinuria (expected excretion of protein: >2,000 mg/m2in 24 hours; usually >3.5 g), typically associated with edema, hypoalbuminemia, and hypercholesterolemia (nephrotic syndrome)
- Idiopathic glomerulonephritis: Minimal change disease, focal sclerosis, membranous or membranoproliferative glomerulonephritis
- Systemic disease: SLE; amyloidosis (in the setting of chronic inflammatory disease or familial Mediterranean fever)
- Less common
- Infections: Bacterial endocarditis, hepatitis, malaria, human immunodeficiency virus infection
- Toxins: Mercury, heroin, gold, penicillamine
- Allergens: Bee stings
- Mechanical: Pericarditis, renal vein thrombosis
- Cancer: Hodgkin disease, lymphoma
- Congenital: Fabry disease and Alport syndrome
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:
- Recent upper respiratory tract infection or skin infections
- Skin rashes, arthralgias, or photosensitivity
- Flank pain, diabetes mellitus (10–14 years of diabetes is usually required before clinical detection of proteinuria; detection of microalbuminuria is possible at earlier stages of disease)
- Intoxications, drug history, bee stings, and other allergic history
- Family history of renal disease
Check for the following:
- Blood pressure; height and weight percentiles
- Vision and hearing screening, especially if hereditary nephritis is a consideration
- Abdominal mass
- Joint examination
- Cardiac examination
- Signs of systemic diseases
Include the following in the evaluation:
- Dipstick tests: Protein, glucose, and blood should be tested. If the dipstick test result is positive for protein, a repeated dipstick test should be performed another one or two times. If protein is still present, a spot urine test for protein/creatinine should be performed.
- Microscopical examination for casts and cells: Examination of sediment is crucial because abnormal results suggest an underlying renal problem. Red
blood cell (RBC) casts suggest glomerulonephritis; white blood cell casts suggest pyelonephritis or interstitial nephritis.
- Spot urine for protein/creatinine: This simple test has replaced timed urine collections for screening purposes. A ratio of 1.0 closely correlates with the daily excretion of protein of 1.73 g/m2. This is based on the fact that the average daily excretion of creatinine is approximately 1,000 mg/24 hours/1.73 m2. To screen for orthostatic proteinuria, a first void specimen obtained immediately on arising is compared with a second specimen obtained at least 4 hours after arising. If the later is at least five times the first specimen, this supports a diagnosis of orthostatic proteinuria.
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.
- If the urine protein/creatinine ratio is >0.5 with no definitive postural change, then further evaluation is indicated. This may include a timed urine collection (ideally 24 hours), serum urea nitrogen and creatinine concentrations; complete blood cell count; concentrations of albumin, antinuclear antibody, and cholesterol; hepatitis B screening tests; complement levels (CH50,C3, C4); and an antistreptolysin O (ASO) titer. Not all tests need be done at once. The clinical history and physical examination should direct the order and amount of testing. Perform the following if signs or symptoms are suggestive of hepatitis, streptococcal infections, or SLE:
- Hepatitis: Measure liver enzymes and hepatitis B surface antigen.
- Recent streptococcal infection: Determine serum complement and antistreptococcal enzyme titers.
- SLE: Determine antinuclear antigen (ANA) and complement levels.
- Renal ultrasonography: Order if renal function is abnormal or nonpostural proteinuria is present. This test yields useful information, such as the number of kidneys present (1 in every 1,000 people is born with a single kidney, a finding that could influence subsequent evaluation and treatment), the size of the kidneys (small kidney size reflects chronic disease), and echogenicity. Although the test is nonspecific, increased renal echogenicity reflects “medical renal disease” that may require further evaluation.
- Renal biopsy: Because of the limited number of treatment options for many renal lesions, the frequent use of therapeutic trials, and the ability to diagnose common lesions on the basis of the history and laboratory findings, the indications for a renal biopsy are now more limited than in the past. A biopsy can help define the nature of the renal disease if the history, physical examination, and laboratory tests are not revealing. A biopsy can also define the severity of the lesion and help in determining its prognosis. This information is very important for teens and their families who are confronted with a diagnosis of renal disease. Refer the patient to a nephrologist for further evaluation and consideration for renal biopsy in the following situations:
- A spot urine protein/creatinine ratio of >1.0 (suggesting the 24-hour protein concentration is >1,000 mg).
- The diagnosis is unclear and significant disease is suspected because of the presence of proteinuria, hematuria, hypertension, or renal insufficiency.
- Nephrotic syndrome is present and has not responded to a therapeutic trial of corticosteroids for minimal change disease.
- Renal function is deteriorating.
- The patient, family, or both express a need for prognostic information.
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
- Glomerular diseases
- Immunoglobulin A (IgA) nephropathy (Berger disease)
- Membranous or membranoproliferative glomerulonephritis
- Focal glomerulonephritis or glomerulosclerosis
- Glomerulonephritis associated with connective tissue diseases, hemolytic uremic syndrome, or Henoch-Schönlein purpura
- Glomerulonephritis associated with infections such as streptococcal infection, shunt infections, or infective endocarditis
- Hereditary: Alport syndrome, polycystic kidney disease, medullary sponge kidney
- Benign familial hematuria: Primary renal hematuria with thin basement membrane
- Nonglomerular diseases
- Vascular diseases
- Malignant hypertension
- Loin-pain hematuria syndrome
- Arteriovenous malformation
- Renal arterial emboli
- Papillary necrosis: Sickle cell disease, diabetes mellitus, alcoholism, analgesic abuse
- Trauma: Usually significant trauma, as from motor vehicle accidents or contusions from contact sports
- Acute pyelonephritis
Urinary Tract Disease
- Hypercalciuria or renal calculi
- Inflammatory: Urethritis, cystitis, or prostatitis
- Neoplasms or arteriovenous malformation within the bladder
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:
- Congenital or acquired coagulation defect
- Use of heparin or warfarin sodium (Coumadin)
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.
- True hematuria: Positive dipstick finding, RBCs on spun urine, clear spun urine, and clear spun serum (unnecessary unless myoglobinuria or hemoglobinuria is suspected)
- False hematuria
- Hemoglobinuria: Positive dipstick finding, negative result of microscopical examination, red spun urine, and pink spun serum
- Myoglobinuria: Positive dipstick finding, negative result of microscopic examination, orange red or brown spun urine, clear spun serum
- Porphyrins or exogenous pigments: Negative dip stick finding, negative result of microscopical examination, red spun urine, clear spun serum
- Menstruation: Must be ruled out because menstrual blood can easily contaminate urine specimens
- Pattern of hematuria: Microscopic versus macroscopic. Macroscopic, or gross, hematuria is more likely with severe trauma, severe cystitis, or IgA nephropathy. The relationship to intercurrent illnesses may indicate possible PSGN or IgA nephropathy.
- Family history of renal disease or hematuria: Suggestive of hereditary nephritis, benign familial hematuria, or polycystic kidneys. Family history of vision problems or hearing loss with renal disease may indicate hereditary nephritis.
- Associated symptoms include the following:
- Dysuria, frequency: Cystitis, urethritis, or (rarely) hypercalciuria
- Colic: Renal stones
- Weight gain: Nephrotic syndrome
- Fever: Cystitis, pyelonephritis, or a systemic illness
- Joint pain and rashes: SLE or Henoch-Schönlein purpura
- Hearing loss: Hereditary nephropathy
- Bleeding tendency: Coagulopathy
- Previous heart murmurs or a history of tooth extractions: Endocarditis
- Loin pain: Loin-pain hematuria syndrome
- Blood clots: Lower genitourinary tract disease
- Drug history: Analgesic abuse; use of warfarin (Coumadin), heparin, or oral contraceptives.
- Relation to exercise: Short-term hematuria after long-distance running or heavy exercise is suggestive of “athletic hematuria.”
- Blood pressure: Elevated blood pressure associated with hematuria suggests renal abnormality.
- Skin: Rashes may indicate connective tissue disease. Ecchymosis is suggestive of Henoch-Schönlein purpura. Petechiae are suggestive of thrombocytopenia.
- Corneal and lens abnormalities and hearing loss suggest hereditary nephritis.
- Abdomen: Abdominal masses and renal enlargement may suggest polycystic disease.
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.
- With signs or symptoms suggestive of infection, obtain a urine specimen for culture.
- Basic laboratory tests should be ordered, as discussed earlier for proteinuria, and should include a complete blood cell count, platelet estimation, and determinations of blood urea nitrogen, creatinine, and complement levels.
- If coagulopathy is suspected, order determinations of the prothrombin time, partial thromboplastin time, platelet count, and bleeding time, as indicated.
- For African-American patients, order sickle cell screening or hemoglobin electrophoresis to evaluate for sickle cell trait.
- In adolescents with signs and symptoms suggestive of connective tissue disease or proteinuria and RBC casts, order the following tests: ANA, anti-DNA antibody, third and fourth components of complement (C3 and C4), ASO titer, audiography, serum albumin, cholesterol, quantitative urinary protein, and creatinine clearance.
- Check urine of first-degree relatives for hematuria. The presence of hematuria in a parent, sibling, or child of an adolescent may indicate either benign familial hematuria (if family members are well) or hereditary nephritis (if family members have renal disease).
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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