eMedicine Specialties > Pediatrics: General Medicine > Nephrology

Hematuria: Differential Diagnoses & Workup

Author: Sanjeev Gulati, MBBS, MD, DNB(Peds), DM, DNB(Neph), FIPN(Australia), FICN, FRCPC(Canada), Associate Professor, Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences; Senior Consultant in Pediatric Nephrology, Department of Nephrology and Transplant Medicine, Fortis Hospitals, India
Coauthor(s): Deogracias Pena, MD, Medical Director of Dialysis, Department of Pediatrics, Cook Children's Medical Center; Clinical Associate Professor, Texas Tech University School of Medicine
Contributor Information and Disclosures

Updated: Feb 24, 2009

Differential Diagnoses

Other Problems to Be Considered

Several conditions are commonly associated with hematuria in children.

Hypercalciuria

Approximately 30% of children with isolated hematuria may have elevated urinary calcium levels. Hematuria can be either gross or microscopic, and may or may not be associated with dysuria. A history of "sandy urine" or actual passage of calculi is sometimes elicited.

A spot urine calcium–to–creatinine ratio of more than 0.2 is considered abnormal. The ratio varies with age and averages 0.86 in infants younger than 7 months, 0.6 in children aged 7-18 months, and 0.42 in children aged 19 months to 6 years. A 24-hour urine collection is recommended if the ratio is high.

An excretion rate of more than 4 mg/kg/d is considered abnormal. Therapy consists of reduction in calcium intake (when excessive) to amounts consistent with the recommended daily allowance (RDA) for age and/or prescription of thiazide diuretics.

IgA nephropathy

IgA nephropathy (ie, Berger nephropathy) is currently the most common cause of chronic glomerulonephritis in the world. It usually presents with painless intermittent gross hematuria, followed by persistent microscopic hematuria. Colicky abdominal or loin pain may occur in some patients who develop clots in the genitourinary tract. The episode of gross hematuria often is preceded by an upper respiratory infection. Depending on the severity of the disease, hypertension, proteinuria, and elevation of serum creatinine may ensue. In some cases IgA nephropathy may present with only microscopic hematuria, asymptomatic microscopic hematuria and proteinuria, acute nephritic syndrome, nephrotic syndrome, or a mixed nephritis-nephrotic syndrome.

The disease appears to be less common in black individuals. A slight male preponderance is observed. Progression to chronic renal failure and end-stage renal disease has been reported to occur in 20-50% of patients, usually 10 or more years from diagnosis. The serum IgA level is elevated in 30-40% of patients but is not sufficient to establish the diagnosis. A kidney biopsy with the characteristic deposition of IgA in the glomerular mesangium is diagnostic. No effective treatment strategy is noted, although prednisone, fish oils, azathioprine, danazol, dipyridamole, and antioxidants (eg, vitamin E) have been used with inconclusive results.

Henoch-Schönlein purpura

Some authors believe that Henoch-Schönlein purpura (anaphylactoid purpura) shares a similar pathophysiology with IgA nephropathy. However, prominent vasculitis and purpura are present only in Henoch-Schönlein purpura.

The peak incidence is approximately age 4-5 years. A slight male preponderance is observed. Its onset is preceded by an upper respiratory infection in at least 30% of patients. Purpuric palpable rash is seen predominantly on the posterior aspects of the body and lower extremities. Abdominal pain, joint pain, and swelling are often present. Urinalysis usually reveals microscopic hematuria and sometimes proteinuria. Hematuria is likely related to deposition of IgA immune complexes and associated inflammatory processes in the glomerular mesangium. Measurements of complement 3 (C3) and antinuclear antibodies (ANA) levels may be needed to rule out systemic lupus erythematosus.

The disease is usually self-limited and requires no treatment. In children with nephritic and/or nephrotic syndrome, antihypertensives may be needed to control hypertension, diuretics may be needed to relieve excessive fluid retention, and corticosteroids may be needed to relieve the inflammation of the joints and the intensity of the purpuric rash. Some cases of Henoch-Schönlein purpura, particularly those that present with nephritis and/or nephrotic syndrome, may progress to chronic renal failure.

Hemolytic uremic syndrome

The hemolytic-uremic syndrome is a common cause of acute renal failure in children. The classic description is of a child that develops a thrombocytopenic microangiopathic hemolytic anemia and renal failure after a preceding bout (1-15 d) of often bloody gastroenteritis. Gross hematuria may be observed in some cases, but the more usual finding is microscopic hematuria.

Hemolytic-uremic syndrome is generally classified into the more common diarrhea-associated hemolytic-uremic syndrome (D+ HUS) and the atypical hemolytic-uremic syndrome (D- HUS). D+ HUS is caused by shiga toxin produced by Escherichia coli O157:H7. It is rare in blacks and has a female preponderance. The disease mostly occurs during the summer and the autumn seasons. Although ingestion of undercooked contaminated ground beef products is the most common source of infection, cases have been reported after the ingestion of raw milk, fruits, and vegetables in contact with manure. Infection has also been reported after swimming in pools or lakes and after exposure to the pathogen in nursing homes and day care centers.

The disease process begins when Shiga toxin is absorbed through damaged colonic mucosa and binds to glycophospholipid globotriaosyl ceramide (Gb3) receptors in vascular endothelial cells. These are internalized by endocytosis, and inactivation of 28S ribosomal subunits, inhibition of protein synthesis, and cell death results. In addition, lipopolysaccharides (released by verotoxin-producing E coli) also are absorbed, resulting in the release of inflammatory mediators. The end result is cell death, increased procoagulant activity, thrombocytopenia, renal vascular microthrombi formation, and the characteristic picture of hemolytic-uremic syndrome. Although involvement of the GI tract, kidney, and the hematologic system are commonly observed, involvement of other organs such as the liver, pancreas, gall bladder, lungs, and the CNS have been frequently reported.

Treatment is mainly supportive. Meticulous care of electrolyte abnormalities, hypertension, and, if necessary, dialysis has resulted in a dramatic decrease in mortality rates (from 40% in the decades when it was first described to the 5-10% seen today).

Postinfectious glomerulonephritis

This is probably the most common cause of gross hematuria in children. Although the disease often is precipitated by various pathogens (viral or bacterial), an antecedent infection (1-4 wk) with a nephritogenic strain of group A beta-hemolytic streptococci is often the culprit.

The child frequently has a history of a recent pharyngitis or skin infection 1- 2 weeks before the onset of symptoms. Streptococcal pharyngitis is more common in the winter and early spring and is seen mostly in children aged 5-15 years. On the other hand, skin infections (pyoderma) frequently occur in younger children in the summer and fall.

Gross hematuria is seen in 25-33% of cases and may range from light pink to a dark "tea" color. Eighty-five percent of patients may develop edema. Hypertension and oliguria are common. RBCs (most are small and dysmorphic) and RBC casts are common in the urine. A fresh urine sample should be used for this purpose. Proteinuria may also be noted but is not usually in the nephrotic range. Elevation of antistreptolysin (ASO) serum levels (80% of untreated patients) and depressed C3 levels are helpful in providing evidence of an antecedent streptococcal infection. Because ASO may not be detected in pyoderma (because the antibody can be bound to lipids in the skin), anti-DNAse B may be more helpful in establishing a diagnosis in these cases. Serial measurements (at least 1 wk apart) of these serologic markers may lend support to the assumption that a prior streptococcal infection is temporally related to the nephritis.

Treatment is mainly supportive. Strict fluid and salt restriction should be observed because the main problems encountered are often caused by fluid retention. Diuresis with loop diuretics is indicated to alleviate volume expansion. Vasodilators, calcium channel blockers, beta-blockers, or angiotensin-converting enzyme inhibitors may be indicated in the management of hypertension.

The C3 levels typically normalize in 68 weeks. Gross hematuria quickly disappears, but microscopic hematuria may persist for years. Most investigators agree that the great majority of children with poststreptococcal glomerulonephritis heal without any residual damage. A kidney biopsy is not needed unless a disease other than poststreptococcal glomerulonephritis is suspected, the child presents with nephrotic syndrome and nephritis, or the child does not recover promptly.

Systemic lupus erythematosus

Approximately two thirds of children with systemic lupus erythematosus have renal involvement. Various combinations of gross hematuria and proteinuria (sometimes in the nephrotic range) and hypertension are found. However, the degree of hematuria does not necessarily directly correlate with the severity of the renal lesions.

The incidence of systemic lupus erythematosus is 0.6 per 100,000 children and adolescents, with a higher frequency among persons of African, Hispanic, or Asian descent. Although more common in girls, the female predominance is not as pronounced in children as in adults. No exact pathogenic mechanism explains the manifestations of systemic lupus erythematosus. However, environmental stimuli interacting with certain genetic determinants or acquired immune defects are generally acknowledged to result in a polyclonal B cell immune response, with various antibodies deposited in target tissues, such as the kidney and other organs. Various serologic and hematologic abnormalities are noted and may include anemia, thrombocytopenia, decreased serum complement levels, elevated ANA levels and anti–double stranded DNA levels.

The degree of renal involvement should be determined histologically. The currently accepted classification is based on the World Health Organization (WHO) system and some modification using the International Study of Kidney Disease in Children (ISKDC) subclassification. Findings may range from mild glomerulitis to diffuse proliferative glomerulonephritis. Treatment and prognosis of the renal disease depends on the histologic classification. The drug therapy chosen depends on the severity of the disease and my include steroids, alkylating agents (cyclophosphamide), antimalarials, calcineurin inhibitors, and, recently, mycophenolate mofetil.

Nutcracker syndrome 

In this entity, left renal vein compression between the aorta and proximal superior mesenteric artery is observed. The hematuria is usually asymptomatic but may be associated with left flank pain. The diagnosis is made by Doppler ultrasonographic assessment of left renal vein diameter and peak velocity. This has mostly been reported in the Asian subcontinent.

Workup

Laboratory Studies

The laboratory tests ordered for the evaluation of hematuria must be based on the clinical history and the physical examination. Identification of a glomerular and extraglomerular etiology of hematuria based on a good history and urine examination can help the physician to avoid requesting tests that may be unnecessary.

• Urinalysis
  • Confirming that a child with red-colored urine has hematuria is mandatory. Dip strip analysis is critically important in patients with dark or abnormal-appearing urine because several substances may discolor the urine and give the appearance of hematuria. The urine dipstick test is currently one of the most useful and sensitive tools in detecting hematuria. This test is based on the peroxidase activity of hemoglobin. It can detect trace amounts of hemoglobin (rather than the presence of RBCs) and myoglobin. False-positive results can occur (certain dyes or drugs, beets, oxalates). Briefly dip the strip in the urine, tap off excess urine, and read the strip at the recommended time (usually 1 min). Dipsticks have a sensitivity of 100% and a specificity of 99% in detecting 1-5 RBCs per high-power field (hpf).
  • The presence of hematuria is most important to confirm, since both normal and abnormal causes (eg, hemoglobinuria, myoglobinuria) can produce false-positive results. Confirmation requires a microscopic examination of the urine for the presence of RBCs and casts. A freshly voided urine specimen should be used. A 10- to 15-mL aliquot of the urine is spun in a centrifuge at 1500 rpm for about 5 minutes. The supernatant is decanted, and the sediment is resuspended in the remaining liquid. The urine sample is then carefully examined under high-power magnification. All noncellular and cellular elements should be noted and recorded. More than 5 RBCs per hpf is generally considered abnormal. RBC casts indicate a glomerulotubular source of hematuria. The absence of RBCs and RBC casts despite a positive dipstick test suggests hemoglobinuria or myoglobinuria.
  • Other cellular elements in the urinary sediment (eg, WBCs, WBC casts) suggest a diagnosis of urinary tract infection. In this latter instance, a urine culture must be performed to determine the causative organism. Crystals, bacteria, protozoa, and other elements may also be seen.
  • Parents of children with isolated microscopic hematuria should be reassured that sufficient time remains to plan a stepwise evaluation. Other investigations should be avoided, and the dipstick and microscopic urinalysis should be repeated twice within 2 weeks.
• Phase contrast microscopy: A careful examination of the urine for the presence of a significant number of dysmorphic RBCs suggests a renal (glomerular) source of the hematuria. A urine sample that predominantly contains eumorphic RBCs suggests an extrarenal (nonglomerular) source. This test has been reported to have a sensitivity of 83-95% and a specificity of 81-95%. The sensitivity and specificity may vary from one examiner to another.
• BUN/serum creatinine: Elevated levels of BUN and creatinine suggest significant renal disease as the cause of hematuria.
• Hematologic and coagulation studies: CBC counts and, sometimes, platelet counts may be performed in selected patients with a clear history of a bleeding disorder. In general, coagulation studies and CBC counts often do not add additional information in the evaluation of hematuria. In certain populations, a sickle cell preparation or a hemoglobin electrophoresis may be useful in establishing the diagnosis of sickle cell disease or trait.
• Urine calcium: Hypercalciuria is a relatively common finding in children. Measurement of the urine calcium excretion using either a timed 24-hour urine collection for calcium or a spot urine calcium-creatinine ratio can be helpful in establishing hypercalciuria as a cause of hematuria. A calcium excretion of more than 4 mg/kg/d or a urine calcium-creatinine ratio of more than 0.21 are considered abnormal.
• Serologic testing: Measuring serum complement levels is important if a glomerular cause of hematuria is suspected. Low serum complement levels are seen in postinfectious glomerulonephritis, systemic lupus erythematosus nephritis, bacterial endocarditis, and membranoproliferative glomerulonephritis. A high antistreptolysin (ASO) titer suggests a recent streptococcal infection. Anti-DNase B levels are also indicative of a recent group B streptococcal infection and may be positive even when the ASO level is normal. This latter statement is relevant in poststreptococcal glomerulonephritis secondary to a skin infection. Antinuclear antibody (ANA) titers and the measurement of double-stranded DNA (dsDNA) levels are most helpful in children with suspected systemic lupus erythematosus nephritis.
• Urine culture: A midstream or clean-catch specimen of urine should be obtained for culture sensitivity whenever a urinary tract infection is suspected. This is especially important in younger children, in whom classical symptoms of a urinary tract infection may be absent.

Imaging Studies

• Renal and bladder ultrasonography: Urinary tract anomalies, such as hydronephrosis, hydroureter, nephrocalcinosis, tumor, and urolithiasis, are readily revealed with ultrasonography. Compared with other imaging studies, sonography is rapid, noninvasive, readily available, and devoid of exposure to radiation. In individuals with severe obesity, a more accurate definition of renal structures and surrounding organs can be achieved using only CT scanning.
• Other imaging studies
  • A spiral CT scan is particularly useful in the detection of urolithiasis, Wilms tumor, and polycystic kidney disease.
  • Voiding cystourethrograms are valuable in detecting urethral and bladder abnormalities that may result in hematuria (eg, cystitis).
  • Radionuclide studies can be helpful in the evaluation of obstructing calculi.
  • Intravenous urography rarely contributes additional information in the evaluation of hematuria and may unnecessarily expose the child to ionizing radiation.

Procedures

• Kidney biopsy
  • A kidney biopsy is rarely indicated in the evaluation of isolated asymptomatic hematuria. Most studies reveal minimal histopathological abnormalities in such children. In a survey of pediatric nephrologists in North America, only 5% of responders indicated that they would perform a kidney biopsy on a child with asymptomatic hematuria. The main reasons for performing a biopsy in that survey were academic interest, parental pressure for a diagnosis, and concern for future economic impact on the child. On the other hand, the simultaneous presence of proteinuria, elevated serum creatinine, hypertension, a suspicious clinical history, or other imaging/laboratory abnormalities may justify a kidney biopsy.
  • Thus, relative indications for performing a kidney biopsy in patients with hematuria are as follows:
    • Significant proteinuria
    • Abnormal renal function
    • Recurrent persistent hematuria.
    • Serologic abnormalities (abnormal complement, ANA, or dsDNA levels).
    • Recurrent gross hematuria.
    • A family history of end-stage renal disease
• Cystoscopy: This is not generally required in children with nonglomerular hematuria. The only indication is a suspicious bladder mass revealed on ultrasonography.

Histologic Findings

In most patients, a renal biopsy is either normal or reveals minor changes, such as thin glomerular basement membranes, focal glomerulonephritis, or mild mesangial hypercellularity. In a minority of patients, histologic findings, together with historical or serologic data, may point to specific conditions.

Histologic Findings 

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A comprehensive physical examination and a detailed history are indispensable to the evaluation of hematuria.

• A urinalysis should be obtained (as described above), and a careful microscopic review of the sample should be performed. A positive dipstick reaction should be followed by a urine analysis to confirm the presence of RBCs and/or casts. The absence of erythrocytes suggests myoglobinuria or hemoglobinuria, whereas the absence of hemoglobin, red cells, or myoglobin should prompt a search for other causes of red urine.
• The next step in the differential diagnosis is localization of the bleeding. The presence of red cell casts and preponderance of dysmorphic cells on phase contrast microscopy are consistent with glomerular bleeding. Other urine characteristics that help in distinguishing between glomerular and nonglomerular hematuria are discussed above.
• A urine culture should be obtained. Significant bacterial growth, indicative of urinary tract infection or pyelonephritis, requires antibiotic treatment and, possibly, further radiologic evaluation of the genitourinary tract for obstruction, vesicoureteral reflux, cystic disease, and other abnormalities. A urine culture showing "no growth" may need to be followed by imaging studies. A urine sample should be sent for determination of the urine calcium-creatinine ratio. An abnormal result should prompt a 24-hour urine collection to confirm the diagnosis of hypercalciuria.
• If hematuria is of glomerular origin, measurements of protein excretion and serology tests may be in order. Low C3 levels should suggest membranoproliferative glomerulonephritis or systemic lupus erythematosus as diagnostic possibilities. The latter should be confirmed by measurements of ANA or dsDNA. A low C3 level in association with an elevated ASO titer or anti-DNAse B, are indicative of poststreptococcal glomerulonephritis. The concomitant presence of hematuria and proteinuria often indicates serious renal disease. A kidney biopsy should be considered if proteinuria is persistent.
• The approach to the evaluation of hematuria varies among physicians and no single method applies in all circumstances. One approach is outlined in Media files 1-3.

Staging

Categorizing patients with hematuria into one of the following groups is helpful:

• Gross hematuria
  • Gross hematuria is alarming for the child's parents and sometimes for their pediatricians.
  • Gross hematuria is an uncommon finding in an unselected population of children. The prevalence of gross hematuria was reported as 0.13%, based on a retrospective review of children seen in an emergency walk-in clinic.
  • Most children with gross hematuria (56%) have an easily recognizable and apparent cause. The most common diagnoses include urinary tract infection, perineal irritation, trauma, meatal stenosis with ulceration, coagulation abnormalities, and urinary tract stones.
  • Less than half (44%) of children with gross hematuria had a cause that was either not obvious or that required additional or more sophisticated examinations. Among the diagnoses in this group are recurrent gross hematuria, acute nephritis, ureteropelvic junction obstruction, cystitis cystica, epididymitis, tumor, hyperuricosuria, and hypercalciuria.
  • These children require referral to a pediatric nephrologist for detailed investigation and management.
• Microscopic hematuria with clinical symptoms
  • A child who presents with either symptoms of an illness or a physical abnormality and is discovered to have concurrent microscopic hematuria should be placed in this category.
  • Some of the clinical conditions with associated renal involvement that may be recognized by the primary physician are acute glomerulonephritis, acute interstitial nephritis, urinary tract infections, familial hematuria (both benign recurrent and progressive hereditary nephritis), Henoch-Schönlein purpura, systemic lupus erythematosus, hypertension, hypercalciuria, and urolithiasis.
  • Unless the patient falls into a clear category of illness that is easily identified, an early consultation with the pediatric nephrologist should be obtained, because most other illnesses require additional expertise in either delineation or management.
  • The child with microscopic hematuria associated with clinical symptoms may have a vast number of diseases or conditions, which makes this a difficult category for which to suggest specific evaluation.
  • The first step in this category is to direct the evaluation based on the symptoms or physical examination findings. The extent and thoroughness of the evaluation depends on the knowledge and experience of the physician.
  • The child with a complicated diagnosis or unexplained cause for the hematuria should be referred to a pediatric nephrologist or, in some cases, to an appropriate subspecialist. If a diagnosis is straightforward, the appropriate therapy or follow-up is administered.
  • If the child has recurrence of the symptoms and associated hematuria or if the hematuria is persistent, referral to a pediatric nephrologist is recommended.
• Asymptomatic microscopic hematuria with proteinuria
  • In the asymptomatic child, simultaneous microscopic hematuria and proteinuria (>50 mg/dL) in 3 consecutive urine samples is unusual and occurred in the Galveston study, with a prevalence of 64 per 100,000 school children (approximately 0.06%).³ All of the children in this survey who were thought to have significant renal disease were included in this group. Despite the obvious concern attendant to this combined finding, almost 50% of the children who were discovered to have both hematuria and proteinuria had spontaneous resolution of both findings during the course of the 5-year follow-up.⁴
  • The significance of the renal involvement, in most cases, correlates directly with the quantity of protein being excreted. Thus, the combination of asymptomatic microscopic hematuria and proteinuria seems to suggest that such patients are more likely to have significant renal disease.
  • The first step in this category is to quantitate the urine protein at the initial or follow-up visit. Asymptomatic patients who are found to have both hematuria and proteinuria in several samples collected over a few weeks should be referred to a pediatric nephrologist for further evaluation and recommendations.
• Asymptomatic microscopic (isolated) hematuria
  • Asymptomatic microscopic hematuria is common in unselected populations of children. The discovery of hematuria alone in an asymptomatic child is merely an indication for repeat testing on one or more occasions.
  • The Galveston County epidemiology study found that, of children who had 3 consecutive urine samples that demonstrated hematuria, only 37% had hematuria 1 year later.³ Thus, the cause for the asymptomatic hematuria had apparently resolved in 63% of the children over the course of a single year. Significant renal disease was almost nonexistent in patients in whom hematuria was the only abnormality found.
  • In cases involving the development of proteinuria or pyuria, the condition of isolated asymptomatic hematuria is no longer observed, and other studies should be performed. If the microscopic hematuria persists unchanged for more than 1-2 years, a few additional studies may be indicated.
  • One possible entity responsible for such an asymptomatic persistence of hematuria is idiopathic hypercalciuria or hyperuricosuria.
  • Familial or hereditary hematuria, whether benign, nonprogressive (ie, "thin basement membrane disease"), or progressive (ie, Alport syndrome or one of its variants), is another condition in which, early in the course, hematuria may be found in the absence of proteinuria.
  • IgA nephropathy may also present with microhematuria.

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