Hematuria Differential Diagnoses

Diagnostic Considerations

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. ^[8]

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. As per the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, children with proteinuria (>0.5-1 g/d/1.73 m²) should be treated with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBS). ^[9]  Corticosteroids have been suggested in children with persistent proteinuria despite 3-6 months of optimized care. Fish oil is another treatment modality that has been suggested in this subgroup of children. Other treatments like mycophenolate mofetil, 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. Cases have been reported of children with IgA nephropathy who later developed Henoch-Schönlein purpura. ^[10] 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 days) 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.

Plasmapheresis has been found to be beneficial in children D-hemolytic uremic syndrome. Eculizumab and anti-CD5 monoclonal antibody are now considered to be the treatment of choice in children with D-hemolytic uremic syndrome. The remainder of 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 may include steroids, alkylating agents (cyclophosphamide), antimalarials, calcineurin inhibitors, and 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.

Familial hematuria

Familial hematuria is defined as a group of genetic disorders of glomerular capillaries that are characterized clinically by the onset of persistent hematuria during childhood . The 2 common causes of familial hematuria are Alport syndrome and thin basement membrane nephropathy (TBMN). Together these account for approximately 30–50% of cases among children with isolated glomerular hematuria referred to pediatric nephrology clinics for consultation. ^[11]

Differential Diagnoses

• Acute Poststreptococcal Glomerulonephritis

• Anti-GBM Antibody Disease

• Hemolytic-Uremic Syndrome

• IgA Vasculitis (Henoch-Schonlein Purpura)

• Hypercalciuria

• Pediatric Bacterial Endocarditis

• Pediatric IgA Nephropathy

• Pediatric Urinary Tract Infection

• Pediatric Urolithiasis

• Systemic Lupus Erythematosus (SLE)