Hematuria is a common issue faced by primary physicians who care for children. While it can cause great anxiety in the patient and family when it presents as gross hematuria, rarely does hematuria alone herald a serious illness during childhood. Indeed, despite thorough evaluation, no cause can be found in a large percentage of children who have hematuria. Nearly 40% of children who present with gross hematuria and 80% of patients with persistent, isolated microscopic hematuria have no identifiable cause despite a thorough investigation. This raises the question of how much investigation should be performed on a child who presents with hematuria, particularly if it is isolated microscopic hematuria because the evaluation can be costly and at times invasive.
How extensive an evaluation is appropriate depends much on the context. Those children who present with gross hematuria or microscopic hematuria with associated signs or symptoms deserve a thorough evaluation. These two groups contain those more likely to have an identifiable cause and include the subset that has an acute or potentially serious illness that can progress to significant morbidity or sequelae if not identified and treated. Associated symptoms and signs that indicate the need for prompt evaluation include other urinary or systemic symptoms that led to testing the urine for blood, and findings of hypertension, edema, poor growth, fever, or other systemic signs at presentation.
The more difficult question is how much testing is required of an apparently healthy child discovered to have isolated microscopic hematuria on routine screening urinalysis. Thorough testing of such a child with no symptoms, a normal physical examination, and no significant family history of kidney disease rarely identifies a cause of hematuria. Therefore, the utility of performing a screening urinalysis in children, with the potential attendant costly and usually uninformative additional investigation, has long been questioned. The American Academy of Pediatrics does not recommend screening urinalysis for early school-aged children. It is reasonable to screen children who have a significant family history of kidney disease, particularly if there is a family history of hereditary nephritis.
Gross Hematuria
(See Nelson Textbook of Pediatrics, p. 2494.)
Gross hematuria, defined as blood in the urine visible to the naked eye, is a dramatic symptom that is usually brought to medical attention, unless an older child with the symptom is too frightened to bring it to the attention of the parents. Carefully defining the appearance of the urine can be the first and a major clue to the origin of the blood. Hematuria emanating from a nonglomerular, lower urinary tract source can present as frankly bloody urine varying in color from dark red, cherry, or pink-tinged urine. On occasion, lower tract hematuria can result in passing blood clots. Seeing blood in the urine only on initiation or at termination of voiding is an additional clue that the source is from the lower tract. Blood seen at the urethral meatus or only on initiation of voiding suggests a urethral source. In contrast, hematuria originating from a glomerular source more often presents with description of other color changes in the urine, such as brown-, cola-, tea-, or on occasion, even green-colored urine.
The first step when presented with this symptom is to perform a urinalysis. If no hemoglobin is found on macroscopic urinalysis, then causes of urine discoloration other than hematuria need to be considered ( Table 20.1 ). One fairly common presentation that can be particularly frightening to a parent is finding a pink or red-tinged wet diaper, thought to be blood in the urine. This most often is from a simple benign entity commonly called red diaper syndrome , caused by precipitation of urate crystals in the diaper. A macroscopic urinalysis negative for heme indicates this to be the most likely cause, and in an otherwise healthy infant, no further investigation is warranted.
| Pink, Red, Cola-Colored, Burgundy | |
| Disease Associated | |
| Porphyrinuria | |
| Associated with Drug or Food Ingestion | |
|
|
| Dark Brown, Black | |
| Disease Associated | |
| Alkaptonuria | Methemoglobinemia |
| Homogentisic aciduria | Tyrosinosis |
| Melanin | Bile pigments |
| Associated with Food or Drug Ingestion: | |
| Alanine | Resorcinol |
| Cascara | Thymol |
If red blood cells are found in the urine of a child with a history suggestive of gross hematuria, then evaluation for potential causes is needed ( Tables 20.2 and 20.3 and Fig. 20.1 ). The first step is a thorough history and physical examination.
| Symptoms | Suspected Glomerulonephritis | Laboratory |
|---|---|---|
| History of preceding pharyngitis, URI, or impetigo | Acute postinfectious GN | C3, C4 complement (low C3, normal C4) |
| Arthralgia, purpura, pedal edema, abdominal pain, hematochezia | Henoch-Schönlein purpura | Skin biopsy |
| Arthritis, rash, fever, oral ulcers, weight loss, alopecia, weakness, central nervous system symptoms, other systemic symptoms | Systemic lupus erythematosus | C3, C4 (both low) ANA, anti-ds DNA (both high) |
| Family history of renal failure, hearing loss, hematuria | Familial nephritis–Alport syndrome | Audiogram, slit lamp exam, genetic testing |
| Recurrent, painless gross hematuria | IgA nephropathy | None (kidney biopsy) |
| Hemoptysis, cough, fevers | Goodpasture syndrome | anti-GBM Ab |
| Rash, sinus disease, hemoptysis, systemic symptoms | ANCA-associated vasculitis | ANCA |
* All patients: serum creatinine, electrolytes, complete blood count, random urine protein:creatinine ratio, 24-hr urine collection for protein.
| Glomerular |
| Primary |
|
| Systemic |
|
| Interstitial Disease |
|
| Vascular |
|
| Neoplastic |
|
| Urinary Tract |
|
| Bleeding Disorders |
|
History
Development of pain with the onset of hematuria usually indicates a lower urinary tract source. Irritative symptoms, such as dysuria, urgency, or frequency can be seen in bleeding from the bladder from a variety of causes. Although not a typical feature of urinary tract infection (UTI), the most common identifiable cause of gross hematuria is a UTI, and is usually accompanied by significant dysuria or abdominal pain, and sometimes fever. Severe and episodic or colicky flank or abdominal pain should raise suspicion for urolithiasis, which may have accompanying dysuria as the stone is being passed. Urinary tract obstruction, such as posterior urethral valves in boys or ureteropelvic junction obstruction in either sex, may remain occult until infection or trauma causes hematuria. In the former, the only preceding symptoms may be a boy who voids only infrequently, commonly strains to void, or has ongoing urinary incontinence beyond the toddler years. Bleeding from renal tumors is an uncommon cause of gross hematuria in children, but should be considered particularly in the setting of associated abdominal pain, a palpable mass, or passing of blood clots.
Gross hematuria due to glomerular disease is rarely accompanied by significant pain, though some may report mild abdominal pain or flank discomfort. An exception is Henoch-Schönlein purpura, a common pediatric systemic vasculitis, which can have variable, including severe, gastrointestinal disease. Clues to underlying glomerular disease may be a recent history of pharyngitis, streptococcal skin infection, or other febrile illnesses, indicating possible acute post-infectious glomerulonephritis. Patients with glomerulonephritis or renal insufficiency may report shortness of breath, edema, or weight gain from fluid retention. They may also have a headache or visual changes secondary to severe hypertension. Abdominal pain, diarrhea, hematochezia, rash, and arthralgias are symptoms indicative of a systemic vasculitis, such as Henoch-Schönlein purpura (HSP). Recurrent, painless gross hematuria is often seen in young patients with IgA nephropathy in association with concurrent respiratory illness. Recurrent fever, weight loss, alopecia, mouth ulcers, chest pain, fatigue, and arthritis suggest systemic lupus erthythematosis. Hemoptysis or cough is seen in pulmonary-renal syndromes caused by antineutrophil cytoplasmic antibody (ANCA) associated disease, and on occasion in lupus and HSP.
The patient’s medical history may be most informative. Stressed neonates from birth asphyxia, infection, or volume depletion can develop renal vein thrombus that presents as gross hematuria. Patients with African ancestry should be queried for personal or family history of sickle cell hemoglobinopathy, since gross hematuria from renal papillary necrosis can occur in those with sickle cell disease as well as in children with simple sickle cell trait. Medication history can uncover a cause of gross hematuria from drug-induced interstitial nephritis, seen with several antibiotics, anticonvulsants, or nonsteroidal antiinflammatory drugs, the latter of which can also cause papillary necrosis. Cyclophosphamide can cause a severe hemorrhagic cystitis, which usually has concomitant prominent bladder symptoms.
A history of frequent or severe bleeding from other sites, such as heavy menses, prolonged nosebleeds, hemarthroses, or significant bleeding associated with surgical procedures suggests an undiagnosed bleeding disorder. Exposure history to tuberculosis should be obtained, as well as a travel history, as parasitic infections such as schistosomiasis of the bladder, uncommon in Western societies, is common in other parts of the world. Questions specific to other potential sources of blood in the urine include those directed at foreign body from self-instrumentation of the urethra, trauma, sexual abuse, and menstruation. Extreme sports activities such as running a marathon or long distance cycling can cause gross hematuria.
Review of the family history is important to uncover hereditary nephritis, hereditary cystic kidney disease, or potential benign familial hematuria. A family history of kidney disease leading to end-stage renal failure, especially if in men in multiple generations and if not clearly due to diabetes mellitus, would suggest Alport syndrome, the most common cause of hereditary nephritis. Alport syndrome is an X-linked recessive disorder that may cause gross hematuria in childhood although more often it is microscopic. When gross hematuria occurs in Alport syndrome, it is often triggered by any infectious process such as a common cold. The gross hematuria then subsequently clears, but microscopic hematuria is a persistent finding. The early clinical features of hereditary nephritis can be exactly the same as benign familial hematuria, but then evolve to develop other features. Early in the course of the disease, there is no associated proteinuria, but that feature develops later, often in childhood as the nephritis progresses. Hearing loss is a common but variable feature of Alport syndrome that tends to run in affected families. Female family members who are carriers usually have persistent and isolated hematuria that does not progress, but on occasion may develop progressive nephritis.
Benign familial hematuria and familial thin basement membrane nephropathy are also responsible for both microhematuria and gross hematuria. The primary difference in family history that separates benign familial hematuria from progressive hereditary nephritis is that members of sequential generations of the family with benign familial hematuria, either male or female, have persistent isolated hematuria that never progresses to significant renal disease. The genetics of benign familial hematuria due to thin basement membrane nephropathy has been defined and includes mutations that are identical to those seen in some patients with autosomal recessive forms of progressive hereditary nephritis. Patients with thin basement membrane nephropathy, or benign familial hematuria, may be carriers of genes that cause autosomal recessive Alport syndrome.
Patients with autosomal dominant polycystic kidney disease (ADPKD) may present initially with gross hematuria from spontaneous bleeding into the macrocysts. Because the course of ADPKD can vary widely from one generation to the next, with some members having very mild disease with minimal clinical features until late adulthood, the family history of the disease may not be apparent on presentation. Early onset of hypertension, during youth or young adulthood in a parent of an affected child, may be the only clue to a family member being affected by ADPKD.
Gross hematuria is a presenting complaint in 15% of children with urolithiasis . Kidney stone disease can be familial and in some cases related to specific genes, as in X-linked recessive nephrolithiasis (Dent disease) or primary hyperoxaluria. Therefore, family history of early-onset nephrolithiasis, especially in siblings, should be sought in children presenting with gross hematuria and symptoms or imaging that indicate kidney stone disease as the cause. A family history of a bleeding disorder such as hemophilia or platelet disorders should be sought.
Physical Examination
The initial focus of the physical examination should be for evidence of systemic disease for which the hematuria is one manifestation, and for potential sequelae of renal disease. Accurate measurement and attention to blood pressure, recognizing age differences in blood pressure, is critical. Hypertension may be the sole feature on physical examination that indicates underlying acute glomerulonephritis, or chronic kidney disease from several causes. The finding of edema in this context is highly suggestive of underlying renal parenchymal disease, either acute or chronic, with likely accompanying renal insufficiency. Poor growth or failure to thrive may indicate chronic renal disease. Pallor, fever, rashes, or musculoskeletal findings suggest systemic vasculitis with renal involvement from diseases such as HSP, SLE, or less often, ANCA-associated disease. Examination of the abdomen may reveal abdominal or flank masses that could be tumors, cystic kidneys, or urinary obstruction. The most common renal tumor in childhood, typically seen in young children (ages 1-4 years), is Wilms tumor, though other types occur. Hydronephrosis or enlarged cystic kidneys may be palpable. Suprapubic tenderness may indicate bladder infection, stone, or other less common causes of bladder pathology as the source of blood. The genitalia may need to be inspected for blood at the urethral meatus that suggests a urethral source, tears or lacerations due to abuse or accidents such as from straddle injuries, or to look for a foreign body.
Evaluation
Laboratory Tests
Macroscopic and microscopic examination of the urine is the first essential step in laboratory evaluation. If no heme is found on macroscopic examination, then other causes of urine discoloration need to be considered (see Table 20.1 and Fig. 20.1 ). If the urine is heme positive on macroscopic examination, but no red cells are found on microscopic examination of the urine sediment, then myoglobinuria or hemoglobinuria need to be considered as the possible source, since rhabdomyolysis and acute hemolysis are both potential life-threatening diseases that require immediate attention. If urine is heme positive but no red cells are seen, and there is no evidence for rhabdomyolysis or acute hemolytic disease, then other reasons for the findings need to be considered. Urine test strips can on occasion be falsely positive for blood if the urine is infected with peroxidase-producing bacteria. More likely is that red cells were present but lysed in urine that either was very dilute or was held for an extended time before microscopic examination was performed. Finding red cell casts in a resuspended pellet of spun urine (centrifuged 3-5 minutes at 1500-2000 rpm) under high-power field is a clear indication that the source of hematuria is glomerular. While the specificity of this finding in localizing the source to the glomerulus is high, the sensitivity of finding red cell casts in the hands of clinical labs is low. When red cell casts have been found in the urine sediment by experienced nephrologists, clinical laboratory reports of finding RBC casts in the urine of the same patients is very low. Unless the urine is thoroughly examined by an experienced clinician, the lack of RBC casts in a lab report does not lower the chance the patient might have a glomerular source of the hematuria. Another finding on microscopic examination of the urine sediment that suggests a glomerular source is the presence of a significant number of dysmorphic red cells (see Fig. 20.1 ). This finding requires careful inspection of erythrocyte morphology and is best done with a phase-contrast microscope. Clinical labs do not report the number of dysmorphic red cells present, in part because differentiating dysmorphic RBCs from simple crenated RBCs (a result of osmotic shrinkage of RBCs) takes an experienced eye. Keeping these caveats in mind, if an experienced clinician finds RBC casts or a significant number of dysmorphic RBCs in a patient with hematuria, subsequent testing can be focused on identifying potential glomerular causes of hematuria, avoiding unnecessary, costly, or potentially invasive imaging procedures.
An additional feature of urinalysi that may help guide to the source of the red cells include the presence of proteinuria. Gross hematuria from lower tract bleeding can result in urine positive for protein, particularly if any lysis of urinary red cells occurs, but usually is <2+ proteinuria by dipstick reading. Anything greater than 2+ proteinuria should raise suspicion of glomerular disease, especially if the hematuria is only microscopic . Bacteria and significant pyuria suggest pyelonephritis or cystitis, but pyuria can also be a feature of acute suppurative glomerulonephritis. Quantification of the gross hematuria using a “urocrit,” with a result >1% can indicate lower tract bleeding.
All patients with suspected glomerulonephritis or suspected chronic kidney disease should have prompt assessment of their renal function with a serum creatinine, and a complete blood count. Serologic studies for immune-mediated glomerulonephritis should be performed including complement levels (C3, C4), antinuclear antibody, and anti–double-stranded DNA antibody. Antineutrophil cytoplasmic antibody titers (ANCA) and anti–glomerular basement membrane antibody titers should also be obtained if vasculitis or pulmonary renal syndromes are suspected (see Table 20.2 and Fig. 20.1 ).
The diagnosis of most cases of postinfectious glomerulonephritis (GN) can be made clinically. The diagnosis of HSP is also made clinically, but skin biopsy of purpuric lesions demonstrating vasculitis with predominantly IgA deposits can be supportive evidence. A kidney biopsy is often needed to define other forms of glomerulonephritis, especially primary, idiopathic glomerulopathies. In addition, even if the diagnosis of vasculitis is made on clinical and serologic criteria, staging of the severity of renal disease with renal pathology, such as in SLE, HSP, or ANCA-positive disease, is important for guiding therapy. High levels of proteinuria are often an indication to obtain a kidney biopsy to provide a diagnosis or stage the severity of the lesion in several forms of glomerulonephritis. The degree of proteinuria can be assessed with a 24-hour urine collection, or with a spot urine protein : creatinine ratio (see Chapter 19 ).
A urine culture is indicated in patients with any bladder symptoms, fever, flank pain, or abdominal pain. Gross hematuria can also be seen with nonbacterial infections such as tuberculosis, adenovirus, or schistosomiasis. In immunocompromised patients, BK polyoma virus can cause prominent cystitis.
Idiopathic hypercalciuria can be a cause of gross hematuria. It is characterized by excessive urinary calcium excretion in the absence of hypercalcemia or other known causes of hypercalciuria ( Table 20.4 ). The hematuria is thought to be secondary to calcium oxalate and phosphate crystals adhering to urothelium. The risk of developing kidney stones is not known. Although often asymptomatic, hypercalciuria is also implicated in causing urinary symptoms including abdominal and flank pain. Therefore, in a patient who has any such symptom concomitant with gross hematuria, especially if UTI and anatomic causes of hematuria are ruled out, urinary calcium should be measured.
