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Home , Athletic incontinence, Glomerulopathy, Hematuria, Hemoglobinuria, Hyperoxaluria, Microhematuria

Urol Clin N Am 31 (2004) 559–573

Evaluation of in children Kevin E.C. Meyers, MBBCh Division of , Department of , Children’s Hospital of Philadelphia, University of Pennsylvania School of , 34th Street and Civic Center Boulevard, Main Building, 2nd Floor, Philadelphia, PA 19104-4399, USA

The detection of even microscopic amounts of Nine milliliters is decanted and the sediment in a child’s alarms the patient, is resuspended and an aliquot examined. The urine parents, and , and often prompts the is examined by microscopy by high power field performance of many laboratory studies. Hema- (hpf) that is 400 magnification. Macroscopic turia is one of the most important signs of renal or hematuria often does not require concentration. bladder disease, but is a more impor- Bright-red urine, visible clots, or crystals with tant diagnostic and prognostic finding, except in normal-looking red blood cells (RBCs) suggests the case of calculi or . Hematuria is from the urinary tract. Cola-colored almost never a cause of . The physician urine, RBC casts, and deformed (dysmorphic) should ensure that serious conditions are not RBCs suggest glomerular bleeding [4]. An absence overlooked, avoid unnecessary and often expen- of RBCs in the urine with a positive dipstick re- sive laboratory studies, reassure the family, and action suggests or . provide guidelines for additional studies if there is The sensitivity and specificity of the dipstick a change in the child’s course [1]. This article method for detecting blood in the urine vary. provides an approach to the evaluation and When tested on urine samples in which a prede- management of hematuria in a child [2,3]. Many termined amount of blood has been placed, dip- tests have been recommended for the child with sticks have a sensitivity of 100 and a specificity of hematuria, but no consensus exists on a stepwise 99 in detecting one to five RBCs/hpf [5]. This evaluation. Although more research is needed to corresponds to approximately 5 to 10 intact resolve certain controversies in management, the RBCs/lL urine [6]. There is no consensus on the suggested approach aims to detect major or definition of microscopic hematuria, although treatable problems and limit the anxiety, cost, more than 5 to 10 RBCs/hpf is considered and energy required by unnecessary testing. significant [7,8]. The author and others recom- mend that at least two of three urinalyses show over 2 to 3 weeks before further Definitions evaluation is performed [3,9]. The American Academy of Pediatrics recommends a screening Macroscopic hematuria is visible to the naked urinalysis at school entry (4–5 years of age) and eye, but microscopic hematuria usually is detected once during adolescence (11–21 years of age) as by a dipstick test during a routine examination. a component of well child–care. Hematuria is confirmed by microscopic examina- tion of the spun urine sediment. Microscopic examination is performed with concentration of Incidence and prevalence the urinary sediment by centrifugation. Ten milli- liters of urine is spun at 2000 rpm for 5 minutes. Pediatricians frequently encounter hematuria in children. Macroscopic hematuria has an esti- mated incidence of 1.3 per 1000 [2]. Microscopic E-mail address: [email protected] hematuria, although more common than gross

0094-0143/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ucl.2004.04.015 560 K.E.C. Meyers / Urol Clin N Am 31 (2004) 559–573 hematuria, has a variably reported incidence depending on the definition used for making the Box 1. Causes of hematuria in children diagnosis. The incidence of microscopic hematu- ria in schoolchildren was estimated at 0.41% Glomerular diseases when four urine samples per child were collected Recurrent gross hematuria (IgA and 0.32% in girls and 0.14% in boys when five nephropathy, benign familial consecutive urine specimens were analyzed over 5 hematuria, Alport’s syndrome) years [10,11]. Microscopic hematuria in two or poststreptococcal more urine samples is found in 1% to 2% of children 6 to 15 years of age. Membranoproliferative glomerulonephritis Systemic erythematosus Pathophysiology Membranous nephropathy Rapidly progressive Hematuria may originate from the glomeruli, glomerulonephritis renal tubules and interstitium, or urinary tract Henoch-Schonlein purpura (including collecting systems, , bladder, and Goodpasture’s disease ) (Boxes 1 and 2). In children, the source of bleeding is more often from glomeruli than from Interstitial and tubular the urinary tract. RBCs cross the glomerular Acute endothelial-epithelial barrier and enter the capil- Acute interstitial lary lumen through structural discontinuities in the capillary wall. These discontinuities seem to be at Hematologic (, the capillary wall–mesangial cell reflections [12].In von Willebrand’s most cases, proteinuria, RBC casts, and deformed disease, renal vein , (dysmorphic) RBCs in the urine accompany he- thrombocytopenia) maturia caused by any of the glomerulonephriti- Urinary tract des. The renal papillae are susceptible to necrotic Bacterial or viral (adenovirus) injury from microthrombi and anoxia in patients –related with a hemoglobinopathy or in those exposed to Nephrolithiasis and hypercalciuria toxins. Patients with renal parenchymal lesions Structural anomalies, congenital may have episodes of transient microscopic or anomalies, polycystic macroscopic hematuria during systemic disease or after moderate exercise. This may be the result Trauma of renal hemodynamic responses to exercise or Tumors fever by undetermined mechanisms. Exercise Medications (aminoglycosides, Initial evaluation amitryptiline, anticonvulsants, aspirin, chlorpromazine, coumadin, Macroscopic hematuria , , The evaluation of a child with gross hematuria , thorazine) differs from that of microscopic hematuria (Fig. 1). Macroscopic hematuria of glomerular origin usu- ally is described as brown, tea-colored, or cola- evaluate children with recurrent nonglomerular colored, whereas macroscopic hematuria from the macroscopic hematuria of undetermined origin lower urinary tract (bladder and urethra) is usually because may be warranted. pink or red. Macroscopic hematuria in the absence of significant proteinuria or RBC casts is an Microscopic hematuria indication for a renal and bladder ultrasound to exclude or cystic renal disease. Re- Microscopic hematuria, defined by more than ferral to a urologist is required when clinical five RBCs/hpf, almost always warrants referral to evaluation and workup indicates that there is a nephrologist rather than an urologist. Figs. 2 a tumor, a structural urogenital abnormality, or and 3 give an approach to the evaluation of an obstructing calculus. A urologist also should asymptomatic and symptomatic microscopic K.E.C. Meyers / Urol Clin N Am 31 (2004) 559–573 561

History Box 2. Causes of asymptomatic isolated microscopic hematuria A history of , frequency, urgency, or flank or abdominal pain suggests a diagnosis of Common or nephrolithiasis. Recent Undetermined trauma, strenuous exercise, menstruation, or blad- Benign familial der catheterization may account for transient Idiopathic hypercalciuria hematuria. A sore throat or skin infection within IgA nephropathy the past 2 to 4 weeks directs the evaluation toward or anemia postinfectious glomerulonephritis. and Transplant toxins may cause either hematuria or - uria (Box 5). A careful family history must include Less common questions about hematuria, hearing loss, hyper- Alport nephritis tension, nephrolithiasis, renal diseases, renal cystic Postinfectious glomerulonephritis diseases, hemophilia, sickle cell trait, and Trauma or transplant. Exercise Nephrolithiasis Physical examination Henoch-Schonlein purpura The presence or absence of or Uncommon proteinuria helps to decide how extensively to Drugs and toxins pursue the diagnostic evaluation. If the blood pressure is normal and the patient is passing Ureteropelvic junction obstruction normal amounts of urine, it is unlikely that Focal segmental microscopic hematuria, whatever its cause, war- Membranous glomerulonephritis rants immediate treatment. If the is Membranoproliferative elevated, the hematuria requires a more intensive glomerulonephritis diagnostic evaluation. The presence of fever or costovertebral angle tenderness may indicate a urinary tract infection. An abdominal mass may Pyelonephritis be caused by a tumor, hydronephrosis, multicystic Vascular malformation dysplastic kidney, or polycystic . Tuberculosis Macroscopic hematuria with proteinuria suggests Tumor glomerulonephritis. and arthritis can occur in Henoch-Schonlein purpura and systemic lupus erythematosus. is an important feature of (Adapted from Lieu TA, Grasmeder M, the (Table 1). Kaplan BS. An approach to the evaluation and treatment of microscopic hematuria. Laboratory studies Pediatr Clin North Am 1991;38:579–92.) Only two diagnostic tests are required for a child with microscopic hematuria: (1) a test for proteinuria and (2) a microscopic examination of hematuria. Most children with isolated micro- the urine for RBCs and RBC casts. Children with scopic hematuria do not have a treatable or serious macroscopic hematuria require urine culture and cause for hematuria and do not require an renal imaging by ultrasound. Proteinuria may be extensive evaluation. The presence of hematuria present regardless of the cause of bleeding, but must be confirmed by microscopy examination of usually does not exceed 2þ (100 mg/dL) if the only spun sediment of urine because other substances source of protein is from the blood. This is besides blood can produce red or brown urine or especially true if the child has microscope hema- give a false positive dipstick test for blood (Box 3). turia. Patients with 1þ to 2þ proteinuria should be Once a positive dipstick result has been con- evaluated for orthostatic (postural) proteinuria. A firmed by microscopic examination of spun sedi- patient with more than 2þ proteinuria should be ment of urine, it is advisable to redirect attention investigated for glomerulonephritis and nephrotic to more specific aspects of the history and physical syndrome. RBC casts, when present, are a highly examination (Box 4). specific marker for glomerulonephritis, but their 562 K.E.C. Meyers / Urol Clin N Am 31 (2004) 559–573

Macroscopic hematuria Check ,, Yes complement C3, , Symptoms and signs of a glomerulonephritis - anti-streptolysin titer, and edema/hypertension/proteinuria/RBC casts streptozyme No

Yes CT scan of abdomen/pelvis History of trauma Tests consistent with post infectious No glomerulonephritis No Yes Yes Urine culture Signs/Symptoms of UTI Renal ultrasound Refer to a Pediatric Supportive No Nephrologist

Yes Hypertension Renal ultrasound Family history of stones 24 hr urine collection Azotemia for metabolic stone profile No

Obstructing stone Renal ultrasound, Urine culture, Test parents for hematuria, Hemaglobin electophoresis, Urine calcium/creatine ratio Refer to a Urologist

Tumor, structural abnormality

Fig. 1. Evaluation of a child with macroscopic hematuria. absence does not rule out glomerular disease and concentration (acute poststreptococcal glomeru- their presence does not prove that glomerular lonephritis), and serum and injury has occurred. RBC casts should be searched concentrations (if there is renal insufficiency). All for diligently, however. Distorted, misshapen children with macroscopic hematuria require re- erythrocytes (dysmorphic) also suggest a glomeru- nal ultrasound upon presentation. Pending the lar origin for bleeding. results of these tests, the child’s blood pressure and urine output must be monitored frequently. If the cause of the hematuria remains unclear Indications for prompt evaluation after the results of the above tests have been The initial evaluation should be directed to- obtained, a 24-hour urine collection for protein, ward important and potentially life-threatening creatinine, and calcium should be obtained. Chil- causes of hematuria in any child who has any of dren with microhematuria and protein excretion of the following in addition to hematuria: hyperten- less than 25 mg/dL (6 mg/h/m2) usually do not have sion, edema , significant proteinuria (more a and can be considered to have than 500 mg per 24 hours), or RBC casts. These isolated microscopic hematuria. Some, however, causes include acute postinfectious glomerulone- may have IgA nephropathy, early or mild Alport’s phritis (PIGN), Henoch-Schonlien purpura syndrome, or thin basement membrane disease. (HSP), hemolytic-uremic syndrome, membrano- There is no specific treatment, however, for any of proliferative glomerulonephritis, IgA nephropa- these conditions. The causes of microscopic hema- thy, and focal segmental glomerulosclerosis. turia with substantial proteinuria include minimal This initial evaluation should include a com- change nephrotic syndrome, IgA nephropathy, plete blood count (hemolytic-uremic syndrome), Alport’s syndrome, membranoproliferative glo- throat culture, streptozyme panel and serum C3 merulonephritis, membranous nephropathy, and K.E.C. Meyers / Urol Clin N Am 31 (2004) 559–573 563

Isolated Microscopic Hematuria - Asymptomatic

Negative Repeat urinalysis weekly x Follow up urinalysis 2 (without exercise) with physical exam Persistent hematuria

Positive Benign Familial Test parents and Hematuria sibs for hematuria

No

Yes Check urine Family history of calcium/creatinine calculi ratio

No

Normal Consider hearing test, renal ultrasound, If no other concerning and hemaglobin electrophoresis depending symptoms/signs then follow on level of concern with yearly urinalysis

Fig. 2. Evaluation of a child with asymptomatic microscopic hematuria. focal segmental glomerulosclerosis. Additional in- are informative, the diagnosis is poststreptococcal vestigations are warranted in this context, some glomerulonephritis. If these tests are not informa- may require treatment, and referral to a pediatric tive, further investigations are warranted to rule nephrologist should be considered. out other causes of glomerulonephritis. IgA ne- phropathy can cause recurrent macroscopic he- maturia with flank or abdominal pain and may be Differential diagnosis and management preceded by an upper respiratory tract infection. of macrohematuria Fever, dysuria, and flank pain with or without Macroscopic hematuria requires prompt eval- voiding symptoms suggests a urinary tract in- uation to exclude potentially life-threatening fection, which is the most common cause of gross causes. A urinalysis must be performed to confirm hematuria in children presenting to an emergency the presence of RBCs and to look for casts and room. A CT scan of the abdomen and pelvis must crystals. Occasionally, Schistosoma hematobium is be obtained promptly with a history of abdominal diagnosed by finding ovae in the urine of an trauma and the child must be referred to a urolo- immigrant child with unexplained macroscopic gist. A family history of renal calculi or severe hematuria [16]. Painful gross hematuria usually is with gross hematuria suggests urinary caused by infections, calculi, or urologic condi- calculi. Hypercalciuria can cause recurrent mac- tions. Glomerular causes of hematuria are pain- roscopic or microscopic hematuria in the absence less. The most common glomerular causes of of calculi on imaging studies. If no obvious cause gross hematuria in children are poststreptococcal is found for macroscopic hematuria by history, glomerulonephritis and IgA nephropathy. physical, and preliminary studies, the differential A detailed history must be obtained to elicit diagnosis includes hypercalciuria, sickle cell trait, the cause of hematuria. An antecedent sore thin basement membrane disease, calculi, and throat, pyoderma, or impetigo proteinuria, edema, vascular or bladder . hypertension, or RBC casts suggests glomer- Cystoscopic examination in children rarely ulonephritis. If the antistreptolysin O titer, reveals a cause for hematuria but should be done streptozyme test, and serum C3 concentration when bladder pathology is a consideration. 564 K.E.C. Meyers / Urol Clin N Am 31 (2004) 559–573

Microscopic hematuria (MH) plus Family history or additional findings

Family history: Family history: No progressive renal disease Progressive renal disease Patient: Isolated microhematuria on urinalysis and /or Patient: Presence of casts or non-postural proteinuria Familial MH Negative Yes Urinary crystals Family Family history of stones member with MH No Isolated MH Normal Follow up Hearing test urinalysis Urine calcium/creatinine ratio Serum creatinine, C3, C4 No family history of MH, Family history of MH normal urine calcium/ creatinine Urine calcium/ creatinine ratio Abnormal results Normal urine calcium ratio > 0.21 on 2-3 samples /creatinine ratio

Refer to Pediatric Observe, repeat Observe, repeat urinalysis in 6- 24 hr urine calcium > Nephrologist/Consider renal Urinalysis in 6-12 12 months 4 mg/m2/day biopsy months Renal ultrasound

Familial MH Isolated MH Hypercalciuria

Fig. 3. Evaluation of a child with symptomatic microscopic hematuria.

Cystoscopy to lateralize the source of bleeding is that require intervention [17,18]. Transient hema- performed best during active bleeding. In young turia may be associated with strenuous exercise. girls with recurrent gross hematuria, it is impor- The type of activity, as well as activity duration tant to inquire about a history of child abuse or and intensity, contributes to its development insertion of a vaginal foreign body; the genital [19,20]. If the hematuria disappears with rest, no area must be examined for signs of injury. further investigation is needed.

Differential diagnosis of transient Differential diagnosis of persistent microhematuria microhematuria Blunt may cause either The precise frequencies of occurrence of the microscopic or gross hematuria. Hematuria after causes of persistent microscopic hematuria have minor blunt abdominal trauma may serve as not been established. Most series have included a marker for congenital anomalies. In a study of patients with macroscopic and microscopic hema- suspected isolated renal trauma, 11 of 78 children turia as well as patients with and without pro- had congenital anomalies, but only two required teinuria. In a study of 33 children with persistent later surgical intervention [17]. A diagnostic study microscopic hematuria, 27 did not have protein- should be done only if there are at least 50 RBCs/ uria. Two of these had ureteropelvic junction hpf, however. Although intravenous urography obstruction, and renal biopsies were done in 21 traditionally has been the study of choice for of the remaining 25 patients, two of which had suspected, isolated, blunt renal trauma, renal IgA nephropathy, one had hereditary nephritis, ultrasonography may be adequate if there are no eight had normal renal biopsies, and 10 had other indications for immediate surgical interven- nonspecific abnormalities [21]. tion. Children with less than 50 RBCs/hpf are The author retrospectively studied 325 children unlikely to have injuries or congenital anomalies with isolated persistent microscopic hematuria K.E.C. Meyers / Urol Clin N Am 31 (2004) 559–573 565

Box 3. Urine color Box 4. Specific history and physical examination in a patient with hematuria Dark yellow or orange Normal concentrated urine History Rifampin pyridium Trauma (recent bladder catheterization, blunt abdominal trauma) Dark brown or black Exercise Methemoglobinemia Menstruation Bile pigments Recent sore throat, skin infection Homogentesic acid, thymol, melanin, Viral illness tyrosinosis, alkaptonuria Dysuria, frequency, urgency, Alanine, cascara, resorcinol Urine color; stream discolored at Red or pink urine initiation, throughout, or at RBCs, free hemoglobin, , termination of micturition porphyrins Abdominal pain, costovertebral angle Benzene, chloroquine, pain, suprapubic pain desferoxamine, , Medications (eg, cyclophosphamide), phenolphthalein environmental toxins, or herbal Beets, blackberries, red dyes in food compounds Urates Passage of a calculus Joint or muscle pain Family history referred to the pediatric nephrology outpatient Hematuria clinics at the Children’s Hospitals of Buffalo and Deafness Philadelphia between 1985 and 1994. Hypercal- Hypertension ciuria was present in 11%. Coagulopathy and voiding cystourography (VCUG) was per- Hemoglobinopathy formed in 87% and 24% of children. There were Calculi no clinically significant findings. Primary physi- Renal failure, dialysis, or transplant cians or urologists ordered 75% of the VCUG Physical examination before referral to a nephrologist [22]. In another Fever, arthritis, study, 2 of 15 patients with persistent microscopic Blood pressure hematuria progressed to end-stage renal failure Edema (one with Alport’s syndrome after 14 years and Nephromegaly one with focal segmental glomerulonephritis after Costovertebral angle tenderness 10 years), but it is not clear when in their courses these patients developed proteinuria. This study supports the author’s minimalist approach to (Adapted from Lieu TA, Grasmeder M, children with isolated persistent microscopic he- Kaplan BS. An approach to the evaluation maturia (see Fig. 2). Because the most common and treatment of microscopic hematuria. diagnoses in children with persistent microscopic Pediatr Clin North Am 1991;38:579–92.) hematuria without proteinuria are benign persis- tent or benign familial hematuria, idiopathic hypercalciuria, IgA nephropathy, and Alport’s syndrome, a more extensive evaluation is indicated there are no life-threatening conditions, that there only when proteinuria or other indicators are is time to plan a stepwise evaluation, and that most present (see Fig. 3). causes of isolated microscopic hematuria in chil- dren do not warrant treatment. In the author’s experience, parents have two main concerns when they learn that their child has microscopic hema- Management of microhematuria turia: (1) will chronic kidney damage occur, and When there are no indications for immediate (2) does my child have (or leukemia)? intervention, the parents should be reassured that Addressing these fears allays concerns and expen- 566 K.E.C. Meyers / Urol Clin N Am 31 (2004) 559–573

In the author’s view, intravenous urography is Box 5. Drugs and toxins associated with of little value in the evaluation of persistent urine dipsticks positive for blood microscopic hematuria because renal ultrasonog- raphy is as reliable as intravenous urography for Hemoglobinuria excluding macroscopic lesions. If the serum cre- Carbon monoxide atinine concentration and blood pressure are Mushrooms normal, it is reasonable to defer further inves- Naphthalene tigations in an asymptomatic child with persistent Sulfonamides microscopic hematuria who does not have hyper- Tin compounds tension, proteinuria, or RBC casts. The author Lead suggests a follow-up examination at least every Methicillin 12 months that includes microscopic urinalysis, a Phenol dipstick test for proteinuria, and blood pressure Sulfonamides measurement. Turpentine In a study of 142 children with microscopic Ticlodipine [14] hematuria on two initial urine samples who had two Hematuria subsequent urinalyses performed in the subsequent Amitriptylene 4 to 6 months, 33 (23%) had persistent hematuria on both follow-up specimens [21]. The parents’ Aspirin urine should be tested with dipsticks [23,24]. Chlorpromazine Although phase-contrast microscopy and size-par- Cyclophosphamide ticle discrimination can distinguish glomerular Toluene [13] from nonglomerular sources of hematuria, identi- Ritonavir, indinavir [15] fication of dysmorphic RBC offers little additional information in the evaluation of microscopic he- maturia in children. A thoughtful history and (Adapted from Lieu TA, Grasmeder M, physical examination with microscopic urinalysis Kaplan BS. An approach to the evaluation and dipstick for proteinuria provide equal diag- and treatment of microscopic hematuria. nostic information. The author cannot recommend Pediatr Clin North Am 1991;38:579–92.) its routine use in the evaluation of microscopic hematuria in children [25,26]. Many other tests may be considered in the sive investigations. The plans for further testing asymptomatic child with persistent microscopic and follow-up should be stated clearly from the hematuria, but the cost and time required for outset. The dipstick and microscopic urinalysis further testing must be weighed against the poten- should be repeated twice within 2 weeks after the tial benefits, which are subjective and depend on initial specimen. If the hematuria resolves, no how much importance the parents and physician further tests are needed. If hematuria persists, with place on establishing a more definite diagnosis and more than five RBCs/hpf and no evidence of prognosis. These considerations apply especially to hypertension, oliguria, or proteinuria on at least the advisability of performing a kidney biopsy on two of three consecutive samples, determination of a patient with isolated microhematuria. Piqueras the serum creatinine concentration is reasonable. and colleagues [27] reviewed the clinical and renal Renal ultrasonography should be considered as biopsy findings in 322 children in whom non- a screening test because it is noninvasive and glomerular causes of hematuria were excluded. provides tangible information on the presence or Isolated microscopic hematuria was present in 155 absence of stones, tumors, hydronephrosis, struc- children, 100 of whom had a thin basement tural anomalies, renal parenchymal dysplasia, membrane (TBM) or Alport’s syndrome, 12 (7%) medical renal disease, inflammation of the bladder, had IgA nephropathy, and 43 (28%) had normal bladder polyps, and posterior urethral valves. The or clinically insignificant glomerular findings. No yield of renal ultrasonography for evaluation of an child required therapy, but the argument was made asymptomatic child with microscopic hematuria that a precise diagnosis is required for prognosis, remains unproven [22]. The value of a normal renal insurance purposes, and genetic counseling. In the ultrasonographic examination in terms of reassur- author’s opinion, should be deferred ance, however, may justify its cost and time. for this reason unless a specific indication exists. K.E.C. Meyers / Urol Clin N Am 31 (2004) 559–573 567

Table 1 Distinguishing features of glomerular and nonglomerular hematuria Feature Glomerular hematuria Nonglomerular hematuria History Burning on micturition No Urethritis, cystitis Systemic complaints Edema, fever, pharyngitis, Fever with urinary tract infections rash, arthralgias severe pain with calculi Family history Deafness in Alport’s Usually negative; may be positive with calculi syndrome, renal failure Physical examination Hypertension Often present Unlikely Edema May be present No Abdominal mass No Important with Wilms’ tumor, polycystic kidneys Rash, arthritis Lupus erythematosus, No Henoch-Schonlein Urine analysis Color Brown, tea, cola Bright red Proteinuria Often present No Dysmorphic red blood cells Yes No casts Yes No Crystals No May be informative

Isolated microscopic hematuria in the absence of infection with Group A beta-hemolytic strepto- a family history of hematuria in a close relative and cocci. episodes of macroscopic hematuria is unlikely to Clinical features of the nephritis manifest 7 to 21 be associated with abnormal renal biopsy findings. days after the preceding infection. Antistreptolysin The main exceptions are IgA nephropathy and O titers may be negative early in the course, but the TBM nephropathy, but there are no specific treat- ments for these conditions. Box 6. A suggested approach for referral of a child with hematuria Specific conditions Nephrologist This section focuses on the more common Acute poststreptococcal causes of hematuria in children and is organized glomerulonephritis if the patient according to the anatomic location for the bleed- has hypertension, azotemia, or ing. Box 6 outlines a suggested approach for hyperkalemia referral of a child with hematuria. Other forms of glomerulonephritis (particularly if the patient has Glomerular causes of hematuria proteinuria, hypertension, or persistent hypocomplementemia) Postinfectious glomerulonephritis Family history of renal failure Patients with acute PIGN often present with Systemic disease acute onset of tea-colored urine (macroscopic hematuria) consistent with glomerular bleeding, Urologist but the hematuria occasionally may be only Reassurance microscopic [28]. Patients with PIGN may be Abnormal genitourinary anatomy asymptomatic or they may complain of malaise, Trauma headache, nausea, vomiting, abdominal pain, and Stones (nephrologist for metabolic oliguria. The physical examination may reveal work-up) edema and an elevated blood pressure that can be Tumor severe enough to cause encephalopathy. PIGN is Nonglomerular gross hematuria accredited most commonly to pharyngitis or skin 568 K.E.C. Meyers / Urol Clin N Am 31 (2004) 559–573 streptozyme test is often positive within 10 days of come in IgA nephropathy [36]. The prognosis of the onset of symptoms [29]. Almost all patients have IgA nephropathy varies, and up to one third of decreased levels of C3 early in the clinical course that children have a guarded long-term renal prognosis normalize 6 to 8 weeks later. The C4 concentration is [37]. There is no specific treatment for IgA usually normal or only slightly decreased. If the C3 nephropathy and no evidence supports the need is persistently low, the patient should be further to make a definitive diagnosis in a child whose investigated for other causes of a persistent hypocom- only manifestation is microscopic hematuria. The plementemic glomerulonephritis, including membra- author disagrees with Schena’s [38] and Piqueras’s noproliferative glomerulonephritis, systemic lupus [39] recommendation that a renal biopsy should erythematosus, and chronic bacteremia. Urinalysis be done in patients with microscopic hematuria typically reveals RBC casts and proteinuria. Blood and suspected IgA nephropathy to confirm the and creatinine can be normal or diagnosis and to increase awareness of the prog- elevated. In most patients hematuria and proteinuria nosis of patients with IgA nephropathy in the resolves within a few weeks. Microscopic hematuria Western world. In a few patients, IgA nephropa- maypersistforaslongas2years.Theprognosisis thy may be inherited, and has been localized to excellent. There are no data that indicate an untoward 6q22-23 [40,41]. outcome of PIGN in a patient whose only manifestation was microscopic hematuria. Rapidly progressive glomerulonephritis Rapidly progressive glomerulonephritis presents Henoch-Schonlein purpura with symptoms and signs similar to PIGN, and Approximately half of children with a clinical although uncommon, requires the urgent atten- diagnosis of HSP manifest renal involvement [30]. tion of a pediatric nephrologist. Laboratory Renal manifestations include hematuria, protein- studies show acute renal failure, and renal biopsy uria, nephrotic syndrome, glomerulonephritis, and demonstrates glomerular crescents. Untreated acute renal failure. Hematuria and proteinuria are RPGN can result in end-stage renal disease usually transient but may persist for several (ESRD) in a few weeks. Many of the causes of months. Relapses and remissions are seen during glomerulonephritis listed in Fig. 1 can present the course of the disease and may manifest with with rapid progression, or RPGN can be idio- episodes of gross hematuria. The long-term prog- pathic [42]. Prompt diagnosis and pulsed methyl- nosis of HSP directly depends on the severity of prednisolone therapy may prevent progression to renal involvement. In an unselected population of ESRD [43]. children with HSP, an estimated 2% develop long- term renal impairment [31]. This figure is consider- Alport hereditary nephritis ably higher in specialized pediatric centers [32]. All Alport’s syndrome is a progressive, inherited patients with HSP who have renal involvement glomerulonephritis accounting for 1% to 2% of should be referred to a pediatric nephrologist. patients who develop ESRD, with an estimated gene frequency of approximately 1 in 5000 [44]. IgA nephropathy Alport’s syndrome is characterized by episodes of IgA nephropathy is probably the most common recurrent or persistent microscopic hematuria, cause of hematuria in children [33]. The condition occasionally gross hematuria, proteinuria, pro- is diagnosed by histopathologic demonstration of gressive renal insufficiency, and progressive, mesangial deposition of IgA. IgA nephropathy high-frequency, sensorineural hearing loss. The usually is detected after periods of gross hematuria phenotype and the course vary widely. Ocular that follow minor infections [34]. Microscopic defects include anterior lenticonus and yellow- hematuria may be present between episodes of white to silver flecks within the macular and gross hematuria. In a school-screening program in midperipheral regions of the retina [45]. Hematu- Japan, dipstick urinalysis detects most children ria that is usually microscopic is the usual initial with microscopic hematuria who have IgA ne- finding in children. In the absence of RBC casts or phropathy on renal biopsy [35]. Predictors of proteinuria, the diagnosis may be delayed or a poorer outcome include crescentic glomerulone- unsuspected, but this does not have serious phritis and an older age of onset, hypertension, consequences for the child unless there are hearing and nephrotic range proteinuria. There is also problems. evidence suggesting that recurrent bouts of mac- A careful family history and urine examina- roscopic hematuria predict a more guarded out- tions must be obtained in every patient who K.E.C. Meyers / Urol Clin N Am 31 (2004) 559–573 569 presents with microscopic hematuria. If there is any reason to suspect familial renal disease, Nephrocalcinosis implies an increase in calcium a hearing test should be done to prevent speech content in the kidney and is distinct from urolith- or educational handicap. Men manifest signs and iasis, although the two conditions often coexist. symptoms earlier than women, and approximately Nephrocalcinosis may be focal, occurring in an 30% can progress to ESRD. Patients who receive area of previously damaged parenchyma, or a renal allograft have a small risk for developing generalized. It is often associated with hyper- Goodpasture disease posttransplant [46]. Some calciuria. The most frequent cause of nephrocalci- women may have a hearing deficit without any nosis is prematurity with and without urinary abnormalities. Alport’s syndrome is a treatment [52]. Nephrocalcinosis associated with genetically heterogeneous disease, usually is in- involves the cortex and medulla, herited as an X-linked semidominant trait, caused whereas the corticomedullary junction is involved by mutations in COL4A5 gene on the X-chromo- most often with metabolic disease. The clinical some, and in less than 10% of cases is caused by manifestations of nephrocalcinosis include ab- mutations of the COL4A3 or the COL4A4 gene dominal pain, dysuria, incontinence, and urinary on chromosome 2q. tract infection in more than one third of patients. Microscopic hematuria usually occurs in the context of hypercalciuria or coexistant renal stone Thin glomerular basement membrane nephropathy disease [53]. The diagnosis of nephrocalcinosis Thin basement membrane nephropathy usually is made by renal ultrasonography [54]. (TBMN) or benign familial hematuria is the most The offending agent (loop , excess vitamin common cause of persistent glomerular bleeding in D) must be withdrawn if possible, and any children and occurs in at least 1% of the popula- underlying disorder (distal ) tion [47]. Benign familial hematuria may be must be treated. Nephrocalcinosis rarely pro- inherited in an autosomal dominant or autosomal gresses to end stage renal failure. recessive manner, and may be associated with Interstitial nephritis mutations in type IV collagen [48,49]. Proteinuria, Interstitial nephritis in children with associated progressive renal insufficiency, hearing deficits, or microscopic or macroscopic hematuria is uncom- ophthalmologic abnormalities almost never occur mon. Analgesics and are implicated in patients with TBMN or their family members most frequently with resolution occurring after [50]. The hematuria is usually microscopic, the discontinuation of the offending medication RBCs may be dysmorphic, and there may be RBC [55,56]. casts. Occasionally, frank hematuria may occur with an upper respiratory tract infection. The Cystic renal disease histopathologic changes are thinning of glomeru- Cysts often are discovered incidentally after lar basement membranes. A renal biopsy is war- mild trauma or when abdominal ultrasound is ranted in TBMN only if there are atypical features, performed for other indications [57]. Cysts may be or if IgA disease or X-linked Alport’s syndrome solitary, associated with dysplasia, or associated cannot be excluded clinically [47]. with polycystic renal disease. Patients with cystic renal disease or with a family history of cystic disease should be referred to a pediatric nephrol- Renal parenchymal cauises of hematuria ogist. Bleeding associated with cystic disease may be considerable and may require immediate neph- Tumors rologic or urologic evaluation. Children with Wilms’ tumor most commonly present with flank mass or macroscopic hematu- Hypercalciuria ria. Although a tumor is listed frequently in the An association between hematuria and hyper- differential diagnosis of hematuria, neither the calciuria was first noted in 1981 in children with author’s search of the literature nor the author’s asymptomatic macroscopic or microscopic hema- experience has produced documented cases of turia without signs of renal stones [58,59]. These tumors presenting with isolated microscopic he- children had increased urinary excretion calcium maturia. Bladder tumors usually manifest with despite normal serum calcium levels. Some were voiding difficulties or occasionally with macro- otherwise asymptomatic, but others eventually scopic hematuria [51]. developed urolithiasis. Because of this, the 570 K.E.C. Meyers / Urol Clin N Am 31 (2004) 559–573 measurement of urinary calcium excretion has look for recurrent or de novo glomerulonephritis become a standard part of the evaluation of with onset of hematuria if proteinuria or de- hematuria in children. terioration of renal function is seen. Many conditions can result in hypercalciuria, including hyperparathyroidism, immobilization, Urinary tract and vascular infection intoxication, and idiopathic hyper- In children the most common cause of hema- calciuria. (See later discussion and recent reviews turia is urinary tract infection. (Please see the of idiopathic hypercalciuria [60,61].) article by Shortliffe elsewhere in this issue for Idiopathic hypercalciuria may result from further exploration of urinary infection.) a tubular leak of calcium (renal hypercalciuria) or from increased gastrointestinal absorption of Trauma calcium (absorptive hypercalciuria). The mecha- Pelvic fractures and abdominal/chest injuries nism whereby hypercalciuria causes hematuria is help identify patients who require evaluation of unclear. It has been assumed either that hematuria the genitourinary tract. The need for genitouri- is the result of irritation of the uroepithelium by nary tract evaluation in pediatric trauma patients microcalculi or that microscopic areas of neph- is based as much on clinical judgment as on the rocalcinosis cause bleeding. Urine erythrocytes presence of hematuria [64]. Children with micro- are shaped normally and RBC cast are absent. scopic hematuria of greater than 50 RBC/hpf or There is often a family history of renal stones, and macroscopic hematuria, even in the presence of some authors recommend evaluation of parents a benign abdominal examination, should undergo and siblings for hypercalciuria. In contrast to imaging with an abdominal CT scan [18]. Signif- benign, idiopathic hematuria, macroscopic bleed- icant renal injuries are unlikely in pediatric ing and occasional blood clots may be seen in patients with blunt renal trauma but no gross or patients with hypercalciuria. Symptoms may in- less than 50 RBC/hpf microscopic hematuria [18]. clude dysuria, suprapubic pain, or renal colic. The Most children with renal injury are managed author does not restrict calcium in children conservatively [65]. When blood is present at the because osteopenia may result, and reserves ther- urethral meatus, cystourethrography is required apy with thiazide diuretics (to enhance calcium to look for urethral or bladder injury [66]. reclamation from the glomerular filtrate) for patients with recurrent episodes of macroscopic Hemangiomas and polyps hematuria or a family history of urolithiasis, or Hemangiomas in the urinary tract may cause those who develop a stone [62]. hematuria, but these are often impossible to locate and are only clinically significant if there is gross Renal transplant bleeding; therefore, hemangiomas require diag- Children with renal transplants are at risk for nostic testing and treatment only if they manifest developing urolithiasis, the only manifestation of with macroscopic hematuria [67]. The most com- which may be hematuria [63]. Review of 21 patients mon presenting symptoms of urinary tract polyps showed that one third had persistent microscopic are hematuria and urinary tract obstruction. hematuria. Patients with and without hematuria Transurethral resection is curative [68]. had similar baseline characteristics. The etiology of hematuria was pre-existing (one patient), re- Loin pain hematuria syndrome current IgA nephropathy (one patient), cytomeg- Loin pain hematuria syndrome (LPHS) was alovirus nephritis (one patient), and unexplained first reported in 1967 by Little and colleagues [69] (four patients). None had renal calculi or hyper- and refers to episodes of unilateral or bilateral calciuria. Three of the four patients with un- lumbar pain accompanied by macroscopic or explained hematuria have chronic allograft microscopic hematuria. The diagnosis is made by nephropathy, and the fourth (original disease exclusion after patients are shown to have normal dysplasia) had hypocomplementemia. Five years renal function, normal genitourinary system, no after onset of hematuria, all patients are alive with infection, no malignancy, no hypercalciuria or stable allograft function. Causes of posttransplant nephrolithiasis, and no previous trauma. Most hematuria, although diverse, are stone disease in patients are women between 20 and 40 years of less than 2% of patients. Whether chronic allo- age, but there are reports of LPHS in children graft nephropathy causes hematuria remains to be [70,71]. The pathogenesis of LPHS is unresolved; determined. Renal biopsies should performed to although a vascular cause seems most likely, renal K.E.C. Meyers / Urol Clin N Am 31 (2004) 559–573 571 biopsy is not helpful [72]. The symptoms of LPHS ology and clinicopathologic evaluation. J Pediatr are similar to those found in parents of children 1979;95:676–84. with Munchhausen syndrome by proxy (MSBP). [11] Dodge WF, West EF, Smith EH, et al. 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