Hematuria is a frequent finding in healthy pediatric patients. Deciding what is pathologic and needs further investigation is the cornerstone of initial management. Generally, there can be up to 25,000 red blood cells (RBC) per hour filtered by the glomerulus. This can result in between 2-4 RBC’s per high powered field (HPF) on microscopic exam. Although there no true consensus on what the normal RBC excretion rate is, more than 5 RBC’s/HPF on a centrifuged urine sample is typically considered abnormal (1). A diagnosis of microscopic hematuria can be made after the persistence of RBC’s in the urine on 2-3 separate occasions over a period of at least 2-3 weeks. The overall prevalence of microscopic hematuria in school aged children is as high as 46% on a single screen. However this number drops to 0.5-1% on repeated screenings (2). Two pioneer studies performed several decades ago looked at the prevalence of microscopic hematuria in the pediatric population. Dodge et al., in1976, studied 12,000 Texas school aged children and found 78 (0.65%) of them to have asymptomatic hematuria that persisted on repeat sampling, none of whom had other laboratory evidence of renal disease (3). Shortly after, a Finnish study in 1979 looked at 8,900 school aged children. Twenty seven (0.3%) had hematuria that persisted >4 months but only 2 of those were found to have identifiable renal disease (4). More recently two studies out of Asia have found the prevalence of asymptomatic microscopic hematuria to be between 0.1 and 0.8% of school age children (5, 6). Therefore it can be postulated that most children with isolated asymptomatic microscopic hematuria do not have significant renal disease. Although the differential can be quite broad, a thorough investigation of associated signs and symptoms can help significantly in narrowing the possibilities. History and physical findings will frequently be enough additional information to discern the likely etiology of persistent hematuria. The initial evaluation of microscopic hematuria includes confirmation of persistence over several weeks on multiple urinalyses. Fever or vigorous exercise can result in transient microscopic hematuria, but this should resolve within a few days. Once persistence has been confirmed, a structured evaluation can follow. An initial complete history and physical are essential. Questioning regarding family history of renal disease, hematuria, hearing loss or stones should be elicited. Any dysuria, gross hematuria or systemic complaints should be elucidated (including rash, joint pain, pulmonary symptoms). Medication history should specifically include query into the use of NSAIDs and antibiotics. Physical exam includes special attention to the presence of edema or other systemic findings, including joints abnormalities. Blood pressure measurements are essential, using an appropriately sized cuff for the patient’s size. A review of growth patterns is warranted, especially for new patients. Laboratory evaluation ideally will include a urinalysis with microscopy performed by a laboratory. This should include a spot urine protein and urine creatinine, to assess any concurrent proteinuria, as well as a spot urine calcium, to evaluate for hypercalcuria. Both a spot protein/creatinine and a spot calcium/creatinine should normally be less than or equal to 0.2 (in children over 1year of age). The microscopy evaluation is vital, as there can be false positive urine dip sticks due to the presence of bacteria or oxidizing substances. It can also help discern if the positive dip is due to actual RBC’s or free hemoglobin (or other pigments, such as myoglobin) as well as the presence of cast structures. An initial evaluation should include a baseline set of chemistries to evaluate renal function. If there is any concern regarding hemolysis or significant bleeding a CBC is warranted. Additionally, complements, ANA, ANCA and an ASO may be added if indicated by the history and physical findings, or if there is evidence of glomerulonephritis (including tea colored urine, proteinuria or dysmorphic red cells). All complete evaluations should include renal imaging. A renal ultrasound is generally the modality of choice, unless there is a strong consideration of stones, which might indicate the need for a CT scan. The above approach to evaluation can be tailored to the circumstances of individual patients. One approach that can be helpful to the primary care physician is to classify patients into one of 4 categories. This can help guide initial work-up and determination of when a referral may be appropriate. The majority of patients can be classified as having gross hematuria, symptomatic microscopic hematuria (including non-renal specific symptoms), asymptomatic microscopic hematuria or asymptomatic microscopic hematuria with proteinuria. This approach has been purposed by Diven and Travis (7). It can assist the primary care physician in directing an appropriate work-up and specialty consultation. Below will be a brief description of the 4 categories and suggested evaluation. Gross Hematuria A relatively uncommon finding in the general pediatric population, reported as a prevalence of 0.13% in an urgent care walk-in clinic in 1977(8). In this group of patients, the gross hematuria is likely the presenting complaint. A through history and physical, to include family history of stones and elucidation of urinary complaints that might be consistent with urinary tract infection or kidney stones is warranted. Lab evaluation should consist of urinalysis and microscopy (for confirmation of RBC’s in the urine) as well as culture if any concern for infection. A spot urine calcium and creatinine should be obtained. Imaging should be considered, unless there is a strong suspicion for infection, at which point deferring until a trial of antibiotics is complete is reasonable. Laboratory evaluation to include CBC, chemistries and C3 should be obtained if infection is not suspected. Symptomatic Microscopic Hematuria Any child who is found to have microscopic hematuria and any other symptoms should be included in this category. Symptoms may be related to the urinary tract (dysuria, frequency, edema, hypertension) or systemic (fever, malaise, rash). These patients should have a symptom specific evaluation initiated and consultation with a specialist unless a clear cut diagnosis is identified. Asymptomatic Microscopic Hematuria As noted above, the finding of asymptomatic hematuria on a screening urinalysis is a frequent finding. Although many patients will have resolution of hematuria over several weeks, a few will have persistent hematuria. This can lead to an extensive evaluation that may yield few positive results. In general, in the absence of proteinuria and any other systemic findings, watchful waiting is an appropriate approach. A thorough history, including family history is warranted. A urine microscopy with spot calcium and creatinine is also indicated. If persistent, a renal ultrasound should be obtained. Laboratory evaluation could be done as a baseline screening, but deferring and relying on close follow-up with urinalysis every several months is an acceptable approach as well. Persistence for greater than 6 months or new development of proteinuria or additional physical findings does merit a referral and expanded evaluation. Asymptomatic Microscopic Hematuria with Proteinuria This group of patients is the most likely to have significant renal pathology. The finding of proteinuria in conjunction with hematuria does increase the likelihood that there is glomerular involvement. A quantification of the proteinuria with a spot urine protein/urine creatinine is necessary. Initiation of a fairly extensive evaluation is in order if there is persistence of this finding over several weeks. This would include a renal ultrasound and laboratory investigations including a CBC, chemistries, complements (C3, C4) and possible ANA and ANCA titers to evaluate for systemic diseases that may be involving the kidneys. Referral to a specialist in these instances is indicated, as further evaluation including a renal biopsy may be necessary. The finding of microscopic hematuria, persistent on multiple samples over the period of several weeks frequently warrants referral to a specialist. Generally, a Pediatric Nephrologist is the appropriate consultant. If the findings are indicative of an acute stone, with or without obstruction, discussion with a Pediatric Urologist may be appropriate as well. Although initiating the work-up can be very helpful in making an initial visit more satisfying for the family, referral should never be delayed while awaiting results, especially if there is concern regarding impaired renal function or progressive disease. Included below is a table, although not inclusive, of the etiologies of hematuria. Questions 1. What is the prevalence of hematuria in the pediatric population? a. 20% b. 1% c. 5% on initial evaluation, decreasing to <1% on subsequent evaluations d. 10% 2. What should be included in the initial evaluation of hematuria? a. Urine dip b. History & Physical c. Urinalysis with microscopy d. Blood work to assess renal function to include complements e. All of the above 3. When should a referral be made? a. After the first finding of hematuria b. After confirmation of hematuria on several samples several weeks apart c. After complete work up has been performed 4. The normal protein/creatinine ratio on a random spot urine sample is? a. 1.0 b. ≤ 0.2 c. 0.5 5. The majority of microscopic hematuria in the pediatric population is associated with progressive renal disease and eventual renal failure. a. True b. False Answers c, e, b, b, b References 1. Massengill, SF: Hematuria. Pediatr Rev, 29: 342-8, 2008. 2. Boineau, FG & Lewy, JE: Evaluation of hematuria in children and adolescents. Pediatr Rev, 11: 101-8, 1989. 3. Dodge, WF, West, EF, Smith, EH & Bruce, H, 3rd: Proteinuria and hematuria in schoolchildren: epidemiology and early natural history. J Pediatr, 88: 327-47, 1976. 4. Vehaskari, VM, Rapola, J, Koskimies, O, Savilahti, E, Vilska, J & Hallman, N: Microscopic hematuria in school children: epidemiology and clinicopathologic evaluation. J Pediatr, 95: 676-84, 1979. 5. Cho, BS & Kim, SD: School urinalysis screening in Korea. Nephrology (Carlton), 12 Suppl 3: S3-7, 2007. 6. Lin, CY, Hsieh, CC, Chen, WP, Yang, LY & Wang, HH: The underlying diseases and follow-up in Taiwanese children screened by urinalysis. Pediatr Nephrol, 16: 232-7, 2001. 7. Diven, SC & Travis, LB: A practical primary care approach to hematuria in children. Pediatr Nephrol, 14: 65-72, 2000. 8. Ingelfinger, JR, Davis, AE & Grupe, WE: Frequency and etiology of gross hematuria in a general pediatric setting. Pediatrics, 59: 557-61, 1977. Vascular Glomerular Interstitial Urinary Tract Hemoglobinopathies Etiologies of Hematuria Trauma Renal vein thrombosis/Renal artery thrombosis Malformations Nutcracker syndrome Acute post-infectious glomerulonephritis Henoch-Schönlein purpura IgA nephropathy Systemic Lupus Erythematosus Membranoproliferative glomerulonephritis Alport’s (hereditary nephritis) Focal Segmental Glomerulosclerosis Minimal Change Nephrotic Syndrome Membranous Hemolytic Uremic Syndrome ANCA disease Benign Familial Hematuria Pyelonephritis Nephrocalcinosis Interstitial nephritis Nephrotoxins Cystic Disease Tumor Acute tubular necrosis Infection Hemorrhagic cystitis Urethritis Nephrolithiasis Hypercalcuria Obstruction Tumor Sickle cell disease Hemophilia