Urinalysis is usually a two-step process: the urine dipstick test is followed, if warranted, by using microscopy to examine the spun sediment from the specimen. Urine specimens are sent to diagnostic laboratories for analysis because microscopes are now rarely used by practitioners. This may result in lysis of cells and imprecision in reporting of casts; the practitioner may not know whether red blood cell casts are present because the type of cast is rarely commented on.
The urine dipstick can be done easily and rapidly by office pediatricians, and it is subject to few problems, provided the instructions are followed. In 2007, the American Academy of Pediatrics (AAP) recommended that routine urine screening should be discontinued.1 This guideline may be modified in the future to include selective screening of children with risk factors for renal disease.2 One reason for this is that although urine dipstick testing is inexpensive, it is a poor screening test for chronic kidney disease and is not a cost-effective procedure for primary care providers.3
Indications for Urinalysis
There are some situations when urinalysis is warranted in a primary care office.
If a patient presents with blood in the urine, an in-office test can be used to confirm the presence of red blood cells on a microscopic analysis and to look for proteinuria, bacteria (nitrite), and white blood cells.
Periorbital and Pedal Edema
Because the presence of proteinuria with edema indicates renal disease, it is important to check a urine analysis in a child with periorbital edema even if there are symptoms suggestive of allergic disease such as rhinorrhea or cough. Nephrotic syndrome presents in childhood with edema and proteinuria and is often not detected at initial evaluation when periorbital edema is attributed to environmental allergies.
Urinary Frequency, Dysuria, Secondary Nocturnal Enuresis
These symptoms may indicate a urinary tract infection (UTI) or urinary stone disease, and they are indications for further evaluation. UTIs are easily detected by dipstick analysis. In children who are not toilet-trained and who present with a fever without a focus, it is advisable to look for a urinary tract infection.
Polyuria and Polydipsia
For patients presenting with elevated thirst, in-office urinalysis is useful to check for low urine specific gravity, as this may be seen in certain renal disorders with urinary concentrating defects or diabetes insipidus.
Suspected Renal Diseases
If a patient presents with persistently elevated blood pressure or has a family history of chronic kidney disease, a urinalysis should be performed to detect acquired or inherited renal disease, such as Alport syndrome.
Indications of Hematuria
Macroscopic hematuria is visible to the naked eye, whereas microscopic hematuria is detected by a dipstick test and is confirmed by microscopic examination of the spun urine sediment. The detection of microscopic amounts of blood in the urine of a well child is of concern. This discovery often results in many unwarranted laboratory studies. The physician must ensure that serious conditions are not overlooked, while avoiding unnecessary and expensive laboratory studies. The physician must be able to reassure the family and provide guidelines for additional studies if there is a change in the child’s course.
Macroscopic hematuria is an important sign of renal or lower urinary tract disease. The hematuria of glomerulonephritis is usually tea- or cola-colored and painless. Bright red, painful hematuria usually occurs in urinary tract infections, especially viral cystitis, and with passage of a calculus. Bright red, painless, macroscopic hematuria without significant proteinuria and/or red blood cell casts must be evaluated as soon as possible by renal and bladder ultrasound examination to exclude a malignancy.
Evaluation of Gross Hematuria
The incidence of gross hematuria in children presenting to an emergency department is 1.3 per 1,000.4 The presence of hematuria must be confirmed by microscopy examination of spun sediment of urine because other substances besides blood can produce red or brown urine or give a false-positive dipstick test for blood. Normal concentrated urine is dark yellow. Dark brown or black urine may be caused by bile pigments and, rarely, by homogentesic acid, thymol, melanin, tyrosinosis, methemoglobinemia, alkaptonuria, alanine, cascara, or resorcinol. Red- or pink-colored urine is usually caused by red blood cells, less often by free hemoglobin, myoglobin, beets, blackberries, rifampin, red food dyes, or urates, and rarely by porphyrins, benzene, chloroquine, desferoxamine, phenazopyridine, or phenolphthalein.
Presence of proteinuria, red blood cell casts, and deformed red blood cells in the urine indicates glomerular hematuria. Differentiating between glomerular and nonglomerular causes of macroscopic hematuria limits the diagnostic possibilities and permits focused investigations. This is done with a careful history, physical examination, and urinalysis (see Table 1). The differential diagnosis of gross hematuria is outlined in Table 2.
Table 1: Distinguishing Glomerular from Nonglomerular Hematuria
Table 2: Causes of Isolated Asymptomatic Hematuria
Evaluation of Glomerulonephritis
Indications for prompt evaluation are any of the following: hypertension, edema, oliguria, significant proteinuria (more than 500 mg per 24 hours), or red blood cell casts. Evaluation includes complete blood count, throat culture, group A streptococcal antibody test such as anti-streptolysin O or anti-deoxyribonuclease B panel, serum C3 concentration, and serum creatinine and electrolyte concentrations. While awaiting the results of these tests, the blood pressure and urine output must be monitored at frequent intervals.
Acute post-streptococcal glomerulonephritis (APSGN) is the most common glomerulonephritis seen in children who present with gross hematuria. It is preceded by a pharyngitis or skin infection 4 to 6 weeks prior to the onset of hematuria; however, even in the absence of this history, APSGN should be suspected because of prevalence of subclinical streptococcal infections. Management of APSGN includes fluid restriction, sodium restriction, and diuretic therapy if there is evidence of fluid overload in the form of hypertension or edema. Gross hematuria associated with pain, dysuria, or with bright red urine should prompt evaluation for nonglomerular causes of hematuria. A renal ultrasound should be obtained to look for a mass, stones, or polycystic kidneys.
Gross hematuria is an important presenting sign of Wilms’ tumor, and von Willebrand’s disease may be an overlooked cause of gross hematuria. Urinary tract arteriovenous malformations and hemangiomas rarely cause episodic macroscopic hematuria and are difficult to diagnose even with cystoscopy and renal angiography. Urethrorrhagia is a cause of painless terminal hematuria in prepubertal and pubertal boys and presents with bright red blood at the tip of the penis or in the underwear. Exercise can cause macroscopic hematuria but should be diagnosed after exclusion of pathological causes.
Evaluation of Microscopic Hematuria
The incidence of microscopic hematuria in children aged 6 to 15 years is 1% to 2%.5 Microscopic hematuria is defined as > 5 red blood cells (RBCs) per high-power field (HPF). Most children with isolated microhematuria do not have a treatable or serious cause for hematuria and do not require an extensive evaluation. If referral is required for microscopic hematuria, it should be to a nephrologist rather than a urologist.
Significant microscopic hematuria is diagnosed when at least three urine analyses are positive for > 5 RBCs/HPF over a 2- to 3-week period. False-positive results occur in the presence of oxidizing agents such as household bleach used to clean urine collection containers. False-negative results occur in samples with high specific gravity or with high ascorbic acid concentrations. Urine that is positive for blood on a dipstick should always be examined microscopically to provide information on the number of red blood cells and to detect other cells, casts, crystals, and bacteria. Table 3 lists common causes of isolated asymptomatic microhematuria.
Table 3: Normal Urinary Protein Excretion
In isolated microhematuria, the urinalysis should be repeated two to three times over several months without preceding exercise before embarking on further investigations. If the microhematuria persists, a careful history should be obtained for use of medications, family history of hematuria, deafness, renal failure, urinary calculi; history of sickle cell disease or trait; and the parents’ urines should be examined for hematuria. If all the inquiries and the examination are negative, the parents should be reassured and further investigations such as renal ultrasound and cystoscopy should be avoided. The child can be re-evaluated annually by urine analysis and further evaluation can be performed if there is a change in the clinical course of the child.
Children with microhematuria and any abnormal finding on history, physical examination, or urine analysis should be investigated for kidney disease. Clues for intrinsic renal disease include edema, hypertension, decreased urine output, rashes, arthralgias, constitutional symptoms, loss of appetite, and weight loss. Patients with any of these signs or symptoms should be tested with a basic metabolic panel, C3 complement levels, and complete blood count. Additional tests are based on clinical suspicions and include antistreptolysin O (ASO) titer, anti-nuclear antibody/DNA binding antibody, anti-neutrophil cytoplasmic antibodies (ANCA), and tests for hepatitis. A child with hematuria and proteinuria without edema or hypertension should have repeated urine analysis if the proteinuria is mild (ie, < 2+ on the dipstick).
If the abnormal urinary findings persist, the above investigations should be done even in the absence of edema or hypertension. Persistent proteinuria should be quantified, and if the excretion is greater than 1 g/day the patient should be referred to a pediatric nephrologist for further evaluation that may include a renal biopsy. Our approach to evaluation of asymptomatic isolated microhematuria is outlined in Figure 1.
Figure 1: Evaluation of microhematuria. PE = physical exam; UA = urinalysis. Figure courtesy of Bernard S. Kaplan, MBBCh.
Indications of Proteinuria
Proteinuria is an important marker of kidney disease. However, transient proteinuria is usually benign when associated with exercise or fever and therefore it is important to differentiate between physiological and pathological proteinuria. Protein excretion in normal children is less than 4 mg/m2/hour and in healthy adults, less than 150 mg per 24≤ hours (see Table 3).
The urine dipstick tests for albuminuria. Low-molecular weight proteins such as beta-2 microglobulins are detected by urine protein electrophoresis and are elevated in Fanconi syndrome, acute tubular necrosis, tubulo-interstitial nephritis, and Dent’s disease. Tubular proteinuria rarely exceeds 1 g to 1.5 g per 24 hours.
Qualitative Detection of Proteinuria
Proteinuria is usually detected by the dipstick method, which mainly detects albumin and not low-molecular weight proteins (see Table 4). Causes of false-positive dipstick reactions for urine protein include prolonged immersion, placing reagent strip directly in the urine stream, alkaline urine pH (pH > 7), quaternary ammonium compounds and detergents, and intravenous contrast. Trace-positive proteinuria by the dipstick method does not imply abnormal proteinuria.
Table 4: Qualitative Evaluation of Proteinuria by Dipstick Tests
A urine sample is positive for protein if the dipstick is ≥ 1+ in a urine sample with a specific gravity (SG) of ≤ 1.015. If the urine specific gravity is > 1.015, the dipstick must be ≥ 2+ to be considered positive. If the urine is very dilute (SG < 1.005) the dipstick can give a false-negative result. At least two of three urine samples collected more than 1 week apart must be positive for a diagnosis of persistent proteinuria.
Quantitative Determination of Proteinuria
A 24-hour urine collection is the best method for quantifying proteinuria. However, accurate timed collections are difficult in a child, hence the 24-hour collection can be substituted by determining the protein-to-creatinine ratio (UP/C) in a urine sample, preferably the first voided sample, which is normally < 0.2. The ratio of the urine protein (mg) to the urine creatinine (mg) correlates with the 24-hour urine protein excretion and is derived from 0.63 × UP/C = urine protein excretion in g/m2/day.6
The prevalence of proteinuria in children varies depending on the definition of proteinuria (degree of positivity on a dipstick) and the number of specimens examined.7 Ten percent of school-aged children have proteinuria defined as 1+ on dipstick test, at some time. If the definition is a positive dipstick reading of ≥ 1+ in two of four specimens the prevalence decreases to 2.5%. The prevalence of proteinuria increases with age and peaks in adolescence (age 13 years in girls and 16 years in boys) and then declines.
Etiology of Proteinuria
The causes of proteinuria are outlined in Sidebar 1.
Etiology of Proteinuria
Fever, exercise, seizures, cold exposure, epinephrine administration, serum sickness, congestive heart failureOrthostatic ProteinuriaGlomerular disease
Minimal change nephrotic syndrome, GN, post-infectious, IgA nephropathy/HSP nephritis, MPGN, membranous nephropathy, lupus nephritis, Alport syndrome, vasculitis (granulomatosis with polyangitis, microscopic polyangitis), HIV-associated nephropathy, sickle cell diseaseTubulointerstitial disease
Interstitial nephritis, Fanconi syndrome, reflux nephropathy, medications (aminoglycosides, penicillin, lithium), ischemic tubular injury, renal hypoplasia/dysplasia
GN = glomerulonephritis; HSP = Henoch-Schönlein purpura; IgA = immunoglobulin A; MPGN = membrano proliferative glomerulonephritis.
Transient proteinuria resolves when the inciting factor remits. It is generally < 2+ on a dipstick. Febrile proteinuria occurs with the onset of fever and resolves within 10 to 14 days, even if the fever remits earlier. Exercise-induced proteinuria usually abates within 48 hours of cessation of exercise.
Orthostatic or Postural Proteinuria
This is defined as abnormally high protein excretion in the upright position only. It is the most common cause of asymptomatic proteinuria in children, especially adolescents. Orthostatic proteinuria usually does not exceed 1 g/day, can be reproduced on repeated measurements, or can be intermittent and transient.
Orthostatic proteinuria is diagnosed by checking the first morning urine sample for protein: a diagnosis of postural proteinuria is made if there is no protein in this sample. A timed split urine collection is a more definitive test: prior to going to bed, the child voids and discards the urine; the next first morning urine is collected in a container marked “recumbent” immediately on rising; all urine produced during the day including the last void of the day is collected in another container labeled “ambulatory”; the start and end times for both samples are recorded. Protein excretion in the recumbent specimen should be normal (< 4 mg/m2/hr), whereas that in the ambulatory collection is two to four times more than in the recumbent collection. Long-term follow-up studies in young adults show a benign course. However, before reassuring the individual and family, the history, physical findings, and laboratory evidence of renal disease must be excluded.
Persistent Asymptomatic Isolated Proteinuria
Persistent asymptomatic isolated proteinuria occurs in an otherwise healthy child whose clinical and laboratory evaluation is normal. The proteinuria should be quantified and monitored every 6 to 12 months. Renal biopsy is indicated for increasing proteinuria over time — the yield of a biopsy is low unless the proteinuria is > 1 g/day;8 however, there is no well-defined criterion for renal biopsy based on the level of proteinuria and different thresholds are used by nephrologists around the world.
Proteinuria occurs in all glomerular diseases. The nephrotic syndrome is defined by the presence of edema, proteinuria, hypoalbuminemia, and hypercholesterolemia. The urine protein excretion in nephrotic syndrome exceeds 40 mg/m2/hr or 50 mg/kg/day to 100 mg/kg/day. Minimal-change disease is the most prevalent type of primary nephrotic syndrome in children, followed by focal segmental glomerulosclerosis (FSGS) in a third of cases of idiopathic nephrotic syndrome. It is important to note that FSGS can present as asymptomatic proteinuria.
Evaluation of Proteinuria
In the absence of edema, hypertension, or hematuria, proteinuria must be confirmed on at least three occasions before initiating further evaluations. The evaluation should be focused on finding the cause using a stepwise approach to avoid unnecessary and invasive investigations.
The first step is to obtain a complete history and perform a careful physical examination with emphasis on the detection of renal diseases (see Table 5). Laboratory investigations should begin with the first morning urine analysis and UP/C followed in stages by tests for renal function, serological tests, and imaging studies of the kidneys. If the first morning UP/C is < 0.2, a diagnosis of orthostatic proteinuria is made and no further tests are indicated.
Table 5: History and Physical Examination in the Evaluation of Proteinuria
Additional investigations are based on the results of the studies listed in Table 6. If these are normal and if there is significant and persistent proteinuria, a renal biopsy may be indicated to rule out specific renal diseases (see Sidebar 2). An approach to evaluation of proteinuria is outlined in Figure 2.
Table 6: Laboratory Studies for Evaluating of Proteinuria
Indications for a Renal Biopsy in the Evaluation of Proteinuria
- Nephrotic range proteinuria
- Family history of chronic glomerulonephritis or unexplained renal failure
- Associated hematuria and red blood cell casts except with APSGN
- Low C3 concentration except with APSGN
- Hypertension and/or elevated serum creatinine concentration except with ASPGN
- Persistent nonorthostatic proteinuria for more than 1 year
APSGN = acute post-streptococcal glomerulonephritis.
Figure 2: Evaluation of asymptomatic proteinuria. ANA = anti-nuclear antibody; UP/C = urine protein to urine creatinine ratio; US = ultrasound. Figure courtesy of Bernard S. Kaplan, MBBCh.