Microscopic hematuria
Microscopic hematuria is usually defined as >5 red blood cells (RBC)
per high power field (hpf) by microscopic examination of the urine. It cannot be
diagnosed by urine dipstick alone, as false-positives may result from other
pigments, such as myoglobin, bilirubin, and some dyes, in the absence of any
blood. The prevalence of microscopic hematuria in schoolchildren has been
estimated to range from 0.5% to 2%, depending on criteria used.[1,2] Up to 6%
may have hematuria on a single urinalysis, but this figure falls dramatically
when the test is repeated.[3] In fact, one study showed an estimated incidence
of only 0.41% when 4 urine samples per child were analyzed over more than a
year.[4] Therefore, in the case of isolated asymptomatic microscopic hematuria
(no proteinuria, edema, hypertension, or gross hematuria), a positive urinalysis
should be confirmed with at least 2 more repeated urinalyses over the next weeks
to month, prior to pursuing more aggressive evaluation. This defines persistent
microscopic hematuria.
The confirmation of persistent microscopic hematuria warrants additional
diagnostic evaluation. Initial work-up should include a family history, in which
findings of chronic kidney disease (CKD), hearing loss, or kidney stones in
family members are adequate reasons for a nephrology referral. A physical
examination with abnormal blood pressure or growth parameters should also lead
to evaluation by a kidney diseases specialist.
Additionally, initial evaluation should include blood testing that
includes a complete blood count (CBC) and a renal function panel (RFP; basic
chemistry panel plus serum albumin) to confirm normal kidney function. As there
is no single serum creatinine value that is universally normal for all children,
even at any given age, the estimated glomerular filtration rate (eGFR) should be
calculated. The best available equation for this purpose currently is the
Schwartz equation,[5-7] which adjusts calculated GFR for body mass utilizing
patient height and a constant dependent on age and gender. (See National Kidney
Foundation Web site for GFR calculator:
http://www.kidney.org/professionals/tools/). A normal eGFR is considered to be
>90 ml/min/1.73 m2.
Although probably of lower yield in the case of persistent microscopic
hematuria, a renal ultrasound is noninvasive and can reasonably rule out many
kidney stones, structural abnormalities, tumors, bladder inflammation, and
hydronephrosis resulting from obstruction.
If this initial evaluation for persistent microscopic hematuria yields
all normal results with a negative family history, follow-up with yearly
urinalysis and blood pressure check should be sufficient. Specialist referral is
usually not necessary at this time, as conditions associated with isolated
microhematuria are generally benign, with no treatment indicated unless further
symptoms or signs develop.
While gross hematuria may warrant referral to an urologist in some
situations (see below), persistent microscopic hematuria with any abnormalities
uncovered in the evaluation suggested above is usually most appropriate for
referral to a kidney diseases specialist (pediatric nephrologist in older
parlance).
The most common diagnoses causing persistent microscopic hematuria
include benign familial hematuria (also known as thin basement membrane disease
or TBMD), idiopathic hypercalciuria (IH), IgA nephropathy, and Alport's
syndrome.[8,9] Sickle cell trait can be another consideration, depending on the
child's ethnic background. A family history of microscopic hematuria with or
without kidney dysfunction (TBMD, IgA nephropathy, Alport's syndrome), hearing
loss (Alport's Syndrome), or kidney stones (IH or other metabolic stone
diseases) can also be helpful in narrowing the differential, as can a patient
report of recent trauma, throat or skin infection, or rash or joint
pain.
Serum complement levels and search for autoimmune disease, such as with
an ANA (antinuclear antibody) test, are often performed, to rule out
post-infectious glomerulonephritis or lupus nephritis, but are not likely to be
of high yield without associated proteinuria, gross hematuria, or other urine,
laboratory, physical, or historical findings. A "spot" urine calcium to
creatinine ratio (normal <0.2) is sometimes used to screen for
hypercalciuria, but is very unreliable. A complete 24-hour urine collection for
calcium (normal <4 mg/kg/day) is more accurate for diagnosis. Even in the
absence of kidney stones, the calcium oxalate crystals of most cases of IH can
be sufficient to cause hematuria with or without associated urinary frequency or
dysuria, and can have implications for systemic bone health.[10] Other work-up
may include a hearing test or hemoglobin electrophoresis, depending on the level
of suspicion.
Kidney biopsy is usually reserved for cases in which IH/kidney stones
have been ruled out and that also have 1 of the following: abnormalities in the
above laboratory evaluation (eg, persistent hypocomplementemia or positive ANA),
a significantly positive family history of kidney disease, or the development of
proteinuria. This approach limits this invasive procedure to patients more
likely to have a parenchymal abnormality that necessitates therapy.
Gross hematuria
Gross or macroscopic hematuria in children has an estimated incidence of
1.3 per 1000.[11] Gross hematuria of glomerular origin is often brown,
cola-colored, or tea-colored, while that from the bladder or urethra is usually
pink or red. A presentation of gross hematuria does require prompt initial
evaluation to rule out potentially life-threatening etiologies. A urinalysis is
again crucial, to confirm the presence of red blood cells as opposed to pigment
changes caused by bilirubin (eg, in hemolysis) or myoglobin (eg, in
rhabdomyolysis). RBC casts or dysmorphic RBCs are also more indicative of a
glomerular or tubular origin, while eumorphic RBCs are more often seen when the
source is urological. Whether the hematuria is painless (more likely with kidney
origin) or painful (more common with infection, kidney stones, or urologic
abnormalities) is another useful piece of information.
Potential etiologies of gross hematuria of kidney origin include the
glomerulonephritides, the most common being acute post-infectious
glomerulonephritis (PIGN). This diagnosis should be suspected with any history
of antecedent sore throat or impetigo. The urinalysis often reveals proteinuria
and the patient manifests varying degrees of edema, hypertension, and sometimes
acute kidney failure with oliguria. The antistreptolysin O (ASO ) titer is often
elevated with this diagnosis, but the most useful study is the serum C3
concentration, which is depressed in the acute phase, but should return to
normal levels by 6 weeks after the initial presentation, if this is the correct
diagnosis. Classic PIGN without
hypertension, edema, azotemia, or oliguria can be successfully managed by a
primary care pediatrician with frequent, often daily, follow-up, and with only
phone consultation of a kidney diseases specialist as needed.
IgA nephropathy may present with recurrent gross hematuria, often
preceded by or with a concurrent respiratory tract infection. TBMD, Alport's
syndrome, and sickle cell trait may present rarely as episodic gross hematuria,
but are more often seen with persistent microscopic hematuria. The renal
involvement of Henoch-Schonlein purpura (HSP ) may also present with gross or
microscopic hematuria with or without proteinuria, but has the characteristic
systemic components to make the diagnosis more evident.
Other causes of gross hematuria can include renal tumors, most commonly
Wilms' tumor in the pediatric population. Bladder tumors are rarer. Interstitial
nephritis associated with analgesic or antibiotic use can also present rarely
with visible urinary blood. Cystic renal disease can be discovered incidentally
during the investigation of hematuria, or after mild trauma. Hemangiomas of the
urinary tract can also cause gross bleeding.
Initial evaluation of gross hematuria, in addition to detailed history,
family history, and physical examination (focusing on edema and hypertension) as
above, should include urinalysis to confirm the presence and formation of RBCs,
and quantification of proteinuria. Blood studies of RFP, CBC, C3, albumin, and
ASO titer can also be of high yield, and must be checked when there is any
suspicion that the hematuria could be of glomerular origin.
A urine culture should be performed to rule out bacterial infection,
although viral infections may produce gross hematuria too and cannot be
cultured. The demonstration of an apparent UTI should not be assumed to be the
only etiology if incongruous findings also exist, such as significant
proteinuria or hypertension.
Renal ultrasound is essential to uncover tumors (although rare), stones,
cysts, or urological abnormalities. A history of trauma will likely necessitate
a computed tomography (CT) scan of the abdomen and pelvis. If family history and
lack of signs pointing to significant kidney disease (eg, no proteinuria or
hypertension, normal kidney function) make stone disease or hypercalciuria more
likely etiologies, a metabolic stone evaluation by a pediatric kidney diseases
specialist is appropriate.
Proteinuria
While most proteinuria is usually discovered by urine
dipstick on routine urinalyses, such dipstick methods are subject to false positive
results when the urine is very concentrated or very alkaline. For this reason,
the presence of abnormal protein excretion needs to be confirmed by other
methods. The gold standard measurement of protein excretion remains the
24-hour urine collection (normal <4 mg/m2/hr or <100 mg/m2/day), although this
may be misleadingly abnormal in a particular benign condition – orthostatic
proteinuria (see below). As a complete 24-hour collection may also be difficult to
reliably obtain in many pediatric patients, a "spot" urine protein to creatinine
ratio (Uprot/UC r) is more typically used, and has been shown to correlate well
with total protein excretion in both adults and children.12,13 A normal UProt/UCr
for children over 2 years of age is <0.2 mgprotein/mgcreatinine(<0.5 in children 2–24
months of age). A 24-hour excretion of >40 mg/m2/hr or a "spot" ratio >2
is considered to be proteinuria in the nephrotic range, although hypoalbuminemia
and hyperlipidemia (often accompanied by edema) are required to make the
specific diagnosis of nephrotic syndrome.
The prevalence of proteinuria is difficult to define. A report describing
the results of the Third National Health and Nutritional Examination Study of
4088 children found that 12% had abnormal albumin excretion on a cross-sectional
sample of random urine specimens, with the highest rates being in
adolescents.[14] This prevalence may adequately estimate the occurrence of
positive results on random 1-time screenings, but it is likely that many of
these subjects had transient or orthostatic proteinuria, both benign
conditions.
Transient proteinuria may be present on 1 or 2 occasions. Persistent
proteinuira is usually defined as 3 or more consecutive urine samples showing
proteinuria.
Orthostatic proteinuria is most common in adolescents and
young adults, and results in elevated urinary protein that resolves with
recumbency. A random dipstick may read as high as 3-4+ in this condition, and a
24-hour protein excretion, while elevated, rarely exceeds 1g/m2/day. To make
this diagnosis, a first morning Uprot/UCr should be obtained, advising the
patient to void just before going to bed, and to remain recumbent until immediately before providing the sample.
If this ratio is normal, and there are no other concerning findings
on urinalysis or physical examination and history, no additional investigation is necessary. Yearly first
morning urine samples should be sufficient for follow-up to assure normal
functional outcomes.
If proteinuria is persistent and non-orthostatic, referral to a kidney
diseases specialist is appropriate. Nephrotic-range proteinuria, especially with
edema, should prompt immediate evaluation for nephrotic syndrome or chronic
kidney disease.
Further investigation of persistent proteinuria will include RFP,
complement levels, ANA, and hepatitis/HIV screening. Renal ultrasound may be
useful, as unknown structural abnormalities may eventually result in glomerular
damage and proteinuria. While the results of these studies may help narrow the
differential, referral to a pediatric nephrologist is key, as a kidney biopsy is
often required to determine precise diagnosis and appropriate therapy. Such
diagnoses may include minimal change disease, focal segmental glomerulosclerosis
(FSGS; primary or secondary to various infections, obstructive uropathy, or
obesity), and membranous glomerulonephritis. When hematuria accompanies the
proteinuria to a larger extent, especially with persistently depressed
complement levels, membranoproliferative glomerulonephritis (MPGN) or lupus
nephritis are more likely diagnoses.
Summary
The finding of
isolated hematuria or proteinuria on random urine screening can be distressing to
pediatric patients and their families. However, available information continues to
support the fact that most patients have a benign condition,[15] and most children and
adolescents found to have a single abnormality on a screening urinalysis do
not have chronic kidney disease. While isolated findings of proteinuria
or microscopic hematuria in an otherwise healthy and asymptomatic child may be
confirmed or shown to be transient by a primary care
physician prior to referral, persistence of findings should lead
to consultation with a pediatric kidney diseases specialist, although this
need varies by situation (Table 1).
The combination of both hematuria and proteinuria indicates a higher
probability of significant renal abnormality, and deserves more extensive and
earlier investigation, as does persistent non-orthostatic proteinuria. In
particular, gross hematuria and any abnormalities accompanied by edema or
hypertension require prompt evaluation.
References
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Vehaskari VM, Rapola J, Koskimies O, et al. Microscopic hematuria in
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[2.] Murakami M, Yamamoto H, Ueda Y, et al. Urinary screening of
elementary and junior high school children over a 13 year period in Tokyo.
Pediatr Nephrol 1991;5:50-53.
[3.] Dodge WF. Cost effectiveness of renal disease screening Am J Dis
Child 1977;131:1274-1280.
[4.] Dodge WF, West EF, Smith EH, et al. Proteinuria and hematuria in
schoolchildren: Epidemiology and early natural history. J Pediatr
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[5.] Schwartz GJ, Haycock GB Edelmann CM Jr, Spitzer A. A simple estimate
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[6.] Schwartz GJ, Feld LG, Langford DJ. A simple estimate of glomerular
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[7.] Schwartz GJ, Gauthier B. A simple estimate of glomerular filtration
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[8.] Lee YM, Baek SY, Kim JH, et al. Analysis of renal biopsies in
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[10.]
García-Nieto V, Ferrández C, Monge M, de Sequera M, Rodrigo MD. Bone
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[11.] Ingelfinger JR, Davis AE, Grupe WE. Frequency and etiology of gross
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[12.] Nagasako H, Kiyoshi Y, Ohkawa T, et al. Estimation of 24-h urine
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[13.] Price CP, Newall RG, Boyd JC. Use of protein:creatinine ratio
measurements on random urine samples for prediction of significant proteinuria:
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[14.] Mueller PW, Caudill SP. Urinary albumin excretion in children:
Factors related to elevated excretion in the United States
population. Ren Fail 1999;21:293-302.
[15.] Park YH, Choi JY, Chung HS, et al. Hematuria and
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