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Hematuria

By Dr. Wasim R. Issa

Hematuria is one of the most common urinary findings that result in children presenting to pediatric nephrologists. Generally, hematuria is defined as the presence of 5 or more RBCs per high-power field in 3 of 3 consecutive centrifuged specimens obtained at least 1 week apart.

In the office setting, a positive reaction on the urine dipstick test is usually the first indication of the presence of hematuria. Hematuria can be - gross (ie, the urine is overtly bloody, smoky, or tea colored) or microscopic. - It may be symptomatic or asymptomatic, - transient or persistent, - isolated or associated with proteinuria and other urinary abnormalities.

Pathophysiology - hematuria of glomerular origin may be the result of a structural disruption in the integrity of glomerular basement membrane caused by inflammatory or immunologic processes. - Chemicals may cause toxic disruptions of the renal tubules, - whereas calculi may cause mechanical erosion of mucosal surfaces in the genitourinary tract, resulting in hematuria.

United States The prevalence of gross hematuria in children is estimated to be 0.13%. In more than half of the cases (56%) this is due to an easily identifiable cause. The most common cause appears to be cystitis (20-25%). Asymptomatic microscopic hematuria is, on the average, 10-fold as prevalent as gross hematuria (1.5%, range 0.44.1%, depending on the criteria used to define hematuria). With repeated evaluations, the prevalence of asymptomatic microscopic hematuria decreases to less than 0.5%, supporting the notion that most cases of hematuria in children are transient. The incidence of simultaneous hematuria and proteinuria is estimated to be only 0.06%, but their coexistence signals significant renal disease.

Mortality/Morbidity In general, children with isolated asymptomatic microscopic hematuria tend to do well, those with associated findings (eg, hypertension, proteinuria, abnormal serum creatinine levels) are more likely to have serious problems. Because hematuria is the end result of various processes, the morbidity and mortality rates of the condition depend on the primary process that initiated it.

Sex Sex may predispose a child to specific diseases that manifest as hematuria. For example, - the sex-linked form of Alport syndrome has a male preponderance, - lupus nephritis is more common in adolescent girls. Age Wilms tumors are more frequent in children of preschool age, acute postinfectious glomerulonephritis is more frequent in the school-aged population. In adults, hematuria is often a sign of malignancy of the genitourinary tract (eg, renal cell carcinoma, bladder tumors, prostatic tumors). These conditions are rare in children.

Race The incidence of hematuria in specific racial groups is determined by the primary cause. For example, idiopathic hypercalciuria is infrequent in black and Asian children, but relatively common in whites. Conversely, hematuria caused by sickle cell disease is more common in blacks than in whites.

History
A history of passage of clots in urine suggests an extraglomerular cause of hematuria. A history of fever, abdominal pain, dysuria, frequency, and recent enuresis in older children may point to a urinary tract infection as the cause of hematuria. A history of recent trauma to the abdomen may be indicative of hydronephrosis. A history of early-morning periorbital puffiness, weight gain, oliguria, the presence of dark-colored urine, and the presence of edema or hypertension suggests a glomerular cause.

Hematuria due to glomerular causes is painless. A history of a recent throat or skin infection may suggest postinfectious glomerulonephritis. A history of joint pains, skin rashes, and prolonged fever in adolescents suggests a collagen vascular disorder.

The presence of anemia cannot be accounted for by hematuria alone, and, in a patient with hematuria and pallor, other conditions such as systemic lupus erythematosus and bleeding diathesis should be considered.

Skin rashes and arthritis can occur in Henoch-Schnlein purpura andsystemic lupus erythematosus. Information regarding exercise, menstruation, recent bladder catheterization, intake of certain drugs or toxic substances, or passage of a calculus may also assist in the differential diagnoses. Because certain diseases that present with hematuria are inherited or familial, asking for a family history that is suggestive of Alport syndrome, collagen vascular diseases, urolithiasis, or polycystic kidney disease is important.

Physical Examination
In the general physical examination, the most important step is - to measure the blood pressure (with an appropriate-sized cuff) and - evaluate for the presence of periorbital puffiness or peripheral edema.[4, 5] A detailed skin examination is necessary to look for purpura. An abdominal examination is indicated to look for palpable kidneys (Wilms tumor or hydronephrotic kidneys). A careful examination of the genitalia is also important. A detailed ophthalmological evaluation is helpful in familial hematurias. ????

Hematuria can be of glomerular or nonglomerular origin. Brown-colored urine, RBC casts, and dysmorphic (small deformed, misshapen, sometimes fragmented) RBCs and proteinuria are suggestive of glomerular hematuria. Reddish or pink urine, passage of blood clots, and eumorphic (normal sized, biconcavely shaped) erythrocytes are suggestive of a nonglomerular bleeding site.

Glomerular hematuria

Nonglomerular hematuria

1.

Thin basement membrane disease (benign familial hematuria)


Alport syndrome Immunoglobulin A (IgA) nephropathy Hemolytic-uremic syndrome

2. 3. 4.

5.
6.

Postinfectious glomerulonephritis
Membranoproliferative glomerulonephritis Lupus nephritis Anaphylactoid purpura (HenochSchnlein purpura)

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

7. 8.

Fever Strenuous exercise Mechanical trauma (masturbation) Menstruation Foreign bodies Urinary tract infection Hypercalciuria/urolithiasis Sickle cell disease/trait Coagulopathy Tumors Drugs/toxins (nonsteroidal antiinflammatory drugs [NSAIDs], anticoagulants, cyclophosphamide, ritonavir, indinavir) 12. Anatomic abnormalities (hydronephrosis, polycystic kidney disease, vascular malformations) 13. Hyperuricosuria

Investigation
Urinalysis
- Confirming that a child with red-colored urine has hematuria is mandatory.

- Dip strip analysis is critically important in patients with dark or abnormal-appearing urine because several substances may discolor the urine and give the appearance of hematuria.
- The urine dipstick test is currently one of the most useful and sensitive tools in detecting hematuria. - This test is based on the peroxidase activity of hemoglobin. Dipsticks have a sensitivity of 100% and a specificity of 99% in detecting 1-5 RBCs per high-power field (hpf).

- The presence of hematuria is most important to confirm, since both normal and abnormal causes (eg, hemoglobinuria, myoglobinuria) can produce false-positive results. - Confirmation requires a microscopic examination of the urine for the presence of RBCs and casts. - More than 5 RBCs per hpf is generally considered abnormal. - RBC casts indicate a glomerulotubular source of hematuria. - The absence of RBCs and RBC casts despite a positive dipstick test suggests hemoglobinuria or myoglobinuria.

- Other cellular elements in the urinary sediment (eg, WBCs, WBC casts) suggest a diagnosis of urinary tract infection. - In this latter instance, a urine culture must be performed to determine the causative organism. - Crystals, bacteria, protozoa, and other elements may also be seen. - dipstick and microscopic urinalysis should be repeated twice within 2 weeks.

Phase contrast microscopy: - A careful examination of the urine for the presence of a significant number of dysmorphic RBCs suggests a renal (glomerular) source of the hematuria. A urine sample that predominantly contains eumorphic RBCs suggests an extrarenal (nonglomerular) source.

- This test has been reported to have a sensitivity of 8395% and a specificity of 81-95%. The sensitivity and specificity may vary from one examiner to another.

BUN/serum creatinine: Elevated levels of BUN and creatinine suggest significant renal disease as the cause of hematuria. Hematologic and coagulation studies:

- CBC counts and, sometimes, platelet counts may be performed in selected patients with a clear history of a bleeding disorder.
- In certain populations, a sickle cell preparation or a hemoglobin electrophoresis may be useful in establishing the diagnosis of sickle cell disease or trait.

Urine calcium: - Hypercalciuria is a relatively common finding in children. - A calcium excretion of more than 4 mg/kg/d or - a urine calcium-creatinine ratio of more than 0.21 are considered abnormal.

Serologic testing: - Measuring serum complement levels is important if a glomerular cause of hematuria is suspected. Low serum complement levels are seen in ( MPGN , PSGN , lupus nephtitis , shunt nephritis , infective endocarditis , A high antistreptolysin (ASO) titer suggests a recent streptococcal infection. Anti-DNase B levels are also indicative of a recent group B streptococcal infection and may be positive even when the ASO level is normal. ASO titer is ve , anti-DNase B is +ve >>> PSGN to a skin infection. Antinuclear antibody (ANA) titers and the measurement of doublestranded DNA (dsDNA) levels are most helpful in children with suspected systemic lupus erythematosus nephritis.

Urine culture:

- A midstream or clean-catch specimen of urine should be obtained for culture sensitivity whenever a urinary tract infection is suspected.
- This is especially important in younger children, in whom classical symptoms of a urinary tract infection may be absent.

Imaging Study
Renal and bladder ultrasonography: Urinary tract anomalies, such as hydronephrosis, hydroureter, nephrocalcinosis, tumor, and urolithiasis . Other imaging studiesA spiral CT scan is particularly useful in the detection of urolithiasis, Wilms tumor, and polycystic kidney disease. Voiding cystourethrograms are valuable in detecting urethral and bladder abnormalities that may result in hematuria (eg, cystitis).

Radionuclide studies can be helpful in the evaluation of obstructing calculi.


Intravenous urography rarely contributes additional information in the evaluation of hematuria and may unnecessarily expose the child to ionizing radiation.

Renal Biopsy : indications for performing a kidney biopsy in patients with hematuria are as follows: 1. Significant proteinuria 2. Abnormal renal function ( BUN , Cr >> high ) 3. Recurrent persistent hematuria. 4. Serologic abnormalities (abnormal complement, ANA, or dsDNA levels). 5. Recurrent gross hematuria. 6. A family history of end-stage renal disease.

- In a survey of pediatric nephrologists in North America, only 5% of responders indicated that they would perform a kidney biopsy on a child with asymptomatic hematuria.
Cystoscopy is not generally required in children with nonglomerular hematuria. The only indication is a suspicious bladder mass revealed on ultrasonography. Skin biopsy with immunostaining for the 5(IV) chain is particularly useful when suspicion of X-linked Alport syndrome is high.

Follow Up
Patients with persistent microscopic hematuria should be monitored at 6-month to 12-month intervals for the appearance of signs or symptoms indicative of progressive renal disease. Prominent among them are proteinuria, hypertension, and a decrease in renal function.

Definitions
Gross (Macroscopic) hematuria blood that can be seen with the naked eye urinary tract ; bright-red, visible clots, or crystals with normallooking RBCs glomerular; Cola-colored, RBC casts, and dysmorphic RBCs Microscopic hematuria detected by a dipstick test during a routine exam. ; should be confirmed by microscopic examination 10 ml of urine, spun at 2000 rpm for 5 min 9 ml, decanted sediment, resuspended and examined by microscopy by Hpf (x 400)

Factors resulting in discolored urine


Pink, red, tea-colored Disease states Hemoglobinuria Myoglobinuria Porphyrinuria Serratia marcescens Bile pigments Urates Ingestions Aminopyrine Beets Benzene Blackberries Ibuprofen Lead Rifampin Dark brown, black Disease states Alkaptouria Homogentisic acid Melanin Methemoglobinuria Tyrosinosis Ingestions Alanine Cascara Resorcinol Thymol

Causes of hematuria in children


Glomerular diseases
Recurrent gross hematuria (IgA nephropathy, Benign familial hematuria, Alports syndrome) Acute PSGN MPGN SLE Membranous nephropathy RPGN Henoch-Schonlein purpura Goodpastures disease renal vein thrombosis, thrombocytopenia)

Urinary tract
Bacterial or viral (adenovirus) infection-related Nephrolithiasis and hypercalciuria Structural anomalies, congenital anomalies, polycystic kidney disease Trauma Tumors Exercise Medications (aminoglycosides, amitryptiline, anticonvulsants, aspirin, chlorpromazine, coumadin, penicilline cyclophosphamide, diuretics, thorazine)

Interstitial and tubular


Acute pyelonephritis Acute interstitial nephritis Tuberculosis Hematologic (sickle cell disease, von Willebrands coagulopathies

Hematuria evaluation Lab studies


Proteinuria may be present regardless of the cause of bleeding blood origin ; usually not >2+(100 mg/dL) (especially, microscopic) 1- 2+ proteinuria ; R/O orthostatic(postural) proteinuria.
a condition in which protein appears in the urine in otherwise healthy people who have been standing for a period of time in approximately 3 -15% of healthy young adults Dx ; 2 urine specimens - one right after waking the second about 2 hours after being upright

2+ proteinuria ; glomerulonephritis & nephritic syndrome RBC casts a highly specific marker for GN, not confirmative Dysmorphic RBC Glomerular origin Additional test (by suspected source of bleeding & Sx and Hx) Serum Cr, CBC, C3/C4, ANA, ASO, urine culture, Ca/Cr ratio

- Hematuria is almost never a cause of anemia . - asymptomatic child at least 2 postive UA of 3 over 2- to 3-week period - symptomatic child in a single urine sample - CBC >> HUS , bleeding disorders - All children with macroscopic hematuria require renal ultrasound upon presentation. - If the blood pressure is normal and the patient is passing normal amounts of urine, it is unlikely that microscopic hematuria, whatever its cause, warrants immediate treatment.

- Only two diagnostic tests are required for a child with microscopic hematuria: (1) a test for proteinuria and (2) a microscopic examination of the urine for RBCs and RBC casts . - Additional test by suspected source of bleeding and patient symptom and history

Gross Hematuria History of trauma?


No Yes

CT of abdomen and pelvis

Signs/symptom s of UTI?
No

Yes

Urine culture, treat appropriately Recheck UA after infection cleared


Imaging (KUB, ultrasound, CT) Urine Cr/Ca ratio or 24 hour urine for calcium

Signs/symptoms of stones?
No No

Yes

Signs/symptoms of GN?(edema, HTN, proteinuria, RBC casts)

Yes

No obvious cause on history, physical or urinanalysis Tests to considers: Urine culture Urine Ca/Cr ratio Test parents for hematuria Hgb electrophoresis Renal U/S Diagnosis apparent?

Check BUN/Cr, electrolytes, CBC, C3/C4, albumin Consider ASO, antiDNAaseB, ANA

Diagnosis consistent with PSGN or HSP?

No

Yes

Yes

No

Supportive treatment with close follow-up Referral to pediatric nephrologist

Treatme nt

Diagnostic approach to M/H s abnl findings


Cause of asymptomatic isolated M/H Uncommon Drugs and toxins Coagulopathy Ureteropelvic junction obstruction Focal segmental glomerulosclerosis Membranous glomerulonephritis Membranoproliferative glomerulonephritis Lupus nephritis Hydronephrosis Pyelonephritis Vascular malformation Tuberculosis Tumor

Isolated microscopic hematuria Lacking contributory history, Physical findings or proteinuria


UA negative

Repeat UA (no exercise before test) weekly x2


Hematuria persist Yes

Follow up prn

Patient on suspected medicine?


No

Hold med and


recheck UA

UA negative

F/U prn

Hematuria persists

Tests to consider: Urine Ca/Cr ratio or 24 urine for Ca Test parents for hematuria Hgb electrophoresis

Diagonosis apparent?
No

Yes

Treat accordingly

Tests to consider (low yield): Renal ultrasound BUN/Creatinine Hearing test Coagulation studies
Results normal

Abnormal results

Referral to pediatric nephrologist

Reassure parents with yearly F/U or consider referral to pediatric nephrologist

Diagnostic approach to M/H c abnl findings


Varied clinical presentation and wide range of diagnositic possibilities Patients with hematuria from glomerular cause have the high risk for morbidity
Microscopic hematuria with substantial proteinuria Minimal change nephrotic syndrome IgA nephropathy Alports syndrome MPGN Membranous nephropathy FSGN

Microscopic hematuria with abnormal findings on history, physical or urinalysis

Yes

Presence of proteinuria, edema or hypertension?

No

Patient acutely ill?


No (proteinuria without edema or HTN) UA(-)

Tailor W/U according to associated findings:


Yes

F/U prn

Recheck UA in one week

Labs to check: Bun/Cr Electrolytes CBC/ C3,C4 Albumin

Hematuria & proteinuria persistent

R/O trauma CT if > 50 RBC/hpf S/Sx of UTI Urine culture, recheck UA S/Sx of stones Imaging studies Urine Ca/Cr or 24 hour urine Ca. Abdominal mass renal ultrasound or CT

Labs to check: BUN/Cr, CBC C3, C4 Albumin

Labs to consider: ASO/antiDNAase B ANA


Elevated BUN/Cr? Nephrotic syndrome? Moderate to severe hypertension? Diagnosis uncertain?
No No Yes

Diagnosis apparent?

Yes

Labs Refer to normal? pediatric Yes nephrologis t Hematuria & Yes proteinuria persistent?
No

No

Refer to pediatric nephrologist

Treat accordingly, follow-up prn

Close follow-up with supportive therapy as needed Development of complication or lack of recovery?
Yes

Follow up prn

No

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