Approach to a child with Hematuria :

Sunil Agrawal

1st year

MD Pediatrics, IOM

Contents:

• Introduction• Pathophysiology• Causes• History• Examination• Investigations• Management

Introduction

Hematuria means blood in urine.It may be Gross or macroscopic and microscopic

hematuriaGross hematuria is seen by naked eyes while

microscopic hematuria needs microscope. Hematuria is defined as the presence of at least 5 red blood cells per HPF of centrifuged urine and/or 5 RBC per microliter in uncentrifuged specimen

• Pathophysiology:

Structural disruption in the integrity of glomerular basement membrane caused by inflammatory or immunologic processes

Toxic disruptions of the renal tubules

Mechanical erosion of mucosal surfaces in the genitourinary tract

Causes of Hematuria:

A) Glomerular hematuria

Isolated renal disease

-Postinfectious GN (Post streptococcal)- IgA nephropathy( Berger ds)- Alport syndrome( hereditary )- Thin Glomerular Basement membrane

disease- Membranoproliferative GN- Membranous nephropathy - Focal segmental glomerulosclerosis - Antiglomerular basement membrane

ds

Multisystem disease

-HSP nephritis -SLE nephritis-HUS-Wegener granulomatosis-Polyarteritis nodosa-Goodpasture syndrome-HIV nephropathy-Sickle cell glomerulopathy

B) Extraglomerular hematuria

Upper Urinary tractTubulointerstitial

PyelonephritisInterstitial nephritisATNPapillary necrosisNephrocalcinosis

AnatomicHydronephrosisPolycystic kidney diseaseTumor (Wilms, Rhabdomyosarcoma, Angiomyolipoma)Trauma

Vascular:• Arterial/venous thrombosis• Malformation (aneurysms, hemangioma)• Nutcracker syndrome• Hemoglobinopathy (Sickle cell trait/disease)Crystalluria: Calcium, Oxalate, Uric acidMedications: NSAIDs, anticoagulants

Lower urinary tractInflammation- infectious and non infectious

CystitisUrethritis

UrolithiasisTraumaCoagulopathyHeavy exercise

Bladder tumorFactitious syndrome / by proxy

Common causes of gross hematuria:

• Urinary tract infection• Meatal stenosis• Perineal irritation• Trauma• Urolithiasis/hypercalciuria• Coagulopathy• Tumor

Glomerular cause of gross hematuriaIgA nephropathyAlport syndromeThin glomerular basement membrane diseasePost infectious glomerulonephritisHSP nephritisSLE nephritis

Causes of Hematuria in the Newborn:

• Renal vein thrombosis (Asphyxia, dehydration, shock)

• Renal artery thrombosis • Autosomal recessive polycystic kidney disease • Obstructive uropathy• Urinary tract infection• Bleeding and clotting disorders• Trauma, bladder catheterization• Cortical necrosis (Hypoxic/ischemic perinatal

insult)• Nephrocalcinosis (Frusemide in premature)

History:

• Age: 2-5yrs: Wilms tumor

5-12yrs: PSGN

• Sex: F>>M in >1-2yrs: UTI

F>>M: SLE nephritis

M>F : X-linked form of Alport syndrome

• Race: whites: Idiopathic hypercalciuria

blacks: Sickle cell disease

Colour of urine:

Colour Causes

Dark yellow Normal concentrated urine

Dark brown or black

Bile pigmentsHomogentisic acid, melanin, tyrosinosis, methemoglobinuria

Cola coloured Glomerular hematuria

Red or pink urine

Extraglomerular hematuria, Hemoglobin, Myoglobin, Porphyrins, Chloroquine, Deferoxamine, Beets, blackberries, Rifampin, Red dyes in food, Urates

Characteristics of urine:• Amount of urine: Reduced in AGN, ARF• Clots in urine: Extraglomerular• Frequency, Dysuria, recent enuresis : UTI• Frothy urine: Suggests Proteinuria seen in

Glomerular diseases• Timing: Initial stream – from urethra (Urethrorrhagia

– spotting in underwear); Terminal (with suprapubic pain, disturbance of micturition) – from bladder

Associated Symptoms:• Fever: Infections, SLE, AGN• Facial puffiness, Oedema of legs, weight gain,

Shortness of breath: Acute Glomerulonephritis • Hypertension (Headache, visual changes, epistaxis,

seizures): AGN, ARF• Abdominal pain: Urolithiasis (Loin to groin), UTI,

clots, Nutcracker syndrome• Painless: Glomerular• Abdominal mass: Hydronephrosis, PKD, Wilm’s

tumour• Joint pain (HSP, SLE)• Rashes (HSP, SLE, PAN)• Neurologic – SLE, HUS (seizures, irritability)• Jaundice: Hemolysis, Obstructive jaundice

• H/o exercise, menstruation, recent bladder catheterization or passage of a calculus

• Recent upper respiratory (1-2wks back), skin infection (3-6 wks): PSGN

• GI infection: HUS, HSP nephritis • Gross hematuria precipitated by URI: Alport

syndrome, IgA Nephropathy • H/o bleeding from other sites: Bleeding disorders,

Hemoptysis in Good Pasture syndrome• H/o Trauma, abdominal surgery, Child abuse (Social

factors - Munchausen), crush injury• H/o ingestion of drugs (ATT – Rifampicin, Ibuprofen,

Chloroquine, Metronidazole, Iron), i.v. contrast agents (Toxic nephropathy, RVT)

• H/o Vision or hearing defects: Alport syndrome

• Family h/o: Hereditary glomerular diseases (Alport syndrome, Thin glomerular Basement Membrane Disease, IgA Nephropathy), Urolithiasis, Hypercalciuria, Sickle cell disease/trait

• H/o consanguinity or affected siblings in ARPKD, Metabolic disorders

Examination:

• Vitals:– BP: in AGN, PKD– Temperature

• Oedema: in AGN• Pallor: Bleeding disorders, HUS, SLE, CRF• JVP: Raised in CHF• Per abdomen: Mass

– Kidney: Hydronephrosis (Urinary tract obstruction), Wilms tumour; B/L in ARPKD, hydronephrosis

– Bladder palpable: Distal obstruction – Tenderness: HSP

• Skin lesions Purpura(HSP) Butterfly rash (SLE) Bruises (Trauma, Child abuse)• Abnormal external genitalia e.g. ambiguous genitalia

in WAGR syndrome (Wilms, aniridia, genital anomalies, mental retardation), Wilms tumour – hypospadias, cryptorchidism, Genital trauma

• Signs of Congestive cardiac failure, HTNsive encephalopathy: AGN

• Joint swelling, tenderness: HSP, SLE• Ophthalmologic: Alport syndrome (Anterior

lenticonus, macular flecks, recurrent corneal erosions), Aniridia (Wilms)

• Hearing assessment: Alport (B/L SNHL)

General Approach to Investigate the child with

Hematuria

Investigations:• Urine dipstick test: Based on the

peroxidase-like activity of hemoglobin

• It can detect trace amounts of hemoglobin and myoglobin.

• Can detect 5-10 intact RBC per mm3 of unspun urine

• False +ve: Urine pH >9, H2O2

• False –ve: High ascorbic acid, formalin

• Also for urine albumin

Investigations:

Glomerular1. Brown, cola coloured or smoky2. RBC casts

3. Proteinuria 2+ or more 4. Deformed urinary RBCs

Non - glomerular1. Bright red, pink2.Terminal hematuria/ Passage of clots3. Proteinuria of < 2+4. Normal morphology of RBCs

Urine microscopy: Presence of RBCs and casts (> 5 RBCs per HPF) in centrifuged urine

Study on Evaluation of hematuria using the urinary albumin-to-total-protein ratio to differentiate glomerular and nonglomerular bleeding

•N. Ohisa · R. Matsuki · H. Suzuki · H. Miura · Y. Ohisa · K. YoshidaDepartment of Clinical Laboratory, Tohoku University Hospital,Sendai, Japan•microscopy-based differentiation is not only tedious but the sensitivity and specificity may vary from one examiner to another. Furthermore, once

the specimen has been frozen, differentiation becomes difficult.•A total of 143 random urine specimens from patients seen at the Division of Nephrology, Endocrinology and Vascular Disease and the Urology Department at Tohoku University Hospital were included in the study. The inclusion criterion

for the study was a diagnosis of glomerular disease based on clinical features or histopathology with hematuria (5 or more RBCs per high-power fi eld). Of the 104 patients diagnosed with glomerular disease and 39 specimens from patients with nonglomerular disease, used as controls in the study.

• With respect to the albumin-to-total-protein ratio, the mean value in the glomerular disease group was 0.72 } 0.10, whereas the mean in the nonglomerular �disease group was 0.35 } 0.17 (� P < 0.001). The distribution of the albumin-to-total-protein ratio in the glomerular and nonglomerular disease groups was clearly differentiated. Sensitivity and specificity as a function of the albumin-to-total-protein ratio. At a ratio cutoff of 0.59, sensitivity and specificity was maximized at 96.2% and 100%, respectively.

Distribution of urinary albumin-to-total-protein ratio in glomerular and nonglomerular hematuria. The mean albumin-to-totalprotein ratio in the glomerular disease group was signifi cantly higher than that in the nonglomerular disease group. A cutoff of 0.59 excluded all nonglomerular disease cases, while detecting all but three glomerular disease cases. Gl, glomerular disease; non-Gl, nonglomerular disease; vertical axis, albumin-to-total-protein ratio; horizontal axis, glomerular disease, nonglomerular disease

Urine albumin-to-total-protein ratio sensitivities and specifi itiesin differentiating glomerular and nonglomerular hematuria. At aratio of 0.59, sensitivity and specificity were 96.2% and 100%, respectively.

Cola/ brown urine?Proteinuria(>30mg/dl)?

RBC cast?Acute nephritic syndrome?

Yes

Glomerular hematuria• CBC• Electrolytes,Ca• BUN/Cr• Serum protein/albumin• Cholesterol• C3/C4• ASO/Anti-DNase B• ANA• Antineutrophil antibody• Throat/ skin culture• 24-hour urine total protein

creatinine clearance

NO

Extraglomerular hematuriaStep 1• Urine cultureStep 2• Urine Ca/Cr• Renal/ bladder USGStep 3• Urinalysis: siblings, parents• Serum electrolytes, Cr, Ca• If crystalluria, urolitiasis or nephrocalcinosis: 24-hr urine for Ca, Cr, Uric acid, oxalate• If hydronephrosis/pyelocaliectasis: cystogram, renal scan

Investigations:• Urine C/S • RFT: Blood urea nitrogen/serum creatinine, Na/K (↓Na in

AGN, ↑K in ARF)• Complete blood counts (CBC): Hb - ↓ in bleeding, HUS, SLE,

CRF; Abnormal TC, DC in infections, HUS, ↓ in SLE;• Platelet counts and Coagulation studies: (history suggestive

of bleeding disorder, HUS), Sickle cell (Hemoglobin electrophoresis)

• PBS: Microangiopathic hemolytic anemia• ESR, CRP - Infections• 24 hr urinary protein, Spot urinary protein: Creatinine ratio,

Serum albumin and cholesterol if associated proteinuria (Nephrotic syndrome)

• Urine calcium: Hypercalciuria is a relatively common finding in children. – 24-hour urinary calcium (>4 mg/kg/d), or– Spot urine calcium-creatinine ratio >0.21

Investigations:• Imaging Studies

– Renal and bladder sonography: Urinary tract anomalies, such as hydronephrosis, hydroureter, nephrocalcinosis, tumor, and urolithiasis, Renal parenchymal disease

– X-Ray KUB: calculi– Doppler study of renal vessels and IVC: Renal vein

thrombosis– Intravenous urography– Spiral CT scan - Urolithiasis, Wilms tumor and polycystic

kidney disease, Renal trauma– Micturating cystourethrograms - Urethral and bladder

abnormalities (eg, cystitis), in recurrent UTI to r/o VUR, anomalies

– Radionuclide studies – Renal function and perfusion– Angiogram– Chest X-Ray (Pulmonary oedema, CHF)

Investigations:• Renal biopsy:

Relative indications -• Significant proteinuria (3+ or more) or nephrotic

syndrome +• Recurrent persistent hematuria (Microscopic

>2yrs)• Abnormal renal function, Persistent HTN • Hematuria, Proteinuria, diminished renal function,

low C3 level persist beyond 2 mo of onset of AGN• Absence of evidence of streptococcal infection• Serologic abnormalities (abnormal ANA or dsDNA

levels) • A family history of end stage renal disease or

evidence of Chronic renal disease in patient

Dx Histology Clinical LabIgA Nephro-pathy

IgA deposition in the mesangium, glomerular sclerosis, proliferative changes, crescents in severe cases

Gross, intermittent, painless hematuria

No specific changes, although increased serumIgA levels observed in some patients

HSP Same as IgA nephropathy Purpura, joint pains, abdominalpain, hematuria, etc

No specific laboratory data

SLE Mild glomerulitis, proliferative changes, immune complex deposition, crescents, immunoglobulin deposition

Hematuria, proteinuria, hypertension, joint pains, rashes, etc

Abnormal C3, C4, ANA, dsDNA, anemia, thrombocytopenia, etc

Dx Histology Clinical LabAlport Syndrome

Some thinning of basement membranes, "basket weave" changes in the glomerular basementmembrane on electron microscopy

Sensorineural hearing loss, corneal abnormalities, hematuria, renal failure

No specific changes

Thin Basement Membrane disease

Average glomerular basement membranes thin (reported to be 100-200 nm)

Persistent microscopic or gross hematuria, significant family history

No specific changes

Mesangio-proliferative GN

Glomerular lobulations, thickening of the mesangial matrix and glomerular basement membranes, crescents, etc

Hematuria, proteinuria, hypertension

C3 levels may be low

Investigations:

• Cystourethroscopy: Terminal hematuria, disturbances of micturition, suprapubic pain (Only if strong suspicion of bladder ulceration, tumours)

• Screening of first degree relatives in persistent hematuria

Summary

For Asymptomatic, isolated microscopic hematuria:

Isolated microscopic hematuria

Repeat urinalysis weekly x 2 (No exercise x 48hrs)

F/U Urine R/M with examination

Test parents for hematuria

Benign Familial Hematuria

Family h/o calculi

+Hearing test, +USG, +X-Ray KUB

Urine Ca/Cr ratio

Yearly Urine R/M, examination, BP

Negative

Positive

Yes

Normal

Persistent hematuria

No

No

Management:

• According to cause:– Reassurance and F/U– Treat cystitis, pyelonephritis, AGN: Antibiotics– Supportive treatment: Diuretics, Fluid and salt

restriction, Antihypertensives– Monitoring – BP, I/O, weight, Urine R/M– Treat Hyperkalemia, ARF, CHF, acidosis, fluid

overload, HTN and its complications– ACE inhibitors useful in proteinuria– Immunosuppressive therapy: Depending on cause

(Steroids, cyclophosphamide)

Management:

– Idiopathic Hypercalciuria: Hydrochlorothiazide, Potassium citrate, Sodium restriction

– Calculi: Plenty of water– ESRD: Dialysis, Renal transplantation– Correct thrombocytopenia, anemia, coagulation factor

deficiency– Renal vein thrombosis: Anticoagulant therapy or

thrombectomy may be needed– Surgical correction: Calculi, PUJ obstruction, Posterior

urethral valves, Wilms tumour

References:

• Nelson Textbook of Pediatrics, 19th Ed• Nelson Essentials of Pediatrics, 6th Ed• O.P. Ghai Essential pediatrics, 7th Ed• Pediatric Nephrology, Shrivastava, Bagga,

4th Ed• Japanese Society of Nephrology 2007• Indian J Pediatrics 1999; 66 : 207-214• Various Websites