Approach to a child with hematuria

1. Approach to a child with H ematuria : Sunil Agrawal 1 st year MD Pediatrics, IOM

2. Contents: Introduction Pathophysiology Causes History Examination Investigations Management

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

4. 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

5. Causes of Hematuria : 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

6. B) Extraglomerular hematuria Upper Urinary tract Tubulointerstitial Pyelonephritis Interstitial nephritis ATN Papillary necrosis Nephrocalcinosis Anatomic Hydronephrosis Polycystic kidney disease Tumor ( Wilms , Rhabdomyosarcoma , A ngiomyolipoma ) Trauma

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

8. Lower urinary tract Inflammation- infectious and non infectious Cystitis Urethritis Urolithiasis Trauma Coagulopathy Heavy exercise Bladder tumor Factitious syndrome / by proxy

9. Common causes of gross hematuria : Urinary tract infection Meatal stenosis Perineal irritation Trauma Urolithiasis / hypercalciuria Coagulopathy Tumor

10. Glomerular cause of gross hematuria IgA nephropathy Alport syndrome Thin glomerular basement membrane disease Post infectious glomerulonephritis HSP nephritis SLE nephritis

11. 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)

12. 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

13. Colour of urine: Colour Causes Dark yellow Normal concentrated urine Dark brown or black Bile pigments Homogentisic 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

14. 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

15. 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

16. 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 )

17. 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

18. 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

19. 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)

20. General Approach to Investigate the child with H ematuria

21. 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 mm 3 of unspun urine False + ve : Urine pH >9, H 2 O 2 False – ve : High ascorbic acid, formalin Also for urine albumin

22. Investigations: Glomerular 1. Brown, cola coloured or smoky 2. RBC casts 3. Proteinuria 2+ or more 4. Deformed urinary RBCs Non - glomerular 1. Bright red, pink 2.Terminal hematuria/ Passage of clots 3. Proteinuria of < 2+ 4. Normal morphology of RBCs Urine microscopy: Presence of RBCs and casts (> 5 RBCs per HPF) in centrifuged urine

23. 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. Yoshida Department 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.

24. 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.

25. 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

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

27. 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 hematuria Step 1 Urine culture Step 2 Urine Ca/Cr Renal/ bladder USG Step 3 Urinalysis: siblings, parents Serum electrolytes, Cr, Ca If crystalluria , urolitiasis or nephrocalcinosis : 24-hr urine for Ca, Cr, Uric acid, oxalate I f hydronephrosis / pyelocaliectasis : cystogram , renal scan

28. 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

29. 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)

30. 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

31. Dx Histology Clinical Lab IgA Nephro-pathy IgA deposition in the mesangium, glomerular sclerosis, proliferative changes, crescents in severe cases Gross, intermittent, painless hematuria No specific changes, although increased serum IgA levels observed in some patients HSP Same as IgA nephropathy Purpura, joint pains, abdominal pain, 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

32. Dx Histology Clinical Lab Alport Syndrome Some thinning of basement membranes, "basket weave" changes in the glomerular basement membrane 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

33. 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

34. Summary

35. 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

36. 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)

37. 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

38. References: Nelson Textbook of Pediatrics , 19 th Ed Nelson Essentials of Pediatrics, 6 th Ed O.P. Ghai Essential pediatrics, 7 th Ed Pediatric Nephrology, Shrivastava , Bagga , 4 th Ed Japanese Society of Nephrology 2007 Indian J Pediatrics 1999; 66 : 207-214 Various Websites

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