Examination by dipstick: (Orthotoluidine & organic peroxidase) Hemoglobin free in urine. Hemoglobin from red blood cells in urine.

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1 Examination by dipstick: (Orthotoluidine & organic peroxidase) Hemoglobin free in urine Hemoglobin from red blood cells in urine Myoglobin

2 Normal erythrocyte excretion rate * /12 h. ( mean ) Upper limit in children * /12 h. T.Addis; J.of Clin Invest, 1926 Concentration ( number of cells per ml ) is highly correlated with excretion rate Detection & quantification of hematuria Screening test ( dipsticks ) mg/dl of Hb, myoglobin - ~5-20 RBC/mm³ Semiquantitative estimation - centrifugation of ml of urine - resuspention of sediment in 1 ml of residual urine - high-power microscopy

3 Microscopic Hematuria Definition > 2 RBC/HPF > 5 RBC/mm³ Hematuria Gross- Blood that can be seen in the urine Microscopic hematuria- microscopical evidence of 2 5 or more red blood cells (RBCs) per high-power field of the urinary sediment > 8000 RBC/ml סיפור מקרה ק.ד בן 14, פניה לרופא מטפל בשל שתן כהה. ספק צבע קוקה קולה. בדיקה גופנית תקינה. ל"ד תקין, ללא סיפור משפחתי. CBC- normal SMA- normal creatinine- 0.5 mg/dl RBC- 20 cell/hpf Protein- neg Ca/cre 0.1 סיפור מקרה בבירור: בדיקות דם: בבדיקות שתן:

4 ANA - neg anti dsdna- neg Immunoglobulins- normal C3 C4- normal TSH- normal סיפור מקרה סונר כליות ודרכי שתן תקין. סיפור מקרה חש בטוב. בדיקה גופנית תקינה. ל"ד תקין. במעבדה- SMA תקין. בשתן RBC מרובים. Transient phenomenon of little significance Hematuria Sign of serious renal disease Hematuria Transient Recurrent Persistent

5 Hematuria Isolated A component of a set of kidney functional abnormalities including proteinuria, hypertension, elevated serum creatinine A part of systemic condition Kidney disease Lesions along the urinary tract Conditions unrelated to kidney and urinary tract Hematuria not representing kidney or urinary tract disorder Following exercise Febrile disorders Gastroenteritis with dehydration Contamination from external genitalia

6 Glomerular hematuria The presence of glomerular hematuria indicates a defect in the glomerular basement membrane (GBM) through which red blood cells (RBCs) egress from the glomerular capillary into the urinary space 22

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8 Glomerular versus extraglomerular bleeding Urinary finding Glomerular Extraglomerular Red cell casts May be present Absent Red cell Dysmorphic Uniform morphology Proteinutia May be present Absent Clots Absent May be present Color May be red or brown May be red Renal causes of Hematuria Glomerular - Acute Postinfectious Glomerulonephritis - IgA Nephropathy - Hereditary Nephritis ( Alport syndrome) - Benign Recurrent or Persistent Hematuria ( Thin Membrane Disease ) 1.Sporadic 2.Familial - Membranoproliferative Glomerulonephritis - Crescentic Glomerulonephritis - Lupus Nephritis - Nephritis of Henoch-Shönlein Purpura - Focal Glomerulosclerosis - Hemolityc-Uremic Syndrome Acute nephritic syndrome Hematuria Proteinuria Reduced renal function Edema Hypertension

9 Renal causes of Hematuria Non-glomerular - Infection ( Pyelonephritis ) - Interstitial Nephritis - Metabolic ( Uric Acid, Nephrocalcinosis ) - Renal Malformation ( Cystic Kidney ) - Tumors ( Wilm s, Acute Leukemia) - Idiopatic Hypercalciuria - Trauma Causes of urinary tract related Hematuria Infection Urolithiasis Obstruction ( UPJ Stenosis ) Trauma Drugs ( Cyclophosphamide ) Persistent asymptomatic isolated microscopic hematuria Persistent- on at least 2 3 separate occasions asymptomatic Isolated- normal serum creatinine level, no proteinuria, no calciuria, normal blood pressure, normal renal imaging, no known or apparent disease Microscopic hematuria- microscopical evidence of 2 5 or more red blood cells (RBCs) per high-power field of the urinary sediment unrelated to exercise, trauma, sexual activity, or menstruation Etiologies of isolated Glomerular Hematuria - Acute Postinfectious Glomerulonephritis - Thin membrane disease( Benign Recurrent or Persistent Hematuria) 1.Sporadic 2.Familial - IgA Nephropathy - Alport syndrome Non-glomerular - Idiopathic Hypercalciuria - Cystic Kidneys - Urinary Tract obstruction - Tumors - Trauma

10 Idiopathic Hypercalciuria Definition: Calcium excretion > 4 mg/kg/day Urinary Ca/Creatinine > 0.2 Possible mechanism of hematuria: microcrystals damaging the tubular or mucosal epithelia. Resolution of hematuria with anticalciuric therapy Persistent asymptomatic isolated microscopic hematuria = benign hematuria? Persistent asymptomatic isolated microscopic hematuria IgA nephropathy Thin basement membrane disease Alport syndrome IgA nephropathy The most common form of primary glomerulonephritis worldwide From benign condition to rapidly progressive renal failure 15 40% of patients will eventually reach ESKD Postinfectious glomerulonephritis

11 IgA nephropathy True prognosis of patients with IgAN manifesting as persistent isolated microscopic hematuria without proteinuria is not completely elucidated. Alport s syndrome Hereditary nephritis Genetically heterogeneous disease Mutations in the genes encoding type IV collagen Clinical, pathologic and prognostic variability. ( hematuria, proteinuria, progressive kidney failure, sensorineural deafness, and ocular abnormalities). ALPORT S SYNDROME Alport syndrome Often the presenting sign of Alport syndrome is persistent isolated microscopic hematuria during childhood A window of opportunity for early intervention.

12 Thin basement membrane disease Recurrent/familial hematuria (idiopathic benign hematuria??) GBM thinning is a pathological description Recent evidence that the disease entity may in fact progress to CKD in some cases

13 14 potential kidney donors with isolated microscopic hematuria 7- Thin basement membrane disease 2 -IgA nephropaty 1 -Focal segmental glomerulosclerosis 4 -non specific findings Vivante, A. et al. JAMA 2011;306:

14 The study cohort was linked to the Israeli treated ESRD registry ( ) Vivante, A. et al. JAMA 2011;306: There is an increased risk for ESRD attributed to primary glomerular disease among subjects with IMH Vivante, A. et al. JAMA 2011;306: % 0.04% Vivante, A. et al. JAMA 2011;306: Presence of persistent asymptomatic isolated microscopic hematuria in persons aged 16 through 25 years was associated with significantly increased risk of treated ESRD for a period of 22 years, although the incidence and absolute risk remain quite low Isolated microscopic hematuria is a common clinical presentation and can indicate the presence of underlying genetic kidney disease In many cases, microscopic hematuria is associated with a genetic defect, and the prognosis varies according to the nature of the molecular change Follow up is necessary

15 RBC- 30 cells/hpf סיפור המקרה- ההמשך באנמנזה - ארוע נוסף של שתן עם מאקרוהמטוריה. בבדיקת שתן: Protein- 700 mg/day ( 19 mg/m2/hr) באיסוף שתן: ביופסיה- IgA nephropathy Evaluation of Hematuria History Detailed review of family history hematuria proteinuria renal insufficiency deafness stones Precipitating factors infection exercise Abdominal pain HSP hydronephrosis pyelonephritis urolithiasis Evaluation of Hematuria Physical Examination Growth failure Hypertension Pallor Edema Rash Abdomen: search for a mass or tenderness External genitalia: bleeding infection trauma

16 Work-up of a child with Hematuria Phase I: Urinalysis ( sediment examination ) RBC s morphology Urine culture BUN, Creatinine, Proteins, Electrolytes Antibodies against strept. & other antigens Complement, ANF, Immunoglobulins Renal US Urinalysis of 1 st degree relatives 24h urine collection: Ca, Creat.,Protein, UA Phase II: Hearing test Cystoscopy Renal biopsy Isolated hematuria The child needs to be monitored for the appearance of new clinical signs: hypertension proteinuria changes in the pattern or severity of hematuria If there is no change in the first year,observation at yearly intervals is adequate Isolated hematuria Possible outcome Disappearance of hematuria Hematuria will persist - follow-up should be continued The hematuria will no longer be isolated - further investigation

17 Has the time come to include dipstick? Genetic consultation for fertile age women? Kidney donation?