Hematuria

Hematuria is defined as the presence of at least 5 red blood cells (RBCs) per microliter of urine and occurs with a prevalence of 0.5-2.0% among school-age children

Cause of gross hematuria• Urinary tract infection• Meatal stenosis• Perineal irritation• Trauma• Urolithiasis• Hypercalciuria• Coagulopathy• Tumor• Glomerular• Postinfectious glomerulonephritis• Henoch-Schönlein purpura nephritis• IgA nephropathy• Alport syndrome (hereditary nephritis)• Thin glomerular basement membrane disease• Systemic lupus erythematosus nephritis

Other causes of red urine• HEME POSITIVE• Hemoglobin• Myoglobin• HEME NEGATIVE• Drugs• Chloroquine• Deferoxamine• Ibuprofen• Iron sorbitol• Metronidazole• Nitrofurantoin• Phenazopyridine (Pyridium)• Phenolphthalein• Phenothiazines• Rifampin• Salicylates• Sulfasalazine

Dyes (Vegetable/Fruit)BeetsBlackberriesFood and candy coloringRhubarbMetabolitesHomogentisic acidMelaninMethemoglobinPorphyrinTyrosinosisUrates

Cause of Hematuria• UPPER URINARY TRACT DISEASE• Isolated renal disease• Immunoglobulin (Ig) A nephropathy (Berger disease) • Alport syndrome (hereditary nephritis)• Thin glomerular basement membrane nephropathy• Postinfectious GN (poststreptococcal GN)• Membranous nephropathy• Membranoproliferative GN• Rapidly progressive GN• Focal segmental glomerulosclerosis• Anti–glomerular basement membrane disease

ContinueMultisystem diseaseSystemic lupus erythematosus nephritisHenoch-Schönlein purpura nephritisGranulomatosis with polyangiitis (formerly Wegener granulomatosis)Polyarteritis nodosaGoodpasture syndromeHemolytic-uremic syndromeSickle cell glomerulopathyHIV nephropathy

Tubulointerstitial diseasePyelonephritisInterstitial nephritisPapillary necrosisAcute tubular necrosis

• Vascular• Arterial or venous thrombosis• Malformations (aneurysms, hemangiomas)• Nutcracker syndrome• Hemoglobinopathy (sickle cell trait/disease)• Crystalluria• Anatomic• Hydronephrosis• Cystic-syndromic kidney disease• Polycystic kidney disease• Multicystic dysplasia• Tumor (Wilms tumor, rhabdomyosarcoma, angiomyolipoma,• medullary carcinoma)• Trauma

LOWER URINARY TRACT DISEASE• Inflammation (infectious and noninfectious)• Cystitis• Urethritis• Urolithiasis• Trauma• Coagulopathy• Heavy exercise• Bladder tumor• Factitious syndrome, factitious syndrome by proxy†

Approach to a patient of hematuria• Hemoglobinuria without hematuria can occur in the presence of acute or

chronic hemolysis. Myoglobinuria without hematuria occurs in the presence of rhabdomyolysis resulting from skeletal muscle injury and is generally associated with a 5-fold increase in the plasma concentration of creatinine kinase.

Upper urinary tract sources of hematuria originate within the nephron (glomerulus, tubular system,or interstitium). Lower urinary tract sources of hematuria originate from the pelvocaliceal system, ureter, bladder, or urethra.

.Hematuria from within the glomerulus is often associated with brown, cola or tea colored, or burgundy urine, proteinuria >100 mg/dL via dipstick, urinary microscopic findings of RBC casts, and deformed urinary RBCs (particularly acanthocytes). Hematuria originating within the tubular system may be associated with the presence of leukocytes or renal tubular casts. Lower urinary tract sources of hematuria may be associated with gross hematuria that is bright red or pink, terminal hematuria (gross hematuria occurring at the end of the urine stream), blood clots, normal urinary RBC morphology, and minimal proteinuria on dipstick (<100 mg/dL).

• history of recent upper respiratory, skin, or gastrointestinal infection suggests postinfectious glomerulonephritis, hemolytic-uremic syndrome, or

• HSP nephritis. Rash and joint complaints suggest HSP or SLE nephritis.

Patients with hematuria can present with a number of symptoms suggesting specific disorders. Tea- or cola-colored urine, facial or body edema, hypertension, and oliguria are classic symptoms of glomerulonephritis. Diseases commonly manifesting as glomerulonephritis include postinfectious glomerulonephritis, immunoglobulin A (IgA) nephropathy, membranoproliferative glomerulonephritis, Henoch-Schönlein purpura (HSP) nephritis, systemic lupus erythematosus (SLE) nephritis, granulomatosis with polyangiitis (formerly Wegener granulomatosis), microscopic polyarteritis nodosa, Goodpasture syndrome, and hemolytic-uremic syndrome

• Hematuria associated with glomerulonephritis is typically painless, but can be associated with flank pain when acute or unusually severe.

• Frequency, dysuria, and unexplained fevers suggest a urinary tract infection, whereas renal colic suggests nephrolithiasis.

• A flank mass can suggest hydronephrosis, renal cystic diseases, renal vein thrombosis, or tumor.

• Hematuria associated with headache, mental status changes, visual changes (diplopia), epistaxis, or heart failure suggests significant hypertension.

. Hereditary glomerular diseases include hereditary nephritis (Alport syndrome), thin glomerular basement membrane disease, SLE nephritis, and IgA nephropathy (Berger disease).

• Several malformation syndromes are associated with renal disease including VATER (vertebral body anomalies, anal atresia, tracheoesophageal fistula, and renal dysplasia) syndrome.

• Abdominal masses may be caused by bladder distention in posterior urethral valves, hydronephrosis in ureteropelvic junction obstruction, polycystic kidney disease, or Wilms tumor.

• Hematuria seen in patients with neurologic or cutaneous abnormalities may be the result of a number of syndromic renal disorders including tuberous sclerosis, von Hippel-Lindau syndrome, and Zellweger (cerebrohepatorenal) syndrome

• The most common cause of gross hematuria is bacterial urinary tract infection.

• Urethrorrhagia, which is urethral bleeding in the absence of urine, is associated with dysuria and blood spots on underwear after voiding. This condition, which often occurs in prepubertal boys at intervals several months apart, has a benign self-limited course

• Recurrent episodes of gross hematuria suggest IgA nephropathy, Alport syndrome, or thin glomerular basement membrane disease.

• Dysuria and abdominal or flank pain are symptoms of idiopathic hypercalciuria, or urolithiasis.

Cola/brown urine?Proteinuria (30 mg/dL)?RBC casts?Acute nephritic syndrome?

YesGlomerular hematuria• CBC with differential• Electrolytes, Ca• BUN/Cr• Serum protein/albumin• Cholesterol• C3/C4• ASO/anti-DNase B• ANA• Antineutrophil antibody• Throat/skin culture(if indicated)• 24-hr urinetotal proteincreatinine clearance

NOExtraglomerular hematuriaStep 1• Urine cultureStep 2• Urine calcium/creatinine• Sickle prep (African American)• Renal/bladder ultrasoundStep 3• Urinalysis: siblings, parents• Serum electrolytes, Cr, Ca• If crystalluria, urolithiasis, ornephrocalcinosis:*24-hr urine for Ca, creatinine,uric acid, oxalate• If hydronephrosis/pyelocaliectasis:*Cystogram, renal scan

Immunoglobulin A Nephropathy(Berger Nephropathy)

• IgA nephropathy is an immune complex disease initiated by excessive amounts of poorly galactosylated IgA1 in the serum causing the production of IgG and IgA autoantibodies.

• C/F:• Hematuria• Proteinuria• Hypertension• Normal c3 level

PATHOLOGY AND PATHOLOGIC DIAGNOSIS

• Focal and segmental mesangial proliferation and increased mesangial matrix are seen in the glomerulus

IgA nephropathy is an immune complex disease initiated by excessive amounts of poorly galactosylated IgA1 in the serum causing the production of IgG and IgA autoantibodies.

Management

• The primary treatment of IgA nephropathy is appropriate blood• pressure control and management of significant proteinuria.• Angiotensin-converting enzyme inhibitors and angiotensin II receptor• antagonists are effective in reducing proteinuria and retarding the rate• of disease progression when used individually or in combination. Fish• oil, which contains antiinflammatory omega-3 polyunsaturated fatty• acids, may decrease the rate of disease progression in adults. If

reninangiotensin• blockade proves ineffective and significant proteinuria• persists, then addition of immunosuppressive therapy with

corticosteroids• is recommended.

Alport Syndrome

• GENETICS• Approximately 85% of patients have X-linked inheritance caused by a

mutation in the COL4A5 gene encoding the α5 chain of type IV collagen

PATHOLOGY

• Kidney biopsy specimens during the 1st decade of life show few changes on light microscopy. Later, the glomeruli may develop mesangial proliferation and capillary wall thickening, leading to progressive glomerular sclerosis. Tubular atrophy, interstitial inflammation and fibrosis, and lipid-containing tubular or interstitial cells, called foam cells, develop as the disease progresses

CLINICAL MANIFESTATIONS

• Asymptomatic hematuria• Proteinuria• anterior lenticonus (extrusion of the central portion of the lens into the

anterior chamber),macular flecks, and corneal erosions• Bilateral sensorineural hearing loss

DIAGNOSIS

• A combination of careful family history, a screening urinalysis of 1stdegree relatives, an audiogram, and an ophthalmologic examination are critical in making the diagnosis of AS. The presence of anterior lenticonus is pathognomonic. AS is highly likely in the patient who has hematuria and at least 2 of the following characteristic clinical features: macular flecks, recurrent corneal erosions, GBM thickening and thinning, or sensorineural deafness

TREATMENT

• Angiotensin-2 receptor inhibitors) can slow the rate of progression.• Careful management of renal failure complications such as hypertension,

anemia, and electrolyte imbalance is critical. Patients with ESRD are treated with dialysis and kidney transplantation

Thin Basement Membrane Disease

. Microscopic hematuria• Gross hematuria• Proteinuria• Hypertension• Renal insufficiency

Thin basement membrane disease (TBMD) is Thin basement membrane disease (TBMD) is defined by the presenceof persistent microscopic hematuria and isolated thinning of the GBM (and, occasionally, tubular basement membranes) on electron microscopy.

Glomerulonephritis Associated with Infection

• Acute PoststreptococcalGlomerulonephritis. CLINICAL MANIFESTATIONS

The typical patient develops an acute nephritic syndrome 1-2 wk after an antecedent streptococcal pharyngitis or 3-6 wk after a streptococcal pyoderm.various degrees of edema, hypertension, and oliguria. Blurred visionSevere headacheAltered mental statusRespiratory distressOrthopneaCoughMalaise Lethargy Abdominal pain

Diagnosis• Urinalysis demonstrates red blood cells, often in association with red

blood cell casts, proteinuria, and polymorphonuclear leukocA rising antibody titer to streptococcal antigen(s) confirms a recent streptococcal infection.

• The antistreptolysin O titer is commonly elevated after a pharyngeal infection but rarely increases after streptococcal skin infection.

The serum C3 level is significantly reduced in >90% of patients in the acute phase, and returns to normal 6-8 wk after onset. Although serum CH50 is commonly depressed

TREATMENT

• Management is directed at treating the acute effects of renal insufficiency and hypertension

• 10 days course of systemic antibiotic therapy with penicillin is recommended to limit the spread of the nephritogenic organisms, antibiotic therapy does not affect the natural history of APSGN Sodium restriction, diuresis (usually with intravenous furosemide)and pharmacotherapy with calcium channel antagonists, vasodilators, or angiotensin-converting enzyme inhibitors, are standard therapies used to treat hypertension

Membranous Nephropathy

• Membranous nephropathy (MN), amongst the most common causes• of nephrotic syndrome in adults, is a rare cause of nephrotic syndrome• in children. MN is classified as the primary, idiopathic form, where• there is isolated renal disease, or secondary MN, where nephropathy• is associated with other identifiable systemic diseases or medications

CLINICAL MANIFESTATIONS

• Most patients also have microscopic hematuria and only rarely present with gross hematuria.

• Approximately 20% of children have hypertension at presentation. • A subset of patients with MN present with a major venous thrombosis,

commonly renal vein thrombosis

TREATMENT

• immunosuppressive therapy with an• extended course of prednisone can be effective in promoting complete

resolution of symptoms.• The addition of chlorambucil or cyclophosphamide appears to provide

further benefit to those not responding to steroids alone. • Rituximab has shown significant promise in adults and has been proposed

by some as first line treatment but has yet to be studied in a randomized controlled trial in any age group.

• For those unresponsive to immunosuppression, or with mild clinical features, proteinuria can be reduced with angiotensin-converting enzyme inhibitors, and by analogy, probably angiotensin-II–receptor blockers.

Goodpasture Disease

• The disease results from attack on these organs(lung and kidney) by antibodies directed against certain epitopes of type IV collagen, located within the alveolar basement membrane in the lung and glomerular basement membrane (GBM) in the kidney.

PATHOLOGY

Kidney biopsy shows crescentic glomerulonephritis in most patients.Immunofluorescence microscopy demonstrates continuous lineardeposition of immunoglobulin G along the GBM

Goodpasture Disease• Clinical feature:• Hematuria• Proteinuria• Hypertension• Renal failure• Anti GBM antibody present• Serum c3 normal.

DIAGNOSIS

The diagnosis is made by a combination of the clinical presentation of pulmonary hemorrhage with acute glomerulonephritis, the presence of serum antibodies directed against GBM (anti–type IV collagen in GBM), and characteristic renal biopsy findings.

PROGNOSIS AND TREATMENT

• Untreated, the prognosis of Goodpasture disease is poor.• The combination of high-dose intravenous methylprednisolone,

cyclophosphamide, and plasmapheresis appears to improve survival

Renal Vein Thrombosis

• Renal vein thrombosis (RVT) occurs in 2 distinct clinical settings: (1)• In newborns and infants, RVT is commonly associated with asphyxia,• dehydration, shock, sepsis, congenital hypercoagulable states, and• maternal diabetes; and (2) in older children, RVT is seen in patients• with nephrotic syndrome, cyanotic heart disease, inherited

hypercoagulable states, sepsis, following kidney transplantation, and following exposure to angiographic contrast agents.

CLINICAL MANIFESTATIONS

• The development of RVT is classically heralded by the sudden onset of• gross hematuria and unilateral or bilateral flank masses. However,• patients can also present with any combination of microscopic hematuria,• flank pain, hypertension, or a microangiopathic hemolytic• anemia with thrombocytopenia or oliguria. RVT is usually unilateral.• Bilateral RVT results in acute kidney failure

TREATMENT

• correction of fluid and electrolyte imbalance and• treatment of renal insufficiency. • The American College of Chest Physicians recommends that the additional

initial treatment of bilateral RVT should include tissue plasminogen activator and unfractionated heparin followed by continued anticoagulation with unfractionated or low-molecular-weight heparin.

Glomerulonephritis Associated with Infection

• AcutePoststreptococcalGlomerulonephritisCLINICAL MANIFESTATIONS

The typical patient develops an acutenephritic syndrome 1-2 wk after an antecedent streptococcal pharyngitisor 3-6 wk after a streptococcal pyoderm

various degrees of edema, hypertension,and oliguria. Patients are at risk for developing encephalopathy and/orheart failure secondary to hypertension or hypervolemia. Hypertensiveencephalopathy must be considered in patients with blurred vision,severe headaches, altered mental status, or new seizuresRespiratory distress,orthopnea, and cough may be symptoms of pulmonary edema andheart failure. Peripheral edema typically results from salt and waterretention and is common; nephrotic syndrome develops in a minority(<5%) of childhood cases. Nonspecific symptoms such as malaise, lethargy,abdominal pain, or flank pain are common

Diagnosis• Urinalysis demonstrates red blood cells, often in association with red

blood cell casts, proteinuria, and polymorph nuclear leukocA rising antibody

• titer to streptococcal antigen(s) confirms a recent streptococcal infection.• The antistreptolysin O titer is commonly elevated after a pharyngeal

infection but rarely increases after streptococcal skin infection .

The serum C3 level is significantly reduced in >90% of patients in the acute phase, and returns to normal 6-8 wk after onset. Although serum CH50 is commonly depressed

TREATMENT

• Management is directed at treating the acute effects of renal insufficiency and hypertension

• Ten days course of antibiotics with penicillin.

Membranous Nephropathy

• It may be primary or it may be secondary.• Secondary membranous nephropathy is common in children.• Cause:• Chronic hepatitis B infection• Congenital syphilis• Malaria• Penicillamine and gold• neuroblaastoma

PATHOLOGY

• Glomeruli have diffuse thickening of the glomerular basement membrane (GBM), without significant cell proliferative changes

• Granular deposits of immunoglobulin G and C3 located on the epithelial side of the GBM.

Hematologic Diseases Causing Hematuria

• ETIOLOGY• The renal manifestations of sickle cell nephropathy (SSN) are generally

related to microthrombosis secondary to sickling in the relatively hypoxic, acidic, hypertonic renal medulla where vascular stasis is present Sickle Cell Nephropathy

CLINICAL MANIFESTATIONS

• Clinical manifestations of SSN include polyuria caused by a urinary concentrating defect, renal tubular acidosis, and proteinuria associated with the glomerular lesions

PATHOGENESIS

TREATMENT

• angiotensin-converting enzyme inhibitors and/or angiotensin II receptor inhibitors can be used to effect a significant reduction in urine protein excretion in patients with daily urine protein excretion exceeding 500 mg, and may slow progression of renal failure. Gross hematuria

• secondary to papillary necrosis may respond to treatment with• ε-aminocaproic acid or desmopressin acetate. Hydroxyurea and

newer• treatments for sickle cell disease

Autosomal Recessive PolycysticKidney Disease

• Also previously referred to as infantile polycystic disease, autosomal• recessive polycystic kidney disease (ARPKD) is an autosomal recessive• disorder occurring with an incidence of 1 : 10,000 to 1 : 40,000, and a• gene carrier rate in the general population of 1/70. The gene for• ARPKD (PKHD1 [polycystic kidney and hepatic disease]) encodes• fibrocystin, a large protein (>4,000 amino acids) with multiple• isoforms

CLINICAL MANIFESTATIONS• The typical child presents with bilateral flank masses during the neonatal• period or in early infancy. ARPKD may be associated with oligohydramnios,• pulmonary hypoplasia, respiratory distress, and• spontaneous pneumothorax in the neonatal period. Perinatal demise• (approximately 25-30%) appears to be associated with truncating• mutations. Components of the oligohydramnios complex (Potter

syndrome), including low-set ears, micrognathia, flattened nose, limbpositioning defects, and intrauterine growth restriction, may be present at death from pulmonary hypoplasia. Hypertension is usually noted within the first few weeks of life, is often severe, and requires aggressive multidrug therapy for control. Oliguria and acute renal failure are uncommon, but transient hyponatremia, often in the presence of acute renal failure, often responds to diuresis. Renal function is usually

• impaired but may be initially normal in 20-30% of patients. Approximately• 50% of patients with a neonatal-perinatal presentation develop end-stage

renal disease (ESRD) by age 10 yr.

TREATMENT• The current treatment of ARPKD is supportive. Aggressive ventilatory• support is often necessary in the neonatal period secondary to pulmonary• hypoplasia, hypoventilation, and the respiratory illnesses of prematurity.• Careful management of hypertension (angiotensin-converting• enzyme inhibitors), fluid and electrolyte abnormalities, osteopenia,• and clinical manifestations of renal insufficiency is essential. Children• with severe respiratory failure or feeding intolerance from enlarged• kidneys can require unilateral or, more commonly, bilateral

nephrectomies, prompting the need for renal replacement therapy. For many children approaching ESRD therapy, significant portal hypertension is present. This in combination with the dramatic improvement in liver

• transplantation survival has led to consideration of dual renal and hepatic transplantation in a carefully selected group of patients. Dual transplantation thus avoids the later development of end-stage liver

• disease despite successful renal transplantation

Autosomal Dominant PolycysticKidney Disease

• The severity of renal disease and the clinical manifestations of ADPKD• are highly variable. Although symptomatic ADPKD commonly occurs• in the 4th or 5th decade of life, symptoms, including gross or microscopic• hematuria, bilateral flank pain, abdominal masses, hypertension,• and urinary tract infection, may be seen in neonates, children,• and adolescents

TREATMENT AND PROGNOSIS

• Treatment of ADPKD is primarily supportive. Control of blood pressure• is critical because the rate of disease progression in ADPKD correlates• with the presence of hypertension. Angiotensin-converting• enzyme inhibitors and/or angiotensin II receptor antagonists are• agents of choice. Obesity, caffeine ingestion, smoking, multiple

pregnancies,• male gender, and possibly the use of calcium channel blockers• appear to accelerate disease progression. Older patients with a family• history of intracranial aneurysm rupture should be screened for cerebral• aneurysms

Lower Urinary TractCauses of Hematuria

• Infectious Causes of Cystitis• Hemorrhagic Cystitis and Urethritis