Hematuria

1. Salwa Ibrahim, MD MRCP (UK) Professor of Nephrology Cairo University Hematuria

2. AGENDA Definition of hematuria Causes Investigations Glomerular causes

3. Definition Macroscopic (gross) Hematuria Visible (Red Urine ) Microscopic Hematuria >3RBC/HPF from two of three urinary sediments without a urinary tract infection, or menstruation on microscopic evaluation

4. Definition of positivity Urine dipstick of a fresh voided urine sample, containing no preservative, is considered a sensitive means of detecting the presence of hematuria . Routine microscopy for confirmation of dipstick haematuria

5. Causes of hematuria

6. Causes of hematuria Hematuria can be caused by a variety of urothelial , vascular, glomerular , interstitial disorders .

7. Glomerular Hematuria brown, tea colored urine proteinuria deformed urinary RBCs RBC casts

8. Glomerular Hematuria RENAL IgA nephropathy Alport syndrome Thin glomerular BM disease Post infectious MPGN MULTI-SYSTEM SLE nephritis HSP nephritis Wegener syndrome Goodpasture syndrome HUS Sickle cell Disease

9. W/U for Glomerular Hematuria CBC C3, C4 antistreptolysin -O titer, HBV, HCV serum electrolytes, BUN, serum Cr, serum albumin Antinuclear cytoplasmic antibody titer ANA, ds DNA

10. Extraglomerular Hematuria Hematuria from lower urinary tract terminal hematuria blood clots nl urinary RBCs minimal proteinuria

11. Extraglomerular Hematuria UPPER URINARY TRACT pyelonephritis ATN papillary necrosis nephrocalcinosis thrombosis malformation SCD tumor PCKD LOWER URINARY TRACT cystitis urethritis urolithiasis trauma coagulopathy heavy excersise UPJ obstruction ureterocele

12. Exercise induced hematuria •Gross or microscopic hematuria that occurs after strenuous exercise and resolves with rest •Direct trauma to the kidneys and/or bladder may be responsible for the hematuria •Renal ischemia due to shunting of blood to exercising muscles •Exercise-induced gross hematuria should be differentiated from two other potential causes of red to brown urine following exercise: myoglobinuria due to rhabdomyolysis ; and march hemoglobinuria •Evaluation is not warranted in patients under age fifty who are not at increased risk for bladder or kidney cancer •Evaluation for other causes of hematuria is warranted if the hematuria persists well beyond one week

13. Gomerular causes of hematuria

14. Causes Any Glomerular disease may present with Hematuria Approximately 50 percent of patients with idiopathic hematuria have a glomerular disease Most patients also have other signs such as proteinuria, red cell casts, or renal insufficiency There are three disorders that account for most cases of persistent isolated hematuria due to glomerular disease: IgA nephropathy, Hereditary nephritis (Alport syndrome), and thin basement membrane nephropathy

15. Thin basement membrane disease or benign familial hematuria Mutations of the type IV collagen genes COL4A3 and COL4A4 TBMN is often familial, probably with autosomal dominant inheritance A family history of hematuria is noted in 30 to 50 percent of cases Persistent or intermittent asymptomatic microscopic hematuria The long-term prognosis is excellent in most patients with true thin basement membrane nephropathy We don't biopsy these patients Slowly progressive renal insufficiency can occur and is often manifested on renal biopsy by focal segmental glomerulosclerosis

16. Uniform thinning of lamina dense of glomerular basement membrane to 200 nm in > 50% of glomerular capillaries

17. Alport syndrome Inherited progressive form of glomerular disease Often associated with sensorineural hearing loss and ocular abnormalities Primary basement membrane disorder arising from mutations in genes encoding several members of the type IV collagen protein family X-linked (80%)• Autosomal recessive (15%)• Autosomal dominant (5%) Initial renal manifestation of Alport syndrome is asymptomatic persistent microscopic hematuria, which is present in early childhood in affected patients ESRD usually occurs between the ages of 16 and 35 years in patients with X-linked or autosomal recessive disease and they end up on dialysis

18. Diagnosis of Alport syndrome

19. The following 10 criteria of which 4 must be met for the diagnosis of Alport syndrome Family history of nephritis of unexplained haematuria in a first degree relative of the index case or in a male relative linked through any numbers of females. Persistent haematuria without evidence of another possibly inherited nephropathy such as thin GBM disease, polycystic kidney disease or IgA nephropathy. Bilateral sensorineural hearing loss in the 2000 to 8000 Hz range. The hearing loss develops gradually, is not present in early infancy and commonly presents before the age of 30 years. A mutation in COL4A. Immunohistochemical evidence of complete or partial lack of the Alport epitope in glomerular , or epidermal basement membranes, or both. Widespread GBM ultrastructural abnormalities, in particular thickening, thinning and splitting. Ocular lesions including anterior lenticonus, kerataconus , posterior subcapsular cataract, posterior polymorphous dystrophy and retinal flecks. Macrothrombocytopenia or granulocytic inclusions. Diffuse leiomyomatosis of esophagus or female genitalia, or both.

20. Light microscopy shows mesangial cell proliferation and capillary wall thickening, progressing to glomerular sclerosis and tubulo -interstitial changes

21. This shows glomerular basement membrane changes including splitting of lamina densa and lamellation

22. Retinal flecks

23. Alport syndrome: lenticonus bulging of lens

24. IgA Nephropathy (Berger's disease)

25. IgA nephropathy IgA nephropathy is the most common cause primary glomerulonephritis 2:1 male to female predominance Greatest frequency in Asians and Caucasians Relatively rare in blacks Negative family history See in someone with a recent history of cold or sore throat and then they have hematuria

26. IgA nephropathy: pathogenesis The initiating event in the pathogenesis of IgA nephropathy is the mesangial deposition of IgA There is reduced galactosylation and variable changes in sialylation of the IgA1 hinge region O- glycans

27. Diagnosis of IgA kidney biopsy = IgA deposition on mesangium-pathognomnic finding = seen on immunofluroescence = prominent, globular deposits of IgA in mesangium and to lesser degree along glomerular capillary wall

28. IgA Nephropathy

29. IgA nephropathy

30. IgA Nephropathy

31. C/P of IgA One or recurrent episodes of gross hematuria, usually following an upper respiratory infection Microscopic hematuria and usually mild proteinuria Nephrotic syndrome Acute rapidly progressive glomerulonephritis

32. Prognosis of IgA if you see high proteinuria then it is a bad prognosis. If you see little proteinuria then there is a good prognosis. Patients with IgA nephropathy and little or no proteinuria (<500 mg/day) have a low risk of progression in the short term. Among patients who develop overt proteinuria and/or elevated serum creatinine concentration, progression to ESRD is approximately 15 to 25 percent at 10 years and 20 to 30 percent at 20 years.

33. Treatment of IgA NONIMMUNOSUPPRESSIVE THERAPIES The optimal approach to the treatment of IgA nephropathy is uncertain Angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARB) both for blood pressure control and to slow progression of the renal disease, cut down on the proteinuria Fish oil, safe to use and does not cause problems 2 . IMMUNOSUPPRESSIVE THERAPY Glucocorticoids Cytotoxic agents

34. Secondary IgA nephropathy A variety of systemic diseases are associated with IgA nephropathy such as liver failure, celiac disease, rheumatoid arthritis, Reiter's disease, ankylosing spondylitis and HIV.

35. Henoch–Schönlein purpura HSP is a systemic vasculitis (inflammation of blood vessels) and is characterized by deposition of immune complexes containing the antibody IgA. Rash, arthritis, abdominal pain and hematuria

36. Acute poststreptococcal glomerulonephritis

37. C/P of poststrept GN In general, the latent period is 1-2 weeks after a throat infection and 3-6 weeks after a skin infection. Dark urine (brown-, tea-, or cola-colored)This is often the first clinical symptom. Dark urine is caused by hemolysis of red blood cells that have penetrated the glomerular basement membrane and have passed into the tubular system. The onset of puffiness of the face or eyelids is sudden. It is usually prominent upon awakening and, if the patient is active, tends to subside at the end of the day In some cases, generalized edema and other features of circulatory congestion, such as dyspnea , may be present. Edema is a result of a defect in renal excretion of salt and water.

38. Laboratory investigations Evidence of preceding streptococcal infection Antibody titers to extracellular products of streptococci are positive in more than 95% of patients with pharyngitis and 80% of patients with skin infections. The antistreptolysin (ASO), antinicotinamide adenine dinucleotidase (anti-NAD), antihyaluronidase ( AHase ), and anti– DNAse B are commonly positive after pharyngitis , and anti– DNAse B and AHase titers are more often positive following skin infections. Serologic findings: Low serum complement levels indicative of an antigen-antibody interaction are a universal finding in the acute phase of APSGN.

39. Red casts and red cells in urine

40. Hypercellularity of the glomeruli The cell types typically present include endothelial and mesangial cells and migrant inflammatory cells, which include polymorphonuclear leukocytes and monocytes

41. Deposits of immunoglobulin G and C3 in a diffuse granular pattern are present along the glomerular capillary wall and mesangium

42. The most consistent and classic diagnostic finding is the presence of glomerular subepithelial electron-dense immune-type deposits

43. DD of acute Nephritis Lupus nephritis Cryoglobulinemia Anti GBM disease Membranoprolilerative GN

44. Localization of Hematuria

45. Localization of Hematuria Glomerular Brown or tea-colored RBC cast, cellular cast Tubular cells Proteinuria >2+ Dysmorphic erythrocytes Non- glomerular Red-pink urine Blood clots No proteinuria or <2 Normal morphology of erythrocytes

46. Hematuria Patient comes to your office complaining that their urine is reddish in color ... What is your first step?

47. Laboratory Diagnosis of Hematuria Urinalysis Even though most urine samples are early morning urine, for analysis of corpuscular elements, the so-called “second morning urine” is more suitable and recommended. Analysis should follow rapidly, preferably within 1 hour for sediment analysis and 2 hours for dipstick testing.

48. Negative Trace (non-hemolyzed) Moderate (non-hemolyzed) Trace (hemolyzed) + (weak) ++ (moderate) +++ (strong) The Urine Dipstick: Blood

49. Significance - Haematuria (nephritis, trauma, etc) - Hemoglobinuria ( hemolysis , etc) - Myoglobinuria ( rhabdomyolysis , etc) Limitations - Cannot distinguish between the above disease processes Uses and Limitations of Urine Blood Detection

50. Myoglobinuria

51. HEMOGLOBINURIA RBC abnormality Defects of RBC membrane structure and function (hereditary spherocytosis ) Deficiency of enzymes ( favism ) Hemoglobinopathy ( thalassemia ) PNH

52. Phase-contrast microscopy to distinguish glomerular from post glomerular bleeding post glomerular bleeding: normal size and shape of RBC glomerular bleeding: dysmorphic RBC ( acanthocyte )

53. EXAMPLE OF PHASE-CONTRAST MICROSCOPY TEST (glomerlar)

54. EXAMPLE OF PHASE-CONTRAST MICROSCOPY TEST (non-glomerlar)

55. Urine Cytology The sensitivity of urine cytology for the diagnosis of urothelial cell cancer is low, and a negative result does not exclude patients from further testing. It has been shown in multiple studies that the addition of urine cytology in the primary analysis of hematuria does not contribute to diagnosis which is usually made by cystoscopy or imaging.

56. Urine Culture The addition of cultures of urine may be indicated if the sediment shows leukocytes.

57. Clinical Chemistry Important to support a nephrologic diagnosis RFT Coagulation profile

58. Immunology Antinuclear antibody (ANA) , Anti-double stranded ( ds ) antibody C3 & C4 complement concentrations Low in SLE, acute post infectious glomerulonephritis , Cryoglobulinemia ASO titre High after streptococcal infection

59. Serology Hepatitis B and C, HIV serology ANCA test for diagnosis of vascuilitis Anti-GBM antibodies in GP syndrome C-ANCA P-ANCA

60. Cystoscopy The American Urological Association best practice policy suggests that, in patients at low risk for urothelial cancer, cystoscopy may be avoided. Imaging of the bladder should preferably precede cystoscopy , so it can aid the urologist and improve diagnostic yield.

61. Radiologic Diagnosis of Hematuria Radiologic imaging plays a pivotal role in the diagnosis of hematuria No specific diagnostic algorithm for hematuria

62. Abdominal Radiographs Its overall sensitivity for renal and ureteral stones is only 45–60% in multiple studies

63. Non-contrast CT It is now the reference standard for stone detection, and even very-low-dose unenhanced CT techniques with a radiation dose comparable to that of abdominal radiographs have shown better results

64. ADPKD

65. Ultrasound Ultrasound is suitable as first-line diagnostic test In comparison with excretory urography , ultrasound showed a higher sensitivity for bladder tumors and equal (i.e., moderate) sensitivity for upper urinary tract tumors. Ultrasound alone is not sensitive (19–32%) for stone detection,

66. ADPKD

67. Excretory Urography For hematuria, multiple studies have now shown the superiority of CT urography over excretory urography . There is also a low sensitivity (< 60%) for renal tumors smaller than 3 cm for excretory urography

68. MR Urography (MRU) MRU has inherent advantages in that it does not require ionizing radiation, has a high contrast resolution, has good sensitivity for contrast media, and has the possibility for better tissue characterization than other imaging techniques do

69. MR Urography (MRU) However, MRU is costly, technically demanding, and not widely practiced. Therefore , MRU expertise is available only in specific dedicated centers. It is good for pediatric diseases and for the evaluation of obstructive disease.

70. Nephrological referral + biopsy Evidence of declining GFR (by >10ml/min at any stage within the previous 5 years or by >5ml/min within the last 1 year) Stage 4 or 5 CKD ( eGFR <30ml/min ) Significant proteinuria Isolated hematuria with hypertension in those aged < 40 Visible haematuria coinciding with intercurrent (usually upper respiratory tract) infection

71. Quiz

72. Quiz time #1 10 yr old boy coming in for school physical. Found to have 30 RBC/ hpf on microscopic analysis. Family Hx reveals uncle used to have “blood in his urine” What is your diagnosis?

73. Quiz time #1 Familial Causes of Hematuria Polycystic kidney disease Thin basement membrane disease Alport syndrome (hereditary nephritis with deafness) Hypercalciuria with family history of nephrolithiasis Sickle Cell ANEMIA

74. Quiz time #2 Gross hematuriain 6 year old boy 3 days following a URI What is your diagnosis?

75. IgA Nephropathy (Berger’s Disease) IgA deposits seen on renal biopsy nl C3 elevated IgA in 15% often hypertensive need long-term f/u

76. Quiz time #3 This kid was in your office 2 weeks ago. Mom is calling and saying his urine looks like coca-cola. What is your diagnosis?

77. Acute Post-Infectious Glomerulonephritis Caused by nephritogenic GAS infections of the pharynx or skin Most children recover complete renal function C3 levels LOW initially, then return to NL after 6-8 wks may have High BP , proteinuria, hematuria for up to 3 mos after initial presentation

78. Quiz time #4 14 years female with hematuria More “tired” lately

79. Lupus nephritis class IV