1. Hematuria

2. HAEMATURIA Common finding Incidental DEFINING HAEMATURIA
Visible haematuria
Non visible haematuria (dipstick and microscopic)

3. Suspected if a red or brown color change of urine
Gross hematuria:
Suspected if a red or brown color change of urine
Medications (phenazopyridine)
Ingestion of certain dyes
Myoglobinuria or hemoglobinuria
If pass clot, indicate urinary source

4. Causes of heme-negative red urine
Medications
Food dyes
Metabolities
Doxorubicin
Beets (in selected patients)
Bile pigments
Chloroquine
Blackberries
Homogentisic acid
Deferoxamine
Food coloring
Melanin
Ibuprofen
Methemoglobin
Iron sorbitol
Porphyrin
Nitrofurantoin
Tyrosinosis
Phenazopyridine
Urates
Phenolphthalein
Rifampin

5. Microscopic hematuria:
Accidental finding from UA or urine dipstick
3 or more RBC/hpf.
No "safe" lower limit below which significant disease can be excluded
Often asymptomatic

6. Dx:
The urine sediment is the gold standard for the detection of microscopic hematuria
Dipsticks for heme are as sensitive as urine sediment examination,
but result in more false positive tests due to the following
A positive dipstick test must always be confirmed with microscopic examination of the urine

7. The evaluation should address the following three questions
1. Are there any clues from the history or physical examination that suggest a particular diagnosis?
2. Does the hematuria represent glomerular or extraglomerular bleeding?
3. Is the hematuria transient or persistent?
16 TI Clinical practice. Microscopic hematuria. AU Cohen RA; Brown RS SO N Engl J Med 2003 Jun 5;348(23):

8. a three-tube test may also help to locate the source of bleeding in selected cases.
Urethral: First mL
Bladder: Final mL
Upper urinary tract: Throughout

9. Goal is to quickly identify
Infection
Kidney stone
Malignant
Need immediate attention

10. History and Physical

11. History 􀂄 Dysuria, frequency, urgency 􀂄 Trauma 􀂄 Strenuous exercise
Abdominal or flank pain
􀂄 Dysuria, frequency, urgency
􀂄 Trauma
􀂄 Strenuous exercise
􀂄 Menstruation
􀂄 Recent URI/ sore throat
􀂄 Skin rashes/ skin infection
􀂄 Diarrhea (especially bloody)
􀂄 Joint pains/swellings
􀂄 Medications/toxins
􀂄 h/o sickle cell disease or sickle trait

12. Family history Hematuria , Hearing loss, HTN, Stones, Renal disease,
Dialysis or transplant,
Sickle cell trait *:
Coagulopathy,

13. Medication Hx Substances and Medications Affecting Urine Color
Artificial food coloring Beets Berries Chloroquine (Aralen) Furazolidone (Furoxone) Hydroxychloroquine (Plaquenil) Nitrofurantoin (Furadantin) Phenazopyridine (Pyridium) Phenolphthalein Rifampin (Rifadin)
Information from Restrepo NC, Carey PO. Evaluating hematuria in adults. Am Fam Physician 1989; 40(2):149-56, and Drugdex system. Englewood: Colo.: Micromedex, Inc., Accessed Sept. 24, 1998.

14. Physical Exam 􀂄 Vital sign: BP, T, HR
Skin: Rashes, evidence or trauma, bruising
􀂄 Abdomen for masses, tenderness (flank, suprapubics), bruits
􀂄 CVS: irregular irregular
􀂄 Edema (especially periorbital)
􀂄 Joint erythema, swelling, warmth
􀂄 Paleness, jaundice
􀂄 Careful inspection of external genitalia
Prostate
If BP is elevated, further evaluation is immediately warranted

15. Physical Examination Findings and Associated Causes of Hematuria
Cause of hematuria
General (systemic) examination
Severe dehydration
Renal vein thrombosis
Peripheral edema
Nephrotic syndrome, vasculitis
Cardiovascular system
Myocardial infarction
Renal artery embolus or thrombus
Atrial fibrillation
Hypertension
Glomerulosclerosis with or without proteinuria
Abdomen
Bruit
Arteriovenous fistula
Genitourinary system
Enlarged prostate
Urinary tract infection
Phimosis
Meatal stenosis

16. Clues from the history that point toward a specific diagnosis
1. Concurrent pyuria and dysuria, indicate UTI, may also occur with bladder malignancy.
2. A recent URI, raise the possibility of either post infectious glomerulonephritis or IgA nephropathy
3. A positive family history of renal disease give suspicion of hereditary nephritis, polycystic kidney disease, or sickle cell disease.
4. Unilateral flank pain radiating to the groin, suggesting ureteral obstruction due to a calculus or blood clot, but can occasionally be seen with malignancy. Flank pain that is persistent or recurrent can also occur in the rare loin pain hematuria syndrome.
5. Symptoms of prostatic obstruction in older men such as hesitancy and dribbling. The cellular proliferation in BPH is associated with increased vascularity, and the new vessels can be fragile.
Concurrent pyuria and dysuria, which are usually indicative of a urinary tract infection, but may also occur with bladder malignancy.
A recent upper respiratory infection, suggesting either postinfectious glomerulonephritis or IgA nephropathy (see "Hematuria following an upper respiratory infection").
A positive family history of renal disease, as in hereditary nephritis, polycystic kidney disease, or sickle cell disease.
Unilateral flank pain, which may radiate to the groin, suggesting ureteral obstruction due to a calculus or blood clot, but can occasionally be seen with malignancy. Flank pain that is persistent or recurrent can also occur in the rare loin pain hematuria syndrome. (See "Loin pain hematuria syndrome").
Symptoms of prostatic obstruction in older men such as hesitancy and dribbling. The cellular proliferation in benign prostatic hyperplasia (BPH) is associated with increased vascularity, and the new vessels can be fragile. There is some controversy about whether hematuria is more common in these patients than in age-matched controls [11,17] . However, there is general agreement that the presence of BPH should not dissuade the clinician from pursuing further evaluation of hematuria, particularly since older men are more likely to have more serious disorders such as cancer of the prostate or bladder. Among those with gross hematuria in whom no other cause can be identified, finasteride usually suppresses the hematuria [18,19] . (See "Medical treatment of benign prostatic hyperplasia").
Recent vigorous exercise or trauma (see "Exercise-induced hematuria").
History of a bleeding disorder or bleeding from multiple sites due to uncontrolled anticoagulant therapy. In contrast, it should not be assumed that hematuria alone can be explained by chronic warfarin therapy. In one report of 243 patients prospectively followed for two years, the incidence of hematuria was similar to that in a control group not receiving warfarin [20] . Furthermore, evaluation of patients who developed hematuria revealed a genitourinary cause in 81 percent of cases. Infection was most common, but papillary necrosis, renal cysts, and several malignancies of the bladder were also found. A smaller study found significant urinary tract disease in nine of 30 patients, two of whom had bladder cancer [21] .
These observations indicate that hematuria in an anticoagulated patient should generally be evaluated in the same fashion as in other patients unless there is evidence of bleeding from multiple sites with markedly abnormal coagulation studies.
Cyclic hematuria in women that is most prominent during and shortly after menstruation, suggesting endometriosis of the urinary tract [22] . Contamination with menstrual blood is always a possibility, and should be ruled out by repeating the urinalysis when menstruation has ceased.
Medications that might cause nephritis (usually with other findings, typically with renal insufficiency).
Black patients should be screened for sickle cell trait or disease, which can lead to papillary necrosis and hematuria. (See "Renal manifestations of sickle cell disease").
Travel or residence in areas endemic for Schistosoma hematobium, or tuberculosis.
Sterile pyuria with hematuria, which may occur with renal tuberculosis, analgesic nephropathy and other interstitial diseases.
22   Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case A 34-year-old woman with endometriosis and bilateral hydronephrosis. N Engl J Med 1992; 327:481.

17. Clues from the history that point toward a specific diagnosis
6. Recent vigorous exercise or trauma
7. History of a bleeding disorder or bleeding from multiple sites due to uncontrolled anticoagulant therapy.
8. Cyclic hematuria in women that is most prominent during and shortly after menstruation, suggesting endometriosis of the urinary tract .
9. Medications that might cause nephritis (usually with other findings, typically with renal insufficiency).
1o. Travel or residence in areas endemic for Schistosoma hematobium .
11.Sterile pyuria with hematuria, which may occur with renal tuberculosis, analgesic nephropathy and other interstitial diseases.

18. Glomerular or Extra Glomerular bleeding?

19. Microscopic hematuria DDx
Glomerular
ARF
primary nephritis (post streptococcal glomerulonephritis, Ig A nephropathy,
Anti-GBM disease)
2nd nephritis(SLE, goodpasture’s syndrome, ANCA related vasculitis)
Alport’s syndrome (hereditary nephritis)
thin basement membrane nephropathy (benign familial hematuria)

20. Microscopic hematuria DDx
non glomerular
Renal
malignancy
vascular disease
(malignant hypertension, AVM, nutcracker syndrome, renal vein thrombosis,
sickle cell trait/disease, papillary necrosis)
infection (pyelonephritis, TB, CMV, EBV)
hypercalciuria
hereditary disease (polycystic kidney disease, medullary sponge kidney)
Nonrenal
malignancy (prostate, ureter, bladder)
BPH
Nephrolithiasis
Coagulopathy
Trauma

21. Rare cause of Microscopic Hematuria
Arteriovenous malformations and fistulas 
Nutcracker syndrome 
Loin pain-hematuria syndrome

22. Arteriovenous malformations and fistulas —  An AV malformation (AVM) or fistula of the urologic tract may be either congenital or acquired. The primary presenting sign is gross hematuria, but high-output heart failure and hypertension also may be seen . The latter is presumably due to activation of the renin-angiotensin system resulting from ischemia distal to the AVM
Nutcracker syndrome — The nutcracker syndrome refers to compression of the left renal vein between the aorta and proximal superior mesenteric artery. Nutcracker syndrome can cause both microscopic and gross hematuria, primarily in children (but also adults) in Asia . The hematuria is usually asymptomatic but may be associated with left flank pain. Nutcracker syndrome has also been associated with orthostatic proteinuria.
Loin pain-hematuria syndrome — The loin pain-hematuria syndrome is a poorly defined disorder characterized by loin or flank pain that is often severe and unrelenting, and hematuria with dysmorphic red cell features suggesting a glomerular origin. Affected patients usually have normal kidney function.

23. Extraglomerular vs Glomerular in UA
Extraglomerular
Glomerular
Color (if macroscopic)
Red or pink
Red, smoky brown, or "Coca-Cola"
Clots
May be present
Absent
Proteinuria
<500 mg/day
May be >500 mg/day
RBC morphology
Normal
Dysmorphic
RBC casts

24. Findings on Microscopy
Erythrocytes of uniform character are classified as isomorphic and suggest hematuria of lower urinary tract origin.
Microscopic clots of clumped erythrocytes in urine are also suggestive of lower urinary tract bleeding.
                                      FIGURE 1. Typical morphology of erythrocytes from a urine specimen revealing microscopic hematuria. (phase contrast microscopy, 3100)

25. Urine sediment showing many red cells and an occasional larger white cell with a granular cytoplasm (arrows). The red cells have a uniform size and shape, suggesting that they are of nonglomerular origin

26. Dysmorphic erythrocytes are characterized by an irregular outer cell membrane and suggest hematuria of glomerular origin.
Red blood cell casts are also associated with a glomerular cause of hematuria.
FIGURE 2. Dysmorphic erythrocytes from a urine specimen. These cells suggest a glomerular cause of microscopic hematuria. (phase contrast microscopy, 3 100)

27. Transient or persistent hematuria

28. Transient hematuria Exception:
Transient microscopic hematuria is a common problem in adults
Fever, infection, trauma, and exercise are potential causes
It is reasonable to repeat an abnormal urinalysis in a few days
Exception:
Malignancy risk in older patients with transient hematuria
In older patients, even transient hematuria carries an appreciable risk of malignancy (assuming no evidence of glomerular bleeding)
The risks includes : age >50, smoker and Hx of analgesic abuse.

29. When persistent hematuria is essentially the only manifestation of glomerular disease, one of three disorders is most likely
IgA nephropathy, in which there is often gross hematuria, and sometimes a positive family history but without any clear pattern of autosomal inheritance
Alport syndrome (hereditary nephritis), in which gross hematuria can occur in association with a positive family history of renal failure, and sometimes deafness or corneal abnormalities.
Thin basement membrane nephropathy (also called thin basement membrane disease or benign familial hematuria), in which gross hematuria is unusual and the family history may be positive (with an autonomic dominant pattern of inheritance) for microscopic hematuria but not for renal failure .

30. Persistent hematuria
Underlying malignancy is greater in patients with persistent hematuria in whom there is no obvious cause from the history
The primary underlying cancers are bladder, renal, and, much less often, prostate

31. Risk Factors for Urothelial Carcinoma
Cigarette smoking
Occupational exposures
Aniline dyes
Aromatic amines
Benzidine
Dietary nitrites and nitrates
Analgesic abuse (e.g., phenacetin)
Chronic cystitis and bacterial infection associated with urinary calculi and obstruction of the upper urinary tract
Urinary schistosomiasis
Cyclophosphamide (Cytoxan)
Pelvic irradiation
Information from Messing EM, Catalona W. Urothelial tumors of the urinary tract. In: Walsh PC, ed. Campbell's Urology. 7th ed. Philadelphia: Saunders, 1998:

32. Laboratory Tests (initial work up)
UA and microscopy to determine the number and morphology of RBC, crystal and casts
Consider urine Cx
CBC, PT, INR, electrolytes, kidney function
Serum chemistries and serologic studies for glomerular causes of hematuria as directed by the medical history
Repeat UA in a few days
Further urologic evaluation is warranted if more than three RBC/phf are found on at least two of three properly collected urine specimens or if high-grade microscopic hematuria (more than 100 red blood cells per high-power field) is found on a single urinalysis.17

33. Further Work up Glomerular causes:
Consider a refer to nephrology for further evaluation and possible renal biopsy

34. Renal Biopsy
A biopsy is not usually performed for isolated glomerular hematuria (i.e., no proteinuria or renal insufficiency,) since there is no specific therapy for these conditions, unless the patient is considering becoming a kidney donor
However, biopsy should be considered if there is evidence of progressive disease as manifested by an elevation in the plasma creatinine concentration, increasing protein excretion, or an otherwise unexplained rise in blood pressure, even when the values remain within the normal range

35. Further Work up Non-glomerular causes:
CT, renal US, and/or IVP: to search for lesions in the kidney, collecting system, ureters, and bladder
Urine cytology: if increased risk for urothelial cancers
Consider a referral to urology for cystoscopy, especially for pt at risk of malignancies

36. Radiologic and other tests for the evaluation of hematuria
Advantages
Disadvantages
Intravenous pyelogram (IVP)
Excellent visualization of the kidney, collecting system, and ureter
May miss bladder lesions; can cause nephrotoxicity, idiosyncratic reactions (1/10,000)
Cystoscopy
Best way to examine the bladder, which is not as well visualized by IVP or ultrasound
Invasive, uncomfortable and expensive
Ultrasound
If of good quality, as sensitive as IVP for renal lesions, with less morbidity and cost
Less sensitive than IVP for ureter and bladder
Retrograde pyelography
The best test for examing the ureters, can be combined with cystoscopy
Invasive, not useful for examining other parts of the urinary collecting system
Urinary cytology
Sensitivity 67 percent, specificity 96 percent for uroepithelial cancer
Useful only for cancer, mainly of the bladder
CT scan
Excellent for examining the renal parenchyma
Expensive
Angiography
Useful for gross hematuria when other tests have not revealed the cause; the only good test for vascular malformations
Invasive, expensive

37. Follow up Recommendation
The combination of negative radiologic examination(s)
( IVP, US, CT scan, cytology, and cystoscopy) is usually sufficient to exclude malignancy in the urinary tract
However, approximately 1% of older pt with an initially negative evaluation will, at 3 to 4 years, have a detectable urinary tract malignancy
Recommendation
Initial and then periodic urine cytology and UA should be performed in pt at high risk for malignancy (at 6, 12, 24 and 36 months)

38. SCREENING FOR HEMATURIA
Not recommended

39. Summary

40. Initial Evaluation of Asymptomatic Microscopic Hematuria*
Adapted with permission from Grossfeld GD, Wolf JS, Litwin MS, Hricak H, Shuler CL, Agerter DC, Carroll P. Evaluation of asymptomatic microscopic hematuria in adults: the American Urological Association best practice policy recommendations. Part II: patient evaluation, cytology, voided markers, imaging, cystoscopy, nephrology evaluation, and follow-up. Urology 2001;57(4) (In press).

41. Adapted with permission from Grossfeld GD, Wolf JS, Litwin MS, Hricak H, Shuler CL, Agerter DC, Carroll P. Evaluation of asymptomatic microscopic hematuria in adults: the American Urological Association best practice policy recommendations. Part II: patient evaluation, cytology, voided markers, imaging, cystoscopy, nephrology evaluation, and follow-up. Urology 2001;57(4) (In press).

42. Thank you