Qiuyang Li, PGY2 Emory Family M edicine

1. Qiuyang Li, PGY2Emory Family Medicine Hematuria

2. Gross hematuria: Suspected if a red or brown color change of urine Intermittent red or brown color urine a/w variety of clinical setting Medications (phenazopyridine, microbid, NSAID) Ingestion of beets or certain dyes Metabolities Myoglobinuria or hemoglobinuria If pass clot, indicate lower urinary source

3. Work up Centrifuge the specimen, Supernatant be tested for heme (hemoglobin or myoglobin) with a urine dipstick.

4. Causes of heme-negative red urine

5. Approach to the patient with red or brown urine

6. Microscopic hematuria: • Accidental finding from UA or urine dipstick • 3 or more RBC/hpf in spun urine sediment. • No "safe" lower limit below which significant disease can be excluded • Often asymptomatic • The degree of hematuria does not correlate with the seriousness of the underlying cause of the bleeding.

7. 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 • Semen is present in the urine after ejaculation • An alkaline urine with a pH greater than 9 or contamination with oxidizing agents used to clean the perineum. • The presence of myoglobinuria. A positive dipstick test must always be confirmed with microscopic examination of the urine

8. Major causes of hematuria by age and duration Schematic representation of the major causes of hematuria in relation to the age at which they usually occur (horizontal axis), transience or persistence (vertical axis), and frequency (blue implies more frequent).

9. 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?

10. a three-tube test may also help to locate the source of bleeding in selected cases. Urethral: First 10-15 mL Bladder: Final 10-30 mL Upper urinary tract: Throughout

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

12. History and Physical

13. History • 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

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

15. Medication Hx

16. Mechanisms by Which Selected Drugs May Cause Hematuria Medication Hx

17. 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

18. Physical Examination Findings and Associated Causes of Hematuria

19. 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.

20. 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). 10. AA should be screened for sickle cell trait or disease, which can lead to papillary necrosis and hematuria. 11. Travel or residence in areas endemic for Schistosoma hematobium . 12.Sterile pyuria with hematuria, which may occur with renal tuberculosis, analgesic nephropathy and other interstitial diseases.

21. Glomerular or Extra Glomerular bleeding?

22. 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)

23. 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

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

25. 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.

26. Extraglomerular vs Glomerular in UA

27. 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)

28. 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

29. 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)

30. Transient or persistent hematuria

31. Transient hematuria 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.

32. 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 .

33. 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

35. 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

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

37. 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

38. 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

39. Radiologic and other tests for the evaluation of hematuria

40. Follow up 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)

41. SCREENING FOR HEMATURIA Not recommended

42. Summary

43. Initial Evaluation of Asymptomatic Microscopic Hematuria*

45. Reference: • Significance of microhaematuria in young adults. AU Froom P; Ribak J; Benbassat J SO Br Med J (Clin Res Ed) 1984 Jan 7;288(6410):20-2. • Asymptomatic microhematuria and urologic disease. A population-based study • Asymptomatic microscopic hematuria in adults: summary of the AUA best practice policy recommendations. AU Grossfeld GD; Wolf JS Jr; Litwan MS; Hricak H; Shuler CL; Agerter DC; Carroll PR SO Am Fam Physician 2001 Mar 15;63(6):1145-54.U Mohr DN; Offord KP; Owen RA; Melton LJ 3d SO JAMA 1986 Jul 11;256(2):224-9 • The left renal entrapment syndrome: diagnosis and treatment. AU Zhang H; Li M; Jin W; San P; Xu P; Pan S SO Ann Vasc Surg. 2007 Mar;21(2):198-203. • Heavy phenacetin use and bladder cancer in women aged 20 to 49 years. AU Piper JM; Tonascia J; Matanoski GM SO N Engl J Med 1985 Aug 1;313(5):292-5. • Recent advances in the diagnosis and treatment of renal arteriovenous malformations and fistulas. AU Crotty KL; Orihuela E; Warren MM SO J Urol 1993 Nov;150(5 Pt 1):1355-9. • Evaluation of Asymptomatic Microscopic Hematuria in Adults. TIMOTHY R. THALLER, M.D University of Kansas Medical Center, Kansas City, Kansas LESTER P. WANG, M.D. Valley Urology Center, Renton, Washington • Am Fam Physician 1989; 40(2):149-56, and Drugdex system. Englewood: Colo.: Micromedex, Inc., 1999. Accessed Sept. 24, 1998. • Am Fam Physician 1989; 40(2):149-56, and Drugdex system. Englewood: Colo.: Micromedex, Inc., 1999. Accessed Sept. 24, 1998. • Urothelial tumors of the urinary tract. In: Walsh PC, ed. Campbell's Urology. 7th ed. Philadelphia: Saunders, 1998:2327-410. • A quick reference for urologist, AUA 2006 • Up to date 2008

46. Thank you