Hematuria

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

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

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

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

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

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):2330-8.

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

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

History and Physical

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

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

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., 1999. Accessed Sept. 24, 1998.

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

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

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 33-1992. A 34-year-old woman with endometriosis and bilateral hydronephrosis. N Engl J Med 1992; 327:481.

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.

Glomerular or Extra Glomerular bleeding?

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)

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

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

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.

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

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)

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

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)

Transient or persistent hematuria

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.

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 .

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

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, 1998:2327-410.

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

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

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

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

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

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)

SCREENING FOR HEMATURIA Not recommended

Summary

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).

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).

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