Approach to the Patient with Hematuria Paul D. Simmons, MD St. Mary’s Family Medicine Residency Grand Junction

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Objectives Define and classify hematuria. Review the pathophysiology of hematuria. Discuss a rational diagnostic approach to the patient with hematuria. Discuss effective use of lab and imaging tests in the hematuria work-up.

The Problem A 40 year old woman presents for a yearly health-maintenance examination. She is not currently on her menstrual period. On her dipstick urinalysis, she has 2+ blood, trace protein, trace leukocyte esterase and negative nitrates.

Hematuria is defined as 2 of 3 samples with: Any number of RBCs per hpf. More than 3 RBCs per hpf. More than 30 RBCs per hpf. 3+ blood on urine dipstick. Visibly red urine.

In this photo, arrows point to WBCs surrounded by monomorphic RBCs. Definitions Hematuria is defined as three or more RBCs per high-powered field on urine microscopy, from 2 of 3 specimens. In this photo, arrows point to WBCs surrounded by monomorphic RBCs.

Unnecessary Referrals Journal of Urology, February 2010: Retrospective analysis of 320 new patient visits to a urology office with the diagnosis “non-macroscopic hematuria.” Of these referrals, only 41% had had microscopic urinalysis prior to referral, and only 24% had 3 or more RBCs/hpf. The Medicare cost of working up these 69 patients without microscopic confirmation was approx. $45,000. Thirty-five of the 69 underwent cystoscopy; only one (with true hematuria) had a malignancy. Moral of the story: Confirm hematuria with microscopy!

Take-Home Point #1: Positive dipsticks for blood should get microscopic confirmation.

Not All Red Urine is Hematuria If the urine is visibly red, tea- or cola-colored, but there are < 3 RBCs/hpf, consider: Hemoglobinuria (false + dipstick) Myoglobinuria (false + dipstick) Beeturia Rhubarburia Medications (phenazopyridine, methyldopa, senna, others) Porphyria

Classification CLINICAL PATHOPHYS Gross frankly bloody Macroscopic red urine Microscopic not discolored PATHOPHYS Glomerular Non-Glomerular

So, back to our 40 year old woman... After her urine dipstick had 2+ blood, her urine was spun and the sediment examined microscopically, showing 10- 15 RBCs per hpf.

What would your next step be in evaluating this patient? History and physical examination. 24 hour urine collection for creatinine clearance, K, Na, protein and UPEP. Renal ultrasound and referral for cystoscopy. Repeat urine dipstick and micro in one year.

History Age is probably the most important factor. ALMOST ALL intermittent hematuria is benign in persons <50 yo. Duration and timing. Urinary symptoms: obstructive, irritative. + pyuria, dysuria: think UTI (or CA) Pain? Quality, radiation, severity, etc. + unilateral flank pain: urolithiasis, clot (or CA). Zebra: loin pain-hematuria syndrome - 1967 report, ?focal renal cortical ischemia, prevalence ~0.012% Review of systems: weight loss, rash, joint pain, fatigue, edema. + recent URI: think PSGN or IgA nephropathy

Age and Hematuria Age (yr) Common Uncommon 0 to 15 15-50 >50 Glomerulopathy (IgA, Alport’s syndrome, thin BM disease, APSGN) Hypercalciuria with stones Congenital obstructive anomalies UTIs Sickle cell disease Viral infection Factitious Fever HUS Hemophilia HSP Schistosomiasis 15-50 Calculi Menstrual contamination Exercise PKD Intercourse Papillary necrosis AVMs or fistulae DIC Goodpasture’s syndrome Loin pain-hematuria syndrome Renal infarction Renal vein thrombosis Medullary sponge kidney >50 BPH Cancer (renal, ureteral, bladder, prostate) Overanticoagulation Prostatitis Cyclic hematuria in women Endometriosis TTP Toxins (cantharidin, djenkol bean) LP-HS

History (cont.) Recent exercise or trauma? Recent travel? (Especially to Africa, Middle East or India.) PMH: coagulopathies (acquired or hereditary), irradiation, chemo. Family Hx: hereditary nephritis, PKD, sickle cell disease. Social Hx: smoking, industrial exposures (tetraethylchloride, benzene, aromatic amines)

RED FLAGS Smoking history Occupational exposure to chemicals or dyes (benzenes or aromatic amines) History of gross hematuria Age >40 years (>50, some sources say) History of urologic disorder or disease (not simple UTIs) History of persistent irritative voiding symptoms History of recurrent or chronic urinary tract infection Analgesic abuse History of pelvic irradiation Source: Urology 2001;57(4)

Physical Examination Vitals Heart Lungs Abdomen Extremities Rectal fever? (pyelo) HTN? (glomerulonephritis) Heart new murmur? (endocarditis) Lungs crackles, rhonchi? (Goodpasture’s syndrome) Abdomen masses? (cancer, obstruction) bruits? (renal ischemia) Extremities edema? (glomerulonephritis) rashes? (HSP, CTD, SLE) Rectal BPH? nodules? (cancer) tenderness? (prostatitis, endometriosis) Osler at the Bedside: Inspection, Auscultation, Palpation/Percussion and Thought.

Take-Home Point #2: Most serious hematuria is going to be due to: 1 Take-Home Point #2: Most serious hematuria is going to be due to: 1. Infection (UTI, prostatitis) 2. Stones 3. Malignancy (anywhere along the urinary system)

Welcome to... YOU MAKE THE DIAGNOSIS! (Sponsored by Illness Scripts)

A 7 year old boy presents 2 weeks after an episode of pharyngitis because his mother noticed his urine was red. He has mild edema on examination. Schistosomiasis Goodpasture’s syndrome Post-streptococcal glomerulonephritis Prostatitis

Hemolytic-uremic syndrome Acute prostatitis A 50 year old man presents with 1 week of vague pelvic discomfort, urinary hesitancy, frequency and nocturia. His examination reveals a temperature of 38.1 C and a tender, boggy prostate. His urinalysis shows 20-30 RBCs/hpf without pyuria or crystals. Urolithiasis Pyelonephritis Hemolytic-uremic syndrome Acute prostatitis

A 38 year old woman with chronic pelvic pain presents with macroscopic hematuria. She has no fever, dysuria or flank pain. She notes that her urine only turns dark red with or soon after her menstrual cycle. Endometriosis Exercise-induced hematuria Polycystic kidney disease Polycystic ovarian disease Both B and C

A 28 year old man presents to the ER with the sudden onset of unilateral, severe flank pain radiating to the ipsilateral groin. He is afebrile, but diaphoretic and nauseous. His urine dipstick shows 3+ blood and trace leukocytes. Drug-seeker Urolithiasis Ectopic pregnancy Schistosomiasis

An 82 year old man presents to the ER with the sudden onset of unilateral, severe flank pain radiating to the ipsilateral groin. He is afebrile, but diaphoretic and nauseous. His urine dipstick shows 3+ blood and trace leukocytes. Drug-seeker Urolithiasis Dissecting AAA Post-streptococcal GN Probably B, but I want to rule out C

Take-Home Point #3: Look for “typical” clusters of symptoms and signs to quickly and roughly differentiate between infection, stones and cancer.

But what if I don’t have an easy “slam-dunk” diagnosis? What next?

Back to the Microscope! Is it glomerular or non- glomerular? Glomerular: acanthocytosis (acantho- , “thorn” or “spike”) or casts. Non-glomerular: isomorphic RBCs.

Glomerular - Casts and Dysmorphic RBCs (arrow)

Glomerular - Acanthocytes

Non-Glomerular - Isomorphic RBCs

Trick Slide - Crenated RBCs (arrowhead) in concentrated urine

We’ve come this far. New Engl J Med 348;23 6/5/03

If it’s glomerular... Again: acanthocytes or casts in the sediment... If no protein or renal failure, you’re done for now. But follow-up regularly! If protein or renal failure, refer to nephrology! (Renal biopsy likely.)

If it’s non-glomerular... Again, regular-appearing, isomorphic RBCs. Ask: where, then, is the bleeding from? Step 1: CT urogram. Looks for the big anatomical lesions. If no lesion, then-- Step 2: Urine cytology (3 first AM samples) if abnormal, go to cystoscopy. Step 3: Is the patient high-risk for malignancy--over 40, toxic exposures, irradiation, etc.? if yes, go to cystoscopy anyway and consider repeating cytology at 6, 12, 24 and 36 months.

CT Urography Journal of Urology, March 2008: Retrospective review of the radiologic, pathologic and urologic records of 468 patients without prior hx of GU cancer. All underwent CT urogram. 50 urinary system neoplasms diagnosed, with CT-U finding 32/50. Sensitivity = 64%, specificity = 98%, PPV = 76%, NPV = 96%. Conclusion: CT-U is moderately sensitive and highly specific for GU neoplasm, but does not replace cystoscopy and urine cytology in high-risk patients with hematuria. In other words: very helpful if abnormal, not very reassuring if normal.

Take-Home Point #4: a. Glomerular or Not. b Take-Home Point #4: a. Glomerular or Not? b. Glomerular - refer if protein or renal failure. c. Not - do a CT-U, then cytology (if needed), then see how worried you still are.

A 55 year old male smoker with isolated microscopic hematuria (no fever, pyuria or prostate symptoms) has isomorphic RBCs, no casts or acanthocytes on urine micro. What test would you order first? Cystoscopy Bilateral renal ultrasound Intravenous pyelogram (IVP) CT urogram

If the test you ordered in the last question failed to show a lesion, which referral would be most appropriate? nephrology psychiatry urology dermatology chiropractic

What Have We Learned? Positive dipsticks for blood should get microscopic confirmation R/O myo- or hemoglobinuria and decide glomerular vs. non-glomerular. Top 3 Suspects are: Infection, Stones and Malignancy. Look for “Illness Scripts” ex: unilateral flank pain, afebrile, N/V (stones) ex: hematuria correlated with menses (endometriosis) ex: obstructive sxs, fever, prostate tenderness (prostatitis) ex: CVAT, fever, dysuria (pyelo) If it’s not easy, ask: Glomerular or Not? Glomerular - protein or renal dz? If so, refer to nephrology. Not - 1. CT-U; 2. Cytology; 3. Cystoscopy.

References Beers MH, et al., Merck Manual of Diagnosis and Therapy (18th print and online editions), “Chapter 226: Approach to the Genitourinary Patient: Isolated Hematuria.” Cohen RA and Brown RS, “Microscopic Hematuria,” New England Journal of Medicine, 348:23, 5 June 2003. Grossfeld GD, et al., “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). Kaplan M, et al., Essential Evidence Plus Online (www.essentialevidence.com), “Hematuria,” updated 9-11-2009, and Rauta V, “EBM Guideline: Haemat-uria” (6-3- 2003). Rao PK, et al., “Dipstick Pseudohematuria: Unnecessary Consultation and Evaluation,” J Urol, 2010 February; 183(2). Rose BD, et al., UpToDate Online(www.uptodate.com), v. 17.3, “Evaluation of Hematuria in Adults.” Sudakoff GS, et al., “Multidetector CT Urography as the Primary Imaging Modality for Detecting Urinary Tract Neoplasms in Patients with Asymptomatic Hematuria,” J Urol, 2008 March, 179(3). Zepf B, “Evaluation of Patients with Microscopic Hematuria,” American Family Physician, 1 March 2004. Schrute D, “Beets and Urine” Pennsylvania Beet Farms, vol 3, no. 6.

Thank You!