1. Barbara Kahn, MD Virginia Urology
Hematuria
Barbara Kahn, MD
Virginia Urology

2. ICD-10 codes R31 Hematuria R31.0 Gross hematuria
 R31.1 Benign essential microscopic hematuria
 R31.2 Other microscopic hematuria
 R31.21 Asymptomatic microscopic hematuria
 R31.29 Other microscopic hematuria
 R31.9 Hematuria, unspecified
N30.01 acute cystitis with hematuria

3. Objectives To define microscopic hematuria
To describe the evaluation and treatment of hematuria

4. Hematuria Classifications
Microscopic hematuria
Glomerular
Non-Glomerular
Macroscopic “Gross” hematuria
Symptoms: pain, burning vs asymptomatic

5. DEFINITION
Microscopic Hematuria 3 or more RBCs/hpf in urinary sediment from 1 properly collected UA *cannot be diagnosed by dipstick
benign causes, such as menstruation, vigorous exercise, viral illness, trauma, and infection, have been excluded.
This is a change from the previous guideline in 2001, which was updated in 2012 and validated in no longer requires 2 specimens
Why? There was no literature supporting the number of specimens needed to prompt a work up; panel decided to use 1 bc hematuria 2/2 to malignancy can be intermittent,
studies that evaluated patients after obtaining one positive sample A meta- analysis of these studies revealed a pooled urinary tract malignancy rate of 3.3%
After 1 positive sample, a meta analysis revelaed rate of calculus 6.0% (95% CI: 3.8 – 9.2%), rates of benign prostatic enlargement ranged from 1.0% to 38.7% with a meta-analyzed rate of 12.9% (95% CI: 6.3 – 24.6%), and rates of urethral stricture ranged from less than 1% to 7.1% with a meta-analyzed rate of 1.4%
Properly collected
-usually a voided midstream urine, urethral meatus is cleansed with a sterilization towelette
-some pts may require catheterization: obese females, contaminated specimens, menstruation
10ml aliquot in 15 ml tube centrifuged at 2000 revs per min for 10 min or 3000 revs per min for 5 min
he supernatant should be poured off, and the sediment resuspended in 0.3 mL supernatant and/or saline, placed on a microscopic slide (75 mm x 25 mm) and covered with a cover slip (22 mm x 22 mm). At least microscopic fields should be examined under 400x magnification.

6. Urine Dipstick
+ dipstick for hematuria = peroxidase reaction to hemoglobin
Hematuria or RBC’s
Myoglobinuria
Hemoglobinuria
Microscopic evaluation is essential for distinguishing hematuria from myo-hemoglobinuria

7. Dipstick False Positives
Menstrual blood – most common
Cath specimen
Dehydration (increased specific gravity)
Oxidizing agents (hypochlorite, povidone, bacterial peroxidases)
Myoglobinuria/hemoglobinuria
Dipstick is generally the first line of investigation though there are a number of conditions that bring about false-positive and false-negative results.
Urine microscopy should be performed to confirm haematuria.

8. Dipstick False Negatives
Reducing agents (high dose Vitamin C)
Low urine pH (< 5.1)
Urine too dilute SG < 1.007
In dilute urine RBCs lyse so # may be artificially reduced

9. Dipstick +, Micro - Repeat urine specimen 3 times
If any test has 3 or more RBC/hpf then work up
If all negative on micro, no further work up
Patients who have a positive dipstick test but a negative specimen on microscopy should have three additional repeat tests. If at least one of the repeat tests is positive on microscopy, then workup should be undertaken. If all three specimens are negative on microscopy, then the patient may be released from care.

10. Medical vs Surgical Hematuria
Renal/Glomerular Hematuria
Proteinuria
Red cell casts
Dysmorphic red blood cells
Renal insuffficiency
Non-glomerular Hematuria
Circular red cells
Absence of casts
Glomerular cause is suggested by the finding of proteinuria on urinalysis or red cell cell casts or dysmorphic red cells on microscopy – though these features are absent in 20% of glomerular causes.
Non-glomerular medical or surgical causes are associated with normal red cell morphology and absence of red cell casts.
The presence of urinary casts, proteins, and/or dysmorphic red blood cells suggests a medical renal etiology for AMH. Nephropathies and nephritis are the most common causes of microhematuria in this category. The processes may be immunological, infectious or drug-induced.
These are not mutually exclusive so the presence of one does not exclude the need to evaluate for the other

11. Medical Renal Disease
Referral to a nephrologist

12. Glomerular Hematuria

13. Hematuria Initial Evaluation
History
Physical Examination
UA dipstick, microscopy
Urine culture if possible infection
eGFR, BUN, Cr
Do not recommend routine urine cytology, NMP22s

14. Important History
Age Gender History of trauma Timing of blood in stream Associated symptoms Association with exercise Recent upper respiratory tract infection Medical, surgical, gynecological history Meds: anticoagulation Tobacco use Radiation exposure Family history Occupation
Anticoagulants use do not preclude work up

15. Cystoscopy
Should be performed in all patients with AMH age 35 years and older, and those younger than 35 with risk factors.
Among the 98 individuals diagnosed with a urinary tract malignancy in the screening studies, 95 individuals (97%) were older than age 35 years.
approximately 1.2% of patients (6 of 504) diagnosed with a urinary tract malignancy were younger than age 35 years.
Infectious risk of cystoscopy is low, and the Best Practice Policy Statement on Urologic Surgery Antimicrobial Prophylaxis (2008)117 specifically recommends against routine use of antibiotics for routine cystoscopy.

17. Risk Factors

18. Imaging CT urogram is gold standard
MR urogram if renal insufficiency/severe contrast allergy/pregnant
US or noncontrast CT with retrograde pyelograms if unable to get CTU or MRU
Among the 98 individuals diagnosed with a urinary tract malignancy in the screening studies, 95 individuals (97%) were older than age 35 years.
1) a pre- enhancement phase to establish baseline densities of tissues and high or variable densities such as calculi, hematomas or fat-containing structures; 2) an arterial phase identifying neoplastic or inflammatory neovascularity; 3) a cortico-medullary or parenchymal phase defining evidence of renal parenchymal changes and equating it to sustained damage; and 4) an excretory phase which demonstrates the collecting system, ureters and bladder and any abnormalities affecting the urothelium. T

21. IV Contrast Allergy May premedicate
Prednisolone 30mg PO 12 hours and 2 hours prior
Initial dose must be >6 hours prior
pre-medication with steroids be given to patients with a documented history of contrast reaction. One generally accepted protocol for corticosteroid prophylaxis consists of prednisolone 30 mg orally to be given 12 and 2 hours before contrast medium (preferably non-ionic) administration. An alternate technique is administration of a prednisolone 30 mg 24 hours and 6 hours prior to contrast exposure. Corticosteroids are not effective if the initial dose is given less than 6 hours before contrast medium administration.

22. Tumor Markers Urine cytology, NMP22, BTA-stat, Uro-vysion FISH
No longer routinely recommended
Urine cytology sensitivity values
ranged from 0% to 100%; specificity values ranged from 62.5% to 100%.
For NMP22, sensitivities ranged from 6.0% to 100% and specificities ranged from 62% to 92%. Only two studies reported on BTA-stat,192, 193 and only specificities could be calculated (69% and 73%, respectively) because no malignancies were detected in the samples. Three studies reported on UroVysion FISH;25, sensitivities ranged from 61% to 100%, and specificities ranged from 71.4% to 93%.
burden of emotional stress that could result from a false positive test and the risks of unnecessary diagnostic procedures

24. Risk of Disease in AMH GU malignancy 4%. (0-9.3%)
Renal, upper tract urothelial, bladder
Stones >5% ( %)
BPH >10% (1-47%)
Urethral Stricture 2% (1-7%)
No pathology %
Risk of pathology higher with gross hematuria
24% GU malignancy
35% significant disease
Thirty-two studies conducted initial work -ups on 9,206 AMH patients;16, 21, 24, 26, 30-32, 34-35, 37, 40-57,
59, patients were diagnosed with a malignancy for an overall rate of 4.0%. Rates in individual studies ranged from 0 to 9.3%.
rates of calculous disease ranged from 1.4% to 25.6% with most studies reporting rates above 5.0%. Rates of benign prostatic enlargement ranged from less than 1.0% to 47.1% with nearly half of the studies reporting rates greater than 10.0%. Urethral stricture rates ranged from less than 1% to 7.1% with more than one-third of studies reporting rates of greater than 2.0%.
No pathological source of MH is found in some 37.3% to 80.6% of patients referred for
evaluation of AMH.

25. Following a Negative Work up
Repeat annual microscopic urinalysis x 2 years
If negative – no further work up
If persistent – continue annual microscoic urinalysis AND repeat work up in 3- 5 years
Neoplasms found in 9% with negative work-up but persistent microhematuria.

27. Association Between Use of Antithrombotic Medication and Hematuria-Related Complications.
More hematuria-related complications (ER visits, hospitalizations, urologic procedures) among patient exposed to antithrombotic agents than not exposed
events per 1000 person-years vs events per 1000 person-years
Patients exposed to antithrombotic agents were more likely to be diagnosed with bladder cancer within 6 months than those note exposed
In JAMA 2017
Population-based, retrospective cohort study including all citizens in Ontario, Canada, aged 66 years and older between 2002 and 2014.
Among 2 518 064 patients, 808 897 (mean [SD] age, 72.1 [6.8] years; 428 531 [53%] women) received at least 1 prescription for an antithrombotic agent over the study period. Over a median follow-up of 7.3 years, the rates of hematuria-related complications were events per 1000 person-years among patients actively exposed to antithrombotic agents vs events per 1000 person-years among patients not exposed to these drugs 
emergency department visit, hospitalization, or a urologic procedure to investigate or manage gross hematuria.

28. Incidence of Visible Haematuria among Antithrombotic Agents: a Systematic Review of Over 175,000 Patients.
Warfarin had the greatest risk of hematuria, but was less likely to cause major hematuria compared to novel antithrombotic agents
Urologic pathology identified in 44%, malignancy in 24%
Gold journal of urology 2017
Incidence of Visible Haematuria among Antithrombotic Agents: a Systematic Review of Over 175,000 Patients
Bhatt, Nikita R. et al.

29. References
Diagnosis, evaluation, and follow up of asymptomatic microhematuria (AMH) in adults: AUA guideline, validated 2016
Jones, S and Rao. CCf Journal (3) How To Evaluate Dipstick Hematuria. What to Do Before You Refer.
Jones, S and Rao. J Urology (2) Dipstick Pseudohematuria: Unneccessary Consultation and Evaluation.
Bhatt, NR. et al. J Urology pii: S (17) Incidence of Visible Haematuria among Antithrombotic Agents: a Systematic Review of Over 175,000 Patients
Wallis, CJD et al. JAMA Oct 3; 318(13): Association Between Use of Antithrombotic Medication and Hematuria-Related Complications.

30. Thank you!