Evaluationof the patient with

Hematuria Meshari Alzahrani

Medical Intern – MBBSAUA Member

29/1/2014

Introduction

TerminologyBasic ScienceGross Hematuria PseudohematuriaMicroscopic Hematuria

Terminology

Haematuria : blood in the urine.– gross, or macroscopic, when there is sufficient blood

present to color the urine red or brown. –  microscopic when the urine is visually normal in color

but is found to contain blood on chemical analysis or microscopic evaluation.

– asymptomatic microhematuria (AMH) is defined as: 3 or greater RBCs / HPF on a properly collected urinary

specimen in the absence of an obvious benign cause.

HPF :  high power field – Normally between 0 – 3 RBCs are seem per HPF

Urine microscopy showing RBCs

Gross Haematuria

Basic Science

RBCs may be excreted in the urine by normal persons.

It is not known precisely how these cells reach the urinary tract.

However, the normal excretion rate is :

0.5 to 2 million RBCs/24 hr, or <5 RBCs/hpf on microscopic examination of a urine specimen.

It is difficult to localize the site of bleeding by routine examination of the patient with hematuria.

However, certain findings may be very helpful depend on size & shape of RBCs. For example, casts form in

the lumina of renal tubules. Therefore, the presence of

RBCs casts localizes the site of bleeding to the renal parenchyma.

Non-glomerular Glomerular* Hematuria

Uniform Irregular Size

Larger Small Shape

Peripheral Nephron Source

*The reason that make Glomerular RBCs irregular & small cause it pass through kidney chemicals & nephron that lead to change in shape & size as long as its pass through these jurney

Common cause of Haematuria

Infection of the urine.  Kidney and bladder stones . Trauma to the urinary tract. Bladder tumors. Prostate tumors. kidney tumors and other kidney

diseases. Blood disorders

Approach to Patient with blood in urine

History takingPhysical examinationDifferential DiagnosisInvestigation, Lab , Radiology

History Taking

Personal :– Gender ( female, male)– Age ( older, younger)

Chief Complaint : Blood in Urine +/- Associated symptoms

Duration : Acute , Chronic . History of presenting illness :– Onset : Sudden , Progressive , transient, persistent,

recurrent – Pattern: gross vs. microscopic, constant vs.

intermittent, glomerular vs. extraglomerular , painless vs. painful

Associated symptoms : – Fever, back pain, dysuria, urgency,

frequency (UTI)– renal colic or previous nephrolithiasis

(renal stone disease)– weight loss, especially with abdominal pain

(RCC)– weight loss with a significant smoking

history, analgesic abuse, or exposure to industrial dyes (bladder carcinoma)

– Symptoms of prostatic obstruction in older men such as hesitancy and dribbling (BPE)

– recent sore throat or skin infection, edema, hypertension (glomerulonephritis)

– recent back, abdominal, or urethral injury or vigorous exercise (trauma)

– history of heart murmur with recent dental or genitourinary manipulation (endocarditis)

– or a history of bleeding from other sites, a previous bleeding disorder, or family history of a bleeding disorder (systemic coagulopathy).

– Cyclic hematuria in women that is most prominent during and shortly after menstruation, suggesting endometriosis of the urinary tract.

– Sterile pyuria with hematuria, which may occur with renal tuberculosis, analgesic nephropathy and other interstitial diseases

– Loin pain-hematuria syndrome (LPHS): (rare) recurrent episodes of severe unilateral or bilateral loin (flank) pain that were accompanied by gross or microscopic hematuria, associated with use of OCPs

Urine Color, pattern: – What color is your urine? – Are you taking rifampicin? Have you eaten

beetroot (Beeturia)? – Is it pure blood or mixed with urine?– Are there any clots? (lower urinary tract

source)– Does it happen all the time when you pass water?– Is it near the beginning, end or during the entire

urine stream? – Post operative , recent urological surgery ?

beetroot

rifampicin

Family History : A personal or family history of hematuria with:

– deafness or ocular abnormalities with hematuria (Alport's syndrome)

– hematuria with progressive chronic renal failure (ADPKD)

– (sickle Cell Anemia) lead to papillary necrosis and hematuria.

Travel History to or Endemic area of:– (Schistosoma haematobium) is a common

cause of hematuria in certain endemic areas

Antibiotics Penicillins (esp. methicillin, ampicillin)

Cephalosporins

Sulfonamides

Rifampin

IsoniazidNSIDs

Indomethacin

Phenylbutazone

Fenoprofen

Naproxen

Tolmetin

Mefenamic acidDiuretics

Thiazides

Furosemide

TriamtereneMiscellaneous

Phenytoin

Cimetidine

Allopurinol

Azathioprine

Drug History : should be taken with special attention to :–Antibiotic : Rifampin ( orange urine)–analgesics (papillary necrosis)–cyclophosphamide (hemorrhagic cystitis)– anticoagulants, –drugs known to cause acute interstitial nephritis

Drugs Associated with Acute Interstitial Nephritis.

Physical Examination

 Vital signs should be checked with special attention to PB ( HTN with RCC & glomerulonephritis, ADPKD) and temperature (fever with UTI)Genital examination :

possible sites of bleeding around the urethral meatus in both sexes Look for Trauma “ Foley’s Catheter Removal while balloon still inflated”For male , look for : BPH, prostatic cancer, do PR For female , look for : GYN/OBS abnormalities (vaginal bleeding)

Inspection : Rash, ecchymoses, or petechiae (coagulopathy)Lens abnormalities and hearing loss (Alport's syndrome)Edema , sore throat , (glomerulonephritis)

Palpation: renal colic flank pain radiate to groin (stone) , costovertebral angle tenderness , abdominal tenderness, and abdominal masses (RCC)Auscultation : Cardiac murmurs (endocarditis)

Alport syndrome :  Hereditary nephritis  characterized by glomerulonephritis , end stage kidney disease, and hearing loss. Alport syndrome can also affect the eyes (lenticonus). The presence of blood in the urine (hematuria) is almost always found in this condition.

Differential Diagnosis of Hematuria

Acquired glomerular and tubulointerstitial renal disease– Primary–  Secondary to systemic disease (pericarditis)

Hereditary renal disease– Alport's syndrome–  Polycystic kidney disease

Infection (Mycobacteria and Schistosoma)

Papillary necrosis– Sickle hemoglobin–  Analgesic abuse

Trauma Calculi Neoplasia– Primary– Metastatic (uncommon)

Coagulopathy– Congenital– Acquired

Differential Diagnosis of Hematuria

Investigation : Lab

RFT : Serum Creatinine Urinalysis with microscopic exam

– Inadequate sample (contaminated with vaginal contents)• Squamous epithelial cells >5/hpf

– Signs of renal disease• Glomerular disease

– Urine brown (Coca-Cola color)– Microscopy

» RBCs casts» Dysmorphic RBCs

– Proteinuria

• Extraglomerular disease– Clots of blood

Voided urine cytology:– No longer recommended for routine Hematuria evaluation

• Cystoscopy has higher Test Sensitivity than either urine cytology or Bladder Cancer detection markers

– Protocol• Obtain three serial fresh specimens• Evaluate for transitional cell cancer

– Bladder Cancer detection markers (no evidence for benefit over standard cytology or cystoscopy)• Fluorescent in situ hybridization (FISH)• Nuclear matrix protein 22 Test• Bladder tumor antigen stat test• Urinary Bladder cancer antigen

Nephropathy or Glomerulonephritis evaluation:• Urine Protein to Creatinine Ratio• Antinuclear Antibody• ASO Titer• Serum complement (C3, C4, C50) : ↓

Prostate:• Prostate Specific Antigen (PSA)

Coagulation Factors:• INR , prothrombin time (PT)• Partial Thromboplastin Time (PTT)

Miscellaneous tests:• Collect 24 hour Urine Calcium, Urine Uric

Acid Urinalysis of "Three Glass Test" :

• Glass 1: Initiation of urine stream– Hematuria in Glass 1 only suggests Urethral

source• Glass 2: Midstream urine

– Hematuria in all glasses suggests Bladder or renal

• Glass 3: Termination of urine stream– Hematuria in Glass 3 only

suggests Prostate source

Investigation : Radiology

• Helical CT Urogram (preferred)• Renal US

– Defines anatomy– Signs of glomerular disease , hydronephrosis, and renal cysts– CT Urogram is usually preferred over US

• Intravenous Pyelogram– Suspected Nephrolithiasis

• Cystoscopy– Extraglomerular source of Hematuria

• MRI Urography– Indicated where CT Urogram is contraindicated (e.g.

Pregnancy, Children)– Identifies urothelial cancer, Nephrolithiasis and renal tumors

http://www.ajronline.org/doi/full/10.2214/AJR.10.4198 American Journal of Roentgenology. 2010

Evaluation Protocol

General 1 2 3 4 5

General Approach– Consider non-urinary source (e.g. vagina, Rectum)– Gross Hematuria should be thoroughly evaluated including

urologic intervention – Confirm adequate sample

•  Microscopic Hematuria• Squamous epithelial cells >5/hpf suggests vaginal contaminant• Urine Dipstick alone is inadequate due to high false positive rate

– False positives occur with Hemoglobinuria, Myoglobinuria and alkalotic urine (pH >9)

– False negatives occur with Vitamin C Supplementation

– Indications for Urologic  intervention regardless of protocols• Gross Hematuria• Anticoagulant use with AMH• Old Age with Painless Hematuria

General

1 2 3 4 5

Gross hematuria

Gross hematuria is suspected because of the presence of red or brown urine.

The color change does not necessarily reflect the degree of blood loss, since as little as 1 mL of blood per liter of urine can induce a visible color change.

Gross hematuria with passage of clots almost always indicates a lower urinary tract source.

The initial step in the evaluation of patients with red urine is centrifugation of the specimen to see if the red or brown color is in the urine sediment or the urine supernatant. 

Approach to the patient with red or brown urine

Causes of Asymptomatic Gross Hematuria by Incidence

• Acute Cystitis (23%)• Bladder Cancer (17%)• Benign Prostatic Hyperplasia (12%)• Nephrolithiasis (10%)• Benign essential Hematuria (10%)• Prostatitis (9%)• Renal cancer (6%)• Pyelonephritis (4%)• Prostate Cancer (3%)• Urethral stricture (2%)

Acute renal failure — Gross hematuria

• occurring in patients with underlying glomerular disease has been associated with the development of transient acute renal failure.

• Renal biopsy shows distension of many renal tubules by intratubular red cells and tubular cell injury consistent with acute tubular necrosis

Microscopic Hematuria

–Urinary tract source•Urethra or Bladder• Prostate•Ureter or Kidney

–Non-Urinary tract source• Vagina• Anus or Rectum

Pseudohematuria (non-Hematuria related Red Urine)

Rifampin Myoglobinuria Hemoglobinuria Bilirubinuria Phenothiazines Porphyria

Pyridium Phenytoin Pyridium Red diaper syndrome Phenolphthalein Laxatives Foods (Beets, Blackberries, Rhubarb)

Step 1:Initial evaluation of isolated Hematuria

Indications:– Urine RBC 3/HPF or more OR– Urine RBC < 3/HPF on 2 samples• Incidental Microscopic Hematuria followed

with 3 urine samples at 6 week intervals• No further evaluation if Hematuria found

only on one of 4 samples

General

1 2 3 4 5

Protocol– Evaluate and treat for secondary cause

• Urinary treat infection• Exercise Hematuria (march Hematuria, e.g. distance

runners)• Menses• Genitourinary infection (STD)• Recent urologic procedure• Trauma• Hematologic causes (consider coagulopathy)

– Repeat Urinalysis with microscopy at 6 weeks following treatment• Negative: No further evaluation required unless symptomatic• Positive: Go to Step 2Gen

eral1 2 3 4 5

Step 2: Evaluate for Renal cause

Indications: – Nephropathy (IgA Nephropathy, Alport Syndrome,

Benign familial Hematuria)• Proteinuria (1+ or greater on dipstick)• Serum Creatinine elevated• Dysmorphic RBCs or RBCs casts

– Suggests glomerular cause– No dysmorphic cells suggests interstitial cause

Protocol :– (if indicated above, otherwise continue to step 3)

• Serum Creatinine with calculated GFR (obtain regardless of urine sediment)

• Urine Protein to Creatinine Ratio• Nephrology ConsultationGen

eral1 2 3 4 5

Step 3: Evaluate for urologic malignancy with imaging

– CT Urogram (preferred) , OR– Alternative imaging modality

• Indications– Low risk of urologic malignancy– Contrast Media Allergy– Poor Renal Function– Radiation contraindication (e.g. pregnancy )

• Modalities (less optimal)– MR Urography or MRI Abdomen and Pelvis– Renal US– Non-contrast CT Abdomen and Pelvis (Stone protocol)– Retrograde pyelogramGen

eral1 2 3 4 5

The most common risk factors for urinary tract malignancy in

AMH patients Age >35 years Smoking history in which the risk correlates with the

extent of exposure Occupational exposure to chemicals or dyes (benzenes or

aromatic amines), such as printers, painters, chemical plant workers

History of gross hematuria History of chronic cystitis or irritative voiding symptoms History of pelvic irradiation History of exposure to cyclophosphamide History of a chronic indwelling foreign body History of analgesic abuse, which is also associated with

an increased incidence of carcinoma of the kidneyThe American Urological Association (AUA)

Transitional cell carcinoma (TCC)

A : IVPB: (CT)C: CT urography

Step 4: Urologic Evaluation

– Protocol• Urology Consultation• Cystoscopy: urethra , prostate & bladder • Consider urine cytology (3 first morning

voids)

– Positive findings on cystoscopy, imaging or labs• Management per urology

–Negative evaluation• Go to step 5Gen

eral1 2 3 4 5

Step 5: Surveillance following negative Hematuria evaluation

– Repeat Urinalysis annually for 2 years following initial evaluation

– Positive Urinalysis on either of the 2 rechecks• Repeat Urinalysis, imaging and cystoscopy

within 3-5 years

–Negative Urinalysis on both of the rechecks• No further testing required unless symptomatic• Risk of future urologic malignancy <1%Gen

eral1 2 3 4 5

Diagnosis, Evaluation, and Follow-up of (AMH) in Adult

AUA guideline 

A systematic review of the literature using the MEDLINE database(search dates January 1980 – November 2011)

Asymptomatic microhematuria (AMH) is defined as: 3 or greater RBCs / HPF

on a properly collected urinary specimen in the absence of an obvious benign cause.

1

A positive dipstick does not define AMH, and evaluation should be based solely on findings from microscopic examination of urinary sediment and not on a dipstick reading.

A positive dipstick reading merits microscopic examination to confirm or refute the diagnosis of AMH.

Expert Opinion

The assessment of the AMH patient should include a:–careful history–physical examination– laboratory examination

to rule out benign causes of AMH such as infection, menstruation, vigorous exercise, medical renal disease, viral illness, trauma, or recent urological procedures.

Clinical Principle2

Once benign causes have been ruled out, the presence of AMH should prompt a urologic evaluation

Recommendation (Evidence Strength Grade C)

3

At the initial evaluation, an estimate of renal function should be obtained (may include calculated eGRF, creatinine, and BUN) because intrinsic renal disease may have implications for renal related risk during the evaluation and management of patients with AMH.

Clinical Principle

4

The presence of dysmorphic RBs, proteinuria, cellular casts, and/or renal insufficiency, or any other clinical indicator suspicious for renal parenchymal disease warrants concurrent nephrologic workup but does not preclude the need for urologic evaluation.Recommendation (Evidence Strength Grade C)

5

Microhematuria that occurs in patients who are taking anti-coagulants requires urologic evaluation and nephrologic evaluation regardless of the type or level of anti-coagulation therapy.

Recommendation (Evidence Strength Grade C)

6

For the urologic evaluation of asymptomatic microhematuria, a cystoscopy should be performed on all patients aged 35 years and older. Recommendation (Evidence Strength Grade C)

7

In patients younger than age 35 years, cystoscopy may be performed at the physician's discretion.

Option (Evidence Strength Grade C)

8

Regardless of age, A cystoscopy should be performed on all patients who present with risk factors for urinary tract malignancies (e.g., irritative voiding symptoms, current or past tobacco use, chemical exposures)

Clinical Principle

9

The initial evaluation for AMH should include a radiologic evaluation:• Multi-phasic computed tomography (CT)• Urography (without and with intravenous (IV)

contrast)

including sufficient phases to evaluate the renal parenchyma to rule out a renal mass and an excretory phase to evaluate the urothelium of the upper tracts, is the imaging procedure of choice because it has the highest sensitivity and specificity for imaging the upper tracts. 

Recommendation (Evidence Strength Grade C)10

For patients with relative or absolute contraindications that preclude use of multi-phasic CT (such as renal insufficiency, contrast allergy, pregnancy):

magnetic resonance urography (MRU) (without/with IV contrast) is an acceptable alternative imaging approach

 Option (Evidence Strength Grade C)

11

For patients with relative or absolute contraindications that preclude use of multiphase CT (such as renal insufficiency, contrast allergy, pregnancy) where collecting system detail is deemed imperative:

(MRI) with retrograde pyelograms (RPGs) provides alternative evaluation of the entire upper tracts Expert Opinion

12

For patients with relative or absolute contraindications that preclude use of multiphase CT (such as renal insufficiency, contrast allergy) and MRI (presence of metal in the body) where collecting system detail is deemed imperative:

combining non-contrast CT or renal ultrasound (US) with retrograde pyelograms (RPGs) provides alternative evaluation of the entire upper tracts.

Expert Opinion

13

The use of urine cytology and urine markers (NMP22, BTA-stat, and UroVysion FISH):

is NOT recommended as a part of the routine evaluation of the AMH patient.

Recommendation (Evidence Strength Grade C)

14

In patients with persistent microhematuria following a negative work up or those with other risk factors for carcinoma in situ (e.g., irritative voiding symptoms, current

or past tobacco use, chemical exposures):cytology may be useful. 

 Option (Evidence Strength Grade C)

15

Blue light cystoscopy :should not be used in the evaluation

of patients with SMH.

(Evidence Strength Grade C)

16

If a patient with a history of persistent AMH has 2 consecutive negative annual urinalyses (one per year for two years from the time of initial evaluation or beyond):

then No further urinalyses for the purpose of evaluation of AMH are necessary.

Expert Opinion

17

For persistent AMH after negative urologic work up:

Yearly urinalyses should be conducted.

 

Recommendation (Evidence Strength Grade C)

18

For persistent or recurrent AMH after initial negative urologic work-up:

Repeat evaluation within 3-5 years should be considered. Expert Opinion

19

References

• AUA http://www.auanet.org/education/asymptomatic-microhematuria.cfm#9

• http://www.fpnotebook.com/ • http://www.ncbi.nlm.nih.gov/books/NBK294/• smith’s General Urology , edi17• Etiology and evaluation of hematuria in

adults : Up To Date 2014

Thanks

Meshari Alqoopisi

29/1/2014