Sandbox:Hematuria overview

Overview

Hematuria is the presence of blood in the urine and is a common condition in urological practice. It accounts for around 20% of urological referrals and is important, as it can be a cardinal symptom of urological malignancy. Around 40% of patients investigated for hematuria are found to have significant underling pathology, half of whom will have a urological malignancy. Therefore, all patients presenting with a single episode of haematuria require urgent investigation. Haematuria in adults should be regarded as a symptom of urological malignancy until proven otherwise.

Definition

Hematuria is the presence of blood cells in the urine. Gross hematuria is when blood is visible in the urine. Microscopic hematuria is defined as 3 or more red blood cells per high-powered field in a properly collected urine sample.

classification

Classification by the extent of hematuria

1. Dipstick hematuria: Detection of hemoglobin within red blood cells using reagent strips in macroscopically normal urine.This describes the use of reagent strips to detect blood chemically within urine.
2. Microscopic hematuria: Defined as the presence of more than two to five red blood cells per high powered field within macroscopically normal urine on a properly collected urinary specimen in the absence of an obvious benign cause.
3. Macroscopic hematuria: Defined as the presence of blood in urine that is visible with naked eye.

Classification by the visibility of hematuria

1. Visible hematuria: Also known as Frank hematuria/ Macroscopic hematuria/ Gross hematuria. Visible hematuria can be visualized with the naked eye and is also known as frank, gross or macroscopic hematuria. Visible hematuria is more likely to be associated with malignancy.
   1. Initial hematuria: May indicate urethral pathology
   2. Terminal hematuria: Hematuria at the end of the stream that comes from the proximal urethra (bladder neck/prostate).
   3. Complete hematuria: Hematuria throughout the entire stream suggests bladder, ureteric or renal pathology.
2. Non-visible hematuria: Non-visible hematuria encompasses dipstick and microscopic hematuria.

Classification by the duration of hematuria

1. Transient hematuria: A single urinalysis with hematuria is common and can result from menstruation, viral illness, allergy, exercise, fever, or mild trauma.
2. Persistent or Significant hematuria: >3 RBCs/HPF on three urinalyses, a single urinalysis with >100 RBCs, or gross hematuria.

Causes

Life Threatening Causes

• Intraperitoneal bladder rupture

• Ureteroarterial fistula

• Hemorrhagic cystitis

• Heart failure

• Malignant hypertension

• Shock

Common Causes

• Benign prostatic hyperplasia

• Bladder cancer

• Exercise

• Nephrolithiasis

• Polycystic kidney disease

• Prostate carcinoma

• Renal carcinoma

• Trauma

• Urinary tract infections

Causes by Organ System

Cardiovascular	Arteriosclerosis, arteriovenous malformations, endocarditis, cholesterol embolism, heart failure, hypertension, malignant hypertension, shock
Chemical / poisoning
Dermatologic	Hereditary hemorrhagic telangiectasis, lupus, Osler's disease, systemic lupus erythematosus, urethral carbuncle
Drug Side Effect	Artemether and lumefantrin, beractant, BCG vaccine, bicalutamide, caspofungin acetate, cefpodoxime, cobimetinib, cyclophosphamide,dicoumarol, ethacrynic acid, febuxostat, felbamate, flurbiprofen, gemcitabine, goserelin, hexaminolevulinate, Ibrutinib, Indinavir, Ifosfamide, Ioxilan, leuprolide, methenamine, micafungin, mitotane, olsalazine, Oxcarbazepine, Oxaprozin penicillamine, phenprocoumon, Pramipexole, probenecid, sodium aurothiomalate, sulfasalazine, tiagabine, tolmetin, tiaprofenic acid, warfarin
Ear Nose Throat	Hereditary hemorrhagic telangiectasis, mononucleosis, Osler's disease
Endocrine	Diabetes mellitus, diabetic glomerulosclerosis, diabetic nephropathy, porphyria
Environmental
Gastroenterologic	Hepatitis B, porphyria
Genetic	Alport syndrome, Berger's disease, Fabry disease, Dent's disease, hemoglobinopathy, hemophilia, IgA nephropathy nail-patella syndrome, Nephrolithiasis type 2Osler's disease, paroxysmal nocturnal haemoglobinuria, polycystic kidney disease, thalassemia,renal arteriovenous malformation, thalassemia
Hematologic	Cold agglutinins, March haemoglobinuria, hemoglobinopathy, hemophilia, hemolytic uremic syndrome, Henoch schonlein purpura, hereditary hemorrhagic telangiectasis, multiple myeloma, paroxysmal cold haemoglobinuria, paroxysmal nocturnal haemoglobinuria, polycythemia vera, porphyria, sickle cell anemia, thalassemia, thrombocytopeniathrombotic thrombocytopenic purpura
Iatrogenic
Infectious Disease	Acute cystitis, acute interstitial nephritis, acute prostatitis, adenovirus, bilharziosis, bladder tuberculosis, chronic cystitis, cystitis, cytomegalovirus, dengue, Dent's disease, E.coli, ECHO viruses endocarditis, filaria, hepatitis B, Influenza, legionella infection, legionella pneumophila, malaria, micafungin mononucleosis, mycoplasma, nephritis, postinfectious glomerulonephritis, prostate tuberculosis, prostatitis pyelonephritis, radiation cystitis, renal tuberculosis, salmonellaschistosomiasis, toxoplasma, trichinella spiralis, tuberculosis, urethritis, vasculitis, pseudomonas, renal tuberculosis, salmonella, schistosomiasis, torulopsis, toxoplasma, trichinella spiralis, tuberculosis, ureter tuberculosis, urethritis, urinary tract infection. urogential tuberculosis
Musculoskeletal / Ortho	Pelvic fracture
Neurologic	Arteriosclerosis, arteriovenous malformations, hereditary hemorrhagic telangiectasis, Osler's disease
Nutritional / Metabolic	Diabetes mellitus Fabry disease
Obstetric/Gynecologic	Endometriosis
Oncologic	Angiomyolipoma, bladder cancer, hypernephroma, multiple myeloma, polycythemia vera, prostate adenoma, prostate cancer, renal adenocarcinoma, renal angiomyolipoma, renal arteriovenous malformation, renal pelvis carcinoma, ureter carcinoma, urethra carcinoma, urothelium carcinoma, Wilms' tumor
Opthalmologic
Overdose / Toxicity
Psychiatric
Pulmonary	Allergic granulomatosis, sarcoidosis, Wegener's granulomatosis
Renal / Electrolyte	Acute cystitis, acute interstitial nephritis Alport syndrome, analgesic nephropathy, Balkan nephropathy, beeturia benign familial hematuria, Berger's disease, calyx diverticulum, cholesterol embolism, chronic cystitis, crescentic glomerulonephritis, cystitis, dense deposit disease, Dent's disease, diabetic glomerulosclerosis, diabetic nephropathy, focal glomerulotnephritis, glomerulonephritis, fibronectin glomerulopathy, hemolytic uremic syndrome, Henoch schonlein purpura, hydronephrosis hypernephroma, IgA nephropathy, Interstitial cystitis, kidney amyloidosis, Loin pain hematuria syndrome,lupus, medullary sponge kidney, membranoproliferative glomerulonephritis, mesangiocapillary glomerulonephritis type iii nephrocalcinosis, nephrolithiasis, nutcracker syndrome, papillary necrosis, polycystic kidney disease, postinfectious glomerulonephritis, post-streptococcal glomerulonephritis, proteinuria, pyelonephritis, radiation nephropathy, renal adenocarcinoma, renal angiomyolipoma, renal artery aneurysm, renal cell carcinoma, renal cyst, renal hyperplasia, renal infarct, renal metastases, renal oncocytoma, renal oncocytoma, renal pelvis carcinoma, renal trauma, renal tuberculosis, renal vein infarct, renal vein thrombosis, shunt nephritis, sponge kidney, systemic lupus erythematosus, thin basement membrane disease, tubulointerstitial nephropathies, urate nephropathy,ureter carcinoma, ureter tuberculosis, urinary tract infection, vesico-ureteral-renal reflux, Wegener's granulomatosis, Wilms' tumor
Rheum / Immune / Allergy	Allergic granulomatosis, Cd59 antigen deficiency, Cold agglutinins, dermatosclerosis, Henoch schonlein purpura, microscopic polyangiitis, polyarteritis nodosa, sarcoidosis, systemic lupus erythematosus, Wegener's granulomatosis
Sexual
Trauma	Pelvic fracture
Urologic	Acute prostatitis, beeturia, benign prostatic hyperplasia, bladder cancer, bladder tuberculosis Dent's disease, foreign body in urethra, hemorrhage from bladder outlet, hemorrhage from urethra hydronephrosis, interstitial cystitis, Loin pain hematuria syndrome, malignancies of the bladder, meatus stenosis, megaureter, polycystic kidney disease, prostate adenoma, prostate cancer, prostate hyperplasia, prostate tuberculosis, prostatectomy, radiation cystitis, urethra carcinoma, urethral carbuncle, urethritis, urinary stones, urinary tract infection, urogential tuberculosis, urolithiasis, urothelium carcinoma
Miscellaneous	Dioctophyma renale, exercise, fistula, foods, Inflammation, infundibulopelvic dysgenesis, Injury, masturbation myoglobinuria, toxins, trauma, tumor, urethral catheterization, urinary catheterization

Causes in Alphabetical Order

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4

Differentiating Hematuria from other Diseases

Gross hematuria(GH) must be distinguished from pigmenturia, which may be due to endogenous sources (e.g., bilirubin, myoglobin, porphyrins), foods ingested (e.g., beets and rhubarb), drugs (e.g., phenazopyridine), and simple dehydration. This distinction can be made easily by urinalysis with microscopy. Notably, myoglobinuria and other factors can cause false-positive chemical tests for hemoglobin, so urine microscopy is required to confirm the diagnosis of hematuria. GH also must be distinguished from vaginal bleeding in women, which usually can be achieved by obtaining a careful menstrual history, collecting the specimen when the patient is not having menstrual or gynecologic bleeding, or, if necessary, obtaining a catheterized specimen. GH may also be detected by the presence of blood spotting on the undergarments of incontinent patients. After ruling out vaginal bleeding and mimics of hematuria, a urologic source must be suspected.

Red discoloration of the urine can have various causes:

• Red blood cells
  • Microscopic hematuria (small amounts of blood, can be seen only on urinalysis or light microscopy)
  • Macroscopic hematuria (or "frank" or "gross") hematuria
• Hemoglobin (only the red pigment, not the red blood cells)
• Other pigments
  • Porphyrins in porphyria
  • Betanin, after eating beets

Differentiating Hemoglobinuria from Myoglobinuria

Centrifuse Result

Sediment Red

Supernatant Red

Hematuria

Dipstick heme

Negative

Positive

❑ Beeturia ❑ Phenazopyridine ❑ Porphyria ❑ Other

❑ Myoglobin ❑ Hemoglobin

Plasma color

Clear

Red

Myoglobinuria

Hemoglobinuria

Epidemiology

2.5% of the general population has asymptomatic hematuria.

Age

Young patients are more likely to have intrinsic renal pathology (i.e. glomerulonephritis whereas malignancy is more common in the elderly).

Sex

Malignancy of the bladder and kidney is at least twice as common in males than in females. Women are more commonly affected by urinary tract infections.

Natural history, complications and prognosis

The prognosis depends on the severity of the disease. Finding the cause is the main factor which determines the prognosis. As hematuria has a vast majority of causes the complications depends on the specific etiology. As the degree of hematuria increases, so does the likelihood of finding clinically significant lesions during evaluation. That is, the difference between the yield of life-threatening lesions in patients with gross versus microscopic hematuria has been found to be highly significant. Specifically, among patients with GH, 50% have been found to have a demonstrable cause, with 20% to 25% found to have a urologic malignancy, most commonly bladder cancer and kidney cancer. Given the increased frequency with which clinically significant findings are associated with GH, the recommended evaluation in this setting is relatively uniform. That is, patients presenting with GH in the absence of antecedent trauma or culture-documented UTI should be evaluated with a urine cytologic examination, cystoscopy, and upper tract imaging, preferably CT urogram. 

Diagnosis

Evaluation of patients with hematuria includes a focused history and physical examination, urinalysis and various blood tests. evaluation of hematuria is best performed in stepwise progression, beginning with simple and noninvasive investigations, followed by more aggressive interventions if positive results are obtained. Most importantly the lower urinary tract should be visualized using cystoscopy, usually using a flexible scope, and the upper tract imaged by a combination of modalities including plain X-ray, ultrasonography, intravenous urography or CT urography.

• Further, patients with GH must be assessed for hemodynamic stability with careful attention to vital signs, anemia with a complete blood count, and, for patients on anticoagulation, coagulation parameters to ensure that levels are within the therapeutic range. After initial stabilization, diagnostic evaluation should then proceed, with cause-specific management. 
• The AUA guidelines recommend evaluating patients with hematuria “in the absence of an obvious benign cause” such as infection and menstruation. Therefore it is imperative that patients who are found to have hematuria in the setting of a suspected benign cause have that benign cause substantiated by clinical evidence and be further evaluated once the suspected benign cause is resolved. For example, the presence of infection should be confirmed with a urine culture and the urinalysis should be repeated after treatment of the UTI to document resolution of the hematuria. In addition, patients who develop hematuria (microscopic or gross) who are taking anticoagulation or antiplatelet medications (e.g., warfarin, enoxaparin, heparin, aspirin, clopidogrel, nonsteroidal anti-inflammatory agents) should undergo a complete evaluation in the same manner as patients not taking such medications,because the prevalence of hematuria, as well as the likelihood of finding genitourinary cancers, among patients.

Urine-based tests

A fresh sample of urine should be dipstick tested for proteinuria (renal disease) or nitrituria (infection). If abnormal the sample should be sent for microbiological assessment (microscopy and culture) and cytology.

Dipstick test

A urine dipstick analysis is a highly sensitive measure for detection of blood, but it lacks specificity (sensitivity of 95% and a specificity of 75%). This translates into a large number of false positives, in which case, the urine dipstick is positive, but microscopy reveals fewer than 3RBC/HPF. This particular combination can be seen in the following benign or pathological circumstances:

1. Ingestion of certain foods: beets, blackberries, food coloring
2. Ingestion of certain medications: Chloroquine, Ibuprofen, Iron, Sorbitol, Nitrofurantoin, Phenazopyridine, Urates or Rifampin (which often produces orange urine)
3. Hemoglobinuria: often in the setting of hemolytic anemia
4. Myoglobinuria: related to muscle damage (rhabdomyolysis), often after vigorous exercise or trauma
5. Urinary tract infection: secondary to the action of bacterial peroxidases on the dipstick
6. Delay in reading urine dipstick after submersion in urine
7. presence of semen in urine.

Given the large number of situations in which a positive dipstick may not represent true hematuria, all urine samples that test positive on dipstick analysis must be sent for microscopy to confirm hematuria.

Microscopy

Urine cytology

Microscopy is performed on urinary sediment (following centrifuging a fresh urine sample) and can quantify the number of erythrocytes. Advantages Useful for detecting urinary casts (suggesting renal disease) Useful for detecting urinary crystals (suggesting calculous disease) Useful for detecting dysmorphology of red cells (suggesting a glomerular cause of hematuria) Useful for detecting atypical or malignant epithelial cells from a tumour are shed into the urine.

Urine cytology is the ‘gold standard’ urine-based test for detecting cancer. Advantages Cytology is best at detecting poorly differentiated tumours and carcinoma in-situ (with poorly-adhesive grossly abnormal cells). But it has a low sensitivity and specificity for low-grade tumours (that have normal looking adherent cells).

Blood tests

• Complete blood count (detects anaemia)
• Coagulation studies (to detect hemoglobinopathies)
• Complement levels ( to detect Nephritic cause of hematuria)
• Serum urea, creatinine and electrolytes (to detect renal impairment)

Investigation of the lower urinary tract

Cytoscopy: It is a key component of the hematuria evaluation because it is the most reliable way to evaluate the bladder for the presence of bladder cancer and provides the opportunity to evaluate the urethra. Cystoscopy should be performed in all adults who meet criteria for hematuria evaluation who are 35 years of age or older and/or have risk factors for malignancy. Flexible cystoscope is useful for the inspection of the urethra and visualization of the bladder mucosa. It is quick, well tolerated and safe procedure. The detection of an abnormality will require subsequent rigid cystoscopy under anesthesia, whereby tissue can be obtained or treatment performed. At the population level, bladder cancer is quite rare (<1 per 100,000) among persons 35 years old or younger, so cystoscopy may be omitted in persons younger than age 35 years without risk factors or clinical suspicion for bladder cancer or urethral pathology. The potential risks include discomfort, injury to the urethra, infection, and the need for additional procedures, such as biopsy.

Investigation of the upper urinary tract

Evaluation of the upper urinary tract is more complex, and requires a balance between the low detection rate of pathology and the number or extent of tests required to visualize the urinary organs. No single imaging modality has the desired attributes of a high sensitivity and specificity, safety (low radiation exposure), low cost and applicability to lots of patients.

Ultrasound (USS)	Intravenous urography (IVU)	Computed tomography (CT)	Endoscopy/Fluoroscopy	MRI
Advantages Ultrasound of the abdomen and pelvis is safe. It is good at detecting Detecting renal parenchymal lesions (e.g. renal cell carcinoma) For characterizing renal cysts Showing renal calculi For determining ureteric obstruction (Hydronephrosis) Disadvantages USS is poor at detecting small lesions within the collecting system (e.g. UCC of the renal pelvis)	Advantages IVU is good at detecting abnormalities of the urothelium (UCC of the ureter and renal pelvis) and stones. Disadvantages Poor at detecting small renal parenchymal lesions that do not distort the renal outline. It cannot distinguish cystic from solid masses.	Advantages Distinguish equivocal cases, for planning treatment options and determining the nature of small renal parenchymal lesions. Has a high specificity and sensitivity for investigating the causes of hematuria. Disadvantages CT is expensive, time consuming and carries a high radiation exposure.	Advantages Used to investigate intravenous urography filling defects and to treat stones. In patient with continued undiagnosed hematuria, this can be used to collect urine or brushings from each ureter, allowing cytology to determine the site of bleeding and the presence of very small tumors of carcinoma in-situ. Disadvantages Requires general anaesthesia for the procedure.	MRI can been used for equivocal cases and planning treatment.

The gold standard investigation protocol for upper urinary tract would combine USS and IVU to evaluate the upper urinary tract. However, an IVU has a large radiation dosage with a small risk of reaction to contrast medium and detects upper tract UCC which are rare (less than 1% of all tumors presenting with hematuria). If looking for stone disease USS and a plain radiograph of the abdomen is recommended and IVU is reserved for equivocal cases, patients with persistent hematuria or patients with a high risk of UCC (elderly, smokers, occupational exposure).

Investigation of a nephrological cause of hematuria

• 24-hours urine collection should also be obtained to assess kidney function (e.g. Creatinine clearance/glomerular filtration rate, urine osmolality, sodium and albumin concentrations).
• Renal biopsy

The initial evaluation of patients presenting with gross hematuria is 3-fold:

• Assess hemodynamic stability
• Determine the underlying cause of hematuria
• Ensure urinary drainage.

Evaluation of patients with haematuria includes a focussed history and physical examination, urinalysis and various blood tests.Most importantly the lower urinary tract should be visualized using cystoscopy, usually using a flexible scope, and the upper tract imaged by a combination of modalities including plain X-ray, ultrasonography, intravenous urography or computed tomography urography.

The treatment options for haematuria depend on the underlying cause.

Hematuria ' One-Stop ' Clinic

In recent years the ‘one-stop’ hematuria clinic has become popular for the investigation of hematuria as this enables synchronous urological and radiological evaluation of the patient, resulting in rapid diagnosis and treatment.This clinic has been set up to save you having repeated visits to the hospital. For most patients, in the course of one visit, all the tests needed to diagnose the cause of the blood in the urine will be undertaken. Occasionally some further tests will be necessary as a result of the findings at the first visit. In the morning you will have either an x-ray or a scan (KUB or Ultrasound) depending on the type of bleeding you have experienced. Early in the afternoon you will be seen by the consultant urologist or one of his team. You will then be examined and finally an internal inspection of your bladder will be performed. By the end of your visit you should know the outcome of all your tests and whether anything further needs to be done.