Microscopic hematuria

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See also: Hematuria

Editor-In-Chief: Steven C. Campbell, M.D., Ph.D., Professor of Surgery, Residency Program Director, Section of Urologic Oncology, Glickman Urological and Kidney Institute, Cleveland Clinic. You can email Dr. Campbell by clicking here. Office phone: 216-444-5595. Ali Poyan Mehr, M.D. [1]; Associate Editor(s)-in-Chief: Venkata Sivakrishna Kumar Pulivarthi M.B.B.S [2]

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Synonyms and Keywords: Microhematuria

Overview

Microscopic hematuria, or microhematuria (MH), is defined as the presence of red blood cells (RBCs) on microscopic examination of the urine not evident on visual inspection of the urine. The prevalence of MH among healthy participants in screening studies is 6.5% (95% confidence interval [CI] 3.4 to 12.2), with higher rates in studies with a predominance of males, older patients, and smokers.

Definition

Definitions for MH vary considerably and range between 1 to 10 red blood cells per high-power fiel. [1] This difference is due to factors affecting related to sample collection and quantification. One of the the most widely used definition of MH is the presence of three or greater red blood cells per high power-field on a properly collected urinary specimen in the absence of an obvious benign cause (e.g. mild trauma or sexual activity preceding the collection).[2]

Point-of-care urinary dipstick does detect MH through colometric reaction with heme. Only 1 to 2 red blood cells per high-power field are sufficient for a positive test result. However urinary dipstick it lacks specificity for MH as it also detects myoglobin and free heme without the presence of any hematuria.

Classification

Classification by Pathophysiology

Common causes of microscopic hematuria may be classified broadly according to the underlying etiology as glomerular and non glomerular, as follows:

Common Causes of Renal Common Causes of Non-Renal Hematuria
Glomerular hematuria Non-glomerular renal hematuria Upper urinary tract Lower urinary Tract
  • Nephrocalcinosis
  • Polycystic kidney disease
  • Renal cell carcinoma
  • Nutcracker syndrome




To view a all causes of microscopic hematuria, click here

Diagnostic Approach [3][4]

Evaluation of Microscopic Hematuria Algorithm.jpg

Differential Diagnosis

Microscopic hematuria should be differentiated from other disease which mimic MH especially hemoglobinuria and myoglobinuria which are dipstick positive but negative for microscopy.

Differentiating Microscopic Hematuria from Other diseases

 
 
 
 
 
 
 
Centrifuge Result
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sediment Red
 
 
 
 
 
 
 
Supernatant Red
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematuria
 
 
 
 
 
 
 
Dipstick heme
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Negative
 
 
 
 
Positive
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
❑ Beeturia
❑ Phenazopyridine
❑ Porphyria
❑ Other
 
 
 
 
❑ Myoglobin
❑ Hemoglobin
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma color
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clear
 
 
 
 
 
Red
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Myoglobinuria
 
 
 
 
 
Hemoglobinuria

Differentiating Causes of Microscopic Hematuria

CATEGORY[5] EXAMPLES COMMON CLINICAL PRESENTATION AND RISK FACTORS
Neoplasm
Any
Male gender, Age older than 35 years, Past or current smoking history, Occupational or other exposure to chemicals or dyes (benzenes or aromatic amines), Analgesic abuse, History of gross hematuria, History of urologic disorder or disease, History of Irritative voiding symptoms, History of pelvic irradiation, History of chronic urinary tract infection, Exposure to known carcinogenic agents or chemotherapy such as alkylating agents, History of chronic indwelling foreign body
Bladder cancer
Older age, male predominance, tobacco, occupational exposures, Irritative voiding symptoms
Ureteral or renal pelvis cancer
Family history of early colon cancers or upper tract tumors, flank pain
Renal cortical tumor
Family history of early kidney tumors, flank pain, flank mass
Prostate cancer
Older age, family history, African-American
Urethral cancer
Obstructive symptoms, pain, bloody discharge
Infection/inflammation
Any
History of infection
Cystitis
Female predominance, dysuria
Pyelonephritis
Fever, flank pain, diabetes, female predominance
Urethritis
Exposure to sexually transmitted infections, urethral discharge, dysuria
Tuberculosis
Travel to endemic areas
Schistosomiasis
Travel to endemic areas
Calculus
Nephroureterolithiasis
Flank pain, family history, prior stone
Bladder stones
Bladder outlet obstruction
Prostatic cause
Benign prostatic enlargement
Male, older age, obstructive symptoms
Medical renal disease
Any
Hypertension, azotemia, dysmorphic erythrocytes, cellular casts, proteinuria
IgA nephropathy
Upper respiratory tract infection, gastroenteritis, synchronous association of pharyngitis, children
Congenital or acquired anatomic abnormality
Polycystic kidney disease Family history of renal cystic disease
Uretero-pelvic junction obstruction History of UTI, stone, flank pain
Ureteral stricture History of surgery or radiation, flank pain, hydronephrosis; stranguria, spraying urine
Urethral diverticulum Discharge, dribbling, dyspareunia, history of UTI, female predominance
Fistula Pneumaturia, Fecaluria, abdominal pain, recurrent UTI, history of diverticulitis or colon cancer
Other
Exercise-induced hematuria
Recent vigorous exercise
Endometriosis
Cyclic hematuria in a menstruating woman
Hematologic or thrombotic disease
Family history of personal history of bleeding or thrombosis
Papillary necrosis
African-American, sickle cell disease, diabetes, analgesic abuse
Interstitial cystitis
Voiding symptoms

Epidemiology and Demographics

Microscopic hematuria is quite common, with a prevalence of approximately 6.5% of adults, varying according to the characteristics of the population.[6] The prevalence of microscopic hematuria ranges from 1-20% depending on the population studied and also varies with on age, gender, frequency of testing, threshold used to define MH and presence of risk factors such as smoking.[6]

The rate of malignancy detected among patients evaluated for a single positive urinalysis was 3.6%. Thus the most recent AUA guideline panel has determined that a single positive urinalysis is sufficient to prompt evaluation.[6]

Physical Examination

Physical examination of the patient with MH should be focused on isolating the underlying cause. The physical examination findings will vary depending on the etiology, as follows:

Genitourinary system

  • Flank tenderness;
  • Masses in the flank, abdomen, suprapubic area, or urethra
  • Enlarged, nodular, tender, or fluctuant prostate.

Coagulopathy

Infection

Renal disease

Urethral stricture or benign prostatic hyperplasia

  • Urine flow rate and postvoid residual measurement may be helpful as well.[5]

Diagnostic Tests

Key points in evaluation of patients with microhematuria include:[5]

  • Evaluation of adults with microscopic hematuria includes a history and physical examination, renal function testing, and upper tract imaging for all patients.
  • White light cystoscopy is recommended in the evaluation of asymptomatic MH for patients 35 years of age or older and/or those with risk factors for malignancy or those without an obvious identifiable cause for microscopic hematuria.
  • CT urogram is the preferred imaging modality for the evaluation of hematuria with the upper urinary tract being the potential source.
  • Urine cytologic examination and biomarkers are not indicated in the initial evaluation of asymptomatic MH.
  • Patients with a negative complete evaluation can be released from care if subsequent urinalyses confirm resolution of MH.
  • Re-evaluation should be considered in patients with persistent/recurrent MH and those with an incomplete initial evaluation.

The AUA guidelines recommend evaluating patients with MH “in the absence of an obvious benign cause” such as infection and menstruation. Therefore it is imperative that patients who are found to have MH 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.

Initial Workup

1. 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.[7]

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:[8]

  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.

A positive dipstick does not define MH 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 MH. 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 work-up should be undertaken. If all three specimens are negative on microscopy, then the patient may be released from care.[9] If the urinalysis with microscopy is not confirmatory, but the clinician remains suspicious, repeat microscopic testing is reasonable with the frequency individualized based on provider judgment.[5]

Microscopy and urine cytology

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. Nevertheless, it has major limitations with regard to its sensitivity.

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).

2. Blood tests

3. 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.[7] At the population level, bladder cancer is quite rare (<1 per 100,000) among persons 35 years old or younger, therefore 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.[10]

4. 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.[7]

Ultrasound (US) Intravenous urography (IVU) Computed tomography (CT) Endoscopy/Fluoroscopy MRI
Advantages

Disadvantages

  • US is poor at detecting small lesions within the collecting system (e.g. urothelial cell carcinoma (UCC) of the renal pelvis)
  • Has limited sensitivity in detecting renal calculi
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.
  • Gold standard for detecting calculi

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.
  • Cystoscopy is performed in the majority of patients with persistent unexplained hematuria.

Disadvantages

  • Requires general anaesthesia for the procedure.
Advantages

Disadvantages

  • MRI is expensive.
  • Contraindicated in patients with specific conditions.( e.g. Pacemaker, Significant renal function compromise (i.e., estimated GFR <30) when the administration of gadolinium risks nephrogenic systemic fibrosis)
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).Because MH has been associated with underlying urologic cancer, the AUA recommends evaluation with cystoscopy and upper tract imaging, preferably with computer tomography (CT) scan, for all patients >35 years of age with this finding.The likelihood of identifying a malignancy is higher among patients with higher levels of microscopic hematuria (>25 RBCs/HPH), gross hematuria, or risk factors for malignancy.[6]

Causes

Causes by Anatomic Location

Microscopic hematuria.jpg

Causes by Organ System

Cardiovascular Hypertension, Malignant hypertension, Shock
Chemical/Poisoning No underlying causes
Dental No underlying causes
Dermatologic No underlying causes
Drug Side Effect Analgesic nephropathy, Anticoagulant therapy, BCG vaccine, Caspofungin, Cobimetinib, Cyclophosphamide, Dicoumarol, Febuxostat, Gemcitabine, Ifosfamide, Micafungin, Oxaprozin, Oxcarbazepine, Phenprocoumon, Pramipexole, Tiaprofenic acid, Warfarin
Ear Nose Throat No underlying causes
Endocrine No underlying causes
Environmental No underlying causes
Gastroenterologic No underlying causes
Genetic Alport's syndrome, Benign familial hematuria, CD59 antigen deficiency, Dent disease, Fabry disease,, HANAC syndrome, Hereditary hemorrhagic telangiectasis, Infundibulopelvic dysgenesis, Osler's Disease, Polycystic kidney disease, Porphyria
Hematologic Bleeding diathesis, Cold agglutinins, Consumption coagulopathy, Haemophilia, Hemoglobinopathy, March haemoglobinuria, Multiple myeloma, Paroxysmal nocturnal haemoglobinuria, Polycythemia vera, Porphyria, Sickle cell disease, Thalassemia, Thrombocytopathies, Thrombocytopenia, Thrombotic thrombocytopenic purpura
Iatrogenic Prostatectomy, Prostatic procedures(biopsy, transurethral resection of the prostate), Radiation cystitis, Radiation nephropathy, Urethral catheterization
Infectious Disease Adenovirus, Bacterial endocarditis, Bilharziosis, Bladder tuberculosis, Chronic cystitis, Cytomegalovirus, Dengue, Dioctophyma renale, E.coli, ECHO viruses, Filaria, Influenza, Legionella pneumophila, Malaria, Plasmodium, Prostate tuberculosis, Prostatitis, Pseudomonas, Renal abscess, Renal tuberculosis, Salmonella, Schistosomiasis, Staphylococci, Streptococci, Torulopsis, Toxoplasma, Trichinella spiralis, Tuberculosis, Ureter tuberculosis, Urinary tract infection, Varicella
Musculoskeletal/Orthopedic No underlying causes
Neurologic No underlying causes
Nutritional/Metabolic No underlying causes
Obstetric/Gynecologic Endometriosis
Oncologic Benign renal mass, Bladder cancer, Hypernephroma, Malignancies of the bladder, Malignant renal mass, Multiple myeloma, Oncocytoma, Prostate adenoma, Prostate cancer, Renal adenocarcinoma, Renal angiomyolipoma, Renal cell carcinoma, Renal oncocytoma, Squamous cell carcinoma of bladder, Transitional cell carcinoma of bladder, Transitional cell carcinoma of kidney, Ureter carcinoma, Urethral cancer, Urothelium carcinoma, Wilms' tumor
Ophthalmologic No underlying causes
Overdose/Toxicity No underlying causes
Psychiatric No underlying causes
Pulmonary No underlying causes
Renal/Electrolyte Acute interstitial nephritis, Analgesic nephropathy, Angiomyolipoma, Balkan nephropathy, Berger's disease, Calyx diverticulum, Crescentic glomerulonephritis, Dense deposit disease, Dent disease, Diabetic glomerulosclerosis, Diabetic nephropathy, Fibronectin glomerulopathy, Focal segmental glomerulonephritis, Glomerulonephritis, Goodpasture syndrome, Hydronephrosis, Hypercalciuria, Hypernephroma, Hyperuricosuria, IgA nephropathy,Interstitial cystitis, Loin pain hematuria syndrome, Malignant renal mass, Medullary sponge kidney, Membranoproliferative glomerulonephritis, Mesangiocapillary glomerulonephritis type iii, Nephrocalcinosis, Nephrolithiasis, Nutcracker syndrome, Papillary necrosis, Postinfectious glomerulonephritis, Post-streptococcal glomerulonephritis, Pyelonephritis, Renal abscess, Renal adenocarcinoma, Renal angiomyolipoma, Renal aretery embolism, Renal arteriovenous malformation, Renal artery aneurysm,Renal cell carcinoma, Renal cyst, Renal hyperplasia, Renal oncocytoma, Renal tuberculosis, Renal vein thrombosis, Shunt nephritis, Thin basement membrane disease, Tubulointerstitial nephropathies, Wilms' tumor
Rheumatology/Immunology/Allergy Allergic granulomatosis, Berger's disease, Cold agglutinins, Dermatosclerosis, Goodpasture syndrome, Hemolytic uremic syndrome, Henoch schonlein purpura, IgA nephropathy, Kidney amyloidosis, Microscopic polyangiitis, Polyarteritis nodosa, Renal infarction, Sarcoidosis, SLE, Vasculitis, Wegener's granulomatosis
Sexual No underlying causes
Trauma Pelvic fracture, Renal trauma
Urologic Acute prostatitis, Benign prostatic hyperplasia, Bladder stone, Foreign body in urethra, Hemorrhage from bladder outlet, Hemorrhage from urethra, Meatal stenosis, Megaureter, Postoperative spindle cell nodule of urinary bladder, Prostate adenoma, Prostate cancer, Prostate hyperplasia, Prostate tuberculosis, Urate nephropathy, Ureteral cancer, Ureter tuberculosis, Ureteroiliac fistula, Ureterolithiasis, Urethral cancer, Urethral carbuncle, Urethral diverticulum, Urethral fibroepithelial polyp, Urethral stone, Urethritis, Urinary tract infection, Urolithiasis, Urothelium carcinoma, Urtethral stricture, Vesical calculi, Vesico-ureteral-renal reflux
Miscellaneous Arteriovenous fistula, Arteriovenous malformation, Cholesterol embolism, Exercise, Masturbation, Transient unexplained

Causes by Alphabetical Order


References

  1. Cohen RA, Brown RS (2003) Clinical practice. Microscopic hematuria. N Engl J Med 348 (23):2330-8. DOI:10.1056/NEJMcp012694 PMID: 12788998
  2. Davis R, Jones JS, Barocas DA, Castle EP, Lang EK, Leveillee RJ et al. (2012) Diagnosis, evaluation and follow-up of asymptomatic microhematuria (AMH) in adults: AUA guideline. J Urol 188 (6 Suppl):2473-81. DOI:10.1016/j.juro.2012.09.078 PMID: 23098784
  3. Sharp VJ, Barnes KT, Erickson BA (2013) Assessment of asymptomatic microscopic hematuria in adults. Am Fam Physician 88 (11):747-54. PMID: 24364522
  4. Cohen, Robert A.; Brown, Robert S. (2003). "Microscopic Hematuria". New England Journal of Medicine. 348 (23): 2330–2338. ISSN 0028-4793. doi:10.1056/NEJMcp012694. 
  5. 5.0 5.1 5.2 5.3 Wein, Alan (2016). Campbell-Walsh urology. Philadelphia, PA: Elsevier. ISBN 978-1455775675. 
  6. 6.0 6.1 6.2 6.3 Davis R, Jones JS, Barocas DA, Castle EP, Lang EK, Leveillee RJ et al. (2012) Diagnosis, evaluation and follow-up of asymptomatic microhematuria (AMH) in adults: AUA guideline. J Urol 188 (6 Suppl):2473-81. DOI:10.1016/j.juro.2012.09.078 PMID: 23098784
  7. 7.0 7.1 7.2 "www.surgeryjournal.co.uk". 
  8. Amin, Nimisha; Zaritsky, Joshua J. (2011). "Hematuria": 258–261. doi:10.1016/B978-0-323-05405-8.00069-3. 
  9. Davis R, Jones JS, Barocas DA, Castle EP, Lang EK, Leveillee RJ et al. (2012) Diagnosis, evaluation and follow-up of asymptomatic microhematuria (AMH) in adults: AUA guideline. J Urol 188 (6 Suppl):2473-81. DOI:10.1016/j.juro.2012.09.078 PMID: 23098784
  10. Pan, Cynthia G. (2006). "Evaluation of Gross Hematuria". Pediatric Clinics of North America. 53 (3): 401–412. ISSN 0031-3955. doi:10.1016/j.pcl.2006.03.002. 
  11. Praga M, Alegre R, Hernández E, Morales E, Domínguez-Gil B, Carreño A; et al. (2000). "Familial microscopic hematuria caused by hypercalciuria and hyperuricosuria.". Am J Kidney Dis. 35 (1): 141–5. PMID 10620556. doi:10.1016/S0272-6386(00)70313-1. 
  12. Young EE, Gandhi N, Stuhldreher P, Bishop JA, Wang MH (2016). "Profound Hematuria in a Toddler Yields an Unusual Diagnosis.". Urol Case Rep. 6: 39–41. PMC 4855982Freely accessible. PMID 27175341. doi:10.1016/j.eucr.2016.02.009. 

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