Gross and Microscopic Hematuria

Etiology

Genitourinary disorders primarily cause hematuria, although systemic diseases can manifest with blood in the urine. The etiology of hematuria is divided into glomerular or nonglomerular hematuria for classification, although the cause in many cases may be idiopathic or undetermined. In general, glomerular sources are often associated with proteinuria.

In infants and young children, hematuria may signal Wilms tumor, polycystic kidney disease, Alport syndrome, inherited nephritis, glomerulonephritis, hypercalciuria, urinary tract infections, and, in the Black population, sickle cell disease. In older individuals, the most common causes are urinary tract infections, various urological malignancies (eg, kidney and bladder cancers), urolithiasis, postinfectious and other types of glomerulonephritis, trauma, prostatic enlargement, and urinary instrumentation. In about 50% of cases, a specific cause of the hematuria can be identified, meaning no definite etiology can be determined about half the time. When hematuria presents with proteinuria, casts, or dysmorphic (ie, malformed) RBCs, this usually signals glomerular pathology with at least moderate kidney disease. Some common glomerular causes of hematuria include:

• Alport syndrome
• Crescentic glomerulonephritis
• Diffuse progressive glomerulonephritis
• Focal segmental glomerulonephritis
• Goodpasture syndrome
• IgA vasculitis (Henöch-Schonlein purpura)
• Hypercalciuria
• IgA nephropathy
• Lupus nephritis
• Membranous glomerulonephritis
• Minimal change disease
• Nephrotic syndrome
• Rapidly progressive (pauci-immune) glomerulonephritis
• Polycystic kidney disease
• Post-streptococcal (post-infectious) glomerulonephritis
• Thin basement membrane disease (formerly benign familial hematuria)

Nonglomerular causes typically demonstrate normal RBCs on microscopic urinalysis without proteinuria or casts. Common nonglomerular causes of hematuria include:

• Bladder calculi
• Benign prostatic hyperplasia
• Endometriosis of the urinary tract
• Strenuous exercise
• Foreign bodies in the urinary tract (eg, stones, catheters, and stents)
• Genitourinary mucosal injury by instrumentation, including biopsies
• Hematological disorders like sickle cell anemia, thrombocytopenia, and coagulopathies
• Hemorrhagic cystitis
• Infections (eg, cystitis, urethritis, and prostatitis)
• Malignancy (eg, renal cell carcinoma, bladder, and prostate cancer)
• Medication-related (eg, cyclophosphamide)
• Nephrolithiasis, urolithiasis
• Nutcracker Syndrome
• Radiation cystitis
• Schistosomiasis (Africa and endemic regions)
• Trauma involving the genitourinary tract

Epidemiology

Gross hematuria is a common presentation in outpatient clinics and emergency departments. Asymptomatic hematuria is thought to be much more prevalent than symptomatic hematuria and may be present for years before it is discovered.[11][12] The evaluation of hematuria, especially microhematuria, is often delayed in women, which can cause poorer outcomes for bladder and other urological cancers in females.[5]

The prevalence of hematuria varies widely according to the definition used and the availability of medical evaluation. In the United States (US), the prevalence of microscopic hematuria is estimated at 6.5% of the population.[3] The prevalence varies worldwide, depending on the population studied and the definition used.[1][3] One study in Japan, where annual health check-ups with urine dipstick are the standard of care, found that 5% to 10% of the population were dipstick-positive for hematuria.[13] Another meta-analysis showed that the prevalence of asymptomatic microhematuria varies from 0.19% to 16%. Prevalence depends greatly on the ages and population studies. Older men have an especially high prevalence of asymptomatic microhematuria, with some estimates as high as 21%.[14]

A primary focus of an evaluation of hematuria is to identify and exclude any underlying malignancy; hematuria is the presenting symptom in most bladder cancers. The overall incidence of discovering a genitourinary malignancy in patients with microscopic hematuria is approximately 3%.[3][5][15] With gross hematuria, the incidence rises to 10% to 20%.[36] This risk is increased in some groups and is related to gender, age, smoking history, some chemical exposures (eg, benzene and aromatic amines), and degree of hematuria.[16][17] The American Cancer Society estimates that there will be about 82,290 new cases of bladder cancer, approximately 62,420 in men and 19,870 in women, in 2023, with 16,710 deaths. The National Cancer Institute has estimated the annual incidence of bladder cancer at 18.7 per 100,000 population. However, the overall incidence is slowly decreasing. For renal cancer, the estimated yearly incidence in the US is around 79,000, about 50,000 men and 29,000 women, with 14,000 mortalities. Worldwide, over 400,000 persons are estimated to be diagnosed with this disease yearly, with about 180,000 deaths annually. The overall incidence appears to be slowly increasing. 

The overall incidence of glomerulonephritis has been reported as high as 134 per 100,000 patient years, but reliable worldwide statistics are difficult to obtain.[18] Nephrolithiasis rates vary with gender, being about twice as common in males as females, ethnicity, and geographic region. The reported incidence of urolithiasis ranges from 7% to 13% in the US and Canada, 5% to 9% in Europe, and 1% to 5% in Asia.[19] UTIs have an overall estimated global prevalence of 0.7%. The main risk factors for UTI are increasing age, previous history of UTI, sexual activity, and diabetes.[20] Acute cystitis is far more common than pyelonephritis; for every pyelonephritis case, there are 18 to 28 cases of acute cystitis.[21] Of note, while UTI is a common cause of microhematuria, the resolution of microhematuria after UTI treatment should be documented, as malignancy and UTI may coexist.[36] 

Benign prostatic hyperplasia (BPH) is extremely common, but most affected individuals initially demonstrate urinary symptoms other than hematuria. Half of the men older than 50 demonstrate some evidence of BPH.[22][23] This increases with age by about 2% to 2.5% yearly.[24] In the US, the incidence of BPH in men aged 60 to 69 years is 70%, which rises to over 80% in men older than 70 years.[25] Polycystic kidney disease affects an estimated 4 to 7 million individuals worldwide and accounts for up to 15% of patients with end-stage kidney disease.[26] Approximately 5% of all traumas involve the kidney. The majority of such traumas come from motor vehicle accidents, followed by sports injuries and falls.[27][28]

Nutcracker syndrome, also known as left renal vein obstruction or entrapment, is a rare, sometimes symptomatic syndrome where the flow of the left renal vein into the inferior vena cava is blocked, often by the superior mesenteric artery.[29] The incidence of this entity is unknown but is most common in adults in the second and third decades. See the StatPearls companion article "Nutcracker Syndrome" for additional information.[30] Asymptomatic hematuria can be found in 4% of normal school-aged children, more often in girls than boys.[31]

Inherited illnesses that cause hematuria are relatively uncommon. Alport syndrome is more common in the US, where the incidence is estimated at 1 in 5,000 population or up to 60,000 total affected individuals. The incidence in Europe is lower, estimated at 1 in 50,000.[32] Approximately 3% of all children in the US with end-stage renal failure have Alport syndrome. Autosomal dominant polycystic kidney disease is found in roughly 1 in every 1,000 live births. The incidence of Goodpasture syndrome is fewer than 2 cases per 1 million population.[33] Thin basement membrane disease, formerly known as benign familial hematuria, affects at least 1% of the population worldwide. Some patients previously thought to have thin basement membrane disease were found to have variations of Alport Syndrome.[32] Additionally, sickle cell disease affects about 100,000 Black Americans, or 1 out of every 365 Black Americans, according to the Centers for Disease Control and Prevention.[34][35] This can cause renal papillary necrosis or other renal infarctions, resulting in microscopic hematuria.[36] Sickle cell trait is found in 1 out of every 12 babies of African ancestry born in the US.

Furthermore, medications can cause hematuria or urinary discoloration due to pseudohematuria (ie, red, pink, or brown urine discoloration), kidney damage, nephrolithiasis or urolithiasis, or hemorrhagic cystitis. Medications that can lead to hematuria include:

• Allopurinol
• Blood thinners, such as warfarin or antiplatelet drugs
• Captopril
• Cephalosporins
• Chlorpromazine 
• Cyclophosphamide
• Dichlorphenamide 
• Furosemide
• Hydralazine
• Indinavir
• Ifosfamide
• Metronidazole
• Nitrofurantoin
• Phenazopyridine
• Phenolphthalein
• Minocycline
• Mirtazapine 
• Penicillin
• Propylthiouracil
• Rifampin
• Senna
• Sulfa drugs
• Thioridazine

Pathophysiology

Hematuria may result from structural alterations due to an injury, infection, or a mass anywhere in the genitourinary tract. Anticoagulation alone does not cause hematuria but may exacerbate this symptom. Patients on anticoagulants or antiplatelet therapy should receive the same evaluation as individuals not on such agents, as their risk of malignancy is the same.[1][37][38][39][40] Immunological or inflammatory processes may damage the integrity of the renal glomerular basement membrane, mesangium, or microvascular endothelium.[41] This usually presents as glomerular bleeding.

Nonglomerular causes of bleeding, including nephrolithiasis, urolithiasis, certain drugs, nephrocalcinosis, genitourinary neoplasms, trauma-related urothelial mucosal damage, catheterization, urological biopsies or similar procedures, benign prostatic hyperplasia, radiation exposure, and various chemicals may cause erosion or otherwise damage the urothelial surface somewhere in the urinary tract, leading to hematuria.

History and Physical

There are many ways to classify hematuria, but the most clinically useful division is gross and microscopic.

Gross Hematuria

Gross hematuria is visible blood in the urine. Gross hematuria may be reddish or pink due to lower tract abnormalities. It can also present as brown or tea-colored urine due to oxidation of urinary heme pigments. Gross hematuria may be associated with significant urological disease whether or not symptoms are present. A patient's history may provide sufficient explanation to explain the hematuria, such as recent urological surgery or instrumentation, a urinary tract infection, or passage of a kidney stone. If unexplained, gross hematuria generally requires further workup, including imaging and cystoscopy, to eliminate urological malignancies, particularly those older than 35. Furthermore, clinicians should be aware that the presence of gross hematuria automatically makes the case high-risk.

Microscopic Hematuria

Microscopic hematuria may be further classified into the following subtypes:

• Asymptomatic: This may be associated with bladder and other urological cancers. Typically, normal RBCs are seen microscopically. Requires further risk-stratified workup.
• Asymptomatic with proteinuria: Proteinuria in asymptomatic patients is suggestive of glomerulonephritis. Dysmorphic, atypical RBCs are frequently seen with microscopic exams. A workup for glomerular disorders should be performed and may require a renal biopsy.
• Symptomatic: This subtype is associated with urinary symptoms and is often suggestive of infection, prostatitis, BPH, or other urinary disorders. Further investigation should be performed with follow-up as warranted.

Clinical Symptoms of Hematuria

A thorough history and focused physical examination can lead to proper evaluation, improved diagnosis, and optimal management. When obtaining a clinical history, other symptoms associated with hematuria may be noted, including:

• Active menstruation
• Back or flank pain 
• Constitutional symptoms like weight loss, anorexia, cachexia
• Fever (unexplained)
• Flank mass
• Hearing loss
• Hemoptysis 
• Joint pains, oral ulcers, rash
• Leg swelling
• Lower abdominal pain
• Passing urinary calculi
• Recent throat or skin infection
• Voiding and urinary symptoms such as:
  • Dysuria
  • Frequency
  • Hesitancy
  • Incomplete emptying
  • Intermittent stream
  • Urgency
  • Weak urinary stream

Female patients during menstruation or with vaginal bleeding should either have a catheterized urine sample, use a tampon with cleaning of any residual blood before voiding, or be reevaluated when the gynecologic bleeding has resolved.[1] After a UTI, at least 4 to 6 weeks should elapse before a repeat urinalysis for hematuria. Patients should be asked about previous such episodes and any family history of hematuria. A detailed medical history, including any recent surgical procedures or biopsies, is essential for a proper evaluation. Medications should be carefully reviewed, particularly about any blood thinners. Certain medications can cause false positive dipstick readings, such as peroxidases from organic sources, semen, metronidazole, and sodium hypochlorite.[5][42] False-negative dipstick results are possible from extremely high urinary ascorbic acid levels.[5] Clinicians should also ascertain the patient's smoking history as 10 pack-years or more is a significant risk factor for urothelial malignancies such as bladder cancer. The risk is higher as the smoking history increases. Even after a negative full evaluation, persistent or recurrent microhematuria is reclassified as either "Intermediate" or "High-Risk."[1][43]

High-Risk Factors for Urothelial Cancers 

Clinical factors that are associated with a high risk for urothelial cancer include:

• Degree and persistence of microhematuria
• Family history of Lynch syndrome or urothelial malignancies
• History of pelvic radiation therapy
• History of unexplained gross hematuria
• Increasing age (especially older than 60 years)
• Indwelling catheters, suprapubic tubes
• Irritative lower urinary tract symptoms
• Male gender
• Occupational exposure to benzene, aromatic amines, and similar chemicals
• Prior chemotherapy drug exposure (cyclophosphamide, ifosfamide)
• Significant smoking history [1][2]

Physical Exam Findings

A complete physical examination can contribute to making a valid differential diagnosis. Important signs to look for when assessing patients with hematuria include:

• Costovertebral angle tenderness
• Edema of the lower extremities
• Fever
• Flank mass or tenderness
• Gynecological abnormalities
• Hearing impairments
• Hypertension
• Joint swelling
• Lymphadenopathy
• Meatal blood, caruncles, or other abnormalities
• Palpable, enlarged, cystic kidneys
• Periorbital edema
• Presence of pallor, icterus, oral ulcers, or rashes
• Pubic or suprapubic tenderness
• Urethral or vaginal discharge, injury, or tear
• Vaginal bleeding [1][2]

Evaluation

Evaluation of hematuria is often deficient, inadequate, or incomplete.[1] More than half or more of the patients identified as having hematuria in primary care practices are not properly worked up or referred to urology promptly.[44] Cystoscopy is underutilized overall, as there is a tendency to rely excessively on diagnostic imaging alone.[1][5] This is particularly disturbing as most of the hematuria caused by cancers are from bladder neoplasms that are optimally diagnosed almost exclusively by cystoscopy.[1][45][46][47][48] Primary care practitioners frequently order renal ultrasonography, where more detailed and accurate imaging (eg, computed tomography urogram) is generally required.[1][49] In most studies, the proper use of appropriate urological imaging and cystoscopy occurs in fewer than 20% of patients with hematuria, with some variation based on gender and race.[1][45][46][47] The evaluation of hematuria, especially microhematuria, is often delayed in women, where it is often assumed to be caused by a urinary tract infection, menstrual flow contamination, or vaginal bleeding. This can cause poorer outcomes for bladder and other urological cancers in females.[5] 

Urinalysis

Urinalysis is the initial and most useful test to detect hematuria. Although urine dipsticks are widely available and can be performed quickly, they can give false-positive or false-negative results and require microscopic analysis to confirm positive findings. The presence of 3 or more RBCs per high power field on microscopic examination of the urine sediment establishes the diagnosis, although there is no "safe" lower limit of hematuria.[1][2] The finding of an abnormal urine appearance or urine pH, proteinuria, white blood cells, nitrites, leukocyte esterase, bacteria, crystals, or casts outside of the reference range helps identify the source of the hematuria. 

Nonglomerular Hematuria Evaluation

Nongomerular hematuria is the finding of normal red blood cells without apparent cause, including no evidence of infection, renal failure, or glomerular disease. The absence of an identifiable cause suggests possible benign prostatic hyperplasia (BPH), urolithiasis, or a urinary tract malignancy and warrants further evaluation based primarily on the overall stratified urological cancer risk as outlined below.[1] 

• Urinary tract infection: Infection is suspected as the source of the hematuria if the urinalysis shows a urine specimen with significant white blood cells, positive nitrites, and leukocyte esterase, together with urinary symptoms of frequency, urgency, or dysuria.[50] A urine culture should be done, and the infection should be treated appropriately.[51] After treating the infection and eliminating any abnormal urinary symptoms, a repeat urinalysis should be performed to verify that the hematuria has resolved. If the hematuria persists, a risk-stratified approach to management should be adopted.[1] See StatPearls companion article on "Acute Cystitis" for additional information on acute cystitis management.[52]

• Bladder, ureteral, and renal malignancies: Cancers are the most potentially troubling etiologies of painless hematuria, especially if the blood is easily visible. A full diagnostic urological evaluation is primarily designed to detect such cancers, not necessarily to identify the source of the hematuria. See StatPearls companion articles on "Renal Cancer" and "Bladder Cancer" for additional information on evaluating these conditions.[53][54]

• Nephrolithiasis: Renal calculi are a common cause of hematuria. The urinalysis will often show crystals, but this alone is not diagnostic. Some patients may be asymptomatic, but others will have a history of chronic infection or develop symptoms of acute renal colic with severe abdominal or flank pain, nausea, and vomiting. Imaging studies, including a renal ultrasound with a kidney, ureter, bladder x-ray, or a computed tomography scan of the abdomen, are required for proper diagnosis and to demonstrate the urinary calculi.[55][56][57] See our companion StatPearls articles on "Nephrolithiasis" and "Urolithiasis." [55][57]

• Prostatic bleeding: In older male patients with known or suspected BPH, hematuria due to a prostatic etiology should be suspected.[58] Unfortunately, there is no way to reliably determine this without completing a full workup, which generally consists of appropriate genitourinary imaging and a cystoscopy.[1] See StatPearls companion article on "Benign Prostatic Hyperplasia" for additional information.[58]

• Traumatic urinary bleeding: Traumatic bleeding can be minimal or severe and potentially life-threatening, which is why evaluating hematuria in a trauma setting requires a more urgent approach. Unstable patients may require immediate surgical exploration without even diagnostic imaging first. Renal trauma should be suspected in any abdominal trauma case, particularly falls and motor vehicle accidents.[27] A possible urological injury should be suspected in all pelvic trauma cases until proven otherwise by appropriate imaging.[59][60] Blood at the urethral meatus or an inability to void is suggestive of a urethral or bladder injury, which should ideally be evaluated by retrograde urethrography before attempting Foley catheterization.[59][60] A cystogram with adequate bladder filling, typically at least 300 mL, will demonstrate any extravasation or abnormal leakage.[59][60] Potential renal trauma requires immediate computed tomography (CT) imaging, if possible.[27][59][60] See StatPearls companion articles on "Kidney Trauma" and "Lower Genitourinary Trauma." [27][60]

The standard evaluation for hematuria traditionally comprises urine cytology, upper tract imaging with an intravenous pyelogram, now considered obsolete, a CT urogram consisting of a CT of the abdomen and pelvis with and without IV contrast, and a cystoscopy. Cystoscopy is 98% sensitive in detecting bladder cancer.[61] Urine cytology and similar biomarkers are not currently recommended in the initial workup for hematuria as they have not demonstrated any substantial value and do not eliminate the need for a cystoscopy.[1] However, the occasional patient with carcinoma-in-situ of the bladder may have a negative cystoscopy and would only be detected by suspicious cytology.[62] Other biomarkers, such as fluorescence-in-situ-hybridization (FISH) assays, are cumbersome and expensive to use but may help in borderline or equivocal cases, determining response to Bacillus Calmette-Guérin (BCG) therapy and identifying urothelial cancer of the upper tracts that may be poorly visualized on imaging.[63] Therefore, there is a role for cytology and possibly other biomarkers like FISH assays in patients with persistent microhematuria who also have other high-risk factors for possible carcinoma-in-situ, such as unexplained irritative urinary symptoms, persistent microhematuria, or patients with a significant smoking history.[1][62]

The 2020 American Urological Association Guideline on Microhematuria Risk Stratification Guide 

The current guideline recommendations for evaluating hematuria rely on a risk-stratification approach to avoid expensive, unnecessary, low-yield, and uncomfortable testing in lower-risk individuals.[1][64][17][65][64]

Low-risk patients

To be classified as low-risk, patients must meet the following criteria:

• Women younger than 50 years
• Men younger than 40 years
• Non-smoker or <10 pack-years
• Number of RBC/HPF of 4 to 10
• No prior episodes of microhematuria
• Estimated cancer risk of <1%

Either of the following approaches may be used for the evaluation of low-risk patients, which should be selected through a shared decision-making process:

• Repeat urinalysis within 6 months
  • If negative: Repeat after 6 more months.
  • Negative repeat urinalysis: No further workup is needed; resume routine surveillance.
• Renal ultrasound and cystoscopy
  • Positive findings: Treat accordingly
  • Negative findings: Repeat urinalysis within 12 months
  • Negative findings with persistent hematuria: Consider CT urogram or bilateral retrograde pyelograms

Intermediate-risk patients

To be classified as intermediate-risk, patients must meet the following criteria:

• Women aged 50 to 59 years
• Men aged 40 to 59 years
• Smoker for 10 to 30 pack-years
• Number of RBCs/HPF of 11 to 25
• One or more high-risk factors (Refer to "High-Risk Factors for Urothelial Cancers" in the History and Physical section for more information)
• Does not meet criteria for high-risk patient classification 
• A previous episode of low-risk hematuria without further evaluation
• Estimated cancer risk of 1% to 2%

In intermediate-risk patients, evaluation with a renal ultrasound and cystoscopy should be performed. Based on the results, the following diagnostic studies are recommended: 

• Positive Findings: Treat accordingly
• Negative Findings: Repeat urinalysis within 12 months
• Negative Findings with persistent hematuria: Consider CT urogram or bilateral retrograde pyelograms

High-Risk patients

To be classified as high-risk, patients must meet the following criteria:

• Women and men aged 60 years or older
• Smoker: More than 30 pack-years
• More than 25 RBCs per HPF
• History of gross hematuria
• Prior episodes of hematuria not previously evaluated by cystoscopy or imaging
• Estimated cancer risk ≥10%

In high-risk patients, evaluation should be performed with a CT abdomen and pelvis without and with IV contrast (ie, CT urogram) and cystoscopy. Based on the results, the following diagnostic studies are recommended: 

• Positive findings: Treat accordingly
• Negative findings: Repeat urinalysis within 12 months. If urine remains negative, resume routine surveillance.
• Negative Findings with persistent hematuria:
  • Consider an evaluation for glomerular bleeding
  • Based on shared decision-making, determine whether to continue observation or repeat the evaluation with cystoscopy and CT urogram.

MRI urography may be substituted if a CT urogram cannot be performed. If neither is possible, a noncontrast CT scan, ultrasound of the abdomen and pelvis, and bilateral retrograde pyelogram may be utilized.[1] Upper tract imaging should be done regardless of risk category in patients with hematuria and a family history of renal cell carcinoma or any genetic predisposition to renal malignancies.[1] Initial imaging during pregnancy should be limited to ultrasonography. Blue light cystoscopy and other enhanced visualization techniques may be useful in patients previously diagnosed with bladder cancer, but their role in evaluating patients with microscopic hematuria has not yet been fully established.[1]

Patients with microscopic hematuria whose initial evaluations are negative have been found to have an ultimate urologic malignancy rate of <1% and, therefore, do not generally require follow-up urological evaluations unless they develop gross hematuria.[66] Nevertheless, a follow-up urinalysis in 12 months is recommended by the guidelines.[1] The patient's primary care physician can perform this. Patients with persistent microscopic hematuria have a higher risk of malignancy than those who test negative on follow-up examinations and, therefore, should be reclassified as intermediate- or high-risk.[1][43]

Cytology and Urinary Biomarkers

Various biomarkers and cytology are not recommended for the initial evaluation of patients with microscopic hematuria due to their high false negative rate and lack of proven benefit in sufficient, large, prospective randomized trials.[1][67][68] Urinary cytology has a relatively low sensitivity for low-grade urothelial bladder malignancies.[67][68] Various other biomarkers are available but lack verification from large prospective randomized studies.[67][68] If a urinary biomarker is done anyway and has a positive result, the patient should be treated as higher risk, and follow-up studies are indicated.[67] Urine cytology remains the only biomarker that has gained consensus acceptance by guidelines, and even cytology is not recommended for the initial evaluation of asymptomatic patients with microscopic hematuria.[1] Urine cytology is best used in patients with persistent or recurrent unexplained microscopic hematuria and irritative voiding symptoms or who present with other risk factors for carcinoma in situ.[1]

Glomerular Hematuria Evaluation

Glomerular hematuria is suggested by the presence of excessive urinary protein (>500 mg/24 hours), dysmorphic RBCs, or casts, especially red cell casts, particularly if associated with clinical findings such as hypertension, peripheral edema, and "frothy" or "foamy" urine.[69][70] Dysmorphic RBCs of >25% per HPF have a specificity of >96% with an excellent positive predictive value of 94.6% but low sensitivity (20%) for glomerulonephritis.[71] RBC casts are rare but highly diagnostic and specific for glomerular pathology.[69] Such patients are usually referred to nephrology for further evaluation, but a risk-based urological evaluation should still be performed.[1]

Glomerulonephritis describes several renal disorders characterized by damage to the glomerular basement membrane, capillary endothelium, or mesangium from abnormal immune system activity. This damage tends to be progressive, resulting in increasing glomerular damage, tubulointerstitial fibrosis, and reduced plasma filtering ability, eventually resulting in sclerotic glomeruli and renal failure in many cases. This damage is also responsible for the hematuria, proteinuria, red cell casts, and loss of renal function associated with the disorder. Glomerulonephritis accounts for 10% to 15% of all patients with end-stage renal failure in the US, making it the third most common cause after diabetes and hypertension.[41] Further evaluation of glomerulonephritis generally includes:

• Urine collection over 24 hours for urea and creatinine clearance and protein measurement
• Antistreptolysin O titer
• Autoantibodies (eg, antinuclear, antineutrophil cytoplasmic, antiglomerular basement membrane, and anti-ds-DNA antibodies)
• C-reactive protein
• Complete blood count (CBC)
• Complement (C3, C4 levels)
• Cryoglobulins
• Immunoglobulins
• Liver function
• Renal function tests (eg, BUN and creatinine)
• Serology for HIV, hepatitis B, and hepatitis C
• Serum electrolytes
• Serum levels of free light chain immunoglobulins and serum immunofixation
• Sickle cell testing (eg, peripheral smear, solubility sickling tests, hemoglobin electrophoresis, isoelectric focusing, high-performance liquid chromatography, PCR-based testing, and genetic testing)
• Urine analysis ratios (eg, albumin to creatinine or protein to creatinine ratios)
• Urinary Bence-Jones proteins [41]

Depending on the clinical evaluation and the results from the above, a renal biopsy may be considered.[41][72] Renal biopsies are often necessary for a definitive diagnosis of glomerulonephritis and related glomerular bleeding.[72] They are typically required when a glomerular source of hematuria appears likely. Although serious complications are rare, renal biopsy can have adverse effects, including life-threatening bleeding. A nephrologist or interventional radiologist usually performs the procedure.[72] Usually, only 2 or 3 biopsy cores are sufficient for diagnostic purposes. Light and electron microscopy and immunofluorescence are performed to examine the glomerular structure for a specific diagnosis. 

Glomerulonephritis leads to 10% to 15% of end-stage renal disease cases in the US.[41] In most instances, the disease becomes progressive without timely intervention, eventually leading to morbidity.[11] This makes chronic glomerulonephritis the third most common cause of end-stage renal disease in the US, following diabetes mellitus and hypertension, accounting for 10% of patients on dialysis.[41] The finding of hematuria together with glomerular podocytopathies (eg, focal segmental glomerulosclerosis, membranous nephropathy, and minimal change disease) is an independent, significant indicator of worse outcomes, more prolonged proteinuria, and increased risk of progressive renal failure.[73] See StatPearls companion article on "Glomerulonephritis" for additional information.[41]

Hematuria in Children

In the pediatric population, gross and microscopic hematuria are relatively common findings with overlapping etiologies.[74] Normal children will have positive urine dipsticks for hematuria 1% to 4% of the time. Unlike adults, hematuria in children rarely occurs due to an underlying malignancy.[75] The family history can suggest a possible underlying hereditary etiology.[31] Asymptomatic, isolated microscopic hematuria is often idiopathic with no identifiable etiology.[74] Microscopic hematuria generally suggests an upper urinary tract source, while gross hematuria is more likely from the bladder or urethra.[31][75] When a specific cause is identified, the most common diagnoses are glomerulonephritis conditions (eg, poststreptococcal or infectious, IgA nephropathy, and thin basement membrane disease), urinary tract infections, or hypercalciuria.[74] The most common glomerulonephritis in children is poststreptococcal or infectious types.[74][75][76] Moreover, proteinuria, fluid overload, casts or dysmorphic RBCs on urinary microscopy, brown "cola" colored hematuria, or hypertension suggests glomerular disease in the pediatric age group, just like in adults.[74][75] 

IgA vasculitis or Henöch-Schonlein purpur is rare, with 10 to 20 cases in 100,000 children. It is immune-mediated glomerulonephritis that occurs mainly in children younger than 10 years.[77] The condition may also affect the gastrointestinal tract, causing bleeding. An infection often precedes hematuria episodes. Renal involvement may be mild or progress to severe crescentic glomerulonephritis.[77] Initial renal involvement is treated with steroids, but ACEI, immunosuppressants, and plasma exchange may also be used.[77] The condition is usually self-limited, and only 1% progress to end-stage renal failure.[77] See StatPearls companion article on "IgA vasculitis." [77] Hemolytic uremic syndrome occurs predominantly in childhood and should be suspected in pediatric hematuria cases with anemia, thrombocytopenia, or azotemia.[78][79][80][81] It occurs in only an estimated 3/100,000 children, follows a bacterial infection often associated with unpasteurized mild or undercooked beef consumption, and may be accompanied by a gastrointestinal disorder.[81] Treatment is mainly supportive. See our companion StatPearls reference article on "Hemolytic Uremic Syndrome." [81]

Treatment / Management

Management depends on the underlying etiology. Observation may be a reasonable approach for asymptomatic intermittent hematuria associated with negative imaging, stable renal function, and absence of proteinuria. Overt gross hematuria needs prompt management. Hemodynamic stability should be assured first. Blood products, transfusions, or medications should be utilized to correct any underlying hematological abnormality. In rare instances, interventional radiology-guided embolization may be required to stop life-threatening bleeding from the renal vasculature or for hemorrhagic cystitis refractory to conventional treatments.[82][83](B3)

Immediate Management of Significant Gross Hematuria

Significant gross hematuria, especially when associated with urinary difficulty, voiding of clots, clot retention, or severe blood loss, will require immediate treatment with a large (ie, ≥22 French) 3-way Foley catheter placement and continuous bladder irrigation (CBI). Evacuation of clots from the bladder by vigorous hand irrigation or transurethral surgical extraction may be required to control the hematuria. A large 30 cc balloon is not recommended except immediately after transurethral prostate resection.[84] Anticoagulant therapy should be stopped or reversed when possible. If all the clots from the bladder are not evacuated and removed, the Foley catheter will likely become clogged, and the clot breakdown products from urokinase activity will act as natural anticoagulants, prolonging the bleeding.

The need to take a patient to the operating room for electrocautery or laser ablation with clot evacuation when initial manual irrigation is unsuccessful can sometimes be avoided by using chemical thrombolysis. The following techniques successfully soften and dissolve retained clots in the bladder, allowing them to be evacuated through the catheter and avoiding surgical clot evacuation.[85][86]

• Instill 40,000 units of chymotrypsin in 50 mL of 5% sodium bicarbonate solution with a large 22- to 24-French Foley catheter and leave it in the bladder for 30 minutes.[85]

• Instill 30 to 50 mL of a hydrogen peroxide irrigation solution with a 1:5 mixture of 3% hydrogen peroxide and 0.9% saline into the bladder and left there for 3 to 5 minutes. The bladder is then manually irrigated and evacuated. The process is then repeated with another installation of the hydrogen peroxide solution placed into the bladder.[86]

• Administer limited palliative radiation therapy in selected cases of otherwise intractable hematuria if ionizing radiation has not been previously utilized.[87][88][89][90][91][92][93][94]
(A1)

• Superselectively embolize a vesicle branch of the hypogastric or prostatic artery in otherwise intractable cases.[95][96]
(B3)

• Place a nephrostomy tube for supravesical urinary diversion and interventional radiological superselective embolization of the prostatic artery or the anterior branch of the internal iliac artery.[95][96]
(B3)

• Perform a cystectomy with urinary diversion as a final treatment of last resort.

Controlling bleeding from hemorrhagic cystitis can be particularly challenging, most often seen after pelvic irradiation (ie, radiation cystitis) or after chemotherapy, particularly with oxazaphosphorines (eg, cyclophosphamide, ifosfamide, and trofosfamide.) Treatment selection typically starts with the least invasive therapy and progresses as necessary. Therapy starts as above but may require intravesical therapy with alum, aminocaproic acid, formalin, prostaglandins, or silver nitrate solutions.[97][98][99] Of these, formalin is the most toxic to the bladder mucosa and is therefore reserved as one of the final options.[97][100][101][102] Hyperbaric oxygen therapy with or without oral pentosan polysulfate can be used and is particularly helpful with radiation-induced hemorrhagic cystitis.[103][104] See StatPearls companion article on "Radiation Cystitis and Hyperbaric Management" for additional information on hyperbaric management.[103] (A1)

More invasive surgical options include nephrostomy tube placement for supravesical urinary diversion and interventional radiological superselective embolization of the prostatic artery or the anterior branch of the internal iliac artery.[95][96] The final treatment of last resort would be a cystectomy with urinary diversion. Treatment selection typically starts with the least invasive therapy and progresses as necessary.(B3)

Nonglomerular Hematuria Management

The management approach selected depends on the underlying etiology of nonglomerular hematuria. Acute urinary tract infections are treated with 3 to 7 days of first-line antibiotics.[72] Complicated infections will take longer to resolve.[105] Bleeding from radiation cystitis can benefit from pentosan polysulfate administration, transurethral electrofulguration/laser treatment, intravesical instillations (silver nitrate, formalin, or alum), or hyperbaric oxygen therapy.[83][98] Severe hemorrhagic cystitis may require transurethral surgery or intravesical instillations (eg, silver nitrate, formalin, or alum).[83] Intractable cases of severe hemorrhagic or radiation cystitis may require a cystectomy. Genitourinary trauma will require specific therapy depending on the hemodynamic stability of the patient and the severity and location of the injury. Most renal injuries can be managed conservatively if the patient is hemodynamically stable.[27] Ureteral trauma is uncommon and will often heal with stenting but may require surgical repair.[59][60] Intraperitoneal bladder ruptures typically need immediate surgery, but extraperitoneal leakages will often heal with catheter drainage alone.[59][60] Urethral injuries may need to be surgically repaired, either immediately or after a reasonable delay of 2 to 3 months, using suprapubic drainage in the interim.[106] Postprocedural hematuria can usually be managed conservatively or with a Foley catheter and irrigation as appropriate.(A1)

Severe bleeding from the prostate can generally be controlled with a standard Foley catheter or a 3-way catheter with continuous bladder irrigation. If this is not adequate, transurethral fulguration, selective prostatic artery embolization, or even a brief course of palliative radiation therapy may be used.[87][88][89][90][91][92][95][96] Less severe hematuria from the prostate can often be managed with 5-alpha reductase inhibitors (eg, finasteride and dutasteride).[107][108](A1)

Nephrolithiasis management is generally supportive, emphasizing pain control, avoiding or treating infection, facilitating stone passage, and administering adequate fluids. Kidney stone size and location may warrant further management.[109] Approximately 90% of stones smaller than 4 mm will pass spontaneously. Larger symptomatic stones may require lithotripsy, ureteroscopy, or percutaneous surgery.[55][110] If complicated by a simultaneous urinary tract infection, preliminary drainage with a nephrostomy or double-J stent will most likely be required until the infection is eliminated and definitive stone treatment can be undertaken.[55][111][112](B2)

Renal cell carcinoma, other malignancies confined to the kidneys, and renal pelvic urothelial cancers will require surgery and possible nephrectomy or nephroureterectomy.[113] Palliative radiation therapy or selective renal arterial branch embolization for hematuria control can be considered in selected patients with bleeding from a kidney.[87][93][94] Various benign renal neoplasms (angiomyolipomas, oncocytomas) may also cause hematuria and require surgical ablation, medical therapy, embolization, or other surgery.[114][115] Transitional cell carcinoma can occur anywhere in the genitourinary tract but is most often found in the bladder. Transurethral resection of the tumor and periodic cystoscopies are the standard recommended therapy. Invasive bladder cancers may require a cystectomy, and high-grade carcinoma-in-situ of the bladder will require intravesical BCG therapy.[116][117] Metastatic cancers will need staging as well as further individualized oncological and radiotherapy or surgical management. (B2)

Glomerular Hematuria Management

The management approach for glomerular hematuria also depends on the underlying cause and the effect on renal function. Some hereditary diseases, like Alport syndrome, thin basement membrane disease, and polycystic kidney disease, require regular monitoring of renal function and periodic follow-up examinations. Poststreptococcal glomerulonephritis requires supportive care, and IgA nephropathy treatment depends on the degree of proteinuria and renal function.[41] Relatively normal creatinine with minimal proteinuria may be managed conservatively. High-risk features, including rising creatinine levels, persistent proteinuria of >1 g/day, and active disease on renal biopsy, are indications to consider immunosuppressive therapy.[118] Nephrotic syndrome and other etiologies generally necessitate a nephrology consultation for further management. See our companion StatPearls reference article on "Nephrotic Syndrome."[119] General treatment for most glomerulopathies includes angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin 2 receptor blockers (ARB), which help control hypertension, reduce proteinuria, and slow disease progression.[41](A1)

The following management approaches are recommended for these inheritable or genetic glomerular disorders:

• Alport syndrome: This is a hereditary disorder of type IV collagen production affecting the renal glomerular basement membranes, eyes, and ears, which is characterized by progressive renal failure, bilateral sensorineural hearing loss, and eye abnormalities. Alport syndrome eventually produces proteinuria, hypertension, progressive azotemia, and end-stage renal disease.[120][121][122] In addition to ACEI or ARB medications, adding a statin and a non-dihydropyridine calcium channel blocker appears helpful. One study shows that ramipril can decrease disease progression in children by almost half.[123] The condition tends to be progressive and may eventually require dialysis or renal transplantation.[120] See our companion StatPearls reference article on "Alport Syndrome."[120]
• Pierson syndrome: This rare syndrome is very similar to Alport syndrome. Pierson syndrome mainly affects the eyes and kidneys, resulting in microcoria, visual problems, and congenital nephrotic syndrome, which is progressive. Hypotonic musculature and blindness may also develop.[124][125]
• Polycystic kidney disease:  Polycystic kidney disease (PKD) is the most common genetic cause of end-stage renal failure in the adult population and accounts for 6% to 8% of patients on dialysis.[26] Fifty percent of patients will need kidney replacement therapy by the age of 60 years. Cyst aspiration with ultrasound or CT guidance can be used for pain from large cysts distorting the genitourinary system. Laparoscopic surgical cyst fenestration may also help. Polycystic kidney disease has no specific treatment; if it progresses to end-stage renal failure, dialysis or renal transplantation can be performed. Nephrectomy is usually recommended at that point.[26] Approximately 20% of patients with polycystic kidney disease will develop nephrolithiasis.[26][126] See  StatPearls companion article on "Polycystic Kidney Disease" for additional management details.[26][126]
• Thin basement membrane disease: Formerly known as familial benign hematuria, this relatively common hereditary renal disorder may present in 5% to 9% of adults.[127][128][129] The finding of diffuse thinning of the glomerular basement membrane on electron microscopy of a renal biopsy is diagnostic. A history of familial hematuria is present in 30% to 50% of cases. This disorder is sometimes associated with focal segmental glomerulosclerosis.[130] Thin basement membrane disease may be a less severe form of Alport syndrome as both involve thinning the glomerular basement membrane.[131][132] The diagnosis of thin basement membrane disease is usually suggested by a benign course, lack of proteinuria, and a positive family history of hematuria without renal failure. In the absence of proteinuria, hypertension, peripheral edema, or renal failure, a renal biopsy may not be required. No treatment is usually necessary as it typically has a benign course, although significant proteinuria and a family history of renal failure suggest a more guarded prognosis.[133][134] Close monitoring and follow-up examinations are suggested.[133][134] See the companion StatPearls article on "Thin Basement Membrane Disease" for additional information.[134]
(A1)

In addition to angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, autoimmune glomerular disorders often require additional therapies. Corticosteroids are used in some cases, especially if there is excessive proteinuria.[41][135] Rituximab is a monoclonal immunosuppressive antibody that lyses B-lymphocytes.[136] It is most useful in membranoproliferative glomerulonephritis, lupus nephritis, and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides.[136][137] Cytotoxic agents (eg, cyclophosphamide and methotrexate) may be used, as well as plasma exchange and calcineurin inhibitors, which reduce T-cell activity.[41] See the companion StatPearls article on "Glomerulonephritis."[41] The following management approaches are recommended for these autoimmune glomerular disorders:

• IgA nephropathy: Also known as Berger disease, this condition is a common cause of microscopic hematuria worldwide that usually presents initially with painless, intermittent gross hematuria often related to upper respiratory infections, which progresses to persistent microhematuria. IgA nephropathy is slightly more common in Whites and males. Progression to chronic renal failure may occur in up to 20% of cases, typically taking 10 years or longer from the initial diagnosis.[138][139] Treatment involves ACEI or ARB and corticosteroids if there is excessive proteinuria.[41][138][139] See the companion StatPearls articles on "IgA Nephropathy" and "Berger Disease" for additional management information.[138][139]

• Crescentic glomerulonephritis: Also known as rapidly progressive glomerulonephritis, crescentic glomerulonephritis is an autoimmune disorder characterized by the presence of extensive glomerular crescents, usually >50% formed of infiltrating macrophages and proliferating epithelial cells from the lining of Bowman's capsule. This condition tends to cause a quick decline in renal function, which accounts for its other name, "rapidly progressive."[133][140] Crescentic glomerulonephritis may also be an associated complication of other glomerular disorders. Initial treatment is glucocorticoids and cyclophosphamide or possibly rituximab in selected patients. Plasma exchange has been useful in some patients. Maintenance therapy may consist of the immunosuppressive azathioprine, methotrexate, or rituximab.[133][140] See the companion StatPearls article "Crescentic Glomerulonephritis" for additional management information.[140]

• Diffuse proliferative glomerulonephritis: A condition often associated with lupus nephritis, the severity of diffuse proliferative glomerulonephritis can vary widely.[141][142] Standard treatment includes ACEI or ARB plus statins due to the high rate of cardiovascular atherosclerosis.[142] More severe disease is treated with corticosteroids. If unresponsive to steroids, calcineurin inhibitors (eg, tacrolimus) can be added. Plasmapheresis, mycophenolate mofetil, and cyclophosphamide are used in selected cases.[142] See the companion StatPearls articles on "Diffuse Proliferative Glomerulonephritis" and "Lupus Nephritis" for additional information.[141][142]

• Antiglomerular basement membrane disease: Also known as Goodpasture syndrome, this condition affects the lungs and kidneys significantly. While there is a genetic predisposition to antiglomerular basement membrane disease (anti-GBM disease), there is usually some additional triggering event to the alveolar capillaries from drugs, medical procedures, or toxic exposure.[33] Anti-GBM disease accounts for about 10% to 20% of all cases of crescentic glomerulonephritis. Patients often present critically ill; initial therapy includes prednisone, cyclophosphamide, and daily plasmapheresis. The associated alveolar hemorrhage, which may be life-threatening, is treated with steroids.[33] Rituximab has also been used successfully in these patients.[143] See the companion StatPearls article on "Goodpasture Syndrome."[33]
(B3)

• Hepatitis-related nephropathy: This autoimmune glomerular disorder can present as membranoproliferative glomerulonephritis or mixed cryoglobulinemia. Treatment is similar to other autoimmune and postinfectious glomerulopathies with the addition of appropriate antiviral therapy.[144][145][146][147][148] 

• Membranous glomerulonephritis: A common cause of nephrotic syndrome worldwide, membranous glomerulonephritis is characterized by immune complex deposition underneath the subepithelial podocytes of the glomerular capillaries. Its etiology is an autoimmune antibody or antigen reaction to the podocytes. About 12 million people are diagnosed with membranous glomerulopathy annually in the US.[149] Systemic lupus erythematosus is the most common cause of secondary membranous nephropathy. Classified as type V lupus nephritis, the usual nephrotic-range proteinuria common to primary membranous nephropathy is accompanied by significant hematuria and hypertension. Kidney biopsy will show staining positive for all 3 Ig types (IgG, IgM, IgA), as well as C3 and C1q. Treatment is similar to other autoimmune glomerular disorders and starts with ACEI and ARB drugs. Immunosuppressives, steroids, cyclophosphamide, calcineurin inhibitors, and rituximab may also be used.[150] See the companion StatPearls article "Membranous Nephropathy" for additional management information.[151]
(B3)

• Poststreptococcal glomerulonephritis: This condition typically appears within 6 weeks of a streptococcal skin infection but only 1 to 2 weeks after a streptococcal sore throat. The inflammatory response to the streptococcal infection results in a significant autoimmune reaction, frequently resulting in a rapid decline in renal function.[152] Symptoms may include gross hematuria (seen in 30%-50% of cases), oliguria, hypertension, peripheral edema found in 65% to 90% of cases, and proteinuria.[152] Skin infections are becoming a more common etiology, although the overall incidence of poststreptococcal glomerulonephritis is declining in developed countries. Even so, poststreptococcal glomerulonephritis remains the most common cause of glomerulonephritis in children, even in the US.[74] Worldwide, 97% of cases are found in underdeveloped regions.[152] Treatment involves supportive therapy along with antibiotics. Furosemide is preferred over thiazides for controlling hypertension and edema, along with fluid and salt restriction.[152] ACEI or ARBs are also recommended, and calcium channel blockers may be used if necessary.[152] Corticosteroids are reserved for patients who develop kidney failure or have crescents on renal biopsy, while immunosuppression does not appear to be helpful in this disorder.[152] Dialysis is reserved for only the most severe cases. See StatPearls companion article "Poststreptococcal Glomerulonephritis" for additional information.[152] 

Differential Diagnosis

The differential diagnosis of hematuria includes etiologies that cause the appearance of discolored red, pink, brown, or yellow urine, including:

• Alkaptonuria
• Bile pigments in urine
• Drug effects
• False positive urine dipstick test not confirmed by microscopy
• Hemoglobinuria
• Hemolytic anemias
• Porphyria
• Rhabdomyolysis
• Phenazopyridine use
• Various foods (eg, beets, blackberries, and fava beans) 

Prognosis

Children with isolated hematuria generally have a good outcome, but the presence of proteinuria, hypertension, or abnormal renal function suggests a glomerular etiology and may lead to a more guarded prognosis. In adults, unexplained hematuria, especially gross hematuria, should always be taken seriously because it may signal a urinary tract malignancy. Nonglomerular hematuria usually has a favorable prognosis, as most etiologies have specific remedies and treatments. Treatment options are less effective and more limited in genetic glomerulopathies, which may be progressive, resulting in end-stage renal failure. Thin basement membrane disease, formerly called benign familial hematuria, has an excellent prognosis and requires no specific treatment. Early diagnosis and optimal therapy can help minimize poor outcomes and preserve renal function. 

Complications

The following issues and complications can be associated with hematuria:

• False positives are common if microscopic urinalyses are not used to confirm positive dipstick findings for hematuria. This causes costly, unnecessary evaluations and consultations.
• Failure to properly evaluate or treat hematuria may result in catastrophic or life-threatening disease. 
• Some conditions may result in progressive loss of renal function, leading to end-stage renal failure.
• Even in these severe cases, patients can still be treated with dialysis or renal transplantation, which may result in associated postsurgical complications (eg, infection, wound dehiscence, and transplantation rejection).