Etiology

Visible (gross) hematuria can originate from any part of the urinary system. Anatomically, the urinary system is divided into the upper tract, which includes the kidneys and ureters, and the lower tract, which includes the bladder and urethra. Localizing the source of bleeding is a key step in determining the etiology of hematuria.[7]

Visible hematuria can be caused by infection, malignancy, trauma, stones, structural abnormalities, and kidney disease. Coagulopathy, caused by clotting disorders or anticoagulation, can induce or exacerbate bleeding from underlying urinary tract lesions. Nephrotoxic medications can cause kidney inflammation and renal papillary necrosis, whereas other medications, such as cyclophosphamide, can cause bleeding from the bladder mucosa. Instrumentation of the urinary bladder by endoscopes and catheters can cause traumatic bleeding that is generally self-limiting.

Benign forms of hematuria can be seen in exercise-induced hematuria and in loin-pain hematuria syndrome, an idiopathic condition of unknown clinical significance.

Visible hematuria should always be distinguished from pseudohematuria, where blood originates from a non-urinary-tract source, or discoloration of the urine by nonheme compounds, which gives the appearance of hematuria.

Infections

  • Urinary tract infections and pyelonephritis are extremely common causes of visible hematuria and often associated with symptoms of urinary frequency, urgency, dysuria, nocturia, small volume voiding, and suprapubic pain.

  • Fever, nausea, vomiting, and flank pain suggest pyelonephritis.

  • Urinalysis may reveal leukocytes, nitrite, or leukocyte esterase.

  • Genitourinary tuberculosis may present with hematuria and leukocytes in the absence of bacteria (sterile pyuria).

Malignancy

Hematuria may be the only symptom of genitourinary malignancy. In men ages >60 years, the positive predictive value of visible hematuria for urologic malignancy is 22.1%, and in women of the same age it is 8.3%.[6]

  • Urothelial carcinoma is the most common form of urologic malignancy, accounting for 90% of bladder cancers. Urothelial carcinoma can occur anywhere along the urinary tract and typically presents as painless hematuria.[8]​​[9]

  • Squamous cell carcinoma and adenocarcinoma are rare types of bladder cancer.

  • Renal cell carcinoma and metastases to the kidney can also cause hematuria, with or without flank pain.

  • Prostate cancer can present with intermittent visible hematuria.[6]

  • Penile cancers are squamous cell carcinomas of the skin, but urethral or vascular invasion may cause visible blood in the urine.

Trauma

  • Penetrating or blunt injury to the kidneys, ureters, bladder, or urethra usually presents as visible hematuria.

  • Renal trauma is caused by blunt injury to the flank or abdomen in 80% to 90% of patients.[10] Other causes include penetrating injuries from gunshots and stab wounds, deceleration injuries in motor vehicle accidents, and laceration by fractured lower ribs.

  • Ureteral trauma is rare, but occurs in the setting of penetrating, blunt, or iatrogenic injury.[11] Iatrogenic transection of the ureter can occur during complicated colorectal or gynecologic procedures. Endoscopic procedures, such as ureteroscopy, are more likely to cause hematuria than transection or ligation of ureters. Percutaneous access of the urinary tract, renal biopsy, or placement of ureteral stents can also cause traumatic bleeding.

  • Bladder trauma causes visible hematuria and is usually seen in motor vehicle crashes or pelvic fractures. Pelvic fractures are associated with bladder rupture in 5% of patients.[12]

  • Urethral injury, generally in males, presents as blood at the urethral meatus. This may be accompanied by the inability to void or voiding with initial or terminal hematuria.

  • Males with pelvic fracture and blood at the urethral meatus must not have a urethral catheter placed until a retrograde urethrogram can rule out urethral disruption.

  • Female urethral injury is rare, due to the shorter length and mobility of the female urethra, but may occur in the setting of pelvic fracture.[13][14]

Urinary stone disease

  • Urolithiasis is caused by the formation of crystalline stones in the kidney or bladder. Obstruction of the upper urinary tract by stones causes severe flank pain. In the absence of obstruction, upper tract stones may cause intermittent pain, although some patients are asymptomatic.

  • Nonvisible (microscopic) hematuria can be seen in up to 85% of patients,[10] but visible hematuria is rare.

Structural abnormalities

  • Benign prostatic hyperplasia (BPH) predisposes men to visible hematuria and clot formation,[15][16] possibly due to increased density of microscopic vessels in the prostate.

  • After relief of acute urinary retention by catheter decompression, visible hematuria can occur in 2% to 16% of patients (hematuria ex vacuo).[17]

  • Cystic renal lesions such as those in polycystic kidney, medullary sponge kidney, and medullary cystic disease may cause visible hematuria.

  • Vascular malformations and arteriovenous fistulas may spontaneously bleed into the urinary tract. Ureteroarterial fistula is a rare complication of urologic surgery.[18]

  • Renal vein thrombosis, which can be caused by renal cell carcinoma or in the setting of nephrotic syndrome, generally presents as flank pain and visible hematuria.

Medical renal disease

Pathology involving the renal parenchyma and glomeruli may present as hematuria that is characterized by dysmorphic red cells and casts of red or white blood cells.[19] Significant proteinuria may be a prominent feature of these disorders, and renal function may be compromised.

Referral to a nephrologist is important for the management of this broad category of disorders. A nephrology consultation should be obtained for patients with renal failure, heavy proteinuria (>3 g/day), or severe hypertension, as prompt treatment or a renal biopsy may be necessary.[20]

  • Benign familial hematuria is caused by a genetic defect that results in thinning of the basement membranes.

  • Alport syndrome is a hereditary disorder of the glomerular basement membrane caused by abnormalities in type IV collagen, and may progress to renal failure. It presents as proteinuria, hematuria, hearing loss, and hypertension.

  • Glomerulonephritides (such as IgA nephropathy, postinfectious glomerulonephritis, membranoproliferative glomerulonephritis, rapidly progressive glomerulonephritis, and systemic lupus erythematosus [SLE]) are a spectrum of immune-mediated diseases that cause inflammation of the glomeruli. Proteinuria and renal failure are also present in these disorders to varying degrees. Renal consultation is essential.

  • Glomerular pathology can be an isolated phenomenon or part of a systemic autoimmune process such as SLE.

Hematologic

  • Sickle cell anemia can present with urinary symptoms including hematuria, dysuria, and polyuria, with isosthenuria (urine that is not concentrated by the kidneys) on urinalysis.

  • Coagulopathic patients may bleed from multiple sites, including the gastrointestinal and genitourinary tract.

  • Patients on anticoagulation therapy may have visible hematuria, but urinary tract bleeding (even in cases of supratherapeutic anticoagulation) often represents an exacerbation of an underlying disease process or urinary tract lesion. A systematic review of patients taking anticoagulants who had visible hematuria reported urologic pathology in 44% and malignancy in 24% of patients.[21]

Gynecologic

  • Placenta percreta is a form of invasive placental implantation where the myometrium of the uterus is penetrated. Between 5% and 7% of patients show this depth of invasion, and in rare cases it extends into the bladder to cause severe hemorrhage and hemodynamic instability.[22] This diagnosis should be suspected in pregnant women with visible hematuria, especially if there is a history of placenta previa or prior cesarean section.

  • Endometriosis where the ectopic endometrial tissue involves the ureters or bladder may present as flank pain, dysuria, and hematuria that is cyclic in nature.

Iatrogenic

  • Instrumentation of the urinary tract by endoscopes or percutaneous access can cause self-limiting bleeding.

  • Catheters or the presence of an indwelling ureteral stent or nephrostomy tube can cause urinary tract bleeding.

  • External beam radiation for pelvic cancers can cause inflammatory radiation cystitis that ranges in severity from microscopic hematuria and urinary frequency to severe hemorrhage, incontinence, and bladder necrosis.

  • Prostate brachytherapy can lead to acute or late hematuria.[23]

  • Medications that can incite tubular necrosis or interstitial nephritis can cause hematuria. Nephrotoxic medications include aminoglycosides, cyclosporine, and some chemotherapeutic agents. Interstitial nephritis can be induced by penicillins, sulfonamides, and nonsteroidal anti-inflammatory drugs.

  • Cyclophosphamide is an important cause of hemorrhagic cystitis that may result in severe bleeding.[24]

  • Anticoagulation with heparin, warfarin, and low-molecular-weight heparin, even at supratherapeutic doses, generally does not cause hematuria unless there is underlying pathology. Further evaluation must be undertaken to rule out important causes of bleeding, such as malignancy.[21]

Idiopathic

  • Exercise-induced hematuria is a benign, self-limiting condition seen in athletes and active people.

  • Loin-pain hematuria syndrome is a benign entity of unknown etiology where symptoms of pain and intermittent hematuria predominate. This occurs primarily in women of childbearing age. The clinical significance of this syndrome as a diagnostic entity is a matter of debate.

Pseudohematuria

  • Cyclic pseudohematuria may occur during menses.

  • Certain foods and medications can discolor the urine, mimicking hematuria. Consumption of beets, blackberries, and rhubarb can discolor the urine. Medications include rifampin, phenytoin, levodopa, methyldopa, and quinine.

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