Aetiology

Visible (gross) haematuria 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. Localising the source of bleeding is a key step in determining the aetiology of haematuria.[7]​​[8]

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

Visible haematuria should always be distinguished from pseudohaematuria, where blood originates from a non-urinary-tract source, or discolouration of the urine by non-heme compounds, which gives the appearance of haematuria.

Infections

  • Urinary tract infections and pyelonephritis are extremely common causes of visible haematuria 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 haematuria and leukocytes in the absence of bacteria (sterile pyuria).

Malignancy

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

  • Urothelial carcinoma is the most common form of urological malignancy, accounting for 90% of bladder cancers. Urothelial carcinoma can occur anywhere along the urinary tract and typically presents as painless haematuria.[9]​​[10]

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

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

  • Prostate cancer can present with intermittent visible haematuria.[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 haematuria.

  • Renal trauma is caused by blunt injury to the flank or abdomen in 80% to 90% of patients.[11] 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.[12] Iatrogenic transection of the ureter can occur during complicated colorectal or gynaecological procedures. Endoscopic procedures, such as ureteroscopy, are more likely to cause haematuria 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 haematuria and is usually seen in motor vehicle crashes or pelvic fractures. Pelvic fractures are associated with bladder rupture in 5% of patients.[13]

  • 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 haematuria.

  • 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.[14][15]

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.

  • Non-visible (microscopic) haematuria can be seen in up to 85% of patients,[11] but visible haematuria is rare.

Structural abnormalities

  • Benign prostatic hyperplasia (BPH) predisposes men to visible haematuria and clot formation,[16][17] possibly due to increased density of microscopic vessels in the prostate.

  • After relief of acute urinary retention by catheter decompression, visible haematuria can occur in 2% to 16% of patients (haematuria ex vacuo).[18]

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

  • Vascular malformations and arteriovenous fistulas may spontaneously bleed into the urinary tract. Ureteroarterial fistula is a rare complication of urological surgery.[19]

  • 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 haematuria.

Medical renal disease

Pathology involving the renal parenchyma and glomeruli may present as haematuria that is characterised by dysmorphic red cells and casts of red or white blood cells.[20] 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.[21]

  • Benign familial haematuria 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, haematuria, hearing loss, and hypertension.

  • Glomerulonephritides (such as IgA nephropathy, post-infectious 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.

Haematological

  • Sickle cell anaemia can present with urinary symptoms including haematuria, 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 haematuria, 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 haematuria reported urological pathology in 44% and malignancy in 24% of patients.[22]

Gynaecological

  • 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 haemorrhage and haemodynamic instability.[23] This diagnosis should be suspected in pregnant women with visible haematuria, especially if there is a history of placenta praevia or prior caesarean section.

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

Iatrogenic

  • Instrumentation of the urinary tract by endoscopes or percutaneous access can cause self-limited 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 haematuria and urinary frequency to severe haemorrhage, incontinence, and bladder necrosis.

  • Prostate brachytherapy can lead to acute or late haematuria.[24]

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

  • Cyclophosphamide is an important cause of haemorrhagic cystitis that may result in severe bleeding.[25]

  • Anticoagulation with heparin, warfarin, and low-molecular-weight heparin, even at supratherapeutic doses, generally does not cause haematuria unless there is underlying pathology. Further evaluation must be undertaken to rule out important causes of bleeding, such as malignancy.[22]

Idiopathic

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

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

Pseudohaematuria

  • Cyclic pseudohaematuria may occur during menses.

  • Certain foods and medications can discolour the urine, mimicking haematuria. Consumption of beetroot, blackberries, and rhubarb can discolour the urine. Medications include rifampicin, phenytoin, levodopa, methyldopa, and quinine.

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