Approach

History

History of presenting complaint

  • Identifying a concomitant history of infection, menses, recent sexual activity, or exercise will avoid an extensive work-up. Typically, haematuria due to intense exercise will clear within a few hours.[22]

  • The presence of dysuria, urgency, urinary frequency, and suprapubic pressure of pain may indicate urinary tract infection (UTI), cystitis, or prostatitis. Vomiting, rigors, and loin pain can occur in pyelonephritis.

  • Flank pain, which may radiate to the groin or testis, may indicate nephrolithiasis.

  • Suprapubic, perineal, or sacral pain can occur in acute prostatitis.

  • Urine outflow obstruction symptoms such as difficulty voiding, changes in urine volume, nocturia, and terminal dribbling may indicate benign prostatic hypertrophy (BPH).

  • Constitutional symptoms such as weight loss, poor appetite, fever, and malaise can occur in patients with urothelial cancer (previously termed transitional cell carcinoma).

  • Sore throat, oedema, rash, arthralgia, dark urine, and oliguria can occur in acute glomerulonephritis.

Past medical history

  • Recent streptococcal infection (may precipitate glomerulonephritis)

  • Recurrent UTIs can occur in patients with anatomical abnormalities of the urinary tract (e.g., bladder diverticulum, nephrolithiasis) or functional abnormalities of the urinary tract (e.g., vesicoureteric reflux)

  • Nephrolithiasis: after a first renal stone, risk of recurrence is 40% by 5 years and 75% by 20 years[23]

  • Systemic lupus erythematosus (SLE) may be complicated by lupus nephritis

  • Recent instrumentation of the urinary tract.

Family history

  • Polycystic kidney disease

  • Glomerular disorders

  • Renal cell carcinoma: a family history of renal cancer increases risk 2.8- to 4.3-fold[24]

  • Prostate cancer: one large case-control study showed a 2-fold increased risk of prostate cancer in men with a family history in a single first-degree relative, a 5-fold risk if there were two affected relatives, and a relative risk of 10.9 when there were three first-degree relatives with prostate cancer[25]

  • Sickle cell anaemia

  • Coagulation disorders (hypercoagulability increases the risk of renal vein thrombosis)

  • Alport's syndrome.

Drug history

  • Prolonged use of non-steroidal anti-inflammatory drugs (NSAIDs) can lead to papillary necrosis.

  • Use of anticoagulants should not prevent investigation of NVH.[1] Anticoagulation does not predispose patients to haematuria and urinary tract disease is present in most anticoagulated patients with haematuria.[26]

  • One case-control study found that exposure to certain antibiotics (sulfas, cephalosporins, fluoroquinolones, nitrofurantoin, and broad-spectrum penicillins) in the previous 3-12 months increased the odds of nephrolithiasis.[27]

Social history

  • Occupational exposures other than those to known environmental nephrotoxins may induce NVH.[28]

Risk factors for urinary tract cancer

  • Age: unusual before 35 years of age;[29][30][31] risk increases with advancing age beyond 35 years.[1][14][30] The incidence below the age of 40 years was found to be 1% to 2.4%.[32]

  • Tobacco use

  • Medications: cyclophosphamide or ifosfamide chemotherapy; aristolochic acid in some herbal weight loss preparations[8]

  • Past medical history: radiation exposure

  • Occupational exposures: dyes, benzenes, aromatic amines.

Obesity and hypertension are risk factors for renal cell carcinoma.[12]

Examination

The physical examination needs to include a search for disorders directly related to the urinary tract, as well as other systemic diseases.[33] For example, blood pressure can be elevated with upper tract glomerular diseases, and petechiae, bruising, or lymphadenopathy may signal bleeding disorders or blood cell cancers.

Examination of the abdomen and of the external genitalia may also reveal a source for NVH. In men, a digital rectal examination will identify BPH and potentially discover prostate cancer.

The physical examination can, like a detailed history, preclude an extensive evaluation if an obvious source is identified.

Basic laboratory tests

Initial laboratory testing should evaluate for systemic disorders in the appropriate clinical settings and include coagulation studies, erythrocyte sedimentation rate, creatinine, and C-reactive protein. A urine culture will confirm UTI if suspected. Prostate-specific antigen testing aids in identifying the prostate as a source for NVH.

Urine microscopy

Before pursuing any work-up, the presence of haematuria should be confirmed by urine microscopy.[1][8] Urine dipstick testing is highly sensitive for blood but lacks specificity.[8][34]

False-positives occur due to povidone-iodine, myoglobin, free haemoglobin, hypochlorite solutions, oxidising agents, and high levels of ascorbic acid.[4] There is consensus that ≥3 red blood cells (RBCs) per high-power field in two of three centrifuged urine specimens signals NVH.[18] Repeat microscopy should be considered in patients whose urine dipstick is positive for blood but whose urine microscopy is negative, taking into account patient preference and risk of malignancy.[1]

Microscopy should examine freshly voided midstream urine, immediately after dipstick testing if dipstick testing is performed.[1][34] Time to analysis of the sample affects the integrity of RBCs: RBC count drops by 5% to 9% after 5 hours and by 29% to 35% after 7 hours.[35]

Microscopy confirms NVH, but it also directs the further work-up by identifying dysmorphic RBCs and RBC casts, which suggest an upper tract glomerular source of bleeding.[1][34]

Urine protein

The presence of proteinuria and NVH together is highly suggestive of an upper tract glomerular source.[1][4][20]​​​​​[36]​​[37] A urine protein to creatinine ratio of ≥0.3 or a urine albumin to total urine protein ratio of ≥0.59 suggests renal parenchymal disease.[8][19] The latter ratio has a sensitivity of 97% for distinguishing glomerular from non-glomerular bleeding. Nephrology consult is warranted and renal biopsy decisions should be directed by the nephrologist, because most often renal biopsy in patients with NVH does not alter management decisions.[4][38] Additionally, renal biopsy is unnecessary if proteinuria does not co-exist with haematuria.[8]

Risk stratification

Guidelines from the American Urological Association advise classifying patients into 3 risk categories: low, medium and high.[1]

Low-risk patients meet all of the following criteria:

  • Women aged <50 years, men aged <40 years

  • Never smoker or <10 pack years

  • 3-10 RBC per high power field on a single urine microscopy

  • No risk factors for urothelial cancer (risk factors include: persistent microhaematuria, visible haematuria).

Intermediate risk patients meet one of the following criteria:

  • Women aged 50-59 years, men aged 40-59 years

  • 10-30 pack year smoking history

  • 11-25 RBC per high power field on a single urine microscopy

  • Low risk patient with no prior evaluation and 3-10 RBC per high power field on repeat urine microscopy

  • Additional risk factor for urothelial cancer (additional risk factors include: irritative lower urinary tract symptoms, prior pelvic radiation therapy, prior cyclophosphamide/ifosfamide chemotherapy, family history of urothelial cancer, family history of Lynch syndrome, occupational exposure to aromatic amines or benzene chemicals, chronic indwelling foreign body in the urinary tract).

High risk patients are defined as:

  • Women and men aged ≥60 years

  • >30 pack year smoking history

  • >25 RBC per high power field on a single urine microscopy

  • History of visible haematuria.

Imaging

Guidelines from the American Urological Association advise further imaging according to risk of urological cancer.[1]

For low-risk patients, urine microscopy may be repeated in 6 months or the urinary tract may be investigated with renal ultrasound and cystoscopy. If NVH persists on repeat testing, the patient is reclassified as intermediate or high risk. Intermediate-risk patients should be offered renal ultrasound and cystoscopy. High-risk patients should be offered axial renal imaging, ideally with multi-phasic computed tomography (CT) urography, and cystoscopy.

Repeat urinalysis within 12 months should be considered for patients whose work up produces a negative result. A positive repeat urinalysis should prompt shared-decision making regarding repeat evaluation or observation.[1]

Ultrasound

Initial investigation with ultrasound for patients at intermediate risk of malignancy is recommended to reduce exposure to ionising radiation in a population with a low incidence of renal cell or urothelial carcinoma.[1] One model estimated 575 radiation-induced cancers in a cohort of 100,000 patients aged ≥35 years investigated with CT urography for haematuria.[39]

Renal and bladder ultrasound has a sensitivity of 85.7% and a negative predictive value of 99.9% to detect renal cell carcinoma and a sensitivity of 14.3% and negative predictive value of 99.7% to to detect upper tract urothelial carcinoma in patients with haematuria.[40]

The American College of Radiology recommends that an ultrasound of the kidneys, bladder, and retroperitoneum should be the first-line investigation for patients in whom renal parenchymal disease is the likely cause of haematuria. Ultrasound can evaluate kidney length, echogenicity, cortical thickness, and parenchymal thickness, which provides useful information about disease progression. Echogenicity on ultrasound correlates with histological changes of glomerulonephritis.[41]

Multi-phasic computed tomography (CT) urography

Multi-phasic CT urography, with and without contrast, has the highest sensitivity and specificity for detecting renal parenchymal and upper urinary tract lesions, with most studies reporting values of 90% or higher.[1] Its use has largely superseded the intravenous urogram (IVU).

There are four distinct phases of multi-phasic CT urography:

  • Pre-enhancement, before giving intravenous contrast, to establish baseline tissue density and identify calculi and haematomas

  • Arterial, to identify areas of neovascularity

  • Corticomedullary, to assess renal parenchymal changes

  • Excretory, to assess the collecting system, ureters, and bladder.[1]

Alternative imaging techniques

Magnetic resonance (MR) urography is an alternative to multi-phasic CT urography for patients with renal insufficiency, allergy to iodinated contrast, pregnancy, or other contraindications to CT urography. Compared with CT, MR urography is less specific for calcifications or small calculi.[41]

If CT or MR urography is not available, non-contrast CT or renal ultrasound may be combined with retrograde pyelography to assess the renal cortex and urothelium, respectively.[1] Non-contrast CT is the preferred investigation for suspected nephrolithiasis.

Cystoscopy

Cystoscopy is recommended as standard in evaluating patients at medium or high risk of malignancy.[1] When a urological malignancy is detected during evaluation of NVH, it is most commonly bladder cancer.

Cystoscopy has a sensitivity of 98% for the diagnosis of bladder cancer.[42]

Cystoscopy may also identify other lower urinary tract causes of NVH, e.g., urethral stricture, urethral or bladder diverticulum and benign prostatic hypertrophy.

CT virtual cystoscopy

A non-invasive test that shows promise in the assessment of haematuria. In small prospective and retrospective studies, CT virtual cystoscopy demonstrated high sensitivity for the detection of bladder tumours.[43][44] CT virtual cystoscopy can also be used to detect bladder stones, diverticulae and papillomas.

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