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 or antiplatelets 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 aged 35 years; risk increases thereafter.[14][29][30][31][32] Urothelial neoplasm incidence of 1% to 2.4% has been reported in young adult and paediatric patients.[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.[1] For example, blood pressure can be elevated with 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][33] False-positive dipstick tests may occur due to contamination of the urine sample with hypochlorite solutions (e.g., bleach), oxidising agents, and bacterial peroxidase.[4] Dipstick testing cannot distinguish myoglobin from haemoglobin; presence of myoglobin in the urine sample may result in a false-positive result.[4]
High levels of ascorbic acid in the urine can give rise to a false-negative dipstick result for haematuria.[4]
Microscopy should examine freshly voided midstream urine, immediately after a positive dipstick test.[1][33] ≥3 red blood cells (RBCs) per high-power field on a midstream, clean-catch urine specimen signals NVH.[1][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 confirms NVH. It also serves to direct further work-up by identifying dysmorphic RBCs and RBC casts that suggest a glomerular source of bleeding.[1][33]
Urine protein
The presence of proteinuria and NVH together is highly suggestive of a glomerular source.[1][4][20][34][35] 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][36] 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 presenting with non-visible haematuria into 3 genitourinary malignancy risk categories: low/negligible, intermediate, and high.[1]
Low-risk patients meet all of the following criteria:
Women aged <60 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 or more of the following criteria:
Women aged ≥60 years, men aged 40-59 years
10-30 pack year smoking history
11-25 RBC per high power field on a single urine microscopy
Patient previously classified as low/negligible-risk with no prior evaluation and 3-25 RBC/HPF on repeat urinalysis
Any 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 meet one or more of the following criteria:
Men aged ≥60 years (women are not categorised as high-risk solely based on age)
>30 pack year smoking history
>25 RBC per high power field on a single urine microscopy
History of visible haematuria
One or more additional risk factors for urothelial cancer (see intermediate-risk patients above), plus any high-risk feature
Imaging
Guidelines from the American Urological Association advise further imaging according to risk of urological cancer.[1]
High-risk patients should be offered axial renal imaging, ideally with multiphasic computed tomography (CT) urography, and cystoscopy.
Intermediate-risk patients should be offered renal ultrasound and cystoscopy.
Patients who want to avoid cystoscopy (and accept the risk of forgoing direct visual inspection of the bladder urothelium), may be offered urine cytology or validated urine-based tumour markers to aid decision-making on cystoscopy. Renal and bladder ultrasound should still be performed in these patients.
If cystoscopy is not performed, urinalysis should be repeated within 12 months, with cystoscopy recommended for those with persistent NVH.
For low-risk patients, urinalysis should be repeated within 6 months rather than performing immediate renal ultrasound or cystoscopy. If NVH persists on repeat testing, the patient is reclassified as intermediate- or high-risk and evaluated according to the revised risk strata.
Patients with a positive repeat urinalysis should be engaged in a prompt shared-decision making process 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.[37]
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.[38]
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.[39]
Multi-phasic computed tomography (CT) urography
Multi-phasic CT urography, with and without contrast, has the high sensitivity (>90%) and specificity for detecting renal parenchymal and upper urinary tract lesions.[1][40] 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
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.[39]
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 intermediate- 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.[41]
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.[42][43] CT virtual cystoscopy can also be used to detect bladder stones, diverticula, and papillomas.
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