Urological investigations

Urine examination 36 Urine cytology 38

Prostatic specific antigen (PSA) 39 Radiological imaging of the urinary tract 40 Uses of plain abdominal radiography (KUB

X-ray—kidneys, ureters, bladder) 42 Intravenous pyelography (IVP) 44 Other urological contrast studies 48

Computed tomography (CT) and magnetic resonance imaging (MRI) 50

Radioisotope imaging 52 Uroflowmetry 54

Post-void residual urine volume measurement 58 Cystometry, pressure-flow studies, and

videocystometry 60

36 CHAPTER 2 Urological investigations

Urine examination

Dipstick testing

Analysis for pH, blood, protein, glucose, and white cells can be done with dipstick testing.

pH

Urinary pH varies between 4.5 and 8, averaging between 5.5 and 6.5.

Blood

Normal urine contains <3 RBCs per high-powered field (HPF) (~1000 erythrocytes/mL of urine; upper limit of 5000–8000 erythrocytes/mL). Positive dipstick for blood indicates the presence of hemoglobin in the urine.

Hemoglobin has a peroxidase-like activity and causes oxidation of a chromogen indicator, which changes color when oxidized. Sensitivity of urine dipsticks for identifying hematuria (>3 RBCs/HPF) is >90%; specificity is lower (i.e., a higher false-positive rate with the dipstick), due to contamination with menstrual blood or dehydration (concentrates what RBCs are normally present in urine).

Hematuria due to a urological cause does not elevate urinary protein. Hematuria of nephrological origin often occurs in association with casts, and there is almost always significant proteinuria.

Protein

Normal, healthy adults excrete about 80–150 mg of protein per day in their urine (normal protein concentration <20 mg/dL). Proteinuria suggests the presence of renal disease (glomerular, tubulointerstitial, renal vascular) or multiple myeloma, but it can occur following strenuous exercise. A dipstick test is based on a tetrabromophenol blue dye color change (green color develops in the presence of protein of >20 mg/dL).

White blood cells

Leukocyte esterase activity detects the presence of white blood cells (WBCS) in the urine. Leukocyte esterase is produced by neutrophils and causes a color change in a chromogen salt on the dipstick. Not all patients with bacteriuria have significant pyuria.

False negatives are due to concentrated urine, glycosuria, presence of urobilinogen, and consumption of large amounts of ascorbic acid. False positives are due to contamination.

Nitrite testing

Nitrites in the urine suggest the possibility of bacteriuria. They are not normally found in the urine. Many species of gram-negative bacteria can convert nitrates to nitrites, and these are detected in urine by a reaction with the reagents on the dipstick that form a red azo dye.

The specificity of the nitrite dipstick for detecting bacteriuria is >90% (false-positive nitrite testing is contamination). Sensitivity is 35–85% (i.e., lots of false negatives); it is less accurate in urine containing fewer than 105 organisms/mL.

URINE EXAMINATION 37

Cloudy urine that is positive for WBCs and is nitrite positive is very likely to be infected.

Urine microscopy

Red blood cell morphology

This is determined by phase-contrast microscopy. RBCs derived from the glomerulus are dysmorphic (they have been distorted by their passage through the glomerulus). RBCs derived from tubular bleeding (tubulointerstitial disease) and those from lower down the urinary tract (i.e., urological bleeding from the renal pelvis, ureters, or bladder) have a normal shape. Glomerular bleeding is suggested by the presence of dysmorphic RBCs, RBC casts, and proteinuria.

Casts

A cast is a protein coagulum (principally, Tamm–Horsfall mucoprotein derived from tubular epithelial cells) formed in the renal tubule and “cast” in the shape of the tubule (i.e., long and thin). The protein matrix traps tubular luminal contents. If the cast contains only mucoproteins it is called a hyaline cast. It is seen after exercise, heat exposure, and in pyelonephritis or chronic renal disease.

RBC casts contain trapped erythrocytes and are diagnostic of glomerular bleeding, most often due to glomerulonephritis. WBC casts are seen in acute glomerulonephritis, acute pyelonephritis, and acute tubulointerstitial nephritis.

Crystals

Specific crystal types may be seen in urine and help diagnose underlying problems (e.g., cystine crystals establish the diagnosis of cystinuria). Calcium oxalate, uric acid, and cystine are precipitated in acidic urine. Crystals precipitated in alkaline urine include calcium phosphate and tri- ple-phosphate (struvite).

38 CHAPTER 2 Urological investigations

Urine cytology

Urine collections for cytology

Exfoliated cells lying in urine that has been in the bladder for several hours (e.g., early morning specimens) or in a urine specimen that has been allowed to stand for several hours are degenerate. Such urine specimens are not suitable for cytological interpretation.

Cytological examination can be performed on bladder washings (using normal saline) obtained from the bladder at cystoscopy (or following catheterization) or from the ureter (via a ureteric catheter or ureteroscope). The urine is centrifuged, and the specimen obtained is fixed in alcohol and stained by the Papanicolaou technique.

Normal urothelial cells are shed into the urine. Under microscopy their nuclei appear regular and monomorphic (diffuse, fine chromatin pattern, single nucleolus).

Causes of a positive cytology report (i.e., abnormal urothelial cells seen—high nuclear–cytoplasmic ratio, hyperchromatic nuclei, prominent nucleoli) include the following:

•Urothelial malignancy (transitional cell carcinoma [TCC], squamous cell carcinoma, adenocarcinoma)

•Previous radiotherapy (especially if within the last 12 months)

•Previous cytotoxic drug treatment (especially if within the last 12 months; e.g., cyclophosphamide, busulphan, cysclosporin)

•Urinary tract stones

Renal adenocarcinoma (clear cell cancer of the kidney) usually does not exfoliate abnormal cells, though occasionally clusters of clear cells may be seen, suggesting the diagnosis.

High-grade urothelial cancer and carcinoma in situ exfoliate cells that look very abnormal, and usually the cytologist is able to indicate that there is a high likelihood of a malignancy. Low-grade bladder TCC exfoliates cells that look very much like normal urothelial cells. The difficulty arises where the cells look abnormal, but not that abnormal—here the likelihood that the cause of the abnormal cytology is a benign process is greater.

Sensitivity and specificity of positive urine cytology for detecting TCC of the bladder depend on the definition of positive—if only obviously malignant or highly suspicious samples are considered positive, then the specificity will be high. Urine cytology may be negative in as many as 20% of high-grade cancers.

If “atypical cells” are included in the definition of abnormal, the specificity of urine cytology for diagnosing urothelial cancer will be relatively poor (relatively high number of false positives) because many cases will have a benign cause (stones, inflammation).

PROSTATIC SPECIFIC ANTIGEN (PSA) 39

Prostatic specific antigen (PSA)

PSA is a 34KD glycoprotein enzyme produced by the columnar acinar and ductal prostatic epithelial cells. It is a member of the human kallikrein family and its function is to liquefy the ejaculate, enabling fertilization. PSA is present in both benign and malignant cells, although the expression of PSA tends to be reduced in malignant cells and may be absent in poorly differentiated tumors. Large amounts are secreted into the semen, and small quantities are found in the urine and blood.

The function of serum PSA is unclear, although it is known to liberate the insulin-like growth factor type 1 (IGF-1) from one of its binding proteins. 75% of circulating PSA is bound to plasma proteins (complexed PSA) and metabolized in the liver, while 25% is free and excreted in the urine. Complexed PSA is stable, bound to A1-antichymotrypsin and A2- macroglobulin. Free PSA is unstable, recently found to consist of two isoforms: pro-PSA is a peripheral zone precursor, apparently elevated in the presence of prostate cancer, and BPSA is the transition zone precursor and associated with benign prostatic hyperplasia (BPH).

The half-life of serum PSA is 2.2 days. A prostate biopsy is often recommended for men with a PSA > 2.5 ng/mL, though this varies with age. Table 2.1 shows a published age-specific normal range (95th percentile).

In the absence of prostate cancer, serum PSA concentrations also vary physiologically, according to race and prostate volume.

Indications for checking serum PSA

•Patient request, following counseling

•Lower urinary tract symptoms

•Abnormal digital rectal examination

•Progressive bone pain, especially back pain

•Unexplained anemia, anorexia, or weight loss

•Spontaneous thromboembolism or unilateral leg swelling

•Monitoring of prostate cancer patients

Table 2.1 Age-adjusted normal range for PSA