INTRODUCTION
An estimated 4–20% of individuals with pulmonary tuberculosis (TB) develop genitourinary involvement, mostly in developing countries.1,2 In patients with miliary disease, 25–62% have been documented to have concomitant renal lesions.3
ETIOLOGY
The most common pathogen associated with TB is Mycobacterium tuberculosis. Uncommonly implicated pathogens include Mycobacterium kansasii, Mycobacterium fortuitum, Mycobacterium bovis, Mycobacterium avium-intracellulare and Mycobacterium xenopi.
PATHOPHYSIOLOGY
Generally primary infection is in the form of pulmonary TB. Genitourinary tract is believed to be involved secondarily. Clinical symptoms usually develop 10–15 years after the primary insult.
Kidney
Kidney is usually infected by hematogenous spread of bacilli from a primary focus of infection. Mycobacterial seeding leads to granuloma formation in proximity to glomeruli which may heal with fibrosis or may caseate and rupture into the tubular lumen.4,5 Destruction of renal papilla can lead to calyceal ulceration or abscess formation. Involvement of the collecting system may result in fibrotic scarring and stenosis with calcification and called “putty kidney”.2
Ureter
Tuberculous ureteritis is always an extension of the disease from the kidney. It often causes ureteral strictures and hydronephrosis. The most common site is the lower third of ureter. Rarely, a pan- ureteric stricture takes the form of corkscrew or pipe stem ureter.
Bladder
Bladder lesions are without exception secondary to renal TB. The earliest forms of infection start around one or another ureteral orifice. It initially manifests as superficial inflammation with bullous edema and granulation. Fibrosis of the ureteral orifice can lead to stricture formation with hydronephrosis or scarring (i.e. golf-hole appearance) with vesicoureteral reflux.
Severe cases involve the entire bladder wall, where deep layers of muscle are eventually replaced by fibrous tissue, thus producing a thick fibrous bladder with progressive reduction of bladder capacity (thimble bladder).
Prostate
Prostatic TB is also the result of hematogenous spread, but involvement is rare. In many cases, pathologists diagnose it incidentally after transurethral resection of the prostate (TURP). On digital rectal examination, it feels like a firm granulomatous nodule, and needs to be differentiated from malignancy. Very rarely, in acute fulminating cases, it spreads rapidly and presents as perianal sinus.
Epididymis and Testis
In children, it is hematological spread, while in adults it seems to directly spread from the urinary tract through the retrograde route. The formation of a draining sinus is uncommon in developed countries, but epididymal induration and beading of the vas are common. Involvement of the testis is usually due to direct extension. Infertility may result from bilateral vasal obstruction. Nodular beading of the vas is a characteristic physical finding. Orchitis and the resulting testicular swelling can be difficult to differentiate from other mass lesions of the testes.3
DIAGNOSIS
Symptoms
The presentation is often vague, and physicians must have a high degree of awareness to make the diagnosis. Symptoms are generally chronic, intermittent, and nonspecific. The most common symptoms are urinary frequency, urgency, dysuria, suprapubic pain, blood or pus in the urine, and fever. Urinary urgency is unresponsive to all treatment when the bladder is extensively involved. Painless gross and microscopic hematuria occurs in approximately 10% and 5% of cases. Unexplained infertility in both men and women may be attributable to genitourinary tuberculosis (GUTB).
Examination
Physical examination is typically unremarkable. Tender testicular or epididymal swelling, nodularity and beading of the spermatic cord and vas may be the most telltale physical signs of GUTB one can find. In late cases, epididymocutaneous sinus formations may develop. Nodularity over the surface of prostate may be felt on digital rectal examination.
INVESTIGATIONS
The diagnosis of GUTB is established by demonstration of tubercle bacilli in the urine; the constellation of dysuria, sterile pyuria, hematuria, and characteristic radiographic findings are highly suggestive of the diagnosis.6 In the absence of alternative explanation for persistent sterile pyuria, 3–6 urine cultures for acid-fast bacilli (AFB) should be performed (regardless of perceived risk for TB) together with radiography.
Purified Protein Derivative Tuberculin
As many as 88% of persons with GUTB have been documented to have a positive purified protein derivative (PPD);7 one study including 100 women with laparoscopically confirmed infection noted a sensitivity and specificity of 55% and 80%, respectively.84
Interferon-gamma Release Assays
There are few data evaluating the utility of interferon-gamma release assays (IGRAs) for diagnosis of GUTB. In one study including 111 Chinese patients with extrapulmonary disease and 8 with GUTB, the sensitivity and specificity of the T-spot IGRA test was 100% and 67%, respectively.9
Urine Studies
Acid-fast Bacillus Smear
Tuberculous bacilli are shed into the urine intermittently, and AFB smear is often negative since the cutoff for a positive smear is 5,000 organisms per milliliter. Serial early-morning urine collection (at least 3) is a specific (89–96%) but less sensitive (approximately 52%) tool.
Acid-fast Bacillus Urine Cultures
It is still considered the criterion standard for evidence of active disease, with sensitivity of 65% and specificity of 100%. Between 11% and 80% of single urine specimens are positive for AFB culture in patients with active disease, depending on the demographic group and stage of infection.10 Therefore, 3–6 first morning midstream specimens should be obtained for AFB culture to maximize the likelihood of a positive result.
Every effort should be made to process the samples immediately after collection. Sending cultures before starting antitubercular treatment and adjusting therapy according to sensitivity in case of resistance is always recommended. The following culture methods are available:
- Solid media: The Lowenstein-Jensen medium yields results in more than 4 weeks.
- Radiometric media: The BACTEC 460 medium yields results in 2–3 days.
Identification of acid-fast organisms in the urine sediment via Ziehl-Neelsen stain or fluorescent dye techniques is not diagnostic for TB, since nonpathogenic mycobacteria may be present. 5False-negative results may occur in the setting of concomitant antituberculous or antibacterial therapy capable of inhibiting mycobacterial growth (particularly fluoroquinolones).
Polymerase Chain Reaction
The polymerase chain reaction (PCR) test has been extensively studied and has been proven highly sensitive, specific, and rapid. In various studies, data show sensitivity ranging from 87% to 100% (usually >90%) and specificity from 92 to 99.8% (usually >95%).11,12 Compare this with cultures (37%), bladder biopsies (47%), and intravenous urography (IVU) examinations (88%). Along with an accurate clinical assessment, PCR is the best tool available for avoiding a treatment delay because results are available in only about 6 hours. The following PCR tests are available with near-equivalent quality:
- Genus-specific 16S ribosomal ribonucleic acid (rRNA) PCR test
- Species-specific IS6110 PCR test
- Roche Amplicor M. tuberculosis PCR test
- Amplified M. tuberculosis Direct Detection Test (AMDT)
Tuberculous Peptide Nucleic Acid Fluorescence in situ Hybridization
Fluorescence in situ hybridization (FISH) using peptide nucleic acid (PNA) probes allows differentiation between tuberculous and nontuberculous mycobacteria in smears of mycobacterial cultures. PNA molecules are pseudo-peptides with deoxyribonucleic acid (DNA)-binding capacity in which the sugar phosphate backbone of DNA has been replaced by a polyamide backbone.
Nucleic Acid Amplification
Nucleic acid amplification allows both detection and identification of M. tuberculosis through enzymatic amplification of bacterial DNA. The most widely used technique is PCR, but transcription mediated amplification (TMA) and strand displacement amplification (SDA) are also commercially used. The sensitivity of this test is higher than that of smear microscopy but it is slightly lower than that of culture techniques. The main advantage of these tests is that they offer quick results, paired with a high level diagnostic accuracy. 6Some individual laboratories offer validated testing, although, thus far, there is no commercial nucleic acid amplification test approved by the US Food and Drug Administration (FDA) for detection of mycobacterial nucleic acid in urine.
Transcription-Mediated Amplification/ Amplified M. tuberculosis Direct Test
Transcription-mediated amplification can identify the presence of genetic information unique to M. tuberculosis directly from preprocessed clinical specimens. Amplified M. tuberculosis Direct (MTD) test (Gen-Probe, Hologic) detects M. tuberculosis rRNA directly and rapidly, with sensitivity similar to that of culture techniques. The sensitivity of this test is of 96% and its specificity is 100% for M. tuberculosis on specimens that are smear-positive for acid-fast bacilli. One other disadvantage of the technique is that positive results are recorded for both viable and dead bacilli.
GeneXpert M. tuberculosis Direct/RIF Molecular System
It detects DNA sequences specific for M. tuberculosis and rifampicin resistance by polymerase chain reaction. Data on use of the GeneXpert for diagnosis of extrapulmonary TB are limited. One study of 91 urine samples from patients with suspected TB or nontuberculous mycobacteria infections (including five culture positive samples) noted sensitivity and specificity of 100 and 98.6%, respectively.13 It simultaneously detects TB and rifampin drug resistance. It provides accurate results within 2 hours. It has been strongly recommended by World Health Organization (WHO) for use in diagnosis of TB since December 2010. TBXpert Project was launched in 2013 by WHO to provide equipment to 21 countries for rapid detection of TB and rifampin resistance.
Imaging Studies
X-ray
Chest and spine radiographs may show old or active lesions. However, chest radiographic findings are negative in 50% cases. 7KUB radiographs reveal calcifications in the kidney and ureter in approximately 50% of patients. Calcifications are intraluminal, as opposed to schistosomiasis, which produces intramural calcifications.
Intravenous Urography
It remains the standard diagnostic imaging studies for renal TB and has 88–95% sensitivity. Approximately 10–15% of patients who present with active renal TB will have normal urographic findings.14
The earliest radiographically detectable changes are cavitary lesions that progress to the papilla and invade the collecting system, causing calyceal disruption. Findings of infundibular stenosis and multiple ureteral strictures are highly suggestive of renal TB. Later findings may include calcifications, scarring and stricture formation (Table 1).15
Ultrasonography
High-resolution transrectal ultrasonography (TRUS) has become a very useful noninvasive technique. TRUS can reveal abnormalities in the seminal vesicles and ejaculatory duct and can help assess the status of the prostate.
Computed Tomography Scan
This imaging test is increasingly being used as the primary modality of investigation in disorders of the genitourinary tract. It is a highly sensitive to detect disease in early stage. It is a useful adjunct to IVP and is helpful in late or advanced disease for assessing the extent of disease.16,17
Advantages over intravenous urography: Depicts the extent of extrarenal spread of infection.
Important Tool Retrograde Pyelography
It is rarely indicated now except in patients with renal failure in whom the kidneys cannot excrete contrast and to evaluate stricture in the upper urinary tract. It also helps for sampling urine from individual kidneys for microbiology.8
Cystoscopy and Bladder Biopsy
- Rarely indicated:
- Assessing the extent of the disease
- Response to chemotherapy
- To rule out acute interstitial cystitis.
- Cystoscopy:
- Bladder filling under direct vision
- Under general anesthesia with a muscle relaxant reduces the risk of hemorrhage.
- Biopsy:
- Only to rule out malignancy
- Not prior to initiation of medical Rx.
Fine Needle Aspiration
Fine needle aspiration (FNA) as a minimally invasive technique plays a prime role in the diagnosis of tubercular epididymitis and epididymo-orchitis. AFB may be detected on FNA smears in up to 60% of these patients.
TREATMENT
“End TB strategy” was adopted by the World Health Assembly in May 2014. It outlines global impact targets to reduce TB deaths by 90%, to cut new cases by 80% between 2015 and 2030.9
MEDICAL CARE
Treatment with standard antituberculous agents for 6 months is generally successful in eradicating active renal infection due to drug-susceptible TB.18 The treatment regimen varies with whether or not the patient has HIV infection or drug-resistant TB. GUTB responds better to a short course of treatment than pulmonary TB because GUTB carries a lower mycobacterial load. Also, isonicotinic acid hydrazide (INH) and rifampin penetrate well into the cavitary lesions associated with GUTB. A high concentration of INH, rifampin, and pyrazinamide are maintained in urine. The primary aims of treatment are to preserve renal parenchyma and function, to make the patient noninfectious, and to manage comorbid conditions. Urine sterilization generally occurs within 2 weeks of initiating therapy.
In one study including seven patients with culture-confirmed urinary tract disease treated with standard therapy, no relapse was observed.19 Relapse rates among patients who require nephrectomy appear to be relatively low; one large study noted a relapse rate <1%; however, one study of 174 cases in Turkey demonstrated a relapse rate of 19% even after 12 months of therapy.20
Among 135 patients treated for renal TB in the 1960s with 6 months of isoniazid, streptomycin, and para-aminosalicylic acid, 97% had negative follow-up urine culture after 10 years of follow- up; 60–90% of patients required a combination of surgical and medical therapy.21 In a follow-up study of 135 patients with renal TB, who were treated with isoniazid, rifampin, and ethambutol for 6–9 months (1970–1974) or isoniazid, rifampin, and pyrazinamide for 6 months (1975–1977), the cure rate was 100% (measured by urine sterilization); relapse occurred in one patient.
Patients on antituberculous therapy should be monitored for signs and symptoms of upper urinary tract obstruction (i.e. flank pain, renal colic, hydronephrosis) during treatment.22 Clinical worsening may be observed in the first few weeks of antituberculous therapy due to inflammation, followed by fibrosis and obstruction of the collecting system. Ureteral strictures may progress during treatment due to scarring and subsequent narrowing of the lumen. In one retrospective study including 21 kidneys in which ureteral 10strictures developed during the course of antituberculous therapy, 76% developed within the initial 2 months of treatment.22 Early endourologic decompression with ureteral stent or percutaneous nephrostomy placement was associated with lower nephrectomy rate compared with treatment with medication alone (27% vs 66 %). Apart from endourologic decompression, other surgical intervention for GUTB should be delayed until the patient has received at least 4 weeks of antituberculosis medical therapy.22
In patients who are HIV-positive, continue treatment for a total of 9 months to 1 year.
Steroids are indicated for:
- Severe bladder symptoms
- Tubular structure involvement (e.g. ureter, fallopian tubes and spermatic cord)
High-dose prednisone (i.e. at least 20 mg thrice daily) for 4–6 weeks is recommended because rifampicin reduces effectiveness and bioavailability of prednisone by 66%.
NEWER DRUGS
Bedaquiline
Bedaquiline (TMC207) is an oral diarylquinoline. It is a novel drug developed specifically for the treatment of TB after more than 40 years since Rifampicin. It was approved by the FDA for the treatment of multidrug-resistant TB in 2012. Bedaquiline binds to adenosine triphosphate (ATP) synthase and interferes with the mycobacterial conversion of adenosine diphosphate into ATP. The recommended dose of bedaquiline is 400 mg daily for 2 weeks, then 200 mg three times per week for the duration of treatment. Bedaquiline has excellent late bactericidal activity, suggesting that it may kill nonreplicating organisms. QT prolongation is observed and therefore caution is advised.23
Delamanid
Delamanid is the second new drug approved for the treatment of multidrug-resistant tuberculosis (MDR-TB). It is a dihydro-nitroimidazooxazole derivative. It acts by inhibiting the synthesis of 11mycobacterial cell wall components, methoxy mycolic acid and ketomycolic acid and is bactericidal in action. QT interval prolongation is a potential side effect.24
SURGICAL MANAGEMENT
Generally, at least 4–6 weeks of chemotherapy with appropriate agents is first tried if immediate surgery is not necessary. In a recent European series, the overall frequency of surgical management in GUTB in the past 20 years was 0.5% of total urological surgical procedures.
Ablative Surgery
Nephrectomy/Nephrouretrectomy
- Indications:
- Nonfunctioning kidney with or without calcification
- Extensive disease involving whole kidney, with hypertension, UPJ obstruction
- Coexisting renal carcinoma.
Partial Nephrectomy
- Indications:
- Localized polar lesion containing calcification that has failed to respond after 6 weeks of intensive chemotherapy.
- An area of calcification that is slowly increasing in size and is threatening to destroy kidney.
Epididymectomy
- Indicated for caseating abscess not responding to short course chemotherapy.
Reconstructive Surgery
Ureteric Stricture
Strictures of the lower end of the ureter occur in approximately 9% of patients. If obstruction at the lower end of the ureter is present at the start of chemotherapy, careful observation is required. These strictures may result from edema, and they respond to chemotherapy.12
Endoscopic Management
If there is deterioration or no improvement after a 6-week period, mild strictures in early stages of the disease can be managed by endoscopic means. Balloon dilatation and placement of doubleJ stent can help resolve the obstruction and give permanent relief in a significant proportion of patients.
Surgical Management
Surgical repair of the stricture is carried out if an initial attempt at dilatation has failed. Ureteric reimplantation is usually sufficient for the most common strictures of lower third of ureter. Psoas hitch or Boari flap procedures may be required if the length of ureter is found to fall short for direct ureteroneocystostomy. For the less common strictures of the middle third of the ureter, excision of the stricture and spatulated end-to end ureteroureterostomy is the first choice. Pan ureteral strictures may necessitate an ileal ureter replacement or rarely an autotransplant.
Augmentation Cystoplasty
The treatment of choice for a contracted bladder is augmentation cystoplasty. A vascularized segment of terminal ileum or sigmoid colon is defunctionalized, detubularized, and attached to the bivalved urinary bladder to increase its capacity. For more severe cases with a thimble bladder, augmentation may not be possible and a neobladder or an ileal conduit may be an appropriate choice.
GENITOURINARY TUBERCULOSIS IN CARCINOMA BLADDER
Intravesical instillation of BCG for the treatment of urothelial carcinoma usually causes only a self-limiting, low-grade, superficial cystitis, but cases of disseminated infection have been recorded, and ureteric involvement with ureteric obstruction was observed in 0.3% cases in a large series.25 Renal involvement was found in 0.1% of the 2,602 patients in this series.13
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- Diagnostic Standards and Classification of Tuberculosis in Adults and Children. This official statement of the American Thoracic Society and the Centers for Disease Control and Prevention was adopted by the ATS Board of Directors, July 1999. This statement was endorsed by the Council of the Infectious Disease Society of America, September 1999. Am J Respir Crit Care Med. 2000;161:1376–95.
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- Davidson AJ, Hartman DS, Choyke PL, et al. Parenchymal disease with normal size and contour. In: Davidson AJ, (Ed). Davidson's Radiology of the Kidney and Genitourinary Tract, 3rd edition. Philadelphia, PA: Saunders, 1999. pp. 327–58.
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