Chun, Helen M. MD; Hale, Braden MD, MPH
Eight to 10 million new cases of tuberculosis (TB) occur annually worldwide. After lymphadenopathy, the most common form of nonpulmonary TB is genitourinary disease, which accounts for 27% of nonpulmonary cases in the United States, Canada, and the United Kingdom.1 Genitourinary tuberculosis (GU TB) was the most common type (54%) of extrapulmonary infection in cases identified during a 10-year period in Israel.2 GU TB is often missed. Many physicians consider the condition a rarity and neglect to consider this in the differential diagnosis of conditions such as sterile pyuria, recurrent urinary tract infection, or hematuria of unknown origin. The following 3 cases of GU TB highlight some of the important aspects of this perplexing disease.
A 55-year-old Filipina was referred for a 1-year history of recurrent urinary tract infections treated with multiple courses of levofloxacin. She reported dysuria, urinary frequency, suprapubic pain, and bloody urine over the last year. She denied fever, chills, night sweats, flank or abdominal pain, cough, hemoptysis, or weight loss. Her husband had been treated for pulmonary TB in 1968. She had a positive TB skin test (purified protein derivative) in 1987, without treatment. Physical examination demonstrated a well-appearing female with suprapubic tenderness to palpation. Laboratory examinations over the previous year revealed multiple urinalyses with "too numerous to count" white and red blood cells, negative nitrite, moderate leukocyte esterase, and no growth on routine culture. Her chest radiograph was unremarkable.
Computed tomography (CT) revealed an atrophic right kidney with multiple low attenuation foci with pelvicaliectasis, periureteric thickening, and 2 nephroliths, measuring about 2 cm each. The left kidney was unremarkable. The radiologic findings reported were "most consistent with xanthogranulomatous pyelonephritis (XGP) of the R kidney" (Fig. 1). A urine culture performed for acid-fast bacilli revealed colonies of Mycobacterium tuberculosis (Mtb). Technetium scan for renal flow/function demonstrated markedly abnormal right renal flow with a differential function of only 7% (Fig. 2). The patient was treated with rifampin (RIF), isoniazid (INH), pyrazinamide (PZA), and ethambutol (EMB) directly observed therapy, but developed significant side effects from PZA and later from RIF. Culture results demonstrated the Mtb to be sensitive to all drugs tested. The patient continued on INH, EMB, and levofloxacin. Given poor function of the right kidney and second-line therapy, a laparoscopic nephrectomy was performed. Histologic examination demonstrated caseating granulomatous inflammation and chronic interstitial inflammation with focal thyroidization of the cortical tubules and associated focal segmental glomerular sclerosis consistent with chronic pyelonephritis (Fig. 3). The patient completed 9 months of therapy postnephrectomy, and urine for AFB cultures remains negative.
A 57-year-old Caucasian male with a past medical history significant for a 2-year history of recurrent prostatitis was referred to urology. The patient reported signs and symptoms of intermittent hematuria, urgency, and frequency treated with antibiotics for recurrent cystitis and prostatitis. He denied a history of fevers, chills, night sweats, weight loss, or back pain. Past urinalyses demonstrated sterile pyuria. The patient reported a remote history of positive purified protein derivative test without treatment. His physical examination was significant for an atrophic right testis consistent with a history of undescended right testicle corrected by orchipexy at age 18. In addition, he was found to have an enlarged, firm left testis and firm left epididymis. He had a normal chest radiograph. A scrotal ultrasound revealed left testis enlargement with a diffuse, echoic pattern consistent with lymphoma or atypical testis mass. The patient underwent a left radical orchiectomy. Histologic examination demonstrated necrotizing granuloma with positive AFB stains consistent with tuberculous epididymo-orchitis. Intravenous pyelography (IVP) demonstrated dilated calyces and right hydroureteronephrosis with distal stricture, consistent with partial obstruction due to tuberculous involvement of his right kidney. The patient was started on 4-drug directly observed therapy with RIF, INH, PZA, and EMB. Follow-up retrograde IVP examination of the right kidney demonstrated a 4-cm to 5-cm distal ureteral stricture. A right renal stent was placed. Sensitivity testing revealed sensitivity to standard anti-TB medications, and the patient was continued on RIF and INH. Twelve months postoperatively, the patient has been asymptomatic with negative screening urine AFB cultures. Concurrent IVP demonstrated right-sided hydronephrosis. Evaluation with a renal flow/function technetium scan was performed, which demonstrated a small cortical remnant of the right upper pole with a differential function of 5%. The patient is scheduled for a right nephrectomy.
A 43-year-old diabetic Filipina with a 5-year history of urinary frequency, urgency, nocturia, and suprapubic pain unsuccessfully treated with multiple courses of antibiotics was referred to our clinic. Urine bacterial cultures taken over a period of 5 years had been repeatedly negative. The patient's past medical history was significant for a positive purified protein derivative test and subsequent INH therapy for 6 months in 1989. Her father had a history of active TB. Urine for AFB culture was positive for Mtb, and the patient was started on 4-drug directly observed therapy with RIF/INH/PZA/EMB. The patient's chest radiograph was normal. A CT scan demonstrated dilatation of the left renal collecting system with areas of cortical thinning in the upper pole and a 2 × 2 cm of heterogeneously enhancing mass in the midpole thought to be the sequelae of chronic infection. IVP demonstrated an irregularity of the upper pole calyces of the left kidney consistent with a prior inflammatory process or possible neoplasm. Cystoscopic evaluation demonstrated multiple areas of irregularity in the bladder with nonspecific evidence of inflammation on biopsy. Renal ultrasound demonstrated hydronephrosis involving the left kidney. A renal flow/function study demonstrated normal function of the right kidney and an obstructed left kidney, with a calculated differential function of 26%. The patient had significant side effects from RIF; subsequent introduction of streptomycin was also not tolerated. Sensitivity results demonstrated resistance to INH, RIF, and ethionamide with sensitivity to PZA, p-aminosalicylate, levofloxacin, and aminoglycosides. The patient's regimen was modified to include EMB, PZA, gatifloxacin, and amikacin. Amikacin was discontinued due to mild vestibular toxicity. A left ureteral stent was placed for obstruction at the ureteropelvic junction. She continues on EMB, PZA, and gatifloxacin with negative AFB cultures.
Renal TB occurs as a result of hematogenous spread following a primary infection in the lung. At the time of presentation, there is frequently no evidence of active pulmonary disease. However, there may be clinical or radiographic evidence of past infection, suggesting renal involvement has reactivated after a period of dormancy. Postmortem studies from the first half of the 20th century revealed that miliary foci of infection typically form bilaterally within the renal cortex (reflecting the distribution of blood flow within the kidney); however, clinically, they usually present unilaterally.3,4 In the kidney, the site of preference is the renal medulla. The lesions measure up to 3 mm in diameter and are usually pale or white.
In a prospective study of 48 patients with urinary TB in Syria between 1982 and 1987, males predominated over females in a ratio of 3:2.5 The majority of patients were from 20 to 40 years old. Minority and foreign-born individuals develop renal and other extrapulmonary manifestations in excess of their population ratio.
In 1991, data from the European Dialysis and Transplant Association registry demonstrated that 195 of 30,064 new patients (0.65%) had renal failure attributable to renal TB6; countries included Portugal, Belgium, Spain, Italy, Greece, and Yugoslavia. In comparison with the United States and Australia, TB is more common as a primary renal diagnosis in these nations (0.7%) than in either the United States (0.004%) or Australia (0.16%).7,8
TB of the urinary tract is easily overlooked. Individuals with renal TB may be asymptomatic or present with dysuria, nocturia, frequency, suprapubic pain, or other lower urinary symptoms of typical cystitis; suspicions of TB arise after no response to usual antibacterial agents or pyuria in the absence of a positive culture on routine media. Renal colic is uncommon. Constitutional symptoms of fever, weight loss, and night sweats are unusual. In a series of 78 patients with GU TB over a 12-year period, 71% (41/51) with active TB of the kidneys, ureters, and bladder presented with urinary tract symptoms (dysuria, 34%; hematuria, 27%; flank pain, 10%). Twenty-one percent of patients were asymptomatic and were detected because of abnormal urinary sediments.9 Because the disease tends to present in an indolent fashion, advanced tissue destruction may occur long before the diagnosis is made. Lesions may calcify, rupture into an adjacent calyx, or form a cavity that communicates with the collecting system. Resulting fibrosis may lead to stricture formation or obstruction involving the infundibulum, pelvis, or ureter. An obstructed renal lobe or the entire kidney may proceed to significant dysfunction or end-stage failure.
The affected area consists of epithelioid granulomata, with or without caseation, leading to local tissue destruction. Organisms can be demonstrated microscopically within these lesions, but are sometimes difficult to find. With effective cell-mediated immunity, the infection is usually contained within the granulomas. These granulomas are not visible on imaging studies and may remain clinically silent for 5 to 25 years. With reactivation, granulomas enlarge and rupture into the renal tubular system, infecting the medullary pyramids and forming tuberculomas. In immunosuppressed patients, caseous necrosis is less frequently seen. The infection may cause vascular insufficiency of the papillae by damaging vessels, and papillary necrosis may ensue. Spread to the renal pelvis produces a tuberculous pyelonephritis that may progress to a pyonephrosis-like lesion with extensive caseous necrosis and renal parenchymal destruction. Scarring develops within the renal pelvis with calcification in 24% of cases, identifiable as renal or ureteric stones in up to 19% of cases.10 Mucosal and mural granulomatous lesions with scarring can occur when the infection spreads down the ureters into the bladder. The destructive renal lesions may spread outside the renal capsule and produce a mass lesion, which can mimic a neoplasm. Keratinizing squamous metaplasia may develop as a late complication of chronic inflammation and infection of the renal pelvis and is a potential risk factor for the development of squamous carcinoma in chronic cases.
Renal and genital TB frequently coexist in males; 80% of male genital TB is associated with renal disease. There is no such correlation in women, as renal TB accompanies genital TB in fewer than 5% of cases. The epididymis, followed by the prostate, is the site most commonly involved in men. Testicular involvement is less common and usually results from direct invasion from the epididymis.11 Genital TB occurs most frequently in men aged 20 to 40 years. It is thought that TB prostatitis results from antegrade infection within the urinary tract. Epididymitis, however, given its presence without urinary tract involvement, is thought to result from blood-borne infection.12 Systemic symptoms are infrequently present in isolated genital TB. The usual clinical finding is a scrotal mass that may be tender or associated with a draining sinus. Genital foci not associated with renal disease can present as a painful testicular or scrotal mass and can be established by lymphohematogenous spread. Response to chemotherapy is excellent. The recommended duration of therapy ranges from 9 to 24 months.13 In women, the most commonly affected genital organs are the fallopian tubes. Further extension can lead to pelvic peritonitis, perioophoritis, endometritis, and, less commonly, cervicitis or vaginitis.9 Presenting initial symptoms include pelvic pain and abnormal vaginal bleeding and can present as pelvic inflammatory disease.14
In individuals with AIDS (CD4 counts usually less than 50, with a high viral load), the tuberculin test is often negative and infection with TB is often disseminated. The kidney may be involved incidentally with a myriad of pathologic manifestations, including granulomatous interstitial nephritis.15
GU TB is often suspected with the finding of pyuria in the absence of isolation of a causative microbiologic organism from the urine or biopsy material. Culture of 3 morning urine specimens for mycobacteria establishes the diagnosis in 80 to 90% of cases. With a renal abnormality and negative mycobacterial urine cultures, cytologic studies, and fine-needle biopsy may be diagnostic. Cystoscopic examination often aids in the diagnosis. The bladder often shows inflammatory changes, most marked in the region of the ureteral orifice leading to the infected kidney.16 Studies show the use of polymerase chain reaction (PCR) in the identification of Mtb in the diagnosis of extrapulmonary TB to be sensitive and very specific.17 In a study performed in India in 42 patients with a clinical suspicion of GU TB, isolation of Mtb by urine AFB culture, bladder biopsy, and urinary PCR for Mtb was 37.14%, 45.83%, and 94.29%, respectively.18 A study using IS6110, an Mtb species-specific DNA insertion sequence, as the PCR primer found the overall sensitivity and specificity in comparison to urine AFB culture in 1000 patients examined with suspected GU TB 95.59% and 98.12%, respectively.19 The purified protein derivative test is a useful adjunctive test and is positive in 95%.9
Most patients with renal TB have chest radiographs that are either normal or show sequela of healed primary infection. Chest x-ray abnormalities are found in 52 to 75%.9 Patients are often unaware of their initial pulmonary infection.
A high proportion (50% to 75%) of men with genital TB have radiologic abnormalities in their urinary tracts. Although both kidneys are typically involved with TB infection, imaging studies frequently demonstrate unilateral abnormalities. Plain films may reveal calcification, a mass, or atrophy.
IVP is the most sensitive image modality in the early stages, where subtle irregularity of calyceal contour can be seen. With progressive illness, IVP may demonstrate areas of cavitation, which communicate with the collecting system, parenchymal necrosis, or strictures that are commonly multiple (producing a "beaded" appearance of the ureter or a rigid, short, "pipestem" ureter).9 In more advanced disease, aside from calyceal distortion and ureteric strictures, there may be bladder fibrosis, hydronephrosis, and autonephrectomy. Poulios and Malovrouvas (1990) noted in 160 cases from 1976 to 1986 of GU TB 13 (8.1%) patients with hydronephrosis and 21 (13.1%) with ureterohydronephrosis on IVP.20
Ultrasound may reveal calyceal dilatation and more overt evidence of obstruction. CT is more sensitive for calcifications than urography and can image extrarenal extension of disease. The CT characteristics of active ureteral involvement are typically seen as regions of marked periureteric thickening or fibrosis.21 A tuberculous kidney may ultimately become calcified and nonfunctioning. Some patients may progress to end-stage renal failure-if anatomic distortion is advanced and bilateral and leads to a fall in glomerular filtration.11
Significant advances have been made in the treatment of urinary TB with a reported mortality rate that has decreased from 80% in 1946 to <8% in 1969.22 Disease-related mortality is even lower today, and the need for nephrectomy to control the infection is rare. However, kidneys with poor function occur in 37% to 47% and nonfunctioning kidneys in 18% to 19% of infected patients.23,24
An initial 2-month intensive phase of treatment with 4 drugs: RIF, INH, PZA, and EMB, followed by a 4-month continuation phase with RIF and INH to eliminate dormant, persisting bacilli is recommended.11 If the isolate is resistant to PZA or if it cannot be included in the initial intensive phase, INH, RIF, and EMB should be given for the 2-month intensive phase, followed by 7 months of INH and RIF administered daily or twice weekly.25 Some authors recommend a minimum of 9 months of treatment with an extended 6 months of therapy if there is evidence of persistent or severe infection.26 Multidrug-resistant TB (bacilli resistant to RIF and INH with or without resistance to other drugs) requires at least 4 drugs based on susceptibility testing with the duration of therapy based on bacteriologic response, but may be 18 months or longer.27 The role of fluoroquinolones in the treatment of GU TB has not been defined.
Streptomycin, other aminoglycosides, and EMB are wholly excreted via the kidney and should be cautiously used in patients with impaired renal function. EMB can lead to irreversible optic neuritis; therefore, ophthalmologic follow-up is recommended. If the glomerular filtration rate is 50 to 100 mL/min, 25 mg 3 times weekly of EMB can be used. If the glomerular filtration rate is 30 to 50 mL/min, twice-weekly administration of EMB is recommended. RIF, INH, PZA, ethionamide, and prothionamide are eliminated in the bile or broken down to metabolites not excreted by the kidney. Patients receiving antiretroviral therapy for HIV should receive rifabutin, in place of RIF, with an extension of therapy to 9 months.28
It is important to note that strictures form as a result of the healing response (fibrosis) and may appear or progress during treatment, leading to obstruction and/or reflux. The most common site of obstruction is at, or near, the lower end of the ureter.29 Frequent pyelograms during therapy are recommended, and if obstruction develops, corticosteroid therapy should be considered, with ureteral reimplantation if the obstruction persists.30
Before the introduction of antituberculous drugs, nephrectomy was the only treatment available for GU TB.31 Indications for surgery include cases of advanced unilateral disease complicated by pain or hemorrhage and for bladder augmentation. Surgical excision of nonfunctioning kidneys or extensive lesions in partly functioning kidneys is controversial. Some authors believe that the existence of a severely damaged kidney inhibits the response to chemotherapy and has the potential for complications such as abscess, fistulae, and hypertension.20 Stenting and percutaneous nephrostomy may relieve ureteric obstruction26 and are recommended in cases of hydronephrosis and progressive renal insufficiency due to obstruction.32
GU TB is believed to be most often the result of recrudescence of longstanding latent tuberculous foci.13 Hematogenous seeding of the kidney results in granulomatous lesions of glomeruli. It is often pathologically bilateral, but unilateral in clinical presentation. If glomerular lesions progress, they caseate and rupture into the tubular lumen. Bacilli are shed in the urine. If organisms lodge in the loop of Henle, they may produce medullary granulomas that can progress to form cavities that can coalesce and destroy the pelvis. Organisms in the urine may produce lesions of the ureter and bladder. GU TB is predominantly a disease of young-aged to middle-aged adults, affecting males more frequently than females. It is often an insidious disease, often unrecognized for prolonged periods with a paucity of constitutional symptoms. The most common radiologic abnormality is dilatation of part or all of the calyceal system. When the calyceal system is eroded, and the parenchyma is destroyed by cavitation, the clinical picture may resemble pyelonephritis. IVP discloses abnormalities in most patients, but CT may be more sensitive. The most important test in the diagnosis of GU TB is the urine culture for acid-fast bacilli.
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