Urogenital Tuberculosis

ABSTRACT

Urogenital tuberculosis is the second most frequent form of extrapulmonary tuberculosis. Starting with a pulmonary focus, 2 to 20% of patients develop urogenital tuberculosis through hematogenous spread to the kidneys, prostate, and epididymis; through the descending collecting system to the ureters, bladder, and urethra; and through the ejaculatory ducts to the genital organs. Urogenital tuberculosis occurs at all age ranges, but it is predominant in males in their fourth and fifth decades. It is a serious, insidious disease, generally developing symptoms only at a late stage, which leads to a diagnostic delay with consequent urogenital organ destruction; there are reports of patients with renal failure as their initial clinical presentation. Although the condition has been long recognized by nephrologists, urologists, and infectious disease specialists, urogenital tuberculosis is still largely unknown. Even when suggestive findings such as hematuria, sterile pyuria, and recurrent urinary infections are present, we rarely remember this diagnostic possibility. Greater knowledge of the features of urogenital tuberculosis then becomes relevant and should emphasize the importance of an early diagnosis.

INTRODUCTION

Tuberculosis has a worldwide distribution, without cyclical or seasonal variations and with greater prevalence in regions of high population densities and poor socioeconomic and sanitary status. It is estimated that 30% of the world’s population (1.7 billion people) are carriers of Mycobacterium tuberculosis (1). In spite of the availability of pharmacological treatment and of technological breakthroughs, the last 3 decades have witnessed a recrudescence of the infection due to the emergence of resistant bacilli, human migration, and the AIDS epidemic. In fact, tuberculosis is still a serious challenge to the world public health, chiefly in developing countries (2).

Starting with a pulmonary focus, 2 to 20% of patients develop urogenital tuberculosis through hematogenous spread to the kidneys, prostate, and epididymis; through the descending collecting system to the ureters, bladder, and urethra; and through the ejaculatory ducts to the genital organs (1, 2). Urogenital tuberculosis occurs at all age ranges, but it is predominant in males in their fourth and fifth decades (3). It is a serious, insidious disease, generally developing symptoms only at a late stage, which leads to a diagnostic delay with consequent urogenital organ destruction; there are reports of patients with renal failure as their initial clinical presentation (3).

Although the condition has been long recognized by nephrologists, urologists, and infectious disease specialists, urogenital tuberculosis is still largely unknown. Even when suggestive findings such as hematuria, sterile pyuria, and recurrent urinary infections are present, we rarely remember this diagnostic possibility. Greater knowledge of the features of urogenital tuberculosis then becomes relevant and should emphasize the importance of an early diagnosis.

EPIDEMIOLOGY

Extrapulmonary tuberculosis occurs in 10% of tuberculosis cases. Urogenital tuberculosis is responsible for 30 to 40% of extrapulmonary tuberculosis cases, second only to lymph node involvement (2, 4–6). Urogenital tuberculosis occurs in 2 to 20% of patients with pulmonary tuberculosis (5, 7–10). While in developed countries the urogenital cases constitute 2 to 10% of cases of pulmonary tuberculosis, the figures are 15 to 20% in developing countries (5, 7–9).

ETIOPATHOGENESIS

Mycobacterium tuberculosis, an acid-fast aerobic bacillus, is the most virulent mycobacterial pathogen in humans. Its slow replication accounts for the insidious nature of the infection and its resistance to ordinary antibiotics, since the latter work during bacterial division. Although the bacillus can stay dormant in the host, not producing symptoms for a long time, reactivation may follow impairment of immunity (2). Other mycobacteria, such as Mycobacterium bovis, important where unpasteurized milk is consumed (4), are less virulent to humans and are only rarely responsible for urogenital lesions.

Once inhaled, the bacilli multiply in the pulmonary alveoli, with primary granuloma formation (1, 2). As few as one to five bacilli in the alveolus may result in infection. Primary pulmonary tuberculosis is usually clinically silent and self-limited. From this pulmonary focus, bacillemia ensues and leads to bacillus implants in other organs. At this point, colonization of the renal and prostate parenchyma may occur. After 6 months, spontaneous cicatrization of primary pulmonary tuberculosis occurs, and the patient enters a latent phase, with a 5% likelihood of disease reactivation in the following 2 years and a 5% additional likelihood of reactivation thereafter. In most active cases of both pulmonary and extrapulmonary disease, latent foci are reactivated by malnutrition, diabetes mellitus, steroid and immunosuppressant use, and immunodeficiency (1, 11).

In the pathophysiology of urogenital tuberculosis, there is gradual development of the initial forms, from minimal urogenital damage and few symptoms to severe disease with contracted bladder, bilateral renal injury, and possible end-stage renal failure (3). A clear understanding of this course is paramount to highlight the importance of early diagnosis. After hematogenous spread from the pulmonary focus, there is colonization of the renal parenchyma, with initially bilateral, cortical, glomerular, and pericapillary renal lesions that are concomitant with other hematogenic foci in the prostate and other organs beyond the urogenital system (12, 13). These foci generally cicatrize, and a latent period ensues, unless there is immunodeficiency and systemically symptomatic miliary tuberculosis develops, with constitutional symptoms and multiple renal abscesses, as has been seen in AIDS patients (Fig. 1) (1, 7). In fact, 25 to 62% of patients with miliary tuberculosis have renal lesions with multiple bilateral foci (12, 14). The latent period between pulmonary infection with bacillemia and clinical urogenital tuberculosis is 22 years on average, ranging from 1 to 46 years, according to the moment when immunity falls and the latent renal foci are reactivated (8).

FIGURE 1.

Post-contrast phase of abdominal computed tomography (CT) in an AIDS patient, with bilateral renal abscesses and dilatation of the collecting system on the right. Retroperitoneal lymph node enlargement with central necrosis is apparent (arrow). From reference 27, with permission.

After reactivation of the renal foci, infection progresses from a single focus, affecting one kidney and sparing the other (13). This accounts for the greater frequency of unilateral renal tuberculosis (Fig. 2) (8, 15). Contiguous involvement of the collecting system leads to bacilluria and descending unilateral spread to the ureter and bladder. In ureteral tuberculosis, multiple stenoses develop throughout the ureter, with ureteral obstruction, ureterohydronephrosis, and consequent risk of renal functional loss. With infection progression, there is bladder damage with progressive fibrosis characterizing a more advanced form known as contracted bladder (Fig. 3 and 4) (16). Progression of bladder tuberculosis reduces bladder capacity and compliance, with distortion of the ureterovesical junctions and development of vesicoureteral reflux; the reflux almost always involves only the initially spared kidney, since ureteral stenosis protects against the radiological manifestation of reflux. Reflux which is secondary to a contracted bladder transforms the collecting system (ureter and pyelocaliceal junction) into an extension of the capacity of the contracted bladder, with ascending transmission of intravesical pressure (16). Unidentified and untreated reflux damages the kidney through infection or transmission of intravesical pressure, leading to end-stage renal failure. In a study of 25 cases of tuberculosis-related contracted bladder (16), the patients with bilateral renal tuberculosis had bilateral ureterohydronephrosis caused by ureteral obstruction on one side (first kidney to be involved) and by high-degree vesicoureteral reflux on the other (second kidney to be involved), pointing to secondary loss of function of one of the kidneys because of vesicoureteral reflux (Fig. 3 and 4). Thus, if diagnosis and treatment do not occur at the initial stages of the infection, urogenital tuberculosis may severely damage the urogenital organs, from unilateral renal loss to contracted bladder-related end-stage renal failure.

FIGURE 2.

Magnetic resonance imaging (A) and CT (B and C) of patients with unilateral renal tuberculosis, with dilatation of the collecting system (caliectasis) and thinning of the renal parenchyma. There is no dilatation of the renal pelvis. From reference 27, with permission.

FIGURE 3.

Sequential exams of patient with urogenital tuberculosis. (A) Initial intravenous urography (IU) with right kidney dysfunction and normal left kidney and bladder. (B) IU after 10 months, with development of contracted bladder and ureterohydronephrosis on the left. (C) Voiding cystography showing high-grade vesicoureteral reflux on the left as a cause of dilatation of the collecting system. From reference 27, with permission.

FIGURE 4.

Sequential exams of a patient with urogenital tuberculosis. (A) Initial IU with normal right kidney and left kidney with ureterohydronephrosis due to stenosis of the middle ureter (arrow) and intrarenal stenoses without pelvic dilatation (typical tuberculosis feature). (B) Cystography with normal bladder and no reflux. (C and D) IU and voiding cystography after 6 months without treatment, showing renal dysfunction on the left and ureterohydronephrosis on the right, with contracted bladder and bilateral vesicoureteral reflux (high grade on the right) as a cause of ureterohydronephrosis. From reference 27, with permission.

AFFECTED ORGANS

Tuberculosis may affect the entire male urinary and genital tracts. Table 1 shows the frequencies of male urinary and genital tract involvement (8, 15, 17).

TABLE 1.

Frequency of affected urogenital organs

Affected organ	Findings in indicated study
	Christensen, 1974, United States (8)	García-Rodríguez et al., 1994, Spain (15)	Mochalova and Starikov, 1997, Russia (17)
Total no. (no. of men)	102 (72)	81 (51)	4,298 (2,888)
Kidney (%)	60.8	93.8	100
Bilateral (%)	29	14.5	83.4
Unilateral (%)	71	85.5	16.6
Ureter (%)	18.6	40.7	NRa
Bladder (%)	15.7	21	10.6
Prostateb (%)	26.4	2	49.5
Epididymisb (%)	22.2	11.8	55.5
Seminal vesicles (%)	6.9	0	NR
Urethra (%)	1.4	2	21.4

^a NR, not reported.

^b In relation to male patients.

Urogenital tuberculosis most frequently affects the kidneys, renal infection being slowly progressive, asymptomatic, and highly destructive, with instances of unilateral renal loss of function and renal failure on diagnosis (18). Kidney destruction might be due to progression of a focal lesion, with caseous granuloma formation, fibrosis, and renal cavitation. Yet obstruction of the collecting system, which may be distal when due to ureteral stenosis or proximal when there are intrarenal stenoses, is the main cause of tuberculosis-related renal dysfunction (6, 19, 20).

Although unilateral renal involvement predominates in tuberculosis (8, 15), bilateral damage may occur, with risk of renal failure. Bilateral renal tuberculosis may be due to three mechanisms. (i) The first is exacerbation of the hematogenous spread period, with the formation of multiple predominantly bilateral parenchymatous foci, seen in patients with immunodeficiency and miliary tuberculosis (Fig. 1) (12). (ii) The second is bilateral focus reactivation with progressive descending spread to the collecting system and bilateral ureteral stenoses, without the presence of a contracted bladder. This presentation is extremely rare: Conte et al. (21) describe a patient with postrenal renal failure due to tuberculosis-related bilateral stenosis of the collecting system, which resolved after specific treatment, and Chattopadhyay et al. (22) describe a case of right autonephrectomy due to obstruction associated with infundibular stenosis of the contralateral kidney. In both cases, there was no bladder tuberculosis. (iii) The third is unilateral renal involvement, with descending spread to the ipsilateral ureter and bladder and then retrograde spread to the contralateral kidney through reflux (16). The last is the main mechanism of bilateral renal damage in tuberculosis. Accordingly, bilateral renal damage in tuberculosis is generally asymmetric, with one of the kidneys more severely damaged (multiple stenoses of the collecting system and asymmetric calyceal dilatation), whereas the other kidney is less involved, with reflux-related ureterohydronephrosis (16). There is a rare subset of patients with bilateral renal tuberculosis who may develop acute or chronic renal failure with histological findings of diffuse interstitial nephritis, with or without granuloma formation but without radiological findings suggestive of tuberculosis, except for renal atrophy in some cases. These cases differ from the classic clinical and radiological presentations of urogenital tuberculosis, since voiding symptoms and radiological alterations are not prominent, and the bacillus can rarely be found in the urine. Diagnosis is generally made on histopathology of a sample obtained through renal biopsy (23, 24).

Ureteral and bladder tuberculosis involvement is secondary to renal disease and consequent descending infection through the collecting or lymphatic system. Descending lymphatic spread was demonstrated in pigs which received direct renal inoculation of the bacillus and developed ureteral tuberculosis even after total occlusion of the ureter (25). In ureteral tuberculosis, multiple stenoses develop throughout the ureter, with predominance of the anatomical narrowings such as the vesicoureteral junction and, to a lesser extent, the ureterorenal junction and the mid-ureter (4, 18). Ureteral stenosis is the main cause of renal dysfunction in tuberculosis, occurring in up to 93.7% of all cases (4).

As previously stated, bladder tuberculosis is secondary to kidney tuberculosis through descendant urinary dissemination. Although urogenital tuberculosis has no initial specific symptoms or radiological findings, bladder tuberculosis has a highly specific clinical and radiological finding: the contracted bladder. In a review of published series of urogenital tuberculosis, contracted bladder was found in 8.9% of urogenital tuberculosis cases, but at differing rates in developed (4.0%) and developing (13.6%) countries (26). Radiologically, contracted bladder presents with diffuse thickening of the bladder wall, without trabeculations or diverticulous bladder. The vesicoureteral junction is located in the lateral upper part of the bladder, and it looks like all bladder has contracted but the bladder trigone (27) (Fig. 4). Clinically, the patient presents with high urinary frequency, with average urinary diurnal frequency less than 20 min and bladder capacity of less than 100 ml. Sometimes incontinence develops. The presence of contracted bladder represents an advanced urogenital tuberculosis infection (16).

In spite of constant urethral exposure to the urinary bacilli, urethral tuberculosis occurs in only 1.9 to 4.5% of all cases of urogenital tuberculosis, and never as an isolated entity. Acute urethritis and urethral discharge with associated prostatic tuberculosis, or chronically developing urethral stenosis and fistulae, are the most common clinical presentations (28, 29).

Tuberculosis affects the entire male genital tract, with lesions in the prostate, seminal vesicles, vas deferens, epididymis, Cooper glands, penis, and testicles, the last through contiguity with the epididymis, since the blood-testicle barrier plays a protective role. Genital tuberculosis occurs through hematogenous spread to the prostate and epididymis or through the urinary system to the prostate and spread from the ejaculatory ducts to the seminal vesicles, vas deferens, and epididymis (30, 31). Genital tuberculosis may be accompanied by renal lesions, but it may manifest in isolation (3). The frequency of genital organ involvement varies according to the criteria used. The prostate is histologically involved in 39.5 to 50% of subjects with urogenital tuberculosis, while epididymitis is the most common clinical manifestation, because prostate tuberculosis is usually subclinical (12, 14, 17).

In prostate contamination, hematogenous spread is more frequent than through the urinary system (32). In an experimental and clinical observational study, bacillus injection in the subcapsular and intracortical renal regions of rabbits was observed to lead to tuberculous prostate foci concomitant with foci in other organs, and discrete renal foci without communication with the urinary collecting system. In the clinical cases, the prostate lesion was not accompanied by mucosal or submucosal impairment of the prostatic urethra, being situated instead in the lateral and peripheral regions, while urethral ulcerative lesions with prostate involvement were seen only in more advanced cases with vesical tuberculosis (Fig. 5) (32). In prostatic tuberculosis, there is caseous necrosis with calcification and development of fibrosis with gland hardening (33). Prostatic tuberculosis is usually asymptomatic and diagnosed as an incidental prostatectomy finding in patients older than those with urogenital tuberculosis (33–35). Prostatic abscesses are rare but occur in AIDS patients (36).

FIGURE 5.

Voiding urethrocystography showing contracted bladder, no vesicoureteral reflux, and prostate tuberculosis, with dilatation and irregularities of the prostatic urethra. From reference 27, with permission.

The epididymis is affected in 10 to 55% of men with urogenital tuberculosis, and scrotal changes are the main sign on physical examination (8, 11, 15, 17). Epididymal tuberculosis is bilateral in 34% of the cases, presenting as a nodule or scrotal hardening in all patients, scrotal fistula in half the cases, and hydrocele in only 5% (37). The presence of a scrotal fistula is a telltale sign of tuberculosis.

Because of ejaculatory duct obstruction with oligo-azoospermia and low-volume ejaculate due to obstruction of the ejaculatory ducts, infertility may be the first symptom of tuberculosis. Multiple stenoses in the ejaculatory duct system make reconstruction impossible and are an indication for assisted reproduction (4, 30, 38). Leukospermia is a less frequent and earlier mechanism underlying tuberculosis-related infertility (30).

Penile tuberculosis is rare, developing after direct contact or secondary to another urogenital focus, with the appearance of an erythematous papule that may ulcerate. Infiltration of the cavernous bodies may lead to penis deformity and urethral fistulae, a situation that may be confused with penile carcinoma (39, 40).

FEMALE GENITAL TUBERCULOSIS

The incidence of female genital tuberculosis ranges from 0.002 to 0.56% among hospitalized women and from 0.2% to a relevant 21% among those with infertility. The condition affects women of childbearing age, with a predominance in the 20- to 40-year age range (41, 42).

Female genital tuberculosis is secondary to hematogenous spread from a primary focus, generally in the lungs or, less commonly, through lymphatic spread from tuberculosis of abdominal organs. However, primary genital tuberculosis might develop after sexual intercourse with a man with tuberculosis of the penis or epididymis. After initial involvement of the fallopian tube, the infection may involve the endometrium and, more rarely, the myometrium, reaching the ovarian cortex through contiguity. The fallopian tubes are affected in 90 to 100% of the cases, normally in a bilateral fashion, with a predominance of lesions in the ampulla (greater vascular supply), followed by the isthmus. In 50 to 70% of the cases, there is a uterine lesion with a predominance of endometrial lesions, the myometrium being more rarely affected. Ovarian tuberculosis is usually a sequela of tubal tuberculosis, when tubo-ovarian masses develop. Vulvar or vaginal tuberculosis is exceedingly rare (41, 42).

Genital tuberculosis generally presents clinically as infertility (40 to 76%), pelvic or abdominal pain (50 to 55%), and menstrual disorders (20 to 25%). Infertility is the main manifestation of the disease, resulting from tubal obstruction or the presence of adhesions and synechiae of the uterine cavity. On radiology, hysterosalpingography may show findings suggestive of tuberculosis: obstruction of the fallopian tube, multiple constrictions along the fallopian tube, and adhesion, deformity, and obliteration of the uterine cavity without previous history of curettage. A pelvic mass mimicking an ovarian tumor may develop in genital tuberculosis. Histopathological diagnosis may be made after uterine curettage or biopsy of the fallopian tube. Culture of menstrual fluid is also feasible. Yet, when there is a suspicion of tuberculosis on clinical and radiological grounds alone, treatment may be started, even without histological or bacteriological confirmation (41, 42).

Pharmacotherapy is the mainstay of treatment for female genital tuberculosis, surgery being reserved for voluminous tubo-ovarian abscesses. Pharmacotherapy and tubal surgery do not restore fertility; assisted reproduction, chiefly in vitro fertilization with embryo transfer, is indicated in such cases. Yet there is anecdotal evidence of parity after treatment of tubal tuberculosis (41, 42).

Vertical transmission of tuberculosis is very rare, with 358 cases described until 1995 and only 18 cases described between 2001 and 2005. It may occur through transplacental transmission, through umbilical veins to the fetal liver and lungs, or by aspiration or swallowing of infected amniotic fluid. The exact risk of vertical transmission in female tuberculosis is not known; however, meningeal, extrapulmonary, and miliary tuberculosis are high risk factors. Mothers who have completed antitubercular treatment and even those with at least 2 weeks’ duration before delivery are less likely to transmit the disease to the newborn than are untreated mothers. Therefore, isoniazid prophylaxis to the neonate is recommended if the mother has received treatment for less than 2 weeks (43).

CLINICAL FEATURES

In a recent review (26) of 9,178 patients described in 39 case series (6 in Latin America, 7 in Africa, 14 in Asia, 4 in the United States, and 8 in Europe), urogenital tuberculosis was seen to affect two males to each female, with a mean age of 40.7 years (range, 5 to 90 years). In only 36.5% of the cases was there clinical history or radiological evidence of previous tuberculosis. Therefore, in most cases, urogenital tuberculosis cannot be suspected on the basis of a history of previous pulmonary disease. Symptoms arise when there is bladder impairment, once, as far as tuberculosis is concerned, the kidneys are mute while the bladder plays the role of the vocal cords (9). Storage symptoms (frequency, nocturia, and urgency) are thus the most common manifestations, followed by hematuria and low back pain, occurring in 50.5, 35.6, and 34.4% of cases, respectively. On physical examination, up to 48.9% of subjects have some scrotal abnormality, with a lump, epididymal hardening, or fistula, which points to the importance of these signs (Table 2).

TABLE 2.

Comparison of patients from developed and developing countries^b

Feature or parameter	Total value	Value for developed countries	Value for developing countries	P valuea
No. of patients	9,178	3,048	1,832
% Men	64.8	62.9	60.6	0.02
% Women	35.2	37.1	39.4	0.02
Age (yrs)
Median	40.7	42.7	39.8
Range	5–90	7–90	5–83
% with previous tuberculosis	36.5	37.9	49.1	<0.01
% with symptoms and signs
Storage symptoms	50.5	44.3	55.2	<0.01
Hematuria	35.6	24.5	44.3	<0.01
Lumbar pain	34.4	28.7	42.3	<0.01
Scrotal mass	48.9	20.6	25.0	0.19
Fever and malaise	21.9	23.2	19.9	0.28
No urinary symptoms	6.4	8.4	0	<0.01
% with diagnosis by the following
Urine	64.2	79.0	55.4	<0.01
Histopathology	21.9	7.8	38.3	<0.01
Clinico-radiographic	10.4	9.6	11.3	0.36
% with normal kidneys	15.2	18.9	13.2	<0.01
% with unilateral nonfunctioning kidney	26.9	22.7	33.3	<0.01
% with renal failure	7.4	1.9	13.6	<0.01
% with contracted bladder	8.6	4.0	13.6	<0.01
% with surgery	54.9	56.6	50.0	<0.01
% with ablative surgery	27.2	35.0	43.7	<0.01

^a P, significance level through chi-square test.

^b From reference 26, with permission.

Autopsy studies revealed that only 50% of the patients with renal tuberculosis were symptomatic, with only 18% having received a clinical diagnosis (12). This diagnostic delay is due to the insidious progression of the disease, paucity and nonspecificity of symptoms, lack of physicians’ awareness, poor care-seeking behavior, and difficult bacteriological diagnosis because of sporadic bacilluria with few organisms (6, 10). Therefore, diagnosis is rarely made before severe urogenital lesions develop (3). A total of 7.4% of patients with urogenital tuberculosis develop end-stage chronic renal failure (Table 2).

Comparison of the disease features between developing countries and developed ones (with the exception of Russia, which has intermediate characteristics) shows significant differences. Patients from developing countries are more likely to have specific symptoms and receive late histological diagnoses. In such countries, tuberculosis is consequently more severe, with a greater frequency of renal failure, unilateral renal obstruction, ablative surgeries, and contracted bladder and a lower frequency of normal upper collecting systems (Table 2). These data underlie the relationship between the severity of urogenital tuberculosis and the timing of the diagnosis.

Although urogenital tuberculosis affects all age ranges, there are few cases in children because of the long interval between pulmonary infection and renal tuberculosis (3). Recurrent urinary tract infection or urinary tract infection that does not respond to conventional antibiotics, pyuria with negative urine cultures (sterile pyuria), hematuria, and epididymo-orchitis are findings suggestive of urogenital tuberculosis in the pediatric population (22).

IMMUNOSUPPRESSION

Immunosuppression favors the development of tuberculosis, which, in these cases, has a unique course, with greater risk of hematogenous spread and extrapulmonary tuberculosis (44). AIDS is now the main factor leading to tuberculosis development. Besides reactivating latent foci, human immunodeficiency virus (HIV)-related immunosuppression may lead to rapid progression of a new infection or reinfection (44). Between 20 and 50% of HIV-infected patients worldwide have active tuberculosis (45, 46). Urogenital tuberculosis seems to be very important in AIDS patients. In the United States, of 1,282 tuberculosis patients seen between 1991 and 1997 in an inner-city hospital, 46% were coinfected with HIV, and, among the patients with urogenital tuberculosis, two-thirds had AIDS (47). In autopsy studies of 46 AIDS patients in Brazil, 54.3% had tuberculosis, with the disseminated form as the most frequent presentation, whereas an astounding 23.9% of AIDS patients had bilateral renal granulomas (45). HIV-positive patients with tuberculosis are younger, have more constitutional symptoms (fever, bacteremia, and fatigue), show more diffuse pulmonary involvement, develop lymph node enlargement and disseminated tuberculosis more frequently, and have higher mortality rates than do HIV-negative subjects (44). Regarding urogenital tuberculosis, HIV-positive patients are younger and more prone to developing kidney and prostate abscesses (47).

From 0.5 to 4.0% of patients with post-renal transplant immunosuppression develop tuberculosis in developed countries; these figures rise to 3.8 to 11.8% in developing countries (48, 49). In transplant patients, pleuropulmonary and disseminated tuberculosis are more common, although urogenital tuberculosis may predominate in developing countries (48, 49). Post-renal transplant patients with urogenital tuberculosis present clinically with fever and without voiding symptoms in two-thirds of cases, and without typical radiological findings in the renal graft. Contrasting with the classic cases of urogenital tuberculosis, only around 20% of these patients have voiding symptoms (48, 49). In a comparison of 72 nonimmunosuppressed patients with urogenital tuberculosis and eight immunosuppressed patients (four with AIDS and four post-renal transplant), the latter had a predominance of constitutional symptoms, disseminated tuberculosis, and multiple parenchymatous renal foci, with a lower frequency of involvement of the collecting system (Table 3). Therefore, immunosuppressed patients develop a form of urogenital tuberculosis that has distinctive clinical and radiological features, resembling severe bacterial infection, with bacteremia and visceral metastatic foci (50).

TABLE 3.

Features of immunocompromised and nonimmunocompromised patients with urogenital tuberculosis^a

Feature	Value for nonimmunocompromised patients	Value for immunocompromised patients with the following:		P value
		AIDS	Transplantation
No.	72	4	4
Median age (yrs)	35	26	51.5
% with symptoms and signs
Storage symptoms	76.4	37.5		0.033
Hematuria	58.3	37.5		0.288
Lumbar pain	30.6	25.0		1.000
Fever	43.1	87.5		0.024
Scrotal mass	22.0	0.0		0.591
No urological symptoms	5.6	37.5		0.019
% with duration of symptoms of <6 mo	2.8	87.5		<0.001
% with previous tuberculosis	26.4	25.0		1.00
% with disseminated tuberculosis	18.1	62.5		0.012
% with diagnosis by the following
Urine	50.0	50.0		1.000
Histopathology	33.3	50.0		0.441
Clinico-radiographic	16.7	0.0		0.599
% with cortical kidney lesions	6.2	87.5		<0.001
Bilateral	3.1	37.5		0.008
Unilateral/grafted	3.1	50.0		0.001
% with excretory kidney lesions	93.8	12.5		<0.001
Bilateral	37.5	12.5		0.248
Unilateral	56.3	0.0		0.005
% with contracted bladder	65.3	12.5		0.001
Mortality (%)	4.2	12.5		0.350

^a From reference 50, with permission.

LABORATORY AND RADIOLOGICAL WORKUP

For around 10.4% of patients with urogenital tuberculosis, diagnosis is presumptive and based on suggestive clinical, laboratory, and radiological data, without microbiological or histological confirmation (26).

Identification of the tuberculosis bacillus in the urine is achieved through Ziehl-Neelsen’s acid-fast staining technique or through urine culture in Lowenstein-Jensen medium (24, 45). The former is quick, with 96.7% specificity but only 42.1 to 52.1% sensitivity (51, 52). Culture is the diagnostic gold standard for urogenital tuberculosis. Because bacilluria is sporadic and faint, three to six early morning midstream samples are required. Sensitivity varies widely, from 10.7 to 90%, and the results can take 6 to 8 weeks to be obtained (3, 10).

Some findings in urine examination, such as pyuria, hematuria, acid urine, and negative culture, suggest that urogenital tuberculosis may be present in up to 93% of patients (3). Yet the suspicion of tuberculosis should not be based on these findings alone, because alterations in the urine have been described in only 22 to 27.6% of cases (42, 53). Usual pathogens are yielded by urine culture for 20 to 40% of urogenital tuberculosis cases and for up to 50% of females (3).

PCR for Mycobacterium tuberculosis identification in the urine, a highly sensitive and specific technique in which small bits of genetic material are amplified, has become the ideal diagnostic tool, as it gives results in 24 to 48 h and allows for the diagnosis to be made even when there are few bacilli, features that make it a potentially ideal method for the diagnosis of urogenital tuberculosis (10, 52). Compared to culture, it was 95.6% sensitive and 98.1% specific (52). Compared to bacteriological, histological, or clinico-radiological diagnoses, it was 94.3% sensitive and 85.7% specific (10). Yet in a systematic review including the analysis of new PCR tests for the diagnosis of urogenital tuberculosis, specificity was high but sensitivity was variable. In spite of the potential role of PCR in the diagnosis of urogenital tuberculosis, there is no present evidence supporting the diagnosis of the condition without culture confirmation (54).

Intradermal injection of tuberculin, a tuberculosis bacillus-derived purified protein, leads to a late hypersensitivity-like local inflammatory reaction with hard nodular formation after 48 to 72 h. Patients are classified according to the induration diameter as nonreactors (below 5 mm), weak reactors (between 5 and 10 mm), and strong reactors (over 10 mm). The exam is not diagnostic, though, once M. bovis BCG-vaccinated subjects are reactors; further, when a nonvaccinated subject reacts, this merely indicates previous contact with the bacillus. Yet when a previously weak reactor becomes a strong one, it indicates recent infection (1, 2). The tuberculin test may contribute to the diagnosis of urogenital tuberculosis in countries without widespread BCG vaccination, a situation in which the test is positive in 85 to 95% of patients with urogenital tuberculosis (5, 14).

Cystoscopy with biopsy is a low-morbidity procedure that may be performed when there is clinical suspicion of tuberculosis and bacillus-negative urine culture, being more useful in the acute phase. The most frequent findings are local hyperemia, mucosal erosion and ulceration, tubercle formation, and irregularity of the ureteral meatuses. Vesical biopsy is only 18.5 to 52% sensitive, though (10, 55).

Imaging techniques are up to 91.4% sensitive for urogenital tuberculosis diagnosis, with intravenous urography and abdominal computerized tomography being used more (10). Findings suggestive of urogenital tuberculosis are calyceal irregularities; infundibular stenosis; pseudotumor or renal scarring; renal loss of function; renal cavitation; urinary tract calcification (present in 7 to 19% of the cases); collecting system thickening, stenosis, or dilatation; contracted bladder; and lesions in other sites beyond the urinary tract, such as lymph nodes, spleen, liver, and vertebrae (3, 10, 27). The simultaneous finding of kidney and bladder lesions is characteristic of tuberculosis, and the earliest findings are outline irregularity and calyceal dilatation due to infundibular stenosis (10).

Multiple stenoses of the collecting urinary system from the renal pelvis to the ureterovesical junction are the findings most suggestive of urogenital tuberculosis, occurring in 60 to 84% of cases (27). In spite of this variability, urogenital tuberculosis involves the urinary tract in a sequential pattern as described above. After unilateral renal and ureteral involvement, with thickening and stenosis of the collecting system leading to hydronephrosis and renal parenchyma atrophy, there may be bladder damage, with diffuse thickening of the bladder walls and development of vesicoureteral reflux, usually unilaterally to the as-yet-undamaged kidney. High-grade reflux may lead to ureterohydronephrosis, reflux nephropathy, and end-stage renal failure (16). Phases in the urogenital involvement of tuberculosis can then be characterized. Radiological investigation of 20 patients with urogenital tuberculosis showed four types of presentation (27): (i) bilateral renal tuberculosis with predominance of parenchymatous involvement (Fig. 1); (ii) unilateral renal tuberculosis without vesical or contralateral renal involvement (Fig. 2); (iii) unilateral renal tuberculosis and contracted bladder, with a radiologically normal contralateral kidney; and (iv) bilateral renal tuberculosis and contracted bladder, with unilateral renal dysfunction and ureterohydronephrosis of the contralateral kidney due to high-grade reflux. In two of these patients disease progress was radiologically demonstrated (Fig. 3 and 4). Understanding these phases is important for early diagnosis, when such complications and more complex reconstructive surgery may be avoided.

Epididymal tuberculosis presents on ultrasonography as a hypoechoic lesion involving the whole epididymis or just its head, with a heterogeneous texture and concomitant testicular involvement in 38.9% of the cases (56).

PHARMACOLOGICAL TREATMENT

The pharmacological treatment of urogenital tuberculosis should be started after microbiological or histological diagnosis has been made and even before diagnostic confirmation, when clinical, laboratory, and radiological data warrant a presumptive diagnosis (57). Bactericidal (e.g., isoniazid, rifampin, pyrazinamide, and streptomycin) and bacteriostatic (e.g., ethambutol and ethionamide) drugs are used (1–3). Since there is 80% relapse with a single drug, 25% with two drugs, and 10% with a triple regimen (5), the most conservative approach is to initiate a four-drug regimen, i.e., isoniazid, rifampin, pyrazinamide, and ethambutol or streptomycin. After 2 weeks of treatment, no bacilli can be identified in the urine (2). Although the optimal treatment duration has not been defined, shorter-term treatments have replaced the traditional 18- and 24-month treatments formerly recommended, and infection with susceptible organisms can usually be managed with regimens suitable for pulmonary tuberculosis as discussed elsewhere. Shorter-term regimens are justified because of the good renal vascularization, high urinary concentration of the drugs used, low bacillary load in the urine, lower cost and toxicity, higher compliance, and efficacy similar to that of longer-duration regimens (47, 58). Four- to six-month treatments with nephrectomy of the excluded kidney have afforded relapse rates lower than 1% (57, 59, 60). Malnutrition and poor social conditions warrant treatment for longer than 9 months, as relapse rates may be as high as 22% after a 6-month regimen and 19% after 1 year (9, 61).

Microbiological relapse of urogenital tuberculosis may occur after initial urine sterilization, even after prolonged treatment and nephrectomy of the excluded kidneys (9, 62, 63). Relapses occur in up to 6.3% of the cases after a mean of 5.3 years of treatment (range, 11 months to 27 years) with bacilli that are sensitive to the drugs initially used (61, 64). Most authors recommend a 10-year follow-up period after pharmacological treatment, because of the possibility of late relapse and the advantage of early treatment of initial lesions in the asymptomatic phase of relapse (9, 62–64). The development of antimicrobial resistance, caused by too short a treatment regimen (up to 60% of the patients), is one of the factors responsible for tuberculosis recrudescence (2).

Pharmacological treatment may cure small renal foci and unblock the collecting system (3, 62). Nevertheless, it has been known since the 1970s that pharmacological treatment may aggravate the renal lesions just a few weeks after its start, with fibrosis leading to obstruction of the collecting system and vesical contraction and with worsening of frequency and development of renal dysfunction (5, 18, 63). Therefore, the placement of a double J stent, to prevent worsening obstruction and consequent renal dysfunction, must be considered during the pharmacological treatment of patients with ureteral stenosis.

SURGICAL TREATMENT

Over half (54.9%) the patients with urogenital tuberculosis undergo surgery, a figure that ranges from 8 to 95%, according to the timing of diagnosis (26). In the series where surgery was less frequent, the patients were diagnosed when still asymptomatic, with lower rates of renal lesions (26). On the other hand, when the diagnosis is delayed, the silent progression of the disease leads to organ destruction, with a greater frequency of surgical interventions (26).

Surgery may be ablative, with removal of the tuberculosis-destroyed kidney or epididymis, or reconstructive for unblocking the collecting system or augmenting the contracted bladder (2, 65). The last decades have witnessed a decrease in the number of ablative surgeries and an increase in the number of reconstructive ones (66). The patient should be operated on after at least 4 to 6 weeks of pharmacological treatment (2, 3, 63).

Most authors recommend nephrectomy without ureterectomy in cases of unilateral renal dysfunction to avoid relapse, eliminate irritative voiding symptoms, treat hypertension, and avoid abscess formation (18, 35, 57, 62, 63). Systemic arterial hypertension is more frequent in patients with urogenital tuberculosis in whom unilateral renal dysfunction develops; nephrectomy can be curative of this condition in up to 64.7% of the cases (62). Relapse is more likely when a nonfunctioning kidney is not removed, because the pharmacological treatment may not sterilize all tuberculous foci, viable bacilli having been identified in kidneys from 8 weeks to 9 months of treatment (6, 62, 63). Conversely, after monitoring 35 patients for up to 22 years without any complication, some authors recommend kidney preservation if there is no pain, infection, or bleeding (53, 67).

Urinary collecting system obstruction is the main cause of kidney loss of function, the likelihood of renal function recovery in this situation being low (53). In selected cases of severe renal function reduction, however, urinary diversion may preserve these kidneys for later reconstruction (6). The positive prognostic factors for functional recovery of obstructed kidneys are distal ureteral stenosis, cortical thickness greater than 5 mm, and glomerular filtration rate above 15 ml/min, as assessed by the nephrostomy output or renal scintigraphy (6, 63). On the other hand, intrarenal stenoses almost always lead to renal dysfunction (18). In the rare instances in which an early diagnosis is made, percutaneous nephrostomy is 80% successful, and a segment of ileum may be interposed between the bladder and the dilated calices (68, 69).

Ureteral stenosis is treated with dilatation or endoscopic incision, with a 50 to 90% success rate, or with reconstructive surgery (2, 18).

Surgery for Contracted Bladder

Among 316 patients in 11 series of surgery for tuberculous contracted bladder (16–18, 70–78), 64% were men and the median age was between 30 and 40 years. Bladder augmentation was performed in 90% of the cases and orthotopic neobladder in 10%. In only three exceptional cases, a cutaneous urethrostomy was done (71). Among bladder augmentation, ileum was used in 35.4% of cases, with detubularization in all but in some cases from the two oldest series in 1969 and 1970. Sigmoid was used in 38.9%, with detubularization in almost all cases and the ileocecal segment used in 25.8%, however, in the tubularized original form in almost all cases. The frequent use of sigmoid and ileocecal segment is explained by the need for ureteral reimplantation in cases of ureteral stenosis or high-grade reflux. In neobladder surgery, the same intestinal segments were used, but the Studer procedure was used in 73.3%. The success criteria were not uniform among the series, but success was usually defined by improvement of urinary frequency and preservation of upper urinary tract. The former was achieved in 80 to 100% of the cases. However, there were cases with progression to terminal renal failure in same series (16, 18, 71, 72, 75) despite an absence of postvoiding residue and no stenosis or reflux of uretero-vesical anastomosis/junction. Different from bladder augmentation due to neurogenic bladder, most patients can void spontaneously with no need of self-catheterization. In 85.8% of cases, patients can void after surgery, and this figure improves to 94.2% after another surgery for desobstruction, such as transurethral prostate resection. In two series (16, 73), urodynamic evaluation after surgery was performed. The pressure flow studies have shown that all patients void through the voluntary increase of abdominal pressure (Valsalva’s maneuver). However, in some cases Valsalva’s maneuver occurred during the involuntary contraction and the patient used this contraction to void. In cystometry, involuntary contractions occur in 72% of cases and are not associated with worsening capacity (16). Rhythmic bowel contractions are triggered by wall distension and seem to persist after bladder augmentation. Worse results were associated with reservoir with small capacity but not with the presence of involuntary contractions (16).

In an impressively large urogenital tuberculosis series with description of 4,298 patients in Russia (17) published in 1997, bladder augmentation with sigmoid had been performed in 426 patients since 1960. The authors propose, after describing frequent stenosis of intestine-bladder anastomoses, the realization of cystoprostatectomy with orthotopic neobladder with cecum with uretero-ileal anastomosis and invagination of the appendix into the remaining part of the urethra. Due to a lack of more detailed data, no conclusion can be made with regard to that proposal.

In conclusion, the aims of contracted bladder surgical treatment are (i) improvement of quality of life through incontinence treatment and restoration of a reasonable urinary interval and (ii) preservation of the upper urinary tract by lowering the bladder pressure. Therefore, a low-pressure, high-capacity reservoir must be created through a bladder augmentation or an orthotopic neobladder. In both cases, the bowel segment used does not affect the results and its detubularization provides higher capacity and compliance of the reservoir, although the cecum may be used successfully with its original tubular configuration. There are no randomized comparative studies between these segments in tuberculosis patients, but there is one nonrandomized retrospective comparative study between detubularized ileocecal and sigmoid segment and nondetubularized sigmoid. Worse results were associated with the nondetubularized sigmoid (16). The detubularization allows a greater reservoir volume, from 18% to 425% improvement, proportional to the length of the segment to be detubularized and inversely proportional to the radius. The cecum possesses a greater radius and volume than the sigmoid and ileum at initial configuration; therefore, the volumetric improvement after the detubularization is unnecessary and may explain the good outcome associated with the tubularized cecum (16). Ureteral reimplantation should be made in cases of stenosis but is not necessary in reflux (77). The choice between bladder augmentation and orthotopic neobladder is not well established, and there are no comparative studies. Neobladder is advised with a very small bladder (less than 15 to 20 ml) or in the presence of pain (suprapubic or perineal) (17, 74, 77). Pain may not improve after augmentation and may be associated with worse results (16). No definitive conclusions can be made. The great majority of patients can void spontaneously after surgery, and with high-volume residue, an initial attempt of desobtructive surgery (prostate resection or uretral stenosis surgery) must be done before a self-catheterization regime. Bladder augmentation in patients with some degree of renal failure allows a better quality of life by improving the urinary pattern, and the augmented bladder may be used to receive kidney transplantation (16).

PERSPECTIVES

After the discovery of specific drugs for tuberculosis treatment in the mid-20th century, there was a profound change in the profile of urogenital tuberculosis, with mortality reduction, cure of initial lesions, reduction of ablative surgeries, and increase in the number of reconstructive surgeries. In recent decades, however, there was no significant change, in spite of technological breakthroughs (37). Since the 1960s, early diagnosis of urogenital tuberculosis has been known to afford greater renal preservation (18). The systematic search for urogenital tuberculosis in patients with pulmonary disease yields 10% culture positivity for the bacillus, with 66.7% of patients asymptomatic and 58% having a normal urine exam and absence of lesions on intravenous urography (79). In two other series, in which cultures were obtained routinely and not as part of any symptom investigation, a greater frequency of asymptomatic patients without lesions on intravenous urography was found (53, 64). Although bacilluria is invariably associated with renal lesion, detection of preclinical bacilluria allows for earlier diagnosis at a time when the initial lesions are amenable to cure and the severe, destructive course of urogenital tuberculosis may be averted (9, 80). A systematic search for the detection of initial cases of urogenital tuberculosis, regardless of symptoms, must be emphasized. A better definition of groups at greater risk (subjects with previous pulmonary tuberculosis or immunosuppression) should be the subject of future studies. We propose that any patient presenting with gross hematuria, persistent microscopic hematuria or pyuria, recurrent urinary tract infection, and persistent irritative micturition symptoms be investigated for urogenital tuberculosis, with six urine samples collected for culture or PCR. We also propose a periodic urine examination for hematuria or pyuria in patients with previous pulmonary tuberculosis or immunosuppressed subjects (AIDS or posttransplantation).