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Etiology and management of genitourinary tuberculosis

Aula Abbara and Robert N. Davidson
Abstract | Genitourinary tuberculosis (GUTB) is the second most common form of extrapulmonary tuberculosis, with more than 90% of cases occurring in developing countries. Postmortem studiesfrom before anti-TB therapy was availablehave provided insight into the prevalence and natural history of the disease. In GUTB, the kidneys are the most common sites of infection and are infected through hematogenous spread of the bacilli, which then spread through the renal and genital tract. Diagnosis of TB is often delayed owing to the nonspecific nature of its presentation; therefore, a high degree of suspicion should be exercised and a systematic approach should be taken during investigation. Appropriate culture samples should be obtained to tailor treatment. Standard treatment should be administered for 6 months; quadruple therapy for 2months and dual therapy for 4months. However, additional drugs and prolonged treatment are required if drug resistance occurs. Although the role of surgery in GUTB has decreased since the advent of anti-TB therapy, it can still have a role as an adjunct to drug treatment. Today, the challenges of GUTB and other forms of TB include increasing rates of drug-resistant cases and co-infection with HIV.
Abbara, A. & Davidson, R.N. Nat. Rev. Urol. 8, 678688 (2011); doi:10.1038/nrurol.2011.172

Continuing Medical Education online

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and Nature Publishing Group. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians. Medscape, LLC designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit(s)TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at http:// www.medscape.org/journal/nruro; (4) view/print certificate. Released: 9 December 2011; Expires: 9 December 2012

Learning objectives
Upon completion of this activity, participants should be able to: 1 Distinguish the most common genitourinary anatomic site of infection with tuberculosis. 2 Evaluate the diagnostic process for GUTB. 3 Assess treatment options for GUTB.

Department of Infection and Tropical Medicine, Lister Unit, Northwick Park Hospital, Harrow, Middlesex HA1 3UJ, UK (A.Abbara, R.N.Davidson). Correspondence to: A.Abbara aula.abbara@ gmail.com

Introduction

Tuberculosis (TB) remains a global health problem, with one-third of the world population infected and ~9.4million new cases reported in 2008. 1 Of these, more than 90% of patients infected were in developing
Competing interests The authors, the journal Chief Editor A. Fenner and the CME questions author C. P Vega declare no competing interests. .

countries, mostly in India (1.62.4million), followed by China (1.01.6 million) and South Africa (0.38 0.57million). 75% of the infected individuals are aged 1554years and economically productive, 1.4 million (15%) of whom are HIV-positive. 78% of HIV-positive patients contracting TB are in Africa. 1 TB accounted for 20% of the 1.8 million AIDS-related deaths in 2009, with most deaths in sub-Saharan Africa. 1 The global prevalence (164 in 100,000 people) and death rate (20 per 100,000 people) of TB have been declining, but the number of infected individuals is actually increasing. Multidrug-resistant (MDR) TB is often associated with poorly managed pharmacotherapy, particularly in middle-income countries. The incidence of MDR TB is increasing and is of global concern.1 Genitourinary TB (GUTB) is the second most common form of extrapulmonary TB (EPTB), after lymph node TB.2,3 GUTB has the propensity to affect both men and women of child-bearing age (that is, 2040years old), is responsible for extensive morbidity and can render patients infertile. The nonspecific presentation of GUTB can result in delayed diagnosis and management of the disease, which could worsen morbidity. The mainstay of GUTB treatment is antimycobaterial chemotherapy, and surgical intervention is reserved for patients with complications such as recurrent infections in a nonfunctioning kidney. In many developing countries, directly observed therapy has been successfully employed to ensure compliance with treatment and reduce the risk of drug resistance.1 In this Review, we will present the epidemiology and pathophysiology of TB and describe the currently available diagnostic tests and imaging techniques. We will
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also elucidate the sites of GUTB in men and women, and explain the treatment options. Future challenges for the management of patients with drug-resistant disease and those with HIV co-infections will also be considered.
Key points
Genitourinary tuberculosis (GUTB) is the second most common form of extrapulmonary tuberculosis (EPTB), after lymph node tuberculosis (TB) in developing countries; nonspecific symptoms can delay diagnosis, resulting in disease progression and complications The kidneys are the most common site of GUTB and are infected through hematogenous spread; from the kidneys, the bacilli can spread to the renal tract, prostate and epididymis CT and intravenous urography can aid diagnosiscalcification, multiple strictures and fibrosis are suggestive features on imaging GUTB is strongly associated with infertility in women, as the Fallopian tubes are affected in most cases, and rates of successful pregnancy remain low even after treatment Standard drug treatment is for 6months, but prolonged treatment with additional drugs is required if resistance occurs or the disease is severe Drug resistance is a growing concern and culture samples should be obtained to identify drug sensitivity; PCR techniques show promise for identification of the organism and drug-resistance genes

Epidemiology

The incidence of EPTB, and GUTB in particular, in the general population has changed in the last century, and the incidence rates differ between developing and developed countries. EPTB accounts for ~10% of overall TB cases, although the estimates vary from 4.5% to 47.9% (Table 1).25 GUTB constitutes up to 40% of EPTB cases, but again, estimates vary.24,68 Up to 20% of patients with pulmonary TB are estimated to have urogenital involvement,5,811 with most cases occurring in developing countries. EPTB is diagnosed less often in white people than other ethnic groups, 3 although GUTB is reported more frequently among people from India than other countries.12,13 GUTB predominantly affects men (4050years of age), with a prevalence twice that which is seen in women. 9,11,14 Up to 50% of HIV-positive individuals have TB,11 but few studies have investigated GUTB in these patients. One study has reported a few differences in the presentation and response to treatment between HIV-positive and HIV-negative patients with GUTB.6 Radiological findings showed that HIV-positive patients had lymph node enlargement, diffuse kidney nodular granuloma, diffuse renal calcification, and perinephric and splenic abscesses.6 A higher rate of EPTB is reported in patients on hemodialysis,15 and those with end-stage renal failure, than in those without, possibly because of their impaired cellular immunity.16 For the same reason, the incidence of all forms of TB is also high in renal transplant recipients, particularly within the first year post-transplantation.17 GUTB accounts for 715% of TB cases in patients who have had a renal transplant.17 A randomized autopsy series in 12,211 people from Germany compared the number of TB and GUTB cases before (19281949) and after (19761989) the advent of

anti-TB drugs and demonstrated that the percentage of TB was reduced from 8.1% to 2.9%, and the proportion of GUTB was reduced from 10.7% to 3.85%. In the era before anti-TB therapy, 27.8% of women and 37.8% of men with renal TB also had GUTB.18

Pathophysiology

TB infection almost always occurs through inhalation of aerosolized Mycobacterium tuberculosis bacilli, which replicate in alveolar macrophages and typically form a Ghon focus. The mycobacteria remain latent (presumably in lung granulomas or lymph nodes) 19 until an altered interaction between the pathogen and the immune cells results in active disease. The mycobacteria reach extrapulmonary organs by hematogenous dissemination and can then spread locally. An immunocompetent host infected with M.tuberculosis has a 10% lifetime risk of developing active TB, and the risk is at the highest level soon after initial infection.19 Unlike bacterial urinary infections, TB of the urinary tract takes a descending route of infection. TB bacilli

Table 1 | Studies demonstrating the prevalence of TB, EPTB and GUTB Study
Forssbohm etal.2 Peto etal.4 French etal.
3

n
26,302 253,299 20,171

Country
Germany USA UK

Study duration TB
19962000 19932006 20012003 NA NA 0.088 (non-UKborn individuals) 0.004 (UK-born individuals) NA NA NA 8.1 2.9

Prevalence (%) EPTB

21.6 18.7 47.9 (non-UKborn individuals) 27.2 (UK-born individuals) NA NA 4.5 NA NA

GUTB
16.9 6.5 2.5 (both UK-born and non-UK-born individuals) 40.9 3.3 20 10.7 3.85

Garcia-Roderiguez etal.7 Christensen etal.8 Alvarez etal.

5

198 102 136 3,741 8,407

Spain USA USA Germany Germany

19781989 19611972 19681977 19281949 19761989

Schubert etal.18 Schubert etal.18

The rates of GUTB are up to 40.9% greater than that of EPTB. Among EPTB cases, GUTB is the second most common type of TB, after lymph node TB. Abbreviations: EPTB, extrapulmonary tuberculosis; GUTB, genitourinary tuberculosis; NA, not applicable; TB, tuberculosis.

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Box 1 | Classification of renal tuberculosis24,74
Tuberculous bacilluria Renal lesion with cystitis Bilateral renal lesion (which requires nephrectomy in the affected kidney) Lesion in the remaining kidney Severe bilateral lesions

Figure 1 | A postmortem specimen demonstrating caseation in the renal cortices of a patient affected by tuberculosis. Following primary pulmonary infection, mycobacteria spread to the renal tract hematogenously. Caseating granulomata can form, which are usually bilateral and cortical; these granulomata can erode into the calyceal system resulting in disease spread to the rest of the renal tract. Reprinted from Slide Atlas of Infectious Diseases, Harold P. Lambert and W. Edmund Farrar, Unit 12 Tuberculosis, Figure12.34 Renal tuberculosis: gross specimens of kidneys ( Gower Medical Publishing, New York, 1988).93

TB affecting the male genital tract can present with a scrotal or epididymal mass, or, rarely, a penile ulcer. Chronic epdidymitis or chronic prostatitis that does not resolve with standard antibacterials should raise suspicion of GUTB. Notably, among the commonly prescribed antibiotics, quinolones (ciprofloxacin, ofloxacin) have powerfulalbeit short-lastingeffectiveness against M.tuberculosis. A scrotal sinus discharging thin, watery and odorless pus is highly suggestive of TB. Women infected with TB can present with menstrual irregularity, abdominal pain, infertility or pelvic inflammatory disease.

Diagnostic tests
Mycobacterial smear and culture The gold standard for the diagnosis of TB in any site is culture to identify M.tuberculosisa member of the M.tuberculosis complex that includes M.africanum and M.bovis. Before the 1950s, M.bovis was a common cause of TB in cattle, and could be transmitted to humans either via consumption of infected milk or via aerosolization. At present, infection via milk consumption is rare owing to the use of pasteurization; however, it still occurs in developing countries. Since M.tuberculosis complex was identified as the causative pathogen for GUTB, M.tuberculosis has been by far the most commonly studied species.19 Samples should be taken from the site of suspected TB and sent for smear and culture. The common stains used to identify acid fast bacilli are the Ziehl-Neelsen stain or auramine stain. The microscopy results of the staining test are available in 1 h. With the exception of sputum from patients with cavitating disease, most samples from suspected sites, even if they give positive results on culture, will be negative on smear; this is because the cut-off point for a positive smear is a concentration of 5,000 organisms per ml of sample.28 Mycobacteria grow slowly; hence it can take up to 6weeks for a culture to be positive.19 If TB of the renal tract is suspected, three early morning urine (EMU) samples should be sent for culture. The low sensitivity, high cost and processing requirements of EMU samples mean that they are not beneficial for the diagnosis of TB outside the genitourinary tract.29 A false-positive result on culture could be caused by the presence of M.smegmatis (a nonpathogenic Mycobacterium) in the urine.26 In GUTB, the rate of positive results on culture can be as low as 10.7%7 or as high as 80%, depending on the disease severity and how the disease is defined.7,8,21,30
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reach the kidneys hematogenously and small renal cortical lesions develop, which can heal spontaneously.20 TB bacilli pass down the renal tubules, eventually involving the calyces. Necrosis and a papillary abscess might form, which can enlarge, cavitate and extend towards the capsule of the kidney (Figure1). Infected material can enter the renal pelvis and implant in the urothelium. Stricture formation can result in hydroureter and hydronephrosis.20 Up to 10% of patients with renal TB have bladder contractures.21 Renal calcification in GUTB is common21,22 and is included in the classification of renal TB as described by Jacobs and Borthwick in 1956 (Box1).23,24

Diagnosis

A combination of symptoms, histological analyses, culture tests and imaging techniques contribute to the diagnosis of GUTB, which usually manifests as several constitutional symptoms, such as fever, weight loss and sweating.25 The nonspecific symptoms and the low yield of culture techniques often delay the diagnosis.

Symptoms Patients with renal TB can present with flank or suprapubic pain, nocturia or hematuria (Table2). If patients do not respond to standard antibiotics, then the presence of irritative urinary symptoms, such as increased urinary frequency and difficulty in voiding, should prompt suspicion of TB. Moreover, sterile pyuria (the presence of white cells in the urine, but negative bacterial culture), hematuria and proteinuria should prompt investigation for TB. Notably, secondary bacterial infections can occur in up to 50% of renal TB cases.8,2527
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Table 2 | Studies investigating the symptoms of GUTB* Study n (study duration) Country Urinary frequency or dysuria
Thailand India Thailand 48.6 (frequency) 42.9 (dysuria) NA NA

Symptoms (%) Urethral pain

20 NA NA

Irritative voiding symptoms

14.3 88.09 NA

Hematuria

Abdominal pain#
25.7 NA NA

Fistula

Renal failure
5.7 NA NA

Scrotal pain or mass

NA NA 75.9

Scrotal abscess or fistula

NA NA 17.2

Tanthanuch etal.27 Hemal etal.9 GomezGarcia etal.60 Gokce etal.94 Simon etal.95 Altintepe etal.96 Kolins etal.45

35 (19992007) 42 (19971998) 543 (19782003) 174 (19802000) 41 (19621974) 26 (19932002) 95 (19621973)

31.4 45.2 NA

14.3 NA NA

Turkey USA Turkey USA

34.4 (frequency) 43.1 (dysuria) 34 (dysuria) 46 (frequency) 46 (dysuria) 43 (frequency) 56 (dysuria)

NA NA NA NA

17 (nocturia) 5.7 (urgency) NA NA 21

39.6 27 12 NA

8 10 33 5

0.5 NA 8 NA

NA NA NA NA

2.8 NA NA NA

NA NA NA 1

*The symptoms of GUTB are related to the site of the disease; they can be nonspecific and can occur in late-stage disease. The most commonly reported symptoms are irritative voiding symptoms and hematuria. Irritative voiding symptoms include urinary frequency, urgency, dysuria and nocturia. #Abdominal pain can be flank or suprapubic. Abbreviations: GUTB, genitourinary tuberculosis; NA, not applicable.

Nucleic acid amplification test Rapid molecular techniques using nucleic acid amplification can detect M.tuberculosis DNA within 48 h of infection, can be applied to any sample and can significantly increase the yield in paucibacillary disease. Using PCR, M.tuberculosis DNA was detected in up to 80.9% of suspected cases with a sensitivity of 87100% and a specificity of 92.298%.31,32 In addition, PCR can detect the genes that confer resistance to drugs; for example, the rpoB gene, which signifies resistance to rifampicin, and can probe for mutations associated with resistance to isoniazid, quinolones and aminoglycosides. 33 This process allows early identification of MDR or extensively drug-resistant (XDR) TB.34 Molecular diagnostic techniques for TB are rapidly evolving and show promise; extrapulmonary samples are being validated on PCR machines, such as the GeneXpert System performing the Cepheid M.tuberculosis and rifampicin resistance (MTB/RIF) assay, which demonstrated a 100% sensitivity on urine samples. 35 This assay is beneficial, as it is a self-contained cassettebased test, which does not require intensive training to use, can give a result in 2 h and was shown to correctly identify 97.6% of rifampicin-resistant bacilli in sputum samples.34,36 As a result, the MTB/RIF assay performed on the GeneXpert System is recommended by the WHO as the first-line test for patients at risk of MDR TB or HIV-associated TB, and for those with smearnegative sputum samples. The role of this test in the diagnosis of EPTB, and of GUTB in particular, requires further evaluation.36 In women with GUTB, the culture yield is as low as 10.6%;3739 however, PCR can increase the detection sensitivity up to 56%, or even higher in infertile women.37,38,40 The best samples for culture can be taken from the macroscopically abnormal tissue during laparoscopy.37
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The Mantoux test The Mantoux test is the most commonly used tuberculin (TB antigen) skin test. A standardized amount of purified protein derivative tuberculin is injected intradermally into the inner surface of the forearm and the reaction is measured in millimeters by measuring the transverse diameter of induration 4872 h after injection. A reaction is considered a positive indication of infection when measured at >5 mm, >10 mm or >15 mm, depending on several factors, such as the immunological status of the patient and history of previous vaccination, and the stronger the reaction, the more likely the diagnosis of TB.19 False-positive results (usually weak reactions) occur after infection with nontuberculous mycobateria, previous BCG vaccination, or incorrect administration or interpretation of the test. False negatives can occur, particularly in immunocompromized patients, the elderly, patients with recent infection or overwhelming disease, or in cases of incorrect administration or interpretation of the test.19 A series of 100 women in India with laparoscopically confirmed GUTB demonstrated a sensitivity of 55% and a specificity of 80% for the Mantoux test.41 Interferon release assays The interferon (IFN)- assays are invitro tests for quantifying the IFN- response to antigens representing M.tuberculosis, such as ESAT-6 or CFP. These antigens are not present in the BCG vaccine, but false-positive results can be caused by previous exposure to environmental mycobacteria. The IFN- release assay has a sensitivity of 8495% and a specificity of 8599%.19,42 Other diagnostic tests To date, no immunological test differentiating active and latent TB has been developed. Only a positive EMU
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bladder. Although ultrasonography is the least specific imaging technique, all three modalities can pick up abnormalities, such as homogenous renal calcification, in advanced disease.
Radiographic imaging Up to 75% of patients with GUTB have radiographic evidence of previous or current TB.8 Plain abdominal radiography can sometimes show calcification in affected organs or lymph nodes. Intravenous urography An IVU can demonstrate changes in a single calyx in early stages of the disease. In late-stage disease, distortion of the calyces, strictures of the ureters and bladder fibrosis can be demonstrated.25 Multiple strictures and dilatation of the collecting system (hydronephrosis or hydroureter) on IVU are suggestive of renal TB (Figure2). Moreover, irregularities of the caliceal or parenchymal contour, calcification or autonephrectomy can also be demonstrated.26,47,48 CT CT can demonstrate in great detail the abnormalities and lesions both within and outside the renal tract that are suggestive of GUTB. 46 Calcification is present in >50% of renal TB cases,49 and CT is the most sensitive technique to detect calcification. The distal ureter is the most common site of strictures.49 CT showing multiple strictures in the ureter and at the pelviureteric junction, followed by dilatation, is highly suggestive of TB. CT can also demonstrate thickening, fibrosis and ulceration along the renal tract, and thickening and fibrosis of the bladder wall, which can suggest tuberculous cystitis.48 Ultrasonography Ultrasonography is less specific than IVU or CT, but the lack of ionizing radiation in this technique is an advantage. Epididymal involvement is thought to result from hematogenous spread, and ultrasonography can show a diffusely enlarged or hypoechoic epididymis with or without focal lesions.50 Some series have demonstrated a predilection for the tail of the epididymis, possibly because it is the most vascular part, or the first part, of the epididymis to be affected by reflux from the vas deferens.48 These abnormalities can appear as homogenous, or heterogeneous hypoechoic regions on ultrasonography,51 and if they are left untreated, sinus tracts can form, which can also be visualized. TB orchitis usually occurs with epididymitis; therefore, it is thought to result from local spread of infection from epdidymis. The ultrasonographic appearance of TB orchitis can include a less distinct separation between the testis and the epididymis than normal testicles, the presence of a hydrocele and calcification.50,51 Other features favoring the diagnosis of infection (rather than neoplasm) include the presence of skin thickening or peritesticular fluid. Neoplastic processes, such as lymphoma or germ cell tumors, can, however, result in epididymitis through local spread.51
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Figure 2 | Intravenous urographic imaging of a patient with urological tuberculosis. Pelvicalyceal dilatation and ureteric stricture can be observed. This feature is characteristic of tuberculosis, particularly if multiple strictures exist with dilatation of the collecting system.

culture can diagnose GUTB. However, urinary mycobacterial lipoarabinomannana glycolipid associated with M.tuberculosishas been investigated as a marker of disease activity. Although it might be a promising diagnostic tool in HIV-positive patients with a CD4 count <200 cells/ml, a study has suggested that it offers small utility in the diagnosis of TB in general.43 Further evaluation of such markers is required.43

Histological analyses The histological analyses of TB show the presence of necrotizing epithelioid cell granulomata. The necrosis is secondary to the release of cytokines, such as tumor necrosis factor and interleukin 1.19 In addition to granulomata, renal biopsies can show tuberculous interstitial nephritis.44 Imaging techniques Abnormalities on radiographic images can support the diagnosis of GUTB. Radiographic imaging, intravenous urography (IVU), ultrasonography and CT have been suggested to detect abnormalities at the site of disease in up to 95% of cases.9,30,45 CT and IVU are similar in their abilities to demonstrate focal scars and hydronephrosis with pelvicalyceal dilatation, but ultrasonography is less sensitive than CT and IVU. Moreover, CT is more sensitive than ultrasonography and IVU at detecting calcification throughout the renal tract.46 However, IVU is the most sensitive imaging modality for showing abnormalities in the
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Other imaging techniques Direct visualization of internal organs with cystoscopy, hysteroscopy or diagnostic laparascopy can improve the accuracy of diagnosis, although organs might appear macroscopically normal. Cystoscopy can be useful for macroscopic visualization of the bladder wall and for obtaining culture samples. Cystoscopic findings might include mucosal ulceration, granulomatous changes, scarring or a contracted bladder. When scarring is present at the vesicoureteric junction, some studies have described the appearance of ureteric orifice as a golf hole.45,52 Hysteroscopy or diagnostic laparoscopy can demonstrate adhesions or granulomas and can be used to collect samples for culture and histological analyses. However, up to 45% of female patients with GUTB still have a macroscopically normal uterus.53

Sites of genitourinary tuberculosis

Kidney, ureter, bladder, and urethra In the presence of urinary symptoms, a lack of response to standard antimicrobials (except quinolones), sterile pyuria, radiographic features that suggest TB, or a positive result on Mantoux test should prompt investigation for TB.25 The urinary tract is thought to be infected via hematogenous dissemination and the contralateral kidney is thought to be affected either together with hematogenous urinary tract infection or via retrograde ascending infection following a contracted bladder, ureteric stenosis and vesicoureteric reflux.9 Clinically evident disease is bilateral in about 13% of cases.22 In unilateral disease, a small reduction in renal function can occur, and in bilateral disease renal function might be normal or slightly reduced. In general, the renal damage in TB is either due to progression of the disease with caseous destruction of the parenchyma or to obstruction from stenosis, which eventually results in renal insufficiency.44 Before anti-TB therapy was available, an observational study demonstrated a 10-year survival of 26.3% in patients with bilateral renal disease who did not have surgery.22 Of patients with renal TB, 1056% have ureteric strictures, and one-third have bladder involvement.9,23 A postmortem study before the advent of anti-TB therapy demonstrated TB lesions in the genitourinary system of 3.1% of 5,424 necropsies studied. Of those with genitourinary lesions, pulmonary lesions were evident in 85%. 65% of renal lesions were miliary, and in 98% of these, the disease was bilateral. In 23% of patients, the renal lesions were caseous, and in 86% of these, bilateral renal involvement was present.54 There is an approximate 3-year delay (ranging from 1year to 10years) between the presentation of extrarenal TB and GUTB.54 If undiagnosed, almost 5.7% of patients with GUTB develop end-stage renal failure.2,11 Renal TB can lead to hypertension via activation of the reninangiotensin system, which, if severe, can be normalized by nephrectomy of the affected kidney.55 Interstitial nephritis is a rarely found form of renal TB that has an insidious course and is often only identified
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in late-stage disease. EMU samples might not culture mycobacteria, but histological analyses can demonstrate tubulointerstitial nephritis with granulomas and caseation.25 In a postmortem series,54 75% of renal lesions were cortical, and most lesions were not macroscopically visible. 88% of cadavers had bilateral renal involvement. Some microscopic cortical lesions might have healed without permanent damage, while others caseated allowing M.tuberculosis to disseminate to the renal and genital tract. TB of the ureter is usually an extension of disease from the kidney and is most commonly found at the ureterovesicular junction, where scarring of the ureter can cause reflux.56 Similarly, TB affecting the bladder results from spread from the kidneys in about 90% of patients;57 in others, the infection can originate from the genital tract. Edema might develop at the vesicular-ureteric orifice resulting in congestion and bullous edema. Tubercles are rarely seen on cystoscopy, but when they are, they initially appear as gray nodules and then as small areas of yellow caseation.57 These tubercles can form ulcers, which can coalesce and, eventually, form scars resulting in fibrosis and a contracted, rigid bladder, often with vesicoureteric reflux and ureteric strictures.

Male genitourinary tract Before an effective drug treatment for TB was available, GUTB was thought to predominantly affect men under the age of 50years58 and was described as a disease of young adults. Later studies showed that GUTB also affects men over 50years of age.7 Similar to other forms of TB, the prevalence of GUTB in men has increased simultaneously with that of HIV. GUTB in the male genitourinary tract results from either hematogenous or retrograde spread,50,59 and does not usually have systemic features. It can be insidious at onset with minimal pain, or patients can present acutely with scrotal swelling, with or without pain affecting the epididymis or testis, and with surrounding edema. Once edema settles, either a residual firm nodule or caseation can form, possibly resulting in fistula formation. If a fistula does form, exuded pus can be used for microbiological analysis. In addition, GUTB can result in scarring of the epididymis, ejaculatory ducts and seminal vesicles resulting in male infertility. Transrectal ultrasonography can reveal atrophic or calcified seminal vesicles in affected patients with ejaculatory duct obstruction. Vasography can help to characterize this obstruction.26 Infertile men with GUTB should consider microscopic epididymal sperm aspiration or testicular sperm extraction with invitro fertilization.26 TB orchitis rarely occurs in isolation and is most often seen in the context of epididymo-orchitis, probably because of the vascular structure of the epididymis. In chronic epididymitis, the entire epididymis can be involvedthe epididymis can feel firm or fluctuant nodules can form, and the scrotal skin can be adherent. Testicular pain and swelling are common symptoms of
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Table 3 | Studies investigating the affected organs and symptoms in women with GUTB Study n (study duration) Fallopian tubes
Nogales-Ortiz etal.53 Namavar Jahromi etal.72 Mondal etal.67 Agarwal etal.
39

Organ involvement (%) Ovaries

11 12.9 14.7 62.5 NA NA

Symptoms (%) Vulva and vagina

0.07 NA NA 0.07 NA NA

Endometrium
79 72.03 55.8 99.5 NA NA

Cervix
24 2.4 5.8 81.5 NA NA

Infertility
94 75.6 6570 68.5 72.5 44

Menstrual dysfunction
NA NA 2025 NA 20 23

Pelvic pain
NA NA 5055 NA 4 25

1436 (19461966) 46* (19891999) 56 (19982008) 501 (19741991) 393 (NR)

100 34.03 23.53 94.7 NA NA

Kumar etal.38 Sutherland etal.

73

711 (19511994)

GUTB is strongly associated with infertility in women; the rates of successful pregnancies are low, even after treatment, as the Fallopian tubes are affected in most cases. The features of GUTB in women are not specific and can occur in late-stage disease. *Sample size was 3,088, of which only 46 had GUTB. Abbreviations: GUTB, genitourinary tuberculosis; NA, not applicable; NR, not reported.

TB epididymo-orchitis, although epididymal swelling can be minimal. If TB epididymo-orchitis is left untreated, granulomas with caseation can cause fistulas, sinuses or caseous abscesses. Recurrent hematospermia is rare, but should raise suspicion of TB epididymo-orchitis. 51 In one series, epididymo-orchitis accounted for 9.2% of patients with GUTB with a mean age of 52years.60 A postmortem series before the anti-TB treatment era demonstrated bilateral disease in 81% of patients with seminal vesicle TB and in 64% of patients with TB epididymitis.54 Moreover, renal TB was shown to be associated with epididymo-orchitis in 64% of patients.60 TB prostatitis is uncommon. Evidence suggests that it results from hematogenous spread or is sexually transmitted, and might be found incidentally during biopsy.61 TB of the penis is very rare and accounts for <1% of all GUTB cases in men. Assays for molecular typing have shown that TB of the penis could be sexually transmitted from a female with GUTB, although primary onset of the disease is also reported.61 In TB of the penis, the skin, glans or cavernous bodies can all be affected.61 It can present as a papulonecrotic tuberculid or as an ulcer at the glans, and can progress to tuberculous cavernositis.30,62

Female genitourinary tract GUTB can cause extensive damage to the female genital tract with considerable physical, psychological and social effects. In early stages, it can present as an asymptomatic disease or with minimal symptoms; therefore, examination does not always reveal any masses. At an intermediate stage, GUTB might be evident with induration and thickening of the Fallopian tubes, and in extensive disease, palpable masses are felt in the adnexa, with associated fever and tenderness in the suprapubic region.63 75% of women with GUTB are aged 2045years.64 Patients might present with constitutional symptoms or be asymptomatic, and can also present with symptoms similar to those of pelvic inflammatory disease, as GUTB can cause Fitz-Hugh Curtis syndrome, a complication of pelvic inflammatory disease.65 GUTB is strongly linked with infertility,6668 and the rate of successful pregnancies in patients with GUTB is low, even after treatment. Primary infertility is present
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in up to 94% of patients, 53 although different studies have found varying rates (Table3).38,66,67 M.tuberculosis can be cultured in the menstrual fluid of up to 8% infertile women, and the presence of M.tuberculosis in menstrual fluid is indicative of the presence of extensive GUTB that involves the Fallopian tubes.68 Even after a complete course of TB treatment, the conception rate is low (about 19.2%) and the rate of live births is even lower (about 7.2%).69 As the Fallopian tubes are almost always involved, intervention via invitro fertilization with embryo transfer is likely to provide the highest rate of successful pregnancies.70 In addition to infertility, women with GUTB might have menstrual disorders and pelvic pain. Although the disease is rare in postmenopausal women, GUTB is thought to account for up to 1% of postmenopausal bleeding.53,64,71,72 The prevalence of GUTB in women has increased since the first descriptions of the disease in the early 20th Century, and remain undiagnosed in up to 11% of patients with infertility.66 In an autopsy series, it was identified in 5.5% of gynaecological specimens.73 Studies also suggested that GUTB could affect up to 13% of women with pulmonary TB (PTB).68 One series found that 1.5% of patients with GUTB had active PTB and 59% had healed PTB.73 This could be caused by M.tuberculosis dissemination to the uterine or peritoneal cavity resulting in endometritis or peritonitis.46 Imaging via hysterosalpingography can demonstrate stenosis of the Fallopian tubes or adhesions of the endometrial cavity, and CT can delineate the presence of tubo-ovarian abscesses. Vulvovaginal TB is a rare type of GUTB that can occur at all ages and can result from direct sexual contact or hematogenous spread of the bacteria. Patients can present with shallow ulcers.39

Management of GUTB
Drug treatment Isoniazid and pyrazinamide were developed for TB treatment in 1952, and the discovery of ethambutol and rifampicin followed in the 1960s. The early treatment regimes advocated 1824months of drug therapy. 74 However, no randomized controlled trials have investigated the optimal duration of treatment for GUTB;
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therefore, a standard regime has not been identified. The recommendations of the American Thoracic Society, the British Thoracic society and the European Association of Urology have stated that 6months of treatment should be effective.7577 The recommended regime involves an intense phase, in which all four drugs are used for 2months, and a maintenance phase, in which a combination of rifampicin and isoniazid is used for 4months (Box2). Dose adjustment is required in patients with renal failure.78 A relapse rate of <1% has been reported after up to 5months of treatment in patients who had nephrectomy of the nonfunctional kidney. Another series reported relapse rates of up to 22% after 6months of treatment.10 Drug resistance is a growing concern for TB management. 10.3% of new TB cases worldwide are resistant to isoniazid.79 MDR TB (resistant to rifampicin and isoniazid) accounts for 2.9% of isolated cases around the world, with the highest rates of MDR TB in China, Russia and India in some parts of Russia, up to 20% of TB cases are MDR. The number of XDR TB (resistance to rifampicin, isoniazid, quinolones and aminoglycosides) cases is also increasing.79 In cases of MDR and XDR, additional anti-TB drugs and a longer course of treatment are required. If resistance develops to first-line drugs, then secondline agents can be used, but such treatment is expensive, prolongs treatment duration and has a higher chance of failure than first-line treatment. New anti-TB agents, such as TMC207 (a diarylquinoline), are being investigated (Box2).80 Drug resistance occurs owing to denovo infections with drug-resistant strain or as a result of inadequate treatment; therefore, adherence to treatment is important to reduce development of drug-resistant disease. The increase in drug resistance, especially with increasing TBHIV co-infection, presents new challenges for TB management, but reinforces the importance of performing drug sensitivity tests before initiating treatment.79 In HIV-infected individuals, special care should be taken to prevent interactions between anti-TB and antiretroviral (ARV) drugs.79 Rifampicin, for example, has been reported to upregulate hepatic cytochrome P450 increasing the metabolism of ARV drugs, including protease inhibitors and non-nucleoside reverse transcriptase inhibitors.81 Moreover, patients with untreated TB who commence ARV treatment might experience an immune reconstitution inflammatory syndrome, as the immune system recovers and responds to TB.81 Adjuvant drug treatments, such as corticosteroids, have been studied in several forms of TB. In some studies, corticosteroids have been used as an adjunct to stents in ureteral stenosis, but the evidence is insufficient to justify their use in treatment of GUTB.74,82 Steroids have also been used in tuberculous nephritis; again, no clinical trials have demonstrated their efficacy.44
Box 2 | Drug treatments for tuberculosis First-line* (oral administration)
Rifampicin Isoniazid Pyrazinamide Ethambutol

Second-line
Aminoglycosides (intravenous administration) Kanamycin Amikacin Streptomycin Fluoroquinolones Moxifloxacin Levofloxacin Ofloxacin Ciprofloxacin Thioamides (oral administration) Ethionamide Protionamide Cyscloserine p-aminosalicylic acid

Third-line
Linezolid Thioacetazone Clarithromycin Imipenem

Other
TMC207# (also called R207910)
*A standard course of treatment for a fully-sensitive isolate is 6months first-line therapy: quadruple therapy (usually rifampicin, isoniazid, pyrazinamide and ethambutol) for 2months and dual therapy (usually rifampicin and isoniazid) for 4months. The efficacy of the third-line drugs is unclear. #TMC-2007 is a diarylquinoline, which is in late-stage clinical trials.

Surgical treatment Surgery is an adjunct method to drug treatment for GUTB, particularly for extensive disease. Surgery can be considered as excision of affected tissue (such as
NATURE REVIEWS | UROLOGY

nephrectomy or epididymectomy) or as a reconstructive therapy (such as enterocystoplasty in cases with ureteric or uretheral strictures).21,83 Excision of the affected tissue, including total or partial nephrectomy of a nonfunctioning kidney, is indicated if pain is ongoing, recurrent secondary bacterial infections occur or severe hypertension develops.84 Cavernotomy (deroofing of a tuberculous renal abscess) is currently not recommended as the abscess can be drained by an interventional radiologist, if required.21 An epididymectomy is required if a caseating abscess does not respond to chemotherapy; testicular atrophy can occur in 6% of patients after epididymectomy, particularly those with severe disease. If a testicular mass is not reduced in size within 3months of TB chemotherapy, the presence of a neoplasm should be considered, even if myco bacterial cultures were positive, as TB and neoplasm can coexist.21,85
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Before the drug treatment era, nephrectomy was advocated for all calcified tuberculous kidneys, as it was thought that there was a high risk of reactivation. Currently, only a proportion of patients require a nephrectomy to prevent future complications.83,8688 Some researchers advocate that surgical intervention should only be performed 4weeks after the initiation of TB treatment, but there is no evidence to support this idea.86 Other investigators suggest that patients should be treated with anti-TB drugs for at least 6months before reconstructive surgery is performed. 84 Interestingly, a 10-year study of 101 patients with confirmed GUTB from Korea showed that more than 50% of these patients required surgical intervention in addition to medical treatment. Surgical interventions included nephrectomy, epididymectomy and stenting.89 Before TB chemotherapy was available, almost all patients with renal TB underwent an open nephrectomy. 90 Today, nephrectomies can be performed laparoscopically, although this procedure can be challenging because of the dense perinephric adhesions, the possibility for the caseous material to spread and the high rate of open conversion.88,91 One study has advocated the conservative management of TB and demonstrated that nephrectomy was only performed in 7% of patients with renal TB. The researchers described ureteric stenosis in 50% of patients, of whom 73% responded to corticosteroid therapy without a need for stenting.92 Other studies advocate surgical intervention if obstruction or abscesses form, which can require a nephrostomy or drainage.84 Strictures occurring at the pelviureteric junction result in great destruction to the kidney. Strictures at the middle of the ureter are rare and respond to stenting. Strictures at the lower end of the ureter can be managed conservatively with chemotherapy, corticosteroid treatment, dilatation or, if there is obstruction or impaired renal function, surgical intervention.21 If fibrosis occurs in the bladder, reducing its capacity to <100 ml and causing severe urinary symptoms, cystoplasty can be performed to increase the bladder capacity. For this procedure, a section of the ileum, colon or caecum is used as graft tissue.83,88 In the presence of vesicoureteric reflux, an ileocystoplasty is recommended, as the ileocaecal valve can be used;21 if reflux is absent, a colocystoplasty using a section of sigmoid colon can be performed.83 Complications of colocystoplasty and ileocystoplasty include incontinence, enuresis and urinary tract infections.21 Urinary diversion procedures including ureterocoloic anastomosis or ileal or colonic conduits are sometimes
1. Treatment of Tuberculosis: Guidelines for National Programmes (4th ed.) WHO [online], http://whqlibdoc.who.int/publications/ 2010/9789241547833_eng.pdf. Forssbohm, M., Zwalhlen, M., Loddnekemper,R. & Rieder, H.L. Demographic characteristics of patients with extrapulmonary tuberculosis in Germany. Eur. Respir. J. 31, 99105 (2008). 3.

necessary.88 The only indication for these procedures is incontinence, which does not respond to chemotherapy if the sphincter mechanism is severely damaged.21 Surgery, such as abdominal hysterectomy, is indicated for women with GUTB in the presence of abdominal pain, recurrent endometrial TB, or excessive uterine bleeding.73 However, a mortality rate of 20% has been reported for abdominal hysterectomy, and the procedure is associated with major postoperative complications including bowel fistulas.73

Conclusions

GUTB remains a cause of morbidity, particularly in developing countries, where the incidence of TB is very high. Sequelae include structural damage, particularly renal failure, and infertility, especially in women. The sequelae result in prolonged morbidity and socioeconomic consequences. A number of small studies have described GUTB in localized populations in developing countries; however, large studies are required and will be a valuable addition to current knowledge of the disease. Owing to the late onset and nonspecific nature of GUTB symptoms, diagnosis is often delayed, which can result in further morbidity. As a result, a high degree of suspicion must be exercised during investigation. A microbiological diagnosis should be sought, but culture yield can be low. Nucleic acid amplification tests show promise in achieving a fast diagnosis and a high sensitivity from extrapulmonary sites, but further evaluation is required. So far, no randomized controlled trials have explored the optimal duration of treatment for GUTB or the role of surgery. As more patients with TB develop drug resistance and the number of HIVTB co-infected patients increases, the need for novel drugs with adequate penetration of the genitourinary tract becomes urgent. New techniques with high sensitivities and specificities should be identified to predict patterns for drug resistance; these techniques will also enable faster diagnosis and improve prognosis.
Review criteria
MEDLINE was searched with terms including genitourinary tuberculosis/TB, urogenital TB, male genital TB, female genital TB, TB epididymoorchitis, TB and infertility, renal TB and ureteric TB. Only fulltext English language papers published after 1900 were included. The reference lists of the identified papers were also searched for further leads.

2.

4.

French, C.E. etal. Tuberculosis in non-UK-born persons, England and Wales, 20012003. Int. J. Tuberc. Lung Dis. 11, 577584 (2007). Peto, H.M., Pratt, R.H., Harrington, T.A., LoBuel,P & Armstrong, L.R. Epidemiology of .A. extrapulmonary tuberculosis in the United States 19932006. Clin. Infect. Dis. 49, 13501357 (2009).

5.

6.

Alvarez, S. & McCabe, W.R. Extrapulmonary tuberculosis revisited: a review of experience at Boston City and other hospitals. Medicine (Baltimore) 63, 2555 (1984). Nzerue, C., Drayton, J., Oster, R. & HewanLowe,K. Genitourinary tuberculosis in patients with HIV infection: clinical features in an innercity hospital population. Am. J. Med. Sci. 320, 299303 (2000).

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REVIEWS
7. Garcia-Rodrigues, J.A. etal. Genitourinary Tuberculosis in Spain: review of 81 Cases. Clin. Infect. Dis. 18, 557561 (1994). Christensen, W.I. Genitourinary tuberculosis: review of 102 cases. Medicine (Baltimore) 53, 377390 (1974). Hemal, A.K. etal. Polymerase chain reaction in clinically suspected genitourinary tuberculosis: comparison with intravenous urography, bladder biopsy, and urine acid fast bacilli culture. Urology 56, 570574 (2000). Gokalp, A., Gultekin, E.Y. & Ozdamar, S. Genitourinary tuberculosis: a review of 83 cases. Br. J. Clin. Pract. 44, 599600 (1990). Figueiredo, A. & Lucon, A.M. Urogenital tuberculosis: update and review of 8961 cases from the world literature. Rev. Urol. 10, 207217 (2008). Grange, J.M., Yates, M.D. & Ormerod, L. P . Factors determining ethnic differences in the incidence of bacteriologically confirmed genitourinary tuberculosis in south east England. J. Infect. 30, 3740 (1995). Ormerod, L.P. Why does genitourinary tuberculosis occur less often than might be expected in the ethnic Indian subcontinent population living in the United Kingdom? J.Infect. 27, 2732 (1993). Figueiredo, A.A., Lucon, A.M., Junior, R.F. & Srougi, M. Epidemiology of urogenital tuberculosis worldwide. Int. J. Urol. 15, 827832 (2008). Chuang, F.R., Lee, C.H., Wang, I.K., Chen, J. & Wu, M.S. Extrapulmonary tuberculosis in chronic hemodialysis patients. Ren. Fail. 25, 739746 (2003). Ates, G. etal. Incidence of tuberculosis disease and latent tuberculosis infection in patients with end stage renal disease in an endemic region. Ren. Fail. 32, 9195 (2010). Queipo, J.A. etal. Mycobacterial infection in a series of 1261 renal transplant recipients. Clin. Microbiol. Infect. 9, 518525 (2003). Schubert, G.E., Haltaufderheide, T. & Golz, R. Frequency of urogenital tuberculosis in an unselected autopsy series from 1928 to 1949 and 1976 to 1989. Eur. Urol. 21, 216223 (1992). Davies, P.D., Barnes, P.F. & Gordon, S.B. (Ed.) Clinical Tuberculosis 4th edn (Hodder Education Group, London, 2008). Lattimer, J.K. & Kohen, R.J. Renal tuberculosis. Am. J. Med. 17, 533539 (1954). Gow, J.G. in Rob & Smiths Operative Surgery: Urology 4th edn (ed McDougal, W. S.) 158163 (Hodder Arnold, London, 1998). Braasch, W.F. & Sutton, E.B. Prognosis in bilateral renal tuberculosis. Can. Med. Assoc. J. 45, 320325 (1941). Gow, J.G. Renal calcification in genito-urinary tuberculosis. Br. J. Surg. 52, 283288 (1965). Borthwick, W.M. Genito-urinary tuberculosis. Tubercle 37, 120136 (1956). Eastwood, J.B., Corbishley, C.M. & Grange,J.M. Tuberculosis and the kidney. J.Am. Soc. Nephrol. 12, 13071314 (2001). Lenk, S. & Shroeder, J. Genitourinary tuberculosis. Curr. Opin. Urol. 11, 9398 (2001). Tanthanuch, M., Karnjanawanichkul, W. & Pripatnanont, C. Tuberculosis of the urinary tract in southern Thailand. J. Med. Assoc. Thai. 93, 916919 (2010). Tostmann, A. etal. Tuberculosis transmission by patients with smear-negative pulmonary tuberculosis in a large cohort in the Netherlands. Clin. Infect. Dis. 47, 11351142 (2008). 29. Mortier E., Pouchot, J., Girard, L., Boussougant,Y. & Vinceneux, P Assessment of . urine analysis for the diagnosis of tuberculosis. BMJ 312, 2728 (1996). 30. Narayana, A. Overview of renal tuberculosis. Urology 19, 231237 (1982). 31. Moussa, O.M., Eraky, I., El-Far, M.A., Osman,H.G. & Ghoneim, M.A. Rapid diagnosis of genitourinary tuberculosis by polymerase chain reaction and non-radioactive DNA hybridization. J. Urol. 164, 584588 (2000). 32. Arisan, S., Snmez, N.C., akr, .C. & Ergenekon, E. Polymerase chain reaction is a good diagnostic tool for Mycobacterium tuberculosis in urine samples. J. Cell Mol. Biol. 2, 99103 (2003). 33. Campbell, P etal. Molecular detection of .J. mutations associated with first- and second-line drug resistance compared with conventional drug susceptibility testing of Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 55, 20322041 (2011). 34. Boehme, C.C. etal. Rapid molecular detection of tuberculosis and rifampin resistance N. Engl. J. Med. 363, 10051015 (2010). 35. Hillemann, D., Rusch-Gerdes, S., Boehme, C. & Richter, E. Rapid molecular detection of extrapulmonary tuberculosis by the automated GeneXpert MTB/RIF system. J. Clin. Microbiol. 49, 12021205 (2011). 36. Connell, D.W., Berry, M., Cooke, G. & Kon, O.M. Update on tuberculosis: TB in the early 21st century. Eur. Respir. Rev. 20, 7184 (2011). 37. Bhanu, N.V. etal. Improved diagnostic value of PCR in the diagnosis of female genital tuberculosis leading to infertility. J. Med. Microbiol. 54, 927931 (2005). 38. Kumar, P etal. Association of tuberculous . endometritis with infertility and other gynecological complaints of women in India. J.Clin. Microbiol. 46, 40684070 (2008). 39. Agarwal, J. & Gupta, J.K. Female genital tuberculosisa retrospective clinicopathological study of 501 cases. Indian J. Pathol. Microbiol. 36, 389397 (1993). 40. Kulshreshta, V., Kriplani, A., Agarwal, N., Singh,U.B. & Rana, T. Genital tuberculosis among infertile women and fertility outcome after antitubercular therapy. Int. J. Gynaecol. Obstet. 113, 229234 (2011). 41. Raut, V.S., Mahashur, A.A. & Sheth, S.S.,The Mantoux test in the diagnosis of genital tuberculosis in women. Int. J. Gynecol. Obstet. 72, 165169 (2001). 42. Mazurek, G.H. etal. Updated guidelines for using interferon gamma release assays to detect mycobacterium tuberculosis infection United States, 2010. 59, 125 (2010). 43. Peter, J. etal. Urine for the diagnosis of tuberculosis: current approaches, clinical applicability and new developments. Curr. Opin. Pulm. Med. 16, 262270 (2010). 44. Mallinson, W.J., Fuller, R.W., Levison, D.A., Baker, L.R. & Cattell. W.R. Diffuse interstitial renal tuberculosisan unusual cause of renal failure. Q. J. Med. 50, 137148 (1981). 45. Kolins, S.A., Hartman, G.W., Carr, D.T. Segura,J.W. & Hattery, R.R. Roentgenographic findings in urinary tract tuberculosisa 10 year review. Am. J. Roentgenol. Radium Ther. Nucl. Med. 121, 487499 (1971). 46. Premkumar, A., Lattimer, J. & Newhouse, J.H. CT and sonography of advanced urinary tract tuberculosis. AJR Am. J. Roentgenol. 148, 6569 (1987). 47. Figueiredo, A.A., Lucon, A.M., Gomes, C.M. & Srougi, M. Urogenital tuberculosis: patient classification in seven different groups according to clinical and radiological presentation. Int. Braz. J. Urol. 34, 422432 (2008). Wang, L.J. etal. Imaging findings of urinary tuberculosis on excretory urography and computerized tomography. J. Urol. 169, 524528 (2003). Leder, R.A. & Low, V.H. Tuberculosis of the abdomen. Radiol. Clin. North Am. 33, 691705 (1995). Chung, J.J., Kim, M.J., Lee, T., Yoo, H.S. & Lee,J.T. Sonographic findings in tuberculosis epididymitis and epididymo-orchitis. J. Clin. Ultrasound 25, 390394 (1997). Trkvatan, A., Kelahmet, E., Yazgan, C. & Oler, T. Sonographic findings in tuberculous epididymoorchitis. J. Clin. Ultrasound 32, 302305 (2004). Pace, J.M. Diagnosis of renal tuberculosis. Am. J. Surg. 56, 230238 (1942). Nogales-Ortiz, F., Taracon, I. & Nogales, F.F. Jr. The pathology of female genital tuberculosis: a 31-year study of 1436 cases. Obstet. Gynecol. 53, 422428 (1979). Medlar, E.M., Spain, D.M. & Holliday, R.W. Postmortem compared with clinical diagnosis of genitor-urinary tuberculosis in adult males. J.Urol. 61, 10781088 (1949). Studer, U.E. & Weidmann, P Pathogenesis and . treatment of hypertension in renal tuberculosis. Eur. Urol. 10, 164169 (1984). Puigvert, A. The ureter in renal tuberculosis. Br. J. Urol. 27, 258266 (1955). Ball, W.G. Some cystoscopic appearances in tuberculosis of the urinary tract. Br. J. Surg. 10, 326333 (1923). Moore, R. Tuberculosis of the prostate gland. J.Urol. 37, 37 (1937). Koyama, Y., Iigaya, T. & Saito S. Tuberculous epididymo-orchitis. Urology 31, 419421 (1988). Gmez Garca, I. etal. Tuberculous orchiepididymitis during 19782003 period: review of 34 cases and role of 16S rRNA amplification. Urology 76, 776781 (2010). Angus, B.J., Yates, M., Conlon, C. & Byren, I., Cutaneous tuberculosis of the penis and sexual transmission of tuberculosis confirmed by molecular typing. Clin. Infect. Dis. 33, E132E134 (2001). Morrison, J.G. & Fourie, E.D. The papulonecrotic tuberculide. From Arthus reaction to lupus vulgaris. Br. J. Dermatol. 91, 263270 (1974). Schaefer, G. Treatment of female genital tuberculosis. Proc. R. Soc. Med. 52, 947950 (1959). Gatongi, D.K. etal. Female genital tuberculosis. J. Obstet. Gynaecol. 7, 7579 (2005). Sharma, J.B., Malhotra, M. & Arora, R. Fitz-HughCurtiz syndrome as a result of genital tuberculosis: a report of three cases. Acta Obstet. Gynecol. Scand. 82, 295297 (2003). Chowdhury, N.N. Overview of tuberculosis of the female genital tract. J. Indian Med. Assoc. 94, 345361 (1996). Mondal, S.K. & Dutta, T.K. A ten year clinicopathological study of female genital tuberculosis and impact on fertility. JNMA J. Nepal Med. Assoc. 48, 5257 (2009). de Vynck, W.E. etal. Genital tuberculosis associated with female infertility in the western Cape. S. Afr. Med. J. 16, 630631 (1990). Tripathy, S.N. & Tripathy, S.N. Infertility and pregnancy outcome in female genital tuberculosis. Int. J. Gynecol. Obstet. 76, 159163 (2002). Parikh, F.R. etal. Genital tuberculosisa major factor causing infertility in Indian women. Fertil. Steril. 67, 497500 (1997). Gungorduk, K., Ulker, V., Sahbaz, A., Ark, C. & Tekirdag, A.I. Postmenopausal tuberculosis

48.

8.

9.

49.

50.

10.

51.

11.

52. 53.

12.

54.

13.

55.

14.

56. 57.

15.

58. 59. 60.

16.

17.

61.

18.

62.

19.

63.

20. 21.

64. 65.

22.

23. 24. 25.

66.

67.

26.

68.

27.

69.

28.

70.

71.

NATURE REVIEWS | UROLOGY

2011 Macmillan Publishers Limited. All rights reserved

VOLUME 8 | DECEMBER 2011 | 687

REVIEWS
endometritis. Infect. Dis. Obstet. Gynecol. 2007, 27028 (2007). Namavar Jahromi, B., Parsanezhad, M.E. & Ghane-Shirazi, R. Female genital tuberculosis and infertility. Int. J. Gynecol. Obstet. 75, 269272 (2001). Sutherland, A.M. Gynaecological tuberculosis since 1951. J. Obstet. Gynaecol. 17, 119122 (1997). Gow, J. G. & Barbosa, S. Genitourinary tuberculosis. A study of 1117 cases over a period of 34years. Br. J. Urol. 56, 449455 (1984). Blumberg, H.M. etal. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am. J. Respir. Crit. Care Med. 167, 603662 (2003). Joint tuberculosis committee of the British Thoracic Society. Chemotherapy and management of tuberculosis in the United Kingdom: recommendations 1998. Thorax 53, 536548 (1998). Cek, M. etal. EAU guidelines for the management of genitourinary tuberculosis. Eur. Urol. 48, 353362 (2005). British Thoracic Society Standards of Care Committee and Joint Tuberculosis Committee etal. Guidelines for the prevention and management of Mycobacterium tuberculosis infection and disease in adult patients with chronic kidney disease. Thorax 65, 557570 (2010). Multidrug and extensively drug-resistant TB (M/ XDR-TB) 2010 Global Report on Surveillance and Response. WHO [online], http://whqlibdoc.who. int/publications/2010/9789241599191_eng. pdf (2010). Diacon, A.H. etal. The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N. Engl. J. Med. 360, 23972405 (2009). Figueiredo, A.A., Lucon, A.M., Ikejiri, D.S., Falci,R. Jr & Srougi, M. Urogenital tuberculosis in a patient with AIDS: an unusual presentation. Nat. Clin. Pract. Urol. 5, 455460 (2008). Kadhiravan, T. & Deepanjali, S. Role of corticosteroids in the treatment of tuberculosis: an evidence-based update. Indian J. Chest Dis. Allied Sci. 52, 153158 (2010). Gupta, N.P Kumar, A. & Sharma, S. ., Reconstructive bladder surgery in genitourinary tuberculosis. Indian J. Urol. 24, 382387 (2008). Carl, P & Stark, L. Indications for surgical . management of genitourinary tuberculosis. World J. Surg. 21, 505510 (1997). Ross, J.C., Gow, J.G. & St Hill, C.A. Tuberculous epididymitis. A review of 170 patients. Br. J. Surg. 48, 663666 (1961). Gupta, N.P etal. Reconstructive surgery for the . management of genitourinary tuberculosis: a single center experience. J. Urol. 175, 21502154 (2006). Kerr, W.K., Gale, G.L. & Peterson, K.S. Reconstructive surgery for genitourinary tuberculosis. J. Urol. 101, 254266 (1969). Krishnamoorthy, S. & Gopalakrishnan, G. Surgical management of renal tuberculosis. Indian J. Urol. 24, 369375 (2008). Lee, J.Y. etal. Clinical characteristics of genitourinary tuberculosis during a recent 10year period in one center. Korean J. Urol. 52, 200205 (2011). 90. Nesbit, R.M., Keitzer, W.A. & Lynn, J.M. The prognosis of renal tuberculosis, treated by nephrectomy, and the outlook of the patient who is considered unsuitable for operative treatment. J. Urol. 54, 227 (1945). 91. Lee, K.S. etal. Laparoscopic nephrectomy for tuberculous nonfunctioning kidney: comparison with laparoscopic simple nephrectomy for other diseases. Urology 60, 411414 (2002). 92. Horne, N.W. & Tulloch, W.S. Conservative management of renal tuberculosis. Br. J. Urol. 47, 481487 (1975). 93. Lambert, H.P & Farrar, W.E. Slide Atlas of . Infectious Diseases Unit 12 Figure12.34 (Gower Medical Publishing, New York, 1988). 94. Gokce, G. etal. Genitourinary tuberculosis: a review of 174 cases. Scand. J. Infect. Dis. 34, 338340 (2002). 95. Simon, H.B., Weinstein, A.J., Pasternak, M.S., Swarts, M.N. & Kunz, L.J. Genitourinary tuberculosis. Am. J. Med. 63, 410420 (1977). 96. Altintepe, L. etal. Urinary tuberculosis: ten years experience. Ren. Fail. 27, 657661 (2005). Acknowledgments C.P. Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape, LLC-accredited continuing medical education activity associated with this article. Author contributions Both authors contributed equally to researching data, discussing the content, writing the article and performing review and/or editing of the manuscript before submission.

72.

80.

81.

73.

74.

82.

75.

83.

84.

76.

85.

86.

77.

78.

87.

88.

89.

79.

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