Urogenital Tuberculosis

Urogenital tuberculosis is infection of the urinary and genital organs by Mycobacterium tuberculosis. It is the commonest form of extrapulmonary tuberculosis after lymph node and pleural disease, accounting for 20 to 40% of extrapulmonary cases in some regions (about 2 to 20% of all tuberculosis). Incidence is highest in endemic countries and in HIV-infected patients.

Pathogenesis:

• Primary infection leads to haematogenous seeding of the renal cortex (glomerular capillaries) during the initial bacillaemia. Years to decades later (latency of 5 to 40 years), reactivation occurs in the renal parenchyma, and caseating granulomas spread to the medulla and papillae, with papillary necrosis, ulcerating cavitation, and extension to the collecting system.
• Descending spread leads to ureteric infection (strictures, particularly at the ureterovesical junction, ureteropelvic junction, and mid-ureter), bladder (tuberculous cystitis, contracted bladder), and genital organs (prostate, seminal vesicles, epididymis, testis, vas deferens in males, and fallopian tubes, endometrium, cervix in females).
• Genital tuberculosis in women also arises from the abdominopelvic or haematogenous spread.

Epidemiology:

• Male predominance 2:1 for renal disease, usual age 20 to 40 years, with a 5 to 15 year interval after the primary infection. Females are more likely to have genital tuberculosis, and it is an important cause of infertility in endemic regions (up to 10 to 15% of female infertility in India and sub-Saharan Africa).
• Risk factors: HIV infection, diabetes, immunosuppression (steroids, biologics such as anti-TNF), renal transplant, silicosis, chronic kidney disease or dialysis, malnutrition, alcoholism, and intravesical BCG therapy (tuberculous infection after bladder BCG for cancer).

Spectrum of disease:

• Renal parenchymal and papillary lesions, ureteric strictures and hydronephrosis, "putty kidney" (autonephrectomy with calcification), tuberculous cystitis with reduced capacity, tuberculous prostatitis, epididymo-orchitis, and female genital infection (salpingitis, endometritis, tubo-ovarian abscess).
• Complications: renal failure (in up to 10% presenting with ESRD), hypertension, secondary bacterial infection, vesicovaginal fistula, urethral stricture, infertility, and scrotal sinus.

Features are often indolent and non-specific, with diagnosis commonly delayed by 1 to 2 years:

• Urinary symptoms (the commonest): persistent dysuria, frequency, nocturia, urgency (cystitis), refractory to standard antibiotics, with sterile pyuria. Haematuria (gross or microscopic), flank pain or colic from clots or strictures.
• Constitutional symptoms: fever, night sweats, weight loss, malaise in only 10 to 20% (and not typical for isolated renal disease).
• Male genital: painless epididymal swelling that may become hard, nodular and beaded (vas deferens beading), chronic scrotal sinus or discharge, prostatic induration, infertility, pyospermia, haematospermia, and dyspareunia.
• Female genital: infertility (the commonest presentation), pelvic pain, menstrual disturbances (amenorrhoea, oligomenorrhoea, menorrhagia), vaginal discharge, postmenopausal bleeding, and pelvic mass.
• Advanced: renal failure, hypertension, and chronic cystitis.

Signs: loin tenderness, enlarged kidney, tender epididymis with thickened vas, scrotal fistula, prostate hard nodules, or no signs. Evidence of extrarenal tuberculosis (pulmonary in about 40%, abnormal chest radiograph in 30 to 50%, spinal Pott disease).

Differential diagnosis: bacterial UTI, urolithiasis, renal tumour, chronic pyelonephritis, xanthogranulomatous pyelonephritis, schistosomiasis, interstitial cystitis, papillary necrosis from analgesics or diabetes, bladder cancer, bacterial epididymitis, testicular cancer, pelvic inflammatory disease, and endometriosis.

Red flags: sterile pyuria with chronic urinary symptoms, urinary symptoms not responding to antibiotics, haematuria with history of TB exposure, hydronephrosis with ureteric strictures, contracted bladder, calcified kidney, HIV or immunosuppression, and epididymal nodularity.

Microbiology

• Early morning urine (EMU), three to six consecutive samples, for acid-fast bacilli smear, culture (Löwenstein-Jensen, MGIT liquid media; positive in 80 to 90% with multiple samples, taking 2 to 8 weeks), and nucleic acid amplification (GeneXpert MTB/RIF Ultra, sensitivity 85 to 95%, provides rifampicin resistance). Smear alone has a low yield (20 to 40%) and may show false positives from Mycobacterium smegmatis.
• Specimens from genital tissue (semen, prostatic secretions, endometrial curettage/menstrual blood, tubal washings, aspirates, biopsy), cold abscess fluid, and sinus discharge.
• Urinalysis: sterile pyuria (acidic urine), microscopic haematuria, mild proteinuria.
• Drug susceptibility testing on all positive cultures.

Immunological tests: tuberculin skin test and interferon gamma release assay indicate infection but not active disease. Positive results support the diagnosis in the context. HIV testing for all.

Imaging

• CT urography (best): papillary necrosis, parenchymal scarring, calyceal clubbing, cavities, cortical thinning, hydronephrosis, calcifications (punctate, curvilinear, or "putty kidney"), thickened renal pelvis, ureteric strictures (multiple, beaded "corkscrew" or "pipe-stem" ureter), thick-walled shrunken bladder (thimble bladder), and genital lesions.
• Intravenous urography (classical, now less used): "moth-eaten" calyces, "ragged" papillae, amputated calyces, infundibular stenosis, and "golf-hole" ureteric orifice.
• Ultrasound: hydronephrosis, mass lesions, epididymal enlargement with heterogeneous echo, bladder wall thickening.
• Chest radiograph (pulmonary involvement), abdominal radiograph (calcification in 50% of renal TB), MRI for pelvic disease, and hysterosalpingography (beaded tubes, rigid pipe-stem tubes, "cobblestone" appearance, intrauterine adhesions) in female infertility (caution in active disease).
• Cystoscopy with bladder biopsy: hyperaemic, ulcerated mucosa, tubercles, golf-hole ureteric orifice, and reduced capacity.
• Laparoscopy and hysteroscopy for female genital TB, with endometrial biopsy (granulomas, caseation, AFB, PCR).

Histology: caseating granulomas with Langhans giant cells and AFB on biopsy of kidney, bladder, epididymis, endometrium or other.

Other: renal function, electrolytes, calcium (hypercalcaemia can occur), HbA1c, HIV serology, liver tests (baseline for therapy), and renography for split function.

Medical therapy (the cornerstone)

• Standard 6-month regimen for drug-susceptible disease (the same as pulmonary): isoniazid 5 mg/kg (maximum 300 mg), rifampicin 10 mg/kg (maximum 600 mg), pyrazinamide 25 mg/kg (maximum 2 g) and ethambutol 15 mg/kg for 2 months (intensive phase), followed by isoniazid and rifampicin for 4 months (continuation phase). Fixed-dose combinations are used for adherence. Some experts extend to 9 to 12 months for severe disease.
• Add pyridoxine 10 to 50 mg daily (25 to 50 mg in diabetes, pregnancy, HIV, renal failure, alcoholism).
• Dose adjustment in renal impairment: isoniazid and rifampicin unchanged, pyrazinamide and ethambutol dosed three times weekly (25 mg/kg and 15 to 25 mg/kg respectively) for creatinine clearance below 30 mL/min or dialysis (give after dialysis).
• Monitoring: baseline and monthly liver function for the first 2 to 3 months, creatinine, uric acid, visual acuity and colour vision (ethambutol), and adherence (directly observed therapy). Stop drugs and manage hepatotoxicity if ALT is over 5 times the upper limit of normal (or 3 times with symptoms), and reintroduce stepwise.
• Rifampicin interactions: oral contraceptives (use non-hormonal contraception), warfarin, calcineurin inhibitors, antiretrovirals, anticonvulsants, and others.
• Drug-resistant disease: guided by susceptibility testing. Multidrug-resistant tuberculosis regimens (bedaquiline, pretomanid, linezolid for 6 months, moxifloxacin).
• Steroids: prednisolone 20 to 40 mg daily tapered over 4 to 6 weeks at the start of therapy to reduce risk of ureteric stricture formation, for ureteric stenosis and when there is evidence of early strictures (evidence is limited).
• HIV co-infection: start anti-tuberculosis therapy first, antiretroviral therapy within 2 weeks if CD4 below 50 and within 8 weeks otherwise, with attention to drug interactions (dolutegravir 50 mg twice daily with rifampicin).

Surgical management

• Aim to preserve renal function and manage complications, after at least 2 to 4 weeks of antituberculous drugs (sometimes earlier for emergencies).
• Relief of obstruction: double J stent placement or percutaneous nephrostomy for hydronephrosis with renal impairment or infection, as part of treatment. Ureteric strictures that persist after chemotherapy are treated with balloon dilatation (with high recurrence), reimplantation (ureteroneocystostomy with psoas hitch or Boari flap) for lower strictures, ureteroureterostomy, ileal interposition, or autotransplantation.
• Nephrectomy: non-functioning (differential function under 10%), calcified, infected kidney, or uncontrolled hypertension, or when malignancy cannot be excluded (done after 4 to 6 weeks of therapy).
• Partial nephrectomy for localised disease and cavities after incomplete chemotherapy response (rare).
• Contracted bladder: augmentation cystoplasty (ileocystoplasty, caecocystoplasty) after 6 months of therapy, when the bladder capacity is below 100 mL and disease is inactive. Urinary diversion if the urethra or sphincter is involved.
• Epididymo-orchitis and scrotal abscess: epididymectomy or orchidectomy for abscess, sinus or poor response.
• Drainage of cold abscesses, and drainage or excision of tubo-ovarian abscesses.
• Female genital TB: medical therapy for 6 months, hysteroscopic adhesiolysis and tubal surgery in selected cases, and assisted reproduction (IVF with embryo transfer) because tubal disease is usually irreversible, and endometrial damage limits success (success rates are low in endometrial involvement).

Follow-up

• Monthly clinical review, early morning urine cultures at the end of the intensive phase, at the end of treatment, and annually for 2 to 3 years (relapse risk). Repeat imaging at 3 to 6 months (ultrasound or CT) to detect strictures and hydronephrosis, which can develop or progress during therapy, and renal function monitoring.
• Treat latent tuberculosis in contacts and in immunosuppressed patients. Contact tracing.
• Prevention: BCG vaccination in endemic areas, screening of high-risk groups, isoniazid preventive therapy in HIV, and careful use of intravesical BCG with monitoring for complications (BCG infection treated with isoniazid, rifampicin and ethambutol for 6 months).

Prognosis

• Cure rates exceed 90% for drug-susceptible disease with timely therapy. Early diagnosis preserves renal function. Delayed diagnosis leads to loss of function, ESRD (in up to 10%), and sterility.