Correspondence *Rua Irineu Marinho 365, apto 801–bloco 3, Bom Pastor–Juiz de Fora, Minas Gerais 36021-580, Brazil

Email andreavaresef@gmail.com

The case

A 38-year-old man presented to hospital with a 3-month history of fevers, bilateral lumbar pain, dysuria and increased urinary frequency. The patient had previously been an intravenous drug user. Six years before presentation he had been diagnosed with pulmonary tuberculosis, for which he had been successfully treated with a 6-month course of isoniazid (400 mg per day) and rifampin (600 mg per day), plus pyrazinamide (2,000 mg per day) for the first 2 months. Sputum culture for Mycobacterium tuberculosis was negative at 2 months and at the end of treatment. AIDS had also been diagnosed at this time. He was receiving antiretroviral therapy with a combination of one non-nucleoside reverse-transcriptase inhibitor (efavirenz, 600 mg per day) and two nucleoside reverse-transcriptase inhibitors (stavudine 40 mg twice-daily and lamivudine 300 mg per day). At presentation, his AIDS was clinically stable, with undetectable HIV viral load (by polymerase chain reaction evaluation of HIV RNA copies) and a stable CD4 count of 185 cells/mm³ (normal range 500–1,500 cells/mm³).

The patient was admitted to hospital for investigation. Physical examination was unremarkable and revealed no tenderness of the abdomen. His serum hemoglobin concentration was 10.2 g/l (normal range 12.0–18.0 g/l) and his white blood cell count was 3,000 cells/ml (normal range 5,000–10,000 cells/ml). His serum electrolyte levels and the results of liver function and coagulation studies were normal. Urinalysis showed 35,000 leukocytes/ml (normal <10,000 leukocytes/ml) and urine culture was positive for Escherichia coli. The direct smear for M. tuberculosis was negative and urine culture for this pathogen was started. Chest radiography was normal and abdominal CT revealed enlarged retroperitoneal lymph nodes with central necrosis and multiple hypodense areas in both kidneys, consistent with renal abscesses (Figure 1A). The right kidney also exhibited dilatation of the collecting system and renal parenchymal atrophy in the upper pole (Figure 1B). The patient's serum creatinine concentration was 1.0 mg/dl (88.4 mol/l; normal range 0.6–1.2 mg/dl [53.0–106.1 mol/l]). He was started on antibiotic therapy with ceftriaxone (1,000 mg twice-daily) and oxacillin (1,000 mg four times per day) for presumed bacterial infection.

Figure 1 Abdominal CT of the patient before treatment.

(A) Imaging revealed bilateral and multiple hypodense kidney areas consistent with renal abscesses and enlarged retroperitoneal lymph nodes with central necrosis (arrow). (B) The right kidney exhibited collecting system dilatation and renal parenchymal atrophy in the upper pole. The left kidney exhibited parenchymal abscesses.

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One month after the initiation of antibiotic therapy, the patient remained in hospital. His fevers and urinary symptoms had not improved, and ultrasonography showed no change in his renal abscesses. Urinalysis showed a persistent elevated leukocyte count (>30,000 leukocytes/ml) but urine culture was negative for usual pathogens. The patient's urine culture for M. tuberculosis, started at initial examination, was positive, and pharmacological treatment for tuberculosis was initiated, consisting of isoniazid 400 mg, rifampin 600 mg, pyrazinamide 2,000 mg and ethambutol 1,200 mg daily for 2 months, with isoniazid and rifampin continued for a further 7 months; the patient's antiretroviral therapy was not adjusted. His symptoms improved after a few days of treatment, with resolution of fever and gradual improvement of urinary symptoms.

After 6 months of treatment, CT revealed a nonfunctioning right kidney, with dilatation of the collecting system and diffuse renal parenchymal atrophy, and a functional left kidney with areas of scarring (Figure 2). The patient's serum creatinine concentration was elevated at 1.9 mg/dl (168.0 mol/l) and his estimated creatinine clearance was 42 ml/min/1.73m² (normal >60 ml/min/1.73m²). The patient refused right nephrectomy and completed his 9-month antituberculosis treatment regimen without any toxic complications. Over a follow-up period of 2 years, he showed no disease recurrence or urinary symptoms. Annual urine culture for M. tuberculosis was negative, his renal function remained stable and annual abdominal ultrasonography showed no further renal changes. The patient had been advised of the risk of tuberculosis recurrence, but was lost to follow-up after 2 years.

Figure 2 Abdominal CT of the patient after treatment.

The right kidney is nonfunctional with collecting system dilatation and diffuse renal parenchymal atrophy. The left kidney shows areas of scarring.

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Discussion of Diagnosis

Around 30% of the world population (1.7 billion people) is estimated to harbor M. tuberculosis infection. The WHO reports around 8 million new cases and 2 million deaths per year, 95% of which occur in developing countries. The spread of HIV is the main factor underlying the resurgence of tuberculosis in the past three decades. AIDS-related immunosuppression can reactivate latent tuberculosis infection or promote rapid progression of newly acquired infection.^{1, 2}

Urogenital tuberculosis occurs in 8–15% of patients with pulmonary tuberculosis.³ It affects more men than women (2:1) at a mean age of around 40 years and has an insidious onset, with urinary symptoms (usually storage symptoms) developing in more-advanced disease.^{4, 5, 6, 7} AIDS infection increases the risk of bacillemia and extrapulmonary tuberculosis,^{1, 2} which might lead to an increased incidence of urogenital tuberculosis in patients with AIDS. In fact, of patients with urogenital tuberculosis, an impressive two-thirds had concomitant AIDS in one US inner-city hospital in 2000.⁸

The diagnosis of urogenital tuberculosis is made by identification of M. tuberculosis bacillus in urine, by histopathology or on the basis of clinical and radiographic evidence. Identification of the tuberculosis bacillus in the urine can be achieved with direct smears (Ziehl–Neelsen stain) or urine culture (Lowenstein–Jensen medium).^{9, 10} The former technique is quick (same-day results), with 96.7% specificity, but only 42.1–52.1% sensitivity.^{9, 10} In the current patient, a negative direct smear necessitated urine culture, which is the diagnostic gold standard for urogenital tuberculosis. As bacilluria is sporadic and faint in urogenital tuberculosis, three to six early-morning, mid-stream samples are required. Reported sensitivity varies widely, from 10% to 90%, and the time to detection of Mycobacterium growth might be as long as 6 weeks.^{3, 9, 10, 11} Faster culture has been achieved with nonradiometric automated or semi-automated liquid culture systems, with results available in 14–17 days.¹¹

Nucleic acid amplification tests for the identification of M. tuberculosis in the urine might become the optimum diagnostic tool, as the results are available within 48 h and the diagnosis can be made even when few bacilli are present in the urine.^{9, 10} These tests have shown relatively high sensitivity and specificity in comparisons with the results of urine culture⁹ and bacteriological, histological or clinicoradiological diagnoses.¹⁰ In one systematic review, however, nine nucleic acid amplification tests showed high specificity but variable sensitivity for urogenital tuberculosis. Although these techniques have a potential diagnostic role, no evidence yet supports their use without accompanying urine culture.¹¹

Some findings on urinalysis, such as sterile leukocyturia and hematuria, are suggestive of urogenital tuberculosis, and these can be present in up to 93% of patients.^{4, 5, 11} The absence of these findings should not, however, exclude urogenital tuberculosis, as they can be seen in as few as 22% of infected patients.⁴ If there is clinical suspicion of tuberculosis but urine culture is negative, cystoscopy with bladder biopsy can be performed. This technique is 18.5–52.0% sensitive for tuberculosis infection, and is most useful in the acute phase.^{9, 10} Nevertheless, in 10% of patients with urogenital tuberculosis, the diagnosis is presumptive and made on the basis of suggestive clinical, laboratory and radiological data, without microbiological or histological confirmation.^{4, 5, 6, 7}

With regard to the pathophysiology of urogenital tuberculosis, after hematogenic spread from pulmonary foci, initial renal lesions are cortical and bilateral, but asymptomatic and without radiographic alterations. After a latent period averaging 22 years (range 1–46 years), a single latent focus in one kidney is reactivated and the infection progresses to collecting-system stricture and hydronephrosis.¹² The most common radiographic sign of renal tuberculosis (on CT or intravenous urography) is, therefore, unilateral hydronephrosis caused by intrarenal or ureteral stricture. In more-advanced cases, a contracted bladder with bilateral hydronephrosis resulting from collecting-system stricture in one kidney and vesicoureteral reflux in the other can be found. The earliest finding is caliceal dilatation caused by infundibular stenosis.^{4, 5, 6, 7, 10} In the context of immunosuppression, the initial hematogenic dissemination phase is exacerbated and systemic symptoms and visceral abscess formation (kidney or prostate) can occur, resulting in unusual clinical and radiographic findings.¹³ The current patient presented with multiple, bilateral renal lesions with predominantly parenchymal involvement, which is not typical of urogenital tuberculosis presentation, but is instead related to systemic exacerbation of bacillemia.

The unusual clinical and radiological findings in patients with AIDS and tuberculosis can make the diagnosis difficult. For patients with tuberculosis, HIV-positive individuals are younger than HIV-negative individuals, and they present more often with fever, fatigue, bacteremia, diffuse pulmonary disease, lymph node disease and disseminated tuberculosis with abdominal visceral disease.^{1, 2} Nzerue et al.⁸ showed that, compared with patients without AIDS, those with AIDS presented with urogenital tuberculosis at a younger age, but with the same symptoms and mortality rates. Despite similar clinical presentations, however, radiological findings differed between the two groups. HIV-positive patients showed lymph node enlargement, diffuse kidney nodular granuloma, diffuse renal calcification, and perinephric and splenic abscess.⁸ In general, patients with AIDS are more prone to kidney and prostate abscesses than are patients without AIDS.¹³

Other conditions in an HIV-positive patient that present as fever and multiple bilateral hypodense kidney masses include infections with kidney abscess formation, and lymphoma. Patients with AIDS are extraordinarily susceptible to opportunistic infection, and can present with unusual clinical and radiological manifestations of infectious diseases, especially if they have a CD4 count below 200 cells/mm³.^{2, 8, 13} Kidney abscesses can be caused by usual bacterial infection (e.g. Staphylococcus aureus or Gram-negative bacilli), tuberculosis and atypical mycobacteria, and by mycotic infection, such as aspergillosis and candidiasis.¹⁴ As in the current patient, urine culture can yield usual pathogens in 20–40% of urogenital tuberculosis cases in men, and in up to 50% in women.⁵ The misdiagnosis of isolated usual urinary tract infection can delay the diagnosis of tuberculosis. A urine culture positive for usual pathogens should, therefore, not exclude urogenital tuberculosis.

AIDS-related lymphomas are usually highly aggressive B-cell lymphomas, and involve the kidney in 6–12% of cases. Radiological findings associated with renal involvement include bilateral parenchymal masses, rather than the diffuse nephromegaly found in HIV-negative patients.¹⁴ In cases such as the present one, therefore, a correct differential diagnosis is essential, and the best way to achieve this is by percutaneous kidney biopsy and abscess aspiration for microscopic examination and culture. Percutaneous renal-mass biopsy with two or three cores guided by ultrasonography, CT or MRI has shown high accuracy, and low failure and complication rates.¹⁵ In the present case, tuberculosis was suspected on the basis of the patient's history and radiographic findings, which were typical of AIDS-related abdominal tuberculosis;² however, the time taken to obtain results of urine culture for M. tuberculosis, the unusual radiographic presentation and the misdiagnosis of isolated usual urinary tract infection delayed the initiation of appropriate therapy. Percutaneous kidney biopsy with abscess aspiration and nucleic acid amplification tests for M. tuberculosis in the urine would have resulted in a quicker diagnosis, with earlier exclusion of lymphoma.

Treatment and Management

Antituberculosis chemotherapy remains the mainstay of treatment for urogenital tuberculosis. An initial 2-month period of daily isoniazid, rifampin, pyrazinamide and eventually ethambutol is followed by a 4-month or 7-month period of daily or twice-weekly isoniazid and rifampin. After 2 weeks of treatment, no bacilli can be identified in the urine.³ Although the optimum treatment duration for urogenital tuberculosis has not been defined, shorter treatments have replaced the traditional 18-month and 24-month regimens that were initially recommended.⁶ Relapse rates lower than 1% have been achieved with 4–5 months' treatment coupled with nephrectomy of the nonfunctional kidney.⁶ Malnutrition and poor social conditions, however, warrant treatment for at least 9 months, as relapse rates can be as high as 22% after a 6-month treatment and 19% after a 1-year treatment in developing countries.^{5, 7} Pharmacological treatment can cause worsening of collecting-system stricture with sometimes inevitable loss of kidney function,¹⁶ as occurred in the current patient. In some cases of isolated ureteral stricture, this sequela can be avoided by urinary diversion with nephrostomy or a double-J catheter.

Current guidelines recommend that AIDS patients with tuberculosis receive the same standard, short-course therapy as HIV-negative patients.² A minimum of 9 months' treatment is recommended, however, as a result of the higher rates of relapse associated with shorter regimens.^{2, 3} Importantly, antiretroviral therapy complicates the management of tuberculosis. Almost all antiretroviral drugs have the potential for hepatotoxicity, as do isoniazid, rifampin and pyrazinamide, and clinical and laboratory monitoring of patients receiving these therapies is advised.^{2, 17} Rifamycins, essential drugs for antituberculosis therapy, induce the activity of cytochrome P-450, which lowers the concentration of protease inhibitors and non-nucleoside reverse-transcriptase inhibitors to subtherapeutic levels and might cause incomplete viral suppression and the emergence of drug resistance.² Despite this drug interaction, however, a rifamycin should be included in tuberculosis treatment for patients receiving antiretroviral therapy, with dose adjustment performed as necessary. Rifabutin is the preferred choice because of its relatively low risk of drug interaction, but rifampin can be safely used in conjunction with efavirenz, a non-nucleoside reverse-transcriptase inhibitor, with no need for dose adjustment.¹⁷ The combination of an efavirenz-based antiretroviral regimen with an antituberculosis regimen including rifampin, as used in the present case, has become the therapy of choice for AIDS patients with tuberculosis.¹⁷

In cases of a unilateral tuberculous nonfunctioning kidney, most authors recommend nephrectomy to avoid relapse, eliminate storage symptoms, treat hypertension, and avoid abscess formation.¹⁶ Relapse is more likely when a nonfunctional kidney is not removed, because the pharmacological treatment might not sterilize all tuberculosis foci. Viable bacilli have been identified in the kidneys after 8 weeks, and even 9 months, of antituberculosis treatment.¹⁶ Conversely, after following 35 patients for up to 22 years, without any observed complications, Bloom et al.¹⁸ recommend kidney preservation if the patient has no pain, infection or bleeding. Patients with AIDS and previous tuberculosis progress to active disease at a rate 10 times greater than those without AIDS and, although there is little supporting data in the literature, nephrectomy of the nonfunctioning kidney can be advised in these patients.^{1, 19} The current patient's decision to refuse nephrectomy put him at high risk of relapse. In such cases, the patient and AIDS physician must be aware of this increased risk, and active surveillance for relapse, as detailed below, is important.

Microbiological relapse of urogenital tuberculosis can occur after initial urine sterilization, even after prolonged pharmacological treatment and nephrectomy of the nonfunctional kidney.^{5, 16} Relapse occurs in up to 6.3% of cases, after a mean treatment duration of 5.3 years (range 11 months to 27 years), with bacilli that were sensitive to the drugs initially used.^{7, 20} Most authors recommend annual urine culture and a 10-year follow-up after pharmacological treatment because of late relapse and the benefits of early treatment of initial lesions in the asymptomatic phase of relapse.^{5, 16, 20} As relapses usually occur with a susceptible organism, the standard four-drug regimen is appropriate in most cases.^{19, 20}

Conclusions

Urogenital tuberculosis in patients with AIDS will be seen more frequently in the coming years as a result of the growing AIDS epidemic, decreasing AIDS-specific mortality rates and the AIDS–tuberculosis association. Tuberculosis in patients with AIDS resembles a systemic bacterial infection with fever, bacteremia and metastatic seeding in visceral organs with abscess formation. As in the present case, urogenital tuberculosis in patients with AIDS can present with unusual clinical and radiological features, making the diagnosis difficult. HIV-negative individuals with urogenital tuberculosis usually show unilateral kidney tuberculosis with hydronephrosis secondary to collecting-system stricture, and an insidious onset. By contrast, the current patient presented with fever, multiple bilateral kidney abscesses and lymph node enlargement. This case highlights the diagnostic problems in immunocompromised patients.

Acknowledgments

Désirée Lie, 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-accredited continuing medical education activity associated with this article.

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