Tuberculosis prophylaxis for the chronically dialysed patient—yes or no?

Asher Korzets and Uzi Gafter

Nephrology Department, Rabin Medical Center, Campus Golda, Petah Tikva, Israel

Correspondence and offprint requests to: Uzi Gafter, Nephrology Department, Rabin Medical Center, Campus Golda, Petah Tikva, Israel.

One in every three people in the world is infected with Mycobacterium tuberculosis, and observed rates of new TB infection are on the increase, especially in the third world [13]. In the `rich' countries, latent TB can be reactivated in a number of `high-risk' patient populations such as AIDS, silicosis, immunosuppression, malnutrition and end-stage renal failure [13]. Worldwide TB infection in dialysis patients ranges from 5–25% [4]. Over 40% of dialysed patients with TB have extrapulmonary manifestations of the disease, and this makes the disease difficult to diagnose, causing delay in commencing curative therapy [4]. For these reasons, TB prophylaxis in chronically dialysed patients is worthy of consideration, especially as isoniazid (INH) prophylaxis effectively reduces reactivation of latent TB for prolonged periods of time. At the same time, it increases overall survival in AIDS patients, another `high-risk' population [5,6]. Unfortunately, only one study has addressed this issue in dialysed patients [7]. In that study, conducted in southern India, 184 haemodialysis patients entered a double-blind, randomized trial of INH prophylaxis. A `trend towards protection from TB' was demonstrated [7]. Therefore, a number of questions still need to be answered. What drug should be given for prophylaxis? What are the possible benefits and complications of such therapy? And finally, which dialysis patients should receive TB prophylaxis?

With what drug should prophylaxis be undertaken?

The drug of choice is isoniazid. It has excellent oral absorption; achieves widespread tissue concentrations far above the MIC needed against M. tuberculosis; it is bactericidal; has a post antibiotic effect and can be given once every 2–3 days; there is no need for dose reduction in patients with impaired renal function and it is cheap [8].

The effectiveness of INH in preventing TB is unquestionable. At least 50–60% of treated patients will enjoy long-term protection from TB after a 6-month period of therapy, and some argue that if the patient is completely compliant, then protection rises to 90% [9,10]. Salpeter et al. also argue that INH prophlaxis, for all low-risk tuberculin skin test reactors older than 35 years of age, will prevent thousands of TB-related deaths [11]. Therefore, why not give INH prophylaxis to all `high-risk' dialysis patients? The reasons not to treat with INH include, treatment failure because of non-compliance, hepatic and neurological toxicity, and the danger of M. tuberculosis resistance to INH. Let us try to deal with each problem separately.

Non-compliance is a problem, but one that should not dissuade nephrologists from attempting therapy in all patients who warrant commencement of INH. Secondly, INH prophylaxis is successful, if the drug is taken under supervision, on a twice or thrice weekly basis (15 mg/kg/dose), a perfect solution for haemodialysis patients [2,5].

Hepatotoxicity remains the major problem associated with INH administration, especially in the elderly, the malnourished and in the alcoholic [2,12]. It generally occurs within the first 4–8 weeks of therapy, but in 20% of patients minor and asymptomatic elevation of hepatic enzymes elevations occur, which is transient and does not necessitate cessation of INH treatment [2]. When transaminase levels increase to 2–3 times above normal, then INH must be stopped. But what of fatal INH-induced hepatitis? In 1996, after monthly liver function monitoring had become the accepted norm, Millard showed that, irrespective of age, the rate of fatal hepatitis is 1–2/100000 treated patients [13]. Also, McGlynn et al. failed to show a greater degree of INH hepatotoxicity in hepatitis B carriers [14]. This observation may be relevant for dialysis patients who are infected with the hepatitis B virus.

Nervous system side-effects have been documented in dialysis patients treated with INH [15]. Isoniazid inhibits phosphorylation of pyridoxine, and this leads to a reduced production of pyridoxal-5-phosphate, a co-enzyme essential in neurotransmission. In dialysis patients, serum pyridoxine levels are normal, but pyridoxine metabolism is not; and the addition of INH therapy makes these patients vulnerable to neurological toxicity. Fortunately, this problem is completely and easily avoidable by concurrent administration of INH and vitamin B6 (100 mg/day) [15].

For persons possibly infected with TB resistant to INH, various alternative therapies have been used [2]. Monotherapy with rifampin is effective, and if maintained for 6 months has a low incidence of side effects [16]. Another drug protocol currently under investigation is combined rifampin and pyrazinamide, with a duration of therapy lasting only 2 months [12].

Which dialysed patients warrant prophylaxis?

Today, any patient with a positive Mantoux skin test (5 U purified protein derivative of tuberculin-a sterile killed concentrate obtained from human tubercle bacilli) should be considered to be infected with M. tuberculosis, even if they have previously received BCG vaccine [9,17]. An indurated area of at least 10 mm, 48–72 h after intradermal injection, is positive in non-AIDS infected, dialysed patients; while in persons with X-ray findings consistent with healed tuberculosis or who have been in close contact with patients known to be infected with pulmonary TB, then an indurated area of 5 mm is regarded as positive [9]. If chronically dialysed patients are regarded at `high risk' for reactivation of latent TB, then one may be tempted to treat all dialysis patients with a positive tuberculin skin test. At the very least, any dialysed patient with a positive tuberculin skin test and who lives or has migrated from an endemic area, has had close contact with any patient with active pulmonary TB, is a recent tuberculin test convertor or has a X-ray suggestive of old TB, should receive prophylaxis. Just recently, Woeltje et al. advised regular tuberculin skin testing and encouraged isoniazid prophylaxis in haemodialysed patients [3].

Uraemia impairs cell mediated immunity and is known to cause anergy. When a high index of suspicion for TB exists, but the skin test is negative, then it should be repeated with a 250 U dose. If this high dose skin test is negative, then skin tests with other antigens should be performed. A negative reaction to these tests indicate an anergic state [9]. Furthermore, false negative results on tuberculin skin testing can be caused by faulty test administration or interpretation, corticosteroid therapy, malnutrition, acute viral disease, Candida infection or overwhelming tuberculosis. But recent studies have demonstrated that properly performed, multiple skin tests will be positive in over 60% of dialysed patients [3]. Therefore the old adage of `most dialysis patients are anergic' is simply not true. Anergic AIDS patients develop overt TB infection rarely, and controversy exists as to whether INH prophylaxis is justified in them [5,18]. Can the same be said of anergic, dialysed patients? We do not know, but if dialysis patients have a `true negative' tuberculin skin test and no other risk factors associated with reactivation of TB, then they, most probably, should not be treated.

In conclusion, routine tuberculin skin testing should be performed in all patients as they enter a chronic dialysis programme. The test must be interpreted by an experienced nurse, and areas of induration documented, without recording the result as either simply `positive' or `negative'. Secondly, INH prophylaxis is cost effective in other `high-risk' populations. It prevents hospitalizations, eliminates a possible need for multidrug therapy for active TB at a future date, and reduces mortality [2,6]. Also, if a patient is successfully treated with prophylaxis, then that patient will not become ill with the disease in the future, and will not be able to pass it on to others [2]. Therefore there are good reasons for TB prophylaxis to be given to chronically dialysed patients with a positive tuberculin skin test, especially as most adverse effects associated with INH can be prevented. This policy was recommended by the Advisory Council for the elimination of Tuberculosis [19]. A 6-month course of INH prophylaxis is beneficial in all cohort groups of patients, and therefore only in the very old or those with severe comorbid disease with a limited life expectancy, should the decision be made individually `to give or not to give' this therapy.

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