MYCOBACTERIAL INFECTIONS IN PATIENTS WITH CHRONIC RENAL DISEASE

INFECTIONS IN PATIENTS WITH CHRONIC RENAL FAILURE

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MYCOBACTERIAL INFECTIONS IN PATIENTS WITH CHRONIC RENAL DISEASE Francis D. Pien, MD, MPH, Barak G. Younoszai, DO, and Brian C. Pien, MD

Patients with chronic renal failure have impaired cell-mediated and humoral immunities (see article by Pesanti). These patients may have diabetes and autoimmune disease in addition to uremia. In the case of renal transplantation, patients are on immunosuppressive therapy. Mycobacterial infections have been described in patients with chronic renal failure undergoing hemodialysis, peritoneal dialysis, and after renal transplantation. MYCOBACTERIAL INFECTIONS IN PATIENTS UNDERGOING MAINTENANCE HEMODIALYSIS Tuberculosis Before 1974 only a few isolated cases of tuberculosis (TB) in patients undergoing maintenance hemodialysis were reported in the literature, and these reports did not suggest TB to be more prevalent in the renal dialysis population. In 1974 Pradhan et a197reported five cases among 136 patients, an incidence 16 times greater than that of the subgroup at next highest risk in New York City. Numerous subsequent publications

From the University of Hawaii, John A. Bums School of Medicine (FDP, BGY); Straub Clinic and Hospital (FDP), Honolulu, Hawaii; and Duke University Medical Center, Durham, North Carolina (BCP) INFECTIOUS DISEASE CLINICS OF NORTH AMERICA VOLUME 15 NUMBER 3 * SEPTEMBER 2001

851

852

PIEN et al

have confirmed that patients on hemodialysis have a greater risk of developing TB (Table 1).In geographic areas with a high general prevalence of TB, the incidence in patients with renal failure is very high, while the risk remains lower in hemodialysis populations from areas with low TB prevalence. Increased risk is not explained by transmission among patients undergoing hemodialysis during dialysis; rather, it appears that most active cases result from TB reactivation, since a highly disproportionate number of cases occur in foreign-born patients from endemic areas.6,18, 26, 67, Most patients develop active infection close to the initiation of hernodialysis when the uremic state is at its worst and associated immunity impairment is greatest (see Table 1).Garcia-Leoni et a136found most infected dialysis patients in Spain are asymptomatic. These findings suggest that in some geographic areas, silent infection may be prevalent enough to justify periodic TB screening for all patients on In patients without renal failure, TB primarily affects lung and pleura, involving extrapulmonary sites in only 10% to 20% of normal patients in North America.6,33, looAmong patients on hemodialysis, extrapulmonary involvement generally occurs in over half of all cases (see Table 1).In addition, although pulmonary and extrapulmonary TB often coexist, predominant or exclusive extrapulmonary disease has been reported in up to 56% of patients.'"'' Lymph nodes appear to be the most common extrapulmonary site, followed by pleural, peritoneal and hepatic disease; less common involvement includes meninges? 32,107 bone marrow,131knee joint,%and gastrointestinal tract.", 67, 71, '07 Miliary TB has been reported in up to 50% of patients,Io7but probably represents less than 15% of cases in most articles.26,7z,s5 Given the high frequency of extrapulmonary TB, it is not surprising that clinical presentation is often variable. Cough and hemoptysis, classic symptoms in patients without renal failure, are helpful when present but are infrequently reported among the population infected with TB and undergoing hemodialysis (mean 22% of cases; range 5% to 71%) (Table 2). Symptoms may instead mimic the uremic state. Malaise (mean 69%; range 29% to 100%) and weight loss (mean 54%; range 10% to 100%) may be the only symptoms, but fever of varying degree is usually present (mean 72%; range 2770 to 100%). Peritoneal and abdominal involvement can produce nonspecific abdominal complaints (mean 19%; range 0% to 50%). Because of the protean nature of symptoms, diagnosis is often difficult and delayed. Most case series had a mean delay of about 2 months with a range extending up to 20 months or even death. Because of frequent lymph node and peritoneal involvement, lymphadenopathy (mean 22%; range 12% to 20%), ascites, and hepatomegaly may be present. Peripheral leukocytosis may occur and sedimentation rate or C-reactive protein may be nonspecifically elevated. One study found polymerase chain reaction tuberculosis serologic testing of samples from sputum and pleural, peritoneal, synovial, and bone marrow aspirates to be 80% sensitive when compared to biopsy and culture specimens.87

w

12

10/172* (10 yr)

25 1.4

10.5

70 28 24 273

7/433 (13 yr)

6/102 (8 yr)

11/137* (2.5 yr)

7/25* (1 yr)

23/110 (12 yr) 23/1140 (3 yr)

36/40? (15 mo)

-

11

13

20/150 (5.5 yr)

2.5

20 39

2

10

6/885 (8 yr)

0

71

30 1

69 65 86

0

27.3

33.3

0

1.3

0

0

75

71

50

43

85

50

60

6-16

12/367 (10 yr)

37.5 88

- 1.4 (before dialysis began) 15

22

10

8/180 (3 yr)

20

40

92

17

15

5/136 (6 yr)

Mortality from TB (% Died)

Extrapulmonary Involvement (YOof Cases)

4.5

Average Duration of Dialysis Prior to Infection (mo)

'Indudes patients undergoing hernodialysis and peritoneal dialysis.

Rutsky et all" 1980, Alabama Malhotra et aln 1981, India Belcon et all1 1982, Ontario Leventhal et al" 1982, Israel Cuss et a P 1986, London M i t ~ a I l i *1991, ~ Saudi Arabia CengizlS1996, Turkey Ozdemir et alS71998, Turkey Oner-Eyuboglu et alS 1999, Turkey

Pradhan et alm1974, New York City Lundin et a l 7 I 1979, Brooklyn, NY Sasaki et allL"1979, Japan Andrew et a161980, San Francis0

Author Year, Location

CasedTotal Dlalysis Patients (Time Studied)

Incidence Relatlve to General Population ( X -fold)

Table 1. CHARACTERISTICS OF TUBERCULOSIS (TB) IN PATIENTS UNDERGOING HEMODIALYSIS

Pradhan et al” Lundin et aln Sasaki et allw Malhotra et a173 Belcon et all1 Leventhal et a16’ Cuss et a126 Mitwalli et alsl Cengiz et all8 Oner-Eyuoglu et a1-

Author

100 75

100 53

10 71 67 27 57 100 28

100

80

100

~

Weight Loss or Anorexia (No. Patients)

~

100 92 75 29 83 27

Fever (No. Patients)

~

~~~

~

~

58

100

45 29

-

71

-

100

-

Malaise or Weakness (No. Patients)

Table 2. SYMPTOMS OF TUBERCULOSIS IN PATIENTS UNDERGOING HEMODlALYSiS ~

-

14 33 0 19

10

20 50 -

Abdominal Symptoms (No. Patients)

42 8

-

20 25 5 71

Cough or Hemoptysis (No. Patients)

MYCOBACTERIALINFECTIONS IN PATIENTS WITH CHRONIC RENAL DISEASE

855

Impairments in cell-mediated immunity are likely responsible for infrequent positive purified protein derivative (PPD) skin tests (mean 27%; range 0% to 63%). Chest roentgenograms often show abnormalities (mean 54%; range 17% to SO%), but may represent old scarring, pleural effusions, infiltrates atypical for TB or other nonspecific findings. Pleural effusions in patients with active infection sometimes have positive acidfast bacilli sputum smears (mean 20%; range 3% to 40%) or cultures. Ascitic fluid analysis similarly can be helpful. The best diagnostic yield comes from tissue biopsies, including pleura, peritoneal, and lymph nodes. The presence of positive acid-fast bacilli smears, positive cultures, or granulomas confirms the diagnosis in the majority of cases. In some patients, organisms are not isolated and diagnosis is made upon response to therapy or a~topsy.6~ In earlier reports (see Table l), mortality from TB was relatively high. Deaths were often attributed to delayed diagnosis and treatment and advanced cases of miliary TB. With increased awareness, mortality is less common and often confined to cases of disseminated TB.

Mycobacterial Infections Other than TB (MOTT)

There have been a few case reports of mycobacterial infections other than TB (MOTT) in patients undergoing hemodialysis.12,'04Of special note is an outbreak of Mycobacterium chelonei subsp abscessus in a Louisiana dialysis unit in 1982 related to reprocessed hemodialyzers.12 Fourteen patients had bacteremia alone, three developed soft tissue infections, and nine developed disseminated disease. Overall mortality was >So%, including 33% in those receiving antimicrobial therapy for M chehei. Environmental sampling of the water treatment system showed nontuberculous mycobacterial contamination in 5 of 31 hemodialyzers that were ready for use. Formaldehyde concentration was <2% in two of three contaminated dialyzers tested. This outbreak required disinfection of water treatment systems with 2 2 % formaldehyde for 48 hours and discontinuation of hemodialyzer reuse. Other studies have found 2% formaldehyde to be insufficient and recommended the use of 4% formaldehyde for 24 hours at 22" to 25OC.I6

MYCOBACTERIAL INFECTIONS IN PATIENTS UNDERGOING PERITONEAL DIALYSIS

Although technical advances in peritoneal dialysis have decreased the incidence of peritonitis, infection remains a significant cause of morbidity. Mycobacterial infections account for <3% of peritoneal dialysis peritonitis cases'"; therefore, the clinician must be alert to order appropriate diagnostic tests and institute prompt treatment.

856

PIENetal

Tuberculosis Although not as common as other bacteria or fungi, TB can cause peritoneal dialysis-associated peritonitis and presents a difficult diagnosis.l18 Patients undergoing peritoneal dialysis are similar to patients on hemodialysis in that they are at higher risk of TB because of reactivation. The diagnosis of TB should be suspected in any patient on peritoneal dialysis with culture-negative peritonitis or in a patient with proven bacterial peritonitis not responding to appropriate antimicrobial therapy, since bacterial coinfection rate with TB has been reported as high as 28y0.51,118 According to Mallat et al,74fever and abdominal pain are present in virtually all cases of TB peritonitis; however, Cheng et a12"found cloudy dialysate to be the most common finding. In their review of 18 cases, only 2 cases (11%)had lymphocytic predominance in peritoneal fluid, possibly caused by deficient cell-mediated immunity. Peritoneal fluid neutrophilic predominance is confirmed by other reports.'", 47, 51 In addition, Hsu et a15z described one tuberculosis patient who developed peritoneal fluid eosinophilia of 54%to 85%.Given that coexistent pulmonary infection is uncommon, chest radiography is often not helpful for the diagnosis of TB peritonitis. Gallium scans are often normal, being positive in only two of five patients in one reportzoand none of three infected patients in another studyY Only 48% of TB peritonitis patients had a positive PPD skin test and 54% had positive peritoneal fluid cultures for Mycobucterium tubercuZosis.'18 Yap et all3*described one patient in which tuberculous peritonitis was diagnosed by polymerase chain reaction analysis on peritoneal fluid. In 21% of cases, diagnosis was made by early laparotomy and bi0psy.4~. 86* 118 Whereas removal of the peritoneal dialysis catheter seems necessary, some authors have reported successful treatment of peritoneal TB without catheter removal or interruption of peritoneal dialysis. The first documented case of uncomplicated treatment and continuation of peritoneal dialysis was reported in 1989 and involved a patient treated with two antituberculous medications for 1 year.74This patient remained on peritoneal dialysis with negative dialysate cultures for 15 months after completion of treatment, but was eventually switched to hemodialysis because of poor ultrafiltration as a possible late consequence of infection. In another report that year, three of five patients undergoing peritoneal dialysis with TB peritonitis were successfully maintained on peritoneal dialysis2";peritoneal clearance and ultrafiltration capacity remained unchanged for up to 16 months in two of these patients, but was reduced by 30% and 50%, respectively, in the third patient. Therapy was initiated in all three patients within 5 weeks of symptom onset, while patients who failed to maintain peritoneal dialysis received anti-TB treatment much later. Baumgartner et all" treated an HN-positive patient infected with TB on peritonitis without catheter removal. Tan et aP9subsequently reported three more patients treated without catheter removal. Although two of these patients had unrelated complications eventually terminating

MYCOBACTERIAL INFECTIONS IN PATIENTS WITH CHRONIC RENAL DISEASE

857

peritoneal dialysis, all three patients were treated successfully without removing the peritoneal dialysis catheter for at least 7 months after initiation of treatment. Lui et a170 recently reported 10 cases of TB peritonitis in Hong Kong from among 601 total peritoneal dialysis patients between 1988 and 1994. Most presented with abdominal pain, fever, and cloudy peritoneal fluid; two had concurrent bacterial peritonitis. None developed extraperitoneal TB. The majority had neutrophilic predominance in their peritoneal fluid. Only one case had a positive acid-fast bacilli peritoneal fluid smear, but all peritoneal fluid cultures eventually grew TB. All 10 patients could be continued on peritoneal dialysis, but 4 eventually were converted to hemodialysis at 3 months because of ultrafiltration failure or bacterial peritonitis. The rest continued to receive peritoneal dialysis without removal of their Tenckhoff catheters. This Hong Kong study had no direct deaths caused by TB peritonitis. Based on these limited data, continuation of peritoneal dialysis seems possible, especially if TB peritonitis is diagnosed and treated early. Talwani and Horvath1l8 reviewed 52 cases of peritoneal TB in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) with a direct mortality of 15% primarily caused by delayed diagnosis. These authors found that in 28 cases peritoneal dialysis could be continued in spite of their infection. Mycobacterial Infections Other than TB (MOTT)

Most mycobacterial infections in peritoneal dialysis patients are not due to M tuberculosis, but instead are caused by MOTT, which have been shown to contaminate water sources at 83% of randomly selected hemodialysis centers within the United States.16The infecting organisms are usually members of Runyon group IV (rapid growers), especially Mycobacteriurn fortuiturn and M c h e l ~ n e i .98, ~ 126 ~ , A few cases of Mycobacteriurn aviurn-intracellulare, Mycobacteriurn gastri, Mycobacteriurn kansasii, Mycobacteriurn gordonae, and Mycobacteriurn xenopi also have been reported.27,37, 43,45,69,98,lo9, lZ6Infections have involved catheter exit sites and caused generalized peritonitis and intraabdominal abscesses. Symptoms of MOlT peritonitis are similar to peritonitis of other microbial causes and include cloudy dialysate, abdominal pain and fever. Peripheral leukocytosis is sometimes present. White blood cell differential of peritoneal fluid usually shows neutrophilic predominance, occasionally followed in time by lymphocytosis. On Gram stain, MOTT appears similar to and is often mistaken for diphtheroids or particle contaminants. The primary isolation of Runyon group lV mycobacteria can require anywhere from 2 to 20 days on ordinary culture media.*26 Acid-fast bacilli smears are sometimes helpful, but they require large numbers of MOTT. Cultures offer definitive diagnosis but can take as long as 2 to 3 weeks with automated mycobacterial culture systems. In all cases of culture-negative peritonitis in peritoneal dialysis patients, MOTT should be suspected.

858

PIENetal

Band et a16 from the Centers for Disease Control reported two serious outbreaks of peritonitis caused by an organism similar to M cheZonei. In one peritoneal dialysis center, 5 of 22 patients developed peritonitis over a 1-month period from a single contaminated dialysis machine. In a second center, five of eight patients became infected, apparently as a result of cross-infection from contaminated machines. Seven additional cases of peritonitis also connected to these centers occurred. In their epidemiologic investigations, these authors analyzed the peritoneal dialysis machines and found several cross-connections that allowed organisms present in the patient’s drainage system to reach parts of the machine from which they could infect subsequent users. There were also problems with the ultraviolet units and their relationship with the reverse osmosis unit. Manufacturers’ recommendations for disinfection between patients were also felt to be inadequate since 2% formaldehyde does not always completely eradicate organisms similar to M chelonei. Whereas the necessity of catheter removal in TB peritonitis remains debatable, MOTT peritonitis in patients on peritoneal dialysis mandates catheter removal. Current medical therapy is only able to suppress infection. Amikacin and a fluoroquinolone are adequate choices of empiric treatment pending sensitivities of the infecting organism. Alternative agents include erythromycin, doxycyche, and trimethoprim-sulfamethoxazole. Resistance to cefoxitin is increasing and this drug is probably no longer as useful in empiric treatment. Although there are little data to support concrete recommendations for duration of treatment for rapid growing mycobacterial peritonitis, previous experience in duration has ranged from 6 to 24 months with some authors recommending dual drug therapy for at least the first 1 to 2 months of therapy, followed by continuation of a single agent for at least 6 months of total treatment, depending on severity of infection and organism susceptibility.lZ6 MYCOBACTERIAL INFECTIONS IN PATIENTS RECEIVING KIDNEY TRANSPLANTS Although advances in transplantation have allowed for lower doses of steroids and decreased the frequency of infections in the posttransplant period, infections still cause significant morbidity and mortality in this population. Tuberculosis Since 1967 TB has been reported in patients receiving kidney transplants. Although TB is considered rare in patients receiving kidney transplants, in areas where TB is more prevalent, this disease can cause significant morbidity and mortality for the transplant population. In

MYCOBACTERIALINFECTIONS IN PATIENTS WITH CHRONIC RENAL DISEASE

859

India, one prospective study found TB to be the most frequent nonpyogenic pulmonary infection within the first year after renal transplantat i ~ nAlthough .~~ some authors have shown a decreased incidence in the posttransplant period compared to the pretransplant period,", lo* most studies support an incidence well above the general population (Table 3). A review of the literature suggested the onset of TB occurs in a bimodal fashion.99 Intense immunosuppressive therapy early (< 6 months) in the posttransplant period likely accounts for the early peak, while sustained suppression renders the patient susceptible throughout the life of the graft (> 24 months). A possible higher incidence of serious miliary TB may justrfy more intensive surveillance and a higher degree of suspicion for TB during the first posttransplantation year.lo1Identifylng risk factors for TB infection has been unrewarding, except for race and immigrant status. Age, gender, and underlying cause of renal failure do not appear to be risk factors. A previous history of adequately treated TB also does not appear to increase patient risk. Although reactivation is thought to account for the majority of active infections, primary infection can result from outbreaks within transplant units. At a university transplant program in Pennsylvania where the incidence of TB was usually one or two cases per year, an outbreak of eight cases occ~rred."~ Six cases were contacted from a single infected transplant patient. Mortality was 37.5% and 19 of 29 previous PPD-negative transpjant nurses underwent PPD conversion. These authors attributed the outbreak to delayed diagnosis of the source patient who died of active TB diagnosed only at autopsy. Prophylactic isoniazid eventually terminated this epidemic. In another study restriction-fragment-length polymorphism by PCR confirmed transmission of TB from one patient to five other patients receiving kidney This epidemic accounted for 60% of TB cases in a 13-month period in which half of 10 infected patients died. Retrospective analysis of exposure history revealed TB incubation periods as brief as 5 weeks, attributed to immunosuppression, further emphasizing the importance for early diagnosis to prevent TB spread. Some studies have described transmission of TB by transplantation of an infected kidney. Peters et a195described two recipients of kidney transplants, each of whom received a kidney from the same cadaver who was later discovered to have died from TB meningitis. One of these recipients died from disseminated TB and the other required removal of the infected kidney. Mourad et a18*also described two allograft recipients who developed disseminated TB from the same cadaver and grew the same strain of M tuberculosis from their urine. One patient lost her transplanted kidney but the other patient had his miliary TB cured with satisfactory renal function. Andany et a15described a 36-year-old Spanish woman who received an infected cadaveric graft, which on subsequent biopsy showed TB-interstitial nephritis. This graft survived with antiTB therapy. Once active infection occurs, TB symptoms are often vague or even absent, secondary to immunosuppressive therapy. Early reports

Coutts et aP4 1979, England Spence et aP3 1983, New Jersey Malhotra et aln 1986, India Riska et allO1 1987, Finland Suleiman et aP5 1988, Malaysia Samhan et allm 1989, Kuwait Al-Sulaiman et a13 1990, Saudi Arabia Qunibi et alB 1990, Saudi Arabia Higgins et alm 1991, England Koselj et al6I 1992, Slovenia Hussain et a1% 1996, Pakistan Park et a P 1996, South Korea Sakhuja et allB 1996, India Tokat et allzo1996, Turkey Zaragoza et allM1996, Mexico Kim et als 1997, South Korea Yildiz et all" 1998, Turkey Jha et a15' 1999, India Sayiner et al'@ 1999, Turkey

Author Year, Location

16.5 [1-65] 21 I11351

1.6 2.7 9.7 4.6 11.8 2.4 5 4.1 [3X] 4.2 16 [lOOX] 4.1

633 188 340 304 305 250 99 1284 520 81 880

[3-111] 37 [3-1111

44

-

23 [2-581 21 [1-84]

-

17 [1-84]

3.5 [50 x 1

-

[0.5-40]

403

23

4.5

390 399

-

14 [2-321 13 [ M O ] 20

[lM]

95 1280 237

[I0441

Mean TB Onset after Transplant (mo) [rangel 52 49

9.5 [ 9 X ] 2.3 [10-50X] 4.2

TB incidence, % of Patients ( x -fold vs. General Population)

400 565

Total Transplant Patients

Table 3. TB INFECTIONS IN RENAL TRANSPLANT PATIENTS

0 47

64

36 57 58 33 56 21

4.5 0 0

0 0 0 11 0

0

10 40 15 14 19 16 11 4 27 0 22

10 0

70

60

7

50 11

10

0 14

7

0 22

0 0 20

25 33

(%I

(%I 25 33

TB Mortality

Genitourinary

71

50 50

78 14 40

80 66

(%o)

Extrapulmonary

MYCOBACTERIAL INFECTIONS IN PATIENTS WITH CHRONIC RENAL DISEASE

861

demonstrated lack of symptoms in half of patients, with diagnostic investigations spurred only by abnormal chest radiographs.” When symptomatic, fever of varying degree is the most common symptom. Cough represents the second most common complaint, primarily caused by pulmonary TB. The composite of symptoms will depend upon the organ system involved, which is frequently extrapulmonary (see Table 3). Pleuropulmonary infection is the most common form of TB in the renal transplant population. Miliary and disseminated forms are associated with higher mortality and may be more common in the early transplantation period. As described previously, graft or genitourinary involvement can be intrinsic to the donor kidney or as the result of dissemination in up to 33% of cases (see Table 3). Renal infection is often asymptomatic, presenting simply as a positive urine smear or culture.2In 1990, Al-Sulaiman et aP reported renal TB, which developed in 22% of their transplant patients. All patients had renal granulomas and interstitial nephritis. Several case reports of infected renal grafts caused by disseminated TB have been published, emphasizing the importance of early diagnosis and treatment to save the life of the patient and his graft.42,78,123,127,128 The diagnosis of TB in patients receiving kidney transplants may require invasive biopsies. Although chest radiographs usually are abnormal with pulmonary infection,. acid-fast bacilli diagnosis requires bronchoscopy. Bronchoalveolar lavage in patients presenting with fever, cough, pulmonary infiltrates, or hypoxia may yield TB in up to 80% of cases.57In genitourinary infection, urinary acid-fast bacilli smears and cultures may not be very sensitive. In a study of four patients with biopsy-proven tuberculous interstitial nephritis, all had negative early morning urine specimens for acid-fast bacilli and all required tissue biopsy for diagnosis.2 Conversely, some patients with urinary TB are asymptomatic and the diagnosis is found only by culture done for “sterile” pyuria.4l There is no consensus upon treatment of TB in patients receiving kidney transplants, which is complicated by the interaction of cyclosporine and rifampin. Rifampin can drastically reduce cyclosporine levels and has been attributed to reversible loss of graft fun~ti0n.l~ Less interaction occurs by using rifabutin, which has about 50% less hepatic cytochrome P-450 enzyme induction compared to rifampin.’” The majority of authors recommend at least 12 to 24 months of treatment but this recommendation is not well-substantiated. Although it seems rational that TB infection would create a poorer prognosis for graft success, there are no concrete data to support this premise, except for a few small studies. Two authors have reported 50% graft failures in each of four cases of genitourinary TB infection?, 66 A high rate of graft failure or rejection episodes may indicate poorer overall health and susceptibility to infection, in addition to renal impairment caused by TB infection. Some authors suggest that rifampin-induced, depressed cyclosporine levels may contribute to rejection, while others state that baseline renal function at the time of diagnosis is more im-

862

PIENet a1

portant. In the report by Sayiner et al,lo8none of 21 patients with initial serum creatinine levels less than 2 mg/dL developed graft failure, while all of the 8.3% of patients who suffered graft failure had initial creatinine levels >2 at the time of TB diagnosis. Samhan et allo6also reported a greater mortality associated with higher creatinine at time of TB diagnosis in a small population of patients receiving kidney transplants. Patients have successfully undergone renal transplantation while In addition, Samhan et undergoing treatment for active tuberc~losis.~~ allo6 concluded that renal transplantation is safe in patients with a previous history of TB infection, provided that they receive anti-TB prophylaxis in the posttransplant period for at least 12 to 18 months.1o6 Of their 13 pretransplant TB patients, 10 were given TB prophylaxis with 100%patient survival and 90% graft survival. Of three patients who did not receive prophylaxis, one died of miliary TB following graft failure. Although routine chemoprophylaxis may not be provided for most transplant patients in developed countries, several authors have advocated TB screening in all transplant recipients and donors, not only those with significant risk factors, owing to the increased incidence of TB in recipients of kidney transplants and to the difficulties in management.35, Screening should be performed with PPD skin tests, including controls for anergy, and chest radiographs. Recipients of kidney transplants who either have tuberculin reactivity, chest radiograph findings suggestive of TB, a clinical history of TB, close contact exposure to active TB, or a kidney from a donor with a history of TB or tuberculin reactivity, should be considered for 1 year of isoniazid (INH) prophylaxis. Whereas chemoprophylaxis has been reported to reduce subsequent TB in up to 80% of patients, the risk of hepatitis increases about five-fold.&In view of the possible adverse effects of INH, it appears that chemoprophylaxis may only be strongly indicated in high-risk groups; however, in a study comparing one Turkish transplant center that provided chemoprophylaxis to another which did not, none of the high-risk patients who received INH for 1 year developed TB, whereas 7% of the untreated group developed active disease after transplantation.lo8Although this difference was not statistically significant, these authors found that none of the 23 patients who received INH prophylaxis suffered hepatotoxicity. Mycobacterial Infections Other Than TB (MOTT)

In their 1994 review, Pate1 et a190 summarized MOTT in patients receiving kidney transplants. These authors collected the following cases: (1) 14 cases of M kansasii, which caused mainly skin and soft tissue infections in addition to pulmonary disease, (2) 7 cases of cutaneous and joint involvement with Mycobacterium haemophilium, and (3) 21 cases of M fortuitum/M chelonei, involving mostly skin and bone sites. Over half of these patients had painful, erythematous multifocal cutaneous involvement without fever, leukocytosis, or lymphadenitis. Most patients

MYCOBACTERTAL INFECTIONS IN PATIENTS WITH CHRONIC RENAL DISEASE

863

were treated with surgical debridement and antibiotic therapy with at least 80% improvement or cure. Other less common MOTT infections have included case reports of Mycobucterium murinum skin infection from a fishing trip," M marinurn dissemination,40and M gustri metacarpophalangeal septic arthritis.94 Treatment of Tuberculosis in Patients with Chronic Renal Failure

There are two major problems in treating patients with chronic renal failure with antituberculous medications: (1) need for dosage adjustment of antituberculous medications (Table 4), and (2) type and duration of therapy, which is mainly anecdotal. Four of the main antitubercular drugs-INH, streptomycin, ethambutol (EMB), and pyrazinamide (PZA)-are significantly affected by renal function. Although INH undergoes hepatic metabolism, including enzymatic acetylation (acetylisoniazid), hydrolysis (isonicotinic acid), and conjugation (probably as isonicotinyl glycine), 75% to 95% of a dose will be excreted in the urine, mostly as rnetabolite~.2~, 49, Nevertheless, the renal clearance of INH is felt to be relatively unimportant compared to hepatic metabolism even in slow acetylators.30,39, 49, l E In anuric renal failure, the half-life of INH is believed to undergo a mild increase from 0.5 to 4 hours to 2 to 10 One study involving 13 control patients and 10 patients with renal impairment showed a trend toward prolonged INH half-life, but the difference was not statistically significant, particularly for patients with serum creatinine concentrations up to 12 mg/dL.14 Another study of 13 patients with systemic lupus erythematosus and varying degrees of renal impairment could demonstrate no correlation between plasma INH half-life and creatinine clearance.63One review calculated that renal excretion contributes approximately 27% and 11%to total body clearance in slow and rapid acetylators, respectively.lE It has been recommended that INH be administered in its usual dosage of 5 mg/kg qd up to 300 mg, which may be reduced to 150 to 200 mg qd to keep trough serum levels less than 1 mcg/mL in slow-acetylators with glomerular filtration rate (GFR) < l o mL/rnin." 9, 28, 91 Some authors, however, have advocated that in renal impairment or dialysis, INH dosages need not be reduced nor serum levels monitored for the following reasons: INH doses as high as 15 mg/kg qd have been well-tolerated, INH metabolites are for the most part nontoxic, and some evidence suggests reduced therapeutic potency with INH dosages below 200 mg qd.29, The risk of INH toxicity, particularly neurotoxic effects, is wellrecognized in patients with renal fai1u1-e.~. =, 130 The explanation for this occurrence has been attributed to the formation of hydrazones, which inhibit pyridoxine phosphorylation used to generate important coenzymes, including pyridoxal-5-phosphate and pyridoxamine phosphate. Pyridoxine plays a role in the metabolism of synaptic amine

24/24

59/9-14

Rifampin

Pyrazinamide (PZ.4)

Ethambutol (EMB) 34/1&11

0.5-4/2-10

Isoniazid (INH)

Drug

Half-Llfe (hr) NormaUAnurlc

1525 mg/kg/day PO up to 1 g/day

25-35 mg/kg/day PO up to 3 g/day

20-60 (peak)

2-5 (peak)

MM mg/da; PO/ N

8-20 (peak)

Hepatic (by way of CYT P450) Hepatic (to pymzinoic acid)

Renal (80%)

5 mg/kg/day up to 300 mg PO/ IM/W

Normal Adult Dose (GFR >80 rnVrnin)

%5 (peak) 1 (trough)

Target Serum Levels (rncslrnl)

Hepatic (by way of acetylation)

Normal Clearance

Unchanged

q 24 hr

15 mg/kg q 24-36 hr

q 24 hr

15 mg/kg q 24 hr ( C A W dose)

Unchanged

Glomerular Filtration Rate 10-50 mUmln

Unchanged

Unchanged

Glomerular Filtration Rate 5 M mUmln

q 48-72 hr OR 40 mg/kg 3 times a wk OR 6Omg/kg2 times a wk OR 12-20 mg/kg/ sd 15 mg/kg q 48 hr OR 8-10 mg/kg/d

Unchanged; May consider 'h dose in slow acetylators Unchanged

Glomerular Filtration Rate 4 0 mUmln

Table 4. DOSAGE ADJUSTMENT OF ANTIMYCOBACTERIAL DRUGS IN RENAL FAILURE AND DIALYSIS PATIENTS

Unchanged

15 mg/kg/d 15 mg/kg q after HD OR 48 hr after 25 mg/kg dialysis 4 4 hr before HD OR 45 mg/kg 2 times a wk OR 90 mg/ kg/wk

25-35 mg/kg No data after HD OR 12-20 mg/ kg/d

Unchanged

Normal dose Normal dose after dialysis after dialysis

Dosage In Dosage In Hernodlalysis Perltoneal (HD) Dlalysis (PD)

10-12/-

5/58

16-69 (mean 45) 3-5

Cydoserine

Capreomycin

Rifabutin

Hepatic Renal (2535) Hepatic

Hepatic

Renal (>95%)

R e d (66%)

*Highly variable, check serum levels.

Clofazimine

10-70 days (Biphasic)

25C-500 mg q 12 hr PO (CAW dose) 20-30 (peak) 25C-500 mg q 12 hrPO 3 W (peak) 1.0 g/day (15-30 10 (steady state) mg/kg) IM for M I 2 0 days, then 1.0 g 2-3 times a wk 0.3-0.9 300 mg/day PO

Hepatic

23/-

Clarihmycin

40-70 (peak)

Renal (85%)

1/23

0.5-2.0

2-7

1-5 (peak)

0.5-1.0 g q 12 hr PO 1CC-200 mg/day PO

3 g q 6-8 hr PO or 4-6 g q 12 hr

Unchanged

Unchanged

Unchanged

q 2448 hr

Unchanged

Avoid in renal impairment

q 12 hr

Unchanged

75%

Unchanged

q 48-72 hr

Unchanged

30%-70% q 12-18 hr (CAW dose)

7.5 mg/kg q 24 hr q 24-72 hr (CAW dose)

7-10 mg/kg up to 60%-90% 1.0 g IM 5 times a wk

Paraaminosalicylic acid (PAS) Ethionamide

Renal (907~98%) 35-45 (peak)

IM5 times a wk

7.5-15 mg/k / day up to l . f g

2-3/30-150

5 4 (trough)

3545 (peak)

Amikacin

Renal (70%-!30%)

23/100

streptomycin

Unchanged

50?& 75% -

Unchanged

WdY

50%

20%-30% q 24-48 hr

q 72-% hr

Unchanged

Unchanged

Replace 15-20 mg/L dialysate/ day N*

ZFY

Replace 2mg/L

Normal dose Unchanged after dialysis Unchanged Unchanged

Unchanged

250-500 mg after dialysis lg3timesa wk after HD

Unchanged

4gq12hr

2/3 normal dose after dialysis'

afterHLT

0.5-1.0 g

866

PIENetal

neurotransmitters and the formation of gamma-aminobutyric acid. Neurotoxicity has been observed to occur more frequently in conditions such as uremia, which also interferes with normal pyridoxine metabolism and other medical conditions (e.g., malnutrition, alcoholism, diabetes mellitus) and slow-inactivators of INH. Patients with chronic renal failure or not on dialysis have been shown to have normal serum pyridoxine levels but deficient levels of pyridoxal-5-pho~phate.~, lo3,11* It has therefore been recommended that pyridoxine supplementation be increased in patients with chronic renal failure from the usual dosage of 10 to 50 mg daily to 50 to 100 mg qd, particularly in patients who experience neurotoxic effects."O As an aminoglycoside, streptomycin demonstrates pharmacokinetics belonging to this drug class. About 70% to 90% of the dose undergoes total urinary excretion by way of glomerular filtration and in anuric renal failure the half-life increases from 2.5 hours to about 100 Dosage adjustment of streptomycin in renal failure is 7.5 mg/kg up to 1.0 g every 24 to 96 hours, depending on the GFR and patient weight. The goal is to achieve serum peak and trough levels of 35 to 45 and 5 4 mg/L, respectively.3°,93 Ethambutol is largely dependent on renal function for its excretion; 54% to 60% of this drug is found in the urine within 24 hours of oral administration, primarily in its unaltered 96 About 80% of the absorbed dose is eventually excreted in the urine.92Normal renal clearance of ethambutol is 7 mL/kg per min involving filtration and tubular secretion.n In anuric renal failure, the half-life of ethambutol can double from 3 to 4 hours to 10 to 11 hours.121Its dosage therefore should be reduced from the usual 15 to 25 mg/kg qd to 15 mg/kg every 24 to 48 hours depending on GFR to obtain peak serum levels of 2 to 5 mcg/ mL.9 Some authors affirm that peak serum levels are critical for optimal effectiveness, thus advocating for the usual dosage amount at wider spaced intervaksOOne study of 13 patients, however, recommended that dosages of 7.2 and 10.8 mg/kg qd be applied to patients with 0% and 50% renal function, respectively.121 Pyrazinamide is almost completely metabolized in the liver. The metabolites of PZA, however, are excreted primarily by renal glomerular filtration. Pyrazinamide is hydrolyzed by hepatic microsomal PZA deaminase to pyrazinoic acid, the active metabolite, then subsequently hydroxylated by xanthine oxidase to 5-hydroxypyrazinoic acid, the major excretory product.n About 4% of the PZA dose appears unchanged and 30% appears as pyrazinoic acid in the urine within 24 hours.3l In anuric renal failure, the half-life increases from about 5 to 9 hours to 9 to 14 hours; therefore, the dosage is reduced from 25 to 35 mg/kg qd to extended intervals of 48 to 72 hours or to 12 to 20 mg/kg qd in patients with GFR
MYCOBACTERIAL INFECTIONS IN PATIENTS WITH CHRONIC RENAL DISEASE

867

25-O-desacetylrifampin, which undergoes biliary excretion with only small amounts appearing in the urine. With repeated rifampin administration, about 6% to 14% of the dose may be recovered in urine,’ but the half-life (2 to 4 hours) is minimally affected by renal impairment. Rifampin, therefore, is given in usual doses in renal failure. Rifampin induces the cytochrome oxidase P-450 system which increases the clearance of corticosteroids two-fold,15 cyclosporine two- to five-fold? 17, 59 and tacrolimus ten-fold?l requiring higher doses of these immunosuppressive agents. For this reason, some authors replace rifampin with rifabutin, PZAZ or EMB in patients receiving kidney transplants to save on the substantial expense of cyclosporine. Hemodialysis alters the pharmacology of some antitubercular medications (Table 5). Isoniazid is dialyzable by hemodialysis; 73% of the One recent study using hemodialytotal dose is removed after 5 sis machines with high-flux dialysis membranes and increased blood flow rates, demonstrated a mean hemodialysis clearance of 124 mL/min for i ~ o n i a z i d In . ~ ~such patients, therefore, INH can be given at the usual 5 mg/kg qd dosage, but after hemodialysis on dialysis days. Streptomycin is highly dialyzable and can be given at a dose of 0.5 to 1 g after hemodialysis to achieve trough serum levels 5 4 mg/L, but should be discontinued after 1 to 2 months to prevent ototoxicity. Because of variability in clearance between modern high flux dialysis membranes, it is important to monitor postdialysis streptomycin levels. In hemodialysis, EMB is cleared at a rate of about 50 to 100 mL/min with an extraction percentage between 2% to 40%.23,64,75 The EMB dosage should be lowered to 15 mg/kg after dialysis to produce peak levels of 5 mcg/mL with careful follow-up of blood levels as well as visual acuity and color per~eption.~ Andrew et a1,6 however, were able to achieve therapeutic EMB levels using dosages of 8 to 10 mg/kg qd in five patients on hemodialysis.6Alternative dosing schedules include 25 mg/ kg of EMB 4 to 6 hours before hemodialysis three times weekly, 45 mg/ kg for twice weekly dosing, and 90 mg/kg for weekly dosing.30In hemodialysis, PZA has been reported to have a dialysis coefficient of ’ ~ study about 50% after 4 hours with a clearance of 90 m L / m h ~ . ~This reported pyrazinoic acid to have a dialysis coefficient of about 60%; however, there was found to be large interindividual variability in PZA levels in patients on hemodialysis, presumably caused by the large water solubility of the drug and interpatient variations in total body water. Another study of PZA found a mean dialysis clearance of 132 mL/min.62 The most recent PZA study, which measured actual drug recoveries in seven patients, collected 45% of the parent compound in dialysate and calculated a median clearance of 270 mL/min.” The recommended dosage adjustment in hemodialysis is 25 to 35 mg/kg after hemodia l y ~ i s .lz9~ ~Ellard30 , recommends that the intermittent dosing schedule described above for renal insufficiency be administered 24 hours before hemodialysis when appropriate. Rifampin is believed to be insignificantly dialyzable because of its relatively high molecular weight, proteinbound fraction, and lipid solubility. There are some limited studies,

166 102 652-668 847 715 473

Ethionamide Cycloserine Capreomycin Rifabutin Clarithromycin Clofazimine

("/I

80 70-90 Poor 20 55 45-70t

Good 75-80 Poor Poor Good

100

Good; Reduced by coadministration of PAS granules

'Both parent and acetylated compounds. tHigher when taken with a large, high-fat meal.

822 123 277 581 782 153

Rifampin Pyrazinamide Ethambutol Streptomycin Amikacin PAS

MW (Daltons)

137

Drug

Isoniazid

Oral Bioavailability

57-80 10-20 20-30 35 4-60 50-73 (15% in some reports) Est. 30 Est. 0 Est. low 71-94 42-72 unknown

10

YOProtein Bound

Table 5. HEMODIALYSIS PROPERTIES OF ANTIMYCOBACTERIALDRUGS

(mg)

1.5-4.0 (est.) 0.2-0.35 0.4 9.0 2.5-4.0 Est. 25-100

0.9 0.6-2.0 0.4-3.0 0.3 0.2 0.8-3.8

0.6

Vd

58 189 34

0 0

206

30-70 0.647* 2 56 34

40 90-270 50-100

124

45-50 2-40

4

9-73

YO Dialyzed

Dialysis Clearance (mvmin)

MYCOBACTERIAL INFECTIONS IN PATIENTS WITH CHRONIC RENAL DISEASE

869

however, which show slight plasma concentration reductions following hernodialysis and peritoneal dialysis. Nevertheless, rifampin dosage recommendations remain unaltered from regimens used in normal renal function. The effects of peritoneal dialysis on TB medications have not been studied well. The usual INH daily dosage can be given after dialysis in patients using intermittent peritoneal dialysis.3O It has been recommended that the amount of streptomycin lost in dialysis (20 to 40 mg/ L dialysate/qd) be replaced intravenously3s; however, daily intravenous administration may not be convenient or practical in the ambulatory setting. In one case of M tuberculosis-positive sputum and peritoneal dialysis fluid, therapeutic streptomycin blood levels were achieved using a regimen of 8.3 mg/kg intramuscularly every 2 weeksm In another case report of recurrent M xenopi peritonitis associated with CAPD, intraperitoneal administration of streptomycin (15 mg/L during three 2L daily daytime exchanges and 100 mg/L during an overnight exchange) resulted in 75% absorption with successful suppression of infection and sustained serum levels of 13 to 15 mcg/L.lo9 Since streptomycin pharmacokinetics may be highly variable in CAPD, it is also important to check serum levels. In CAPD, the recommended dosage of EMB is 15 mg/kg every other day, dosing after dialysis.%,51 Alternatively, some authors have recommended the administration of 5 to 10 mg/kg qd,'9 but this probably does not achieve sufficient peak serum drug levels. The dosage for PZA in CAPD is unknown. The effect of renal function on second-line antitubercular agents can be summarized as follows. Para-aminosalicylic acid (PAS) largely relies on renal excretion. About 85% of the dose appears in the urine as the free acid and various degradation products, including the acetylated compound which comprises about 50% of the excreted dose. In renal failure, the half-life increases greatly from 1 to 23 hours: In renal disease not requiring dialysis, PAS should be avoided because of accumulation of the inactive acetylated salicylate, which may exacerbate gastrointestinal upset symptoms and uremia-associated platelet dysfunction. Since the PAS acetyl metabolite has been shown to be significantly removed by hemodialysis, PAS may be given in normal doses in such patients.76 Although PAS metabolism is not changed with rapid or slow acetylator status, PAS inhibits INH metabolism and prolongs drug half-life by 20% to 30%, not felt to be clinically significant.%The PAS granule formulation appears to inhibit rifampin absorption, so it is recommended that PAS and rifampin be administered 8 to 12 hours apart.13Two-thirds of cycloserine is excreted by the kidneys unchanged, including 50% within the first 12 hours." In anuric renal failure, therefore, cycloserine may accumulate, leading to central nervous system toxicity. Cycloserine is dialyzable with a median hemodialysis clearance of 189 mL/min and 56% median dialysate drug recovery.76In normal renal function, the drug half-life is 10 hours and dosage is 250 to 500 mg every 12 to 24 hours. In hemodialysis, the cycloserine dosage recommendation is that this dose be administered three times per week after dialysis.76Ethion-

870

PIEN et a1

amide is a derivative of INH and is therefore metabolized hepatically, whereas its metabolites undergo renal excretion. Less than 1%of ethionamide in its active form is excreted in the urine. The normal ethionamide half-life is 2.1 whereas the anuric half-life remains undetermined. In severe renal insufficiency (GFR < 10 mL/min), it is recommended that the ethionamide dose be reduced by 50%.38There has been no recommended dosage adjustment in any form of dialysis. Ethionamide undergoes acetylation by way of the same enzyme as INH and has been shown to inhibit INH acetylation in vitro. Pyridoxine supplementation of INH is thus particularly recommended. Capreomycin is a polypeptide antibiotic derived from Streptomyces cupreolus and resembles the aminoglycosides. About 50% of the dose is renally excreted un~ renal clearance is 44 mL/min and in changed within 8 h o ~ r s . 4Normal anuric renal failure, the half-life increases greatly from 5.2 to 58 hours; thus in renal disease, a capreomycin dosage adjustment is required.= Capreomycin is readily dialyzable with an extraction percent of 40% to 60% and a clearance rate of 42 mL/min. Anti-MOTT agents are mainly metabolized in the liver. Rifabutin is a spiropiperidyl derivative of rifamycin S and bears similar in vitro efficacy as rifampin against M tuberculosis, when used in combination with at least two other antitubercular agents. Rifabutin possesses greater in vitro activity than rifampin against M uviurn-intrucellulure complex and greater intracellular neutrophil penetration. Rifabutin undergoes hepatic conversion to over 20 metabolites, hcluding biologically active 25-0-deacetyl-rifabutin. Although only 5% to 9% of the rifabutin dose is excreted unchanged into urine, about 40% to 50% of the total dose appears in the urine primarily as metabolites."' Whereas the metabolites of rifabutin depend significantly on renal excretion, no cases of toxicity have been reported in renally impaired patients, allowing rifabutin to be applied at its usual dosage in most renal patients. Clarithromycin is a macrolide antibiotic metabolized by way of the cytochrome oxidase P450 system to at least eight products, including the biologically active 14-hydroxyclarithromycin.The hepatic metabolism appears to be saturable and exhibit nonlinear dose-dependent elimination half-life ranging from 3.3 to 4.9 hours.lo2 Although hepatic metabolism is important for clarithromycin, renal disease has a significantly greater impact on clearance. About 40% to 45% of repeatedly administered 250- and 500mg dosages are excreted in the urine within 12 hours as either the parent compound or 14-hydroxy metabolite. When creatinine clearance falls below 30 mL/min, the clarithromycin half-life increases to 21.6 hours; therefore, in renal disease in which creatinine clearance is <30 mL/min, it has been recommended that a 500-mg loading dose followed by 250 mg bid yields approximate serum levels to 500 mg bid in normal patients.44It has also been suggested that the 250 mg qd clarithromycin dosage be applied in renal failure to achieve similar levels as 250 mg bd dosage in normal patients. Clofazimine is useful in the treatment of leprosy and M uvium-intracellulure complex. This drug demonstrates a complex elimination half-life owing to extensive tissue uptake and long-

MYCOBACTEIUAL INFECTIONS IN PATIENTS WITH CHRONIC RENAL DISEASE

871

term retention. The half-life of clofazimine ranges from 10 to 70 days and is primarily metabolized by the liver and excreted in feces. Less than 1%of the dose is found in the urine even after prolonged (4weeks) administrationmThe dosage of clofazimine therefore does not seem to be affected by renal impairment and may be given in usual doses pending further studies. Clofazimine has been shown to be undetectable in hemodialysate,76 and thus does not require dialysis dosage adjustment. Tuberculosis Treatment Regimens

There have been no controlled studies or consensus regimens for the treatment of TB in patients with renal failure.83Many authorities apply the same treatment regimens in patients on dialysis as those in patients not on dialysis, based on TB or MOTT susceptibilities. Special risk groups such as HIV-positive patients'O or patients receiving kidney transplants are treated for much longer periods of time (12 to 24 months) with multiple drug regimens (3 to 5) depending on severity of disease, type and susceptibility of mycobacterium, and time to resolution of clinical symptoms, radiographs, and cultures. SUMMARY

In this article, the authors have provided a comprehensive review of TB and MOTT infections in patients on renal dialysis and receiving kidney transplants. Because most published series are small retrospective studies or case reports, there are several uncertainties still involved in the diagnosis and treatment of such patients. Unanswered questions include selection of optimal dosage and duration of therapeutic agents; the best tests for screening and diagnosis, especially in high prevalence areas; and the best management of MOl'T infections because of unavailability of highly effective therapy.

References 1. Acogella G Clinical pharmacokinetics of rifampin. Clin Pharmacokinet 3108, 1978 2. AI-Sulaiman MH, Dhar JM, AI-Hasani MK, et a1 Tuberculous interstitial nephritis after kidney transplantation. Transplantation 50162, 1990 3. Al-Sulaiman MH, Dhar JM, Al-Khader M. Successful use of rifampicin in the treatment of tuberculosis in renal transplant patients immunosuppressed with cyclosporine. Transplantation 50:597,1990 4. Amsden G W Tables of antimicrobial agent pharmacology. In Mandell GL, Bennett JE, D o h R (eds): Principles and Practice of Infectious Diseases, ed 5. Philadelphia, ChurchilI Livingstone, 2000, p 551 5. Andany MA, Falcon TG, Lozano IR, et al: Tuberculous interstitial nephritis of the renal graft. Nephron 68:143,1994 6. Andrew OT, Schoenfeld PY, Hopewell PC, et al: Tuberculosis in patients with endstage renal disease. Am J Med 6859, 1980

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7. Asnis DS, Bhat JG, Melchert AF.Reversible seizures and mental status changes in a dialysis patient on isoniazid preventive therapy. Ann Pharmacother 27444, 1993 8. Band JD, Ward JI, Fraser DW: Peritonitis due to a Mycobacteriurn chelonei-like organism associated with intermittent chronic peritoneal dialysis. J Infect Dis 145:9, 1982 9. Bartlett JG: Tables of antimicrobial agents. In Gorbach SL, Bartlett JG, Blacklow NR (eds): Infectious Diseases, ed 2. Philadelphia, WB Saunders, 1998, p 428 10. Baumgartner DD, Arterbery VE, Hale AJ, et a1 Peritoneal dialysis-associated tuberculous peritonitis in an intravenous drug user with acquired immunodeficiency syndrome. Am J Kidney Dis 14154,1989 11. Belcon MC, Smith EKM, Kahana LM, et a1 Tuberculosis in dialysis patients. Clin Nephrol 1714, 1982 12. Bolan G, Reingold AL, Carson LA, et ak Infections with Mycobuctm’urn chelonei in patients receiving dialysis and using processed hemodialyzers. J Infect Dis 152:1013, 1985 13. Boman G, Hanngren A, Malmborg A S Drug interaction: Decreased serum concentrations of rifampicin when given with PAS. Lancet 1:800,1971 14. Bowersox DW, Winterbauer RH, Stewart GL, et ak Isoniazid dosage in patients with renal failure. N Engl J Med 28984,1973 15. Buffington GA, Dominguez JH, Piering WF, et al: Interaction of rifampin and glucocorticoids: Adverse affect on renal allograft function. JAMA 2361958, 1976 16. Carson LA, Bland LA, Cusick LB, et al: Prevalence of nontuberculous mycobacteria in water supplies of hernodialysis centers. Appl Environ Microbiol 54:3122,1988. 17. Cassidy MJD, Zyl-Smit RV, Pascoe MD, et a 1 Effect of rifampicin on cyclosporin A blood levels in a renal transplant patient. Nephron 41:207,1985 18. Cengiz K: Increased incidence of tuberculosis in patients undergoing hemodialysis. Nephron 73421, 1996 19. Chan PCK, Yeung CK, Chan MK: Tuberculosis in peritoneal dialysis patients. Sing Med J 29:103,1988 20. Cheng IKP, Chan PCK, Chan MK Tuberculous peritnnitis complicating long-term peritoneal dialysis. Am J Nephrol 9355, 1989 21. Chenhsu RY, Loong CC, Chou MH, et a1 Renal allograft dysfunction associated with rifampin-tacrolimus interaction. Ann Pharmacother 3427, 2000 22. Cheung WC, Lo CY, Lo WK, et a 1 Isoniazid induced encephalopathy in dialysis patients. Tuber Lung Dis 74136,1993 23. Christopher TG, Blair AD, Forrey AW, et al: Hemodialyzer clearances of gentamicin, kanamycin, tobramycin, amikacin, ethambutol, procainamide, and flucytosine, with a technique for planning therapy. J Pharmacokin Biophamaceutics 4427,1976 24. Coutts ZI, Jegarajah S, Stark JE: Tuberculosis in renal transplant recipients. Br J Dis Chest 73:141, 1979 25. Coward RA, Raftery AT, Brown CB: Cyclosporin and antituberculous therapy. Lancet 1:1342, 1985 26. Cuss FMC, Carmichael DJS, Linington A, et a1 Tuberculosis in renal failure: A high incidence in patients born in the third world. Clin Nephrol25129,1986 27. Dunmire RB 111, Breyer JA: Nontuberculous mycobacterial peritonitis during continuous ambulatory peritoneal dialysis: Case report and review of diagnostic and therapeutic strategies. Am J Kidney Dis 18:126,1991 28. Editors: Tuberculosis in patients having dialysis. Br Med J 280349, 1980 29. Ellard GA, Gammon PT:Pharmacokinetics of isoniazid metabolism in man. J Pharmacokin Biopharmaceutics 4933, 1976 30. Ellard G A Chemotherapy of tuberculosis for patients with renal impairment. Nephron 64369,1993 31. Ellard GA: Absorption, metabolism and excretion of pyrazinamide in man. Tubercle 50:144,1969 32. Fang JT, Huang CC: Isolated dural tuberculosis presenting as seizure disorder in a dialysis patient. Nephrol Dial Transplant 13194,1998 33. Fanning A. Tuberculosis: 6. Extrapulmonary disease. Can Med Assoc J 1601597,1999 34. Faroqui MA, Berenson C, Lohr JW:Mycobacterium marinurn infection in a renal transplant recipent. Transplantation 671495, 1999

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35. Felger J, Halff GA, Ester1 RM. Exposure to Mycobacterium tubercuhis (MTB) in a renal transplant candidate: What further preoperative screening tests are available? Clin Transplant 11:142, 1997 36. Garcia-Leoni ME, Martin-Scapa C, Rodeno P, et al: High incidence of tuberculosis in renal patients. Eur J Clin Microbiol Infect Dis 9:283, 1990 37. Giladi M. Lee BE, Berlin GW, et al: Peritonitis caused bv Mvcobucferium kunsusii in a patient undergoing continuous ambulatory peritoneal dialysis. Am J Kidney Dis 19597, 1992 38. Gilbert DN, Moellering RC Jr, Sande MA. The Sanford Guide to Antimicrobial Therapy, ed 30. Hyde Park, Antimicrobial Therapy, Inc, 2000, pp 121-125 39. Gold CH, Buchanan N, Tringham V, et al: Isoniazid pharmacokinetics in patients in chronic renal failure. Clin Nephrol6365,1976 40. Gombert ME, Goldstein EJC, Corrado ML, et a 1 Disseminated Mycobucteriurn murinum infection after renal transplantation. Ann Intern Med 94:486,1981 41. Gomez E, Aguado S, Baltar J, et al: Sterile leukocyturia as a manifestation of urinary tuberculosis in renal transplant patients. Nephrol Dial Transplant 13:1610, 1998 42. Goncalves ARP, Caetano MA, Paula FJ, et a 1 Tuberculous interstitial granulomatous nephritis in renal transplants: Report of three cases. Transplant Proc 241911, 1992 43. Hakim A, Hisam N, Reuman P D Environmental mycobacterial peritonitis complicating peritoneal dialysis: Three cases and review. Clin Infect Dis 16:426, 1993 44. Hardy DJ, Guay DRP, Jones RN: Clarithromycin, a unique macrolide: A pharmacokinetic, microbiological, and clinical overview. Diagn Microbiol Infect Dis 15:39, 1992 45. Harro C, Braden GL, Morris AB, et al: Failure to cure Mycobucteriurn gordonue peritonitis associated with continuous ambulatory peritoneal dialysis. Clin Infect Dis 24:955, 1997 46. Haskell LP, Tannenberg AM: Tuberculous arthritis in a hemodialysis patient. Am J Nephrol 7:404, 1987 47. Herrera CM, Delgado RM, Riscos AG, et a1 Mycobucterium tuberculosis as a cause of peritonitis in a patient undergoing continuous ambulatory peritoneal dialysis. Nephron 73:318,1996 48. Higgins RM, Cahn AP, Porter D, et a1 Mycobacterial infections after renal transplantation. Q J Med 78145,1991 49. Holdiness MR: Clinical pharmacokinetics of the antituberculosis drugs. Clin Pharmacokinet 9511, 1984 50. Holdiness MR Clinical pharmacokinetics of clofazimine: A review. Clin Pharmacokinet 16:74, 1989 51. Holley HP Jr, Tucker CT, Moffatt TI,, et a1 Tuberculous peritonitis in patients undergoing chronic home peritoneal dialysis. Am J Kidney Dis 1522,1982 52. Hsu SC,Lan RR, Tseng CC, et ak Extrapulmonary tuberculous infection manifested as peritoneal fluid eosinophilia in a continuous ambulatory peritoneal dialysis patient. Nephrol Dial Transplant 15:284,2000 53. Hussain Z , Naqvi R, Hafiz S, et a1 Tuberculosis in renal allograft recipients. Transplant Proc 281516,1996 MacDonald FM, Mendoza E: A study of the renal clearances, metabolic 54. Jenne JW, inactivation rates, and serum fall-off interaction of isoniazid and para-aminosalicylic acid in man. Am Rev Respir Dis 84:371,1961 55. Jenner PJ, Ellard GA, Gruer PJK, et a 1 A comparison of the blood levels and urinary excretion of ethionamide and prothionamide in man. J Antimicrob Chemother 13267,1984 56. Jereb JA, Burwen DR, Dooley SW, et a 1 Nosocomial outbreak of tuberculosis in a renal transplant unit: Application of a new technique for restriction fragment length polymorphism analysis of Mycobucferium tuberculosis isolates. J Infect Dis 168:1219, 1993 57. Jha V, Sakhuja V, Gupta D Successful management of pulmonary tuberculosis in renal allograft recipients in a single center. Kidney Int 56:1944, 1999 58. Kim SI, Kim MS, Kim YS, et al: Is pulmonary tuberculosis a major risk factor on patient and graft survival in kidney transplantation? Transplant Proc 29:820,1997 ,

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