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Tuberculosis in Renal Transplant

Recipients: The Evidence for Prophylaxis

Article in Transplantation · October 2010

Impact Factor: 3.83 · DOI: 10.1097/TP.0b013e3181ecea8d · Source: PubMed

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 OVERVIEW

Tuberculosis in Renal Transplant Recipients: The

Evidence for Prophylaxis
Andrew C. Currie,1 Simon R. Knight,1 and Peter J. Morris1,2

Background. Tuberculosis (TB) remains a leading cause of death in endemic countries and is 20 to 70 times more
common in renal transplant recipients, where it contributes to both increased morbidity and mortality. This review will
focus on the epidemiology of TB in renal transplant recipients and critically appraise the published literature on
isoniazid prophylaxis in renal transplantation.
Methods. A literature search for randomized and nonrandomized studies investigating the use of isoniazid prophylaxis
in renal transplant recipients was conducted using Ovid MEDLINE, the Cochrane Library, the Transplant Library, and
EMBASE. Relative risks (RRs) with 95% confidence intervals (CIs) are reported. Meta-analysis of the randomized
controlled trials (RCTs) was performed with a fixed-effects model.
Results. Eleven relevant studies were identified; six nonrandomized and five RCTs. The nonrandomized studies
indicate a reduced risk of TB with isoniazid prophylaxis. The RCTs demonstrated conflicting results, with two studies
finding a reduction in TB with prophylaxis and two studies finding no difference. Meta-analysis of the 709 patients from
the four RCTs demonstrated a reduced risk of TB with isoniazid prophylaxis (RR, 0.31; 95% CI, 0.19 – 0.51). No
significant difference was found in the incidence of hepatitis (RR, 1.22; 95% CI, 0.91–1.65).
Conclusion. Both randomized and nonrandomized studies support the value of isoniazid as TB prophylaxis in renal
transplant recipients at risk of active infection. Clinicians should consider prophylaxis in renal transplant recipients in
endemic areas or in recipients in nonendemic countries who are at risk. However, the evidence for the benefit of
isoniazid prophylaxis in renal transplantation is not robust and there is still a need for a large multicenter trial of
isoniazid prophylaxis in kidney transplantation in an endemic area.
Keywords: Renal transplant, Tuberculosis, Prophylaxis, Systematic review.
(Transplantation 2010;90: 695–704)

nfection with Mycobacterium tuberculosis is still a leading
I cause of death in endemic countries (1). Tuberculosis (TB)
tends to behave as an opportunistic infection in patients with
organ transplants (2, 3). The prevalence of TB among renal
transplant recipients has been reported in a number of obser-
vational studies worldwide (Table 1), and the incidence of
infection among such patients anywhere is estimated to be
from 20 to 70 times higher than that for the general popula-
tion (2). This prevalence mimics the endemic prevalence of
S.K. has received a travel grant from Roche. P.J.M. chairs a Data, Safety and
Monitoring Board for Bristol Myers Squibb and has received honoraria and
travel grants in the past from Novartis, Roche, Astellas, and Genezyme
(P.J.M.).
1
Centre for Evidence in Transplantation, Royal College of Surgeons of En-
gland and London School of Hygiene and Tropical Medicine, University
of London, London, United Kingdom.
2
Address correspondence to: Peter J. Morris, A.C., F.R.S., F.R.C.S., Centre
for Evidence in Transplantation, Royal College of Surgeons of England,
35-43 Lincoln’s Inn Fields, London WC2A 3PE, United Kingdom.
E-mail: pmorris@rcseng.ac.uk
P.J.M. conceived the idea for the paper. A.C. and P.J.M. undertook the literature
search and reviewed the papers. S.R.K. assisted with the meta-analysis. All
authors were involved with writing the manuscript.
Received 11 January 2010. Revision requested 10 March 2010.
Accepted 14 June 2010.
Copyright © 2010 by Lippincott Williams & Wilkins
ISSN 0041-1337/10/9007-695
DOI: 10.1097/TP.0b013e3181ecea8d
the relevant country. The prevalence of TB among renal
transplant recipients in the Indian subcontinent (India and
Pakistan) is 13.0%, in the Far East (China, Thailand, and
Taiwan) is 2.0%, and among western European and North
American populations ranges from 0.07% to 1.7%. Most of
the data are pooled from single-center registries over pro-
longed periods of time, but some of the studies are multi-
center sampling from various areas within the same country.
In the transplant population, TB contributes to graft dys-
function, both through direct effects on the graft and as a result
of drug interactions, and thereby increases mortality (2, 4). Man-
agement is complex as antituberculous treatment, particularly
rifampicin, can lower the levels of the commonly used cal-
cineurin inhibitors (e.g., cyclosporine and tacrolimus) by the
induction of cytochrome P450 in the liver, and hence increases
the risk of graft rejection (5). Antituberculous medications are
not without risk in the posttransplant period and specifically
isoniazid (INH) has been shown to be associated with the develop-
ment of hepatic dysfunction in a variety of immunocompetent and
immunocompromisedstates(6).ReducingtheriskofTBinatrans-
plant recipient is an important priority in organ transplantation,
especially in the countries in which TB is endemic.
TB infection among renal transplant recipients presents
important diagnostic difficulties because of the greater incidence
of extrapulmonary involvement and the atypical presentation

Transplantation • Volume 90, Number 7, October 15, 2010 www.transplantjournal.com | 695

696 | www.transplantjournal.com Transplantation • Volume 90, Number 7, October 15, 2010

TABLE 1. The prevalence of Mycobacterium tuberculosis drawn from observational studies of tuberculosis in renal
transplant recipients in both single and multiple centers and in the general population of the same country
TB prevalence in general N (transplant N (patients Prevalence
Country population % (51) recipients) with TB) (%) References

Argentina 0.048 384 14 3.64 Lattes et al. (52)

Belgium 0.011 2502 9 0.36 Vandermarliere et al. (53)
Brazil 0.055 982 44 4.5 Matuck et al. (26)
China 0.201 1947 25 1.28 Zhang et al. (54)
Hong Kong Not listed 440 23 5.2 Lui et al. (55)
India 0.299 305 36 11.8 Sakhuja et al. (56)
1414 166 13 John et al. (32)
77 10 13 Jha et al. (57)
163 21 12.96 Sharma et al. (58)
202 27 13 Ram et al. (5)
Iran 0.028 1510 8 1.4 Aslani and Einollahi (59)
12820 44 0.3 Basiri et al. (60)
1350 52 3.9 Ghafari et al. (61)
Mexico 0.025 545 10 1.8 Melchor et al. (62)
Pakistan 0.263 850 130 15.2 Naqvi et al. (50)
Slovenia 0.015 273 8 2.9 Koselj et al. (63)
South Africa 0.692 487 22 4.5 Hall et al. (64)
Spain 0.024 1261 27 2.1 Queipo et al. (65)
Taiwan Not listed 756 29 3.8 Chen et al. (66)
404 6 1.5 Hsu et al. (67)
Thailand 0.197 151 5 3.3 Ruangkanchanasetr et al. (68)
Tunisia 0.028 368 5 1.3 Dridi et al. (7)
359 9 2.5 Kaaroud et al. (69)
Turkey 0.032 443 20 4.5 Atasever et al. (70)
261 8 3.06 Cavusoglu et al. (4)
274 16 5.8 Apaydin et al. (27)
520 22 4.2 Yildiz et al. (23)
880 36 4.1 Sayiner et al. (28)
283 10 3.1 Ergun et al. (71)
935 19 2.0 Koseoglu et al. (72)
UK 0.012 633 11 1.7 Higgins et al. (25)
USA 0.003 15870 66 0.4 Klote et al. (73)
3921 3 0.07 Jie et al. (74)
Yugoslavia 0.041 456 13 3.13 Lezaic et al. (75)

of the disease, specifically reactivation of the latent form, which
more commonly occurs in the immunocompromised state (7).
However, diagnosis of latent TB infection (LTBI) is problematic
because the tuberculin skin test (TST), which has been exten-
sively used for more than 100 years, has several limitations. False-
positive results caused by exposure to non-TB mycobacteria or
prior Bacille Calmette-Guerin vaccination, false-negative results
due to cutaneous anergy with underlying immunosuppression,
interobserver variability, and the booster effect reduce the effi-
ciency of a strategy of targeted use of the TST and treatment of
LTBI (8 –10). Newly developed interferon (INF)-␥ release assays
(IGRAs) measure the INF-␥ secretion of T cells on stimulation
with M. tuberculosis specific antigens (11, 12). The IGRAs benefit
from the availability of a positive control to exclude anergy and
allow a more accurate diagnosis of LTBI in immunocompetent
patients (13).
Chemoprophylaxis with INH has been shown in ran-
domized controlled trials (RCTs) to be effective in reducing
the development of TB by 60% to 90% in immunocompetent
individuals in large-scale studies (14, 15) and also in HIV pos-
itive individuals (16, 17). Given the difficulties in diagnosing and
treating established TB infection in the immunocompromised
transplant recipient, along with the risks to graft function that it
poses, there is interest in similar chemoprophylaxis regimens.
This review will critically appraise the published literature on
prophylaxis in renal transplantation, because there is a paucity of
data in the transplantation of other organs.
MATERIALS AND METHODS
A systematic literature search was performed using Ovid MEDLINE,
EMBASE, the Cochrane Central Registry of Controlled Trials, the Transplant
Library from the Centre for Evidence in Transplantation, and Clinical Trial
© 2010 Lippincott Williams & Wilkins
Registries (clinicaltrials.gov, current controlled trials, the National Research
Register, and the Cochrane Renal Group Register). No date or language
limits were applied. Search terms included all aliases for TB, combined with
terms for kidney transplantation and INH prophylaxis. The search strategy
included any form of hepatic dysfunction, including hepatitis. Given the
change in terminology over the years and between reporting groups, the
greatly varying methods of diagnosis, and in the interests of brevity, this
review will use “hepatitis” as the collective for all these terms.
Inclusion criteria included studies involving adult kidney transplant re-
cipients receiving INH prophylaxis for TB. Both randomized and nonran-
domized studies were included. Studies involving patients receiving other
organ transplants, or receiving INH for indications other than prophylaxis
were excluded. The primary outcome in this analysis was the development of
active TB infection. This is defined differently in each of the RCTs and ad-
dressed in the text. The secondary outcome was the development of hepatitis.
RCTs were assessed for quality first using the Jadad score (18). The Jadad
score is a composite system for ranking RCT quality on the basis of appro-
priate randomization, blinding, and follow-up of all patients, including with-
drawals (a score of 3 or greater is considered a good quality trial). Second, to
this potential score of 5, the Centre for Evidence in Transplantation has
added Intention-To-Treat Analysis and Allocation Concealment (19) to pro-
vide a more comprehensive assessment. Quality was scored independently by
two of the reviewers (A.C. and P.M.).
Whenever appropriate, meta-analysis was used to combine the results of
individual studies to give a summary effect. Relative risks (RRs) for dichot-
omous data were calculated with 95% confidence intervals (CIs). In the ab-
sence of significant heterogeneity, a fixed effects meta-analysis was applied.
When no events occurred in one arm of the study, a value of 0.5 was
imputed. Heterogeneity in the results of the trials was assessed using a
chi-square test of heterogeneity (significance level P⬍0.1) and the I2 mea-
sure of inconsistency (20).
RESULTS
A total of 11 reports met the inclusion criteria in the review
of INH prophylaxis (Fig. 1), of which six were nonrandomized
or observational studies (Table 2). Five reports of four RCTs
conducted from 1994 to 2009 were reviewed (Table 4). One of
these RCTs was reported twice, once in 2006 (21) and again in
2009 (22), in an analysis of the same patients but with a longer
follow-up, albeit with slightly discrepant numbers. After con-
tacting the authors, we have used the later article (22) with the
longer follow-up in our analysis. The methodologic quality of
these RCTs was moderate (Table 3) and meta-analysis was un-
dertaken of the data in these four trials.
Observational Studies
INH prophylaxis in renal transplant recipients has been
reported to be beneficial in observational studies by Yildiz et
al. (23), Spence et al. (24), Higgins et al. (25), and Matuck et
al. (26). In contrast studies by Apaydin et al. (27) and Sayiner
et al. (28) could not determine any benefit from chemopro-
phylaxis. Study characteristics and results are summarized in
Table 2.
In the study from Turkey by Yildiz et al. (23), 23 renal
transplant recipients who had a history, or TB sequelae on
chest radiograph, were given isoniazed 300 mg/day for 1 year
and one patient with a history of TB did not receive prophy-
laxis. None of the 23 patients who received prophylaxis de-
veloped TB, whereas the one patient with a history of TB, and
who did not receive prophylaxis, developed TB.
In the United Kingdom, Higgins et al. (25) identified 39
patients at increased risk of developing TB by virtue of previ-
ous residence in an endemic area or by exposure to a relative
Currie et al. 697
150 potentially relevant articles identified by
literature searching:
OVID Medline Cochrane Trials Registry
EMBASE Transplantation Library
111 articles excluded
•Duplicate publication (n=10)
•Excluded on the basis of
title/abstract (n=102)
39 full text articles suitable for inclusion in
review
Five RCTs of INH prophylaxis 34 observational studies for
(1 RCT reported twice) inclusion in narrative review
F
Four RCT
RCTs suitable
it bl ffor meta
t
analysis
Six observational studies of
INH prophylaxis
FIGURE 1. CONSORT diagram to show the inclusion and
exclusion of studies. INH, isoniazid; RCT, randomized con-
trolled trial.
with pulmonary TB. Twelve transplant recipients received
prophylaxis with INH 200 mg/day for 1 year and 27 patients
did not receive chemoprophylaxis. There were no cases of TB
in the 12 high-risk patients who received prophylaxis, but six
(22%) of 27 patients who did not receive prophylaxis devel-
oped TB. No statistics were reported.
Spence et al. (24) from the United States reported INH
prophylaxis for 1 year in 14 patients with pretransplant expo-
sure to TB and none developed TB. Mean follow-up was 32
months in this study. The study from Brazil by Matuck et al.
(26) was in a subset of 30 patients with a clinical history of TB.
Of these 30 patients who received INH, only one (3.4%) de-
veloped TB.
The study from Turkey by Apaydin et al. (27) also ret-
rospectively evaluated 274 renal transplant recipients. A total
of 51 recipients received INH prophylaxis, 200 mg/day for 6
months after transplantation, whereas 223 recipients received
no prophylaxis. The prophylaxis and nonprophylaxis groups
had a mixture of those with and without previous TB. The
mean follow-up was 37.2⫾18.5 months in the prophylaxis
group and 52⫾34 months in the nonprophylaxis group.
Three (6%) patients in the prophylaxis group and 13 (8.8%)
patients in nonprophylaxis group developed TB. They also
noted that two of 15 patients in the prophylaxis group and
four of 28 patients in the nonprophylaxis group, with a his-
tory of TB, developed TB.
In a further study from Turkey, Sayiner et al. (28) ana-
lyzed a subset of 36 patients with a clinical history of TB or
radiographic changes suggestive of TB on chest radiographs.
698 | www.transplantjournal.com Transplantation • Volume 90, Number 7, October 15, 2010

Twenty three of these patients were given 300 mg/day INH

prophylaxis
prophylaxis for 1 year and 13 others received no prophylaxis.
Incidence of TB (%)

7.7

8.8
NA

NA
No

100

22
The group receiving prophylaxis did not develop TB, whereas
in the nonprophylaxis group one case (7.7%) of TB occurred.
The studies by Matuck et al. (26), Higgins et al. (25),
Prophylaxis

Sayiner et al. (28), and Yildiz et al. (23) were retrospective

3.4 over 21, 15, 14, and 13 years, respectively, and the length of
follow-up of study patients was not reported.
0

0
A majority of the patients in the study by Apaydin et al.
(27) developed TB during the first year of the study. The
posttransplant (mo),

median time to diagnosis of TB was 6 months (range, 3–119

months) after transplant. Nine (5.6%) patients developed TB
Timing of TB

mean (range)
infection

within the first posttransplant year.

(1–129)
Nil TB

36.7

44.4
In the study by Sayiner et al. (28), the time interval
36

between transplantation and diagnosis of TB was 36.7⫾4.9

months (range, 3–111 months). TB developed in the first year
posttransplantation in eight patients (22%), whereas it oc-
curred in 28 patients (77.8%) after the first year of transplan-
56.9 (INH) 30.3

37.2 (INH) 52.4

tation (28). In the study by Matuck et al. (26), the average

transplant
Follow-up
(mo) after
Summary of key findings in observational studies of INH prophylaxis in renal transplant recipients

time to diagnosis of TB was 3 years, but no range was re-

(control)

(control)
32

NR

NR

NR

ported. A quarter of the cases occurred in the first year and the
rest in the 5 years after transplantation (26). TB was diag-
nosed at 44.4⫾33.5 months (range, 3–111 months) post-
transplantation in the study by Yildiz et al., and in 18 (82%)
prophylaxis

patients, TB was diagnosed after the first year of transplanta-

tion. No data regarding time to TB diagnosis were published
0

13

223

27
No

in the articles of Spence et al. (24) and Higgins et al. (25).

No. patients

Four of six observational studies suggest a potential

benefit of using INH as chemoprophylaxis in renal transplant
Prophylaxis

recipients. Clearly, the conclusions that can be drawn from

such observational data are limited—all these studies lacked
14

30

23

51

23

12

randomization, none report comparative statistics, and two

studies lack a suitable control group. However, they do pro-
vide strong rationale for RCTs to further assess the clinical
Previous exposure/residence

utility of prophylaxis.
Previous infection/CXR

Previous infection/CXR
Method of patient

Randomized Studies
selection

Previous exposure

Previous infection

in endemic area

Four RCTs have been undertaken examining the ef-

fect of INH prophylaxis in renal transplant recipients.
Variable risk

Quality assessment is shown in Table 3 and, as can be seen,

changes

changes

the overall methodologic quality of the reports ranges

from poor to good. Study characteristics are shown in Ta-
ble 4. All the studies were carried out in India or Pakistan, with
a mixture of pre- and posttransplant prophylaxis used. Primary
(pre-/posttransplant)

INH, isoniazid; NR, not reported; NA, not applicable.

immunosuppression, when reported, consisted of cyclosporine,

Commencement of

azathioprine, and prednisolone. In the RCTs, the recipients re-

prophylaxis

ceived INH for 1 year. The reported follow-up posttransplanta-

Post

Post

Post

Post

Post
Pre

tion ranged from 2 (29) to 4 years (22).

John et al. (29) in a study of primary INH prophylaxis
in dialysis and renal transplant recipients in India found a
trend toward lower incidence of TB in INH recipients. How-
ever, it did not reach statistical significance. In this study, 184
Country

patients on hemodialysis were studied in a double-blind, ran-

Turkey

Turkey

Turkey
Brazil
USA

domized, placebo-controlled trial with INH. There were 92

UK

patients in each group and the randomization was performed

using random number tables. No information is provided on
Yildiz et al. (23)

immunosuppressive protocol, and no assessment of LTBI is

et al. (24)

et al. (26)

et al. (28)

et al. (27)

et al. (25)
TABLE 2.

mentioned. The INH 300 mg/day and placebo were contin-

Apaydin

ued after transplantation for duration of 1 year. Seven pa-

Higgins
Matuck

Sayiner
Spence

tients in the INH group developed TB in the first year (but in

four patients there was incomplete prophylaxis) compared
© 2010 Lippincott Williams & Wilkins Currie et al. 699

TABLE 3. Methodologic quality of reports of randomized controlled trials of INH prophylaxis in postrenal transplant
tuberculosis
Jadad ITT Allocation
Randomizationa Blindingb Withdrawalsc score analysis concealmentd

John et al. (29) 2 1 1 4 Yes Yes

Agarwal et al. (30) 1 0 1 2 Yes No
Vikrant et al. (31) 2 0 1 3 Yes No
Naqvi et al. (22) 2 0 0 2 No No
Naqvi et al. (21) 1 0 0e 2 Yesf No
a
Jadad Score Key: 0 ⫽ not randomized, or randomized but inappropriate method; 1 ⫽ described as randomized; 2⫽ described as randomized with an
appropriate method.
b
0 ⫽ not blinded, or blinded but inappropriate method; 1 ⫽ described as blinded; 2 ⫽ described as blinded with appropriate method.
c
0 ⫽ inadequate description of participant withdrawal and outcome; 1 ⫽ adequate description of participant withdrawal and outcome.
d
The investigators are unable to determine to which intervention the patient has been allocated.
e
Although 12 withdrawals were reported, it was not stated in which arm of the trial these occurred.
f
No withdrawals occurred in the study by Naqvi et al. (21).
ITT, intention-to-treat.

with 10 in the placebo arm. In this study, 32 (35%) patients in
the INH group and 33 (36%) patients in the placebo group
developed clinical hepatitis and the drug was discontinued in
the intervention arm. No description of how active TB was
diagnosed was reported.
A prospective randomized trial by Agarwal et al. (30),
again from India, of INH prophylaxis (administered for 1
year or until the development of TB) in renal transplant re-
cipients, found that INH-treated patients were no less likely
than control patients to develop TB (risk ratio, 0.36; 95% CI,
0.10 –1.32; P⫽0.12). No protocols for immunosuppression
are published. The mechanism of randomization is not spec-
ified. No formal testing for LTBI is mentioned. Active TB was
diagnosed on the basis of microbiological culture, histology,
or response to antituberculous treatment criteria, but no de-
tails of the number of cases in each category was reported.
Vikrant et al. (31) reported another randomized trial
from the same institution in India. Randomization was pro-
duced by random number generating computer software.
INH prophylaxis was compared with no prophylaxis, but the
INH prophylaxis was started in the pretransplantation pe-
riod, while the patients were still in dialysis. LTBI was tested
using the Mantoux reaction, with eight on the INH group
having positive tests compared with five in the placebo group
(statistically nonsignificant). Similar levels of TB history were
noted in both the groups. In this population, TB occurred in
18 (32.7%) patients in the placebo arm compared with 9
(16.7%) in the INH arm after 2 years of follow-up (P⫽0.03;
95% CI, 0.17– 0.92). The mean follow-up was 113 weeks
(range, 3–200 weeks). Active TB was diagnosed on culture
(⬃40% of both INH and placebo groups) and on trial of
antituberculous treatment in the remaining cases. Hepatitis
was seen in both arms but rather more in the INH group
(50% vs. 31%). In this study, 33% of patients in the INH
group and 20% of patients in the control group developed
mild increase in transaminase levels, which did not require
discontinuation of INH therapy.
The randomized trial conducted by Naqvi et al. (22) was
carried out in renal transplant recipients in Pakistan and the
most recent report has a 4-year follow-up; 181 of 400 patients
received INH for 1 year. Randomization was achieved using
random number tables. Immunosuppression comprised
mostly cyclosporine, azathioprine, and prednisolone mainte-
nance; most patients did not receive induction therapy. A small
number of recipients had tacrolimus and mycophenalate
maintenance or induction therapy with interleukin-2 recep-
tor and antithymocyte globulin in both the INH and placebo
groups. TB history was similar in both INH and placebo (9 vs.
12, P⫽0.82) groups. Tuberculin skin testing for LTBI was not
performed. One patient from the INH group and 16 patients
from the nonisoniazid group developed TB in the first 4 years
after transplantation (P⬍0.0001); none of the patients re-
quired discontinuation of INH (22). The diagnosis of
active TB was felt to be definitive by the authors in 12
nonprophylaxis cases by culture and histology and “prob-
able” on the basis of radiology or polymerase chain reac-
tion in the remaining four nonprophylaxis patients and the
single prophylaxis case of TB.
Meta-Analysis
The primary outcome was development of TB after re-
nal transplantation (Fig. 2). In all trials, TB infections were
defined on the basis of clinical evaluation and not only by
microbiology. The secondary outcome was development of
hepatitis after renal transplantation (Fig. 3). The trials in-
cluded adults who received INH for TB prophylaxis after re-
nal transplantation. A total of 771 patients were randomized
in the four trials.
Primary Outcome
RR of TB infection was significantly reduced with INH
prophylaxis (4 studies, 771 patients, RR 0.31, 95% CI 0.19 –
0.51; Fig. 2). No significant heterogeneity was found (␹2⫽3.7
[P⫽0.29]; I2⫽19.0%).
Secondary Outcome
No significant difference in the incidence of hepatitis
was identified between the prophylaxis and nonprophylaxis
arms (4 studies, 771 patients, RR 1.24, 95% CI 0.92–1.67; Fig.
3). No significant heterogeneity was found (␹2⫽4.03
[P⫽0.26]; I2⫽26.0%).
700 | www.transplantjournal.com Transplantation • Volume 90, Number 7, October 15, 2010

P (INH vs.
DISCUSSION

Nil stated

Nil stated
placebo)
TB in the renal allograft recipient is a common prob-
lem, especially when the incidence and prevalence are exten-
NS

NS
sive in the general population. The nonrandomized studies
Nil stated Hepatitis, 32 (34.8)
Hepatitis, 33 (35.9)

Hepatitis, 17 (30.9)
examined in this review suggested that there is a potential

0.0003 Transient elevated

dysfunction (%)

Hepatitis, 27 (50)
Hepatitis, 1 (3.3)
value of INH similar to chemoprophylaxis in populations of
Hepatic

bilirubin, 1
renal transplant recipients at risk of development of active TB
infection, namely patients in regions in which TB is endemic

(0.55)
and in patients with evidence of previous TB infections or
exposure.
Nil

Nil
There are only four RCTs assessing the benefits of INH
P (INH vs.
placebo)

prophylaxis. The methodologic quality of the articles is mod-

erate. Our meta-analysis demonstrated a statistically signifi-
0.04
0.1

cant benefit of administering INH prophylaxis to prevent TB

TABLE 4. Summary of key findings in randomized controlled trials of INH prophylaxis in postrenal transplant tuberculosis

in renal transplant recipients. However, two of the studies

analyzed prophylaxis from the pretransplantation period,
TB (%)

3.25
4.34

0.55

7.73
16.7
49.1

while the patients were still on dialysis. This would seem ap-
10
25

propriate in view of the immunocompromised state of all

forms of renal replacement therapy, but does further con-
TB

3
4
3
15
9
27
1

16

found any analysis. Furthermore, all four RCTs were carried

out in high-risk patients in endemic areas (India and Paki-
92
92
30
60
54
55
181

207
N

stan). Thus, firm conclusions about the role of prophylaxis

are difficult to make based on such a small number of trials
Intervention

and certainly the findings cannot be extrapolated to renal

Placebo

Placebo

Placebo

Placebo

transplant populations in regions in which TB is not endemic.

INH

INH

INH

INH

The major risk factors for TB in a large prospective

analysis in an Indian population were chronic liver disease
CSA, cyclosporin A; AZA, azathioprine; INH, isoniazid; TB, tuberculosis; NS, not significant; NR, not reported.

(2 times increased risk), age, other coexisting infections, par-

Mantoux, clinical

ticularly deep mycoses, pneumocystis pneumonia and nocar-

Clinical history
Latent TB
screening

dia (1.6 times), OKT3 usage (1.8 times), and cytomegalovirus

infections (2.25 times) (32). Disseminated disease may also be
history

more common with the use of OKT3 and in the presence of

cytomegalovirus infection. Cyclosporine use seems to ad-
NR

NR

vance the time of onset to an earlier date, and patients on

Immunosuppression posttransplant

cyclosporine seldom develop TB later than 6 years after trans-

Follow-up

plantation (32). The factors associated with death on uni-

2 yr

2 yr

4 yr
NR

variate analysis were the recipient age, human leukocyte

antigen mismatching, prednisolone–azathioprine immu-
nosuppression, pretransplantation TB, posttransplant TB
(after 2 years), chronic liver disease (⬎6 years), diabetes
CSA, prednisolone,

CSA, prednisolone,

mellitus, posttransplant diabetes mellitus (⬎5 years), and

the presence of other coexisting infections (32). A recent study
by Basiri et al. (33) from Iran also reported an increased risk of
posttransplant TB with increasing numbers of rejection episodes
AZA

AZA

and duration of pretransplant dialysis, both being associated

NR

NR

with decreased immunocompetence.

A number of the nonrandomized and randomized
studies used radiographic changes suggestive of TB as a defi-
Posttransplant

Pakistan Posttransplant
prophylaxis

Pretransplant

Pretransplant
Timing of

nition of an LTBI in addition to clinical indicators such as

history or previous treatment. The radiographic indicators of
previous TB contact include apical cavitation and other pa-
renchymal changes. Studies in the general population suggest
that chest radiograph can appear normal in up to 15% of cases
Country

of TB (1). Furthermore, studies of renal transplant patients

India

India

India

have shown the expected changes of previous TB infection in

less than 60% (33). Therefore, relying on radiographic
et al. (30)

et al. (31)

et al. (22)

changes as an indicator of previous disease may miss a num-

John et al.

Agarwal

ber of cases. The ability of tuberculin skin testing (Mantoux)

Vikrant
(29)

Naqvi

in dialysis patients or patients with incipient renal failure,

who are both often anergic, to detect LTBI has shown a low
© 2010 Lippincott Williams & Wilkins Currie et al. 701

FIGURE 2. Meta-analysis and forest plot of development of tuberculosis in RCTs of INH prophylaxis for postrenal trans-
plant tuberculosis. Blue boxes represent individual studies, black diamond represents the overall effect size, and horizontal
lines demonstrate 95% confidence intervals. INH, isoniazid; CI, confidence interval; RCT, randomized controlled trial.

FIGURE 3. Meta-analysis and forest plot of development of hepatitis in RCTs of INH prophylaxis for postrenal transplant
tuberculosis. Blue boxes represent individual studies, black diamond represents the overall effect size, and horizontal lines
demonstrate 95% confidence intervals. INH, isoniazid; CI, confidence interval; RCT, randomized controlled trial.

sensitivity and specificity (34, 35). The newer assays that mea-
sure the release of INF-␥ may offer a solution to this dilemma.
However, limited studies have addressed the diagnostic per-
formances of an IGRA for LTBI in renal transplant recipients.
Several studies addressed the diagnostic performances of
IGRA for LTBI in renal dialysis patients (36 –38) or in patients
with chronic liver disease awaiting transplantation (39, 40).
Manuel et al. (39) showed that Quantiferon-TB Gold (a form
of IGRA) results were associated with high clinical risk factor
for LTBI in liver transplant candidates. In hemodialysis pa-
tients (38), no association was found between clinical risk for
LTBI and positivity on T-SPOT.TB (an alternative IGRA
technique) or TST in renal transplant recipients. In contrast,
Quantiferon-TB Gold results showed a statistically significant
association with clinical risk factor for LTBI (38). However,
the evidence for IGRAs in renal transplant recipients and in
those awaiting transplant requires further clarification in
long-term studies. Thus, the definition of patients at risk of
developing TB after renal transplantation must be based on
combination of a relevant clinical history of exposure or
abode in an endemic region as well as available diagnostic
investigation.
In the included studies, both randomized and nonran-
domized, a definitive diagnosis of M. tuberculosis infection
was not established by culture in all cases. Often a positive
acid-fast bacilli smear was all that was used, or, on occasions,
a positive response to antituberculous therapy. As the num-
bers of TB cases involved in both the randomized and non-
randomized studies are small, it is imperative to accurately
diagnose all possible TB and definitively rule out all non-TB
cases to effectively establish the effect of any potential pro-
phylactic therapy. Direct microscopy for acid-fast bacilli is
not specific for M. tuberculosis, and nontuberculous myco-
bacteria cannot be ruled out (1). Any future trials would have
to ensure effective and accurate diagnosis.
The duration of INH prophylaxis was 1 year in the four
RCTs included in this review. The current recommendations
from the European Best Practice Guidelines for Renal Trans-
plantation (41) and the American Society of Transplantation
(42) are for a 9-month course of INH prophylaxis. There is no
evidence suggesting the appropriate time to commence pro-
phlyaxis. The RCTs reviewed commenced INH prophylaxis
in both the pre- and posttransplant periods. However, some
commentators believe that pretransplant would be the most
appropriate and, considering the immunosuppressive state of
renal replacement therapy, that would seem justified when
the recipient is to have a living donor transplant, but is not
practical in those awaiting a deceased donor transplant.
Hepatotoxicity remains the major problem associated
with INH administration, especially in the elderly, the mal-
nourished, and in the alcoholic patient (6), and it generally
occurs within 4 to 8 weeks of therapy. Our meta-analysis
demonstrated no statistically significant difference in the risk
for hepatotoxicity between patients receiving INH and those
not. In patients in whom INH was discontinued because of
significant hepatitis, the majority if them were subsequently
found to have hepatitis C and B infection in the study by
Vikrant et al. (31). Unlike the situation with significant hep-
atitis, INH was safely continued in patients with mild hepa-
titis, which resolved over time in both prophylaxis and
control groups and no patient in either group had a posi-
tive viral marker. This suggests that significant hepatic dysfunc-
tion is likely to be associated with viral hepatitis rather than INH.
A significant incidence of hepatitis was reported in the
study by John et al. (29). Half of the patients who developed
TB were actually ones who had been removed from INH ther-
702 | www.transplantjournal.com
apy because of hepatitis, with hepatitis B virus infection in the
most of them. One patient in each of the studies by Agarwal et
al. (30) and Naqvi et al. (22) developed hepatic dysfunction
while receiving prophylaxis.
In a retrospective case series of INH prophylaxis in 83
renal transplant recipients by Antony et al. (43), 31% of the
patients experienced mild self-limiting hepatitis usually
within 4 weeks of INH therapy in posttransplant patients.
This hepatic dysfunction resolved with continuation of INH
therapy and no patients required the prophylaxis to be
stopped. Eight patients had laboratory evidence of chronic
hepatitis B or hepatitis B viral infection. None of the patients
developed clinical hepatotoxicity or required discontinuation
of INH. Although preexistent hepatitis does not seem to
increase the risk of INH hepatotoxicity, it may render deter-
mination of the etiology of hepatic dysfunction difficult in
transplant recipients. Furthermore, if INH is discontinued
early then its beneficial effect may not be seen.
Balancing antituberculous and immunosuppressive
therapy presents a significant therapeutic challenge because
competent cellular immunity is essential for eliminating TB
infection, but this threatens the survival of the allograft. In
addition, antituberculous medications, specifically INH, are
known for their hepatotoxicity and their ability to induce the
cytochrome P450 enzyme system, mostly with rifampicin
therapy. This system metabolizes many immunosuppressant
drugs, but particularly calcineurin inhibitors such as cyclo-
sporine and tacrolimus. Although mostly no longer used as a
primary agent in Western renal transplantation, cyclosporine
continues to be used in poorer nations, such as India (44),
while tacrolimus would also be at risk from similar pharma-
cokinetics. Antituberculous drugs, especially rifampicin, are
known to reduce cyclosporine levels by up to two to five times
through induction of the P450 system (5). The evidence sur-
rounding INH and cyclosporine is less clear. Reduction of
cyclosporine levels has been described in patients on INH
(45, 46), although these cases are confounded by the co-
administration of rifampicin. Peschke et al. (47) found that
INH administration did not alter cyclosporine levels. Sud et
al. (48) also reported that co-administration of INH does not
alter cyclosporine bioavailability. Therefore, despite the
apparent possible risks, altering immunosuppressive drug
function does not seem to be a significant risk of using INH
prophylaxis when used in conjunction with adequate thera-
peutic drug monitoring.
There is no great deal of data in other organ transplants,
but a recent systematic review of TB in liver transplant recip-
ients also suggests that INH prophylaxis should be used in
patients at risk of developing TB (49). Indeed the authors
recommend that all liver transplant recipients should be tu-
berculin skin tested and regarded as having LTBI if positive;
this contrasts with tuberculin skin testing in the anergic renal
failure population. It is also relevant that active TB infection is
associated with a high mortality after liver transplantation.
As shown in this review, the significant burden of post-
transplantation TB is in endemic regions of the world where
resources are severely limited. In Pakistan, the average cost of
immunosuppression and drug monitoring in a patient with-
out TB is 2000 US$ annually, which becomes 5000 US$ an-
nually for a renal transplant recipient who has developed TB
(50). Therefore, there is a need to balance the cost of provid-
Transplantation • Volume 90, Number 7, October 15, 2010
ing INH prophylaxis against the extra cost of maintaining
immunosuppression in a recipient needing to take rifampicin
for treatment of active TB.
CONCLUSION
TB is a significant clinical infection in renal transplant
patients. Both nonrandomized and randomized studies point
to a possible benefit of INH chemoprophylaxis in preventing
posttransplant TB. Our meta-analysis of the four RCTs pro-
vides further evidence of the potential of INH as TB prophy-
laxis after renal transplantation in the endemic areas of India
and Pakistan.
Nevertheless, the available evidence is not robust and
there is need for a large multicenter randomized and prefer-
ably blinded controlled trial performed in an endemic area,
such as India or Pakistan, Any such study should use, if pos-
sible, more recent diagnostic procedures for LTBI. Such stud-
ies should also concentrate on helping to determine which
subsets of patients will derive the greatest benefit from pro-
phylaxis. In reviewing the literature, the most significant risk
factors are previous contact or previous TB treatment, and any
prospective trial should focus on this population. However, the
available evidence does suggest that INH prophylaxis should be
considered in potential renal transplant recipients in endemic
areas or in recipients in developed countries who are at risk for
TB infection.
REFERENCES
1. API Consensus Expert Committee. API TB Consensus Guidelines
2006: Management of pulmonary tuberculosis, extra-pulmonary tu-
berculosis and tuberculosis in special situations. J Assoc Physicians India
2006; 54: 219.
2. Munoz P, Rodriguez C, Bouza E, et al. Mycobacterium tuberculosis
infection in recipients of solid organ transplants. Clin Infect Dis
2005; 40: 581.
3. Moosa MR. Renal transplantation in developing countries. In: Morris
PJ, ed. Kidney Transplantation: Principles and Practice [ed. 6]. Phila-
delphia, Elsevier 2008.
4. Cavusoglu C, Cicek-Saydam C, Karasu Z, et al. Mycobacterium tu-
berculosis infection and laboratory diagnosis in solid-organ trans-
plant recipients. Clin Transplant 2002; 16: 257.
5. Ram R, Swarnalatha G, Prasad N, et al. Tuberculosis in renal transplant
recipients. Transpl Infect Dis 2007; 9: 97.
6. Krance MB, Fisher MA. Prophylaxis of mycobacterial infections in
immunocompromised patients. Am Fam Physician 1996; 54: 1981.
7. Dridi A, Kaaroud H, Boubaker K, et al. Tuberculosis in renal transplant
recipients. Transplant Proc 2003; 35: 2682.
8. Sepulveda RL, Ferrer X, Latrach C, et al. The influence of Calmette-
Guerin bacillus immunization on the booster effect of tuberculin test-
ing in healthy young adults. Am Rev Respir Dis 1990; 142: 24.
9. Huebner RE, Schein MF, Bass JB Jr. The tuberculin skin test. Clin Infect
Dis 1993; 17: 968.
10. Wang L, Turner MO, Elwood RK, et al. A meta-analysis of the effect of
Bacille Calmette Guerin vaccination on tuberculin skin test measure-
ments. Thorax 2002; 57: 804.
11. Lalvani A. Diagnosing tuberculosis infection in the 21st century: New
tools to tackle an old enemy. Chest 2007; 131: 1898.
12. Menzies D, Pai M, Comstock G. Meta-analysis: New tests for the
diagnosis of latent tuberculosis infection: Areas of uncertainty and
recommendations for research. Ann Intern Med 2007; 146: 340.
13. Pai M, Riley LW, Colford JM Jr. Interferon-gamma assays in the im-
munodiagnosis of tuberculosis: A systematic review. Lancet Infect Dis
2004; 4: 761.
14. Centers for Disease Control and Prevention. The use of preventive
therapy for tuberculosis infection in the United States. Recommenda-
tions of the Advisory Committee for the Elimination of Tuberculosis.
MMWR Morb Mortal Wkly Rep 1990; 39: 9.
© 2010 Lippincott Williams & Wilkins
15. International Union Against Tuberculosis Committee on Prophylaxis.
Efficacy of various durations of isoniazid preventive therapy for tuber-
culosis: five years of follow-up in the IUAT trial. Bull World Health
Organ 1982; 60: 555.
16. Pape JW, Jean SS, Ho JL, et al. Effect if isoniazid prophylaxis on inci-
dence of active tuberculosis and progression of HIV infection. Lancet
1993; 342: 268.
17. Whalen CC, Johnson JL, Okwera A, et al. A trial of three regimens to
prevent tuberculosis in Ugandan adults infected with the human
immunodeficiency virus. N Engl J Med 1997; 337: 801.
18. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of
randomized clinical trials: Is blinding necessary? Control Clin Trials
1996; 17: 1.
19. Pengel L, Barcena L, Morris PJ, et al. Registry of randomized controlled
trials in transplantation. Transplantation 2005; 80: 432.
20. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-
analysis. Stat Med 2002; 21: 1539.
21. Naqvi R, Akhtar S, Noor H, et al. Efficacy of isoniazid prophylaxis in
renal allograft recipients. Transplant Proc 2006; 38: 2057.
22. Naqvi R, Naqvi A, Akhtar S, et al. Use of isoniazid chemoprophylaxis in
renal transplant recipients. Nephrol Dial Transplant 2010; 25: 634.
23. Yildiz A, Sever MS, Turkmen A, et al. Tuberculosis after renal trans-
plantation: Experience of one Turkish centre. Nephrol Dial Transplant
1998; 13: 1872.
24. Spence RK, Dafoe DC, Rabin G, et al. Mycobacterial infections in renal
allograft recipients. Arch Surg 1983; 118: 356.
25. Higgins RM, Cahn AP, Porter D, et al. Mycobacterial infections after
renal transplantation. Quart J Med 1991; 78: 145.
26. Matuck TA, Brasil P, Alvarenga Mde F, et al. Tuberculosis in renal
transplants in Rio de Janeiro. Transplant Proc 2004; 36: 905.
27. Apaydin S, Altiparmak MR, Serdengecti K, et al. Mycobacterium tuber-
culosis infections after renal transplantation. Scand J Infect Dis 2000; 32:
501.
28. Sayiner A, Ece T, Duman S, et al. Tuberculosis in renal transplant
recipients. Transplantation 1999; 68: 1268.
29. John GT, Thomas PP, Thomas M, et al. A double-blind randomized
controlled trial of primary isoniazid prophylaxis in dialysis and trans-
plant patients. Transplantation 1994; 57: 1683.
30. Agarwal SK, Gupta S, Dash SC, et al. Prospective randomised trial of
isoniazid prophylaxis in renal transplant recipient. Int Urol Nephrol
2004; 36: 425.
31. Vikrant S, Agarwal SK, Gupta S, et al. Prospective randomized control
trial of isoniazid chemoprophylaxis during renal replacement therapy.
Transplant Infect Dis 2005; 7: 99.
32. John GT, Shankar V, Abraham AM, et al. Risk factors for post-transplant
tuberculosis. Kidney Int 2001; 60: 1148.
33. Basiri A, Hosseini-Moghaddam SM, Simforoosh N, et al. The risk fac-
tors and laboratory diagnostics for post renal transplant tuberculosis: A
case-control, country-wide study on definitive cases. Transplant Infect
Dis 2008; 10: 231.
34. Klote MM, Agodoa LY, Abbott KC. Risk factors for Mycobacterium
tuberculosis in US chronic dialysis patients. Nephrol Dial Transplant
2006; 21: 3287.
35. Shankar MS, Aravindan AN, Sohal PM, et al. The prevalence of tuber-
culin sensitivity and anergy in chronic renal failure in an endemic area:
Tuberculin test and the risk of post-transplant tuberculosis. Nephrol
Dial Transplant 2005; 20: 2720.
36. Passalent L, Khan K, Richardson R, et al. Detecting latent tuberculosis
infection in hemodialysis patients: A head-to-head comparison of the
T-SPOT.TB test, tuberculin skin test, and an expert physician panel.
Clin J Am Soc Nephrol 2007; 2: 68.
37. Hursitoglu M, Cikrikcioglu MA, Tukek T, et al. Acute effect of low-flux
hemodialysis process on the results of the interferon-gamma-based
QuantiFERON-TB Gold In-Tube test in end-stage renal disease pa-
tients. Transpl Infect Dis 2009; 11: 28.
38. Triverio PA, Bridevaux PO, Roux-Lombard P, et al. Interferon-gamma
release assays versus tuberculin skin testing for detection of latent tu-
berculosis in chronic haemodialysis patients. Nephrol Dial Transplant
2009; 24: 1952.
39. Manuel O, Humar A, Preiksaitis J, et al. Comparison of Quantiferon-TB
gold with tuberculin skin test for detecting latent tuberculosis infection
prior to liver transplantation. Am J Transplant 2007; 7: 2797.
Currie et al. 703
40. Lindemann M, Dioury Y, Beckebaum S, et al. Diagnosis of tuberculosis
infection in patients awaiting liver transplantation. Hum Immunol
2009; 70: 24.
41. Berthoux F, Abramowicz D, Bradley B, et al. Section IV: Long-term
management of the transplant recipient. Nephrol Dial Transplant 2002;
17: 3.
42. Subramanian A, Dorman S. Mycobacterium tuberculosis in solid organ
transplant recipients. Am J Transplant 2009; 9(suppl 4): S57.
43. Antony SJ, Ynares C, Dummer JS. Isoniazid hepatotoxicity in renal
transplant recipients. Clin Transplant 1997; 11: 34.
44. Agarwal SK, Srivastava RK. Chronic kidney disease in India: Challenges
and solutions. Nephron Clin Pract 2009; 111: c197.
45. Langhoff E, Madsen S. Rapid metabolism of cyclosporin and pred-
nisolone in kidney-transplant patient receiving tuberculostatic treat-
ment. Lancet 1983; 2: 1031.
46. Mibu H, Yoshida K, Kagebayashi Y, et al. Low ciclosporin blood levels
induced by antituberculous drugs in a renal transplant patient. Jpn J
Transplant 1999; 34: 46.
47. Peschke B, Ernst W, Gossmann J, et al. Antituberculous drugs in kidney
transplant recipients treated with cyclosporine. Transplantation 1993;
56: 236.
48. Sud K, Muthukumar T, Singh B, et al. Isoniazid does not affect bio-
availability of cyclosporine in renal transplant recipients. Methods Find
Exp Clin Pharmacol 2000; 22: 647.
49. Holty JE, Gould MK, Meinke L, et al. Tuberculosis in liver transplant
recipients: A systematic review and meta-analysis of individual patient
data. Liver Transpl 2009; 15: 894.
50. Naqvi A, Rizvi A, Hussain Z, et al. Developing world perspective of
posttransplant tuberculosis: Morbidity, mortality, and cost implica-
tions. Transplant Proc 2001; 33: 1787.
51. WHO. World Health Organisation Report 2008: Global tuberculosis
control. Surveillance, Planning, Financing. Geneva, WHO 2008.
52. Lattes R, Radisic M, Rial M, et al. Tuberculosis in renal transplant
recipients. Transplant Infect Dis 1999; 1: 98.
53. Vandermarliere A, Van Audenhove A, Peetermans WE, et al. Mycobac-
terial infection after renal transplantation in a Western population.
Transplant Infect Dis 2003; 5: 9.
54. Zhang XF, Lv Y, Xue WJ, et al. Mycobacterium tuberculosis infection in
solid organ transplant recipients: Experience from a single center in
China. Transplant Proc 2008; 40: 1382.
55. Lui SL, Tang S, Li FK, et al. Tuberculous infection in southern Chinese
renal transplant recipients. Clin Transplant 2004; 18: 666.
56. Sakhuja V, Jha V, Varma PP, et al. The high incidence of tuberculosis
among renal transplant recipients in India. Transplantation 1996; 61:
211.
57. Jha R, Narayan G, Jaleel MA, et al. Pulmonary infections after kidney
transplantation. J Assoc Physicians India 1999; 47: 779.
58. Sharma AK, Tolani SL, Rathi GL, et al. Tuberculosis after renal trans-
plantation. Transplant Proc 2000; 32: 1959.
59. Aslani J, Einollahi B. Prevalence of tuberculosis after renal transplan-
tation in Iran. Transplant Proc 2001; 33: 2804.
60. Basiri A, Moghaddam SM, Simforoosh N, et al. Preliminary report
of a nationwide case-control study for identifying risk factors of
tuberculosis following renal transplantation. Transplant Proc 2005;
37: 3041.
61. Ghafari A, Makhdoomi K, Ahmadpoor P, et al. Tuberculosis in Iranian
kidney transplant recipients: A single-center experience. Transplant
Proc 2007; 39: 1008.
62. Melchor JL, Gracida C, Ibarra A. Increased frequency of tuberculosis in
Mexican renal transplant recipients: A single-center experience. Trans-
plant Proc 2002; 34: 78.
63. Koselj M, Kandus A, Ales A, Bren AF et al. Mycobacterial infection in
renal transplant recipients. Transplant Proc 2000; 32: 152.
64. Hall CM, Willcox PA, Swanepoel CR, et al. Mycobacterial infection in
renal transplant recipients. Chest 1994; 106: 435.
65. Queipo JA, Broseta E, Santos M, et al. Mycobacterial infection in a
series of 1261 renal transplant recipients. Clin Microbiol Infect 2003; 9:
518.
66. Chen CH, Lian JD, Cheng CH, et al. Mycobacterium tuberculosis infec-
tion following renal transplantation in Taiwan. Transplant Infect Dis
2006; 8: 148.
67. Hsu MS, Wang JL, Ko WJ, et al. Clinical features and outcome of
tuberculosis in solid organ transplant recipients. Am J Med Sci 2007;
334: 106.
704 | www.transplantjournal.com
68. Ruangkanchanasetr P, Natejumnong C, Kitpanich S, et al. Prevalence
and manifestations of tuberculosis in renal transplant recipients: A sin-
gle-center experience in Thailand. Transplant Proc 2008; 40: 2380.
69. Kaaroud H, Beji S, Boubaker K, et al. Tuberculosis after renal trans-
plantation. Transplant Proc 2007; 39: 1012.
70. Atasever A, Bacakoglu F, Toz H, et al. Tuberculosis in renal transplant
recipients on various immunosuppressive regimens. Nephrol Dial
Transplant 2005; 20: 797.
71. Ergun I, Ekmekci Y, Sengul S, et al. Mycobacterium tuberculosis infection in
renal transplant recipients. Transplant Proc 2006; 38: 1344.
Transplantation • Volume 90, Number 7, October 15, 2010
72. Koseoglu F, Emiroglu R, Karakayali H, et al. Prevalence of mycobacterial in-
fection in solid organ transplant recipients. Transplant Proc 2001; 33: 1782.
73. Klote MM, Agodoa LY, Abbott K, et al. Mycobacterium tuberculosis
infection incidence in hospitalized renal transplant patients in the
United States, 1998 –2000. Am J Transplant 2004; 4: 1523.
74. Jie T, Matas AJ, Gillingham KJ, et al. Mycobacterial infections after
kidney transplant. Transplant Proc 2005; 37: 937.
75. Lezaic V, Radivojevic R, Radosavljevic G, et al. Does tuberculosis after
kidney transplantation follow the trend of tuberculosis in general pop-
ulation? Ren Fail 2001; 23: 97.