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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, 0.911.65).
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: 695704)

nfection with Mycobacterium tuberculosis is still a leading

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 observational 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 population (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 England 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 Lincolns 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

Transplantation Volume 90, Number 7, October 15, 2010

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 prolonged periods of time, but some of the studies are multicenter sampling from various areas within the same country.
In the transplant population, TB contributes to graft dysfunction, both through direct effects on the graft and as a result
of drug interactions, and thereby increases mortality (2, 4). Management is complex as antituberculous treatment, particularly
rifampicin, can lower the levels of the commonly used calcineurin 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 development of hepatic dysfunction in a variety of immunocompetent and
immunocompromisedstates(6).ReducingtheriskofTBinatransplant 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
www.transplantjournal.com |

695

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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
Country

TB prevalence in general
population % (51)

N (transplant
recipients)

N (patients
with TB)

Prevalence
(%)

References

Argentina
Belgium
Brazil
China
Hong Kong
India

0.048
0.011
0.055
0.201
Not listed
0.299

384
2502
982
1947
440
305
1414
77
163
202
1510
12820
1350
545
850
273
487
1261
756
404
151
368
359
443
261
274
520
880
283
935
633
15870
3921
456

14
9
44
25
23
36
166
10
21
27
8
44
52
10
130
8
22
27
29
6
5
5
9
20
8
16
22
36
10
19
11
66
3
13

3.64
0.36
4.5
1.28
5.2
11.8
13
13
12.96
13
1.4
0.3
3.9
1.8
15.2
2.9
4.5
2.1
3.8
1.5
3.3
1.3
2.5
4.5
3.06
5.8
4.2
4.1
3.1
2.0
1.7
0.4
0.07
3.13

Lattes et al. (52)

Vandermarliere et al. (53)
Matuck et al. (26)
Zhang et al. (54)
Lui et al. (55)
Sakhuja et al. (56)
John et al. (32)
Jha et al. (57)
Sharma et al. (58)
Ram et al. (5)
Aslani and Einollahi (59)
Basiri et al. (60)
Ghafari et al. (61)
Melchor et al. (62)
Naqvi et al. (50)
Koselj et al. (63)
Hall et al. (64)
Queipo et al. (65)
Chen et al. (66)
Hsu et al. (67)
Ruangkanchanasetr et al. (68)
Dridi et al. (7)
Kaaroud et al. (69)
Atasever et al. (70)
Cavusoglu et al. (4)
Apaydin et al. (27)
Yildiz et al. (23)
Sayiner et al. (28)
Ergun et al. (71)
Koseoglu et al. (72)
Higgins et al. (25)
Klote et al. (73)
Jie et al. (74)
Lezaic et al. (75)

Iran

Mexico
Pakistan
Slovenia
South Africa
Spain
Taiwan

0.028

0.025
0.263
0.015
0.692
0.024
Not listed

Thailand
Tunisia

0.197
0.028

Turkey

0.032

UK
USA

0.012
0.003

Yugoslavia

0.041

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 extensively used for more than 100 years, has several limitations. Falsepositive 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 efficiency 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 randomized 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 positive 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

Currie et al.

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 recipients receiving INH prophylaxis for TB. Both randomized and nonrandomized 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 addressed 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 appropriate randomization, blinding, and follow-up of all patients, including withdrawals (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 provide 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 dichotomous data were calculated with 95% confidence intervals (CIs). In the absence 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 P0.1) and the I2 measure 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 contacting 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 undertaken 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 chemoprophylaxis. 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 prophylaxis. None of the 23 patients who received prophylaxis developed 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 previous residence in an endemic area or by exposure to a relative

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

(1 RCT reported twice)
F
Four
RCT
RCTs suitable
it bl ffor meta
t
analysis

34 observational studies for

inclusion in narrative review

Six observational studies of

INH prophylaxis

FIGURE 1. CONSORT diagram to show the inclusion and

exclusion of studies. INH, isoniazid; RCT, randomized controlled 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 developed TB. No statistics were reported.
Spence et al. (24) from the United States reported INH
prophylaxis for 1 year in 14 patients with pretransplant exposure 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%) developed TB.
The study from Turkey by Apaydin et al. (27) also retrospectively 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 37.218.5 months in the prophylaxis
group and 5234 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 history of TB, developed TB.
In a further study from Turkey, Sayiner et al. (28) analyzed a subset of 36 patients with a clinical history of TB or
radiographic changes suggestive of TB on chest radiographs.

22
0
44.4

27

23

12

Post
Turkey

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

Post
Turkey

Post

Post
Turkey

UK
Higgins
et al. (25)

Pre
Brazil

Previous infection/CXR
changes
Previous exposure/residence
in endemic area

223
51

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

prophylaxis for 1 year and 13 others received no prophylaxis.
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),
Sayiner et al. (28), and Yildiz et al. (23) were retrospective
over 21, 15, 14, and 13 years, respectively, and the length of
follow-up of study patients was not reported.
A majority of the patients in the study by Apaydin et al.
(27) developed TB during the first year of the study. The
median time to diagnosis of TB was 6 months (range, 3119
months) after transplant. Nine (5.6%) patients developed TB
within the first posttransplant year.
In the study by Sayiner et al. (28), the time interval
between transplantation and diagnosis of TB was 36.74.9
months (range, 3111 months). TB developed in the first year
posttransplantation in eight patients (22%), whereas it occurred in 28 patients (77.8%) after the first year of transplantation (28). In the study by Matuck et al. (26), the average
time to diagnosis of TB was 3 years, but no range was reported. A quarter of the cases occurred in the first year and the
rest in the 5 years after transplantation (26). TB was diagnosed at 44.433.5 months (range, 3111 months) posttransplantation in the study by Yildiz et al., and in 18 (82%)
patients, TB was diagnosed after the first year of transplantation. No data regarding time to TB diagnosis were published
in the articles of Spence et al. (24) and Higgins et al. (25).
Four of six observational studies suggest a potential
benefit of using INH as chemoprophylaxis in renal transplant
recipients. Clearly, the conclusions that can be drawn from
such observational data are limitedall these studies lacked
randomization, none report comparative statistics, and two
studies lack a suitable control group. However, they do provide strong rationale for RCTs to further assess the clinical
utility of prophylaxis.

NR

100
0
6

8.8
6
(1129)

7.7
0
36.7
13
23

Previous infection/CXR
changes
Variable risk

56.9 (INH) 30.3

(control)
37.2 (INH) 52.4
(control)
NR

NA
3.4
36
0
30
Previous infection

NR

NA
0
Nil TB
32
0
14
Post
USA

Previous exposure

No
prophylaxis
Country

Commencement of
prophylaxis
(pre-/posttransplant)

Method of patient
selection

Prophylaxis

Follow-up
(mo) after
transplant
No. patients

Transplantation Volume 90, Number 7, October 15, 2010

Spence
et al. (24)
Matuck
et al. (26)
Sayiner
et al. (28)
Apaydin
et al. (27)
Yildiz et al. (23)

TABLE 2.

Summary of key findings in observational studies of INH prophylaxis in renal transplant recipients

Timing of TB
infection
posttransplant (mo),
mean (range)

Prophylaxis

No
prophylaxis

www.transplantjournal.com

Incidence of TB (%)

698 |

Randomized Studies
Four RCTs have been undertaken examining the effect of INH prophylaxis in renal transplant recipients.
Quality assessment is shown in Table 3 and, as can be seen,
the overall methodologic quality of the reports ranges
from poor to good. Study characteristics are shown in Table 4. All the studies were carried out in India or Pakistan, with
a mixture of pre- and posttransplant prophylaxis used. Primary
immunosuppression, when reported, consisted of cyclosporine,
azathioprine, and prednisolone. In the RCTs, the recipients received INH for 1 year. The reported follow-up posttransplantation 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. However, it did not reach statistical significance. In this study, 184
patients on hemodialysis were studied in a double-blind, randomized, placebo-controlled trial with INH. There were 92
patients in each group and the randomization was performed
using random number tables. No information is provided on
immunosuppressive protocol, and no assessment of LTBI is
mentioned. The INH 300 mg/day and placebo were continued after transplantation for duration of 1 year. Seven patients in the INH group developed TB in the first year (but in
four patients there was incomplete prophylaxis) compared

699

Currie et al.

2010 Lippincott Williams & Wilkins

TABLE 3. Methodologic quality of reports of randomized controlled trials of INH prophylaxis in postrenal transplant
tuberculosis

John et al. (29)

Agarwal et al. (30)
Vikrant et al. (31)
Naqvi et al. (22)
Naqvi et al. (21)

Randomizationa

Blindingb

Withdrawalsc

Jadad
score

ITT
analysis

Allocation
concealmentd

2
1
2
2
1

1
0
0
0
0

1
1
1
0
0e

4
2
3
2
2

Yes
Yes
Yes
No
Yesf

Yes
No
No
No
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 recipients, 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; P0.12). No protocols for immunosuppression
are published. The mechanism of randomization is not specified. 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 details 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 produced by random number generating computer software.
INH prophylaxis was compared with no prophylaxis, but the
INH prophylaxis was started in the pretransplantation period, 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 (P0.03;
95% CI, 0.17 0.92). The mean follow-up was 113 weeks
(range, 3200 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 maintenance; most patients did not receive induction therapy. A small
number of recipients had tacrolimus and mycophenalate
maintenance or induction therapy with interleukin-2 receptor and antithymocyte globulin in both the INH and placebo
groups. TB history was similar in both INH and placebo (9 vs.
12, P0.82) 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 (P0.0001); none of the patients required 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 probable on the basis of radiology or polymerase chain reaction in the remaining four nonprophylaxis patients and the
single prophylaxis case of TB.
Meta-Analysis
The primary outcome was development of TB after renal 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 included adults who received INH for TB prophylaxis after renal 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 (23.7
[P0.29]; I219.0%).
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 0.921.67; Fig.
3). No significant heterogeneity was found (24.03
[P0.26]; I226.0%).

Nil stated

NS

Nil stated

DISCUSSION

7.73
CSA, cyclosporin A; AZA, azathioprine; INH, isoniazid; TB, tuberculosis; NS, not significant; NR, not reported.

16
207
Placebo

Clinical history
CSA, prednisolone,
AZA
Naqvi
Pakistan Posttransplant
et al. (22)

4 yr

CSA, prednisolone,
AZA
Pretransplant
Vikrant
India
et al. (31)

2 yr

NR
NR
NR
Posttransplant
Agarwal
India
et al. (30)

NR
Pretransplant

2 yr

Mantoux, clinical
history

92
92
30
60
54
55
181
INH
Placebo
INH
Placebo
INH
Placebo
INH

3
4
3
15
9
27
1

3.25
4.34
10
25
16.7
49.1
0.55

Nil stated Hepatitis, 32 (34.8)

Hepatitis, 33 (35.9)
0.1
Hepatitis, 1 (3.3)
Nil
0.04
Hepatitis, 27 (50)
Hepatitis, 17 (30.9)
0.0003 Transient elevated
bilirubin, 1
(0.55)
Nil

NS

Transplantation Volume 90, Number 7, October 15, 2010

India
John et al.
(29)

Country

Timing of
prophylaxis

Follow-up
Immunosuppression posttransplant

NR

Latent TB
screening

Intervention

TB

TB (%)

P (INH vs.
placebo)

Hepatic
dysfunction (%)

P (INH vs.
placebo)

www.transplantjournal.com

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

700 |

TB in the renal allograft recipient is a common problem, especially when the incidence and prevalence are extensive in the general population. The nonrandomized studies
examined in this review suggested that there is a potential
value of INH similar to chemoprophylaxis in populations of
renal transplant recipients at risk of development of active TB
infection, namely patients in regions in which TB is endemic
and in patients with evidence of previous TB infections or
exposure.
There are only four RCTs assessing the benefits of INH
prophylaxis. The methodologic quality of the articles is moderate. Our meta-analysis demonstrated a statistically significant benefit of administering INH prophylaxis to prevent TB
in renal transplant recipients. However, two of the studies
analyzed prophylaxis from the pretransplantation period,
while the patients were still on dialysis. This would seem appropriate in view of the immunocompromised state of all
forms of renal replacement therapy, but does further confound any analysis. Furthermore, all four RCTs were carried
out in high-risk patients in endemic areas (India and Pakistan). Thus, firm conclusions about the role of prophylaxis
are difficult to make based on such a small number of trials
and certainly the findings cannot be extrapolated to renal
transplant populations in regions in which TB is not endemic.
The major risk factors for TB in a large prospective
analysis in an Indian population were chronic liver disease
(2 times increased risk), age, other coexisting infections, particularly deep mycoses, pneumocystis pneumonia and nocardia (1.6 times), OKT3 usage (1.8 times), and cytomegalovirus
infections (2.25 times) (32). Disseminated disease may also be
more common with the use of OKT3 and in the presence of
cytomegalovirus infection. Cyclosporine use seems to advance the time of onset to an earlier date, and patients on
cyclosporine seldom develop TB later than 6 years after transplantation (32). The factors associated with death on univariate analysis were the recipient age, human leukocyte
antigen mismatching, prednisoloneazathioprine immunosuppression, pretransplantation TB, posttransplant TB
(after 2 years), chronic liver disease (6 years), diabetes
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
and duration of pretransplant dialysis, both being associated
with decreased immunocompetence.
A number of the nonrandomized and randomized
studies used radiographic changes suggestive of TB as a definition 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 parenchymal changes. Studies in the general population suggest
that chest radiograph can appear normal in up to 15% of cases
of TB (1). Furthermore, studies of renal transplant patients
have shown the expected changes of previous TB infection in
less than 60% (33). Therefore, relying on radiographic
changes as an indicator of previous disease may miss a number of cases. The ability of tuberculin skin testing (Mantoux)
in dialysis patients or patients with incipient renal failure,
who are both often anergic, to detect LTBI has shown a low

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Currie et al.

701

FIGURE 2. Meta-analysis and forest plot of development of tuberculosis 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.

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 measure the release of INF- may offer a solution to this dilemma.
However, limited studies have addressed the diagnostic performances 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 patients (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 nonrandomized, 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 numbers of TB cases involved in both the randomized and nonrandomized 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 prophylactic 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 Transplantation (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 prophlyaxis. 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 malnourished, 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 hepatitis, INH was safely continued in patients with mild hepatitis, which resolved over time in both prophylaxis and
control groups and no patient in either group had a positive viral marker. This suggests that significant hepatic dysfunction 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-

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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 determination 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 cyclosporine 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 pharmacokinetics. 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 surrounding 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 coadministration 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 therapeutic drug monitoring.
There is no great deal of data in other organ transplants,
but a recent systematic review of TB in liver transplant recipients 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 tuberculin 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 posttransplantation 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 without TB is 2000 US$ annually, which becomes 5000 US$ annually 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 provides further evidence of the potential of INH as TB prophylaxis 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 preferably blinded controlled trial performed in an endemic area,
such as India or Pakistan, Any such study should use, if possible, more recent diagnostic procedures for LTBI. Such studies should also concentrate on helping to determine which
subsets of patients will derive the greatest benefit from prophylaxis. 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.

2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.

API Consensus Expert Committee. API TB Consensus Guidelines

2006: Management of pulmonary tuberculosis, extra-pulmonary tuberculosis and tuberculosis in special situations. J Assoc Physicians India
2006; 54: 219.
Munoz P, Rodriguez C, Bouza E, et al. Mycobacterium tuberculosis
infection in recipients of solid organ transplants. Clin Infect Dis
2005; 40: 581.
Moosa MR. Renal transplantation in developing countries. In: Morris
PJ, ed. Kidney Transplantation: Principles and Practice [ed. 6]. Philadelphia, Elsevier 2008.
Cavusoglu C, Cicek-Saydam C, Karasu Z, et al. Mycobacterium tuberculosis infection and laboratory diagnosis in solid-organ transplant recipients. Clin Transplant 2002; 16: 257.
Ram R, Swarnalatha G, Prasad N, et al. Tuberculosis in renal transplant
recipients. Transpl Infect Dis 2007; 9: 97.
Krance MB, Fisher MA. Prophylaxis of mycobacterial infections in
immunocompromised patients. Am Fam Physician 1996; 54: 1981.
Dridi A, Kaaroud H, Boubaker K, et al. Tuberculosis in renal transplant
recipients. Transplant Proc 2003; 35: 2682.
Sepulveda RL, Ferrer X, Latrach C, et al. The influence of CalmetteGuerin bacillus immunization on the booster effect of tuberculin testing in healthy young adults. Am Rev Respir Dis 1990; 142: 24.
Huebner RE, Schein MF, Bass JB Jr. The tuberculin skin test. Clin Infect
Dis 1993; 17: 968.
Wang L, Turner MO, Elwood RK, et al. A meta-analysis of the effect of
Bacille Calmette Guerin vaccination on tuberculin skin test measurements. Thorax 2002; 57: 804.
Lalvani A. Diagnosing tuberculosis infection in the 21st century: New
tools to tackle an old enemy. Chest 2007; 131: 1898.
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.
Pai M, Riley LW, Colford JM Jr. Interferon-gamma assays in the immunodiagnosis of tuberculosis: A systematic review. Lancet Infect Dis
2004; 4: 761.
Centers for Disease Control and Prevention. The use of preventive
therapy for tuberculosis infection in the United States. Recommendations of the Advisory Committee for the Elimination of Tuberculosis.
MMWR Morb Mortal Wkly Rep 1990; 39: 9.

Currie et al.

2010 Lippincott Williams & Wilkins

15.

16.

17.

18.

19.
20.
21.
22.
23.

24.
25.
26.
27.

28.
29.

30.

31.

32.
33.

34.

35.

36.

37.

38.

39.

International Union Against Tuberculosis Committee on Prophylaxis.

Efficacy of various durations of isoniazid preventive therapy for tuberculosis: five years of follow-up in the IUAT trial. Bull World Health
Organ 1982; 60: 555.
Pape JW, Jean SS, Ho JL, et al. Effect if isoniazid prophylaxis on incidence of active tuberculosis and progression of HIV infection. Lancet
1993; 342: 268.
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.
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.
Pengel L, Barcena L, Morris PJ, et al. Registry of randomized controlled
trials in transplantation. Transplantation 2005; 80: 432.
Higgins JP, Thompson SG. Quantifying heterogeneity in a metaanalysis. Stat Med 2002; 21: 1539.
Naqvi R, Akhtar S, Noor H, et al. Efficacy of isoniazid prophylaxis in
renal allograft recipients. Transplant Proc 2006; 38: 2057.
Naqvi R, Naqvi A, Akhtar S, et al. Use of isoniazid chemoprophylaxis in
renal transplant recipients. Nephrol Dial Transplant 2010; 25: 634.
Yildiz A, Sever MS, Turkmen A, et al. Tuberculosis after renal transplantation: Experience of one Turkish centre. Nephrol Dial Transplant
1998; 13: 1872.
Spence RK, Dafoe DC, Rabin G, et al. Mycobacterial infections in renal
allograft recipients. Arch Surg 1983; 118: 356.
Higgins RM, Cahn AP, Porter D, et al. Mycobacterial infections after
renal transplantation. Quart J Med 1991; 78: 145.
Matuck TA, Brasil P, Alvarenga Mde F, et al. Tuberculosis in renal
transplants in Rio de Janeiro. Transplant Proc 2004; 36: 905.
Apaydin S, Altiparmak MR, Serdengecti K, et al. Mycobacterium tuberculosis infections after renal transplantation. Scand J Infect Dis 2000; 32:
501.
Sayiner A, Ece T, Duman S, et al. Tuberculosis in renal transplant
recipients. Transplantation 1999; 68: 1268.
John GT, Thomas PP, Thomas M, et al. A double-blind randomized
controlled trial of primary isoniazid prophylaxis in dialysis and transplant patients. Transplantation 1994; 57: 1683.
Agarwal SK, Gupta S, Dash SC, et al. Prospective randomised trial of
isoniazid prophylaxis in renal transplant recipient. Int Urol Nephrol
2004; 36: 425.
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.
John GT, Shankar V, Abraham AM, et al. Risk factors for post-transplant
tuberculosis. Kidney Int 2001; 60: 1148.
Basiri A, Hosseini-Moghaddam SM, Simforoosh N, et al. The risk factors and laboratory diagnostics for post renal transplant tuberculosis: A
case-control, country-wide study on definitive cases. Transplant Infect
Dis 2008; 10: 231.
Klote MM, Agodoa LY, Abbott KC. Risk factors for Mycobacterium
tuberculosis in US chronic dialysis patients. Nephrol Dial Transplant
2006; 21: 3287.
Shankar MS, Aravindan AN, Sohal PM, et al. The prevalence of tuberculin 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.
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.
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 patients. Transpl Infect Dis 2009; 11: 28.
Triverio PA, Bridevaux PO, Roux-Lombard P, et al. Interferon-gamma
release assays versus tuberculin skin testing for detection of latent tuberculosis in chronic haemodialysis patients. Nephrol Dial Transplant
2009; 24: 1952.
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.

40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.

61.
62.
63.
64.
65.
66.
67.

703

Lindemann M, Dioury Y, Beckebaum S, et al. Diagnosis of tuberculosis

infection in patients awaiting liver transplantation. Hum Immunol
2009; 70: 24.
Berthoux F, Abramowicz D, Bradley B, et al. Section IV: Long-term
management of the transplant recipient. Nephrol Dial Transplant 2002;
17: 3.
Subramanian A, Dorman S. Mycobacterium tuberculosis in solid organ
transplant recipients. Am J Transplant 2009; 9(suppl 4): S57.
Antony SJ, Ynares C, Dummer JS. Isoniazid hepatotoxicity in renal
transplant recipients. Clin Transplant 1997; 11: 34.
Agarwal SK, Srivastava RK. Chronic kidney disease in India: Challenges
and solutions. Nephron Clin Pract 2009; 111: c197.
Langhoff E, Madsen S. Rapid metabolism of cyclosporin and prednisolone in kidney-transplant patient receiving tuberculostatic treatment. Lancet 1983; 2: 1031.
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.
Peschke B, Ernst W, Gossmann J, et al. Antituberculous drugs in kidney
transplant recipients treated with cyclosporine. Transplantation 1993;
56: 236.
Sud K, Muthukumar T, Singh B, et al. Isoniazid does not affect bioavailability of cyclosporine in renal transplant recipients. Methods Find
Exp Clin Pharmacol 2000; 22: 647.
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.
Naqvi A, Rizvi A, Hussain Z, et al. Developing world perspective of
posttransplant tuberculosis: Morbidity, mortality, and cost implications. Transplant Proc 2001; 33: 1787.
WHO. World Health Organisation Report 2008: Global tuberculosis
control. Surveillance, Planning, Financing. Geneva, WHO 2008.
Lattes R, Radisic M, Rial M, et al. Tuberculosis in renal transplant
recipients. Transplant Infect Dis 1999; 1: 98.
Vandermarliere A, Van Audenhove A, Peetermans WE, et al. Mycobacterial infection after renal transplantation in a Western population.
Transplant Infect Dis 2003; 5: 9.
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.
Lui SL, Tang S, Li FK, et al. Tuberculous infection in southern Chinese
renal transplant recipients. Clin Transplant 2004; 18: 666.
Sakhuja V, Jha V, Varma PP, et al. The high incidence of tuberculosis
among renal transplant recipients in India. Transplantation 1996; 61:
211.
Jha R, Narayan G, Jaleel MA, et al. Pulmonary infections after kidney
transplantation. J Assoc Physicians India 1999; 47: 779.
Sharma AK, Tolani SL, Rathi GL, et al. Tuberculosis after renal transplantation. Transplant Proc 2000; 32: 1959.
Aslani J, Einollahi B. Prevalence of tuberculosis after renal transplantation in Iran. Transplant Proc 2001; 33: 2804.
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.
Ghafari A, Makhdoomi K, Ahmadpoor P, et al. Tuberculosis in Iranian
kidney transplant recipients: A single-center experience. Transplant
Proc 2007; 39: 1008.
Melchor JL, Gracida C, Ibarra A. Increased frequency of tuberculosis in
Mexican renal transplant recipients: A single-center experience. Transplant Proc 2002; 34: 78.
Koselj M, Kandus A, Ales A, Bren AF et al. Mycobacterial infection in
renal transplant recipients. Transplant Proc 2000; 32: 152.
Hall CM, Willcox PA, Swanepoel CR, et al. Mycobacterial infection in
renal transplant recipients. Chest 1994; 106: 435.
Queipo JA, Broseta E, Santos M, et al. Mycobacterial infection in a
series of 1261 renal transplant recipients. Clin Microbiol Infect 2003; 9:
518.
Chen CH, Lian JD, Cheng CH, et al. Mycobacterium tuberculosis infection following renal transplantation in Taiwan. Transplant Infect Dis
2006; 8: 148.
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 |
68.
69.
70.
71.

www.transplantjournal.com

Ruangkanchanasetr P, Natejumnong C, Kitpanich S, et al. Prevalence

and manifestations of tuberculosis in renal transplant recipients: A single-center experience in Thailand. Transplant Proc 2008; 40: 2380.
Kaaroud H, Beji S, Boubaker K, et al. Tuberculosis after renal transplantation. Transplant Proc 2007; 39: 1012.
Atasever A, Bacakoglu F, Toz H, et al. Tuberculosis in renal transplant
recipients on various immunosuppressive regimens. Nephrol Dial
Transplant 2005; 20: 797.
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.
73.
74.
75.

Koseoglu F, Emiroglu R, Karakayali H, et al. Prevalence of mycobacterial infection in solid organ transplant recipients. Transplant Proc 2001; 33: 1782.
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.
Jie T, Matas AJ, Gillingham KJ, et al. Mycobacterial infections after
kidney transplant. Transplant Proc 2005; 37: 937.
Lezaic V, Radivojevic R, Radosavljevic G, et al. Does tuberculosis after
kidney transplantation follow the trend of tuberculosis in general population? Ren Fail 2001; 23: 97.