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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 the relevant country. The prevalence of TB among renal
I cause of death in endemic countries (1). Tuberculosis (TB)
tends to behave as an opportunistic infection in patients with
transplant recipients in the Indian subcontinent (India and
Pakistan) is 13.0%, in the Far East (China, Thailand, and
organ transplants (2, 3). The prevalence of TB among renal Taiwan) is 2.0%, and among western European and North
transplant recipients has been reported in a number of obser- American populations ranges from 0.07% to 1.7%. Most of
vational studies worldwide (Table 1), and the incidence of the data are pooled from single-center registries over pro-
infection among such patients anywhere is estimated to be longed periods of time, but some of the studies are multi-
from 20 to 70 times higher than that for the general popula- center sampling from various areas within the same country.
tion (2). This prevalence mimics the endemic prevalence of In the transplant population, TB contributes to graft dys-
function, both through direct effects on the graft and as a result
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
of drug interactions, and thereby increases mortality (2, 4). Man-
travel grants in the past from Novartis, Roche, Astellas, and Genezyme agement is complex as antituberculous treatment, particularly
(P.J.M.). rifampicin, can lower the levels of the commonly used cal-
1
Centre for Evidence in Transplantation, Royal College of Surgeons of En- cineurin inhibitors (e.g., cyclosporine and tacrolimus) by the
gland and London School of Hygiene and Tropical Medicine, University
of London, London, United Kingdom.
induction of cytochrome P450 in the liver, and hence increases
2
Address correspondence to: Peter J. Morris, A.C., F.R.S., F.R.C.S., Centre the risk of graft rejection (5). Antituberculous medications are
for Evidence in Transplantation, Royal College of Surgeons of England, not without risk in the posttransplant period and specifically
35-43 Lincoln’s Inn Fields, London WC2A 3PE, United Kingdom. isoniazid (INH) has been shown to be associated with the develop-
E-mail: pmorris@rcseng.ac.uk
P.J.M. conceived the idea for the paper. A.C. and P.J.M. undertook the literature
ment of hepatic dysfunction in a variety of immunocompetent and
search and reviewed the papers. S.R.K. assisted with the meta-analysis. All immunocompromisedstates(6).ReducingtheriskofTBinatrans-
authors were involved with writing the manuscript. plant recipient is an important priority in organ transplantation,
Received 11 January 2010. Revision requested 10 March 2010. especially in the countries in which TB is endemic.
Accepted 14 June 2010.
Copyright © 2010 by Lippincott Williams & Wilkins
TB infection among renal transplant recipients presents
ISSN 0041-1337/10/9007-695 important diagnostic difficulties because of the greater incidence
DOI: 10.1097/TP.0b013e3181ecea8d of extrapulmonary involvement and the atypical presentation
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
of the disease, specifically reactivation of the latent form, which Chemoprophylaxis with INH has been shown in ran-
more commonly occurs in the immunocompromised state (7). domized controlled trials (RCTs) to be effective in reducing
However, diagnosis of latent TB infection (LTBI) is problematic the development of TB by 60% to 90% in immunocompetent
because the tuberculin skin test (TST), which has been exten- individuals in large-scale studies (14, 15) and also in HIV pos-
sively used for more than 100 years, has several limitations. False- itive individuals (16, 17). Given the difficulties in diagnosing and
positive results caused by exposure to non-TB mycobacteria or treating established TB infection in the immunocompromised
prior Bacille Calmette-Guerin vaccination, false-negative results transplant recipient, along with the risks to graft function that it
due to cutaneous anergy with underlying immunosuppression, poses, there is interest in similar chemoprophylaxis regimens.
interobserver variability, and the booster effect reduce the effi- This review will critically appraise the published literature on
ciency of a strategy of targeted use of the TST and treatment of prophylaxis in renal transplantation, because there is a paucity of
LTBI (8 –10). Newly developed interferon (INF)-␥ release assays data in the transplantation of other organs.
(IGRAs) measure the INF-␥ secretion of T cells on stimulation
with M. tuberculosis specific antigens (11, 12). The IGRAs benefit MATERIALS AND METHODS
from the availability of a positive control to exclude anergy and A systematic literature search was performed using Ovid MEDLINE,
allow a more accurate diagnosis of LTBI in immunocompetent EMBASE, the Cochrane Central Registry of Controlled Trials, the Transplant
patients (13). Library from the Centre for Evidence in Transplantation, and Clinical Trial
© 2010 Lippincott Williams & Wilkins Currie et al. 697
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
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),
mean (range)
infection
36.7
44.4
In the study by Sayiner et al. (28), the time interval
36
(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
13
223
27
No
30
23
51
23
12
utility of prophylaxis.
Previous infection/CXR
Previous infection/CXR
Method of patient
Randomized Studies
selection
Previous exposure
Previous infection
in endemic area
changes
Post
Post
Post
Post
Pre
Turkey
Turkey
Brazil
USA
et al. (26)
et al. (28)
et al. (27)
et al. (25)
TABLE 2.
Sayiner
Spence
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
with 10 in the placebo arm. In this study, 32 (35%) patients in random number tables. Immunosuppression comprised
the INH group and 33 (36%) patients in the placebo group mostly cyclosporine, azathioprine, and prednisolone mainte-
developed clinical hepatitis and the drug was discontinued in nance; most patients did not receive induction therapy. A small
the intervention arm. No description of how active TB was number of recipients had tacrolimus and mycophenalate
diagnosed was reported. maintenance or induction therapy with interleukin-2 recep-
A prospective randomized trial by Agarwal et al. (30), tor and antithymocyte globulin in both the INH and placebo
again from India, of INH prophylaxis (administered for 1 groups. TB history was similar in both INH and placebo (9 vs.
year or until the development of TB) in renal transplant re- 12, P⫽0.82) groups. Tuberculin skin testing for LTBI was not
cipients, found that INH-treated patients were no less likely performed. One patient from the INH group and 16 patients
than control patients to develop TB (risk ratio, 0.36; 95% CI, from the nonisoniazid group developed TB in the first 4 years
0.10 –1.32; P⫽0.12). No protocols for immunosuppression after transplantation (P⬍0.0001); none of the patients re-
are published. The mechanism of randomization is not spec- quired discontinuation of INH (22). The diagnosis of
ified. No formal testing for LTBI is mentioned. Active TB was active TB was felt to be definitive by the authors in 12
diagnosed on the basis of microbiological culture, histology, nonprophylaxis cases by culture and histology and “prob-
or response to antituberculous treatment criteria, but no de- able” on the basis of radiology or polymerase chain reac-
tails of the number of cases in each category was reported. tion in the remaining four nonprophylaxis patients and the
Vikrant et al. (31) reported another randomized trial single prophylaxis case of TB.
from the same institution in India. Randomization was pro-
duced by random number generating computer software. Meta-Analysis
INH prophylaxis was compared with no prophylaxis, but the The primary outcome was development of TB after re-
INH prophylaxis was started in the pretransplantation pe- nal transplantation (Fig. 2). In all trials, TB infections were
riod, while the patients were still in dialysis. LTBI was tested defined on the basis of clinical evaluation and not only by
using the Mantoux reaction, with eight on the INH group microbiology. The secondary outcome was development of
having positive tests compared with five in the placebo group hepatitis after renal transplantation (Fig. 3). The trials in-
(statistically nonsignificant). Similar levels of TB history were cluded adults who received INH for TB prophylaxis after re-
noted in both the groups. In this population, TB occurred in nal transplantation. A total of 771 patients were randomized
18 (32.7%) patients in the placebo arm compared with 9 in the four trials.
(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 Primary Outcome
(⬃40% of both INH and placebo groups) and on trial of RR of TB infection was significantly reduced with INH
antituberculous treatment in the remaining cases. Hepatitis prophylaxis (4 studies, 771 patients, RR 0.31, 95% CI 0.19 –
was seen in both arms but rather more in the INH group 0.51; Fig. 2). No significant heterogeneity was found (2⫽3.7
(50% vs. 31%). In this study, 33% of patients in the INH [P⫽0.29]; I2⫽19.0%).
group and 20% of patients in the control group developed
mild increase in transaminase levels, which did not require Secondary Outcome
discontinuation of INH therapy. No significant difference in the incidence of hepatitis
The randomized trial conducted by Naqvi et al. (22) was was identified between the prophylaxis and nonprophylaxis
carried out in renal transplant recipients in Pakistan and the arms (4 studies, 771 patients, RR 1.24, 95% CI 0.92–1.67; Fig.
most recent report has a 4-year follow-up; 181 of 400 patients 3). No significant heterogeneity was found (2⫽4.03
received INH for 1 year. Randomization was achieved using [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
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)
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
3
4
3
15
9
27
1
16
207
N
Placebo
Placebo
Placebo
INH
INH
INH
NR
2 yr
4 yr
NR
CSA, prednisolone,
AZA
NR
Pakistan Posttransplant
prophylaxis
Pretransplant
Pretransplant
Timing of
India
India
et al. (31)
et al. (22)
Agarwal
Naqvi
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- bacteria cannot be ruled out (1). Any future trials would have
sure the release of INF-␥ may offer a solution to this dilemma. to ensure effective and accurate diagnosis.
However, limited studies have addressed the diagnostic per- The duration of INH prophylaxis was 1 year in the four
formances of an IGRA for LTBI in renal transplant recipients. RCTs included in this review. The current recommendations
Several studies addressed the diagnostic performances of from the European Best Practice Guidelines for Renal Trans-
IGRA for LTBI in renal dialysis patients (36 –38) or in patients plantation (41) and the American Society of Transplantation
with chronic liver disease awaiting transplantation (39, 40). (42) are for a 9-month course of INH prophylaxis. There is no
Manuel et al. (39) showed that Quantiferon-TB Gold (a form evidence suggesting the appropriate time to commence pro-
of IGRA) results were associated with high clinical risk factor phlyaxis. The RCTs reviewed commenced INH prophylaxis
for LTBI in liver transplant candidates. In hemodialysis pa- in both the pre- and posttransplant periods. However, some
tients (38), no association was found between clinical risk for commentators believe that pretransplant would be the most
LTBI and positivity on T-SPOT.TB (an alternative IGRA appropriate and, considering the immunosuppressive state of
technique) or TST in renal transplant recipients. In contrast, renal replacement therapy, that would seem justified when
Quantiferon-TB Gold results showed a statistically significant the recipient is to have a living donor transplant, but is not
association with clinical risk factor for LTBI (38). However, practical in those awaiting a deceased donor transplant.
the evidence for IGRAs in renal transplant recipients and in Hepatotoxicity remains the major problem associated
those awaiting transplant requires further clarification in with INH administration, especially in the elderly, the mal-
long-term studies. Thus, the definition of patients at risk of nourished, and in the alcoholic patient (6), and it generally
developing TB after renal transplantation must be based on occurs within 4 to 8 weeks of therapy. Our meta-analysis
combination of a relevant clinical history of exposure or demonstrated no statistically significant difference in the risk
abode in an endemic region as well as available diagnostic for hepatotoxicity between patients receiving INH and those
investigation. not. In patients in whom INH was discontinued because of
In the included studies, both randomized and nonran- significant hepatitis, the majority if them were subsequently
domized, a definitive diagnosis of M. tuberculosis infection found to have hepatitis C and B infection in the study by
was not established by culture in all cases. Often a positive Vikrant et al. (31). Unlike the situation with significant hep-
acid-fast bacilli smear was all that was used, or, on occasions, atitis, INH was safely continued in patients with mild hepa-
a positive response to antituberculous therapy. As the num- titis, which resolved over time in both prophylaxis and
bers of TB cases involved in both the randomized and non- control groups and no patient in either group had a posi-
randomized studies are small, it is imperative to accurately tive viral marker. This suggests that significant hepatic dysfunc-
diagnose all possible TB and definitively rule out all non-TB tion is likely to be associated with viral hepatitis rather than INH.
cases to effectively establish the effect of any potential pro- A significant incidence of hepatitis was reported in the
phylactic therapy. Direct microscopy for acid-fast bacilli is study by John et al. (29). Half of the patients who developed
not specific for M. tuberculosis, and nontuberculous myco- TB were actually ones who had been removed from INH ther-
702 | www.transplantjournal.com Transplantation • Volume 90, Number 7, October 15, 2010
apy because of hepatitis, with hepatitis B virus infection in the ing INH prophylaxis against the extra cost of maintaining
most of them. One patient in each of the studies by Agarwal et immunosuppression in a recipient needing to take rifampicin
al. (30) and Naqvi et al. (22) developed hepatic dysfunction for treatment of active TB.
while receiving prophylaxis.
In a retrospective case series of INH prophylaxis in 83 CONCLUSION
renal transplant recipients by Antony et al. (43), 31% of the
TB is a significant clinical infection in renal transplant
patients experienced mild self-limiting hepatitis usually
patients. Both nonrandomized and randomized studies point
within 4 weeks of INH therapy in posttransplant patients.
to a possible benefit of INH chemoprophylaxis in preventing
This hepatic dysfunction resolved with continuation of INH
posttransplant TB. Our meta-analysis of the four RCTs pro-
therapy and no patients required the prophylaxis to be
vides further evidence of the potential of INH as TB prophy-
stopped. Eight patients had laboratory evidence of chronic
laxis after renal transplantation in the endemic areas of India
hepatitis B or hepatitis B viral infection. None of the patients
and Pakistan.
developed clinical hepatotoxicity or required discontinuation
Nevertheless, the available evidence is not robust and
of INH. Although preexistent hepatitis does not seem to
there is need for a large multicenter randomized and prefer-
increase the risk of INH hepatotoxicity, it may render deter-
ably blinded controlled trial performed in an endemic area,
mination of the etiology of hepatic dysfunction difficult in
such as India or Pakistan, Any such study should use, if pos-
transplant recipients. Furthermore, if INH is discontinued
sible, more recent diagnostic procedures for LTBI. Such stud-
early then its beneficial effect may not be seen.
ies should also concentrate on helping to determine which
Balancing antituberculous and immunosuppressive
subsets of patients will derive the greatest benefit from pro-
therapy presents a significant therapeutic challenge because
phylaxis. In reviewing the literature, the most significant risk
competent cellular immunity is essential for eliminating TB
factors are previous contact or previous TB treatment, and any
infection, but this threatens the survival of the allograft. In
prospective trial should focus on this population. However, the
addition, antituberculous medications, specifically INH, are
available evidence does suggest that INH prophylaxis should be
known for their hepatotoxicity and their ability to induce the
considered in potential renal transplant recipients in endemic
cytochrome P450 enzyme system, mostly with rifampicin
areas or in recipients in developed countries who are at risk for
therapy. This system metabolizes many immunosuppressant
TB infection.
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 REFERENCES
continues to be used in poorer nations, such as India (44), 1. API Consensus Expert Committee. API TB Consensus Guidelines
while tacrolimus would also be at risk from similar pharma- 2006: Management of pulmonary tuberculosis, extra-pulmonary tu-
berculosis and tuberculosis in special situations. J Assoc Physicians India
cokinetics. Antituberculous drugs, especially rifampicin, are 2006; 54: 219.
known to reduce cyclosporine levels by up to two to five times 2. Munoz P, Rodriguez C, Bouza E, et al. Mycobacterium tuberculosis
through induction of the P450 system (5). The evidence sur- infection in recipients of solid organ transplants. Clin Infect Dis
rounding INH and cyclosporine is less clear. Reduction of 2005; 40: 581.
3. Moosa MR. Renal transplantation in developing countries. In: Morris
cyclosporine levels has been described in patients on INH PJ, ed. Kidney Transplantation: Principles and Practice [ed. 6]. Phila-
(45, 46), although these cases are confounded by the co- delphia, Elsevier 2008.
administration of rifampicin. Peschke et al. (47) found that 4. Cavusoglu C, Cicek-Saydam C, Karasu Z, et al. Mycobacterium tu-
INH administration did not alter cyclosporine levels. Sud et berculosis infection and laboratory diagnosis in solid-organ trans-
al. (48) also reported that co-administration of INH does not plant recipients. Clin Transplant 2002; 16: 257.
5. Ram R, Swarnalatha G, Prasad N, et al. Tuberculosis in renal transplant
alter cyclosporine bioavailability. Therefore, despite the recipients. Transpl Infect Dis 2007; 9: 97.
apparent possible risks, altering immunosuppressive drug 6. Krance MB, Fisher MA. Prophylaxis of mycobacterial infections in
function does not seem to be a significant risk of using INH immunocompromised patients. Am Fam Physician 1996; 54: 1981.
prophylaxis when used in conjunction with adequate thera- 7. Dridi A, Kaaroud H, Boubaker K, et al. Tuberculosis in renal transplant
recipients. Transplant Proc 2003; 35: 2682.
peutic drug monitoring. 8. Sepulveda RL, Ferrer X, Latrach C, et al. The influence of Calmette-
There is no great deal of data in other organ transplants, Guerin bacillus immunization on the booster effect of tuberculin test-
but a recent systematic review of TB in liver transplant recip- ing in healthy young adults. Am Rev Respir Dis 1990; 142: 24.
ients also suggests that INH prophylaxis should be used in 9. Huebner RE, Schein MF, Bass JB Jr. The tuberculin skin test. Clin Infect
patients at risk of developing TB (49). Indeed the authors Dis 1993; 17: 968.
10. Wang L, Turner MO, Elwood RK, et al. A meta-analysis of the effect of
recommend that all liver transplant recipients should be tu- Bacille Calmette Guerin vaccination on tuberculin skin test measure-
berculin skin tested and regarded as having LTBI if positive; ments. Thorax 2002; 57: 804.
this contrasts with tuberculin skin testing in the anergic renal 11. Lalvani A. Diagnosing tuberculosis infection in the 21st century: New
failure population. It is also relevant that active TB infection is tools to tackle an old enemy. Chest 2007; 131: 1898.
12. Menzies D, Pai M, Comstock G. Meta-analysis: New tests for the
associated with a high mortality after liver transplantation. diagnosis of latent tuberculosis infection: Areas of uncertainty and
As shown in this review, the significant burden of post- recommendations for research. Ann Intern Med 2007; 146: 340.
transplantation TB is in endemic regions of the world where 13. Pai M, Riley LW, Colford JM Jr. Interferon-gamma assays in the im-
resources are severely limited. In Pakistan, the average cost of munodiagnosis of tuberculosis: A systematic review. Lancet Infect Dis
immunosuppression and drug monitoring in a patient with- 2004; 4: 761.
14. Centers for Disease Control and Prevention. The use of preventive
out TB is 2000 US$ annually, which becomes 5000 US$ an- therapy for tuberculosis infection in the United States. Recommenda-
nually for a renal transplant recipient who has developed TB tions of the Advisory Committee for the Elimination of Tuberculosis.
(50). Therefore, there is a need to balance the cost of provid- MMWR Morb Mortal Wkly Rep 1990; 39: 9.
© 2010 Lippincott Williams & Wilkins Currie et al. 703
15. International Union Against Tuberculosis Committee on Prophylaxis. 40. Lindemann M, Dioury Y, Beckebaum S, et al. Diagnosis of tuberculosis
Efficacy of various durations of isoniazid preventive therapy for tuber- infection in patients awaiting liver transplantation. Hum Immunol
culosis: five years of follow-up in the IUAT trial. Bull World Health 2009; 70: 24.
Organ 1982; 60: 555. 41. Berthoux F, Abramowicz D, Bradley B, et al. Section IV: Long-term
16. Pape JW, Jean SS, Ho JL, et al. Effect if isoniazid prophylaxis on inci- management of the transplant recipient. Nephrol Dial Transplant 2002;
dence of active tuberculosis and progression of HIV infection. Lancet 17: 3.
1993; 342: 268. 42. Subramanian A, Dorman S. Mycobacterium tuberculosis in solid organ
17. Whalen CC, Johnson JL, Okwera A, et al. A trial of three regimens to transplant recipients. Am J Transplant 2009; 9(suppl 4): S57.
prevent tuberculosis in Ugandan adults infected with the human 43. Antony SJ, Ynares C, Dummer JS. Isoniazid hepatotoxicity in renal
immunodeficiency virus. N Engl J Med 1997; 337: 801. transplant recipients. Clin Transplant 1997; 11: 34.
18. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of 44. Agarwal SK, Srivastava RK. Chronic kidney disease in India: Challenges
randomized clinical trials: Is blinding necessary? Control Clin Trials and solutions. Nephron Clin Pract 2009; 111: c197.
1996; 17: 1. 45. Langhoff E, Madsen S. Rapid metabolism of cyclosporin and pred-
19. Pengel L, Barcena L, Morris PJ, et al. Registry of randomized controlled nisolone in kidney-transplant patient receiving tuberculostatic treat-
trials in transplantation. Transplantation 2005; 80: 432. ment. Lancet 1983; 2: 1031.
20. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta- 46. Mibu H, Yoshida K, Kagebayashi Y, et al. Low ciclosporin blood levels
analysis. Stat Med 2002; 21: 1539. induced by antituberculous drugs in a renal transplant patient. Jpn J
Transplant 1999; 34: 46.
21. Naqvi R, Akhtar S, Noor H, et al. Efficacy of isoniazid prophylaxis in
47. Peschke B, Ernst W, Gossmann J, et al. Antituberculous drugs in kidney
renal allograft recipients. Transplant Proc 2006; 38: 2057.
transplant recipients treated with cyclosporine. Transplantation 1993;
22. Naqvi R, Naqvi A, Akhtar S, et al. Use of isoniazid chemoprophylaxis in
56: 236.
renal transplant recipients. Nephrol Dial Transplant 2010; 25: 634.
48. Sud K, Muthukumar T, Singh B, et al. Isoniazid does not affect bio-
23. Yildiz A, Sever MS, Turkmen A, et al. Tuberculosis after renal trans- availability of cyclosporine in renal transplant recipients. Methods Find
plantation: Experience of one Turkish centre. Nephrol Dial Transplant Exp Clin Pharmacol 2000; 22: 647.
1998; 13: 1872. 49. Holty JE, Gould MK, Meinke L, et al. Tuberculosis in liver transplant
24. Spence RK, Dafoe DC, Rabin G, et al. Mycobacterial infections in renal recipients: A systematic review and meta-analysis of individual patient
allograft recipients. Arch Surg 1983; 118: 356. data. Liver Transpl 2009; 15: 894.
25. Higgins RM, Cahn AP, Porter D, et al. Mycobacterial infections after 50. Naqvi A, Rizvi A, Hussain Z, et al. Developing world perspective of
renal transplantation. Quart J Med 1991; 78: 145. posttransplant tuberculosis: Morbidity, mortality, and cost implica-
26. Matuck TA, Brasil P, Alvarenga Mde F, et al. Tuberculosis in renal tions. Transplant Proc 2001; 33: 1787.
transplants in Rio de Janeiro. Transplant Proc 2004; 36: 905. 51. WHO. World Health Organisation Report 2008: Global tuberculosis
27. Apaydin S, Altiparmak MR, Serdengecti K, et al. Mycobacterium tuber- control. Surveillance, Planning, Financing. Geneva, WHO 2008.
culosis infections after renal transplantation. Scand J Infect Dis 2000; 32: 52. Lattes R, Radisic M, Rial M, et al. Tuberculosis in renal transplant
501. recipients. Transplant Infect Dis 1999; 1: 98.
28. Sayiner A, Ece T, Duman S, et al. Tuberculosis in renal transplant 53. Vandermarliere A, Van Audenhove A, Peetermans WE, et al. Mycobac-
recipients. Transplantation 1999; 68: 1268. terial infection after renal transplantation in a Western population.
29. John GT, Thomas PP, Thomas M, et al. A double-blind randomized Transplant Infect Dis 2003; 5: 9.
controlled trial of primary isoniazid prophylaxis in dialysis and trans- 54. Zhang XF, Lv Y, Xue WJ, et al. Mycobacterium tuberculosis infection in
plant patients. Transplantation 1994; 57: 1683. solid organ transplant recipients: Experience from a single center in
30. Agarwal SK, Gupta S, Dash SC, et al. Prospective randomised trial of China. Transplant Proc 2008; 40: 1382.
isoniazid prophylaxis in renal transplant recipient. Int Urol Nephrol 55. Lui SL, Tang S, Li FK, et al. Tuberculous infection in southern Chinese
2004; 36: 425. renal transplant recipients. Clin Transplant 2004; 18: 666.
31. Vikrant S, Agarwal SK, Gupta S, et al. Prospective randomized control 56. Sakhuja V, Jha V, Varma PP, et al. The high incidence of tuberculosis
trial of isoniazid chemoprophylaxis during renal replacement therapy. among renal transplant recipients in India. Transplantation 1996; 61:
Transplant Infect Dis 2005; 7: 99. 211.
32. John GT, Shankar V, Abraham AM, et al. Risk factors for post-transplant 57. Jha R, Narayan G, Jaleel MA, et al. Pulmonary infections after kidney
tuberculosis. Kidney Int 2001; 60: 1148. transplantation. J Assoc Physicians India 1999; 47: 779.
33. Basiri A, Hosseini-Moghaddam SM, Simforoosh N, et al. The risk fac- 58. Sharma AK, Tolani SL, Rathi GL, et al. Tuberculosis after renal trans-
tors and laboratory diagnostics for post renal transplant tuberculosis: A plantation. Transplant Proc 2000; 32: 1959.
case-control, country-wide study on definitive cases. Transplant Infect 59. Aslani J, Einollahi B. Prevalence of tuberculosis after renal transplan-
Dis 2008; 10: 231. tation in Iran. Transplant Proc 2001; 33: 2804.
34. Klote MM, Agodoa LY, Abbott KC. Risk factors for Mycobacterium 60. Basiri A, Moghaddam SM, Simforoosh N, et al. Preliminary report
tuberculosis in US chronic dialysis patients. Nephrol Dial Transplant of a nationwide case-control study for identifying risk factors of
2006; 21: 3287. tuberculosis following renal transplantation. Transplant Proc 2005;
37: 3041.
35. Shankar MS, Aravindan AN, Sohal PM, et al. The prevalence of tuber-
61. Ghafari A, Makhdoomi K, Ahmadpoor P, et al. Tuberculosis in Iranian
culin sensitivity and anergy in chronic renal failure in an endemic area:
kidney transplant recipients: A single-center experience. Transplant
Tuberculin test and the risk of post-transplant tuberculosis. Nephrol
Proc 2007; 39: 1008.
Dial Transplant 2005; 20: 2720.
62. Melchor JL, Gracida C, Ibarra A. Increased frequency of tuberculosis in
36. Passalent L, Khan K, Richardson R, et al. Detecting latent tuberculosis Mexican renal transplant recipients: A single-center experience. Trans-
infection in hemodialysis patients: A head-to-head comparison of the plant Proc 2002; 34: 78.
T-SPOT.TB test, tuberculin skin test, and an expert physician panel. 63. Koselj M, Kandus A, Ales A, Bren AF et al. Mycobacterial infection in
Clin J Am Soc Nephrol 2007; 2: 68. renal transplant recipients. Transplant Proc 2000; 32: 152.
37. Hursitoglu M, Cikrikcioglu MA, Tukek T, et al. Acute effect of low-flux 64. Hall CM, Willcox PA, Swanepoel CR, et al. Mycobacterial infection in
hemodialysis process on the results of the interferon-gamma-based renal transplant recipients. Chest 1994; 106: 435.
QuantiFERON-TB Gold In-Tube test in end-stage renal disease pa- 65. Queipo JA, Broseta E, Santos M, et al. Mycobacterial infection in a
tients. Transpl Infect Dis 2009; 11: 28. series of 1261 renal transplant recipients. Clin Microbiol Infect 2003; 9:
38. Triverio PA, Bridevaux PO, Roux-Lombard P, et al. Interferon-gamma 518.
release assays versus tuberculin skin testing for detection of latent tu- 66. Chen CH, Lian JD, Cheng CH, et al. Mycobacterium tuberculosis infec-
berculosis in chronic haemodialysis patients. Nephrol Dial Transplant tion following renal transplantation in Taiwan. Transplant Infect Dis
2009; 24: 1952. 2006; 8: 148.
39. Manuel O, Humar A, Preiksaitis J, et al. Comparison of Quantiferon-TB 67. Hsu MS, Wang JL, Ko WJ, et al. Clinical features and outcome of
gold with tuberculin skin test for detecting latent tuberculosis infection tuberculosis in solid organ transplant recipients. Am J Med Sci 2007;
prior to liver transplantation. Am J Transplant 2007; 7: 2797. 334: 106.
704 | www.transplantjournal.com Transplantation • Volume 90, Number 7, October 15, 2010
68. Ruangkanchanasetr P, Natejumnong C, Kitpanich S, et al. Prevalence 72. Koseoglu F, Emiroglu R, Karakayali H, et al. Prevalence of mycobacterial in-
and manifestations of tuberculosis in renal transplant recipients: A sin- fection in solid organ transplant recipients. Transplant Proc 2001; 33: 1782.
gle-center experience in Thailand. Transplant Proc 2008; 40: 2380. 73. Klote MM, Agodoa LY, Abbott K, et al. Mycobacterium tuberculosis
69. Kaaroud H, Beji S, Boubaker K, et al. Tuberculosis after renal trans- infection incidence in hospitalized renal transplant patients in the
plantation. Transplant Proc 2007; 39: 1012. United States, 1998 –2000. Am J Transplant 2004; 4: 1523.
70. Atasever A, Bacakoglu F, Toz H, et al. Tuberculosis in renal transplant 74. Jie T, Matas AJ, Gillingham KJ, et al. Mycobacterial infections after
recipients on various immunosuppressive regimens. Nephrol Dial kidney transplant. Transplant Proc 2005; 37: 937.
Transplant 2005; 20: 797. 75. Lezaic V, Radivojevic R, Radosavljevic G, et al. Does tuberculosis after
71. Ergun I, Ekmekci Y, Sengul S, et al. Mycobacterium tuberculosis infection in kidney transplantation follow the trend of tuberculosis in general pop-
renal transplant recipients. Transplant Proc 2006; 38: 1344. ulation? Ren Fail 2001; 23: 97.