The number of kidney transplanted patients has grown significantly in developing
countries, primarily driven by an epidemic of chronic kidney disease.11 Medina-Pestana JO, Duro-Garcia V. Strategies for establishing organ
transplant programs in developing countries: the Latin America and Caribbean
experience. Artif Organs 2006;30:498-500. DOI:
http://dx.doi.org/10.1111/j.1525-1594.2006.00250.x
http://dx.doi.org/10.1111/j.1525-1594.20...
In Brazil alone, over 100,000 patients are
maintained on chronic dialysis program, and such prevalence is in constant growth.22 Sesso RC, Lopes AA, Thomé FS, Lugon JR, Watanabe Y, dos Santos DR.
Report of the Brazilian Chronic Dialysis Census 2012. J Bras Nefrol 2014;36:48-53.
DOI: http://dx.doi.org/10.5935/0101-2800.20140009
http://dx.doi.org/10.5935/0101-2800.2014...
,33 Sesso RC, Lopes AA, Thomé FS, Lugon JR, Watanabe Y, dos Santos DR.
Brazilian Chronic Dialysis Survey 2013 - Trend analysis between 2011 and 2013. J Bras
Nefrol 2014;36:476-84
Kidney transplant recipients are a risk group for primary infections and reactivation of
latent Mycobacterium tuberculosis infection, with diagnostic and
treatment challenges that are specific to this group of patients: difficulty in
diagnosing tuberculosis (TB), not always with typical clinical features, high risk of
spread, high mortality rate and low sensitivity of diagnostic techniques available in
locations distant from major transplant centers, in addition to the high toxicity; and
interactions between anti-TB drugs with anti-rejection immunosuppressive agents.44 British Thoracic Society Standards of Care Committee and Joint
Tuberculosis Committee; Milburn H, Ashman N, Davies P, Doffman S, Drobniewski F, Khoo
S, et al. Guidelines for the prevention and management of Mycobacterium tuberculosis
infection and disease in adult patients with chronic kidney disease. Thorax
2010;65:557-70. PMID: 20522863
5 Morris MI, Daly JS, Blumberg E, Kumar D, Sester M, Schluger N, et al.
Diagnosis and management of tuberculosis in transplant donors: a donor-derived
infections consensus conference report. Am J Transplant 2012;12:2288-300. DOI:
http://dx.doi.org/10.1111/j.1600-6143.2012.04205.x
http://dx.doi.org/10.1111/j.1600-6143.20...
6 Reis-Santos B, Gomes T, Horta BL, Maciel EL. Tuberculosis prevalence in
renal transplant recipients: systematic review and meta-analysis. J Bras Nefrol
2013;35:206-13. DOI: http://dx.doi.org/10.5935/0101-2800.20130033
http://dx.doi.org/10.5935/0101-2800.2013...
-77 Hsu MS, Wang JL, Ko WJ, Lee PH, Chou NK, Wang SS, et al. Clinical
features and outcome of tuberculosis in solid organ transplant recipients. Am J Med
Sci 2007;334:106-10. PMID: 17700199 DOI:
http://dx.doi.org/10.1097/MAJ.0b013e31812f5a4e
http://dx.doi.org/10.1097/MAJ.0b013e3181...
Most cases of tuberculosis in renal transplant patients (TBTxR) occur by reactivation of
a latent infection in the first months after surgery and during the period of most
intense immunosuppression. However, primary infections have been reported as well as
exceptional cases of tuberculosis transmitted by the renal graft itself.55 Morris MI, Daly JS, Blumberg E, Kumar D, Sester M, Schluger N, et al.
Diagnosis and management of tuberculosis in transplant donors: a donor-derived
infections consensus conference report. Am J Transplant 2012;12:2288-300. DOI:
http://dx.doi.org/10.1111/j.1600-6143.2012.04205.x
http://dx.doi.org/10.1111/j.1600-6143.20...
The incidence of this serious complication after renal transplantation is related to
global geographic areas, ranging from 0.35% to 15% - being more common in developing
countries with high TB prevalence in the general population.66 Reis-Santos B, Gomes T, Horta BL, Maciel EL. Tuberculosis prevalence in
renal transplant recipients: systematic review and meta-analysis. J Bras Nefrol
2013;35:206-13. DOI: http://dx.doi.org/10.5935/0101-2800.20130033
http://dx.doi.org/10.5935/0101-2800.2013...
,77 Hsu MS, Wang JL, Ko WJ, Lee PH, Chou NK, Wang SS, et al. Clinical
features and outcome of tuberculosis in solid organ transplant recipients. Am J Med
Sci 2007;334:106-10. PMID: 17700199 DOI:
http://dx.doi.org/10.1097/MAJ.0b013e31812f5a4e
http://dx.doi.org/10.1097/MAJ.0b013e3181...
In a recent
meta-analysis, pooled TB prevalence in kidney transplanted patient was 2.51%; and based
on publications from the last 15 years, that is about 14 times higher than the reported
prevalence in the general population; for countries with high TB prevalence, the
meta-regression analysis reported a TBTxR prevalence 43 times higher than that for the
general the population.66 Reis-Santos B, Gomes T, Horta BL, Maciel EL. Tuberculosis prevalence in
renal transplant recipients: systematic review and meta-analysis. J Bras Nefrol
2013;35:206-13. DOI: http://dx.doi.org/10.5935/0101-2800.20130033
http://dx.doi.org/10.5935/0101-2800.2013...
Thus, TBTxR prevalence
is very high in Asian patients (up 14.7%), falling to mean values near 2.5-3.0% in
Central Europe, Northern Africa, and Latin America, being 0.5% in Western Europe and
North America (Table 1).
Tuberculosis prevalence in kidney transplanted patients, according to geographic regions [ref 66 Reis-Santos B, Gomes T, Horta BL, Maciel EL. Tuberculosis prevalence in renal transplant recipients: systematic review and meta-analysis. J Bras Nefrol 2013;35:206-13. DOI: http://dx.doi.org/10.5935/0101-2800.20130033
http://dx.doi.org/10.5935/0101-2800.2013... ,99 Muñoz P, Rodríguez C, Bouza E. Mycobacterium tuberculosis infection in recipients of solid organ transplants. Clin Infect Dis 2005;40:581-7. PMID: 15712081 DOI: http://dx.doi.org/10.1086/427692
http://dx.doi.org/10.1086/427692... modif]
Given these TBTxR prevalence rates in developing countries, it is mandatory that every
kidney recipient and donor be submitted to a well-established routine concerning TB
diagnosis (and latent TB infection). The physician should take a thorough medical
history (occupation, travels, TB past and exposure and use of anti-TB drug), and imaging
tests (chest radiograph). In specific cases, the use of tuberculin skin test (PPD) and
interferon-gamma release tests - IGRA (QuantiFERON-TB Gold and T-SPOT.TB) may aid in the
diagnosis of latent TB. However, a study analyzing the accuracy of these tests showed
low sensitivity (31%, 53% and 50%, respectively) and specificity (63%, 69% and 67%,
respectively), with PPD showing lower sensitivity and comparable specificity.88 Ferguson TW, Tangri N, Macdonald K, Hiebert B, Rigatto C, Sood MM, et
al. The Diagnostic Accuracy of Tests for Latent Tuberculosis Infection in
Hemodialysis Patients: A Systematic Review and Meta-Analysis. Transplantation 2014
Oct 3. [Epub ahead of print] DOI:
http://dx.doi.org/10.1097/TP.0000000000000451
http://dx.doi.org/10.1097/TP.00000000000...
In addition to the epidemiological risk of each region, TBTxR risk factors include:
recipient characteristics (advanced age, diabetes, chronic liver disease, and previous
transplantation), medical history (lung images compatible with TB, positive PPD,
exposure to TB), post-transplant complications (CMV, pneumonia by Pneumocystis
jiroveci and Nocardia) and use of more intensive
immunosuppression.99 Muñoz P, Rodríguez C, Bouza E. Mycobacterium tuberculosis infection in
recipients of solid organ transplants. Clin Infect Dis 2005;40:581-7. PMID: 15712081
DOI: http://dx.doi.org/10.1086/427692
http://dx.doi.org/10.1086/427692...
All TB high risk patients should be submitted to prophylaxis, taking into account that
most cases of TBTxR are associated with reactivation of latent infections with
immunosuppression and that there are difficulties with the correct diagnosis of this
disease. The overall prophylaxis is not recommended due to the high incidence of drug
complications.1010 Currie AC, Knight SR, Morris PJ. Tuberculosis in renal transplant
recipients: the evidence for prophylaxis. Transplantation 2010;90:695-704. DOI:
http://dx.doi.org/10.1097/TP.0b013e3181ecea8d
http://dx.doi.org/10.1097/TP.0b013e3181e...
The drug of choice for this
prophylaxis is isoniazid, used in the first months after the transplant.
TB diagnosis in kidney transplanted patients is usually difficult, challenging and
almost always late.44 British Thoracic Society Standards of Care Committee and Joint
Tuberculosis Committee; Milburn H, Ashman N, Davies P, Doffman S, Drobniewski F, Khoo
S, et al. Guidelines for the prevention and management of Mycobacterium tuberculosis
infection and disease in adult patients with chronic kidney disease. Thorax
2010;65:557-70. PMID: 20522863,77 Hsu MS, Wang JL, Ko WJ, Lee PH, Chou NK, Wang SS, et al. Clinical
features and outcome of tuberculosis in solid organ transplant recipients. Am J Med
Sci 2007;334:106-10. PMID: 17700199 DOI:
http://dx.doi.org/10.1097/MAJ.0b013e31812f5a4e
http://dx.doi.org/10.1097/MAJ.0b013e3181...
Extrapulmonary and disseminated manifestations are
not uncommon, with nonspecific symptoms which are different from those seen in the
general population. In this context, TB should be part of the differential diagnosis of
febrile conditions in renal transplant patients. Diagnosis is confirmed by finding the
acid-fast bacilli (AFB) in material collected from the patient, its growth in specific
culture media, or characteristic histological diagnosis of TB and the use of PCR
(polymerase chain reaction).
Recommendations for TB treatment in kidney transplanted patients follow the traditional
regimens proposed,44 British Thoracic Society Standards of Care Committee and Joint
Tuberculosis Committee; Milburn H, Ashman N, Davies P, Doffman S, Drobniewski F, Khoo
S, et al. Guidelines for the prevention and management of Mycobacterium tuberculosis
infection and disease in adult patients with chronic kidney disease. Thorax
2010;65:557-70. PMID: 20522863,55 Morris MI, Daly JS, Blumberg E, Kumar D, Sester M, Schluger N, et al.
Diagnosis and management of tuberculosis in transplant donors: a donor-derived
infections consensus conference report. Am J Transplant 2012;12:2288-300. DOI:
http://dx.doi.org/10.1111/j.1600-6143.2012.04205.x
http://dx.doi.org/10.1111/j.1600-6143.20...
,77 Hsu MS, Wang JL, Ko WJ, Lee PH, Chou NK, Wang SS, et al. Clinical
features and outcome of tuberculosis in solid organ transplant recipients. Am J Med
Sci 2007;334:106-10. PMID: 17700199 DOI:
http://dx.doi.org/10.1097/MAJ.0b013e31812f5a4e
http://dx.doi.org/10.1097/MAJ.0b013e3181...
,99 Muñoz P, Rodríguez C, Bouza E. Mycobacterium tuberculosis infection in
recipients of solid organ transplants. Clin Infect Dis 2005;40:581-7. PMID: 15712081
DOI: http://dx.doi.org/10.1086/427692
http://dx.doi.org/10.1086/427692...
and early treatment is
critical to good patient outcome. Another concern is the interaction between anti-TB
drugs with immunosuppressive agents. Rifampicin is an inducer of P450 cytochrome
enzymes, reducing serum levels of calcineurin inhibitors (cyclosporine and tacrolimus),
mTOR inhibitors (sirolimus and everolimus) and corticosteroids, which may result in
renal allograft rejection and loss.77 Hsu MS, Wang JL, Ko WJ, Lee PH, Chou NK, Wang SS, et al. Clinical
features and outcome of tuberculosis in solid organ transplant recipients. Am J Med
Sci 2007;334:106-10. PMID: 17700199 DOI:
http://dx.doi.org/10.1097/MAJ.0b013e31812f5a4e
http://dx.doi.org/10.1097/MAJ.0b013e3181...
TBTxR
patient mortality is also high in relation to TB in the general population, with rates
up to 34.9% being described.77 Hsu MS, Wang JL, Ko WJ, Lee PH, Chou NK, Wang SS, et al. Clinical
features and outcome of tuberculosis in solid organ transplant recipients. Am J Med
Sci 2007;334:106-10. PMID: 17700199 DOI:
http://dx.doi.org/10.1097/MAJ.0b013e31812f5a4e
http://dx.doi.org/10.1097/MAJ.0b013e3181...
,99 Muñoz P, Rodríguez C, Bouza E. Mycobacterium tuberculosis infection in
recipients of solid organ transplants. Clin Infect Dis 2005;40:581-7. PMID: 15712081
DOI: http://dx.doi.org/10.1086/427692
http://dx.doi.org/10.1086/427692...
,1010 Currie AC, Knight SR, Morris PJ. Tuberculosis in renal transplant
recipients: the evidence for prophylaxis. Transplantation 2010;90:695-704. DOI:
http://dx.doi.org/10.1097/TP.0b013e3181ecea8d
http://dx.doi.org/10.1097/TP.0b013e3181e...
In this issue of the Journal of Nephrology, Higuita et al. show tuberculosis data in kidney transplant patients from Colombia.1111 Higuita LMS, Nieto-Ríos JF, Daguer-Gonzalez S, Ocampo-Kohn C, Aristizabal-Alzate A, Velez-Echeverri C, et al. Tuberculosis in renal transplant patients: The experience of a single center in Medellin-Colombia, 2005-2013. J Bras Nefrol 2014;36:512-8. The authors analyzed 641 transplant patients, with 12 confirmed cases of TB (gross incidence of 1.87%) in eight years of monitoring. As described, extrapulmonary presentation was observed in one third of the cases, a high incidence of hepatotoxicity associated with anti-TB drugs, TBTxR related to acute rejection and renal allograft dysfunction, and high mortality (16.7%).
Recently in Brazil, transplant centers of excellence have described their experiences
with TBTxR. Guida et al. reported 23 cases of TBTxR among 1,342
transplants performed (1984-2007), an incidence of 1.71%, with 3 deaths caused by
TB.1212 Guida JP, Bignotto Rosane D, Urbini-Santos C, Alves-Filho G, Ribeiro
Resende M, Mazzali M. Tuberculosis in renal transplant recipients: a Brazilian center
registry. Transplant Proc 2009;41:883-4. DOI:
http://dx.doi.org/10.1016/j.transproceed.2009.01.075
http://dx.doi.org/10.1016/j.transproceed...
In another retrospective analysis,
Matuck et al. analyzed 982 transplants (1981-2002); of these, 44
developed TB after transplantation and the overall mortality was 34.9%.1313 Matuck TA, Brasil P, Alvarenga Mde F, Morgado L, Rels MD, da Costa AC,
et al. Tuberculosis in renal transplants in Rio de Janeiro. Transplant Proc
2004;36:905-6. DOI:
http://dx.doi.org/10.1016/j.transproceed.2004.03.093
http://dx.doi.org/10.1016/j.transproceed...
Already with data from the last decade
(2000-2010), Marques et al. reported 43 (2.8%) TBTxR cases among 1,549
transplant recipients, with an incidence of 803 cases/100,000 patients.1414 Marques ID, Azevedo LS, Pierrotti LC, Caires RA, Sato VA, Carmo LP, et
al. Clinical features and outcomes of tuberculosis in kidney transplant recipients in
Brazil: a report of the last decade. Clin Transplant 2013;27:E169-76. DOI:
http://dx.doi.org/10.1111/ctr.12077
http://dx.doi.org/10.1111/ctr.12077...
Only 7% of the cases had a history of TB, and TB
prophylaxis was not routinely employed. The incidence of rejection was high and
mortality was 12%, all attributed to TB.
More recently, de Lemos et al. reported 535 kidney transplant patients,
with 274 considered of high risk for TB.1515 de Lemos AS, Vieira MA, Halpern M, Quaresma RG, Borchardt AC, Santos MA,
et al. Results of implementation of preventive recommendations for tuberculosis after
renal transplantation in an endemic area. Am J Transplant 2013;13:3230-5. DOI:
http://dx.doi.org/10.1111/ajt.12470
http://dx.doi.org/10.1111/ajt.12470...
The
overall cumulative incidence was 2.1%. Among patients at low risk for TB, the incidence
of TBTxR was 1%, while among those at high risk, the incidence of TBTxR was only 0.7%
for those treated prophylactically, and 7% among 75 high risk patients who did not
receive isoniazid prophylaxis. Thus, the authors concluded on the importance of
chemoprophylaxis in patients at high risk for TB.
In conclusion, several studies show increased risk of TBTxR in developing countries,
with no concrete evidence of the effectiveness of strategies for prevention, early
diagnosis and reducing rates of morbidity and mortality in these patients.66 Reis-Santos B, Gomes T, Horta BL, Maciel EL. Tuberculosis prevalence in
renal transplant recipients: systematic review and meta-analysis. J Bras Nefrol
2013;35:206-13. DOI: http://dx.doi.org/10.5935/0101-2800.20130033
http://dx.doi.org/10.5935/0101-2800.2013...
Clinical monitoring of renal transplant recipients
in developing countries should consider constant monitoring, maintaining a high index of
clinical suspicion for TB, following the particularities of this patient population.
Referências
-
1Medina-Pestana JO, Duro-Garcia V. Strategies for establishing organ transplant programs in developing countries: the Latin America and Caribbean experience. Artif Organs 2006;30:498-500. DOI: http://dx.doi.org/10.1111/j.1525-1594.2006.00250.x
» http://dx.doi.org/10.1111/j.1525-1594.2006.00250.x -
2Sesso RC, Lopes AA, Thomé FS, Lugon JR, Watanabe Y, dos Santos DR. Report of the Brazilian Chronic Dialysis Census 2012. J Bras Nefrol 2014;36:48-53. DOI: http://dx.doi.org/10.5935/0101-2800.20140009
» http://dx.doi.org/10.5935/0101-2800.20140009 -
3Sesso RC, Lopes AA, Thomé FS, Lugon JR, Watanabe Y, dos Santos DR. Brazilian Chronic Dialysis Survey 2013 - Trend analysis between 2011 and 2013. J Bras Nefrol 2014;36:476-84
-
4British Thoracic Society Standards of Care Committee and Joint Tuberculosis Committee; Milburn H, Ashman N, Davies P, Doffman S, Drobniewski F, Khoo S, et al. Guidelines for the prevention and management of Mycobacterium tuberculosis infection and disease in adult patients with chronic kidney disease. Thorax 2010;65:557-70. PMID: 20522863
-
5Morris MI, Daly JS, Blumberg E, Kumar D, Sester M, Schluger N, et al. Diagnosis and management of tuberculosis in transplant donors: a donor-derived infections consensus conference report. Am J Transplant 2012;12:2288-300. DOI: http://dx.doi.org/10.1111/j.1600-6143.2012.04205.x
» http://dx.doi.org/10.1111/j.1600-6143.2012.04205.x -
6Reis-Santos B, Gomes T, Horta BL, Maciel EL. Tuberculosis prevalence in renal transplant recipients: systematic review and meta-analysis. J Bras Nefrol 2013;35:206-13. DOI: http://dx.doi.org/10.5935/0101-2800.20130033
» http://dx.doi.org/10.5935/0101-2800.20130033 -
7Hsu MS, Wang JL, Ko WJ, Lee PH, Chou NK, Wang SS, et al. Clinical features and outcome of tuberculosis in solid organ transplant recipients. Am J Med Sci 2007;334:106-10. PMID: 17700199 DOI: http://dx.doi.org/10.1097/MAJ.0b013e31812f5a4e
» http://dx.doi.org/10.1097/MAJ.0b013e31812f5a4e -
8Ferguson TW, Tangri N, Macdonald K, Hiebert B, Rigatto C, Sood MM, et al. The Diagnostic Accuracy of Tests for Latent Tuberculosis Infection in Hemodialysis Patients: A Systematic Review and Meta-Analysis. Transplantation 2014 Oct 3. [Epub ahead of print] DOI: http://dx.doi.org/10.1097/TP.0000000000000451
» http://dx.doi.org/10.1097/TP.0000000000000451 -
9Muñoz P, Rodríguez C, Bouza E. Mycobacterium tuberculosis infection in recipients of solid organ transplants. Clin Infect Dis 2005;40:581-7. PMID: 15712081 DOI: http://dx.doi.org/10.1086/427692
» http://dx.doi.org/10.1086/427692 -
10Currie AC, Knight SR, Morris PJ. Tuberculosis in renal transplant recipients: the evidence for prophylaxis. Transplantation 2010;90:695-704. DOI: http://dx.doi.org/10.1097/TP.0b013e3181ecea8d
» http://dx.doi.org/10.1097/TP.0b013e3181ecea8d -
11Higuita LMS, Nieto-Ríos JF, Daguer-Gonzalez S, Ocampo-Kohn C, Aristizabal-Alzate A, Velez-Echeverri C, et al. Tuberculosis in renal transplant patients: The experience of a single center in Medellin-Colombia, 2005-2013. J Bras Nefrol 2014;36:512-8.
-
12Guida JP, Bignotto Rosane D, Urbini-Santos C, Alves-Filho G, Ribeiro Resende M, Mazzali M. Tuberculosis in renal transplant recipients: a Brazilian center registry. Transplant Proc 2009;41:883-4. DOI: http://dx.doi.org/10.1016/j.transproceed.2009.01.075
» http://dx.doi.org/10.1016/j.transproceed.2009.01.075 -
13Matuck TA, Brasil P, Alvarenga Mde F, Morgado L, Rels MD, da Costa AC, et al. Tuberculosis in renal transplants in Rio de Janeiro. Transplant Proc 2004;36:905-6. DOI: http://dx.doi.org/10.1016/j.transproceed.2004.03.093
» http://dx.doi.org/10.1016/j.transproceed.2004.03.093 -
14Marques ID, Azevedo LS, Pierrotti LC, Caires RA, Sato VA, Carmo LP, et al. Clinical features and outcomes of tuberculosis in kidney transplant recipients in Brazil: a report of the last decade. Clin Transplant 2013;27:E169-76. DOI: http://dx.doi.org/10.1111/ctr.12077
» http://dx.doi.org/10.1111/ctr.12077 -
15de Lemos AS, Vieira MA, Halpern M, Quaresma RG, Borchardt AC, Santos MA, et al. Results of implementation of preventive recommendations for tuberculosis after renal transplantation in an endemic area. Am J Transplant 2013;13:3230-5. DOI: http://dx.doi.org/10.1111/ajt.12470
» http://dx.doi.org/10.1111/ajt.12470
Publication Dates
-
Publication in this collection
Oct-Dec 2014
History
-
Received
05 Oct 2014 -
Accepted
08 Oct 2014