Tuberculosis in renal transplant patients : The experience of a single center in Medellín-Colombia , 2005-2013

Introduction: Tuberculosis is a common opportunistic infection in renal transplant patients. Objective: To obtain a clinical and laboratory description of transplant patients diagnosed with tuberculosis and their response to treatment during a period ranging from 2005 to 2013 at the Pablo Tobón Uribe Hospital. Methods: Retrospective and descriptive study. Results: In 641 renal transplants, tuberculosis was confirmed in 12 cases. Of these, 25% had a history of acute rejection, and 50% had creatinine levels greater than 1.5 mg/dl prior to infection. The disease typically presented as pulmonary (50%) and disseminated (33.3%). The first phase of treatment consisted of 3 months of HZRE (isoniazid, pyrazinamide, rifampicin and ethambutol) in 75% of the cases and HZME (isoniazid, pyrazinamide, moxifloxacin and ethambutol) in 25% of the cases. During the second phase of the treatment, 75% of the cases received isoniazid and rifampicin, and 25% of the cases received isoniazid and ethambutol. The length of treatment varied between 6 and 18 months. In 41.7% of patients, hepatotoxicity was associated with the beginning of anti-tuberculosis therapy. During a year-long follow-up, renal function remained stable, and the mortality rate was 16.7%. Conclusion: Tuberculosis in the renal transplant population studied caused diverse nonspecific symptoms. Pulmonary and disseminated tuberculosis were the most frequent forms and required prolonged treatment. Antituberculosis medications had a high toxicity and mortality. This infection must be considered when patients present with a febrile syndrome of unknown origin, especially during the first year after renal transplant. AbstrAct


IntroductIon
Tuberculosis is an infectious disease caused by the microorganism Mycobacterium tuberculosis.This bacterium usually affects the lungs but can involve any organ.Tuberculosis is a frequent infection in the general population, with an overall prevalence of 169 per 100.000. 1 In transplant patients, tuberculosis becomes a serious opportunistic infection.Tuberculosis occurs on average 14 times more frequently in transplant patients than in the general population 2 and 50 to 100 times more frequently in endemic areas. 3,4The prevalence of tuberculosis in renal transplant patients varies widely in different parts of the world.][7][8][9][10] The route of transmission in the transplant population is typically from the reactivation of a latent focus of infection.][13][14] The high prevalence of tuberculosis in transplant patients is explained by the use of immunosuppressive therapies. 15These drugs lead to changes in cellular immunity and block key defense mechanisms against mycobacterial infections. 12,15,16The diagnosis of tuberculosis in renal transplant patients is difficult, 17 and treatment leads to a high risk of drug interactions and toxicity, 5,11,12,15,[18][19][20][21] which increases the risk of dysfunction and graft loss. 22This objective of this study was to obtain a clinical and laboratory description of transplant patients diagnosed with tuberculosis and their response to treatment during a period ranging from 2005 to 2013 at the Pablo Tobón Uribe Hospital in Medellín-Colombia, which is an endemic area for tuberculosis.

method
This work is a retrospective study conducted at the Pablo Tobón Uribe Hospital in Medellín-Colombia, a tertiary referral center serving a population of 4 million inhabitants.Patients who underwent a renal transplant during the period of 2005 to 2013 and were diagnosed with tuberculosis were included in this study.Tuberculosis infection was confirmed by histology, molecular testing, or positive culture for the mycobacterium.All data were obtained from medical records and recorded in a database in Excel.Demographic data such as age, sex, and the etiology of renal disease were recorded.Risk factors associated with tuberculosis, such as a history of previous rejection diagnosed by renal biopsy, induction therapy used at the time of transplantation, and immunosuppressive medication, were documented.The pharmacological treatment, associated complications, and treatment time for tuberculosis were recorded.Several outcomes were also evaluated, including mortality and graft survival.
SPSS software (version 18) was used for statistical analysis.A descriptive analysis of the data was performed by calculating frequencies and percentages of qualitative variables.Quantitative variables were described as means or medians with their respective standard deviation or quartiles according to the distribution of the data identified by the Shapiro Wills test.
The Ethics Committee of the Pablo Tobón Uribe Hospital approved this study.Furthermore, the ethical standards for human research stipulated in resolution 008430 of 1993 of the Department of Social Protection of the Republic of Colombia were followed.Researchers pledged to respect the confidentiality and privacy of the information recorded in clinical records.This work did not involve interventions on the population studied, such as direct physical examination, laboratory tests, or treatment application, and therefore posed no risk to the participants.

results
Between 2005 and 2013, 641 renal transplants were performed; a PPD was done on 570 patients (88.9%), for whom 163 had a positive result (≥ 5 mm).234 patients received Isoniazid (the 163 patients with a positive PPD plus 71 patients for whom the test was not performed).During the study period 12 cases of tuberculosis were diagnosed.The baseline characteristics of these patients are presented in Table 1.All patients received a renal transplant from a deceased donor; 7 patients were men, and 5 were women.Ten patients (83.3%) received alemtuzumab (30 mg) followed by three intravenous methylprednisolone boluses (500 mg on day 1, 250 mg on day 2, and 125 mg on day 3).The other two patients received thymoglobulin and daclizumab as induction therapy during the transplant.Three patients (25%) had at least one episode of acute rejection prior to infection.These patients were treated with methylprednisolone (500 mg intravenously daily for 3 days).The immunosuppressive medication was adjusted in two patients, and plasmapheresis was performed on the third patient.Six patients (50%) had graft dysfunction before the diagnosis of tuberculosis and creatinine levels greater than 1.5 mg/dl.
The age at the time of tuberculosis infection ranged from 17 to 73 years old with a median of 52.5 years old (p25-75 = 35-66.8).The average time between transplantation and diagnosis varied from 2 to 69 months (median of 9 months, p25-75 = 2.3-32.8).The time between the onset of symptoms and diagnosis was between 10 and 102 days (median of 25 days, p25-75 = 17.3-30).Eight patients developed tuberculosis in the first year after transplantation.
The first phase of the treatment consisted of three months of HZRE for 75% of the cases or HZME for 25% of the cases.Ten patients received between 9 and 10 months of treatment, one patient received 6 months of treatment, and another patient received 18 months of treatment (median of 10 months p25-75 = 9-10).The second phase of the treatment was conducted in 75% of cases with isoniazid and rifampicin and in 25% of cases with isoniazid and ethambutol.Five patients (41.7%) experienced hepatotoxicity associated with the use of isoniazid and rifampicin.
Coinfections with systemic cytomegalovirus infection, syphilis, candidiasis, and invasive E. coli infections were observed.Two patients died; the first patient died as a result of sepsis after 7 days of treatment, and the second patient died as a result of a severe bronchopleural fistula 6 months after starting the Anti-tuberculosis medications.
Renal function remained stable during follow-up.Creatinine levels had a median value of 1.4 mg/ dl (p25-p75 = 1.03-1.87)before diagnosis, 1.25 mg/dl (p25-p75 = 0.9-1.57)after 6 months and 1.35 mg/dl (p25-p75 = 0.96-1.7)after one year of follow-up (Table 4).During the year of follow-up, mortality was 16.7%; of the surviving patients, one exhibited acute rejection with graft loss and resumed renal replacement therapy.Ten patients (83.3%) successfully completed the tuberculosis treatment and remain without relapses at the time of publication.to 5 mm receive isoniazid prophylaxis.Furthermore, patients for whom we could not perform a PPD due to lack of availability are given prophylaxis as well due to the high prevalence of tuberculosis in our country.This protocol has been proven to be successful in other studies to decrease the incidence of tuberculosis after renal transplant. 10For example, a meta-analysis revealed that isoniazid prophylaxis in patients with latent tuberculosis, diagnosed either by tuberculin or interferon gamma testing, significantly improves the prevention of tuberculosis in renal transplant patients. 22Currently, the British Thoracic Society suggests that all patients on the transplant waiting list should be screened for latent tuberculosis.If these patients are found positive, they are treated with 300 mg isoniazid for prophylaxis for 6 months. 19lemtuzumab, used as induction therapy in 83.3% of the patients, could also have accounted for the low incidence of tuberculosis in the population studied.
Alemtuzumab is a humanized monoclonal antibody that leads to a rapid and sustained depletion of T lymphocytes. 6Previous studies have demonstrated a low incidence of mycobacterial infection in patients induced with alemtuzumab. 6n the group of patients studied here, tuberculosis occurred mainly during the first year after transplantation (66.6%), which could be explained by a possible reactivation of undetected latent tuberculosis; the median time to the emergence of symptoms was 9 months, similar to the data reported in other studies by Marques et al. 9 (median of 6.53 months), Lattes et al. 23 (13 months), and Lopez de Castilla et al. 7 (11.2months).For this reason, tuberculosis should be considered as part of the differential diagnosis performed in patients with fever of unknown origin, especially during the first year after renal transplant.
In this study, the time between onset of symptoms and diagnosis had a median of 25 days, which is similar to results reported by Marques et al. 9 and to those found in the general population. 24This late diagnosis is due to the differences observed in the clinical manifestations of tuberculosis between renal transplant patients and the general population.Tuberculosis in renal transplant patients is characterized by nonspecific symptoms, frequent extrapulmonary manifestations 3 and symptoms indistinguishable from other infections. 20In our study, the most frequent form of manifestation was pulmonary tuberculosis (50%), followed by disseminated tuberculosis (33.3%) and extrapulmonary tuberculosis (16.6%).In our study, chest radiographs or HRCT suggested the presence of opportunistic infections such as tuberculosis in all patients with respiratory complications.This indicates that these two diagnostic methodologies are complementary rather than exclusive.
Four drugs were included in the three months of the first phase of the anti-tuberculosis medications (HZRE in most patients).Two drugs were used in the second phase, which lasted 6 to 9 months.This treatment is recommended by clinical practice guidelines and has been documented in other studies. 3,9Furthermore, an anti-tuberculosis medication of renal transplant patients for less than nine months is associated with an increase in mortality. 9One of the major findings of this study is that hepatotoxicity associated with the use of isoniazid and rifampin was observed in a higher percentage of patients than in other studies. 3,9,16herefore, the use of fluoroquinolones may be a treatment option in these patients.
It is also important to consider that the interactions between the anti-tuberculosis medications and immunosuppressive drugs, such as rifampicin, can lower serum levels of calcineurin inhibitors 6,22 and increase the risk of a renal graft rejection.For this reason, it is important to monitor the serum levels of these drugs and make appropriate adjustments.In this study, renal function remained stable in most patients, and only one patient suffered acute rejection and therefore lost the organ (8.3%).This incidence was lower than the results reported in other studies by Marquez et al. 9 (44%) and Chen et al. 3 (19%).
In this study, patient mortality associated with tuberculosis was 16.7% and was higher than mortalities reported by Marquez et al. 9 (12%), Lattes et al. 23 (9.1%) and Chen et al. 3

(12.9%).
In conclusion, we found that tuberculosis in renal transplant patients manifested with varied and nonspecific symptoms.Pulmonary and disseminated tuberculosis were the most common subtypes and required longer anti-tuberculosis medications.These treatments had a very high toxicity, high mortality, and important rates of rejection and graft loss.This infection should be considered when the patient manifests febrile syndrome of unknown origin, especially during the first year after renal transplantation, and its treatment should be rigorous and strictly monitored.

tAble 2
evolution of the pAtients After six months And one yeAr of treAtment 9,21ussIonThe prevalence of tuberculosis in a group of renal transplant patients from a single center was 1.87%.This level is lower than those reported in other South American studies by Marquez (2.8%), Biz (2.4%) and Matuck (4.5%).9,21Thislowprevalence of tuberculosis might be due to the integration of the tuberculin test as part of our pre-transplant protocol and the fact that patients with tuberculin values greater or equal tAble4NA: Not applicable.