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Table of Contents
ORIGINAL ARTICLE
Year : 2022  |  Volume : 16  |  Issue : 3  |  Page : 316-321

Tuberculosis in kidney transplant recipients: A retrospective study from a tertiary care center - An observational study


Department of Nephrology, Government Stanley Medical College, Chennai, Tamil Nadu, India

Date of Submission10-Mar-2022
Date of Acceptance05-Sep-2022
Date of Web Publication30-Sep-2022

Correspondence Address:
Dr. K Thirumalvalavan
Government Stanley Medical College, 1, Old Jail Road, Royapuram, Chennai - 600 001, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_33_22

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  Abstract 


Background: The incidence of tuberculosis (TB) among transplant recipients varies from 5% to 15% across the globe. We conducted a retrospective study to identify the incidence of TB among kidney transplant recipients in our transplant unit. Materials and Methods: We assessed the patients who underwent kidney transplantation in our transplant unit during the study period from January 2014 to June 2018 and included those recipients who had bacteriologically confirmed TB. We excluded the patients who had TB before transplant and those recipients who were initiated on antituberculosis treatment (ATT) empirically. The details collected were: 1. Clinical data, the presenting symptoms, and clinical findings. 2. Diagnostic investigation: Microbiological/histopathological/radiological/bronchoalveolar lavage/fluid (pleural/peritoneal/cerebrospinal fluid) analysis. 3. Antituberculous regimen, dose, and duration of the therapy. 4. Relapse/patient and graft outcome after treatment.Results: The total number of patients who underwent kidney transplantation during the study period was 177. TB occurred in 21 patients after transplantation. The incidence of TB in our transplant unit was 11.86%. In these 21 recipients, 8 had pulmonary TB and the remaining 13 had extrapulmonary/disseminated TB, which included two patients with disseminated TB and one patient with allograft dysfunction with thrombotic microangiopathy which was attributed to TB as it responded to first-line antituberculous drugs. The mortality rate was 23.8%, as five patients expired. After excluding patients who expired, the graft survival at 1 year after ATT completion was 90.5%. Conclusion: For most developing nations, the World Health Organization's “End TB Strategy” remains far from their dream. An ideal investigation to detect TB in its early stage is essential in posttransplant recipients to reduce the morbidity and mortality associated with it.

Keywords: Kidney transplant recipient, posttransplantation, tuberculosis


How to cite this article:
Surendran S, Thirumalvalavan K, Anand S M, Prasad N D, Fernando M E. Tuberculosis in kidney transplant recipients: A retrospective study from a tertiary care center - An observational study. Indian J Transplant 2022;16:316-21

How to cite this URL:
Surendran S, Thirumalvalavan K, Anand S M, Prasad N D, Fernando M E. Tuberculosis in kidney transplant recipients: A retrospective study from a tertiary care center - An observational study. Indian J Transplant [serial online] 2022 [cited 2022 Nov 27];16:316-21. Available from: https://www.ijtonline.in/text.asp?2022/16/3/316/357607




  Introduction Top


Kidney transplantation is a form of kidney replacement therapy for patients with end-stage renal disease, which, when compared with dialysis, improves overall survival as well as the quality of life at a much lower cost.[1],[2] With the better understanding of transplant immunobiology, the past three decades have seen a huge expansion of the immunosuppressive medications, which have increased the overall long-term graft survival at the cost of numerous untoward complications such as infections and malignancies.[3],[4],[5],[6] Tuberculosis (TB) is one such common infection after transplantation. It is a major health problem in developing nations. The Global TB report released by the World Health Organization (WHO) states that in 2017, the incidence of TB was around 10 million and India tops the list with 26% of the total incidence.[7] The exact incidence of TB among posttransplant recipients in India is not known, but ranges between 5% and 15%. The immunosuppressive medications impair the pathogen-specific T cell response, a vital defense against the bacilli, and this makes the recipient more vulnerable to TB. Apart from acquiring TB after transplant, the recipients are also at high risk for activation of the latent infection.[8] The diagnosis of TB in a posttransplant recipient is often delayed, as the symptoms are often atypical.


  Materials and Methods Top


In this retrospective study, we assessed the medical reports of patients who underwent kidney transplantation in our transplant unit during the study period of January 2014 to June 2018 and included those recipients who had bacteriologically confirmed TB.

We excluded the patients who had TB before transplant and those recipients who were initiated on antituberculosis treatment (ATT) empirically.

The details collected were:

  1. Clinical data (age, gender, years since transplantation, induction agent used, immunosuppressive medications during the episode of TB, episodes of rejection, and other comorbidities), the presenting symptoms, and clinical examination findings
  2. Diagnostic investigation: Microbiological/histopathological/radiological/bronchoalveolar lavage/fluid (pleural/peritoneal/cerebrospinal fluid) analysis
  3. Antituberculous regimen, dose, and duration of the therapy
  4. Current clinical condition/relapse.


The definition of cases were adapted from Definitions and Reporting Framework for Tuberculosis – 2013 revision, Geneva, W.H.O., and used as follows:

  1. Bacteriologically confirmed TB case: One from whom a biological specimen is positive by smear microscopy, culture or WHO approved rapid diagnostics (cartridge-based nucleic acid amplification test and line probe assay)
  2. Disseminated TB: Defined as having TB in two or more noncontiguous sites resulting from lymphohematogenous spread of the bacilli
  3. Cured: A pulmonary TB patient with bacteriologically confirmed TB at the beginning of treatment who is smear or culture negative in the last month of treatment and on at least one previous occasion
  4. Completed treatment: A TB patient who completed treatment without evidence of failure but with no record to show that sputum smear or culture results in the last month of treatment and on at least one previous occasion were negative, either because tests were not done or because results were unavailable
  5. Treatment success: Sum of cured and completed treatment.


Statistical analysis

The collected data were analysed using appropriate statistical methods.

Declaration of patient consent

The patient consent has been taken for participation in the study and for publication of clinical details and images. Patients understand that the names and initials would not be published, and all standard protocols will be followed to conceal their identity.

Ethics statement

Ethics statement was obtained from Stanley Medical College ethical committee. All protocols were followed as per the declaration of Helsinki. The study was performed according to the guidelines in Declaration of Helsinki ECR/131/INST/TN/2013/R-22.


  Results Top


Incidence and baseline characteristics

The total number of patients who underwent kidney transplantation during the study period (January 2014 to June 2018) was 177. TB occurred in 21 patients after transplantation. The incidence of TB in our transplant unit was 11.86%. Among 21 patients, 2 had TB within 1 month of transplantation, 10 patients during 1–6 months of transplantation, 4 patients during 7–12 months of transplant, and 5 patients had TB after 1 year of transplant [Table 1].
Table 1: Incidence of tuberculosis based on its onset after transplantation

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Among 21 recipients, 14 of them were men (66.7%). Living-related kidney transplantation was performed in 11 recipients (52.38%) and deceased donor kidney transplant was performed in 10 patients (47.62%). The mean time taken to diagnose TB from the onset of symptom was 18 ± 12.4 days. The probable reason for this late diagnosis was its atypical manifestation. Antithymocyte globulin was used as an induction agent in 10 recipients (47.6%) and basiliximab in 1 patient (4.8%). Among the 11 patients who were exposed to the induction agent, 6 patients developed TB within first 6 months of posttransplantation. In the remaining 10 patients who were not given induction agent, TB still occurred in 6 patients within 6 months after transplantation.

Risk factors

Socioeconomic status

Numerous factors which predispose the transplant recipients to TB infection were analyzed. Socioeconomic status was calculated using modified Kuppuswamy scoring system (2018 Update).[9]

The four components assessed under 2018 updated Kuppuswamy scoring system were as follows:

  1. Occupation of the head of the family
  2. Education of the head of the family
  3. Total monthly income of the family
  4. Kuppuswamy Socioeconomic Status Scale 2018.


The overall score ranges from 3 to 29 and it categorizes families into upper, upper middle, lower middle, upper lower, and lower.

In our study, the incidence of TB was common among patients in upper lower (62%) and lower (26%) socioeconomic status. However, considering the fact that most of our transplant recipients (90.4%) hail from lower middle, upper lower, and lower strata of this classification, these data had no significance.

Others

The number of patients with posttransplant diabetes mellitus (PTDM) was 9 (42.9%) and high C0 serum tacrolimus trough level (as measured by chemiluminescent micro-particle immunoassay- >10 ng/ml within 6 months after transplant, >8 ng/ml from 2nd months to 1 year posttransplant and >5 ng/ml after 1 year of transplant) was noted in 7 recipients (33.3%). Cytomegalovirus (CMV) infection and hepatitis C viral infection were seen in single patient each. None of them had a history of recent contact with patients with TB. [Table 2] shows the relationship between various risk factors and incidence of TB.
Table 2: Risk factors for posttransplant tuberculosis

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Clinical features

Although fever was the most common presenting symptom of TB in our study population, it was seen in only 6 (28.6%) patients. Weight loss was the second most common symptom seen in 4 (19%) patients. Others had organ-specific symptoms such as cough with sputum production in 3 (14.2%) patients, localized pain in 3 (14.2%) patients, and headache, dyspnea, and diarrhea in single patient each [Figure 1].
Figure 1: Symptoms at presentation

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Organs involved

Based on the involvement of the organs, the patients were divided into two broad categories: patients with pulmonary TB and patients with extrapulmonary TB. Among the 21 recipients, 8 had pulmonary TB and the remaining 13 had extrapulmonary/disseminated TB. The various diagnostic methods used are shown in [Table 3].
Table 3: Diagnostic method adopted to diagnose tuberculosis

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Among the 13 patients, 2 had disseminated TB. One patient who presented with allograft dysfunction had thrombotic microangiopathy, which was attributed to TB as it responded to first-line antituberculous drugs. Another patient presented with pain in the right leg and foot and was later diagnosed with myositis and cellulitis of tuberculous etiology. Joint involvement was seen in two patients. One among them had left knee joint involvement and the other patient had TB in the right 2nd metacarpophalangeal joint which was proved by biopsy from the synovium. Spine, bladder, and intestinal TB were seen in single patient each. Meningeal involvement and pleural involvement (without lung involvement) were seen in two patients each. The clinical profile are shown in [Table 4].
Table 4: Clinical profile of patients with posttransplant tuberculosis

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Antituberculosis treatment regimen followed and outcome: Single organ involvement

Intensive Phase: 2 Months (isoniazid [INH] [H] −5 mg/kg + ethambutol [E] −20 mg/kg + pyrazinamide [Z] 25 mg/kg + ofloxacin [O] 200 mg).

Maintenance Phase: Pulmonary: HZE for 7 months; extrapulmonary: 10–16 months.

Disseminated TB

Intensive phase: 2–3 months of HZE + rifampicin (R) −10 mg/kg.

Maintenance phase: 14–22 months of HR.

Dose of tacrolimus was frequently adjusted according to C0 levels when coadministered with rifampicin. Dose adjustments of anti-TB drugs were made if the patient had allograft dysfunction.

Outcome

Among the 21 recipients, 5 of them expired despite ATT initiation; mortality rate: 23.8%. Treatment success (sum of cured and completed treatment) was observed in 13 (62%) patients. The number of patients on treatment was 3 (14.3%). Relapse was seen in a single recipient (4.8%). None of the recipients had long-term sequelae of TB.

Drug-related issues

Adverse effects of antituberculosis treatment

Anti-TB drug-induced severe hepatitis was seen in a single patient. His liver enzymes were >1000 IU/L and hence INH, rifampicin, and pyrazinamide were stopped and second-line ATT drugs were initiated.

Another patient developed INH-induced peripheral neuropathy, which was treated with pyridoxine. [Table 5] shows ATT-related adverse events.
Table 5: Antituberculosis treatment-related adverse effects seen in our patients

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Drug resistance

Resistance to first-line antituberculous drug was noted in none of our patients.


  Discussion Top


The incidence of TB in our transplant unit was 11.86% and its incidence was higher within first 6 months of transplantation. The incidence of TB varies widely and it is reported as 0.3%–1% in United States, and that in Spain ranges from 0.8% to 3%.[10],[11] The incidence of posttransplant TB is much higher in countries like India, South-Africa, and Turkey where its prevalence ranges from 5% to 15%.[12],[13],[14] The obvious reason behind this gross discrepancy is the difference in overall incidence of TB among the general population of these countries.

Pathogenesis of TB involves a complex interplay between the microbe and the host. In immune competent hosts, the TB infection is aborted by the cell-mediated immunity, whereas in posttransplant recipients, the cell-mediated immunity is impaired due to immune suppressive mediations and hence the TB infection goes unchecked. The other risk factors include chronic liver disease, other coexisting infections particularly deep mycoses, pneumocystis pneumonia, and CMV infections.[15]

TB is known for its diverse manifestations. In a posttransplant recipient, atypical manifestations of TB may delay its diagnosis and this may contribute to its morbidity and mortality. Identification of granuloma in biopsy specimens from extrapulmonary sites suggests the possibility of disseminated TB.

In our study, the classical features of TB such as weight loss and fever were found in only 19% (n = 4) and 28.6% (n = 6) of recipients. Pulmonary TB was seen in eight patients (38%) and the remaining 13 patients had extrapulmonary or disseminated TB.

TB presenting as thrombotic microangiopathy is extremely rare. Although the exact pathogenesis is not known, it may be secondary to direct endothelial injury. As suggested by Toscano et al., thrombotic microangiopathy may be secondary to the increased procoagulant activity of interleukin 1.[16]

TB rarely affects muscles due to low oxygen content and high lactate content. One of our patients presented with myositis/cellulitis which was treated with 2 months of intensive phase drugs: rifampicin-free regimen. He responded to the treatment and currently he is on maintenance phase of ATT.

As multidrug resistance is so common, it is appropriate to initiate patient on 4 agents: INH, rifampicin or rifabutin, ethambutol, and pyrazinamide for at least 2 months, if susceptibility tests are not available, in intensive phase and then with 2 drugs, namely, INH and rifampicin in continuation phase for 10–18 months depending on the organ involvement. As rifampicin is a potent inducer of CYP3A group of enzymes and affects the metabolism of tacrolimus and reducing its levels, rifabutin, which has less enzyme-inducing activity than the former, is preferable. In transplant population, we generally prefer rifampicin-free regimen for TB confined to single organ and if the infection at the initiation of treatment is not life threatening. Even with rifabutin, CNI dose adjustment and close monitoring of serum levels of CNI is recommended. In single organ confined TB, we prefer to add ofloxacin with required kidney dose modification to the other 3 drugs, namely, INH, ethambutol, and pyrazinamide.

With regard to immunosuppression, we stopped antiproliferative agents such as mycophenolate and azathioprine once diagnosis of TB was confirmed. If the patient had life threatening/disseminated TB, CNIs were also terminated and the patient was maintained on low-dose immunosuppression.

In our study, most of the recipients with pulmonary TB responded to the 9 months of ATT (2 months of intensive phase followed by 7 months of continuation phase). For other organ involvement, we extended the continuation phase to 12–16 months based on response and on our previous experience.

The most common adverse effect associated with antituberculous regimen is hepatitis, as all first-line drugs (INH > pyrazinamide > rifampicin/rifabutin) other than ethambutol are known for their hepatotoxicity. Peripheral neuropathy is common with INH and ethambutol is known for causing optic neuritis. It is preferable to add pyridoxine to prevent INH-related neuropathy. Rifampicins are known to cause neutropenia. In our study, one patient (4.76%) had hepatitis and peripheral neuropathy each.

According to previous studies, the mortality rate among posttransplant recipients with TB was around 20%–30%, which was closer to the mortality rate of 23.8% in our study. Among the five patients who expired, 2 had disseminated TB, one had pulmonary TB with fungal infection, and yet other patient had TB confined to the lung.

In our study, after excluding patients who expired (19%), the graft survival at 6 months of ATT initiation in patients who were on ATT during the study and graft survival at the time of completion of ATT for those recipients who had completed ATT at the time of study was 94%. One of the 17 recipients had graft dysfunction due to chronic allograft injury following discontinuation of immunosuppression for disseminated TB. In the multicenter study done in France, the graft survival at 10 years was 67%.[17]

Patients with profound immunosuppression in the form of antithymocyte globulin induction, high C0 tacrolimus concentration in serum, and PTDM were more prone for developing TB.[12] The Infectious Disease Society of America[18] guidelines for treating TB in posttransplant recipients suggest that prolonged course of ATT (9–24 months) was associated with better clinical outcome, low relapse rate (4.8%), and had less side effect profile. Mortality was high among recipients with disseminated TB. Resistance to ATT was not found in any of our recipients.

Limitation

This was a retrospective cohort study. Randomized clinical trials with a large sample size are required to decide about the adequate dose and duration of ATT.


  Conclusion Top


TB in posttransplant recipient has atypical manifestations, which usually delays the time to diagnosis. An ideal investigation to detect TB in its early stage is essential in posttransplant recipients, to reduce the morbidity and mortality associated with it. For most developing nations, the WHO's “End TB Strategy” remains far from their dream. In spite of effective drugs against TB, mortality seems to be significant in this population.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LY, et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 1999;341:1725-30.  Back to cited text no. 1
    
2.
Laupacis A, Keown P, Pus N, Krueger H, Ferguson B, Wong C, et al. A study of the quality of life and cost-utility of renal transplantation. Kidney Int 1996;50:235-42.  Back to cited text no. 2
    
3.
Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McIntosh MJ, Stablein D. Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Engl J Med 2000;342:605-12.  Back to cited text no. 3
    
4.
Sayegh MH, Carpenter CB. Transplantation 50 years later-progress, challenges, and promises. N Engl J Med 2004;351:2761-6.  Back to cited text no. 4
    
5.
Dantal J, Pohanka E. Malignancies in renal transplantation: An unmet medical need. Nephrol Dial Transplant 2007;22 Suppl 1:i4-10.  Back to cited text no. 5
    
6.
Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med 2007;357:2601-14.  Back to cited text no. 6
    
7.
Global Tuberculosis Report 2018- WHO. Available from: www.who.int/tb/data. [Last accessed on 2018 Sep 18].  Back to cited text no. 7
    
8.
Subramanian A, Dorman S, AST Infectious Diseases Community of Practice. Mycobacterium tuberculosis in solid organ transplant recipients. Am J Transplant 2009;9 Suppl 4:S57-62.  Back to cited text no. 8
    
9.
Shiek Mohd S. Modified kuppusamy scale updated for year 2018. Indian J Res 2018;7:218.  Back to cited text no. 9
    
10.
Klote MM, Agodoa LY, Abbott K. Mycobacterium tuberculosis infection incidence in hospitalized renal transplant patients in the United States, 1998-2000. Am J Transplant 2004;4:1523-8.  Back to cited text no. 10
    
11.
Aguado JM, Torre-Cisneros J, Fortún J, Benito N, Meije Y, Doblas A, et al. Tuberculosis in solid-organ transplant recipients: Consensus statement of the group for the study of infection in transplant recipients (GESITRA) of the Spanish society of infectious diseases and clinical microbiology. Clin Infect Dis 2009;48:1276-84.  Back to cited text no. 11
    
12.
Hall CM, Willcox PA, Swanepoel CR, Kahn D, Van Zyl Smit R. Mycobacterial infection in renal transplant recipients. Chest 1994;106:435-9.  Back to cited text no. 12
    
13.
John GT, Shankar V, Abraham AM, Mukundan U, Thomas PP, Jacob CK. Risk factors for post-transplant tuberculosis. Kidney Int 2001;60:1148-53.  Back to cited text no. 13
    
14.
Naqvi A, Rizvi A, Hussain Z, Hafeez S, Hashmi A, Akhtar F, et al. Developing world perspective of posttransplant tuberculosis: Morbidity, mortality, and cost implications. Transplant Proc 2001;33:1787-8.  Back to cited text no. 14
    
15.
Sundaram M, Adhikary SD, John GT, Kekre NS. Tuberculosis in renal transplant recipients. Indian J Urol 2008;24:396-400.  Back to cited text no. 15
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Toscano V, Bontadini A, Falsone G, Conte R, Fois F, Fabiani A, et al. Thrombotic thrombocytopenic purpura associated with primary tuberculosis. Infection 1995;23:58-9.  Back to cited text no. 16
    
17.
Canet E, Dantal J, Blancho G, Hourmant M, Coupel S. Tuberculosis following kidney transplantation: Clinical features and outcome. A French multicentre experience in the last 20 years. Nephrol Dial Transplant 2011;26:3773-8.  Back to cited text no. 17
    
18.
Subramanian AK, Theodoropoulos NM, Infectious Diseases Community of Practice of the American Society of Transplantation. Mycobacterium tuberculosis infections in solid organ transplantation: Guidelines from the infectious diseases community of practice of the American Society of Transplantation. Clin Transplant 2019;33:e13513.  Back to cited text no. 18
    


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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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