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REVIEW ARTICLE
Year : 2013  |  Volume : 12  |  Issue : 3  |  Page : 143-147  

Peculiarities of tuberculosis in kidney transplant recipients


Department of Medicine, Bayero University/AKTH, Kano, Nigeria

Date of Web Publication5-Sep-2013

Correspondence Address:
Bappa Adamu
Nephrology Unit, Department of Medicine, Aminu Kano Teaching Hospital
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1596-3519.117620

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   Abstract 

Renal transplant is becoming increasingly available in developing countries. Significant advances have been made globally since the first successful kidney transplant in 1954, with the advent of newer, more effective and more selective immunosuppressants. As a result, allograft and patient survival has increased, leaving infection and malignancy as major challenges. The incidence rate of tuberculsis in renal transplant recipients is directly proportional to the prevalence in the general population with the developing countries having the highest rates. The objective of this paper is to review the existing literature on post renal transplant tuberculosis with a view to highlighting its peculiarities compared to tuberculosis in the general population.
Several databases (Medline, EMBASE, Cochrane data base, Google Scholar and AJOL) were searched for articles using the key words Tuberculosis (MESH), Renal (OR Kidney), AND transplant. Hand search was also made of reference list of retrieved articles. Full text of relevant original articles were retrieved and appraised.
Several studies have demonstrated increased risk of tuberculosis in renal transplant recipients, especially in developing countries. Tuberculosis in renal transplant recipients has peculiarities such as difficulty in diagnosing latent TB, atypical presentations, increased risk of dissemination, increased mortality and interactions of anti-Tb drugs with transplant medications.
Clinicians managing renal transplant recipients especially in developing countries should have a high index of suspicion for TB and be aware of its peculiarities in this patient population.

   Abstract in French 

Transplantation rénale devient de plus en plus disponible dans les pays en développement. Des avancées significatives ont été apportées à l'échelle mondiale depuis le premier rein réussi transplant en 1954, avec l'avènement de nouveaux immunosuppresseurs plus efficaces et plus sélectives. En conséquence, survie allogreffe et patient a augmenté, laissant l'infection et la malignité des défis aussi majeurs. Le taux d'incidence de tuberculsis chez des receveurs de transplantation rénale est directement proportionnel à la prévalence dans la population générale, avec les pays en développement ayant les taux les plus élevés. L'objectif de cet article est d'examiner la littérature existante sur le post transplantation rénale la tuberculose en vue de mettre en évidence ses particularités par rapport à la tuberculose dans la population générale. Plusieurs bases de données (Medline, EMBASE, base de données de Cochrane Google Scholar et AJOL) ont effectué une recherche pour articles à l'aide de la clé des mots la tuberculose (MESH), rénaux (rein ou), AND transplantation. Fouille manuelle a été effectuée aussi de la liste de référence des articles récupérées. Texte intégral des articles originaux pertinents ont été récupérée et évalué. Plusieurs études ont démontré un risque accru de tuberculose chez des receveurs de transplantation rénale, en particulier dans les pays en développement. La tuberculose chez des receveurs de transplantation rénale a des particularités comme la difficulté à diagnostiquer une tuberculose latente, présentations atypiques, un risque accru de diffusion, une mortalité accrue et interactions des médicaments anti-TB avec transplantation médicaments. Les cliniciens gestion des greffés rénaux notamment dans les pays en développement devraient ont un indice élevé de suspicion de tuberculose et être conscient de ses particularités dans cette population de patients.
Mots clés: Les pays en développement, greffe de rein tuberculose

Keywords: Developing countries, kidney transplant, tuberculosis


How to cite this article:
Adamu B. Peculiarities of tuberculosis in kidney transplant recipients. Ann Afr Med 2013;12:143-7

How to cite this URL:
Adamu B. Peculiarities of tuberculosis in kidney transplant recipients. Ann Afr Med [serial online] 2013 [cited 2017 Apr 29];12:143-7. Available from: http://www.annalsafrmed.org/text.asp?2013/12/3/143/117620


   Introduction Top


Kidney transplant is increasingly becoming available in developing countries. Indeed in 2004, three of the top five countries performing the greatest number of kidney transplant procedures were developing countries (India, Brazil and China). [1] In Nigeria, following the first successful kidney transplant in a private hospital in 2000, [2] several government hospitals have initiated kidney transplant activities. [3],[4],[5],[6],[7] Tuberculosis (TB) poses peculiar challenges in the post-transplant setting especially in developing countries where the burden is high. The aim of this review is to highlight the peculiarities of TB after kidney transplant especially as it applies to developing countries.


   Increased Risk of Development of TB in Kidney Transplant Recipients Top


One of the several peculiarities of TB in kidney transplant recipients [Table 1] is the increased risk of development of TB compared to the general population. The risk is directly proportional to the prevalence of TB in the general population with rates of TB in renal transplant populations of 0.5-1.0% reported in North America, 0.7-5% in Europe and 5-15% in India and Pakistan. [8],[9] This represents a 50 to 100-fold increase in the frequency of TB compared to the general population in the respective geographic regions. [10] Most cases of TB infections in kidney transplant recipients (KTRs) occur as a result of reactivation of quiescent foci of Mycobacterium tuberculosis that persist after initial asymptomatic infection [11] which explains why the prevalence of TB in KTRs is directly proportional to the prevalence in the general population. However, other potential routes of infection in KTRs include transmission by an infected graft or transmission from actively infected persons post-transplant. The increased risk of TB in KTRs is mainly as a result of iatrogenic immunosupression caused by post-transplant medications. Indeed, more potent immunosuppressant medications such as tacrolimus and mycophenolate mofetil have been shown to be associated with the development of TB earlier in the transplant period compared to other immunosupressants such as azathioprine and cyclosporine. [12]
Table 1: Peculiarities of TB in KTRs and their clinical implications

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The markedly increased risk of TB in KTRs makes it pertinent for all clinicians vested with the care of these patients to have high index of suspicion of TB for early detection and treatment.


   Difficulty in Diagnosis of Latent TB Top


Since most cases of TB in KTRs occur as a result of reactivation of latent infection, screening and treatment of latent TB in End Stage Renal Disease (ESRD) patients pre-transplant as well as post-transplant would have provided a good opportunity of the control of TB in these patient populations. Unfortunately, diagnosis of latent TB is fraught with difficulties both in pre-transplant as well as transplant recipients. Cutaneous anergy is reportedly high in ESRD patients and KTRs which can lead to false negative tuberculin reactivity test (Mantoux test). Machiraju et al found higher rates of anergy and lower rates of tuberculin reactivity in Indian ESRD patients compared to healthy controls. [13] In the same study the authours found that pre-transplant mantoux positivity has low sensitivity and specificity for predicting post-transplant tuberculosis. Another peculiarity of diagnosis of latent TB in transplant patients is that it requires an induration of only 5mm on a tuberculin test (because of iatrogenic immunosuppression post-transplant), not the 10mm induration as in the general population or dialysis patients. [8]

Despite the limitation of tuberculin test, clinical practice guidelines such as the European Best Practice Guidelines for Renal Transplantation and the American Society of Transplantation Guidelines for the Prevention and Management of Infectious Complications of Solid Organ Transplantation have recommended use of prophylactic isoniazid in patients with a past or current positive tuberculin skin test, and/or a history of TB without adequate documented treatment. [8],[14]

Interferon-gamma release assays such as T-SPOT. TB and QuantiFERON are an alternative to the tuberculin skin test for detecting latent TB infection in the general population. Unfortunately, their sensitivity and specificity have not been systematically evaluated in KTRs. Current evidence from studies on chronic kidney disease (CKD) stage five patients suggest important limitations for detecting latent TB infection which does not support their routine use in this patient population at present. [15],[16],[17],[18]


   Uncertainty of Effectiveness of Universal Anti-TB Prophylaxis in KTRs Top


Considering the very high risk of TB in KTRs and the unreliability of the diagnosis of latent TB infection in stage five CKD and KTRs, it looks reasonable to give universal prophylaxis for TB in post transplant period when there is highest immunosupression (first six months to one year) particularly in developing countries. Randomized controlled trials carried out in India and Pakistan have evaluated the benefit of prophylactic treatment with isoniazid for KTRs. [19],[20],[21],[22] Results of these studies suggest reduced risk of TB in patients who are treated with Isoniazid. However, these studies should be interpreted with caution as they are relatively small studies, open-labelled, with no placebo control and therefore are susceptible to bias, especially detection bias. Despite the limitations of these trials, the overall evidence supports the use of isoniazid prophylaxis in KTRs in TB endemic regions of the world. A systematic review and meta-analysis of these trials and other observational studies, by Currie et al concluded that isoniazid is valuable for TB prophylaxis in KTRs at risk of active TB infection. [23] Another on-going meta-analysis [24] will possibly further clarify the evidence especially if there are any new trials published after the meta-analysis by Currie et al. [23] In addition, several observational studies have demonstrated benefits of anti-TB prophylaxis in renal transplant recipients. [25],[26],[27],[28]

One factor against universal prophylaxis for TB in KTRs is that some observational studies showed no benefit of prophylaxis. [29],[30] Other factors against universal prophylaxis include potential hepatotoxicity of Isoniazid, development of resistance, and increased pill burden in these patients who are already on many medications.

Larger randomized controlled trials with placebo control and adequate blinding are needed to clarify the benefits and harms of TB prophylaxis in KTRs, considering the global importance of TB and the markedly increased risk in KTRs.


   Difficulty and Delay in Diagnosis of Clinical TB Top


Diagnosis of active TB in transplant patients is the same as in the general population, requiring confirmation by the demonstration of acid fast bacilli (AFB) in study materials, its growth in special culture media, demonstration of caeseating granulomata with or without AFB in histological materials, and more recently, the use of polymerase chain reaction (PCR). While establishing the diagnosis may be straight forward in some cases, [31] t may be delayed or difficult to establish in KTRs because of some peculiarities. As a result of drug induced imminosupression, symptoms may be attenuated, leading to delayed diagnosis. [32],[33] There are many reports of TB co-existing with other infections such as fungal infections, cytomegalo virus infection, as well malignancies such as Kaposi's sarcoma, which may all lead to atypical presentations and therefore delayed or difficult diagnosis. [34],[35],[36]


   Drug Interactions between anti-TB and Immunosupressants and Consequent Graft Loss Top


Another peculiarity of TB in KTRs is the interaction of anti-TB medications with immunosuppressants. Rifampicin for example, is an inducer of cytochrome P450 micro enzymes, leading to reduced levels of calcineurin inhibitors, mammalian target of rapamycin inhibitors and steroids. [37] In one study, this was associated with a 30% incidence of graft rejection and 20% incidence of graft loss. [38] In order to minimize this untoward effect, several steps have been recommended. First, blood levels of calcineurin inhibitors and mammalian target of rapamycin inhibitors should be closely monitored during treatment with rifampicin. [10] Secondly, rifabutin can be substituted for rifampicin since rifabutin achieves similar therapeutic efficacy while minimizing the potential for drug-drug interactions. [10] However, these two approaches may not be the best options in resource limited countries where rifabutin may not be available and frequent therapeutic drug monitoring adds additional cost of patient care. An alternative approach is rifampicin avoidance, in which rifampicin is substituted with a fluoroquinolone, and taken with isoniazid, ethambutol and pyrazinamide for the first two months of TB therapy. After this, pyrazinamide and ethambutol are stopped and fluoroquinolone and isoniazid continued for another 10-12 months. This approach has also been shown to be effective in the treatment TB in KTRs. [39],[40]


   Increased Morbidity and Mortality Top


Many studies have demonstrated that KTRs who develop TB are at increased risk of developing extra-pulmonary/disseminated TB and therefore increased morbidity. [32],[41],[42] Some studies report pulmonary TB as the commonest mode of presentation, but even in these reports, extra-pulmonary TB occurs in a significant proportion of patients. [33],[43],[44]

Mortality is also increased in KTRs with TB compared to TB in the general population, reportedly up to ten-fold. [10] Although there are no studies directly comparing mortality in kidney transplant and non-transplant populations, many observational studies from both developed and developing countries [26],[45],[46] revealed high mortality in KTRs with TB compared to TB mortality in the general population, with TB mortality up to 34.9% in one study. [26] The reported mortality rates in these studies are higher than TB mortality rates in the general population both in developed and developing countries. [47]


   Conclusion Top


Several studies have demonstrated increased risk of tuberculosis in renal transplant recipients, especially in developing countries. Tuberculosis in renal transplant recipients has peculiarities such as difficulty in diagnosing latent TB, atypical presentations, increased risk of dissemination, increased mortality and interactions of anti-Tb drugs with transplant medications.

Clinicians managing renal transplant recipients especially in developing countries should have a high index of suspicion for TB and be aware of its peculiarities in this patient population. Prophylaxis with Isoniazid in the first six months to one year after transplant should be given to KTRs in TB endemic regions of the world even though more trials are desirable in future to make this a strong evidence-based recommendation.

 
   References Top

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