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Saudi Journal of Kidney Diseases and Transplantation
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EDITORIAL Table of Contents   
Year : 2002  |  Volume : 13  |  Issue : 4  |  Page : 445-450
Post-transplant Tuberculosis


Department of Nephrology, Christian Medical College & Hospital, Vellore, Tamil Nadu, India

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How to cite this article:
Thomas PP. Post-transplant Tuberculosis. Saudi J Kidney Dis Transpl 2002;13:445-50

How to cite this URL:
Thomas PP. Post-transplant Tuberculosis. Saudi J Kidney Dis Transpl [serial online] 2002 [cited 2014 Jul 30];13:445-50. Available from: http://www.sjkdt.org/text.asp?2002/13/4/445/33096
Infectious complications are major causes of morbidity and mortality following organ transplantation. Increased frequency of tuberculosis has been demonstrated in solid organ transplant recipients. This has been attributed to the immunosuppressive agents used after transplantation. Most cases of tuberculosis after renal transplantation are due to reactivation of old dormant tuber­culosis. [1] Hence the incidence of post transplant tuberculosis can vary and can be expected to be more frequent in those countries of South East Asia, East Asia, South America and Africa where tuberculosis is more common in addition to China and Russia. The reported prevalence of post transplant tuberculosis is low in countries where this disease is not very common in the general population. The prevalence is 1% in Germany, [2] 1.7% in UK, [3] 2-3.1% in Eastern Europe, [4],[5] 2.4-3.6% in South America, [6],[7] 3.5% in Saudi Arabia, [1] 4.2% in Spain, [8] 4.1­5.8% in Turkey, [9],[10] 4.5-4.9% in South Africa [11],[12] and 9.5-14.7% in India. [13],[14],[15] The prevalence is 5-50 times more than in general population. [1],[7],[8]


   Risk Factors Top


Opportunistic infections, such as tuber­culosis, usually occur after six months of renal transplantation. Rubin identified these patients as those with serum creatinine concentration higher than 176 µgm/L (2 mg/dl), those on a daily prednisone dose of more than 20 mg, those receiving multiple anti­rejection therapies and patients with chronic viral infections such as Hepatitis C. [16] In a multivariate analysis, it was found that patients on cyclosporine immunosuppression had the highest risk of developing tuber­culosis with a relative risk of 2.5. Patients with diabetes mellitus had a relative risk of 2.2 and those with chronic liver disease had a relative risk of 1.7 for developing post transplant tuberculosis. [13] The transplanted kidney has been suspected to transmit tuberculosis. [17] Disseminated tuberculosis occurred in allograft recipients of kidneys procured from a donor who was found to have tuberculosis subsequently. [18]


   Clinical Features Top


Symptoms and signs of tuberculosis that are usually obvious in the normal host can be subtle in the immunosuppressed transplant recipient. Fever, cough and infiltrates on chest x-ray are the usual presenting features. [19] Pyrexia of unknown origin (PUO) may be the presentation in 15.7-68% of the patients. [13],[14],[20],[21] The involvement was pulmonary in 40.2-63% [1],[20] and disseminated in 19.3-38.7%. [1],[13],[22] In another study, the majority of patients with tuberculosis after transplantation had high intermittent fever, while the majority of patients with tuber­culosis on hemodialysis had persistent low­grade fever. [14] Tubercular peritonitis is an unusual presentation after transplantation unlike in hemodialysis patients. [14] Tuber­culous involvement is pulmonary in most post transplant patients as compared to predominant lymph nodal involvement in patients on hemodialysis. [23] Some patients may reveal granulomatous interstitial nephritis on renal biopsy. [24] The diagnosis is suspected and established only retros­pectively following clinical response to empiric anti tubercular treatment of PUO in 15.7% or of pleural effusion or pulmonary lesion in 10.2%. [13] There is an increased incidence of atypical mycobacterial infection among kidney transplant recipients. [3] Atypical mycobacteria were responsible for 29% of disseminated infections, 8% of pulmonary infections and all cases of cutaneous and articular tuberculosis.[1] Some patients may present with rectal bleeding and tuberculosis may be diagnosed on hemicolectomy and colonic biopsy. [25],[26] Rarely, it can present with acute hepatitis, [27] tuberculous meningo-encephalitis, or bowel perforation. Non-healing skin ulcer, pyomyositis and cerebral abscess are other rare presenting diagnosis. Chest radiograph findings revealed consolidation in 64%, miliary pattern in 18%, pleural effusion in 13.6%, tuberculoma and cavitation in 9% of the cases. [11] It was diagnosed in the first year after transplantation in 18-58% of the patients. [22],[28] Post transplant tuberculosis occurs earlier in cyclosporine treated patients as compared to those receiving prednisone and azathioprine for immunosuppression. In patients receiving immunosuppressive therapy with prednisolone and azathioprine, only 14.7% of tuberculosis cases occurred within one year, while in patients on cyclosporine 65% of the cases occurred within one year of transplantation. [29] In another report, 35% of tuberculosis occurring in patients on cyclosporine was disseminated, while all patients receiving azathioprine and prednisone had exclusively pulmonary disease. [7] The reason for the early occurrence and dissemi­nated nature of post transplant tuberculosis in patients on cyclosporine is not known. It is possible that cyclosporine, by down regulating the release of IL2 and TNF alpha, depresses lymphocyte proliferation and macrophage function leading to occurrence of tuberculosis. In one report, 57% of patients with post transplant tuberculosis also had other significant infections such as CMV, Nocardia, Pneumocystis or disseminated Herpes simplex [6] and hence co-infections should be excluded in all patients.


   Diagnosis Top


It is important to have a high index of suspicion in an appropriate clinical setting as late diagnosis due the slow growth of the bacteria in culture and delay in instituting [30],[31] treatment may be fatal.Temporary effervescence following antibiotic therapy with ofloxacin can contribute to the fatal diagnostic delay and death. [32] Early broncho alveolar lavage (BAL) may help in diagnosis and treatment. [33],[34] In a group of 199 patients who were either sputum negative for acid fast bacillus (AFB) or had had no expectoration, AFB was identified in gastric aspirate of 23 patients. BAL only revealed an additional 3 cases of tuberculosis. The remaining patients on follow up had no evidence of tuberculosis. [35] Thus the sensitivity of the test is 88.5% and hence useful in an area of high endemicity. The specificity of the test has to be established. Use of polymerase chain reaction may assist in the rapid detection of mycobacteria from body fluids or tissue samples. [36]


   Mortality Top


The mortality of tuberculosis after renal transplantation varies from 14.3 to 31.9%. [4],[5],[9],[13],[22],[28] The mortality rate from disseminated disease was 37% and from all other forms of tuberculosis was 11%. [1] In another study, 31.9% patients with post transplant tuberculosis died, 10.2% due to the post transplant tuberculosis itself and 6.6% due to other infections associated with tuberculosis. [13]

Tuberculosis following bone marrow transplantation (BMT)

Tuberculosis has been reported in solid organ transplantations other than the kidneys. Tuberculosis occurred in 4.9% of orthotopic liver transplantation. [12] Of five BMT series with a total of more than 5,000 patients, only 10 cases of Mycobacterium tuberculosis infection were described, with an overall incidence of 0.19%. [19] Relative risk for tuberculosis was 23.7 in allogenic BMT, 4.9 for total body irradiation and 3.6 for graft-versus-host disease. [19] The low prevalence of post transplant tuberculosis after BMT may be due to shorter duration of immunosuppression used in these patients.


   Treatment Top


Active infection by M. tuberculosis should be treated with four anti-tuberculous drugs in view of the emergence of isoniazid resistant and multi drug resistant tuber­culosis. [37] It is recommended to start with isoniazid, pyrazinamide, ethambutol, and ofloxacin or streptomycin. Rifampicin can be used instead of ofloxacin or strepto­mycin but it should be remembered that rifampicin can accelerate the hepatic metabolism of cyclosporine, tacrolimus, sirolimus and prednisolone so that rejection can be a sequela to the treatment of tuberculosis. [38] In bone marrow transplant recipients, this might aggravate graft versus host disease. [39] Rejection occurred in 5 of 10 patients on cyclosporine who were treated with rifampicin despite increasing the dose of cyclosporine in eight. [6] Use of rifampicin necessitated a mean of 2-fold increase in the cyclosporine dose. [10] In another study of 6 patients on cyclosporine and rifampicin, the total daily dose of cyclosporine had to be increased 3-5 fold, with the frequency of administration increased from twice to thrice daily. With this regimen, satisfactory cyclosporine levels were attained and there was no adverse effect on graft function. [40] The accelerated glucocorticoid metabolism with rifampicin has been known to cause graft rejection even in pre-cyclosporine era. [41] Hence the dose of steroids should also be doubled. Rifampicin co-administration caused the abrupt decrease in tacrolimus blood concentrations, leading to an appro­ximate tenfold increase in its daily dose. [42]

Because of the known cyclosporine­lowering effect of rifampicin resulting in increased cost of immunosuppressive therapy, patients were treated successfully with rifampicin-sparing therapy. [14] A four-drug regime without rifampicin given for 18 months is effective for pulmonary tuber­culosis in patients on cyclosporine. [43] Some authors have suggested that immunosup­pression should be stopped as part of the overall therapy of tuberculosis and that loss of allograft is generally of secondary importance. [44] This is neither practical in countries where post transplant tuberculosis is common nor necessary in view of the drugs that are available for treatment of tuberculosis. Isoniazid does not affect the bioavailability of cyclosporine. [45] However, hepatotoxiciy of the drugs should be closely monitored. Sensitivity test should be followed up as drug resistance may occur. [35],[46] Drugs such as clarithromycin effective against atypical mycobacterial infection such as M. avium can be administered to patients on rifampicin as it partially neutralizes the effect of rifampicin on cytochrome P4503A. [47],[48]

Hepatotoxicity of antitubercular drugs

Hepatotoxicity occurred in 10-33% patients on antituberculous therapy. [7],[10],[20] Hepato­toxicity occurred in 50% of patients receiving four or more antituberculous drugs compared to 21% in patients receiving three drugs. [20] Hence liver functions should be closely monitored after starting antitubercular therapy.

Isoniazid Prophylaxis

Many physicians use chemoprophylaxis with isoniazid. The duration of prophylaxis may be 12 to 18 months. In a study of 633 renal transplant recipients, mycobacterial infections did not occur in any of the patients receiving isoniazid prophylaxis, though it occurred in 6 of the 27 patients not receiving chemoprophylaxis. [3] In another study, tuberculosis occurred in Asian dialysis patients but not in Asian transplant recipients as the latter were on isoniazid prophy­laxis. [31] A double blind placebo controlled trial of isoniazid prophylaxis showed a trend towards lower risk of tuberculosis. Unfortunately due to the high incidence of hepatitis in the study population the drug had to discontinued in many patients. [49] It appears that the risk of renal transplant recipients developing serious hepatotoxicity with the administration of isoniazid is low and not different from normal individuals. [50] Atypical mycobacteria, which accounts for 10% of infection, may not be susceptible to isoniazid and hence these infections may not be prevented by isoniazid prophylaxis. Secondary prophylaxis for the duration of immunosuppressive regime may be desirable.


   Conclusion Top


The varied presentation of tuberculosis after transplantation is a challenge to the diagnostic ability of the physician. Early diagnosis and effective therapy can subs­tantially reduce the morbidity and mortality from this condition. One should be aware of the interaction between drugs used against tuberculosis and for immunosuppression. Efficacy of preventive measures need to be evaluated in specific populations at high risk for post transplant tuberculosis.

 
   References Top

1.Qunibi WY, Al-Sibai MB, Taher S, et al. Mycobacterial infection after renal trans­plantation--report of 14 cases and review of the literature. Q J Med 1990;77(282):1039-60.  Back to cited text no. 1    
2.Hirata N, Koerner MM, Tenderich G, et al. Influence of cytoimmunological state on the development of tuberculosis in heart transplant recipients. Surg Today 2001; 31(6):482-6.  Back to cited text no. 2    
3.Higgins RM, Cahn AP, Porter D, et al. Mycobacterial infections after renal trans­plantation. Q J Med 1991;78(286):145-53.  Back to cited text no. 3    
4.Rowinska D, Durlik M, Gradowska L, et al. Tuberculosis in patients after kidney trans­plantation. Pneumonol Alergol Pol 1994; 62(5-6):272-9.  Back to cited text no. 4    
5.Lezaic V, Radivojevic R, Radosavljevic G, et al. Does tuberculosis after kidney trans­plantation follow the trend of tuberculosis in general population? Ren Fail 2001; 23(1):97-106.  Back to cited text no. 5    
6.Lattes R, Radisic M, Rial M, Argento J, Casadei D. Tuberculosis in renal transplant recipients. Transpl Infect Dis 1999;1(2):98-104.  Back to cited text no. 6    
7.Biz E, Pereira CA, Moura LA, et al. The use of cyclosporine modifies the clinical and histopathological presentation of tuber­culosis after renal transplantation. Rev Inst Med Trop Sao Paulo 2000;42(4):225-30.  Back to cited text no. 7    
8.Garcia-Leoni ME, Martin-Scapa C, Rodeno P, Valderrabano F, Moreno S, Bouza E. High incidence of tuberculosis in renal patients. Eur J Clin Microbiol Infect Dis 1990;9(4):283-5.  Back to cited text no. 8    
9.Apaydin S, Altiparmak MR, Serdengecti K, Ataman R, Ozturk R, Erek E. Mycobacterium tuberculosis infections after renal transplan­tation. Scand J Infect Dis 2000;32(5):501-5.  Back to cited text no. 9    
10.Sayiner A, Ece T, Duman S, et al. Tuber­culosis in renal transplant recipients. Trans­plantation 1999;68(9):1268-71.  Back to cited text no. 10    
11.Hall CM, Willcox PA, Swanepoel CR, Kahn D, Van Zyl Smit R. Mycobacterial infection in renal transplant recipients. Chest 1994;106(2):435-9.  Back to cited text no. 11    
12.Botha JF, Spearman CW, Millar AJ, et al. Ten years of liver transplantation at Groote Schuur Hospital. S Afr Med J 2000; 90(9):880-3.  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(3):1148-53.  Back to cited text no. 13    
14.Vachharajani T, Abreo K, Phadke A, Oza U, Kirpalani A. Diagnosis and treatment of tuberculosis in hemodialysis and renal transplant patients. Am J Nephrol 2000; 20(4):273-7.  Back to cited text no. 14    
15.Malhotra KK, Dash SC, Dhawan IK, Bhuyan UN, Gupta A. Tuberculosis and renal transplantation­observations from an endemic area of tuberculosis. Postgrad Med J 1986;62(727):359-62.  Back to cited text no. 15    
16.Rubin RH. Infection in the renal and liver transplant patient. In Rubin RH, Young LS, EDS. Clinical approach to infection in the immunocompromised host. 2nd edition, New York, Plenum Press 1988, p 557-621.  Back to cited text no. 16    
17.Mourad G, Soulillou JP, Chong G, Pouliquen M, Hourmant M, Mion C. Transmission of myco­bacterium tuberculosis with renal allografts. Nephron 1985;41(1):82-5.  Back to cited text no. 17    
18.Peters TG, Reiter CG, Boswell RL. Trans­mission of tuberculosis by kidney transplan­tation. Transplantation 1984;38(5):514-6.  Back to cited text no. 18    
19.Ip MS, Yuen KY, Woo PC, et al. Risk factors for pulmonary tuberculosis in bone marrow transplant recipients. Am J Respir Crit Care Med 1998;158(4):1173-7.  Back to cited text no. 19    
20.Aguado JM, Herrero JA, Gavalda J, et al. Clinical presentation and outcome of tuber­culosis in kidney, liver, and heart transplant recipients in Spain. Spanish Transplantation Infection Study Group, GESITRA. Transplan­tation 1997;63(9):1278-86.  Back to cited text no. 20    
21.Naqvi A, Akhtar F, Naqvi R, et al. Problems of diagnosis and treatment of tuberculosis following renal transplantation. Transplant Proc 1997;29: 3051-52.  Back to cited text no. 21  [PUBMED]  [FULLTEXT]
22.Sakhuja V, Jha V, Varma PP, Joshi K, Chugh KS. The high incidence of tuberculosis among renal transplant recipients in India. Transplantation 1996;61(2):211-5.  Back to cited text no. 22    
23.John GT, Infections after renal transplantation in India, Transplantation Reviews 1999;13:183-91.  Back to cited text no. 23    
24.Napathorn S, Praditpornsilpa K, Yenrudi S. Granulomatous interstitial nephritis in renal transplant recipient. J Med Assoc Thai 1996; 79(1):44-8.  Back to cited text no. 24    
25.Forslund T, Laasonen L, Hockerstedt K, Stenman S, Edgren J. Tuberculosis of the colon in a kidney transplant patient. Acta Med Scand 1984;215(2):181-4.  Back to cited text no. 25    
26.Ahsan N, Blanchard RL, Mai ML. Gastro­intestinal tuberculosis in renal transplantation: a case report and review. Clin Transplant 1995; 9(4):349-52.  Back to cited text no. 26    
27.Mat O, Abramowicz D, Peny MO, et al. Tuber­culosis presenting as acute hepatitis in a renal transplant recipient. Transplant Int 1994;­7(1):67-9.  Back to cited text no. 27    
28.Yildiz A, Sever MS, Turkmen A, et al. Tuber­culosis after renal transplantation: experience of one Turkish centre. Nephrol Dial Transplant 1998;13(7):1872-5.  Back to cited text no. 28    
29.John GT, Vincent L, Jeyaseelan L, Jacob CK, Shastry JC. Cyclosporine immunosuppression and mycobacterial infections. Transplantation 1994;58(2):247-9.  Back to cited text no. 29    
30.Aljurf M, Gyger M, Alrajhi A, et al. Myco­bacterium tuberculosis infection in allogeneic bone marrow transplantation patients. Bone Marrow Transplant 1999;24(5):551-4.  Back to cited text no. 30    
31.Kwan JT, Hart PD, Raftery MJ, Cunning-ham J, Marsh FP. Mycobacterial infection is an important infective complication in British Asian dialysis patients. J Hosp Infect 1991;19(4):249-55.  Back to cited text no. 31    
32.Schorn TF, Merscher S, Franz A, et al. Disseminated tuberculosis after renal trans­plantation. A report of two cases. Transpl Int 1990;3(2):113-5.  Back to cited text no. 32    
33.Jha R, Narayan G, Jaleel MA, et al. Pulmonary infections after kidney transplantation. J Assoc Physicians India 1999;47(8):779-83.  Back to cited text no. 33    
34.Ruiz LA, Gil P, Zalacain R, et al. [Usefulness of bronchoalveolar lavage in the renal transplant patient with suspected respiratory infection] Arch Bronconeumol 1998;34(8):388-93.  Back to cited text no. 34    
35.John GT, Juneja R, Mukundan U, et al. Gastric aspiration for diagnosis of pulmonary tuber­culosis in adult renal allograft recipients. Transplantation 1996;61(6):972-3.  Back to cited text no. 35    
36.Mitarai S, Tanoue S, Sugita C, et al. Potential use of Amplicor PCR kit in diagnosing pulmonary tuberculosis from gastric aspirate. J Microbiol Methods 2001;47(3):339-44.  Back to cited text no. 36    
37.John GT, Mukundan U, Vincent L, Jacob CK, Shastry JC. Primary drug resistance to Myco­bacterium tuberculosis in renal transplant recipients. Natl Med J India 1995;8(5):211-2.  Back to cited text no. 37    
38.Offermann G, Keller F, Molzahn M. Low cyclosporin A blood levels and acute graft rejection in a renal transplant recipient during rifampin treatment. Am J Nephrol 1985;5(5):385-7.  Back to cited text no. 38    
39.de la Camara R, Martino R, Granados E, et al. Tuberculosis after hematopoietic stem cell trans­plantation: incidence, clinical characteristics and outcome. Spanish Group on Infectious Com­plications in Hematopoietic Transplantation. Bone Marrow Transplant 2000;26(3):291-8.  Back to cited text no. 39    
40.Al-Sulaiman MH, Dhar JM, Al-Khader AA. Successful use of rifampicin in the treatment of tuberculosis in renal transplant patients immuno­suppressed with cyclosporine. Transplantation 1990;50(4):597-8.  Back to cited text no. 40    
41.Buffington GA, Dominguez JH, Piering WF, Hebert LA, Kauffman HM Jr, Lemann J Jr. Interaction of rifampin and glucocorticoids. Adverse effect on renal allograft function. JAMA 1976;236(17):1958-60.  Back to cited text no. 41    
42.Chenhsu RY, Loong CC, Chou MH, Lin MF, Yang WC. Renal allograft dysfunction asso­ciated with rifampintacrolimus interaction. Ann Pharmacother 2000;34(1):27-31.  Back to cited text no. 42    
43.Jha V, Sakhuja V, Gupta D, et al. Successful management of pulmonary tuberculosis in renal allograft recipients in a single center. Kidney Int 1999;56(5):1944-50.  Back to cited text no. 43    
44.Kusne S, Rafael M. Infectious complications in renal transplantation, eds, Shapiro R, Simmons RL, Starzl TE, Appleton & Lane 1997;p 315­32.  Back to cited text no. 44    
45.Sud K, Muthukumar T, Singh B, et al. Isoniazid does not affect bioavailability of cyclosporine in renal transplant recipients. Methods Find Exp Clin Pharmacol 2000;22(8):647-9.  Back to cited text no. 45    
46.Wallas RJ, O'Brien, R, Glasroth J, et al. Diagnosis and treatment of disease caused by nontuberculous mycobacteria. Am Rev Respir Dis 1990;142(4):940-53.  Back to cited text no. 46    
47.Plemmons RM, McAllister CK, Garces MC, Ward RL. Osteomyelitis due to Mycobacterium haemophilum in a cardiac transplant patient: case report and analysis of interactions among clarithromycin, rifampin, and cyclosporine. Clin Infect Dis 1997;24(5):995-7.  Back to cited text no. 47    
48.Spicer ST, Liddle C, Chapman JR, et al. The mechanism of cyclosporine toxicity induced by clarithromycin. Br J Clin Pharmacol 1997; 43(2):194-6.  Back to cited text no. 48    
49.John GT, Thomas PP, Thomas M, Jeyaseelan L, Jacob CK, Shastry JC. A double-blind randomized controlled trial of primary isoniazid prophylaxis in dialysis and transplant patients. Transplantation 1994;57(11):1683-4.  Back to cited text no. 49    
50.Antony SJ, Ynares C, Dummer JS. Isoniazid hepatotoxicity in renal transplant recipients. Clin Transplant 1997;11(1):34-7.  Back to cited text no. 50    

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Correspondence Address:
Paulose P Thomas
Department of Nephrology, Christian Medical College & Hospital, Vellore, Tamil Nadu
India
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