Tuberculosis in Renal Transplant Recipients

Abstract

Background: Renal transplant recipients should be considered at high risk for development of Mycobacterium tuberculosis infection (tuberculosis, TB). TB is relatively more frequent among transplant recipients than general population, depending on its epidemicity in the geographic region. Clinical manifestations in this group of patients may be atypical and deserve aggressive investigations for diagnosis. Tuberculin skin test has several limitations regarding diagnosis in chronic renal failure patients. In this retrospective study, we aimed to explore the prevalence and clinical manifestations of TB in renal transplant patients. Materials and methods: We retrospectively analyzed the data for TB prevalence, clinical presentations, and patient and graft survivals of total 320 pediatric and adult renal transplant recipients in our center between 1992 and 2010. Results: The prevalence of TB was 2.8%. Five patients received kidney from living-donor related and four from cadaveric donors. Cadaveric-donor patients received antithymocyte globulin for induction, and four patients received pulse steroid for acute rejection. The median duration of time between transplantation and TB was 21 (1–150) months, and between induction/pulse therapy and infection was 5 (1–100) months. The immunosuppressive protocols included prednisolone and cyclosporine/rapamycin with or without mycophenolate mofetil/azathioprine. The major symptoms were fever (77%), cough (66%), and abdominal pain (22%). Extrapulmonary TB with intestinal (2/9), pericardial (1/9), lymph node (1/9), and cerebral (1/9) involvements developed in five patients. One patient had both pulmonary and testicular involvements. All patients received quartet of anti-TB therapy for a median duration of 9 months. One patient died at the second month of therapy because of dissemination of TB, and one patient returned to hemodialysis because of chronic allograft nephropathy. Conclusion: The prevalence of TB was 2.8% in our renal transplant patients. The quartet of anti-TB treatment including rifampicin resulted in success in a majority of patients.

• renal transplantation
• tuberculosis
• immunosuppression
• tuberculin test

INTRODUCTION

Tuberculosis (TB) is still an important public health problem and a leading cause of death in endemic countries. The risk of infection is high in special conditions, such as AIDS, underlying chronic diseases, alcoholism, malignities, and immunosuppressive states like solid organ transplantations.^1,2

Table 1. Overall characteristics of the patients.

Age (mean ± SD, years)	46.7 ± 11.7
Sex (M/F)^a	5/4
Cause of renal failure
Chronic pyelonephritis	3
Chronic glomerulonephritis	1
Amyloidosis	1
Hypertension	2
Unknown	2
Donor type^a
Living-related	5
Cadaveric	4
Type of tuberculosis^a
Pulmonary	4
Extrapulmonary	5
Disseminated	1
Duration of dialysis before transplantation (median, months)	18 (1–48)
Immunosuppressive protocols^a
Pred + AZA + CsA	4
Pred + MMF + CsA	4
MMF + CsA	1
Time elapse from transplantation to the diagnosis of TB (median, months)	21 (1–150)

Note: ^aValues represent the number of patients.

The incidence of Mycobacterium tuberculosis infection after solid organ transplantation has not been well defined, and is mainly determined by the epidemiological risk in that country. The prevalence of posttransplantation TB depending on the endemic area varies from 1.2% to 15%.³ The data from our country demonstrated that TB prevalence after solid organ transplantations was 2.63%, which was 8.5-fold higher than in the general Turkish population (0.3%).⁴ Primary infection in renal transplant patients is rare and occurs commonly as a result of transmission by donor kidney. Majority of the cases are due to reactivation of latent infection.^4–6 TB infection among renal transplant recipients carries important diagnostic difficulties because of frequent extrapulmonary involvement and the atypical presentation.² Tuberculin skin test has several limitations in diagnosis of latent TB infection since cutaneous anergy rate due to underlying immunosuppression and false positivity due to exposure to non-TB mycobacteria or prior bacille Calmette–Guérin vaccination among these patients are high.^2,7

This study was undertaken to report the experience with posttransplantation TB in a single center.

MATERIALS AND METHODS

We retrospectively analyzed the records of all kidney transplant patients in our center between 1992 and 2010. The medical records of the TB patients were reviewed for demographic data, transplantation features (living-related or cadaveric), time of occurrence of clinical manifestations, characteristics of TB infection, methods of diagnosis, treatment regimen, and outcome.

In our center, all patients before transplantation had chest X-rays to exclude active TB, and the patient with active disease was not allowed to proceed with transplantation. We do not include tuberculin skin test in pretransplant evaluation.

TB prophylaxis is not routinely administered to our patients. The diagnosis was made according to the following criteria: (1) demonstration of acid-fast bacilli or cultivation of M. tuberculosis in specimens; (2) histological evidence of caseating granuloma; (3) response to anti-TB treatment in patients with clinical and radiological findings of highly suggestive TB, but without any microbiological or pathological confirmation.

RESULTS

TB was diagnosed in 9 out of 320 kidney allograft recipients (2.8%). Overall characteristics of the patients were shown in Table 1. In comparison to non-TB patients, mean age (46.7 ± 11.7 vs. 43 ± 12.9, p = 0.42) and gender were not significantly different (p = 0.9). The distribution of organ donor source between TB and non-TB groups were similar as well (p = 0.73).

Table 2. Characteristics and outcome of patients with tuberculosis.

Case no.	Sex	Age of TB	Source of donor organ	Time from tx to TB (months)	Reject attack	Clinical symptoms	TB site	Diagnosis	Maintenance immunosuppressive	Anti-TB	Graft outcome /patient outcome
1	F	32	L	31	1	Fever, cough, sputum, headache	Lung + cerebral	BAL culture	Pred + CsA + AZA	Q	Failure/survival
2	M	54	C	4	–	Fever, cough, sputum	Lung + disseminated	BAL culture	Pred + CsA + MMF	Q	Failure/mortality
3	F	33	C	4	1	Dyspnea, fever, cough	Lung	BAL culture	Pred + CsA + MMF	Q	Survival/survival
4	M	46	C	1	–	Fatigue, inguinal mass	Lymph node	Excisional biopsy	Pred + CsA + MMF	Q	Survival/survival
5	M	52	C	5	–	Hematochezia abdominal pain, fever	Colon + Lung	Biopsy, BAL culture	Pred + CsA + MMF	Q	Survival/survival
6	M	16	L	74	–	Fever, cough testicular swelling	Lung	BAL culture	Pred + CsA + AZA	Q	Survival/survival
7	F	32	L	21	1	Fever, abdominal pain, cough	Lung + terminal ileum	BAL culture	Pred + CsA + AZA	Q	Survival/survival
8	F	67	L	100	1	Fever, exertional dyspnea	Pericard	Xenodiagnosis, biopsy revealed fibrinoid necrosis	CsA + MMF	Q	Survival/mortality
9	M	45	L	150	1	Fever, cough	Lung	BAL stain, MRI	Pred + CsA + AZA	Q	Survival/survival

Note: M, male; F, female; L, live; C, cadaveric; tx, transplantation; TB, tuberculosis; BAL, bronchoalveolar lavage; Pred, prednisolone; CsA, cyclosporine; MMF, mycophenolate mofetil; AZA, azathioprine; Q, quadruple, ethambutol + isoniazid + morphozinamide + rifampin.

Time elapsed from the date of transplantation to the onset of symptoms ranged from 1 month to 12.5 years although four of the patients (44%) developed TB within 1 year of transplantation (Table 2). Fever was the most common symptom in the patients (77%), followed by cough (66%), sputum production (33%), abdominal pain (22%), and dyspnea (11%). Seven patients had positive acid-fast stains in the materials obtained by bronchoalveolar lavage and/or culture positivity (77%), three had histologic evidence of caseating granuloma (33%). One patient was diagnosed based on MRI demonstrating supportive features. One patient with fever of unknown origin responded to anti-TB therapy and so diagnosed accordingly.

Five patients (55.5%) had extrapulmonary TB [gastrointestinal (two), lymph node (one), pericardial (one), and cerebral (one)]. One patient had both pulmonary and suspected testicular involvement.

All patients received quartet of anti-TB protocol of isoniazid (INH) (5 mg/kg/day), rifampicin (10 mg/kg/day), ethambutol (15–25 mg/kg/day), and morphazinamide (1000 mg/day) for a median duration of 9 months (range, 2–12 months).

We cured seven patients with well-functioning graft, one patient died because of dissemination of the disease, and one patient returned to hemodialysis following anti-TB therapy due to chronic allograft nephropathy and retransplanted from deceased donor in 2010 with still well-functioning graft. None developed significant drug adverse effects.

DISCUSSION

TB is a serious infection with high mortality rate (ranging from 22% to 31%) in solid organ transplant recipients.¹ The observed mortality rate in our study might be incidentally low due to limited number of cases. The risk is mainly determined by endemicity of the infection in specific geographic area. Cavusoglu et al.⁴ reported that TB prevalence after solid organ transplantations was 2.63%, which was 8.5-fold higher than the prevalence in the general Turkish population (0.3%). The rate of occurrence of M. tuberculosis infection according to data from WHO was estimated to be 45/100,000 in Turkey.⁵ Majority of cases are due to reactivation of latent infection. Primary infection in renal transplant patients is rare and occurs commonly as a result of transmission by donor kidney.⁴

In our study, the prevalence of TB was 2.8% owing to the high frequency of TB in general Turkish population, and 44% of the patients developed TB within 1 year after transplantation that may be due to reactivation of latent infection. Ergun et al.⁶ reported the prevalence as 3.5% in their study. In our patients, the time elapsed from transplantation to diagnosis of TB ranged from 1 to 156 months with a median of 21 months. The study among solid organ transplant recipients conducted in another center in Turkey concluded that TB developed within 2–33 months after transplantation, with a median of 15 months.⁴ In accordance with our result, data from Southern China and Thailand, where TB epidemicity was also high, demonstrated prevalence rates ranging from 1.76% to 12.96%.^8,9

Diagnosis of TB depends on demonstration of acid-fast bacilli in study materials, cultivating the microorganism in special media, and presence of caseating granuloma with or without acid-fast bacilli in histological specimens. The tuberculin skin test, on the other hand, is a screening test to reveal the history of contact with M. tuberculosis. However, in patients with chronic renal failure tuberculin test shows high rates of anergy due possibly to impaired cellular immunity because of uremia, and hence has a low sensitivity and specificity in detecting latent TB infection.^2,10,11 In the study conducted by Kantarci et al., prevalence of tuberculin positivity and anergy in asymptomatic chronic renal failure patients waiting for transplantation were 42.1% and 43.3%, respectively. And 14.5% of positives had a previous TB history.⁷ Besides, in a recent Spanish cohort, authors demonstrated that only 0.9% of patients with a positive tuberculin test developed TB, therefore tuberculin test positivity was not found to be a risk factor. But they could not rule out the possibility that this finding was due to a lack of statistical power so they kept the current recommendations for chemoprophylaxis for high risk patients who were described by tuberculin test positivity, co-residence with a person with active TB, and inappropriately treated TB.³ The evidence for the benefit of INH prophylaxis in renal transplantation is a challenging issue. Yildiz et al.¹² had demonstrated that INH prophylaxis prevented posttransplant TB in patients with high risk of TB. Apaydin et al.¹³ retrospectively evaluated 274 renal transplant patients. In his study, 51 out of 274 patients received 6 months INH prophylaxis, whereas 223 recipients did not, and 3 patients (6%) in the prophylaxis group and 13 patients (8.8%) in the nonprophylaxis group developed TB. In a further study, Sayiner et al.¹⁴ analyzed subset of 36 patients with suggestive TB history or radiographic findings. They gave INH prophylaxis to 23 of these, and 13 others were not given INH prophylaxis. The prophylaxis group did not develop TB, whereas one case occurred in the nonprophylaxis group.

We considered reactivation of TB in all our patients although chest radiographs appeared normal. One patient died because of disseminated disease. As immunosuppressive agents greatly hamper the control of TB, up to one-third of patients may present with disseminated disease.⁸

Basiri et al.¹⁵ in their recent case–control study underscored that the long duration of hemodialysis before transplantation (mean 30.3 months) in cases compared to controls (mean 18.2 months) was associated with high risk for TB. They also emphasized that rejection episodes or use of antithymocyte globulin (ATG) or antilymphocyte globulin increase the risk of posttransplant TB by tapering cell-mediated immune function, and help reactivate dormant infections. In our study also, majority of the patients (6/9) have duration of dialysis more than 18 months. Four of our patients received ATG for induction, and five had rejection episode and received pulse steroid therapy accordingly. As this is not a comparative study, there is a limitation to demonstrate the relation between rejection episodes and/or use of ATG and the frequency of TB. Risk factors for posttransplant TB have to be made clear by further large case–control studies.

The symptoms did not differ in frequency as reported previously in other studies as fever being the most prevalent symptom.^1,8,9

Seven of the patients in our study were successfully treated by rifampicin-included quartet of therapy for a median duration of 9 months. All had well-functioning allografts. None developed serious drug side effects. One patient died within 2 months of therapy due to dissemination of disease, and one returned to hemodialysis following infection due to chronic allograft nephropathy. The latter had retransplantation from deceased donor in 2010, still well-doing with functioning graft, and without TB.

TB in solid organ transplant recipients is a potential threat with high mortality rate, and may have unusual clinical presentations, therefore diagnosis and treatment presents several challenges. It is needed to maintain a high index of suspicion, and initiate prophylaxis in those at high risk for reactivation of latent infection. As the problem of drug-resistant TB is getting high in our country, the control program for this challenging disease should be overemphasized by primary healthcare systems.

As a conclusion, although currently we do not administer chemoprophylaxis, our frequency rate of TB was not found to be higher than other centers in our country. It is possible to treat the majority of patients with quadrat of anti-TB therapy without significant impairment of graft function.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.