Tuberculosis in Renal Transplant Recipients

R. Lattes M. Radisic M. Rial J. Argento D. Casadei

Key words: tuberculosis; kidney transplant; immunosuppression; PPD

Tuberculosis in renal transplant recipients

Abstract: Tuberculosis (TB) has been described in kidney transplant recipients as an infection with predominantly pulmonary involvement. We report the impact of TB in kidney transplantation. Clinical records of adult kidney recipients, transplanted between 1 January 1986 and 31 December 1995 were analyzed for sex, age, graft origin, immunosuppressive therapy, TB sites, diagnostic methods and concomitant infections. Annual incidence, mean time of onset, relation to rejection treatment, tuberculin skin test (PPD) and outcome were analyzed. Patients with a history of TB or graft loss in the first month were excluded. TB was diagnosed in 14 of 384 (3.64%). Mean age at transplantation was 35 years. Twelve of these received the graft from a living donor. All had triple immunosuppression with cyclosporine. Ten had pulmonary TB, three extrapulmonary infection and one disseminated disease. In 13 cases an invasive diagnostic procedure was performed. Mycobacterium tuberculosis cultures were positive in all cases; microscopy revealed acid-fast bacilli (AFB) in 6, and adenosine deaminase was elevated in CSF and pleural effusion in 2. Annual incidence varied from 0% to 3.1%. At the time of TB presentation 8 patients had other concomitant infections (cytomegalovirus, nocardia, Pneumocystis carinii, disseminated herpes simplex virus). Median time of onset was 13 months. Diagnostic results became available post-mortem in 2 cases, and one had TB in a failing allograft. TB was treated with 4 drugs including rifampin in 10 patients. Cyclosporine was discontinued in one, lowered in one and increased in 8. During treatment 5 patients had rejection episodes. At 1 year, graft survival was 72.7% and patient survival 90.9%. TB was more prevalent when recipient and donor were both PPD positive. In summary: although TB is a growing threat in the transplant setting, early and aggressive diagnosis with meticulous monitoring of immunosuppression allows a successful outcome for both patient and graft. Optimal prophylaxis guidelines have yet to be completely defined.

Tuberculosis (TB) is the main cause of death as a single infectious disease in the entire world, causing some three million deaths per Received 19 January, revised, accepted for publication 25 March 1999 Copyright c Munksgaard 1999 Transplant Infectious Disease . ISSN 1398-2273 Transpl Infect Dis 1999: 1: 98–104 Printed in Denmark . All rights reserved

98

year (1). The occurrence of TB has been linked to malnutrition and recently to the AIDS epidemic. Urban homelessness, neglect of TB control programs and immigration from countries where TB is endemic are contributing to the increased incidence of TB in developed

Authors’ affiliation: R. Lattes, M. Radisic, M. Rial, J. Argento, D. Casadei Instituto de Nefrologı´a, Buenos Aires, Argentina Correspondence to: Roberta Lattes Instituto de Nefrologı´a Cabello 3889 Buenos Aires 1425 Argentina Tel/Fax: π54-1 807 0719 e-mail: kurlat/datamarkets.com.ar

Lattes et al : Tuberculosis in renal transplant recipients

countries. The incidence of TB in immunosuppressed patients is

of 5 mm or more, whereas donors were considered positive with

expected to rise as TB increases world-wide. The optimal program

the conventional 10 mm or more. Skin tests were performed in an

for prophylaxis and management of TB in the transplant setting

independent setting (Liga Argentina de Lucha Contra la Tubercu-

remains to be defined. In Latin American countries TB is endemic

losis). The diagnosis of TB was defined as the presence of acid-fast

and has been intensified by the AIDS epidemic. In Argentina the

bacilli (AFB) on the smear or high levels of adenosine deaminase

disease is concentrated in a sub-population with lower socio-eco-

(ADA) in appropriate samples (CSF, ascites, pleural effusion, etc.)

nomic status and with poor access to health care. This situation

with adequate clinical features or caseating granulomas in histo-

paradoxically coexists with high-tech medical practices such as

pathology. Diagnosis was confirmed by positive cultures with

transplant medicine. In spite of mandatory BCG immunization in

identification of Mycobacterium tuberculosis.

childhood, TB annual prevalence is 0.4% (2). Adults with a positive

Patients with a history of active tuberculosis prior to transplan-

tuberculin skin test and without evidence of active infection have

tation, significant abnormalities on chest x-ray and graft loss in the

been accepted as organ donors and recipients. At our institution

first 30 days post-transplant were excluded from analysis.

prophylaxis with isoniazid has been given only to those recipients

Statistical analysis included mean and median time of TB onset

with a confirmed history of active TB prior to transplantation. Re-

after transplantation, actual patient and graft survival rate and

nal transplant recipients are considered to be at special risk of reac-

Fisher’s exact test. Significance was accepted with p-value ,0.05.

tivating old tuberculous lesions due to chronic immunosuppression. This risk has been considered greatest during the first months posttransplant, when immunosuppression is maximal. Accordingly, TB has been considered one of the ‘‘early period’’ opportunistic infec-

Results

tious diseases, although it has been diagnosed at any time after transplantation (3, 4). Interaction between antituberculous drugs

Between 1 January 1986 and 12 December 1995, 406 patients re-

and immunosuppressive agents is noteworthy, and is central to the

ceived a kidney graft and 384 met the criteria for further evaluation.

management of TB in the transplant recipient.

Tuberculosis was diagnosed in 14 patients (3.64%), of whom 10

This report assesses the annual incidence of TB in a cohort of kid-

were men. The mean age of TB patients at transplant was 35 years.

ney transplant recipients in an endemic region, evaluates the tools

Twelve had received an organ from a living related donor and two

used for the diagnosis of TB, evaluates the management of anti-tu-

a cadaveric kidney. Triple immunosuppression (cyclosporin A, aza-

berculous treatment and concomitant immunosuppression, and re-

thioprine and corticosteroids) was used in all patients. OKT3 was

lates these factors to graft and patient survival in renal transplant

used as prophylaxis in cadaveric kidney recipients and was followed

recipients. The relationship between a positive intradermal skin test

by triple therapy.

(PPD) prior to transplantation in recipients and living donors to the occurrence of TB in the allograft recipient is also considered.

Mean time to the diagnosis of tuberculosis after transplantation was 21.8 months (range 2–98), with 24.6 months for pulmonary cases and 14.7 months for extrapulmonary infections, whereas median time was 13 months (13.5 for pulmonary cases and 11 for

Patients and methods

extrapulmonary cases).

Site of the disease The clinical records of adult kidney transplants recipients were reviewed for all transplants performed at this institute between Jan-

Pulmonary tuberculosis was diagnosed in 10 patients (71.4%). The

uary 1986 and December 1995. Data collected for analysis included

disease was disseminated in 1 (7.1%) and extrapulmonary in 3

TB occurrence, graft origin, immunosuppressive regimen, TB site

(21.4%). The sites involved in extrapulmonary disease were the

and mean time of onset after transplantation, concomitant infec-

meninges, the hip joint and the small bowel (one patient each).

tions, rejection episodes, management of immunosuppressive drugs during TB treatment, the results of tuberculin testing and graft and

Annual incidence of tuberculosis

patient outcomes. For an intradermal skin test, 2 TU of protein purified derivative (PPD) was used for both recipients and living

All patients on follow-up were considered to be at risk of developing

donors at the time of pre-transplant evaluation. Patients on the wait-

TB. The annual incidence of new TB cases varied between 0% and

ing list were considered to have a positive reaction with a nodule

3.1%. (Fig. 1). Transplant Infectious Disease 1999: 1: 98–104

99

Lattes et al : Tuberculosis in renal transplant recipients

Net state of immunosuppression: rejection episodes in the year prior to TB onset When history of rejection episodes in the year prior to onset of TB was analyzed, it was found that the rejection/patient/year rate was 1.75, and 7 episodes were associated temporally with the diagnosis of TB. Rejection episodes were initially treated with corticosteroid boluses; when rejection was steroid-resistant, monoclonal (OKT3), Fig. 1. Annual incidence of TB in renal transplant patients 1986– 1995

polyclonal antilymphocyte antibodies (Pasteur–Merieux antilymphocyte globulin or antitymocyte globulin) or high-dose intravenous immunoglobulin (IVIgHD from Novartis) were used as rescue treatment. No correlation could be assessed between rejection treatment and TB outcome.

Microbiologic diagnosis The diagnosis of TB was confirmed in all patients by means of a positive culture for M. tuberculosis (Table 1).

Management of immunosuppression during TB treatment In two cases (one disseminated TB and one meningeal TB) the diag-

Concomitant Infections

nosis of TB became available post-mortem. In one case, the graft Ten additional infections were diagnosed at the time of TB onset,

was lost at the time of TB diagnosis and the patient returned to

in eight different patients. The associated infections were: cytomeg-

hemodialysis before treatment was started. Of the remaining 11

alovirus in 5, cytomegalovirus and disseminated nocardiosis in 1,

cases, 10 were treated with isoniazid, rifampin, pyrazinamide and

disseminated nocardiosis in 1, Pneumocystis carinii pneumonia with

ethambutol. Cyclosporine was discontinued in one patient and

disseminated mucocutaneous Herpes simplex in 1. Both nocardial

lowered in another (azathioprine dose was then increased). In 8 pa-

infections had abscesses in the central nervous system of which one

tients the cyclosporine dose was increased until levels within the

required surgical drainage and one also had subcutaneous involve-

therapeutic range were reached. One patient did not receive rifam-

ment.

pin and no change in immunosuppressive therapy was needed.

Table 1

Tuberculosis diagnosis: positive samples

Sample

Bacilloscopy

Culture

Sputum smear

(π)

(π)

BAL

(π)

(π)

Adenosine deaminase

Histology

Cases 1

NA

2

BAL

Negative

(π)

NA

2

Transbronchial biopsy

Negative

(π)

Granuloma

1

Pleural biopsy

Negative

(π)

Negative

1

Surgical lung biopsy

(π)

(π)

Caseum necrosis

1

Surgical lung biopsy

Negative

(π)

Pleural effusion

Negative

(π)

Abscess drainage (hip)

(π)

(π)

Small bowel biopsy

(π)

(π)

CSF

Negative

(π)

Graft and lung biopsies

(π)

(π)

Elevated

1 1

NA

1

Ulcers and granulomas Elevated

BAL, bronchoalveolar lavage; CSF, cerebrospinal fluid; NA, not available.

100

Caseum necrosis NA

Transplant Infectious Disease 1999: 1: 98–104

1 1

Caseum necrosis

1

Lattes et al : Tuberculosis in renal transplant recipients

berculosis can be due to airborne spread in the community, to the

Intradermal skin test Recipient/Donor

Evaluated

TB cases

p(Rª/ Dª) vs. other

Rª / Dª Rπ/ D π Rπ/ Dª Rª / D π

126 7 18 22

4 2 0 0

0.032 NS NS

reactivation of quiescent lesions (more commonly) or to the transmission with the transplanted organ (6). A high index of suspicion

Table 2

should be retained in the long-term follow-up of the transplant recipient, given the importance of early diagnosis and specific treatment to the chance of graft and patient survival. The incidence of TB in transplant recipients has been consistently reported to be several-fold higher than its rate in the general population. The risk of developing TB after transplantation is directly related to the local

Graft and patient survival

epidemiological risk. The incidence of TB in transplant recipients in the United States has been reported to be between 0% and 1.3%

As previously stated, 2 patients died of TB and 1 returned to hemo-

(7). A series from Spain has revealed that 0.8% of transplant recipi-

dialysis before anti-tuberculous treatment was started. In patients

ents developed TB after transplantation (6). In contrast, in countries

treated for TB, survival was 90.9% (10/11) and graft survival was

with high rates of TB in the general population, its incidence in

72.7% (8/11) at 1-year follow-up. In one patient who had cyclospor-

transplant patients has been much higher: 3.5% has been reported

ine dosing reduced, fatal massive hemoptysis developed during the

in Saudi Arabia (4); 11% in South Africa (8); 11.8% in India (9); and

first month of TB treatment. In this patient, CMV viremia was diag-

14.5% in Pakistan (10).

nosed concurrently with TB but rejection was not documented. In

In Argentina, TB incidence varies in the general population be-

a patient who had cyclosporine discontinued while receiving anti-

tween 50 and 320 cases/100 000 according to the geographic area

tuberculous treatment (with rifampin), chronic rejection developed

and to the local economic status, whereas racial background is not

with graft loss 6 months later. No rejection episodes occurred in the

considered a risk factor (2). With an expected TB incidence in the

single patient not recieving rifampin or altered cyclosporine dosing.

local population of 65 cases/100 000 (2), TB incidence in this series

Among the 8 patients who had cyclosporine dosing raised, 5 pa-

reached 3.1%; i.e. almost a hundred times the incidence in our coun-

tients had acute rejection episodes during the course of TB treat-

try as a whole. Classical risk factors such as protein-caloric malnu-

ment, of which one resulted in graft loss. All cases were treated

trition or recent tuberculin conversion (11) were not present in the

with corticosteroid boluses, and because of lack of response IVIgHD

patients included in this series. Of notice the rejection rate for the

was added in 2 and OKT3 in one.

year prior to TB diagnosis (1.75 rejection/patient/year) was much higher than the expected rate at the same transplant center (0.65

Intradermal skin test evaluation

rejection/patient/year). The possible contribution of mycobacterial infection to the inci-

Data on intradermal skin tests were available for 173 recipient/do-

dence of graft rejection or renal dysfunction remains unclear. Crude

nor pairs among 384 clinical records of transplant recipients ana-

and TB-related mortality in this series was 21.4%; of the 11 patients

lysed. TB was somewhat more prevalent for PPD-positive recipients

who received anti-tuberculous treatment only one died (9%). Careful

who received the graft from a PPD-positive donor (Table 2).

management of immunosuppression allowed a graft survival of 72.7% at 1 year, in spite of a high acute rejection rate. In this series, disseminated infection occurred in less than 25%

Discussion

of total cases, despite a high rate of graft rejection in the year prior to TB diagnosis with increased immunosuppression. Similar rates of disseminated infection have been reported by Malhotra et al. (9)

TB has a major impact on renal transplantation in endemic regions.

Naqvi et al. (10) and Aguado et al. (6). Early diagnosis could be

Although TB has been considered as one of the ‘‘early period’’ op-

the result of extensive local experience with tuberculosis and might

portunistic infections (3), it can be diagnosed at any time after trans-

explain the low rates of disseminated tuberculosis diagnosis. Thus,

plantation (4). Cellular immune impairment, as can be found in ca-

in this series, TB was aggressively sought even in the presence of

loric-protein malnutrition, AIDS, end-stage renal disease or trans-

unusual manifestations (12): in only one case was it possible to

plantation, can facilitate the reactivation of quiescent bacilli in

obtain a diagnosis through a sputum smear, while all the others

residual lesions as well as the development of an uncontained pri-

required invasive diagnostic procedures. Smear positivity is related

mary infection (5). In the transplant setting the development of tu-

to the presence of cavitation (13). The caseation and tissue destrucTransplant Infectious Disease 1999: 1: 98–104

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Lattes et al : Tuberculosis in renal transplant recipients

tion that lead to cavitation require a robust immune response which

cipients) supports prolongation of therapy, with a lower mortality

is absent in transplant recipients (14). Accordingly, immunosup-

for patients receiving more than 9 months of treatment (6). The

pressed patients have lower rates of sputum smear positivity (15),

treatment of tuberculosis in kidney transplant patients requires

and invasive procedures are more often required. Nonetheless in

attention to both the specific antimicrobial therapy and the careful

some particular sites TB diagnosis can be difficult to confirm even

management of the immunosuppressive agents and drug interac-

with the most aggressive diagnostic procedures: bacilloscopy is fre-

tions. The appropriate level of immunosuppression must be deter-

quently negative, and culture results may take too long for adequate

mined for each patient. Rifampin is a first-choice drug for TB treat-

decision-making in the clinical setting.

ment: the unique pharmacology and mycobactericidal activity of

Because of these limitations there is a growing interest in using

RFP has changed TB therapy, allowing treatment to be shortened

sensitive and rapid tools for TB diagnosis. The measurement of

from 18 months to 6–9 months (25). The interaction between rifam-

ADA levels in the appropriate specimens can be considered one

pin and immunosuppressive drugs requires special care. Rifampin

such tool: it is an inexpensive and simple procedure, and has proved

induces hepatic microsomal enzymes and intestinal cytochrome P-

to be a sensitive and specific diagnostic test. Adenosine deaminase

450 enzymes (26), causing a reduction in cyclosporine serum levels

is an ecto-enzyme that is present on the surface of mononuclear

(27, 28). Hence, cyclosporine doses generally must be increased and

cells. It has an enzymatic function and an immunomodulatory activ-

serum levels monitored closely. A doubling of the usual cortico-

ity (16). Tuberculous inflammatory response is associated with high

steroid dose has also been recommended (6) owing to the effect

ADA concentrations at the involved site. In the immunocompetent

that rifampin has on corticosteroid catabolism (27, 29). It has been

host, this feature is specific and sensitive enough to make the ADA

suggested that rifampin use should be avoided in patients receiving

determination a useful diagnostic aid. High levels of ADA are

cyclosporine, since interference between these drugs could lead to

strongly suggestive of tuberculosis when measured in the cerebro-

rejection with a significant risk for crude and TB-related mortality

spinal fluid (17, 18), pericardial (19) and pleural effusions (20), as-

(6). This remains a controversial issue. Fluoroquinolone anti-

cites (21), and even when measured in bronchoalveolar lavage fluid

microbials are the only drugs with a similar pharmacological profile

(22). Information about specificity and sensitivity of ADA measure-

which could substitute for rifampin. However, fluoroquinolones

ment in patients with cellular immunity impairment is still insuf-

have the capacity to induce interleukin-2 and g-interferon (30, 31)

ficient, but there have been reports supporting the usefulness of

and to antagonize the cyclosporine-dependent inhibition of interleu-

ADA level results as a diagnostic aid in HIV-positive patients (23,

kin-2 production. (32). These characteristics could prove to be clin-

24). In the two cases (Table 1) where it was sought, high ADA levels

ically relevant (33) and might increase the risk of acute rejection.

induced the initiation of specific anti-TB treatment early in the diag-

In this series, 5 (62.5%) of the 8 patients who received rifampin

nostic work-up. Diagnosis was later confirmed by positive cultures.

developed acute rejection in spite of having cyclosporine levels in

It is unclear whether the aggressive approach contributes to an

therapeutic range. Even though rejection was treated with cortico-

improved survival rate. In this series, of the 11 patients with a

steroid boluses, high-dose IVIgG and monoclonal antibodies (the

functioning graft in whom diagnosis was made while alive, only

use of which has been associated with higher TB mortality) (6), TB-

one died with a massive hemoptysis, which is usually the conse-

related complications were not seen and rifampin withdrawal was

quence of the erosion of a pulmonary artery in a developing cavity

not required. However, one patient lost the graft. These results show

(Rasmussen’s aneurysm) (5).

that it is possible to use rifampin successfully in the treatment of

The high rate of co-infections due to CMV and Nocardia spp.

TB in kidney transplant patients.

reflect the degree of immunosuppression in TB patients and re-

Since the occurrence of TB after transplantation is of real con-

inforce the need for an extensive search of more than one pathogen

cern, new methods to establish the potential risk of infection and to

in the severely immunologically impaired patient. The standard

evaluate prophylactic regimens are needed. The effort should be

treatment for TB at our institution includes the administration of

focused on identifying those recipients and donors who have old

isoniazid (INH), rifampin (RFP), pyrazinamide (PZN) and ethambu-

tuberculous lesions at risk for reactivation under maximal immuno-

tol (EMB) for 2 months, followed by INH and RFP for another 10

suppression. All patients and donors from endemic regions with

months. When rifampin cannot be used, the treatment is started

radiological findings such as micro-calcified lung nodules could be

with the other three drugs and extended to 18 months using INH

considered to have had primary TB infection and might benefit

and EMB or PZN. Although there is no consensus regarding opti-

from prophylaxis (34). A positive skin test could be useful for de-

mal treatment for this group of patients, a recent series of solid-

cision making even if no other stigmata are present. However, im-

organ transplant patients (which included 33 kidney transplant re-

munological impairment due to chronic disease enhances the

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Transplant Infectious Disease 1999: 1: 98–104

Lattes et al : Tuberculosis in renal transplant recipients

chances of false negative results (35), hence a negative PPD result

the use of INH is not without concern in this setting owing to the

is not an accurate predictor of TB occurrence (36). We chose to

potential hepatotoxicity of the drug (11, 37). Recent reports seem to

consider the 2 TU skin test as positive, for patients on the waiting

show that the use of INH is relatively safe in the absence of liver

list, when a nodule of 5 mm or more was found (as in HIV-reactive

disease (32). The potential for increased mycobacterial resistance to

patients). However, an enhanced risk of developing TB in patients

antimicrobials with extended low-dose prophylaxis merits further

with a positive skin test prior to transplant could not be established.

investigation.

In our patient population, BCG vaccination in childhood is routine.

At this time we recommend prophylaxis in all PPD-positive pa-

However, a positive skin test more than 10 years after the last BCG

tients receiving an organ from a PPD-positive donor. A prospective

dose raises the suspicion of active TB. Active disease must be thor-

study of INH in all PPD-positive recipients and recipients of organs

oughly investigated in such patients prior to transplantation. In this

from PPD-positive donors is under way.

series, a correlation was found between TB occurrence and positiv-

Although TB is a significant threat in the transplant setting,

ity of both the recipient and donor skin tests. Whether this obser-

early and aggressive diagnosis with meticulous monitoring of im-

vation reflects the additive risk of infection from both donor and

munosuppression allows a successful outcome for both patient and

recipient as another mechanism is not clear. Although prophylaxis

graft. Optimal prophylaxis guidelines have yet to be completely de-

has been recommended for recipients with a positive skin test (11),

termined.

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