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Saudi J Kidney Dis Transpl 2017;28(6):1362-1368


© 2017 Saudi Center for Organ Transplantation Saudi Journal
of Kidney Diseases
and Transplantation

Renal Data from the Arab World

The Diagnosis of Tuberculosis in Dialysis Patients


Hela Jebali1, Sana Barrah1, Lamia Rais1, Rania Kheder1, Nihal Khouja2, Salma Nadia Mhiri2,
Majed Beji2, Rim Abdelmalek3, Hanene Tiouiri3, Wided Smaoui1, Soumaya Beji1, Fethi Ben
Hmida4,5, Lilia Ben Fatma1, Mohamed Karim Zouaghi1

Departments of 1Nephrology, Dialysis and Transplantation, 2Pneumology and 3Infectiology, La


Rabta Hospital, 4Research Laboratory of Kidney Diseases (LR00SP01), Charles Nicolle Hospital,
5
Faculty of Medicine, Tunis El Manar University, Tunis, Tunisia

ABSTRACT. The incidence of tuberculosis (TB) is high in patients undergoing chronic dialysis
than it is in the general population. The diagnosis of TB is often difficult and extrapulmonary
involvement is predominant. This study investigates the spectrum of clinical presentations and
outcome in dialysis patients during a nine-year period. TB was diagnosed in 41 patients. Anti-TB
drugs, adverse effects of therapy, and outcome were noted. Thirty-eight patients (92.6%) were on
hemodialysis and three were on peritoneal dialysis (7.3%). The mean age at diagnosis was 50.8
years and the male/female ratio was 1.16. Four patients had a history of pulmonary TB.
Extrapulmonary involvement was observed in 32 (78 %) patients. The bacteriological confir-
mation was made in 41.46% and histological confirmation was made in 26.83%, and in the rest,
the diagnosis was retained on the criterion presumption. Nineteen patients (46.34%) developed
adverse effects of antitubercular drugs. Eight patients (19.51%) died during the study from TB or
adverse effects of treatment. Low urea reduction ratio and female sex were associated with poor
prognosis in our study. The clinical manifestations of TB in patients on dialysis are quite non-
specific, making timely diagnosis difficult, and delaying the initiation of curative treatment,
which is a major determinant of the outcome.

Introduction Worldwide, TB infection in dialyzed patients


ranges from 5%–25% and a 6.9–52.5-fold risk
Tuberculosis (TB) remains a major health of TB is reported as compared to the general
problem, particularly in endemic regions.1 population.2,3 In a previously published
Correspondence to: Tunisian prospective study, the authors found
10% as a rate of active TB among hemo-
Dr. Sana Barrah, dialysis (HD) patients; this rate represents 15
Department of Nephrology, Dialysis and times of the general population TB incidence
Transplantation, La Rabta Hospital, in our country (23/100,000).4,5 Several factors
Tunis, Tunisia. related to dialysis contribute to impairment of
E-mail: barrahsana@gmail.com cell-mediated immunity, including nutritional
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The diagnosis of tuberculosis in dialysis patients 1363

abnormalities (reduction of protein intake and diseases. TST was carried out by the intra-
micronutrient deficiency), iron overload, and dermal method and was read 48-72 hours later.
bio-incompatibility of the dialysis system. In Positivity was defined as an induration dia-
addition, frequent hospital contact, older age meter ≥10 mm. Malnutrition was defined as
of dialysis recipients, diabetes mellitus, low BMI <20 kg/m2 and hypoalbuminemia <30
body mass index (BMI), and the use of immu- g/L. Iron overload was defined as hyper-
nosuppressive drugs are additional factors ferritinemia >500 µg/L.
which contribute to the higher prevalence of Treatment response was evaluated according
TB in these patients.6-8 The diagnosis of TB to improvement of the general condition, func-
disease is often delayed in dialysis patients due tional signs, radiological signs, and biological
to nonspecific symptoms.2,9 This causes the data.
delay in initiation of TB treatment which
adversely patient outcomes.10,11 Statistical Analysis
There are limited data about the prevalence
and the patient characteristics of TB cases Data were analyzed using the Statistical
among dialysis patients in Tunisia. The aim of Package for the Social Sciences for Windows
this study was to evaluate clinical characte- version 11.0 (SPSS Inc., Chicago, IL., USA).
ristics, diagnostic tests, treatment modalities, The results were expressed in terms of number
and outcomes of TB among patients with end- of cases and/or percentage for categorical
stage renal disease undergoing chronic dialysis. variables and in terms of averages for quanti-
tative variables. We used Chi-square test for
Patients and Methods the comparison of percentages and test ana-
lysis of ANOVA variances for comparison of
This was a retrospective study and included averages. P <0.05 was considered statistically
all patients with diagnosed with TB under- significant.
going either HD or peritoneal dialysis (PD)
over a period of nine years between April Results
2007 and July 2016. We identified 41 cases of
TB. We analyzed the clinical and laboratory Forty-one cases of TB were diagnosed during
features at the time of TB diagnosis including the study period. The average age of this popu-
epidemiological characteristics and signs sug- lation was 50.8 years ± 15.23 (22–85 years).
gestive of a pulmonary or extrapulmonary Twenty-two patients (53.6%) were male and
involvement. 19 (46.3%) were female. Of these, 38 patients
Diagnosis of TB was based on the following (92.6 %) were on HD and three (7.3 %) on PD.
criteria: (1) positive culture of any specimen or The mean interval between the onset of
a tissue for Mycobacterium tuberculosis and dialysis and the time of diagnosis of TB was
(2) histopathological evidence of M. Tubercu- about 1.7 years (range: 1 week–9.2 years).
losis (granulomatous with caseating necrosis). Comorbidities, primary renal disease, and
In cases without bacteriological or pathological corticoids and/or immunosuppressive therapy
confirmation, TB was defined as clinical (un- are summarized in Table 1. Four patients
explained fever, impaired general condition), (9.7%) had a prior history of a pulmonary TB.
biological (high C-reactive protein (CRP), Thirty-two patients (78%) have been vacci-
hypoalbuminemia, lymphocyte predominance, nated against TB. The most common clinical
and exudative effusion of peritoneal, peri- features were weight loss (97.5 %), anorexia
cardial, and pleural fluid), imaging (pleural (97.5 %), and fever (51.2 %). The main biolo-
lesions, pulmonary lesions) and/or histopatho- gical characteristics of our patients are summa-
logical (noncaseating granulomas), and/or po- rized in Table 2. High CRP (>10 mg/L) was
sitive tuberculin skin test (TST) and/or history noted in 39 patients (95.12%). Hypoalbumi-
of active TB, and the exclusion of other nemia (<30 g/L) was noted in 12 cases (29.2%).
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1364 Jebali H, Barrah S, Rais L, et al

Table 1. Epidemiological features


Number (%)
Age (years) 50.8 years (22–85 years)
Sex ratio (M/F) 22/19( 1.15)
Dialysis modality (HD/PD) 38/3 (92.6/7.3)
Primary renal disease
Glomerulonephritis 15 (36.5%)
Tubulointerstitial nephritis 9 (21.9%)
Nephroangiosclerosis 2 (4.8%)
Unknown origin 15 (36.5%)
Comorbidities
Diabetes 11(26.8%)
Hypertension 23(56.1%)
Neoplasia 3 (7.3 %)
Corticoids and/or immunosuppressive therapy 5(12.2%)
M: Male, F: Female, HD: Hemodialysis, PD: Peritoneal dialysis.

Hematological abnormalities included anemia diagnosis was about 113.52 days (30–360
in 85.3% (35 patients), hyperleukocytosis in days). Confirmation of TB was done in 68.3%
21.95% (9 patients), and leukopenia in 4.8% of cases (28 patients), 17 cases (41.46%) on
of cases (2 patients). Six patients had hyper- bacteriological findings, and 11 cases (26.83%)
calcemia and parathyroid hormone levels on histological findings (Table 3). In the
below 150 pg/mL (14.63%). An analysis of remaining cases (13 patients, 31.7%), the diag-
peritoneal, pericardial, and pleural fluids nosis of TB was made on strong clinical, labo-
showed lymphocyte predominance and exuda- ratory, histopathological, and/or radiological
tive effusion in all cases. TST was performed suspicion.
on all patients before initiation of therapy. A Thirty-nine patients were treated with rifam-
positive result was seen in 15 patients (36.5%). picin, isoniazid, ethambutol, and pyrazinamide,
The clinical presentation of TB was varied in whereas two patients received rifampicin, iso-
our study population. It was unifocal in 29 niazid, and pyrazinamide. Planned for all
patients (70.73%), bifocal in nine patients patients involved the use of all antitubercular
(21.95%), and three patients had multisystem drugs in the first two months, isoniazid and
involvement (7.3%). Extrapulmonary TB was rifampicin treatment continued thereafter. The
observed in 78% of cases (32 patients). mean duration of treatment was 198.3 days (4–
Isolated pulmonary TB was noted in 21.95% 365 days). Nonadherence of treatment was
of cases (9 patients), whereas eight patients observed in 34.1% of cases (14 patients). The
presented pulmonary TB associated with determination of acetylator phenotype was
another placement (Tables 3 and 4). The mean carried out on 25 patients. Twenty-one patients
interval between the onset of symptoms and TB were slow acetylators, whereas four patients

Table 2. Biological features.


Parameters Minimum Maximum Average
C-reactive protein (mg/L) 5 298 65.8±55.4
Leukocytes 2530 16900 7494 ±3029
Hemoglobin (g/L) 4.6 11.8 8.4±1.7
PTH (pg/mL) 5 2238 397.6±482.3
Calcemia (mg/L) 76 133.6 97.7±13.1
Albuminemia (g/L) 16.2 43.20 30.9±6.7
Urea reduction ratio 47.9 77 64.7±7.4
Ferritin 20 2450 661.1±623.7
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The diagnosis of tuberculosis in dialysis patients 1365

Table 3. TB diagnosis.
TB site Number Bacteriological Histological Presumptive
HD PD
localization (%) diagnosis diagnosis criteria
Pulmonary 17 (41.4) 17 0 9 1 7
Urinary 9 (21.9) 7 2 7 1 1
Pleural 9 (21.9) 8 1 0 3 6
Lymph node 7 (17) 7 0 0 6 1
Peritoneum 5 (12.2) 5 0 1 0 4
Bone 3 (7.3) 3 0 0 0 3
Hematopoietic 3 (7.3) 3 0 0 0 3
Pericardial 1 (2.4) 1 0 0 0 1
TB: Tuberculosis, HD: Hemodialysis, PD: Peritoneal dialysis.

had fast phenotype. The mean dose of isonia- cessation of isoniazid in one case. Several
zid for slow group was 130 mg/day (ranging patients presented more than one adverse
from 50 mg and 200 mg/day), and the mean effect. According to acetylator phenotype, 11
dose for fast group was 200 mg/day (ranging slow acetylators developed adverse effects
from 150 mg and 300 mg/day). Nineteen related to isoniazid and only one fast acety-
patients developed adverse effects (46.34%). lator presented digestive disorders.
Cutaneous manifestations of drug allergy and The mean period of follow-up was 9.32
hypersensitivity occurred in seven patients; all months (3 days to 3 years). Clinical response
drugs were stopped and restarted gradually was achieved in 82.9% (34 patients) (Table 4).
with good tolerance. Hepatotoxicity developed One patient developed reactivation of pulmo-
in six patients (cytolysis in 2, cholestasis in 2, nary TB after cessation of treatment. Fifteen
and acute liver failure in 2), requiring cessation patients (36.58%) died during the treatment
of all drugs in two patients, and adjustment of from TB or adverse effects related to the treat-
doses in two cases. Hematologic abnormalities ment in eight patients (multiorgan failure in 5,
were observed in six patients (aggravation of acute liver failure in 1, isoniazid intoxication
anemia in 4, leukopenia in 1, and thrombo- in 1, and acute respiratory failure in 1 patient,
cytopenia in 1 patient). Five patients presented respectively). The remaining deaths were related
with reversible digestive disorders and required to cardiovascular and/or cerebrovascular events.
Table 4. Comparison with the literature.
Our study Hassine (Tunisia) Malik (KSA) Sen (Turquie)
Hemodialysis 92.6 % 100% 77% 77.8%
Peritoneal dialysis 7.3% 0 23% 22.2%
Mean age 50.8 42 55.65 52.33
Sex ratio 1.16 2 2 1.6
Mean interval for diagnosis
31 17.8 24 19.5
(months)
Diabetes 26.8% 16.6% 29.2% –
Weight loss 97.5 % 100% 18.5% –
Anorexia 97.5 % 50% 14.58% –
Fever 51.2 % 66.6% 66.6% –
Tuberculin skin test positive 36.5% 33.4% 35% –
Pulmonary 41.4% 33.3% 48% 22.2
Pleural 21.9% 0% _ 28.6
Lymph node 17% 16.6% 23% 35.7
Urinary 21.9% 0% 6.25% –
Peritoneum 12.1% 50% 31.25% –
Clinical response 82.9% 80% 72.92% 89%
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1366 Jebali H, Barrah S, Rais L, et al

Table 5. Prognosis factor.


Prognosis Factor P Odds Ratio
Female sex 0.009 6.4
Diabetes 0.15 0.357
Hypertension 0.79 1.19
Neoplasia 0.27 0.26
Corticoids 0.42 2.54
Immunosuppressive therapy 0.42 2.54
CRP >10 mg 0.28 1.62
Hyperleukocytosis 0.95 0.95
Leukopenia 0.058 0.33
Lymphopenia 0.11 2.5
Anemia 0.28 0.3
Hyperferritinemia 0.46 2.25
Hypercalcemia 0.37 0.4
PTH <150 pg 0.71 0.72
Albumin<30 g 0.69 1.4
Hypocholesterolemia <1.3 0.10 0.16
URR <65% 0.026 0.08

For the patients treated according to the


criteria of presumption, clinical response was
achieved in 84.61% (11/13) of cases. Overall
survival at one year was 62% (Figure 1).
Univariate analysis showed that the female sex
(P = 0.009), and urea reduction ratio <65% (P
= 0.026) were negative prognosis factors in
our patients (Table 5).

Discussion

In this study, we diagnosed 41 active TB


patients undergoing chronic dialysis treatment
for a period of nine years. Our data suggested
that TB diagnosis was often difficult in these
patients. In fact, the mean interval between the
onset of symptoms and TB diagnosis was
about 113.52 days in our patients, and diag- Figure 1. Survival curve.
nosis of TB was made on presumption criteria
in 31.7% of cases. in these patients cannot be used to eliminate
In our study, 26.83% of patients were diabetic the possibility of latent or active TB.13-16 In our
and 12.19% were on immunosuppressive treat- study, only 36.5% of patients with a clinical
ment. The majority of our patients had iron diagnosis of TB presented positive TST.
overload and malnutrition In this study, impaired general condition and
In our study, 9.7% of patients had a history of fever were noted in 97.56% and 51.22% of
active pulmonary TB. This frequency varies cases, respectively, while increasing CRP and
according to the authors between 0% and 27%. anemia were noted in 95.12% and 85.3%,
TB infection in chronic dialysis patients is respectively. Lymphocyte-predominant exudates
probably secondary to reactivation of latent were presented in all cases with pleural,
TB.12 A negative TST due to its poor sensitivity pericardial, or peritoneal TB in our series. On
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The diagnosis of tuberculosis in dialysis patients 1367

the other hand, hypercalcemia could be a sign diagnostic procedures.


of TB in dialysis patients caused by an
increased form of Vitamin D released by gra- Conclusion
nulomas. In our study, six patients developed
hypercalcemia (14.63%).17 Our study highlights the predominance of
In our study, urinary, pleural, and lympha- extrapulmonary TB in dialysis patients and the
denitis were the more frequent location, frequency of adverse effects from antituber-
whereas bifocal or multifocal TB occurred in cular treatment and death related to TB or
12 patients. In our study, the bacterial diag- treatment. This study demonstrates the chal-
nosis was of TB which was positive in only 17 lenges posed for diagnosing TB in this popu-
(41.46%) of pulmonary cases (Table 3). In our lation despite high index of suspicion.
study population, histological examination was
positive in 11/41 patients (26.83%) (Table 3). References
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