Renal Failure, 32:9195, 2010 Copyright Informa UK Ltd. ISSN: 0886-022X print / 1525-6049 online DOI: 10.

3109/08860220903367528

CLINICAL STUDY
LRNF

Incidence of Tuberculosis Disease and Latent Tuberculosis Infection in Patients with End Stage Renal Disease in an Endemic Region
Gungor Ates and Tekin Yildiz
Tuberculosis in Hemodialysis Patients

University of Dicle, Faculty of Medicine, Department of Chest Disease, Diyarbakir, Turkey

Ramazan Danis
Department of Nephrology, Diyarbakir State Hospital, Diyarbakir, Turkey

Levent Akyildiz
Department of Pulmonology, MardinPark Hospital, Mardin, Turkey

Baykal Erturk
Diyarbakir Chest Hospital, Diyarbakir, Turkey

Huseyin Beyazit and Fusun Topcu

University of Dicle, Faculty of Medicine, Department of Chest Disease, Diyarbakir, Turkey

Aim. Patients in chronic renal failure suffer impaired cellular immunity and have an increased risk of tuberculosis (TB). Our aim in this multicenter study was to determine the incidence of TB and to evaluate latent tuberculosis infection (LTBI) in hemodialysis patients. Methods. We retrospectively evaluated the frequency of TB in 779 dialysis patients at 13 hemodialysis centers in five different cities in Southeast Turkey. The tuberculin skin test (TST) was conducted in 733 patients to detect LTBI. Results. The mean age of the patients was 51.2 15.9 years; 398 (51.1%) of the patients were female, and 53.9% of patients had a BCG scar. The mean dialysis duration time was 35.1 33.4 months. TB was diagnosed in 34 cases. The incidence rate of TB in patients undergoing hemodialysis was 3.1%. Ten patients had a history of TB before beginning hemodialysis, and 24 patients had a history of TB after beginning hemodialysis. A diagnosis of TB was made based on clinical data in eight patients and microbiologically or pathologically in 26 patients. The median time between the initiation of dialysis to the diagnosis of TB was 11 months. Extrapulmonary TB occurred in 45.8% of cases, and the

most common site of involvement was the lymph nodes. The TST was positive in 61.8% of TB patients and in 37.5% of those with no history of TB. Conclusions. The incidence of TB is high in hemodialysis patients, and they should be evaluated periodically to exclude insidious infection and reduce morbidity and mortality. Keywords hemodialysis, latent tuberculosis, renal disease, tuberculin skin test, tuberculosis

INTRODUCTION Tuberculosis (TB) is a major cause of illness and death worldwide, especially in Asia and Africa. Globally, 9.2 million new cases and 1.7 million deaths from TB occurred in 2006.[1] Because of systemic immunosuppression, human immunodeficiency virus (HIV)-infected patients, transplant recipients, patients who are using tumor necrosis factor (TNF)-a blockers, and hemodialysis patients with Mycobacterium tuberculosis infection are at increased risk of progression to active disease.[24] There is a 6.9- to 52.5-fold increase in the incidence of TB in dialysis patients compared to the general population, which results from uremic immunodeficiency.[47] Additionally, a higher rate of primary infection due to 91

Received 25 July 2009; revised 9 September 2009; accepted 24 September 2009. Address correspondence to Dr. Gungor Ates, University of Dicle, Faculty of Medicine, Department of Chest Disease, Turgut zal Bulvari, 21280, Diyarbakir, Turkey; Tel.: +90 412 248 8001; Fax: +90 412 248 8523; E-mail: gungorates@yahoo.com

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regular visits to dialysis units, advanced age, and immunosuppressive medication may further increase the risk of infectious complications in immunocompromised patients.[811] TB diagnosis is more complex and difficult in hemodialysis patients because of an increased frequency of extrapulmonary TB, atypical clinical presentation, and non-specific symptoms and findings.[7,12] The use of the tuberculin skin test (TST) remains controversial in patients with end-stage renal disease (ESRD) due to its high rate of false negative results.[2,13] Accumulating clinical evidence indicates that the new interferon (IFN)-g release assays are more specific than the skin test because they are not confounded by prior Bacillus CalmetteGurin (BCG) vaccination, but these tests are not used widely.[14,15] Therefore, preventing the development of active TB and identifying latently infected individuals are critically important issues.[2,7,10] In Turkey, the frequency of TB and latent tuberculosis infection (LTBI) in dialysis patients has typically been reported as a single-center experience. Our aim in this multicenter study was to determine the incidence of TB and to evaluate the current LTBI status in ESRD patients on hemodialysis in an endemic region.

with a flexible ruler. A positive TST result was defined as an induration of 10 mm or larger.

Statistics Nominal data were presented as proportions and compared using the chi-square test with or without continuity correction when appropriate. Continuous variables were expressed as the mean standard deviation (SD) and compared using the Students t-test. Variables were analyzed using a binary logistic regression model to determine the independent predictors associated with TB and positive TST results. p 0.05 was considered statistically significant.

RESULTS In total, 999 patients were treated in the five outpatient hemodialysis centers, and 779 were included this study. The remaining patients were not enrolled because they did not meet the inclusion criteria, refused to participate in the study, or declined hospital admission. Of the remaining 779, 290 were participants in another study.[15] The mean age of the patients was 51.2 15.9 years (range, 1586 years). There were 398 (51.1%) females, and 420 (53.9%) patients had received a BCG vaccination. DM was reported in 162 (20.8%) patients. The mean dialysis duration time was 35.1 33.4 months (range, 1200 months). None of the subjects reported that they were HIV-seropositive, had a malignant disease, or were currently being treated with immunosuppressive medication. Thirty-four cases had a TB diagnosis. Ten patients had a history of TB before beginning hemodialysis, and 24 patients had a history of TB after beginning hemodialysis. The incidence rate of TB in patients undergoing hemodialysis was 3.1% (24/779). The diagnosis of TB was made based on clinical data in eight patients and microbiologically or pathologically in 26 patients. The median time between beginning dialysis and diagnosing TB was 11 months (range, 140 months); 54.1% of these diagnoses were established during the first 12 months and 71% during the first 24 months. Sixty-four cases had a history of contact with active TB patients. Thirty percent of TB patients in the pre-dialysis period and 45.8% of TB patients in the post-dialysis period had extrapulmonary TB, but the differences were not significant. None of the patients with extrapulmonary TB had pulmonary involvement; the most common sites of involvement were the lymph nodes (see Table 1). We found a relationship between TB history and close contact with TB patients (see Table 2).

MATERIALS AND METHODS This study was conducted between 15 February and 15 July 2008. The patients were recruited from 13 outpatient hemodialysis centers from five cities (viz., Diyarbakir, Sanliurfa, Mardin, Batman, and Siirt) in southeast Turkey. Patients taking immunosuppressive medicine, those with a malignant disease, or those younger than 15 years of age were excluded from the study. Demographic information and medical history of the patients were recorded on a standard questionnaire. The patients were also investigated for any lifetime selfreported history of TB or history of TB contact, date of dialysis initiation, period between initiation of dialysis to diagnosis of TB, BCG vaccination, diabetes mellitus (DM), HIV status, history of intravenous drug use, and other possible immunodeficiency conditions. Participants with BCG scars were considered BCG vaccinated. The medical records of patients who had a TB history were examined. The patients were screened for active TB through clinical evaluation, chest radiographs, and, if necessary, sputum cultures for M. tuberculosis. TSTs were administered and interpreted according to the American Thoracic Society guidelines.[4] Briefly, a trained nurse performed a one-step TST using the Mantoux technique by injecting 0.1 mL (five tuberculin units) of purified protein derivative (PPD; Tween 80, BB-NCIPP Ltd, Sofia, Bulgaria) into the volar surface of the forearm. A skilled nurse measured the transverse axis of the induration

Tuberculosis in Hemodialysis Patients Table 1 Distribution of tuberculosis according to type before and after hemodialysis (n, %) Extrapulmonary TB Pulmonary TB TB before hemodialysis TB after hemodialysis 7 (70%) 13 (54.2%) LNTB 1 (10%) 5 (20.8%) PTB 2 (20%) 4 (16.7%) GUTB 0 2 (8.3%) Total 10 (100%) 24 (100%)

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Abbreviations: TB = tuberculosis, LNTB = lymph node tuberculosis, PTB = pleural space tuberculosis, GUTB = genitourinary tuberculosis.

Table 2 Binary logistic regression analysis for TB risk factors among dialysis patients p value Age Gender Duration of hemodialysis Previous TB contact BCG vaccination Diabetes 0.93 0.35 0.49 0.001 0.15 0.35 Odds ratio 1.0 1.5 1.0 5.2 2.0 1.8 95% Confidence interval 0.971.03 0.623.81 0.991.02 1.9214.49 0.765.42 0.516.69

a positive TB history was 9.4 5.7 mm compared to 7.2 5.8 mm in those with no previous history (p = 0.03). There is no statically significant difference between TST (+) and TST () subjects with previous TB disease regarding the presence of DM, sex, BCG status, duration of dialysis, or age.

DISCUSSION This is the first multicenter study to investigate the prevalence of TB and LTBI in Turkey. Increased TB incidence in dialysis patients has been recognized as a medical concern since 1974.[16] However, the reported frequency of TB in patients with ESRD differs among centers and among nations; for example, the incidence of TB in various hemodialysis populations around the world varies from 1.6 to 28%.[4,7,11,1719] In Turkey, the reported incidences of TB in hemodialysis patients range from 3.1 to 23.6%.[1821] In most studies, the reported TB incidence rates in dialysis patients are generally from a single-center experience. According to data from the Directorate of the Struggle Against Tuberculosis, which is affiliated with the Ministry of Health, the incidence of TB in Turkey is 27.9/ 100.000.[22] However, our multicenter study revealed an incidence of 3.1% in patients undergoing hemodialysis. Several studies have reported that a high frequency of TB cases are discovered in the first year of dialysis, which was attributed to the poor general health and compromised host immunity during that stage.[4,5,11,20,21] Consistent with these previous studies, we found that the majority of patients who developed TB did so during the first year of dialysis. The median time between initiating dialysis and a TB diagnosis was 11 months, and TB contact history was the only factor associated with TB development. Therefore, during periodic assessments, hemodialysis patients should be queried regarding previous close contact with an infected individual. Various studies have suggested that extrapulmonary TB is common in dialysis patients and occurs in 5078% of dialysis patients with TB.[12,20,21] However, different

Abbreviations: TB = tuberculosis, BCG = Bacillus CalmetteGurin.

The TST was conducted in 751 participants, but valid results were available for only 733 patients. The TST was positive in 61.8% of those who reported a history of TB and in 37.5% of those who did not have an active TB history; this difference was statistically significant (see Table 3). The mean induration of the TST in patients with

Table 3 Descriptive statistics in the TST-negative vs. TST-positive subgroups Negative Sex (female/male) BCG vaccination (yes/no) Previous TB contact (yes/no) Previous TB disease (yes/no) 231/219 218/214 32/418 13/438 Positive 143/139 150/122 31/252 21/262 p value 0.62 0.22 0.07 0.005

Values shown in the table represent number of patients. Abbreviations: TB = tuberculosis, BCG = Bacillus CalmetteGurin.

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G. Ates et al. 2. Sester M, Sester U, Clauer P, et al. Tuberculin skin testing underestimates a high prevalence of latent tuberculosis infection in hemodialysis patients. Kidney Int. 2004;65: 18261834. 3. Hamilton CD. Infectious complications of treatment with biologic agents. Curr Opin Rheumatol. 2004;16:393398. 4. American Thoracic Society. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respire Crit Care Med. 2000;161:S221S247. 5. Chia S, Karim M, Elwood RK, Fitzgerald JM. Risk of tuberculosis in dialysis patients: A population-based study. Int J Tuberc Lung Dis. 1998;2:989991. 6. Andrew OT, Schoenfeld PY, Hopewell PC, and Humphreys MH. Tuberculosis in patients with end-stage renal disease. Am J Med. 1980;68:5965. 7. Hussein MM, Mooij JM, and Roujouleh H. Tuberculosis and chronic renal disease. Semin Dial. 2003;16:38. 8. Wauters A, Peetermans WE, Van den Brande P, et al. The value of tuberculin skin testing in hemodialysis patients. Nephrol Dial Transplant. 2004;19:433438. 9. Rutsky EA, Rostand SG. Mycobacteriosis in patients with chronic renal failure. Arch Intern Med. 1980;140:5761. 10. Korzets A, Gafter U. Tuberculosis prophylaxis for the chronically dialysed patientyes or no? Nephrol Dial Transplant. 1999;14:28572859. 11. Hussein M, Mooij J. Tuberculosis and chronic renal disease. Saudi J Kidney Dis Transpl. 2002;13:320330. 12. Erkoc R, Dogan E, Sayarlioglu H, et al. Tuberculosis in dialysis patients, single centre experience from an endemic area. Int J Clin Pract. 2004;58(12):11151117. 13. Smirnoff M, Patt C, Seckler B, Adler JJ. Tuberculin and anergy skin testing of patients receiving long-term hemodialysis. Chest. 1998;113:2527. 14. Menzies D, Pai M, Comstock G. Meta-analysis: New tests for the diagnosis of latent tuberculosis infection: Areas of uncertainty and recommendations for research. Ann Intern Med. 2007;146:340354. 15. Ates G, Ozekinci T, Yildiz T, Danis R. Comparison of interferon-gamma release assay versus tuberculin skin test for latent tuberculosis screening in hemodialysis patients. Biotechnol Equip. 2009;23:12421246. 16. Pradhan RP, Katz LA, Nidus BD, Matalon R, Eisinger RP. Tuberculosis in dialyzed patients. JAMA. 1974;229: 798800. 17. Rutkowski B, Sulima-Gillow A, Kustosz J, Liberek T, Zdrojewski Z. Increasing incidence of tuberculosis in hemodialysis patients. Dial Transplant. 1997;26:2123. 18. Cengiz K. Increased incidence of tuberculosis in patients undergoing hemodialysis. Nephron. 1996;73:421424. 19. Taskapan H, Utas C, Oymak FS, Gulmez I, Ozesmi M. The outcome of tuberculosis in patients on chronic hemodialysis. Clin Nephrol. 2000;54:134137. 20. Sen N, Turunc T, Karatasli M, Sezer S, Demiroglu YZ, Oner-Eyuboglu F. Tuberculosis in patients with end-stage renal disease undergoing dialysis in an endemic region of Turkey. Transplant Proc. 2008;40:8184. 21. Kayabasi H, Sit D, Kadiroglu AK, Kara IH, Yilmaz ME. The prevalence and the characteristics of tuberculosis patients

hemodialysis centers have reported that pulmonary TB is more frequent among dialysis patients (6170%).[18,19,23] In Turkey, pulmonary TB is much more common, occurring in 70% of the entire TB population.[22] Taskapan et al. found extrapulmonary TB involvement in 38% of hemodialysis patients and in 22.2% of patients with tuberculous lymphadenitis.[19] In our study, the cumulative incidence rates of extrapulmonary TB during the pre- and post-dialysis periods were 30% (10 patients) and 45.8% (24 patients), respectively. Consistent with previous studies, we found that tuberculous lymphadenitis was the most frequent localization of extrapulmonary TB.[19,21] To our knowledge, this the first study comparing the incidence of tuberculosis before and after the hemodialysis period in patients with ESRD. The prevalence of anergy is significantly higher in the ESRD population than in the general population.[3,13,24,25] Smirnoff et al. reported the prevalence of anergy at 40%.[13] In contrast to this, Woeltje et al. reported that the prevalence of anergy among dialysis patients is unclear due to increased dialysis quality and dose.[25] We found that the TST was positive in 61.8% of patients who reported a TB history and in 37.5% of those who had no active TB history (p = 0.01). Moreover, we did not find any association between contact with tuberculosis patients and TST. The TST was negative in 49.2% of those who reported close contact with contagious tuberculosis patients. Additionally, the effect of BCG vaccination on TST results was unclear. Consistent with previous studies, BCG vaccination status had no effect on TST results in hemodialysis patients.[15,24] The main limitation of this study was its retrospective design; we could not gather more information regarding risk factors, additional comorbidities, or diagnostic procedures. In conclusion, the risk for TB in dialysis patients is significantly higher than in the general population, indicating that dialysis patients should be considered the main risk group for LTBI and monitored carefully over time.

ACKNOWLEDGMENTS The authors would like to thank Dr. Fesih Azboy and Adil Alp from the Office of TB Control at the Government Health Department at Diyarbakir for their assistance in this investigation. The authors declare no conflicts of interest.

REFERENCES
1. WHO. Global tuberculosis controlsurveillance, planning, financing. WHO Report 2008. Available at: http:// www.who.int/tb/publications/global_report/2008/download_ centre/en/index.html (accessed Feb 2009).

Tuberculosis in Hemodialysis Patients undergoing chronic dialysis treatment: Experience of a dialysis center in southeast Turkey. Ren Fail. 2008;30:513519. 22. Bozkurt H, Trkkani MH, Musaonbasioglu S, et al. Trkiyede Verem Savasi, 2009 Raporu. Verem Savasi Dairesi Baskanligi. Ankara, Turkey; 2009. 23. Ozdemir FN, Guz G, Kayatas M, Sezer S, Turan M. Tuberculosis remains an important factor in the morbidity and mortality of hemodialysis patients. Transplant Proc. 1998;30:846847.

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24. Machiraju S, Shankar R, Aravindan AN, Sohal PM, Kohli HS, Sud K, Gupta KL, Sakhuja V, Jha V. The prevalence of tuberculin sensitivity and anergy in chronic renal failure in an endemic area: Tuberculin test and the risk of posttransplant tuberculosis. Nephrol Dial Transplant. 2005;20: 27202724. 25. Woeltje KF, Mathew A, Rothstein M. Tuberculosis infection and anergy in hemodialysis patients. Am J Kidney Dis. 1998;31:848852.

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