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NDT Advance Access originally published online on September 12, 2006
Nephrology Dialysis Transplantation 2006 21(11):3287-3292; doi:10.1093/ndt/gfl488
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Risk factors for Mycobacterium tuberculosis in US chronic dialysis patients*

Mary M. Klote1, Lawrence Y. Agodoa2 and Kevin C. Abbott3,4

1Allergy Immunology Department, Walter Reed Army Medical Center, Washington, DC, 2NIDDK, NIH, Bethesda, MD, 3Nephrology Service, Walter Reed Army Medical Center, Washington, DC and 4Uniformed Services University of the Health Sciences, Bethesda, MD, USA

Correspondence and offprint requests to: Mary M. Klote, MC, Allergy Immunology, Walter Reed Army Medical Center, Washington, DC 20307-5001. Email: mary.klote{at}amedd.army.mil



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. End-stage renal disease is known to disrupt the cell-mediated immune response that is responsible for the killing of intracellular organisms such as Mycobacterium tuberculosis. Risk factors that contribute to the development of tuberculosis (TB) disease in the US dialysis population have not been studied on a large scale.

Methods. A retrospective cohort study of TB disease in 272 024 patients in the US Renal Data System initiated on dialysis therapy between 1 April 1995 and 31 December 1999 with Medicare or Medicaid as primary payer were analysed. A total of 21 risk factors were analysed.

Results. Among the US population studied, there is a 1.2 and 1.6% cumulative incidence of TB in patients undergoing either peritoneal or haemodialysis, respectively. Ten risk factors for TB that proved to be statistically significant included advanced age (P < 0.001), unemployment (P < 0.001), Medicaid insurance (P < 0.001), reduced body mass index (P < 0.001), decreased serum albumin (P < 0.001), haemodialysis (P = 0.019), both Asian (P = 0.010) and Native American (P = 0.020) race, ischaemic heart disease (P = 0.032), smoking (P = 0.010), illicit drug use (P = 0.018) and anaemia (P = 0.028). TB was independently associated with increased mortality, adjusted hazard ratio (AHR) 1.42 (95% CI 1.18–1.70, P < 0.001).

Conclusions. The prevalence of TB disease in the US dialysis population is low compared with worldwide rates; however, the disease is associated with increased mortality. Of the 10 significant risk factors identified, five are potentially modifiable.

Keywords: dialysis; end-stage renal disease; risk factors; tuberculosis



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
The most recent estimate of the incidence of Mycobacterium tuberculosis infection in North America and Western Europe is <10/100 000 persons in the general population, and the prevalence <20/100 000 persons [1]. A report from the Centers for Disease Control and Prevention reported rates of tuberculosis (TB) per 100 000 by race in 1999 were: non-Hispanic White 2.2, non-Hispanic Black 16.8, American Indian/Alaska Native 11.8, Hispanic 12.4 and Asian 35.3 [2]. Worldwide rates are higher primarily due to the endemic rates of TB. Dialysis patients are at an increased risk for TB worldwide with a recent summary article documenting a 6.9–52.5-fold increased risk [3]. For the US population, reporting has been spurious with the last major report in 1980 involving 172 patients on haemodialysis. Prevalence of 5.8% over 10 years was reported [4]. Prior to that report, estimates from 1974 to 1980 ranged from 3 to 10% [5–7]. The true prevalence of latent TB infection (LTBI), detected through the use of the purified protein derivative skin test prior to the start of dialysis, has never been known, likely due to anergy among the dialysis population [8]. End-stage renal disease (ESRD) and particularly uraemia is a known contributor to immunosuppression [9,10]. The causative factors of the immunosuppression are complex and disrupt the cell-mediated immune (CMI) response [11]. T-cells are primarily responsible for CMI and their functions include identification and killing of intracellular pathogens such as M. tuberculosis. It is the delayed type hypersensitivity response of the CMI system that is responsible for the reaction to the tuberculin skin test. Therefore, while new methods for determining infection with TB are developed, identifying risk factors for TB among this population may aid in developing appropriate counselling and more targeted screening.

Many risk factors have been identified and evaluated independently in their contribution to TB infection in other disease populations in the US. The US dialysis population has not been studied for risk factors contributing to TB on a national level. Among US renal transplant patients, only systemic lupus erythematosus as the cause of renal failure has been independently associated with TB [12].



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
A national registry [the US Renal Data System (USRDS) database] was analysed in an historical cohort study of the rate, risk factors and mortality associated with TB infection in ESRD patients on dialysis therapy. The variables included in the USRDS standard analysis files (SAFs), as well as data collection methods and validation studies, are listed at the USRDS website, under ‘Researcher's Guide to the USRDS Database’, Section E, ‘Contents of all the SAFs’ (Standard Analysis Files), and published in the USRDS (www.usrds.org). The demographics of the dialysis population have been previously described (2002 USRDS report). The files SAF.PATIENTS were used as the primary data set, including cause of renal disease (PDIS) and cause and date of patient death. SAF.MEDEVID was used for additional information coded in the medical evidence form starting in 1995, and has been validated for use in research [13]. Therefore, patients who presented with ESRD on or after 1 April 1995 until 31 December 1999 were selected for the study and followed through 31 December 2000. Study eligibility was restricted to patients with evidence of Medicare or Medicaid as primary payer as indicated from the PAYHIST file.

Outcomes
Outcomes included Medicare claims for TB, both in-patient and out-patient. Other outcomes included death from any cause. Time to Medicare claims for TB were defined as the time from the first dialysis session until the date of Medicare Claim for TB, with patients censored for death or the end of the study period (31 December 2000), whichever came first. Time to death was defined as time after the date of first dialysis until death, censored for the end of the study period, in this case considered 30 September 2001.

All analyses were performed using SPSS 13.0 TM (SPSS, Inc., Chicago, IL) and Stata SE 9.0 (Stata Corp, College Station, TX). Files were merged and converted to SPSS files using DBMS/Copy (Conceptual Software, Houston, TX). Statistical significance was defined as P < 0.05. Univariate analysis was performed with Chi-square testing for categorical variables (Fisher's exact test for violations of Cochran's assumptions) and Student's t-test (Mann–Whitney for non-normal distributions) for continuous variables. Variables with P < 0.10 in univariate analysis for a relationship with TB, including race, age, gender, year of first dialysis session and additional variables from the medical evidence form (Table 1) were entered into multivariate analysis as covariates [14].


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  		Table 1. Factors assessed in US chronic dialysis patients, 1 April 1995–31 December 1999, Medicare or Medicaid as primary payer

 
Patient survival curves were calculated using Kaplan–Meier analysis with patients censored at time of loss to follow-up. Survival was calculated from the date of the first dialysis session until death, last follow-up visit, or loss to follow-up occurring after the first dialysis session. Covariates were as for univariate analysis. Stepwise Cox regression analysis was also performed for survival analysis, adjusting for age, race, gender, year of first dialysis and comorbidities in the Medical Evidence Form (2728). Both formal and graphical methods were used to assess the validity of the proportional hazards assumption over time.

Risk factors that were analysed included race, gender, age, unemployment, diabetes, alcoholism, illicit drug use, smoking, cancer diagnosis, systemic lupus erythematosus, diabetes, unemployment, erythropoietin use prior to dialysis, Medicaid insurance, serum albumin level, haematocrit, body mass index (BMI), heart failure, inability to ambulate, ischaemic heart disease, peripheral vascular disease, chronic obstructive pulmonary disease, renal transplant and the year of first dialysis service.



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
From 1 April 1995 to 31 December 1999, 366 738 patients started long-term dialysis. Of these, 272 024 were documented as having Medicare (81.7%) or Medicaid (18.3%) as primary payer at the time of the first dialysis session. Among these patients, 4340 dialysis patients were diagnosed with TB infection during this time period. Of these, 90% were haemodialysis patients and they represented 92.4% of the TB cases. Characteristics of the study population are shown in Table 1. Two hundred and four cases of TB were found prior to the start of dialysis in this population and they are not included in this analysis. The incidence of TB in the study was 0.8% per year and the risk was constant over time (Figure 1). Race and ethnicity showed a statistically significant difference with whites having the lowest rate of 5.3/1000 person years at risk (PYAR) and Asians and Hispanics having the highest rate of infection with 9.9/1000 PYAR. Both African American and Native Americans had the same rate of 9.6/1000 PYAR. The combined incidence rate of TB after the start of dialysis was 6.9/1000 PYAR.


Figure 1
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  		Fig. 1. Time to diagnosis of TB after the start of dialysis.

 
Risk factors that proved to be independently statistically significant for TB infection included age (P < 0.001), haemodialysis (vs peritoneal dialysis, P = 0.019), unemployment (P < 0.001), reduced BMI (P < 0.001), ischaemic heart disease (P = 0.032), smoking history (P = 0.010), illicit drug use (P = 0.018), reduced serum albumin (P < 0.001), and African American (P = 0.001) and Asian (P = 0.002) race. A history of systemic lupus erythematosus (P = 0.069) trended toward significance.

The results of the Cox regression are shown in Figure 2.


Figure 2
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  		Fig. 2. Survival function Asian race vs all other.

 
TB infection was independently associated with increased mortality as a time dependent variable, AHR 1.42 (95% CI 1.18–1.70, P < 0.001); however, there were no mortality differences by race and ethnicity (Figure 2).



   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
Endemic exposure is likely to be the most important risk factor for the development of TB outside the United States. In the United States, both health care workers in dialysis units as well as other patients in the dialysis units have been implicated in the spread of TB infection [15]. In this population, there is a 10% increased risk of TB within the haemodialysis subgroup. It is likely that the proximity of the patients to each other during frequent contacts, suboptimal isolation and screening limited to tuberculin skin test (TST) and chest X-ray (CXR) contribute to this risk.

Ten factors were identified as associated with increased risk of TB infection. Whether the risk factor contributes to or is a result of the infection cannot be determined through a review of the registry. Specifically, employment status and serum albumin were recorded at the start of dialysis therapy and thus most likely preceded actual infection, although we cannot exclude the possibility that patients had a brewing infection that was not recognized prior to starting dialysis. This is particularly the case since prior to starting dialysis many patients receive only infrequent medical care, while after starting dialysis, they undergo greater surveillance.

Given the limits of the registry, this is the most specific estimate of the true incidence of TB in the US dialysis population. Estimates of prevalence and conversion would likely be improved if the recommended two-step TST [16] were used prior to the start of dialysis. The clinical presentation of the TB infection was not attainable through the registry. Another limitation of the registry is the availability of Medicare hospitalization and claims data. Death-registry data is available till 2001, but claims data is only available till 2000, thus the two study end points.

HIV status was only recorded in 16% of the charts and was therefore not included in the major analysis. Among those patients with HIV infection documented, only 4.6% (80) developed TB infection and it was not a significant factor in adjusted analysis.

The findings of this study with relation to risk factors can be used to develop counselling specific for populations beginning dialysis and help to target TB testing in the populations at risk. Risk factors deemed modifiable should be addressed prior to the start of dialysis. Illicit drug use and smoking should be addressed in all patient populations but should be highlighted as a risk factor for TB. As a continuous variable BMI was significant, when analysed independently the lowest quartile of BMI was a significant risk factor for incident TB infection. This likely represents confounding by poor nutrition, consistent with the association of low serum albumin with risk for TB. Low haematocrit should be addressed but the use of erythropoietin prior to dialysis was not a risk factor for TB (P = 0.639). Erythropoetin use was implemented as a surrogate for pre-ESRD care as well as a factor for nosocomial exposure since patients have to attend hospital for erythropoietin injections in order for Medicare or Medicaid to reimburse. One can speculate why unemployment and Medicaid as an insurer are independent risk factors, as socioeconomic factors have been associated with an increased risk of TB [17], however, the USRDS database does not have data that could help clarify such issues. Analysis of the data reported from the ESRD Network regions to the USRDS for TB cases showed that ESRD Networks 8 and 6 accounted for 36% of the TB cases, in contrast to ESRD Network 16 that had the lowest (0.62%) cases of TB (Table 2).


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  		Table 2. USRDS Network TB cases by region (1995–1999)

 
In those patients affected by ischaemic heart disease (IHD) when dialysis is started, it is a non-modifiable factor. However, for patients with disease states that lead to ESRD, a careful history of risk factors for IHD should be taken and measures to control the IHD should be implemented.

Non-modifiable factors include age, race and ethnicity. Advanced age is known to be associated with decreased delayed type hypersensitivity (DTH) responsiveness [18,19] which may mask the presence of LTBI by current testing. A new study by Pawelec et al. [20] reviews the difficulty in interpreting immune function data in the elderly and targets the T-cell as a marker of immunosenescence. Patients starting dialysis after the age of 65 years were at the highest risk.

Race may represent genetic variability in susceptibility to TB infection or may serve as a marker of the rate of early endemic exposure. Race and ethnicity may reflect the socioeconomic status; they may also serve as markers in the disparity of health-care distribution that is beyond the scope of this article.

More specific tests are being developed to detect latent TB infection. Among the anergic population, there is currently no test clinically available. Sester et al. [21] recently reported on in vitro testing for LTBI with particular attention to early secretory antigenic target-6 (ESAT-6). ESAT-6 is a protein specific to M. tuberculosis. With this protein it is possible to distinguish LTBI from reactivity to Mycobacterium bovis strains that were used in the formulation of bacillus Calmette–Guerin (BCG) vaccine in those who were vaccinated. This test requires a blood sample and flow cytometric analysis but may prove to be a cost-effective alternative in high risk populations such as the haemodialysis and renal transplant populations due to the morbidity and mortality associated with active TB infection.

The accurate identification of dialysis patients with TB goes beyond the importance of identifying and treating this disease in a setting of dialysis. Many dialysis patients are listed for transplant, and currently evaluation of potential kidney transplant recipients relies on history, physical and skin testing (with no anergy control). Chest X-ray screening is not universal. TB can certainly worsen in the face of aggressive immunosuppression which is routinely used after kidney transplantation. Analysis of the USRDS has previously shown the risk factors and poor prognosis of hospitalized TB infection after kidney transplantation [22]. Better methods for identifying TB infection, especially among potential kidney transplant recipients, are therefore needed.

In summary, TB infection among US chronic dialysis patients, while lower than reported among other dialysis populations in the world, is not infrequent and associated with an increased risk of death. The frailest dialysis patients (the oldest, those with poor nutrition, and most comorbid conditions) are at the greatest risk of contracting TB. The incidence rate of 0.8% per year raises the possibility of nosocomial spread of TB. Racial groups at high risk of TB in the general population (Blacks, Hispanics, Native Americans, Asians) are also at high risk on dialysis. Finally, accurate identification of TB infection among potential kidney transplant patients is critical to avoid the morbidity and mortality associated with TB infection after kidney transplantation.

Conflict of interest statement. None declared.



   Notes
 
* The data reported here have been supplied by the United States Renal Data System (USRDS). The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy or interpretation of the US government. Back



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

  1. Dye C, Scheele S, Dolin P, et al. (1999) For the WHO Global Surveillance and Monitoring Project. Global burden of tuberculosis estimated incidence, prevalence, and mortality by country. JAMA 282:677–686.[Abstract/Free Full Text]
  2. Centers for Disease Control and Prevention Division of Tuberculosis Elimination. found at: http://www.cdc.gov/nchstp/tb/surv/surv99/surv99pdf/table2_3.pdf. Accessed 2 May 2006.
  3. Hussein MM, Mooji JM, Roujouleh H. (2003) Tuberculosis and chronic renal disease. Sem in Dial 16:38–44.
  4. Andrew OT, Schoenfeld PY, Hopewell PC, Humphreys MH. (1980) Tuberculosis in patients with end stage renal disease. Am J med 68:59–65.[CrossRef][Web of Science][Medline]
  5. Pradhan RP, Katz LA, Nidus BD, et al. (1974) Tuberculosis in dialyzed patients. JAMA 229:798–800.[Abstract/Free Full Text]
  6. Rutsky EA and Rostand SG. (1980) Mycobacteriosis in patients with chronic renal failure. Arch Int Med 140:57–61.[Abstract/Free Full Text]
  7. Lundin AP, Adler AJ, Berlyne GM, et al. (1979) Tuberculosis in patients undergoing maintenance haemodialysis. Am J Med 67:597–602.[CrossRef][Web of Science][Medline]
  8. Smirnoff M, Patt C, Seckler B, et al. (1998) Tuberculin and anergy skin testing of patients receiving long-term hemodialysis. Chest 113:25–27.[Abstract/Free Full Text]
  9. Pesanti EL. (2001) Immunologic defects and vaccination in patients with chronic renal failure. Infect Dis Clin North AM 15:813–832.[CrossRef][Web of Science][Medline]
  10. Cohen G, Haag-Weber M, Horl WH. (1997) Immune dysfunction in uremia. Kid Int 52:Supp 62, 579–582.
  11. Dammin GJ, Couch NP, Murray JE. (1957) Prolonged survival of skin homografts in uremic patients. Ann NY Acad Sci 64:967–976.[Web of Science][Medline]
  12. Klote MM, Agodoa LY, Abbott KC. (2004) Mycobacterium tuberculosis Infection Incidence in Hospitalized Renal Transplant Patients in the United States, 1998–2000. Am J Transplant 4:1523–1528.[CrossRef][Web of Science][Medline]
  13. Longenecker JC, Coresh J, Klag MJ, et al. (2000) Validation of comorbid conditions on the end-stage renal disease medical evidence report: the CHOICE study. Choices for healthy outcomes in caring for ESRD. J Am Soc Nephrol 11:520–529.[Abstract/Free Full Text]
  14. Szklo M and Nieto FJ. Epidemiology: Beyond the Basics. Chapter 7, ‘Stratification and Adjustment: Multivariate Analysis in Epidemiology,’ page 257. © 2000. (Aspen Publishers, Gaithersburg, MD).
  15. Linquist JA, Rosaia CM, Riemer B, Heckman K, Alvarez F. (2002) Tuberculosis exposure of patients and staff in an outpatient hemodialysis unit. Am J Infect Control 30:307–310.[CrossRef][Web of Science][Medline]
  16. Centers for Disease Control and Prevention Targeted Tuberculin Testing; treatment of LTBI. MMWR 2000; 49(RR-6).
  17. Kim S and Crittenden KS. (2005) Risk factors for tuberculosis among inmates: a retrospective analysis. Public Health Nurs 22:108–118.[CrossRef][Web of Science][Medline]
  18. Dworsky R, Paganini-Hill A, Arthur M, Parker J. (1983) Immune responses of healthy humans 83-104 years of age. J Natl Cancer Inst 71:256–258.
  19. Yung RL. (2000) Changes in immune function with age. Rheum Dis Clin N Am 26:455–473.[CrossRef][Web of Science][Medline]
  20. Pawelec G, Ouyang Q, Wagner W, Wikby A. (2003) Pathways to a robust immune response in the elderly. Immunol Allergy Clin N Am 23:1–13.[CrossRef][Web of Science][Medline]
  21. Sester M, Sester U, Clauer P, et al. (2004) Tuberculin skin testing underestimates a high prevalence of latent tuberculosis infection in hemodialysis patients. Kid Int 65:1826–1834.[CrossRef][Web of Science][Medline]
  22. Klote MM, Agodoa LY, Abbott K. (2004) Mycobacterium tuberculosis infection incidence in hospitalized renal transplant patients in the United States, 1998–2000. Am J Transplant 4:1523–1528.[CrossRef][Web of Science][Medline]
Received for publication: 29. 3.06
Accepted in revised form: 20. 7.06


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