Impact of chronic renal failure on anti-tuberculosis treatment outcomes

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INT J TUBERC LUNG DIS 18(3):352–356 © 2014 The Union http://dx.doi.org/10.5588/ijtld.13.0726

Impact of chronic renal failure on anti-tuberculosis treatment outcomes P. Baghaei,* M. Marjani,* P. Tabarsi,* A. Moniri,* F. Rashidfarrokhi,† F. Ahmadi,‡ A-A. Nassiri,† M-R. Masjedi,‡ A. A. Velayati,* A. Cattamanchi§ * Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Disease (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, † Department of Nephrology and Haemodialysis, Masih Daneshvari Hospital, Tehran, ‡ Chronic Respiratory Disease Research Center, NRITLD, Shahid Beheshti University of Medical Sciences, Tehran, Iran; § Division of Pulmonary and Critical Care Medicine and Curry International Tuberculosis Center, San Francisco General Hospital, University of California San Francisco, San Francisco, California, USA SUMMARY SETTING:

National Referral Centre for Tuberculosis (TB), Tehran, Iran. O B J E C T I V E : To determine the impact of chronic renal failure (CRF) on TB treatment outcomes. D E S I G N : A retrospective study was conducted among adult TB patients with CRF and age- and sex-matched TB controls without CRF treated at the National Research Institute of Tuberculosis and Lung Disease from 2004 to 2011. Multivariate analysis was performed to determine the impact of CRF on drug-induced hepatitis (DIH), treatment failure and all-cause mortality. R E S U LT S : A total of 55 TB cases with CRF and 165 TB cases without CRF were included in the study. Baseline demographic and clinical characteristics were similar, except that TB cases with CRF were more likely to be of

Iranian nationality (94.5% vs. 83%, P = 0.04). During anti-tuberculosis treatment, 40 (18.2%) patients developed DIH, none failed treatment and 15 (6.8%) died. Patients with CRF were more likely to develop DIH (27.3% vs. 15.2%, P = 0.04) and to die during treatment (16.4% vs. 3.6%, P = 0.001). CRF remained significantly associated with all-cause mortality (HR 4.87, 95%CI 1.73–13.65) in multivariate analysis, whereas the relationship with DIH was not. C O N C L U S I O N : TB patients with CRF are at increased risk of death. More intensive monitoring of patients with CRF should be considered by the National TB Programme. K E Y W O R D S : tuberculosis; CRF; glomerular filtration rate; drug-induced hepatitis

CHRONIC RENAL FAILURE (CRF) is an established risk factor for tuberculosis (TB).1–3 Both TB incidence and prevalence are known to be higher in patients with CRF than in the general population.2,4–6 CRF is becoming increasingly common in Eastern Mediterranean countries, including Iran. The incidence and prevalence of patients on haemodialysis are respectively 4.9 and 13 per 100 000 population, and 35 000 CRF patients are estimated to currently live in Iran.7 Despite the relatively high populationlevel burden of CRF and increased risk of TB among patients with CRF, there are limited data on outcomes of CRF patients treated for TB.8 The majority of data to date are from case series, some of which have reported high and others low rates of adverse events and mortality. Few studies have directly compared outcomes in TB patients with and without CRF.9–12 To better inform anti-tuberculosis treatment guidelines for patients with CRF, treatment outcomes were compared among new TB cases with and those with-

out CRF treated at the National Research Institute of Tuberculosis and Lung Disease (NRITLD), Masih Daneshvari Hospital, in Tehran, Iran. The objective was to determine whether patients with CRF are at increased risk of drug-induced hepatitis (DIH), treatment failure or death.

MATERIALS AND METHODS Design and setting A retrospective case-control study of TB patients diagnosed at the NRITLD was conducted from January 2004 to September 2011. This institute is one of the World Health Organization collaborating centres for the Eastern Mediterranean Region (EMRO), and has been certified as the National Referral Laboratory for the EMRO region. The study protocol was approved by the NRITLD Scientific and Ethics Committee. In accordance with national and international

Correspondence to: Majid Marjani, Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Disease, Masih Daneshvari Hospital, Darabad, Niyavaran St, Tehran, Iran 1955841452. Tel: (+98) 21 2610 9590. Fax: (+98) 21 2610 9590. e-mail: [email protected] Article submitted 1 October 2013. Final version accepted 11 November 2013.

CRF in TB patients

guidelines, new TB cases diagnosed at the NRITLD are treated with a standard four-drug regimen consistency of isoniazid (INH), rifampicin (RMP), pyrazinamide (PZA) and ethambutol (EMB) for 2 months, followed by INH and RMP for 4 months.13 In patients with end-stage renal disease, PZA and EMB are given three times per week after haemodialysis.2 Baseline laboratory evaluations include measurement of liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase and total and direct bilirubin), urea and creatinine. In addition, viral markers for hepatitis and human immunodeficiency virus testing are obtained in all TB patients. For patients with CRF, additional baseline evaluations include renal ultrasonography and evaluation by a nephrologist if deemed necessary by the treating physician. After discharge from hospital, treatment is continued at peripheral health centres. Patients are monitored for adverse drug reactions based on clinical signs and symptoms, and are referred back to our centre for further laboratory investigation and management when an adverse drug reaction is suspected. In addition, patients with preexisting liver disease undergo scheduled monitoring of liver function tests (three times/week for 2 weeks and every 2 weeks thereafter during the intensive phase of treatment). For all patients, sputum smear and culture are repeated at month 5 or at the end of treatment to evaluate for treatment failure. Patient selection All new adult TB patients with CRF were included. CRF was defined as glomerular filtration rate (GFR) Table 1

< 60 ml/min per 1.73 m2 for at least 3 months, regardless of cause.14–16 GFR was calculated using the Cockroft-Gault formula.14 For each case, an ageand sex-matched control without a history of CRF and GFR > 60 ml/min/1.73 m2 was selected randomly. For both cases and controls, all pulmonary TB patients had a positive sputum acid-fast bacilli (AFB) smear and culture result, and all extra-pulmonary TB patients had positive histopathology, polymerase chain reaction, AFB smear or culture of a sample obtained from the site of disease. Data collection and outcomes Standard demographic and clinical data were abstracted from patient medical records. The primary study outcomes were DIH, treatment failure and allcause mortality. DIH was defined as a treatmentemergent increase in serum ALT greater than three or five times the upper limit of normal, with or without symptoms of hepatitis (nausea, vomiting, abdominal pain, severe and new onset weakness or anorexia).17 Treatment failure was defined as a positive sputum AFB smear after 5–6 months of antituberculosis treatment. Data analysis Categorical variables were compared using the χ2 or Fisher’s exact test, and the Mann-Whitney U test for non-normally distributed continuous variables. Multivariate logistic regression adjusting for age and sex was performed to determine whether CRF was independently associated with DIH. Other predictors were included in the model if they were associated

Characteristics of TB patients with and those without CRF CRF

Characteristic Age, years, mean ± SD Iranian nationality Male sex History of smoking History of opium use HIV Diabetes mellitus Pulmonary TB Symptom duration, months, mean ± SD Smear grade 3+ 2+ 1+ Scanty Negative Cavitary disease Viral hepatitis

Overall (N = 220) n (%)

Yes (n = 55) n (%)

No (n = 165) n (%)

P value*

65.92 ± 13.38 189 (85.9) 96 (43.6) 57 (25.9) 34 (15.5) 2 (1.2) 63 (28.6) 200 (90.9)

66.27 ± 13.36 52 (94.5) 24 (43.6) 13 (23.6) 10 (18.2) 0 15 (27.3) 48 (87.3)

65.92 ± 13.38 137 (83) 72 (43.6) 44 (26.7) 24 (14.5) 2 (1) 48 (29.1) 152 (92.1)

1 0.042 1 0.657 0.518 1 0.796 0.279

3.94 ± 3.39

4.20 ± 3.65

3.85 ± 3.31

0.51

72 (32.7) 29 (13.2) 40 (18.2) 31 (14.1) 48 (21.8) 68 (30.9) 9 (4.1)

353

14 (25.5) 7 (12.7) 11 (20) 8 (14.5) 15 (27.3) 12 (21.8) 5 (9.1)

58 (35.2) 22 (13.3) 29 (17.6) 23 (13.9) 33 (20) 56 (33.9) 4 (2.4)

0.673 0.092 0.031

* Student’s t-test and χ2 test or Fisher’s exact test is used when appropriate. TB = tuberculosis; CRF = chronic renal failure; SD = standard deviation; HIV = human immunodeficiency virus.

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Table 2

Factors associated with DIH in bivariate analysis DIH Overall (N = 220) n (%)

Yes (n = 40) n (%)

No (n = 180) n (%)

P value*

65.92 ± 13.38 189 (85.9) 96 (43.6) 57 (25.9) 34 (15.5) 5 (2.3) 2 (1) 63 (28.6) 200 (90.9)

66.63 ± 13.36 35 (87.5) 13 (32.5) 6 (15) 3 (7.5) 0 1 (2.5) 9 (22.5) 37 (92.5)

65.87 ± 13.38 154 (85.6) 83 (46.1) 51 (28.3) 31 (17.2) 5 (2.8) 1 (0.6) 54 (30) 163 (90.6)

0.775 0.749 0.116 0.082 0.151 0.587 0.331 0.343 1

3.94 ± 3.39 145 (65.9) 55 (25) 9 (4.1)

3.65 ± 2.93 24 (60) 15 (37.5) 4 (10)

3.40 ± 3.49 121 (67.2) 40 (22.2) 5 (2.8)

0.957 0.383 0.044 0.06

Characteristic Age, years, mean ± SD Iranian nationality Male sex History of smoking History of opium use Alcohol use HIV Diabetes mellitus Pulmonary TB Symptom duration, months, mean ± SD Comorbidity CRF Viral hepatitis

DIH = drug-induced hepatitis; SD = standard deviation; HIV = human immunodeficiency virus; TB = tuberculosis; CRF = chronic renal failure.

with both CRF and DIH in bivariate analysis, at P < 0.2. Kaplan-Meier survival analysis was performed to examine the relationship between CRF and poor treatment outcomes (i.e., treatment failure or allcause mortality). Survival curves were compared using the log-rank test, with follow-up time truncated at 6 months. In addition, Cox proportional hazard modelling was performed to determine whether CRF was an independent risk factor for poor treatment outcome. Patients were censored if they were lost to follow-up or transferred for care to another treatment centre. Diabetes mellitus and smoking were included as predictors as they are known to impact treatment outcomes;18,19 DIH was not included, as it was presumed to be on the causal pathway between CRF and poor treatment outcomes. Other predictors were included if they were associated with both CRF and poor treatment outcomes in bivariate analysis, at P < 0.2. All data were analysed using SPSS version 11.5 (Statistical Product and Service Solutions, Chicago, IL, USA).

RESULTS Of 2743 confirmed TB cases treated during the study period, 55 (2%) had CRF and 165 were age- and sexmatched controls. The median GFR among CRF patients was 19.2 ml/min (interquartile range [IQR] 12–24); 18 (32.7%) were receiving haemodialysis. Table 3

The median duration from diagnosis of CRF to diagnosis of TB was 7 months (IQR 2–36). Demographic and clinical characteristics were similar between patients with and those without CRF, except that patients with CRF were more likely to be of Iranian nationality (94.5% vs. 83%, P = 0.03; Table 1). Drug-induced hepatotoxicity Overall, 40 patients developed DIH, including 15 (27.3%) patients with CRF and 25 (15.2%) without (unadjusted odds ratio [OR] 2.10, P = 0.04). In addition to CRF, viral hepatitis was the only other characteristic associated with DIH in bivariate analysis (Table 2). After adjusting for age, sex and viral hepatitis, CRF did not remain independently associated with DIH (adjusted OR 1.91, P = 0.092; Table 3). Of note, the proportion of patients with other selfreported adverse drug reactions, including rash and neuropathy, was similar between patients with and those without CRF (23% vs. 39%, P = 0.57). Treatment outcomes Eighteen patients were lost to follow-up before the end of treatment, including 4 (7.3%) with CRF and 14 (8.5%) without. Among the remaining 202 patients, there were no treatment failures and 15 deaths (Table 4). The cumulative incidence of all-cause mortality at 6 months was higher in patients with CRF than in those without (16.4% vs. 3.6%, P < 0.001;

Association between CRF and treatment outcomes

DIH* All-cause mortality†

CRF n (%)

No CRF n (%)

Unadjusted OR (95%CI)

Adjusted OR (95%CI)*

15 (27.3) 9 (16.4)

25 (15.2) 6 (3.6)

2.10 (1.01–4.36) 5.18 (1.74–15.38)

1.91 (0.90–4.10) 4.87 (1.73–13.65)

* Adjusted for age, sex and viral hepatitis. † Hazard ratio from Cox proportional hazards model after adjustment for age, sex, diabetes, smoking and nationality. CRF = chronic renal failure; OR = odds ratio; CI = confidence interval; DIH = drug-induced hepatitis.

CRF in TB patients

Table 4

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Factors associated with mortality in bivariate analysis Mortality

Characteristic Age, years, mean ± SD Iranian nationality Male sex History of smoking History of opium use HIV Diabetes mellitus Pulmonary TB Symptom duration, months, mean ± SD Smear grade 3+ 2+ 1+ Scanty Negative Cavitary disease CRF DIH Viral hepatitis

Overall (N = 202) n (%)

Yes (n = 15) n (%)

No (n = 187) n (%)

P value*

65.80 ± 13.52 173 (85.6) 86 (42.6) 51 (25.2) 32 (15.8) 2 (1) 61 (30.2) 183 (90.6)

69.33 ± 15.90 15 (100) 7 (46.7) 5 (33.3) 3 (20) 0 7 (46.7) 14 (93.3)

65.50 ± 13.32 158 (84.5) 79 (42.2) 46 (24.6) 29 (15.5) 2 (1) 54 (28.9) 169 (90.4)

0.351 0.135 0.739 0.454 0.711 1 0.149 1

3.93 ± 3.40

3.73 ± 3.08

3.94 ± 3.43

0.935 0.095

67 (33.2) 26 (12.9) 39 (19.3) 26 (12.9) 44 (21.8)

3 (20) 1 (6.7) 1 (6.7) 3 (20) 7 (46.7)

64 (34.2) 25 (13.4) 38 (20.3) 23 (12.3) 37 (19.8)

62 (30.7) 51 (25.2) 38 (18.8) 9 (4.8)

5 (33.3) 9 (60) 4 (26.7) 0

57 (30.5) 42 (22.5) 34 (18.2) 9 (4.8)

0.818 0.001 0.490 1

SD = standard deviation; HIV = human immunodeficiency virus; TB = tuberculosis; CRF = chronic renal failure; DIH = drug-induced hepatitis.

Figure). After adjustment for age, sex, diabetes mellitus, smoking and nationality, CRF remained independently associated with all-cause mortality (hazard ratio 4.87, P = 0.003; Table 3).

DISCUSSION The present study shows that TB patients with CRF are at higher risk of all-cause mortality. DIH was also more common among TB patients with CRF; however, CRF was not an independent risk factor for DIH in multivariate analysis. DIH is one of the main adverse effects of antituberculosis treatment, and is most commonly asso-

Figure Survival of tuberculosis patients with and those without chronic renal failure. Log rank P < 0.001. CRF = chronic renal failure.

ciated with INH, RMP and PZA.13 Several studies have reported on the extraordinarily high frequency of hepatic adverse effects related to anti-tuberculosis treatment in patients on dialysis. However, in the absence of control groups, the relationship between DIH and CRF could not be investigated adequately.20–22 In our study, DIH occurred in 27% of TB patients with CRF compared to 15% of TB patients without CRF (P = 0.04). Of note, the frequency of DIH in the control group was similar to that of all TB patients (13%) in a previous study from our hospital.23 The higher frequency may be related to other factors that are common among CRF patients, as CRF was not independently associated with DIH after adjusting for age, sex and viral hepatitis. Nonetheless, clinicians should recognise that DIH is common in patients with CRF. The results of previous studies evaluating outcomes of anti-tuberculosis treatment in a CRF setting are varied, with some reporting high frequency of mortality24–26 and others favourable outcomes.4,27,28 In our study, all-cause mortality was more common among TB cases with CRF. As the duration of TB symptoms was not significantly different between TB patients with and those without CRF, the higher mortality rate in patients with CRF is unlikely to be related to delayed diagnosis, but rather to more severe adverse drug reactions. However, we cannot exclude the fact that excess mortality was unrelated to TB, as autopsies are not routinely performed in our centre. Major strengths of our study are the evaluation of TB complications and outcome of anti-tuberculosis

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treatment in CRF patients and comparison with a relevant control group selected at random from the same study base. Despite the clinical implications of this report, the study has some limitations. As it was undertaken at a referral centre, our findings may not be representative of all TB-CRF patients. Nonetheless, it is likely that TB patients with CRF treated in centres with less expertise would have even worse treatment outcomes. Second, we did not consider the aetiology of CRF such as diabetes mellitus, hypertension or unknown causes. However, there is little evidence to suggest that once kidney disease has progressed to end-stage, the particular aetiology is relevant to anti-tuberculosis treatment outcomes. Finally, our sample size was too small to separate CRF patients on dialysis and those who were not in the analysis. In summary, this study shows that DIH is common among TB patients with CRF and that CRF is independently associated with mortality. More intensive monitoring of patients with CRF should be considered by national TB programmes. Further studies are needed to clarify the reasons for excess mortality.

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Acknowledgements

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The authors thank the American Thoracic Society (ATS) MECOR (Methods in Epidemiology, Clinical, and Operations Research) Program for help with this study, in particular S Buist, Director of the ATS MECOR Program. Conflict of interest: none declared.

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CRF in TB patients

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RÉSUMÉ C O N T E X T E : Centre National de Référence de la Tuberculose (TB), Téhéran, Iran. O B J E C T I F : Déterminer l’impact de l’insuffisance rénale chronique (IRC) sur le résultat du traitement de la TB. S C H É M A : Une étude rétrospective a été réalisée chez des patients tuberculeux avec une IRC et des patients appariés sur l’âge et le sexe, mais sans IRC, comme témoins traités à l’Institut National de Recherche sur la Tuberculose et les Maladies Respiratoires de 2004 à 2011. Une analyse multivariée a permis de déterminer l’impact de l’IRC sur l’hépatite induite par les médicaments (DIH), les échecs thérapeutiques et la mortalité toutes causes confondues. R É S U LTAT S : Au total, 55 cas de TB avec IRC et 165 cas de TB sans IRC ont été inclus. Les données démographiques et les caractéristiques cliniques initiales

étaient similaires, si ce n’est que les cas de TB avec IRC étaient plus souvent de nationalité iranienne (94,5% vs. 83% ; P = 0,04). Au cours du traitement de la TB, 40 (18,2%) patients ont présenté une DIH, il n’y a eu aucun échec thérapeutique et 15 (6,8%) patients sont décédés pendant le traitement. Les patients atteints d’IRC avaient plus souvent une DIH (27,3% vs. 15,2% ; P = 0,04) et avaient une mortalité plus élevée au cours du traitement (16,4% vs. 3,6% ; P = 0,001). L’IRC était significativement associée avec la mortalité de toutes causes (HR 4,87 ; IC95% 1,73–13,65) en analyse multivariée, tandis que la relation avec la DIH ne l’était pas. C O N C L U S I O N : Les patients tuberculeux avec IRC avaient un risqué de décès accru. Les programmes nationaux de lutte anti tuberculeuse devraient envisager de leur accorder une surveillance plus intensive. RESUMEN

El Centro Nacional de Referencia de la Tuberculosis (TB) de Teherán, en Irán. O B J E T I V O : Determinar la repercusión de la insuficiencia renal crónica (CRF) en el desenlace del tratamiento antituberculoso. M É T O D O : Se llevó a cabo un estudio retrospectivo de pacientes adultos con diagnóstico de TB e CRF, comparados con un grupo testigo conformado por pacientes con TB pero sin CRF, apareados por edad y sexo. Todos los pacientes recibieron tratamiento en el Instituto Nacional de Investigación sobre Tuberculosis y Enfermedades Respiratorias entre el 2004 y el 2011. Se practicó un análisis multifactorial con el fin de determinar la repercusión de la CRF sobre la hepatitis inducida por medicamentos, el fracaso terapéutico y la mortalidad por todas las causas. R E S U LTA D O S : Participaron en el estudio 55 pacientes en el grupo experimental y 165 casos en el grupo testigo. Las características demográficas y clínicas iniciales MARCO DE REFERENCIA:

fueron equivalentes, con excepción de la nacionalidad, que fue con mayor frecuencia iraní en los pacientes con TB e CRF (94,5% contra 83%; P = 0,04). Durante el tratamiento antituberculoso, 40 pacientes sufrieron hepatitis inducida por los medicamentos (18,2%), no se presentaron fracasos terapéuticos y 15 pacientes fallecieron (6,8%). Fue más frecuente que los pacientes con CRF presentaran hepatitis inducida por los medicamentos (27,3% contra 15,2%; P = 0,04) y que fallecieran durante el tratamiento (16,4% contra 3,6%; P = 0,001). En el análisis multifactorial, la CRF conservó una asociación significativa con todas las causas de mortalidad (HR 4,87; IC95% de 1,73 a 13,65), pero no fue así con la hepatitis medicamentosa. C O N C L U S I Ó N : Los pacientes tuberculosos que sufren CRF presentan un mayor riesgo de muerte. Los programas nacionales contra la TB deben considerar la posibilidad de practicar un seguimiento más atento a los pacientes con CRF.