Part One Assessment Of The Association Of Vitamin D And The Risk Of Tuberculosis Among End-Stage Kidney Disease Population

Abstract

We investigated the role of vitamin D in the risk of tuberculosis (TB) among patients with end-stage kidney disease (ESKD). The retrospective cohort was conducted with data of 20,985 patients with kidney disease and 20,985 controls without kidney disease (1:1 matching on the age of cohort entry and sex) in the duration of 1997–2010 from the Taiwan National Health Insurance database. Then, by a case–cohort study, among 20,985 kidney disease, 3194 ESKD patients were identified with matched 3194 non-ESKD patients. Multivariate analyses revealed a significant association between kidney disease and tuberculosis (adjusted incidence rate ratio (IRR) 1.57 (1.33–1.86)), and the risk increased after 3 years of follow-up the (adjusted IRR 3.79 (2.55–5.62)), but after more years of follow-up, no significance was observed. We also found that ESKD increases the risk of tuberculosis (adjusted IRR 3.67 (2.27–5.93)). However, vitamin D usage was not related to tuberculosis risk in ESKD patients (p > 0.1783). Our study showed an increased risk of tuberculosis in kidney disease and ESKD patients, and vitamin D was not beneficial in ESKD.

Keywords

retrospective cohort study; kidney disease; end-stage kidney disease; vitamin D; tuberculosis.

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Introduction

End-stage kidney disease (ESKD) inflicts significant health and economic burdens on both individuals and the public population [1]. Chronic kidney disease (CKD) is a structural and functional progressive kidney damage lasting for more than 3 months. When kidney disease reaches the end stage, that is, stages 4 and 5, high levels of fluid, electrolytes, and waste products can build up in the body; this might cause a severe decline of GFR over periods of months or years [2]. The symptoms of worsening kidney function might include leg swelling, vomiting and confusion, and reduced appetite; however, this disease can complicate hypertension, heart failure, bone disease, and anemia. CKD has since been an increasing endemic, with a worldwide prevalence of 8% to 16% [3]. Taiwan has the highest prevalence of CKD, and the reported prevalence of ESKD is 6.9% in adult populations in Taiwan [4]. The major causes of CKD in Taiwan are older age, diabetes, hypertension, smoking, obesity, regular use of herbal medicine, chronic lead exposure and hepatitis C, chronic glomerulonephritis, and chronic interstitial nephritis [5]. There has since been a gap in the findings about the relationship between CKD and pulmonary TB. Not many studies have reported the high prevalence of TB among patients with CKD.

According to the World Health Organization (WHO), tuberculosis (TB) remains one of the leading infectious diseases in the world. The World Health Organization estimates 10.4 million new TB cases worldwide and 1.3 million related deaths in 2016. The relationship between active tuberculosis (TB) and chronic kidney disease (CKD) was first reported in a 1974 case reported on a dialysis patient. According to the National Institute for Health and Care Excellence guidelines, the relative risk for developing active TB is 10% to 25% in patients with CKD at any stage [6]. This relationship has since been an emerging global syndemic. There is a hypothesis that CKD may increase the risk of developing TB and related immunosuppression, especially in kidney transplant recipients. Due to this fact, diagnosis may be challenging because of the nonspecific symptoms, which are the same as extrapulmonary TB and peritoneal disease in patients receiving renal replacement therapy. This circumstance may cause TB diagnosis in dialysis patients to be delayed because of the extrapulmonary manifestations. Initially, it was believed that hemodialysis patients have a higher incidence of latent tuberculosis than peritoneal dialysis. Studies have argued this phenomenon is caused by the fact that hemodialysis patients have more frequent hospital visits and longer hospital stays. A study in Pakistan reported that low vitamin D levels were associated with a five-fold increased risk for progression to tuberculosis [7]. Given the rising scientific evidence regarding vitamin D’s multisystem role, the association between chronic kidney disease [8] with the loss of functional renal function to convert 25(OH)D to 1,25(OH)2D, calcitriol is reduced leading to a decline in plasma 1,25(OH)2D [9]. Vitamin D status in CKD patients is most commonly assessed based on the plasma concentration of 25-hydroxyvitamin D or calcidiol. Vitamin D deficiency thresholds for population health are defined as 25(OH)D serum levels < 25 or 30 nmol/L [10,11] The effects were shown to depend on the stage of the disease.

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Observational studies in patients treated with hemodialysis showed that the use of active vitamin D sterols was associated with a lower risk of all-cause mortality, regardless of parathyroid hormone levels [12]. Vitamin D supplementation in CKD is to prevent and treat the complications associated with secondary hyperparathyroidism in ESKD [13]. However, in the Japan Dialysis Active Vitamin D (J-DAVID) trial, treatment with alfacalcidol did not reduce the risk of composite cardiovascular events or the risk of all-cause mortality in hemodialysis patients without secondary hyperparathyroidism [14]. Some studies have researched the effectiveness of vitamin D supplementation on plasma parathormone (PTH) concentrations, and it has been discovered to reduce PTH concentrations. Some studies have argued that this effect depends on the patient’s characteristics [15], the dose–response of vitamin D supplementation, and the response in PTH. The optimal concentration ranges of PTH and 25(OH)D for the management and prevention of CKD–MBD are not well established for each stage of CKD [16]. Some studies suggest that vitamin D supplementation, especially calcidiol, is not effective in CKD patients with hyperthyroidism due to the interaction of the medication cinacalcet, which reduces the parathyroid hormone (PTH) [16,17]. Studies have shown that there was a negative correlation between 25(OH)D and PTH levels [18].

Patients with ESKD are increasing, and they need dialysis; this is a major health problem because even TB is a commonly associated infectious disease. Many studies have argued that hemodialysis patients visit the hemodialysis room frequently, so they are more likely to acquire a Mycobacterium tuberculosis infection than peritoneal dialysis patients through airborne transmission in the HD rooms [19]. It is believed that vitamin D insufficiency arises at an early stage of the disease and tends to worsen with the progressive loss of renal function [20].

In this study, the main objective is to see through this research gap by conducting a cohort study using data from the National Health Insurance database in Taiwan to assess the relationship between patients with CKD and TB and more knowledge on the outcomes in patients taking vitamins D in ESKD renal patients.

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Materials and Methods

1. Source of Data and Study Population

We conducted a nationwide, population-based retrospective cohort study to clarify the role of renal disease in the risk of tuberculosis, taking advantage of a well-established and large-size data set available from the Taiwan National Health Insurance Research Database (NHIRD). The Longitudinal Health Insurance Database 2010 (LHID2010) constitutes registration and claims data collected by the NHIRD program for a nationally representative group of 1 million individuals. The NHIRD contains all claims-related data, including patient personal information (e.g., age and gender), clinical diagnoses, prescribed medicines, and healthcare use. Disease diagnosis is assigned according to the International Classification of Diseases, 9th Revisions, and the Clinical Modification (ICD-9-CM) diagnostic codes. To protect patient confidentiality, all their identification numbers and medical institutions were encrypted before the release of the data for research purposes. Because no patient could be identified, informed consent was waived. The study protocol was reviewed and approved by the Institutional Review Committee of Kaohsiung Medical University Hospital (KMUHIRB-EXEMPT (I)-20190011), Taiwan.

The flowchart illustrating the selection process of participants is shown in Figure 1. From 1,000,023 people (LHID 2010), we excluded 445,173 people, due to birth after 1 January 1977 (age < 20) (n = 444,812), tuberculosis diagnosed before 1 January 1997 (n = 8), kidney disease diagnosed before 1 January 1997 (n = 348) and vitamin D used before 1 January 1997 (n = 5), respectively. A total of 554,850 people are enrolled with kidney disease (n = 35,617) and the compared group (n = 519,233). From the kidney disease patients, we excluded those with a prior diagnosis of tuberculosis (n = 520), kidney disease and incidence of tuberculosis with follow-up of less than 1 month (n = 33), kidney disease patients with a follow-up of less than 1 month (n = 221), kidney disease patients with clinic visits < 2 (n = 13,584), tuberculosis patients with drug use less than 60 days (n = 105) and vitamin D drug use before kidney disease (n = 169), respectively. From the compared group, the incidence of tuberculosis with follow-up of less than 1 month (n = 28), tuberculosis patients with drug use of fewer than 60 days (n = 1059), and vitamin D drug use (n = 1724) were excluded. The final kidney disease patients (n = 20,985) were matched with the compared group (matched 1:1 on the age of cohort entry and sex). The presence of kidney disease and tuberculosis was defined based on the fulfillment of the following criteria: tuberculosis—3 or more clinic visits. The index date was the date of the first diagnosis of kidney disease. The main study outcome was TB diagnosis. We considered incident TB from the first kidney disease diagnosis to the date of TB diagnosis or the end of the study. The follow-up period began on 1 January 1997 and ended on the date of the first TB events, the end of the study (31 December 2010), or the end of the follow-up, whichever occurred first.

2. Ascertainment of Kidney Diseases and Tuberculosis

In total, 20,985 patients with kidney disease and 20,985 without kidney disease (matched 1:1 on the age of cohort entry and sex) were included in this study. The outcome of interest was the documentation of tuberculosis by a physician. Assessment of renal disease (by ICD-9-CM code 403.01, 403.11, 403.91, 404.02, 404.03, 404.12, 404.13, 404.92, 404.93, 582. x, 583.0–583.7, 585. x, 586. x, 588.0, V42.0, V45.1, V56.x) was carried out during an outpatient or inpatient visit. Assessment of TB was conducted with ICD-9-CM codes of TB (010-018) plus the prescription of more than two anti-tuberculosis medications (i.e., isoniazid, rifampin, pyrazinamide, ethambutol, river, refinish, streptomycin, cycloserine, prothionamide, amikacin, kanamycin, ciprofloxacin, moxifloxacin and levofloxacin) for more than 60 days. Subjects with kidney disease were followed from the index date to the date of the first diagnosis of kidney disease. The ESKD patients were divided into hemodialysis (HD) and peritoneal dialysis (PD) cohorts according to the dialysis modalities with different operation codes (HD, 3995; PD, 5498), and the administration code was used to define renal dialysis (D8, hemodialysis and D9, peritoneal dialysis). The primary case definition of renal transplant recipients was having a physician-recorded primary diagnosis of a kidney replaced by transplant (ICD-9-CM V420) or having complications of the transplanted kidney (996.81) at either an outpatient or inpatient visit in NHIRD data sets. The ESKD patients receiving a prescription of vitamin D included alfacalcidol and calcitriol (Anatomical Therapeutic Chemical [ATC] code A1CC03 and A11CC04).

3. Comorbidities

In addition to the demographic risk factors of age, sex, and region, we evaluated other potentially confounding factors for alcohol abuse, lipid disorders, obesity hypertension, myocardial infarction, congestive heart failure, peripheral vascular disease, and cerebral. vascular disease, chronic pulmonary disease, rheumatologic disease, liver disease, diabetes Mellitus, and any malignancy. These comorbidities were diagnosed according to ICD-9-CMcodes (21].

4. Statistical Analysis

Propensity analysis was performed to obtain a match of the propensity score for each patient with the covariates, such as the age of cohort entry and sex. Continuous and categorical variables were analyzed using a t-test or Wilcoxon rank sum test and a chi-squared test, respectively, and the values obtained for the renal disease group and matched-renal disease group were compared. The Kaplan-Meier method was used to estimate the survival curves for each group and the log-rank test was used to test for homogeneity among the survival curves. The incident rate ratio (IRR) was calculated using the PROCGENMOD generalized linear model to perform Poisson regression analysis, which is a log-linear model. Potential risk factors, such as comorbidities, were incorporated into the model. Significant results were those with p < 0.05. All statistical analyses were performed using SAS statistical software (version 9.4, SAS Institute, Cary, NC, USA)

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Sithembiso Tiyandza Dlamini 1 , Kyaw Moe Htet 1 , Ei Chue Chue Theint 1 , Wei-Ming Li 2,3,4 , Hsin-Wen Chang 5,6, and Hung-Pin Tu 7,8,

1 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan

2 Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan

3 Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan

4 Department of Urology, Ministry of Health and Welfare, Pingtung Hospital, Pingtung 900, Taiwan

5 Department of Applied Psychology, Hsuan Chuang University, 48 Hsuan Chuang Rd., Hsinchu City 30092, Taiwan

6 Center for General Education, Hsuan Chuang University, Hsinchu City 30092, Taiwan

7 Department of Public Health and Environmental Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung 80708, Taiwan

8 Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan