The Association between Influenza Vaccine and Risk of Chronic Kidney Disease/Dialysis in Patients with Hypertension

Backgrounds: Influenza vaccination could decrease the risk of major cardiac events in patients with hypertension. However, the vaccine’s effects on decreasing the risk of chronic kidney disease (CKD) development in such patients remain unclear. Methods: We retrospectively analysed the data of 37,117 patients with hypertension (≥55 years old) from the National Health Insurance Research Database during 1 January 2001 to 31 December 2012. After a 1:1 propensity score matching by the year of diagnosis, we divided the patients into vaccinated (n = 15,961) and unvaccinated groups (n = 21,156). Results: In vaccinated group, significantly higher prevalence of comorbidities such as diabetes, cerebrovascular disease, dyslipidemia, heart and liver disease were observed compared with unvaccinated group. After adjusting age, sex, comorbidities, medications (anti-hypertensive agents, metformin, aspirin and statin), level of urbanization and monthly incomes, significantly lower risk of CKD occurrence was observed among vaccinated patients in influenza season, non-influenza season and all season (Adjusted hazard ratio [aHR]: 0.39, 95% confidence level [C.I.]: 0.33–0.46; 0.38, 95% C.I.: 0.31–0.45; 0.38, 95% C.I.: 0.34–0.44, respectively). The risk of hemodialysis significantly decreased after vaccination (aHR: 0.40, 95% C.I.: 0.30–0.53; 0.42, 95% C.I.: 0.31–0.57; 0.41, 95% C.I.: 0.33–0.51, during influenza season, non-influenza season and all season). In sensitivity analysis, patients with different sex, elder and non-elder age, with or without comorbidities and with or without medications had significant decreased risk of CKD occurrence and underwent hemodialysis after vaccination. Moreover, the potential protective effect appeared to be dose-dependent. Conclusions: Influenza vaccination decreases the risk of CKD among patients with hypertension and also decrease the risk of receiving renal replacement therapy. Its potential protective effects are dose-dependent and persist during both influenza and noninfluenza seasons.


Introduction
Hypertension is a major common risk for coronary artery disease, stroke, heart failure, atrial fibrillation, aortic dissection, renal failure, and peripheral artery disease [1]. The presence of hypertension increases risk of renal disease and is an independent predictor of decreased glomerular filtration rate in the general population [2]. During middle and old age, blood pressure has direct and strong relationship with vascular and overall mortality [3]. The prevalence of hypertension in developing countries is increasing rapidly and the health burden of hypertension is growing worldwide [4]. The interaction between neurohormonal, renal, vascular mechanisms contributes different hemodynamic forms of hypertension. Over the nature course of hypertension, early endothelial dysfunction and increasing cardiac output usually progress into the late stage with increased peripheral vascular resistance and subsequently end organ damage with irreversible changes.
Chronic kidney disease (CKD) is a rapidly increasing public health problem and its prevalence is around 8-16% worldwide [5]. Several studies showed that CKD was associated with multiple complications and increased risk of cardiovascular disease [6]. Inflammation is the complex response of the tissue to various injuries. Inflammation can contribute to the progression of CKD by inducing cytokine release, increasing adhesion molecule production, and activating inflammatory cells [7]. Influenza viruses are one of most important causes of respiratory tract infection and cause widespread morbidity and mortality by inducing severe immunopathology of multiple organs with excessive innate immune response, resulting in 3-5 million infections and 250,000-500,000 lethal patients annually [8][9][10]. Complications of influenza include pneumonia, myositis, rhabdomyolysis, kidney injury, neurological diseases, and cardiovascular diseases [11]. Although most influenza infections are self-limited, severe complications of influenza in elderly patients can result in hospitalization or death [12]. Renal complications of influenza virus infection are uncommon but might be dangerous and lethal, reported by several studies [13,14].
Previous researches demonstrated influenza infection associated with increasing cardiovascular diseases, including acute myocardial infraction, myocarditis, cardiac arrhythmia, pericarditis, and heart failure [15,16]. In a study by Kristin, influenza vaccination in the elderly was associated with reduced risk of hospitalization for heart disease and cerebrovascular disease [17]. In a global meta-analysis of randomized clinical trials, the use of influenza vaccination significantly decreased the risk of major adverse cardiovascular events, especially in the highest-risk patients with more active coronary artery disease [18]. Although lots of studies investigated the protective effect of influenza vaccine on cardiovascular diseases and confirmed the benefit, the effect of influenza vaccine on renal complications is still unknown. In order to clarify the potential benefit of influenza vaccination on kidney diseases in a group of the elderly Taiwanese patients with hypertension with high risk of developing CKD, we conducted a population-based cohort study using reimbursement claims from Taiwan's National Health Insurance Research Database (NHIRD).

Data Source
The Taiwan National Health Insurance (NHI) program was initiated in 1995 and has been providing thoroughly health care for 99% of the population of more than 23 million residents in Taiwan. The NHIRD, which was administered and held by the National Health Insurance Administration, consisted of outpatient visits, emergent department visits, hospital admissions, prescriptions, diseases, management, and treatments of all NHI enrollees. In order to protect patient privacy, data from the NHIRD that could be used to identify patients, medical institutions, and physicians, are encrypted and delinked before releasing the database to all researchers. Furthermore, all researchers using NHIRD must sign a written agreement declaring that they do not have any intention to acquire information which could potentially invade the privacy of patients or care providers. This study had been approved by the Joint Institutional Review Board of Taipei Medical University (approval No. N201804043).

Study Cohort
This study screened all patients who were diagnosed as having hypertension based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code 401.X-405.X and who visited health-care facilities in Taiwan over 12 years from 1 January 2000, to 31 December 2012. In the first part, hypertension was diagnosed in at least two out-patient clinic records or at least one in-patient record, and patients who had received at least two prescriptions of anti-hypertension drugs. We excluded 86,179 patients due to following reasons: Patients were aged <55 years (n = 77,142), and patients with any inpatient or outpatient diagnosis related to CKD before the date of cohort enter (n = 6399), and patients with any inpatient or outpatient diagnosis related to hemodialysis before the date of cohort enter (n = 16), and patients with any inpatient or outpatient diagnosis related to renal transplantation before the date of cohort enter (n = 3), and patients had already had any Vaccinated within 6 months before the date of cohort enter (n = 2619). Finally Included in the Study Cohort (n = 37,117; Figure 1). In addition, a 1-year washout period (2000) was included to ensure that all patients in this cohort had no CKD or dialysis before enrollment. The influenza vaccines were all given by intramuscular injection. The vaccination status was recognized based on the presence of code V048 or the use of the vaccine [confirmed by drug codes of Vaxigrip ® (inactivated trivalent influenza vaccine, Sanofi Pasteur, France); AdimFlu S ® (inactivated trivalent influenza vaccine, Adimmune Corporation, Taiwan), Fluvirin ® (inactivated trivalent influenza vaccine, Novartis, UK)]. The primary endpoints of our study were the incidence of CKD (ICD-9-CM code 585.X) and the requirement of dialysis (NHI procedure codes) in patients with hypertension. All cohorts were followed up until the date of the diagnosis of CKD, dialysis, death, disenrollment from the NHI, or the end of 2012.

Potential Confounders
The following diagnoses were recorded to establish the baseline comorbidity history for each participant: diabetes; cerebrovascular diseases; dyslipidemia; heart diseases; hepatitis B virus; hepatitis C virus; cirrhosis; moderate and severe liver disease; asthma; and prescriptions for medications that include statin, metformin, aspirin, and prescriptions for anti-hypertension medications included diuretics, beta-blockers, calcium channel blocker, renin angiotensin aldosterone system (RAA) blocker. The cohort was also classified based on sociodemographic characteristics: age (categorized into 3 groups: 55-64, 65-74, and ≥75 years old), gender (male, female), Level of Urbanization (urban, suburban, and rural area), and income on monthly basis (0, 1-20,100, 20,100-30,301, and ≥30,301 in New Taiwan Dollar (NT$)).

Statistical Analysis
A propensity score (PS) is used to reduce selection bias and estimate the effect of vaccination by accounting for covariates that predict receiving the intervention (vaccine) by using a logistic regression model. Covariates in the main model were adjusted for PSs for age, sex, diabetes, dyslipidemia cerebrovascular diseases, heart diseases, hepatitis B virus, hepatitis C virus, cirrhosis, moderate and severe liver disease, asthma, anti-hypertension medications, statin, metformin, aspirin, level of urbanization, monthly income (Table 1). Categorical variables were compared using the chi-square test to determine the significance of differences between the vaccinated and unvaccinated groups in terms of the relationship among characteristics listed in Table 1. The unvaccinated group served as the reference arm. The hazard ratio (HR) and 95% confidence interval (CI) for the association between influenza vaccination and the risks of CKD and dialysis in patients with Hypertension were calculated using Cox proportional hazards regression. To examine the dose effect of influenza vaccination on the incidence of CKD and dialysis, we categorized patients into four groups by vaccination status: unvaccinated and those receiving 1, 2-3, and ≥4 vaccination, respectively. These data were stratified according to patients' age, sex, comorbidity, and associated medication use. Sensitivity analysis was performed to evaluate the difference and consistency between the use of influenza vaccination and the risks of CKD and dialysis in patients with Hypertension. All statistical analyses were performed using SPSS 22.0 and SAS 9.4 software. A p value of <0.05 indicated statistical significance.

Risk of Developing Chronic Kidney Disease
After adjusting the age, sex, diabetes, dyslipidemia cerebrovascular diseases, heart diseases, hepatitis B virus, hepatitis C virus, cirrhosis, liver disease, asthma, all class of antihypertensive agents, statin, metformin, aspirin, level of urbanization and monthly income by propensity score matching, vaccinated group had significantly lower risk of developing CKD than unvaccinated group in influenza season, non-influenza season and all season (aHR: 0. 39

Risk of Receiving Hemodialysis
Among the vaccinated patients, risk of receiving hemodialysis was significantly lower than unvaccinated patients in influenza season, non-influenza season and all season (aHR: 0. 40  In patients with age <65 year-old or >65 year-old, the risk of receiving hemodialysis significantly reduced after vaccination in influenza season, non-influenza season and all season. Both female and male patients had reduced risk of receiving hemodialysis after vaccination in influenza season, non-influenza season and all season (Table 3).

Sensitivity Analysis of Vaccination in CKD Occurrence
In influenza season, with more times of vaccination, the risk of developing CKD significantly decreased after adjusting the age, sex, comorbidities, medications, level of urbanization and monthly income         Patients who took either diuretic agent, beta-blocker, calcium channel blocker or RAA for more than 28 days all had decreased risk of receiving hemodialysis after more than 2 times of vaccination. Patients who took statin either for less than 28 days, 28-365 days and more than 365 days had decreased risk of hemodialysis after more than 2 times of vaccination. Patients who took metformin less than 28 days had reduced risk of hemodialysis after 1 time of vaccination (aHR: 0.57 [95% CI: 0.35-0.94], 0.39 [95% CI: 0.23-0.65], 0.25 [95% CI: 0.14-0.45], receiving 1, 2-3 and ≥4 times of respectively). In patients who took metformin more than 365 days, the risk of receiving hemodialysis reduced after more than  (Table 9).

Discussion
In this nationwide population based observational study, there are several main findings. First, we found that patients with hypertension, without any history of kidney diseases, hemodialysis, or having received renal transplantation, who had received influenza vaccination, had a lower rate to develop CKD in the future. Second, the risk of receiving dialysis therapy among patients with hypertension significantly decreased after vaccination. Third, the potential renal protective effect of influenza vaccine was observed in both males and females, patients with or without chronic comorbidities and with or without medications usage. Fourth, the risk reduction of CKD occurrence or receiving dialysis decreased after influenza vaccination appeared to be dose-dependent. Fifth, the potential renal protective effect was observed during influenza season, non-influenza season and all seasons.
Previous epidemiological researches established that blood pressure was related to CKD and proteinuria [19,20]. In Hanratty's retrospective cohort study for a medium of 3.67-year follow-up, 12.1% of 43,305 hypertensive patients developed CKD and systolic blood pressure was found associated with incident CKD [21]. Hypertension has been an important risk factor for CKD and responsible for 27% of all end-stage renal disease(ESRD) patients in America [22]. Besides, infections, such as urinary tract infection, are also known associated with renal cell damage and scarring, leading to CKD and ESRD [23]. Sepsis often results in multiple organ dysfunction and acute kidney injury, occurring in about 19% patients with moderate sepsis, 23% with severe sepsis, and 51% with septic shock [24]. Certain studies demonstrated that inflammation played a pivotal role in kidney function decline and the pathogenesis of CKD [25][26][27][28][29]. Hypertension and infection are major risk factors contributing to CKD.
In the first case report by Myking, influenza virus infection was shown associated with severe renal failure [30]. Since then, although renal complications of influenza were uncommon, small series of influenza virus infection complicated by renal failure were still reported constantly. The renal complications of influenza infection include acute kidney injury (AKI), rhabdomyolysis, hemolytic uremic syndrome, acute glomerulonephritis, disseminated intravascular coagulation, Goodpasture's syndrome, and tubulointerstitial nephritis. In Watanabe et al.'s study, in 45 hospitalized children with influenza A virus infection, 24.4% of the patients had renal involvement and sepsis with multiple organ failure [31]. According to certain studies, approximately one third of patients with influenza virus infection during hospitalization developed AKI and some even required renal replacement therapy [32][33][34].
There are several possible mechanisms contributing development of kidney injury in patients with influenza infection. Soto-Abraham et al. reported one of five patients who died of influenza infection had acute tubular necrosis (ATN) [35]. Another study demonstrated 21 patients who died of influenza infection all exhibited mild to moderate severity of ATN and four patients had myoglobin pigment deposited in the renal tubules [36]. Carmona et al. analyzed the autopsy findings of five patients who died of influenza infection and found ATN existed in all patients without evidence of direct virus-induced kidney injury [37]. These researches implicate ATN often complicate patients with influenza infection and leading to kidney injury. Rhabdomyolysis is a lethal-threatening syndrome characterized by the release of muscle contents, including electrolytes, myoglobin, enzymes, and other sarcoplasmic proteins into the circulatory system. Acute kidney injury is a quite common complication that developed in 13% to approximately 50% patients with rhabdomyolysis [38,39]. Several studies had indicated that influenza virus infection was associated with rhabdomyolysis and led to kidney injury [40,41]. There were also some studies showing that influenza virus could be detected in urine and implicated that influenza virus would directly invade the urinary system and lead to kidney injury [42,43]. In addition, influenza infection would evoke cell mediated immunity with secretion of Th17 and Th1 cytokines. Dysregulation of cytokine expression due to viral antigen deposition in the kidney results in T-cell mediated kidney injury was found in patients with influenza virus infection [44].
There are several limitations of the present study. First, this study retrospectively analyzed population data retrospectively. Risk factors that contribute to increasing risk of CKD or dialysis were adjusted using the propensity score method to minimize the potential bias. However, future prospective studies are warranted to validate the results of present study. Second, based on the limitation of NHIRD, confounding variables such as body mass index, laboratory data such as estimated glomerular filtration rate, proteinuria and creatinine level, and smoking or alcohol consumption status could not be collected. Third, the effectiveness of the influenza vaccine could be affected by the mutation of the influenza virus in different years. In the present study, the potential renoprotective effect was also observed during the non-influenza season. However, future studies aim to compare the different vaccine effectiveness and the risk of CKD or receiving hemodialysis is warranted.

Conclusions
The risk of CKD potentially decreased after receiving influenza vaccination among patients with CKD. Moreover, the risk of dialysis also significantly decreased after influenza vaccination. The potential renoprotective effects of influenza vaccination was observed in all seasons and appeared to be dose-dependent.