Chronic kidney disease is associated with increased risk of sudden sensorineural hearing loss and Ménière’s disease: a nationwide cohort study

Several studies have demonstrated the harmful effects of chronic kidney disease (CKD) on the audiovestibular system. Through a time-to-event analysis, we aimed to compare the association of CKD with sudden sensorineural hearing loss (SSNHL), and Ménière’s disease against a control population without CKD. We used a total of 1,025,340 patients from the Korean National Health Insurance Service database from 2002 to 2013. The CKD group (n = 2572) included patients diagnosed with CKD more than three times between January 2003 and December 2005. The non-CKD group (n = 5144) consisted of two patients without CKD for every patient with CKD. Each patient was monitored until December 2013. We calculated the incidence, survival rate, and hazards ratio (HR) of SSNHL and Ménière’s disease. In the CKD group, the incidence of SSNHL and Ménière’s disease was 1.39 and 3.64 per 1000 person-years, respectively. Patients with CKD showed an adjusted HR of 2.15 and 1.45 for SSNHL and Ménière’s disease, respectively. Middle-aged patients with CKD were associated with a higher incidence of developing SSNHL and Ménière’s disease than those without CKD. Female patients with CKD had a higher risk of developing SSNHL; however, there was no significant difference in the risk of Ménière’s disease in patients with CKD according to sex. Our findings suggest that CKD is associated with an increased incidence of SSNHL and Ménière’s disease. Therefore, audiovestibular surveillance should be considered in patients with CKD.


Results
We selected 2572 patients with CKD and 5144 comparison participants (non-CKD) using propensity score matching. The details of the study population and group characteristics are presented in Table 1. We observed no significant differences between the CKD and comparison groups regarding sex, age, residential area, household income, hypertension (HTN), or diabetes mellitus (DM). This indicates that group matching was performed appropriately. Additionally, to indicate good matching, we presented the balance plot before and after matching (Fig. 1). This showed a good matching balance along with our sensitivity analysis.
In this study, we examined a total of 78,915.7 person-years and 78,453.3 person-years of SSNHL and Ménière's disease, respectively, which included 56,559.9 person-years and 56,172.7 person-years in the comparison group, and 22,355.8 person-years and 22,280.6 person-years in the CKD group, respectively. Our results showed that the incidence of SSNHL and Ménière's disease per 1000 person-years was 1.39 and 3.64, respectively, for the CKD group, compared to 0.60 and 3.38, respectively, for the comparison group.
We analyzed the hazards ratios (HR) for the development of SSNHL and Ménière's disease during the 8-year follow-up period using univariate and multivariate Cox regression models; these findings are presented in Tables 2 and 3. After adjusting for sociodemographic factors (sex, age, residential area, household income, hypertension [HTN], and DM), we observed that patients with CKD had a significant association with the prospective development of SSNHL (adjusted HR = 2. 15 Fig. 2, which depicts the cumulative incidences of SSNHL and Ménière's disease in the patient and comparison groups.  Table 4). Additionally, we observed that female patients with CKD were more strongly associated with the development of SSNHL than male patients (Table 5). However, there was no significant relationship between Ménière's disease and CKD according to sex (Table 4).

Discussion
CKD is a major global health burden due to its high prevalence, economic cost, and harmful effects on other organs. In this longitudinal study, we examined the association between CKD and SSNHL or Ménière's disease in 2572 patients with CKD and 5144 sociodemographically matched comparison participants, whose data were extracted from a nationwide 8-year longitudinal cohort database of 1,025,340 South Korean patients. Interestingly, we observed that patients with CKD had a significantly increased incidence of SSNHL and Ménière's disease, with an HR of 2.15 and 1.45, respectively, after adjusting for sociodemographic factors and the presence of www.nature.com/scientificreports/ comorbidities. Moreover, we observed that middle-aged patients with CKD had a significantly increased risk of SSNHL and Ménière's disease. Further, the risk of developing SSNHL was higher in female patients with CKD than in male patients.
Research has shown that patients with CKD are prone to developing otologic symptoms related to audiovestibular dysfunction. These symptoms are often permanent, difficult to control, and have a significantly negative influence on the patient's quality of life. Among the described audiovestibular dysfunctions, the possible cause linking CKD with SSNHL and Ménière's disease remains unclear. However, the nephrons of the kidney and the stria vascularis of the cochlea show very similar anatomical, physiological, and pharmacological characteristics 17 . Additionally, antibodies formed against the nephrons may be immunologically deposited in the stria vascularis of the cochlea 18,19 . Moreover, CKD-related electrolytic and osmotic alterations that affect the cochlea can influence the labyrinth 13 . Furthermore, hemodialysis and renal transplantation may induce electrolyte disturbances and osmotic alterations in the inner ear, resulting in sensorineural hearing loss, tinnitus, and vertigo 9 . Prolonged hemodialysis may also result in the accumulation of amyloid in the inner ear tissues 20 . Thus, despite the exact pathogenesis of SSNHL and Ménière's disease in patients with CKD remaining unclear, the suggested potential etiologic factors may explain the relationship between CKD and the subsequent development of SSNHL and Ménière's disease.
To the best of our knowledge, this is the first study to investigate the association of developing SSNHL and Ménière's disease in patients with CKD. Interestingly, we observed that CKD resulted in a significantly increased risk of SSNHL and Ménière's disease. Consistent with our results, previous studies have shown that patients with CKD are at greater risk of tinnitus, SSNHL, and vestibular dysfunction than the normal population 15,16,21 . However, we also observed that middle-aged patients with CKD exhibited significantly increased risks of SSNHL and Ménière's disease. Previous epidemiological studies have shown that SSNHL and Ménière's disease have peak ages ranging between 30 and 60 years 22,23 . Thus, we consider that in middle-aged patients, the neuro-otologic organs may be more vulnerable to disturbances in water and electrolyte homeostasis. Additionally, we detected an increased risk of SSNHL in female patients with CKD compared to male patients. It remains unclear why female patients with CKD exhibited a significantly increased risk of SSNHL. However, another population-based study in South Korea showed that SSNHL has a slight female preponderance 24 ; thus, we thought our finding may be due to this different sex preponderance.
This study has several unique strengths. First, we used a large national population-based database, which enabled us to effectively analyze all incidences of SSNHL and Ménière's disease. Second, our cohort had a relatively long follow-up period (8 years). Third, the inclusion criteria of this study were based on an established Table 2. Incidence per 1000 person-years and hazards ratio (95% confidence interval) of sudden sensorineural hearing loss. CKD, Chronic kidney disease; SSNHL, Sudden sensorineural hearing loss; HR, Hazard ratio; CI, Confidence interval. *P < 0.05, **P < 0.010, and ***P < 0.001. www.nature.com/scientificreports/ diagnostic code, with the additional requirement of pure-tone audiometry for diagnosis. Finally, a prior study for validation of the KNHIS-NSC data revealed that the prevalence of 20 major diseases was similar for each year; thus, the reliability of the KNHIS-NSC data was defined as "fair to good. " Therefore, our findings suggest that CKD increases the risk of SSNHL and Ménière's disease.
Our study also has some notable limitations. First, we could not obtain any specific personal health data, including body mass index, GFR level, lipid profiles, and information regarding behavioral risk factors, such as smoking or alcohol consumption. Second, SSNHL and Ménière's disease were diagnosed based on the diagnostic code, which might be less accurate compared to the data obtained from medical charts that included details such Table 3. Incidence per 1000 person-years and hazards ratio (95% confidence interval) of Meniere's disease. CKD, Chronic kidney disease; SSNHL, Sudden sensorineural hearing loss; HR, Hazard ratio; CI, Confidence interval. *P < 0.05, **P < 0.010, and ***P < 0.001. www.nature.com/scientificreports/ as the medical history, imaging findings, or audiometry results. Third, we could not access the specific data such as the severity of hearing and vestibular impairment due to lacking in our registry; therefore, we were unable to investigate whether CKD influenced the severity of SSNHL and Ménière's disease. Finally, family history, genetic conditions, and radiographic findings for SSNHL (such as enlarged vestibular aqueducts) could affect the potential for SSNHL and Ménière's disease. However, in this cohort study, we could not include these variables as control variables, because our national insurance service does not cover these findings. Future clinical studies that investigate a wider range of factors and diagnostic criteria are needed to provide additional evidence for the link between CKD and SSNHL or Ménière's disease.
In conclusion, this study investigated the possible link between CKD and the prospective development of SSNHL and Ménière's disease. Interestingly, we observed that patients with CKD had a significantly higher risk of developing SSNHL and Ménière's disease than non-CKD patients during an 8-year follow-up period. This Table 4. Hazard ratios of sudden sensorineural hearing loss or Meniere's disease by age between patients with and without chronic kidney disease. SSNHL, Sudden sensorineural hearing loss; CKD, Chronic kidney disease; CI, Confidence interval (*P < 0.05).  www.nature.com/scientificreports/ finding suggests that CKD may be a risk factor for the development of SSNHL and Ménière's disease; therefore, clinicians should consider patients with CKD to be at a high risk of developing SSNHL and Ménière's disease and take specific measures to reduce the risk of developing these sequelae.

Methods
Data source and study population. This nationwide propensity score-matched cohort study was reviewed and approved by the Institutional Review Board of Hallym Medical University Chuncheon Sacred Hospital (Chuncheon, Korea). The Institutional Review Board of Hallym Medical University Chuncheon Sacred Hospital waived the written informed consent for this study due to the KNHIS-NSC dataset consists of de-identified secondary data for research purposes. This study adhered to the tenets of the Declaration of Helsinki. All citizens in Korea are obligated to enroll in the KNHIS, and a centralized large database provides access to nearly all data of the health insurance system. Therefore, the KNHIS contains reimbursement records from all medical facilities, including hospitals, private clinics, and public centers in South Korea. Claims are accompanied by data regarding diagnostic codes, procedures, prescription drugs, personal information about the patient, information about the hospital, the direct medical costs of both inpatient and outpatient care, and dental services. This study utilized the data of a Independent variables. The study population was divided into two groups according to sex, three groups according to age (< 45, 45-64, and > 64 years), three groups according to household income (low: 0-30%, middle: 30-70%, and high: 70-100% of the median), and three groups according to area of residence (Seoul: the largest metropolitan region in South Korea, 2nd area: other metropolitan cities in South Korea, and 3rd area: small cities and rural areas). We also analyzed HTN and DM as comorbidities using the ICD-10 codes and prescription lists from the KNHIS-NSC database. HTN was defined as a previous diagnosis of hypertension (I10-11) and the use of antihypertensive drugs. DM was defined as a previous DM diagnosis ( E10-14) and the use of one or more oral hypoglycemic agents or insulin. We defined the presence of comorbidities as any diagnoses of these codes between 2003 and 2004 prior to the diagnosis of SSNHL or Ménière's disease.
Statistical analysis. The risks of SSNHL and Ménière's disease were compared between the CKD and comparison groups as person-years at risk, which were defined as the duration between either the date of CKD diagnosis or January 1, 2003 (for the comparison group), and the patient's respective endpoint. Incidence rates per 1000 person-years for SSNHL or Ménière's disease were obtained by dividing the number of patients with incidence of specific diseases by person-years at risk. Person-years consisted of the following 3 cases: (1) In the case of death, the number of years from the date of initial diagnosis of CKD to the date of death; (2) In the case of side effects, the number of years from the first diagnosis of CKD to the date of the first diagnosis of side effects; (3) If there are no side effects, the number of years from the date of initial diagnosis of CKD to '2013-12-31' , the study endpoint. To identify whether CKD increased the risk of occurrence of specific diseases, we used Cox proportional hazards regression analyses to calculate the HRs and 95% CIs, adjusted for other predictor variables.