Investigation of the relationship between sensorineural hearing loss and associated comorbidities in patients with chronic kidney disease: A nationwide, population-based cohort study.

Hearing impairment was observed in patients with chronic kidney disease (CKD). Our purpose was to investigate the relationship between sensorineural hearing loss (SNHL) and associated comorbidities in the CKD population. We conducted a retrospective, population-based study to examine the risk of developing SNHL in patients with CKD. Population-based data from 2000-2010 from the Longitudinal Health Insurance Database of the Taiwan National Health Insurance Research Database was used in this study. The population sample comprised 185,430 patients who were diagnosed with CKD, and 556,290 without CKD to determine SNHL risk factors. Cox proportional hazard regression analysis demonstrated the CKD group had a significantly increased risk of SNHL compared with the non-CKD group [adjusted hazard ratio (HR), 3.42; 95% confidence interval (CI), 3.01-3.90, p < 0.001]. In the CKD group, the risk of SNHL (adjusted HR, 5.92) was higher among patients undergoing hemodialysis than among those not undergoing hemodialysis (adjusted HR, 1.40). Furthermore, subgroup analysis revealed an increased risk of SNHL in patients with CKD and comorbidities, including heart failure (adjusted HR, 7.48), liver cirrhosis (adjusted HR, 4.12), type 2 diabetes mellitus (adjusted HR, 3.98), hypertension (adjusted HR, 3.67), and chronic obstructive pulmonary disease (adjusted HR, 3.45). CKD is an independent risk of developing SNHL. Additionally, hemodialysis for uremia can increase the risk of SNHL. Cardiovascular, lung, liver, and metabolic comorbidities in CKD patients may further aggravate the risk of SNHL by inter-organ crosstalk. We should pay attention to SNHL in this high-risk population.

Introduction

Chronic kidney disease (CKD) is characterized by a progressive reduction in the renal function and can affect several organs. CKD is continually becoming more prevalent and a public health issue of global concern [1]. Problems associated with the auditory system are common in patients with CKD and can negatively affect the quality of life [2].

The genetic condition that links the kidneys to the ears is Alport’s syndrome. Reportedly, the nephron shares anatomical, physiological, immunological, and pharmacological similarities with the stria vascularis. Epithelial cells of nephron and stria vascularis are in close contact with their vascular supply [3]. The sodium–potassium pump, carbonic anhydrase, calcium-ATPase, and calcium-binding proteins actively transport fluid and electrolytes in both organs [4-6]. Common antigenicity testing has demonstrated antibody deposition in both nephron and stria vascularis [3, 7]. Various drugs act on both organs such as aminoglycosides associated with both nephrotoxic and ototoxic effects [3, 4].

Recently, a high prevalence of CKD has been reported globally [1]. Hearing loss is highly prevalent in patients with CKD compared with the general population [8]. As renal insufficiency progresses, uremic toxin accumulates, which has adverse pathological effects [4]. Furthermore, hearing impairment and uremia have been shown to be associated with each other [9], and can negatively impact the patient’s quality of life by limiting communication and thereby introducing a risk of social isolation and emotional difficulties [8, 10].

CKD patients often suffer associated comorbidities such as hypertension, type 2 diabetes mellitus (DM), heart failure (HF), stroke, chronic obstructive pulmonary disease (COPD), and liver cirrhosis [11]. To identify the relationship of developing SNHL among CKD and comorbidities, a population-based retrospective cohort study was conducted using data from the Taiwan National Health Insurance Research Database (NHIRD).

Materials and methods

Data sources

The National Health Insurance Program is a universal health-care system which contracts with 97% of the medical providers and covers medical expenses of more than 99% of the 23 million inhabitants of Taiwan. The Bureau of National Health Insurance randomly reviews the records of 1 in 100 ambulatory care visits and 1 in 20 in-patient claims to verify the accuracy of the diagnoses. The accuracy and validity of the diagnoses have been demonstrated [12, 13]. Therefore, the NHIRD was used as the data source. The study used data from 2000 to 2010 from the Longitudinal NHIRD to analyze the relationship of developing SNHL in patients with CKD. The International Classification of Disease (9th Revision) Clinical Modification (ICD-9-CM) codes for diagnoses and procedures and of genders and dates of birth recorded in the NHIRD were used. The study protocol was approved by the Ethics Committee of Human Studies at the Tri-Service General Hospital, Taiwan (TSGH IRB No. B-109-13).

Study design and participants

A 10-year retrospective cohort study was designed and 986,713 consecutive patients from January 1, 2000 to December 31, 2010 were enrolled. Patients newly diagnosed with CKD (ICD-9-CM codes, 585–586) before 1999, who had received a renal transplantation (ICD-9-CM code, V42.0), who had SNHL (ICD-9-CM code, 389.1) or tinnitus (ICD-9-CM code 388.3) before tracking, who aged <18 years, and who were without tracking or of unknown gender were excluded. After matching the CKD participants with thrice comparison subjects (index year, month, gender and age), 185,430 patients with first diagnosis of CKD and 556,290 participants without CKD were included in the CKD and comparison groups, respectively. The occurrence of SNHL (ICD-9-CM code, 389.1) that was diagnosed by otorhinolaryngologists at least thrice, continued for at least 4 weeks, and tracked until December 31, 2010 (Fig 1). Additionally, a subgroup analysis was conducted for identifying the relationship of developing hearing loss in patients with CKD undergoing and those not undergoing hemodialysis.

Fig 1

The flowchart of study sample selection.

The covariates of gender, age groups (18–29, 30–39, 40–49, 50–59, ≥60 years), and insured premium [in New Taiwan Dollars; <18,000, 18,000–34,999, ≥35,000] were analyzed. Baseline comorbidities such as hypertension (ICD-9-CM codes, 401–405), type 2 DM (ICD-9-CM code, 250), HF (ICD-9-CM code, 428), stroke (ICD-9-CM codes, 430–438), chronic obstructive pulmonary disease (COPD) (ICD-9-CM codes, 490–496), and liver cirrhosis (ICD-9-CM code, 571) were included as covariates. Medical histories of aminoglycosides and loop diuretics in the individuals for at least one week were also accessed.

Statistical analysis

In this population-based, retrospective cohort study, all analyses were performed using the SPSS software version 22 (SPSS Inc., Chicago, Illinois, USA). We present standardized difference and standardized mean difference for categorical and continuous variable distributions, respectively. Meanwhile, Chi-square (χ2) and t-tests were used. The results are presented as Wald coefficient and hazard ratios (HR) with a 95% confidence interval (CI). Multivariable cox proportional hazards regression analysis was used to determine the risk of developing hearing loss. We also performed a competing-risks regression (Fine-Gray model) because SNHL risk might compete with the risk of death [14]. The cumulative incidence competing risk (CICR) method was used to estimate the difference in the risk of developing hearing loss between the CKD and comparison groups [15]. The significance threshold of p-value was set at 0.05. The 19 weighted indicators of 17 comorbidities were used to calculate the Charlson Comorbidity Index (CCI) [16]. The variables, including CKD, type 2 DM, HF, stroke, COPD, and liver cirrhosis, have been removed to calculate CCI_R.

Results

In total, 185,430 patients with CKD and 556,290 participants without CKD were enrolled in the study (Fig 1). Compared with the comparison group, the CKD group demonstrated significantly higher rates of hypertension, type 2 DM, HF, and liver cirrhosis (p < 0.001) and lower rates of stroke, COPD and Meniere’s disease (p < 0.001). A higher CCI_R was reported in the CKD group (p < 0.001) (Table 1).

Table 1

Characteristics of study in the baseline.

	Overall (n = 741,720)		With CKD (n = 185,430)		Without CKD (n = 556,290)		P	Standardized difference	Standardized mean difference
Variables	n	%	n	%	n	%
Gender							0.999	0.000	0.000
Male	402,880	54.32	100,720	54.32	302,160	54.32
Female	338,840	45.68	84,710	45.68	254,130	45.68
Age (years)	67.31 ± 13.55		67.30 ± 14.20		67.31 ± 13.33		0.783	-1.995	-0.363
Age groups (yrs)							0.999	0.000	0.000
18–29	10,226	1.38	2,559	1.38	7,667	1.38
30–39	24,428	3.29	6,107	3.29	18,321	3.29
40–49	63,152	8.51	15,788	8.51	47,364	8.51
50–59	111,160	14.99	27,790	14.99	83,370	14.99
≧60	532,744	71.83	133,186	71.83	399,558	71.83
Insured premium (NT$)							<0.001***	-0.032	-0.002
<18,000	732,832	98.80	183,435	98.92	549,397	98.75
18,000–34,999	7,780	1.05	1,788	0.96	5,992	1.08
≧35,000	1,158	0.16	207	0.11	951	0.17
Comorbidities
HTN	156,363	21.08	42,234	22.78	114,129	20.52	<0.001***	0.023	0.001
T2DM	144,996	19.55	63,178	34.07	81,818	14.71	<0.001***	0.202	0.001
HF	38,776	5.23	21,441	11.56	17,335	3.12	<0.001***	0.084	0.001
Stroke	69,462	9.36	13,180	7.11	56,282	10.12	<0.001***	-0.030	-0.001
COPD	66,119	8.91	11,927	6.43	54,192	9.74	<0.001***	-0.003	-0.001
Liver cirrhosis	41,886	5.65	10,910	5.88	30,976	5.57	<0.001***	0.003	0.001
Meniere's disease	13,890	1.87	1,434	0.77	12,456	2.24	<0.001***	-0.015	<0.001
CCI_R	1.24 ± 2.06		2.63 ± 1.61		0.77 ± 1.98		<0.001***	1.942	0.005
Medications
Aminoglycoside	4,585	0.62	600	0.32	3,985	0.72	<0.001***	-0.003	-0.001
Loop diuretics	4,733	0.64	1,634	0.88	3,099	0.56	<0.001***	0.004	0.001

P: Chi-square / Fisher exact test on category variables and t-test on continue variables.

*P < 0.05, **P < 0.01

***P < 0.001. CKD: chronic kidney disease, HTN: hypertension, T2DM: type 2 diabetes mellitus, HF: heart failure, COPD: chronic obstructive pulmonary disease.

After adjusting for variables like age, gender, comorbidities, and drug intake, the highest HR of SNHL was 3.42 times (95% CI = 3.01–3.90) in patients with CKD, followed by that for stroke (HR, 1.52; 95% CI, 1.31–1.77), COPD (HR, 1.21; 95% CI, 1.04–1.53), and liver cirrhosis (HR, 1.19; 95% CI, 0.94–1.55). The HR for aminoglycoside and loop diuretics were lower (Table 2). The cumulative incidence competing risk analysis indicated that patients with CKD had a significantly higher incidence of developing SNHL over time than comparison participants (p < .001) (Fig 2).

Table 2

Factors of sensorineural hearing loss by using Cox regression and Fine & Gray's competing risk model.

	No competing risk in the model					Competing risk in the model
	Wald	Adjusted HR	95% CI	95% CI	P	Wald	Adjusted HR	95% CI	95% CI	P
CKD (Reference: Without)	239.14	3.19	2.80	3.64	<0.001***	303.22	3.42	3.01	3.90	<0.001***
Gender (Reference: Female)	19.14	1.30	1.16	1.45	<0.001***	19.68	1.32	1.19	1.48	<0.001***
Age groups (yrs) (Reference: 18–29)
30–39	1.54	0.52	0.19	1.40	0.192	1.71	0.53	0.20	1.43	0.205
40–49	0.01	0.95	0.45	2.21	0.896	0.02	0.99	0.42	2.30	0.969
50–59	<0.01	0.99	0.44	2.24	0.968	<0.01	1.05	0.46	2.37	0.931
≧60	0.02	0.12	0.51	2.53	0.790	0.07	1.28	0.57	2.86	0.568
Comorbidities (Reference: Without)
HTN	2.51	0.89	0.79	1.01	0.052	3.82	0.84	0.75	0.95	0.009**
T2DM	4.25	0.86	0.76	1.01	0.051	4.19	0.85	0.75	1.00	0.046*
HF	21.70	0.52	0.40	0.69	<0.001***	22.57	0.55	0.42	0.73	<0.001***
Stroke	21.80	1.49	1.29	1.74	<0.001***	26.22	1.52	1.31	1.77	<0.001***
COPD	4.02	1.22	1.04	1.45	0.026 *	3.94	1.21	1.04	1.53	0.019 *
Liver cirrhosis	0.01	1.13	0.89	1.45	0.338	0.83	1.19	0.94	1.55	0.192
Meniere's disease	568.85	8.51	7.11	10.17	<0.001***	546.06	7.81	6.53	9.34	<0.001***
CCI_R (Reference: Without)	8.77	0.95	0.93	0.98	0.006**	16.38	0.97	0.94	1.00	0.027*
Medications
Aminoglycoside	1.02	0.37	0.12	1.14	0.267	1.86	0.37	0.12	1.18	0.143
Loop diuretics	5.51	0.19	0.05	0.75	<0.001***	11.04	0.21	0.05	0.86	0.005*

Adjusted HR (hazard ratio): Adjusted variables listed in the table; CI = confidence interval

*P < 0.05

**P < 0.01

***P < 0.001

Fig 2

The cumulative incidence competing risk (CICR) method for the incidence of sensorineural hearing loss among patients aged 18 and over stratified by CKD (p < .001).

In the CKD group, 87,361 patients (47.11%) were undergoing hemodialysis and 98,069 (52.89%) were not undergoing hemodialysis. In patients with CKD undergoing hemodialysis, the incidence of SNHL was 133,761.97 per 105 person-years, with these patients having a higher risk of developing SNHL (adjusted HR, 5.92; 95% CI, 3.03–11.79) than those not undergoing hemodialysis (adjusted HR, 1.40, 95% CI = 1.01–3.23) (Table 3).

Table 3

Factors of sensorineural hearing loss stratified by with / without hemodialysis by using Cox regression and Fine & Gray's competing risk model.

					No competing risk in the model					Competing risk in the model
	Populations	Events	PYs	Rate	Wald	Adjusted HR	95% CI	95% CI	P	Wald	Adjusted HR	95% CI	95% CI	P
Without CKD	556,290	960	1,168,647.66	82.146		Reference					Reference
With CKD	185,430	368	334,193.43	110.116	239.14	3.19	2.80	3.64	<0.001***	303.22	3.42	3.01	3.90	<0.001***
without hemodialysis	98,069	198	200,431.46	98.787	99.38	1.31	0.99	3.01	0.058	107.05	1.40	1.01	3.23	0.046*
with hemodialysis (ESRD)	87,361	170	133,761.97	127.091	485.42	5.52	2.82	10.98	<0.001***	515.62	5.92	3.03	11.79	<0.001***

PYs = Person-years; Rate: per 100,000 PYs; Adjusted HR (hazard ratio): Adjusted variables listed in Table 1; CI = confidence interval

*P < 0.05, **P < 0.01

***P < 0.001; ESRD: end-stage renal disease.

In the subgroups stratified by gender, age, comorbidities and drug intake, patients with CKD who had comorbid HF, liver cirrhosis, type 2 DM, hypertension, and COPD had higher risks of developing SNHL than those without these comorbidities. In competing risks model, the adjusted HRs of hearing loss were 7.48 and 3.29 in those with and without HF, 4.12 and 3.39 in those with and without liver cirrhosis, 3.98 and 3.24 in those with and without type 2 DM, 3.67 and 3.36 in those with and without hypertension, and 3.45 and 3.35 in those with and without COPD, respectively (Table 4). The increased values of adjusted HRs may indicate the possible influence of CKD and comorbidities for SNHL.

Table 4

Factors of sensorineural hearing loss stratified by variables listed in the table by using Fine & Gray's competing risk model.

		With CKD			With CKD			With CKD vs. Without CKD (Reference)
Variables	Strarified	Events	PYs	Rate	Events	PYs	Rate	Wald	Adjusted HR	95% CI	95% CI	P
	Overall	368	334,193.43	110.12	960	1,168,647.66	82.15	303.22	3.42	3.01	3.90	<0.001***
Gender	Male	198	174,093.39	113.73	595	629,014.38	94.59	132.92	2.98	2.50	3.54	<0.001***
	Female	170	160,100.04	106.18	365	539,633.28	67.64	177.97	4.31	3.44	5.15	<0.001***
Age groups (yrs)	18–29	6	2,450.49	244.85	0	4,350.17	0.00	0.011	∞	-	-	0.897
	30–39	6	8,722.15	68.79	5	15,192.58	32.91	2.266	3.37	0.77	14.82	0.724
	40–49	32	24,547.77	130.36	23	69,293.14	33.19	19.729	4.30	2.34	7.89	<0.001***
	50–59	40	54,197.86	73.80	99	305,306.51	32.43	3.838	1.61	1.08	2.41	0.041*
	≧60	284	244,275.16	116.26	833	744,505.26	111.89	278.74	3.67	3.18	4.23	<0.001***
HTN	Without	216	196,821.62	109.74	677	823,506.35	82.21	184.95	3.36	2.85	3.99	<0.001***
	With	152	137,371.81	110.65	283	345,141.31	82.00	121.14	3.67	2.95	4.62	<0.001***
T2DM	Without	244	226,763.67	107.60	782	902,618.82	86.64	196.28	3.24	2.77	3.77	<0.001***
	With	124	107,429.76	115.42	178	266,028.84	66.91	99.19	3.98	3.08	4.85	<0.001***
HF	Without	338	302,066.10	111.90	936	1,085,462.92	86.23	265.05	3.29	2.87	3.76	<0.001***
	With	30	32,127.33	93.38	24	83,184.74	28.85	38.87	7.48	4.08	13.78	<0.001***
Stroke	Without	329	303,790.75	108.30	793	1,031,091.16	76.91	270.73	3.48	3.03	4.02	<0.001***
	With	39	30,402.68	128.28	167	137,556.50	121.40	28.67	2.99	2.06	4.35	<0.001***
COPD	Without	342	313,272.56	109.17	830	1,024,602.66	81.01	275.41	3.39	2.96	3.90	<0.001***
	With	26	20,920.87	124.28	130	144,045.00	90.25	27.73	3.45	2.23	5.32	<0.001***
Liver cirrhosis	Without	344	317,482.25	108.35	915	1,108,300.52	82.56	280.16	3.39	2.97	3.88	<0.001***
	With	24	16,711.18	143.62	45	60,347.14	74.57	24.31	4.12	2.42	7.03	<0.001***
Meniere's disease	Without	356	331,468.23	107.40	834	1,131,989.89	73.68	308.07	3.58	3.13	4.10	<0.001***
	With	12	2,725.20	440.33	126	36,657.77	343.72	1.69	1.64	1.01	3.12	0.047*
Aminoglycoside	Without	366	332,526.32	110.07	953	1,161,049.27	82.08	137.94	3.41	3.00	3.92	<0.001***
	With	2	1,667.11	119.97	7	7,598.39	92.12	134.65	3.33	2.83	3.83	<0.001***
Loop diuretics	Without	367	331,401.74	110.74	957	1,157,557.93	82.67	138.02	3.42	3.00	3.93	<0.001***
	With	1	2,791.69	35.82	3	11,089.73	27.05	135.29	3.39	2.96	3.86	<0.001***

PYs = Person-years; Rate: per 100,000 PYs; Adjusted HR (hazard ratio): Adjusted variables listed in the table; CI = confidence interval

*P < 0.05, **P < 0.01

***P < 0.001

We next focus our investigation on identifying and quantifying the multiplicative interaction of comorbidities on CKD. In Table 5, the highest Wald coefficient and adjusted HR were 49.34 and 7.69 in those with Meniere’s disease, 38 and 2.73 in those with stroke, 27.86 and 2.98 in those with liver cirrhosis, 22.57 and 2.6 in those with COPD, 18.16 and 2.37 in those with HTN, 9.39 and 1.92 in those with HF, and 3.8 and 1.31 in those with Type 2 DM, respectively (Table 5). Interestingly, we demonstrated that the interactions of comorbidities on CKD was significant for SNHL.

Table 5

Factors of sensorineural hearing loss by using Cox regression and Fine & Gray's competing risk model.

	No competing risk in the model					Competing risk in the model
	Wald	Adjusted HR	95% CI	95% CI	P	Wald	Adjusted HR	95% CI	95% CI	P
HTN × CKD	18.29	2.37	2.00	2.81	<0.001***	18.16	2.37	2.00	2.80	<0.001***
T2DM × CKD	4.01	1.32	1.01	1.73	0.045*	3.80	1.31	1.02	1.71	0.048*
HF × CKD	6.66	1.78	1.24	2.56	0.012*	9.39	1.92	1.34	2.76	0.005**
Stroke × CKD	32.18	2.52	1.83	3.47	<0.001***	38.00	2.73	1.99	3.76	<0.001***
COPD × CKD	19.27	2.39	1.62	3.53	<0.001***	22.57	2.60	1.74	3.79	<0.001***
Liver cirrhosis × CKD	23.16	2.70	1.80	4.05	<0.001***	27.86	2.98	1.99	4.46	<0.001***
Meniere's disease × CKD	54.84	8.59	4.86	15.15	<0.001***	49.34	7.69	4.35	13.58	<0.001***
Aminoglycoside × CKD	0.84	1.24	0.68	1.86	0.416	0.96	1.46	0.75	1.99	0.375
Loop diuretics × CKD	0.75	1.37	0.72	2.04	0.529	0.83	1.59	0.89	2.11	0.428

Adjusted HR (hazard ratio): Adjusted variables listed in Table 2; CI = confidence interval

*P < 0.05

**P < 0.01

***P < 0.001

Reference: Without

Discussion

In this study, a large cohort of patients with newly diagnosed CKD was evaluated for the relationship of developing SNHL. It was observed that the prevalence of CKD was 25% of patients receiving out-patient care, particularly in male ones. Additionally, CKD itself could be a critical role for developing SNHL. Moreover, organ crosstalk between CKD and several comorbidities such as Meniere’s disease, stroke, liver cirrhosis, COPD, hypertension, HF, and type 2 DM were found to increase the interaction of developing SNHL in patients with CKD.

CKD patients are more prone to develop SNHL, which results from the delayed conduction between the auditory nerve and pathway [17, 18]. Uremic toxins can cause serial damage in the cochlea [18-20]. The decrease in the adenosine triphosphatase sodium–potassium pump (Na+–K+–ATPase) activity [4] and amplitudes of cochlear potentials [21], and further reduction in velocity conduction in auditory nerve [22] leaded to hearing impairment. Furthermore, cochlear microcirculation plays an important role in cochlear physiology. Non-conventional risk factors such as chronic inflammation, oxidative stress, asymmetric dimethylarginine, sympathetic nerve hyperactivity, prothrombotic state, and hyperhomocysteinemia cause vascular injury and endothelial dysfunction in patients with CKD [23-25]. Although hemodialysis is a renal replacement therapy for uremia, it is a risk factor for developing SNHL [26]. Osmotic disequilibrium of endolymph, ischemia and subsequent reperfusion may lead to the hearing deficiency associated with dialysis [26, 27]. Because of severe CKD and influence of hemodialysis, the higher incidence of SNHL in CKD patients with hemodialysis was noticed. Notably, in this study, having CKD for longer time was associated with more significantly heightened incidence of developing SNHL (Fig 2). The similar findings were also noticed in patients with type 2 DM, cardiovascular diseases and COPD [28-36]. Time as a risk factor was also confirmed in CKD animal models, where the impairment of cochlear function was exacerbated over time [19, 37]. Furthermore, SNHL is also associated with tinnitus [21], as diminished output from the damaged cochlea causes an increased spontaneous activity in the dorsal cochlear nucleus [38, 39].

CKD patients often have multiple systemic dysfunctions such as cardiovascular, lung, liver, metabolic, brain, immune system, and chronic inflammation further resulting in various comorbidities [40-42]. Cardiovascular disease, type 2 DM and liver cirrhosis have been strongly considered as risk factors of CKD because of inflammation, ischemia, hemodynamic change, and the overactivity of renin–angiotensin–aldosterone and sympathetic nervous systems [43-50]. In recent studies, COPD may be another risk factor of CKD while it is a disease with irreversible airway obstruction and contributes to systemic inflammation that may induce vessel disease [51, 52]. Furthermore, there was significant risk of type 2 DM for SNHL [28-29]. There were higher values of HR in our patients with cardiovascular diseases such as stroke. Coronary artery disease was linked to the occurrence of SNHL [19, 30]. Cardiovascular disease may be an important factor of developing SNHL [30-34]. Recent reports presented the close relation between SNHL and COPD [35]. Additionally, smoking was a risk factor of SNHL in patients with COPD [36]. There was no study indicating the association between liver cirrhosis and SNHL. However, our result presented no significant correlation between them. In contrast, previous studies showed various effects of different causes of liver cirrhosis for SNHL such as hepatitis B and C increased the risk [53, 54], while a person with drinking alcohol habit had less chances [55]. (Table 2).

Our study highlighted the significant interaction of developing SNHL in patients with CKD and comorbidities such as stroke, liver cirrhosis, COPD, hypertension, HF, and type 2 DM (Table 5). Organ crosstalk is essential for maintaining physical homeostasis; however, dysfunction in one or more organs may lead to functional and structural pathological states in other organs. CKD may be a factor to aggravate the synergetic effect of developing SNHL in patients with other systemic diseases by inter-organ crosstalk, which may contribute to chronic inflammation, oxidative stress, and sympathetic nerve hyperactivity [43, 48, 50, 51, 54, 56]. The future research for underlying mechanism is necessary to preserve hearing function.

The strengths of this study are its population-based research, use of well-established cohort data with a large sample size, and extended follow-up period to identify CKD as a risk factor for developing SNHL. However, this study also has few limitations. Firstly, the lack of comparison for several possible other risk factors such as smoking history and noise exposure may create bias. Secondly, although NHIRD coding in recording diseases has been validated [12, 13], there is no data regarding laboratory and audiometry parameters for coding the accuracy and accessing the severity of diseases. Nevertheless, in an attempt to increase the validity of diagnosis, this study matched diagnosis to three indices and restricted the diagnosis of hearing loss by an otorhinolaryngologist only. The severity of CKD with and without hemodialysis for SNHL was identified (Table 3). However, the influence of the stage 1–5 of CKD on the degree and type (low or high frequency) of SNHL cannot be analyzed. Thirdly, there was an association between different routes of administration of loop diuretic and ototoxicity [57]. However, we were unable to compare the influence of oral and intravenous loop diuretic therapy since sequential intravenous-to-oral and oral-to-intravenous switch regimens were often used in clinical practice. Moreover, the other ototoxic drugs or genetic effects [58] that were not included may contribute bias. Finally, we did not investigate the underlying pathophysiological mechanism associating CKD with SNHL. Future work and analysis are needed to understand the occurrence of SNHL in this high-risk population.

Conclusion

This study revealed that the incidence of developing SNHL was higher in patients with CKD and that this incidence considerably increased with CKD duration. Having CKD with comorbidities increased the interaction of developing hearing loss. Based on our results, the future study of mechanism in this high-risk population is necessary to develop effective strategies of hearing protection. Collectively, these findings provide important and required insight into the relationship between SNHL and associated comorbidities in CKD patients.

20 Nov 2019

Submitted filename: 1081120 response to reviewers (PLOS ONE).docx

Click here for additional data file.

12 May 2020

PONE-D-19-29457

Investigation of the relationship between sensorineural hearing loss and associated comorbidities in patients with chronic kidney disease: a nationwide, population-based cohort study

PLOS ONE

Dear Dr. Hsiao,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

We would appreciate receiving your revised manuscript by Jun 25 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Natasha McDonald

Associate Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: No

Reviewer #3: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: In this paper the authors investigate the relationship between sensorineural hearing loss and associated

comorbidities in patients with chronic kidney disease.

The study is retrospective and population-based, and the number of enrolled subjects is the major strength.

However, some issues need to be clarified:

1. It is not clear why only few cardiovascular comorbidities were considered in the models. Authors recognize the importance of ischaemic events, but coronary heart disease, cardiac ischemia or myocardial infarction are not included. A possible explanation is that they are included in the CCI, but even in this case, including in a model such score together with the other comorbidities there is the risk of co-linearity. A possible explanation could be that all these variables have been removed to calculate CCI_R, but in this case it is not clear what this index contains. Please explain.

2. The author attest that CKD is the variable which influences the most the onset of sensorineural hearing loss, because the HR of CKD is higher than HRs of the other variables included in the model. However this is not totally true, as in order to score the importance of one variable the Wald coefficient must be taken into account. Please report this value in the tables.

3. Figure 2 reports Kaplan-Meier for cumulative risk of sensorineural hearing loss among patients aged 18 and over stratified by CKD with log-rank test in competing risk model. The end the curves are quite peculiar, as they look like a huge number of events occurred during last year of follow-up. Has proportionality of risk been assessed? Please explain. Secondly, it is possible to use a sort of K-M analysis to deal with competing risk (the name is cumulative incidence competing risk (CICR) method), but anyway log-rank test cannot be used to compare the curves (Verduijn M, Grootendorst DC, Dekker FW et al. The analysis of competing events like cause-specific mortality—beware of the Kaplan–Meier method. Nephrol Dial Transplant 2011; 26: 56–61; Bland JM, Altman DG. The logrank test. BMJ 2004; 328: 1073).

4. In table 3 it is not clear how models were built. It is confusing to have in the same table no CKD, CKD and CKD with/without haemodialysis. What has been compared to what?

5. At page 14, line 197, authors write “The increased values of adjusted HRs indicated synergetic effect of CKD and comorbidities for SNHL”. This is not the correct approach to understand if two variables act sinergically on a specific outcome, as the increase must be higher than the sum of HRs of the single variables (additive interaction) or that their product (multiplicative interaction). The easiest way to assess if a variable act on another one to determine a specific outcome is to introduce in the model a multiplicative term (i.e., if I want to assess the interaction between CKD and DM, I enter in the model CKD, DM and CKD*DM). I suggest to perform again the analysis by using this approach rather than a simple stratification.

Minor comments:

� I suggest to remove the word “matched” from the description of the cohort, as it evokes case-control studies and another type of analysis.

� In Table 2, please unify the columns of 95% CI

� It is not CKD which compete with the risk of death, but hearing loss.

Reviewer #2: General: The main reservation I have is that association does not necessarily imply causality, and while these associations may be regarded as statistically relevant and likely important, the authors have not demonstrated causality or proved that they are “risk factors”.

Lines 88-101 authors evaluate comorbidities to “identify the risk of developing SHML”. What the authors evaluated was statistical association; they have not evaluated or demonstrated causality, and therefore “risk factors”. This interpretation is repeated multiple times throughout the manuscript (line 114). In assessing the importance of comorbidities in SNHL it is important to identify statistical associations (which the authors did in this study); the next step is to identify possible causality (mechanisms of disease that can be acted upon); followed by intervention and prevention/therapy. This study can only claim the first step. There are well documented mechanisms why CKD can result in SNHL; mechanisms have not been evaluated for comorbidities and SNHL. Comorbidities were more common in the group with CKD; undoubtedly, SNHL will be statistically more common in patients who take the elevator to the CJD clinic; however, although it is a statistically significant association, the elevator to the clinic represents no causality on SNHL. It is true that comorbidities evaluated are a risk factor for CKD through many different mechanisms. In order to understand the role of comorbidities in the pathogenesis of SNHL it would be important to evaluate the presence of SNHL in patients with these comorbidities WITHOUT chronic kidney disease. The authors’ large database should provide this information. “Inter-organ cross talk” is a very vague definition that does not provide a well-defined pathogenetic mechanism.

Was there any correlation between the duration of comorbidities or their severity and SNHL?

Sentences in lines 240-241 should be rephrased and misspelling (controversal) corrected.

Sentences in lines 268-269 should be rephrased.

Lines 204-205 authors state It was observed that the incidence of CKD was 25%. What does this mean?

The authors evaluated the use of aminoglycosides and loop diuretics; what about use of other ototoxic drugs?

Why the authors evaluate monthly income, and was there any association?

Can the authors evaluate if there is an association between the severity of the chronic kidney disease and the presence of SNHL?

Specific: Lines 88 and 90: both the organs – should read: both organs.

Line 95 …have been showed… should read …have been shown…

Reviewer #3: Dear Authors,

Congratulations on a well written manuscript.

This is a well written paper on an increasingly recognised association between CKD and hearing loss. The sample size is quite large and despite retrospective nature, authors have used rigorous statistical methods including multivariate regression to adjust for confounders.

However, from an ENT perspective, I would be curious to know how the SNHL was classified in the patients (degree of hearing loss) and whether the association varied with the severity as well as the type (high vs low frequency) of SNHL. These factors might be important to the clinician.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Jishana Jamaldeen

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

29 Jun 2020

Response to Reviewer 1:

General comments

In this paper the authors investigate the relationship between sensorineural hearing loss and associated comorbidities in patients with chronic kidney disease. The study is retrospective and population-based, and the number of enrolled subjects is the major strength.

Remedy: We are grateful for your positive comments and careful reading of our manuscript. We have revised our manuscript according to your comments and the corresponding changes in the revised manuscript have been highlighted in red font. The itemized responses to your comments are below.

Major Comments:

Point 1. It is not clear why only few cardiovascular comorbidities were considered in the models. Authors recognize the importance of ischaemic events, but coronary heart disease, cardiac ischemia or myocardial infarction are not included. A possible explanation is that they are included in the CCI, but even in this case, including in a model such score together with the other comorbidities there is the risk of co-linearity. A possible explanation could be that all these variables have been removed to calculate CCI_R, but in this case it is not clear what this index contains. Please explain.

Remedy: We thank the valuable comment. The cardiovascular diseases are a group of disorders of the heart and blood vessels. We had analyzed the correlation between SNHL and cardiovascular diseases such as heart failure (HF), stroke and HTN in our study. The link between severity of coronary artery disease and degree of sensorineural hearing loss had been reported [30]. We revised the sentence, “There were higher values of HR in our patients with cardiovascular diseases such as stroke. Coronary artery disease was linked to the occurrence of SNHL [19,30]. Cardiovascular disease may be an important factor of developing SNHL [30-34].” (please see Discussion, Lines 243-246)

In Charlson Comorbidity Index (CCI), there are 19 indicators of 17 disease including myocardial infarction, congestive heart failure, peripheral vascular disease, CVA or TIA, dementia, COPD, connective tissue disease, peptic ulcer disease, liver disease, diabetes mellitus, hemiplegia, moderate to severe chronic kidney disease, solid tumor with or without metastasis, leukemia, lymphoma and AIDS. We used CCI_R after removing CKD, type 2 DM, CHF, stroke, COPD, and liver cirrhosis to evaluate the risk of developing SNHL. In our manuscript, “The 19 weighted indicators of 17 comorbidities were used to calculate the Charlson Comorbidity Index (CCI) [16]. The variables, including CKD, type 2 DM, HF, stroke, COPD, and liver cirrhosis, have been removed to calculate CCI_R.” (please see Materials and Methods, Lines 157-159)

Reference

30. Erkan AF, Beriat GK, Ekici B, Doğan C, Kocatürk S, Töre HF. Link between angiographic extent and severity of coronary artery disease and degree of sensorineural hearing loss. Herz. 2015;40:481-6.

Point 2. The author attest that CKD is the variable which influences the most the onset of sensorineural hearing loss, because the HR of CKD is higher than HRs of the other variables included in the model. However, this is not totally true, as in order to score the importance of one variable the Wald coefficient must be taken into account. Please report this value in the tables.

Remedy: We completely agree with this comment. We have added Wald coefficient in Tables 2-5 to score the influence of variables.

Point 3. Figure 2 reports Kaplan-Meier for cumulative risk of sensorineural hearing loss among patients aged 18 and over stratified by CKD with log-rank test in competing risk model. The end the curves are quite peculiar, as they look like a huge number of events occurred during last year of follow-up. Has proportionality of risk been assessed? Please explain. Secondly, it is possible to use a sort of K-M analysis to deal with competing risk (the name is cumulative incidence competing risk (CICR) method), but anyway log-rank test cannot be used to compare the curves (Verduijn M, Grootendorst DC, Dekker FW et al. The analysis of competing events like cause-specific mortality—beware of the Kaplan–Meier method. Nephrol Dial Transplant 2011; 26: 56–61; Bland JM, Altman DG. The logrank test. BMJ 2004; 328: 1073).

Remedy: We completely agree with this invaluable comment. Our study is a 10-year retrospective cohort study. We have made the corrections immediately and evaluated the risk of sensorineural hearing loss among patients aged 18 and over stratified by CKD with cumulative incidence competing risk (CICR) method and presented the results proportionally (Figure 2). The sentences were revised, “The cumulative incidence competing risk (CICR) method was used to estimate the difference in the risk of developing hearing loss between the CKD and comparison groups [15].” (Materials and Methods, line 154-156) and “The cumulative incidence competing risk (CICR) analysis indicated that patients with CKD had a significantly higher incidence of developing SNHL over time than comparison participants (p <.001) (Fig 2). “(please see Results, Lines 178-181)

Reference:

15. Verduijn M, Grootendorst DC, Dekker FW, Jager KJ, le Cessie S. The analysis of competing events like cause-specific mortality--beware of the Kaplan-Meier method. Nephrol Dial Transplant. 2011;26:56-61.

Figure 2. The cumulative incidence competing risk (CICR) method for the incidence of sensorineural hearing loss among patients aged 18 and over stratified by CKD (p <.001).

Point 4. In table 3 it is not clear how models were built. It is confusing to have in the same table no CKD, CKD and CKD with/without haemodialysis. What has been compared to what?

Remedy: We greatly appreciate this comment. The patients with CKD classified by ICD-9 included ones with ESRD who received hemodialysis and ones with CKD who did not receive hemodialysis. In previous study, hemodialysis is a risk factor for developing SNHL. Osmotic disequilibrium of endolymph, ischemia and subsequent reperfusion may lead to the hearing deficiency associated with dialysis. We aimed to evaluate this association. The advanced analysis was performed to differentiate it and presented in Table 3.

Point 5. At page 14, line 197, authors write “The increased values of adjusted HRs indicated synergetic effect of CKD and comorbidities for SNHL”. This is not the correct approach to understand if two variables act sinergically on a specific outcome, as the increase must be higher than the sum of HRs of the single variables (additive interaction) or that their product (multiplicative interaction). The easiest way to assess if a variable act on another one to determine a specific outcome is to introduce in the model a multiplicative term (i.e., if I want to assess the interaction between CKD and DM, I enter in the model CKD, DM and CKD*DM). I suggest to perform again the analysis by using this approach rather than a simple stratification.

Remedy: The authors thank to the valuable suggestion and amend our manuscript. The interaction of CKD and comorbidities for SNHL has been analyzed in Table 5. We amend our manuscript “We next focus our investigation on identifying and quantifying the multiplicative interaction of comorbidities on CKD. In Table 5, the highest Wald coefficient and adjusted HR were 49.34 and 7.69 in those with Meniere’s disease, 38 and 2.73 in those with stroke, 27.86 and 2.98 in those with liver cirrhosis, 22.57 and 2.6 in those with COPD, 18.16 and 2.37 in those with HTN, 9.39 and 1.92 in those with CHF, and 3.8 and 1.31 in those with Type 2 DM, respectively (Table 5). Interestingly, we demonstrated that the interactions of comorbidities on CKD was significant for SNHL.” (please see Results: Lines 198-202)

Minor comments

Point 1. I suggest to remove the word “matched” from the description of the cohort, as it evokes case-control studies and another type of analysis.

Remedy:

The authors thank to the valuable suggestion and we have removed “matched”. (please see Lines 102, 120, 146)

Point 2. In Table 2, please unify the columns of 95% CI

Remedy:

The authors thank to the valuable suggestion and unified the columns of 95% CI.

Point 3. It is not CKD which compete with the risk of death, but hearing loss.

Remedy: We greatly appreciate this comment. The sentence has been corrected that “We also performed a competing-risks regression (Fine-Gray model) because SNHL risk might compete with the risk of death” (please see Lines 152-154)

Last, we are deeply honored by the time and effort you spent in reviewing this manuscript. In reviewing and revising our manuscript, we are motivated to read more and thus learn more from your criticisms.

Response to Reviewer 2:

General comments:

The main reservation I have is that association does not necessarily imply causality, and while these associations may be regarded as statistically relevant and likely important, the authors have not demonstrated causality or proved that they are “risk factors”.

Remedy: We are grateful for your positive comments and careful reading of our manuscript. We have revised our manuscript according to your comments and the corresponding changes in the revised manuscript have been highlighted in red font. The itemized responses to your comments are below.

Major concerns:

Point 1. Lines 88-101 authors evaluate comorbidities to “identify the risk of developing SHML”. What the authors evaluated was statistical association; they have not evaluated or demonstrated causality, and therefore “risk factors”. This interpretation is repeated multiple times throughout the manuscript (line 114). In assessing the importance of comorbidities in SNHL it is important to identify statistical associations (which the authors did in this study); the next step is to identify possible causality (mechanisms of disease that can be acted upon); followed by intervention and prevention/therapy. This study can only claim the first step. There are well documented mechanisms why CKD can result in SNHL; mechanisms have not been evaluated for comorbidities and SNHL. Comorbidities were more common in the group with CKD; undoubtedly, SNHL will be statistically more common in patients who take the elevator to the CKD clinic; however, although it is a statistically significant association, the elevator to the clinic represents no causality on SNHL. It is true that comorbidities evaluated are a risk factor for CKD through many different mechanisms. In order to understand the role of comorbidities in the pathogenesis of SNHL it would be important to evaluate the presence of SNHL in patients with these comorbidities WITHOUT chronic kidney disease. The authors’ large database should provide this information. “Inter-organ cross talk” is a very vague definition that does not provide a well-defined pathogenetic mechanism.

Remedy: We fully agreed your concern. The correlations between CKD and associated comorbidities had been reported in previous studies. The relation of hearing loss and CKD and other systemic diseases had also been demonstrated. We have designed the advanced study to investigate the relationship of hearing loss in patients with CKD and associated comorbidities. Taiwan NHIRD was used as the database. We avoided to use “risk” in our results. The multiplicative interaction of comorbidities on CKD for hearing loss revealed statistical significance of increased adjusted HRs in Table 5. “Inter-organ cross talk” between kidney and other organs may be a mechanism for this issue, but more research and analysis are needed to understand the occurrence of SNHL in this high-risk population. We have revised the paragraph, “Our study highlighted the significant interaction of developing SNHL in patients with CKD and comorbidities such as stroke, liver cirrhosis, COPD, hypertension, HF, and type 2 DM (table 5). Organ crosstalk is essential for maintaining physical homeostasis; however, dysfunction in one or more organs may lead to functional and structural pathological states in other organs. CKD may be a factor to aggravate the synergetic effect of developing SNHL in patients with other systemic diseases by inter-organ crosstalk, which may contribute to chronic inflammation, oxidative stress, and sympathetic nerve hyperactivity [43,48,50,51,54,56]. The future research for underlying mechanism is necessary to preserve hearing function. “ (please see Discussion: Lines: 254-262)

Point 2. Was there any correlation between the duration of comorbidities or their severity and SNHL?

Remedy: Thank you for your suggestion. We focused on the influence of CKD with comorbidities. The correlation between duration of CKD and hearing loss was analyzed in our studies. In previous studies, the significant result of the duration of comorbidities in SNHL had been demonstrated [1-8]. In National Health Insurance database (NHIRD) of Taiwan, there is no data regarding laboratory and audiometry parameters for accessing the severity of diseases. The influence of the severity of diseases on the severity and type (low or high frequency) of SNHL cannot be analyzed. Nevertheless, in an attempt to evaluate the severity of CKD for SNHL, CKD with and without hemodialysis for SNHL were analyzed in Table 3. We amend the sentences “Because of severe CKD and influence of hemodialysis, the higher incidence of SNHL in CKD patients with hemodialysis was noticed.” (please see Discussion: Lines: 225-227), “Notably, in this study, having CKD for longer time was associated with more significantly heightened incidence of developing SNHL (Figure 2). The similar findings were also noticed in patients with type 2 DM, cardiovascular diseases and COPD [28-36].” (please see Discussion: Lines: 227-230), and “Secondly, although NHIRD coding in recording diseases has been validated [12,13], there is no data regarding laboratory and audiometry parameters for coding the accuracy and accessing the severity of diseases. Nevertheless, in an attempt to increase the validity of diagnosis, this study matched diagnosis to three indices and restricted the diagnosis of hearing loss by an otorhinolaryngologist only. The severity of CKD with and without hemodialysis for SNHL was identified (Table 3). However, the influence of the stage 1-5 of CKD on the degree and type (low or high frequency) of SNHL cannot be analyzed.” (please see Discussion: Lines: 267-275)

1. Sterling MR, Lin FR, Jannat-Khah DP, Goman AM, Echeverria SE, Safford MM. Hearing Loss Among Older Adults With Heart Failure in the United States: Data From the National Health and Nutrition Examination Survey. JAMA Otolaryngol Head Neck Surg. 2018;144:273-5.

2. Schade DS, Lorenzi GM, Braffett BH, Gao X, Bainbridge KE, Barnie A, et al. Hearing Impairment and Type 1 Diabetes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Cohort. Diabetes Care. 2018;41:2495-501.

3. Helzner EP, Contrera KJ. Type 2 Diabetes and Hearing Impairment. Curr Diab Rep. 2016;16:3.

4. Sterling MR, Silva AF, Charlson ME. Sensory Impairments in Heart Failure-Are We Missing the Basics?: A Teachable Moment. JAMA Intern Med. 2018;178:843-44.

5. Agrawal Y, Platz EA, Niparko JK. Prevalence of hearing loss and differences by demographic characteristics among US adults: data from the National Health and Nutrition Examination Survey, 1999-2004. Arch Intern Med. 2008;168:1522-30.

6. Gates GA, Cobb JL, D'Agostino RB, Wolf PA. The relation of hearing in the elderly to the presence of cardiovascular disease and cardiovascular risk factors. Arch Otolaryngol Head Neck Surg. 1993;119:156-61.

7. Arash Bayat, Nader Saki, Soheila Nikakhlagh, Golshan Mirmomeni, Hanieh Raji, et al. Is COPD associated with alterations in hearing? A systematic review and meta-analysis. Int J Chron Obstruct Pulmon Dis. 2019;14:149-62.

8. Kamenski G, Bendova J, Fink W, Sönnichsen A, Spiegel W, Zehetmayer S. Does COPD have a clinically relevant impact on hearing loss? A retrospective matched cohort study with selection of patients diagnosed with COPD. BMJ Open. 2015;5:e008247.

Point 3. Sentences in lines 240-241 should be rephrased and misspelling (controversal) corrected.

Remedy: We revised these sentences, “However, our result presented no significant correlation between them. In contrast, previous studies showed various effects of different causes of liver cirrhosis for SNHL such as hepatitis B and C increased the risk [53,54], while a person with drinking alcohol habit had less chances [55]. (Table 2).” (please see Discussion: Lines 249-253)

Point 4. Sentences in lines 268-269 should be rephrased.

Remedy: Thank your suggestion. We revised this sentence,” Future work and analysis are needed to understand the occurrence of SNHL in this high-risk population.

” (please see Discussion: Lines 281-282)

Point 5. Lines 204-205 authors state It was observed that the incidence of CKD was 25%. What does this mean?

Remedy: Thank you for the reminder. In our study, the prevalence of CKD was 25% of patients receiving out-patient care which was higher than 13-15% of general population. We corrected it “It was observed that the prevalence of CKD was 25% of patients receiving out-patient care, particularly in male ones.” (please see Discussion: Lines 207-208)

Point 6. The authors evaluated the use of aminoglycosides and loop diuretics; what about use of other ototoxic drugs?

Remedy: Thank your command. In patients with CKD, aminoglycoside and loop diuretics are commonly used to control infection and fluid status, so we tried to evaluate the effect. However, other ototoxic drugs were not included in our study. So, we added the sentence that “Moreover, the other ototoxic drugs or genetic effects that were not included may contribute bias.” in the limitation of discussion.

(please see Discussion: Lines 277-278)

Point 7. Why the authors evaluate monthly income, and was there any association?

Remedy: Thank your suggestion. The insured premium of National Health Insurance Program was set by our government according to monthly income. Higher incurred premium means higher social-economic level in Taiwan. The acceptable burden of insured premium was designed to cover medical expenses of more than 99% of the 23 million inhabitants. Our study reviewed the similar socio-economic distribution in patients with CKD and without CKD. We revised it, “The covariates of gender, age groups (18–29, 30–39, 40–49, 50–59, ≥60 years), and insured premium [in New Taiwan Dollars; <18,000, 18,000–34,999, ≥35,000] were analyzed.” (please see Materials and Methods: Lines 137-139)

Point 8. Can the authors evaluate if there is an association between the severity of the chronic kidney disease and the presence of SNHL?

Remedy: Thank your suggestion. The ICD-9 code of disease was recorded in NHIRD. The stage 1-5 of CKD and severity and type of hearing loss could not be evaluated in our study. However, the severity of CKD with and without hemodialysis was identified to evaluate the influence of SNHL in Table 3. We descripted this issue in discussion, “Because of severe CKD and influence of hemodialysis, the higher incidence of SNHL in CKD patients with hemodialysis was noticed.” (please see Discussion: Lines: 225-227), and “Secondly, although NHIRD coding in recording diseases has been validated [12,13], there is no data regarding laboratory and audiometry parameters for coding the accuracy and accessing the severity of diseases. Nevertheless, in an attempt to increase the validity of diagnosis, this study matched diagnosis to three indices and restricted the diagnosis of hearing loss by an otorhinolaryngologist only. The severity of CKD with and without hemodialysis for SNHL was identified (Table 3). However, the influence of the stage 1-5 of CKD on the degree and type (low or high frequency) of SNHL cannot be analyzed.” (please see Discussion: Lines: 267-275)

Point 9. Specific: Lines 88 and 90: both the organs – should read: both organs.

Remedy: Thank your suggestion. We made the corrections immediately. (please see Discussion: Lines 88 and 90)

Point 10. Line 95 …have been showed… should read …have been shown…

Remedy: Thank your suggestion. We made the corrections immediately. (please see Discussion: Line 95)

Last, I am deeply honored by the time and effort you spent in reviewing this manuscript. In reviewing and revising our manuscript, I was motivated to read more and thus learn more from your criticisms.

Response to Reviewer 3:

General comments

Dear Authors,

Congratulations on a well written manuscript.

This is a well written paper on an increasingly recognised association between CKD and hearing loss. The sample size is quite large and despite retrospective nature, authors have used rigorous statistical methods including multivariate regression to adjust for confounders.

Remedy: We are grateful for your positive comments and careful reading of our manuscript. We have revised our manuscript according to your comments and the corresponding changes in the revised manuscript have been highlighted in red font. The itemized responses to your comments are below.

Major Comments:

Point 1. However, from an ENT perspective, I would be curious to know how the SNHL was classified in the patients (degree of hearing loss) and whether the association varied with the severity as well as the type (high vs low frequency) of SNHL. These factors might be important to the clinician.

Remedy: We thank the valuable comment. In NHIRD, the ICD-9 code of disease was recorded without parameters of laboratory examination and audiometry. The association of stage 1-5 of CKD and severity and type of hearing loss could not be evaluated in our study. However, the severity of CKD with and without hemodialysis was identified to evaluate the influence of SNHL in Table 3. We descripted this issue in discussion, “Because of severe CKD and influence of hemodialysis, the higher incidence of SNHL in CKD patients with hemodialysis was noticed.” (please see Discussion: Lines: 225-227), and “Secondly, although NHIRD coding in recording diseases has been validated [12,13], there is no data regarding laboratory and audiometry parameters for coding the accuracy and accessing the severity of diseases. Nevertheless, in an attempt to increase the validity of diagnosis, this study matched diagnosis to three indices and restricted the diagnosis of hearing loss by an otorhinolaryngologist only. The severity of CKD with and without hemodialysis for SNHL was identified (Table 3). However, the influence of the stage 1-5 of CKD on the degree and type (low or high frequency) of SNHL cannot be analyzed.” (please see Discussion: Lines: 267-275)

Last, I am deeply honored by the time and effort you spent in reviewing this manuscript. In reviewing and revising our manuscript, I was motivated to read more and thus learn more from your criticisms.

Submitted filename: 1090625 plos one response to reviewers.docx

Click here for additional data file.

27 Aug 2020

Investigation of the relationship between sensorineural hearing loss and associated comorbidities in patients with chronic kidney disease: a nationwide, population-based cohort study

PONE-D-19-29457R1

Dear Dr. Hsiao,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

CLAUDIA TORINO

Guest Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #4: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #4: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #4: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #4: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #4: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Dear authors, I thank you to have carefully addressed all the raised issues. I have no further comments.

Reviewer #4: Dear authors,

Thank you for your efforts. All points were tackled in a professional way. You answered all comments by reviewers and the current version of the manuscript is better to e considered for publication

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #4: No

3 Sep 2020

PONE-D-19-29457R1

Investigation of the relationship between sensorineural hearing loss and associated comorbidities in patients with chronic kidney disease: a nationwide, population-based cohort study

Dear Dr. Hsiao:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. CLAUDIA TORINO

Guest Editor

PLOS ONE