Audiological findings in patients submitted to kidney transplant

Purpose: To investigate the auditory behavior of patients with chronic renal failure (CRF) undergoing kidney transplantation. Methods: Thirty patients were evaluated, 10 (33.33%) females and 20 (66.67%) males, aging from 13 to 26 years (average, 16.97 years; standard deviation, 3.60 years). Patients underwent the following procedures: anamnesis, otolaryngological examination, audiological evaluation (pure tone and high frequency), acoustic impedance measurements and central auditory processing evaluation. A control group was used to compare the high-frequency audiometry results. Results: The following observations were made: absence of auditory complaints at the time of anamnesis; pure-tone audiometry was predominantly normal; patients presented lower hearing levels at the high-frequency audiometry, when compared to the control group, and as for the acoustic impedance measurements, curves of the type A were predominant; there was a change of the central auditory processing for 14 patients (46.67%) in the Staggered Spondaic Word Test (SSW); there was a significant difference between the age variable and the result of the pure-tone audiometry, that is, hearing sensitivity in thresholds from 250Hz to 8,000Hz decreased with advancing age; and the relation between the type of donor and the SSW test result was significant. Rates were higher when the patients had been transplanted from deceased donors compared to living donors. Conclusion: There were no changes in conventional audiological and high-frequency evaluation, or in the central auditory processing. Professionals involved in the care of kidney transplantation recipients must be better informed about the care, prevention, and early identification of auditory disorders.


INTRODUCTION
Chronic renal failure (CRF) is a silent disease that causes slow, progressive, and irreversible loss of the kidney functions (1) .Nowadays, it is considered to be a public health problem.The number of patients undergoing dialysis in Brazil has doubled in the past nine years, and the incidence of new cases increases by 8% per year (2) .Data from the 2011 survey by the Brazilian Society of Nephrology (SBN) showed that 91.314 patients -out of 192,38 million inhabitants in Brazil -were under dialysis treatment (3) .Early diagnosis is important to delay the progression of the disease, to prevent complications and comorbidities, and to adequately prepare renal replacement therapy (2) .
Hearing loss has been identified in renal patients since the past century.Alport (1) suggested, in 1927, a classic genetic syndrome connecting hearing impairment with renal failure.Later on, patients who developed renal failure and did not meet the genetic basis were shown to have hearing loss from unknown causes in different stages of the disease.Some authors (4) have observed that large numbers of hemodialysis(HD) sessions or repeated kidney transplants may result in electrolyte, biochemical, immunological, osmotic, and vascular changes that may disturb the function of the inner ear.These changes may cause hearing symptoms, such as loss of perception of treble frequencies, and vestibular symptoms or even cause hearing loss over the course of the disease.
Ototoxic medications -the aminoglycoside antibiotics being the most common ones -are likely to cause irreversible damage to the hair cells of the spiral organ (5) .Cell damage is related to complex substances formed in the reaction between the drug and the cell membrane phosphoinositides (6) .
The kidney and the cochlear duct have microscopic anatomical similarities, as well as comparable physiologic, immunological, and pathological behaviors.The renal glomerulus as much as the tubules are similar to the stria vascularis, an epithelial structure directly related to the vascular system; therefore, nephrotoxic drugs may also be ototoxic (6) .The cochlear duct has been shown to be vulnerable to such drugs by functional and morphological studies.Its basis is affected first, which causes hearing loss starting from high frequencies.The monitoring of hearing function aimed at early detection of high-frequency hearing loss during ototoxic treatment allows for the identification of the ototoxicity progression since its onset (7) .
Moreover, the professionals involved in the kidney transplant recipient's care must be familiar with the handling, prevention, and early identification of hearing impairment, as well as with the consequences of the ototoxic treatment, the secondary diseases and the exposure to noise, factors that can cause or worsen hearing loss.Audiological follow-up must be performed to ensure early identification of any alteration.
The purpose of this paper is to analyze the hearing function behavior of CRF patients submitted to kidney transplantation.

METHODS
This study has been approved by the Ethics Committee of Hospital Pequeno Príncipe, protocol number 0715-09, and all participants or caregivers signed the informed consent.
Thirty patients were assessed in the Research Group, RG (10 females, 33.33%, and 20 males, 66.67%, aging from 13 to 26 years -mean age= 16.97 years; SD= 3.6 years), all of them presenting CRF with different causes and having been submitted to kidney transplantation.They were all referred from Hospital Pequeno Príncipe to the branch of Otoneurology at Universidade Tuiuti do Paraná, Curitiba (PR), Brazil.
Patients receiving kidney transplants were enrolled in the study regardless of CRF cause, time of disease, time or type of previous treatment, and type of organ donor.All of them had been transplanted for at least five months and at most 13 years.Patients presenting psychological, visual, or musculoskeletal disturbances that could hinder the examinations, as well as those with ear diseases and under the age of 13, were excluded from the study.
The sample included patients whose length of dialysis treatment prior to transplant ranged from one to 13 years (mean=6.77years; SD=3.80 years).Eight patients had been through peritoneal dialysis (PD), 17 to HD, and five to both modalities.
Twenty-one patients had received transplants from living donors and nine from deceased donors, but the time between the death of the donor and the transplantation was not indicated on the medical records.
The length of hospital stay ranged from five to 120 days (mean=26.60days; SD=27.41 days), and the time of transplant varied from six months to nine years (mean=4.87;SD=2.37 years).
All patients selected were then submitted to anamnesis, otolaryngological and audiological evaluation, acoustic immittance, and central auditory processing testing.

Anamnesis
A questionnaire comprising audiological signs and symptoms and family and personal history -based on the anamnesis protocol used by the Otoneurology Service -was applied to all participants.Information was, therefore, obtained from the participants' or caregivers' responses and from medical reports.

Otolaryngological evaluation
This was performed by an otolaryngologist, aimed at excluding alterations that could interfere in certain tests.

Audiological evaluation
Patients were submitted to Pure-Tone Threshold Audiometry at 250-8 kHz by air conduction and at 500-4 kHz by bone conduction, and also to Speech Reception Threshold (SRT) and Speech Discrimination (SD) testing.All tests were performed in acoustically treated rooms to prevent interference from outside noises.An Itera Madsen GN Otometrics ® audiometer was used, gauged according to ISO 8253 standards, equipped with TDH-39 earphones and set by dBNA threshold levels.Some criteria were used to characterize the degree and type of hearing loss (8) .
Afterward, hearing thresholds were assessed at high frequencies (9-16 kHz) with the use of Koss ® HV/PRO earphones.For the purpose of comparison, we used a control group from a previous study (9) which held 25 patients -11 females (44%) and 14 males (56%), aging 10 to 28 years old (mean=14.40years; SD=4.06 years).

Acoustic immittance testing
This was performed to evaluate the eardrum and the ossicular chain by assessing the tympanometric curve and the acoustic reflex.Otoflex impedance meter with TDH 39P earphones was used, and some criteria were used to interpret the results (10) .

Patients underwent the Staggered Spondaic Word Test (SSW) and the Random Gap Detection Test (RGDT).
SSW is composed of 40 items subdivided into four groups of 10 items each.The first and the fourth groups are applied separately to each ear, that is, without conflict, while the second and third groups are applied to both ears simultaneously.Therefore, the test has four conditions: competitive right (CR), competitive left (CL), non-competitive right (NCR), and non-competitive left (NCL).There is an interval between conditions which allows for the patient's verbal response.SSW was applied according to criteria proposed by authors (11) , and the stimulus used in conduction was at 50 dBNS, the tritone average.Normality standard was set at 90%.
The RGDT consists of pure-tone pairs at the frequencies of 500 Hz, 1, 2, and 4 kHz, with interval between tones ranging from 0 to 40 ms (0, 2, 5, 10, 15, 20, 25, 30, or 40 ms) and of 4.5 ms between stimuli for patient's response.The intervals between sound stimuli are random, and the procedure is repeated for each frequency.
In all subtests, patients were informed that they would hear two very similar sounds and should raise one of their finger upon hearing one sound stimulus and two fingers upon hearing two sound stimuli.The test was presented at 50 dBNS in the frequencies tested in binaural conditions.The result corresponded to the shorter interval at which the patient started identifying two stimuli, being calculated for each frequency tested.The test was carried out in compliance with criteria proposed in previous studies (12) .

Statistical analysis
The Fisher's exact test was used to analyze the association between variables -gender, age, length and type of treatment before transplant, type of donor, length of hospital stay post-transplantation, and time elapsed since transplant -and the results.The level for null hypothesis rejection was set at 0.05 or 5%.
Tests comprising quantitative variables (age, length of treatment time elapsed since transplant and length of hospital stay after transplantation) were given two response categories in order to enable statistical analysis, as summarized in tables.Finally, the Mann-Whitney test was used to compare threshold values.

RESULTS
Nobody from the study group had hearing complaints at anamnesis.
Fourteen patients (46.67%) presented alterations at audiometry and SSW testing, out of which five (16.67%) had unilateral changes and nine (30%) bilateral; 16 patients (53.33%) had normal results.The most common change found at audiometry was lowering in the perception of the 6-8 kHz frequency range.At RGDT, two patients (6.67%) presented alterations and 28 patients (93.33%) were normal.At immittance testing, 20 patients (66.67%) had type A tympanometric curve for both ears, nine (30%) had type As tympanometric curve for both ears, and one patient (3.33%) had type Ad tympanometric curve for both ears.No difference was observed between the variable gender and the pure-tone audiometry tests (p=0.0632 for unilateral changes and p=0.1557 for bilateral changes), the SSW testing (p=0.4499 for unilateral changes and p=0.2871 for bilateral changes), and RGDT (p=0.4368).
The relation between age and bilateral changes at pure tone audiometry was considered to be significant.Patients under the age of 17 presented fewer changes than those above this age (Table 1).We found no association of the length of dialysis treatment with audiological changes in transplant recipients (Table 2).
Regarding the length and type of treatment prior to transplantation, no significant differences were found, that is, regardless of the length and type of treatment, changes may occur in audiological exams at the same proportion (Table 3).
The Fisher's exact test showed a relation between the type of donor and bilateral changes at SSW testing (Table 4).
Descriptive results of hearing thresholds at high frequencies in both study and control groups are summarized in Table 5. Figures 1 and 2 show the comparison between mean high-frequency thresholds for both groups with regard to right and left ears, respectively.There was a significant difference between groups as to thresholds at 11.2 kHz (p=0.0456) and 16 kHz (p=0.0211) in the right ear and at 9 kHz (p=0.0074) and 11.2 kHz (p=0.0204) in the left ear.
When considering the gender, groups presented differences at 16 kHz (p=0.0328) in right ears for males, at 10 kHz (p=0.0305) and 11.2 kHz (p=0.0403) in right ears for females, and at 9 kHz (p=0.0131) in left ears also for females.

DISCUSSION
CRF patients are likely to present hearing signs and symptoms.In this paper, none of the studied patients had complaints though.Some authors (4,6) have stated that these patients report otologic symptoms such as tinnitus, dizziness, and hypoacusis.In the literature reviewed, the authors do not mention the patient's length of hospital stay, so it was not possible to make a comparison in this regard with the data obtained from the present study.Some papers (13)(14)(15)(16)(17) show that hearing loss is diagnosed in 7.60%-87.30% of patients with renal failure, which is in agreement with our data.It is believed that the causes of hearing loss in CRF patients is associated with extrinsic factors, such as ototoxic side-effects of uremia; ototoxic medications (14,17) ; degree of hyponatremia (13) ; exposure to noises; presbycusis; mumps; inherited dysacusis (14) ; exogenous and endogenous factors (6) ; multifactors (18,19) ; Alport syndrome; age and exposure to noise; vascular, electrolytic, and metabolic alterations; metabolic alterations secondary to renal failure and comprising hair cells; plasma viscosity; use of gentamicin in high-frequency hearing loss; endolymphatic hydrops in low frequency; and length of treatment (13)(14)(15) .
A study (20) reported that hearing loss is neither related to the use of ototoxic medications nor to inherited nephritis and that such loss cannot be reversed with improvement of uremia.Another study (17) stated that the cause is unknown; thus, so it can be attributed to both CRF or HD.It is known that the kidney and the cochlear duct share some antigens; therefore, an autoimmune defect can occur.There are microscopic similarities in anatomy and in physiological, immunological, and pathological behavior of these organs, which suggests that a possible defect in electrolyte transport across cell membranes could be the cause of hearing loss (6,13) .
In our study, we could not establish a relation between hearing loss and its possible causes in the group holding 30 kidney transplant recipients.Although we have observed a higher frequency of hearing impairment in patients above the age of 17, it could be associated with many factors other than age.
The studied sample presented alterations at central auditory processing evaluation.The auditory processing disorder (APD) is known to be an alteration in the group of specific auditory abilities on which individuals depend to discriminate what they hear..Legend: RE = right ear; LE = left ear; SD = standard deviation.
Legends: CG = control group; SG = study group We found no published study about the abilities of the auditory processing.A study comprising the cognitive aspect concluded that that P300 was able to evaluate the cognitive function of CRF patients -even asymptomatic ones -and showed that PD can be a better treatment when it comes to prevention of cognitive impairments as compared to HD (21) .Some authors (22) showed a significant delay in the latency of the I, III, and V waves and I-III and I-V interpeaks in the auditory steady state on the brainstem of CRF patients, which demonstrates central and peripheral involvement on the central nervous system (CNS).
The alteration found in SSW testing were related to difficulty in figure ability and binaural integration, that is, CRF patients struggled to receive and recognize information in both ears.This difficulty may onset in cases of pathologies involving the brainstem and connections.The CNS structures responsible for this ability are olivary complex, which is linked to both ears and compares sound characteristics between them, and the auditory brain cortex, which uses the differences in intensity and time of information reception to determine where the sound comes from (23) .
In the present study, all participants with complaint of hearing impairment also presented changes in audiometry.Authors (24) have reported that hearing loss cannot be considered determining to alterations in the hearing process, although it is a worsening factor.From this study, we can infer that central alterations could well be consequences of the hearing loss and of extrinsic and intrinsic factors.
The present study has reinforced the results of previous ones (13,22) that did not find correlations between audiometric findings and gender.The association of age with pure-tone audiometry, however, was significant: patients under 17 years were shown to have fewer alterations than those above 17 years.These data agree with the study by Yassin et al. (13) and disagree with that by Jakic et al. (19) .Other authors (7) have reported significant differences in the hearing thresholds regarding age, where there is a gradual worsening in the hearing perception of high frequencies along with aging.
We did not find a correlation between the type of treatment prior to transplant and audiological results, which agrees with data from other studies as to type (17) and time (16,18,25) of treatment.Another study (26) reported a higher prevalence of hearing loss among patients who received dialysis treatment for longer periods, even though it was not significant in comparison with other groups of patients.A study also reported an association between the time of renal disease and auditory threshold (27) .According to Oda et al. (4) , 37.5% of their sample of patients who had undergone more than 264 HD sessions or had been transplanted presented auditory and vestibular symptoms; on the other hand, patients who had undergone less than 59 sessions had no hearing impairment.
A previous study (18) reported 75% of CRF patients without any auditory changes along a 4-year follow-up.In another research (28) that considered the period of 6-26 months for the normalization of blood chemical parameters, a regression of the hearing loss was found.
In the present study, the relation between time elapsed from the transplantation and the pure-tone audiometry, SSW, and RGDT was not significant.However, other studies (29) stated the need for otologic follow-up for transplant recipients, for they use immunosuppressant medications (such as cyclosporine A and corticosteroids) that may cause changes in plasma viscosity and in the inner ear vascular system.
The effect of kidney transplant on the hearing function is controversial.It has been suggested that kidney transplant initially improves the hearing ability, but, in the long term, it worsens it (28) .Some authors reported no improvement in the hearing function after kidney transplantation (29) , while others stated that it resulted in improvement or stabilization of hearing loss (22) .
According to Alves and Ribeiro (30) , stabilization or even slower progression of hearing loss is deemed understandable after kidney transplantation, since the hearing loss results from changes in basal membranes because of the damage caused to type IV collagen, their main constituent.
The association between the type of donor -living or deceased -and SSW, results was significant.The rate of changes in function was higher in cases of deceased donors, but there are no data in the literature to support this finding.
Moreover, the association between length of hospital stay after transplantation and pure-tone audiometry, SSW, and RGDT results was not significant.The literature reviewed could not support or confront this finding either.
At audiometry, we found a worsening of high-frequency thresholds in the study group when compared to the control group.The literature attests that high-frequency audiometry is an important resource for early diagnosis of hearing loss as much as for function monitoring.Some studies (7,16,29) reported alterations in the examination of CRF patients and reinforce the importance of high-frequency audiometry for the early detection of ototoxicity.
A previous research (16) reported that all individuals presenting hearing loss at pure-tone threshold audiometry also presented low thresholds at high-frequency audiometry.Our study corroborates these findings, although the results of highfrequency audiometry have been shown lower among patients with normal pure-tone audiometry results.
Histological studies have shown that hearing impairment starts from the basis of the cochlear duct and progresses to its apex; thus the hearing loss is initially identified at higher frequencies.Therefore, auditory monitoring at high frequencies may detect ototoxicity before the frequencies of conventional audiometry are affected (15) .
Finally, high-frequency audiometry is important for auditory monitoring in patients under ototoxic treatment (chemotherapeutic or renal function conservation drugs) and aims to prevent permanent hearing impairment; many studies (6,7,29) reinforce the clinical importance of this test for this purpose.

CONCLUSION
The investigation of hearing behavior in kidney transplant recipients shows function impairment.Conventional audiological evaluation at high frequencies and central auditory processing evaluation have shown evidence of changes; thus, there is a need to orient the professionals involved in the care of CRF patients who underwent kidney transplantation as to management, prevention, and early diagnosis of audiological changes.
*KFKDA was responsible for the data collection, bibliographical research, and writing; BSZ assisted in the data collection, bibliographical research, and final review; PBNL assisted in the bibliographical research, writing, and final review; LCS assisted in the writing and final review; ALJ assisted in the writing and final review; JMM assisted in the writing, statistical analysis (descriptive and analytical).

Figure 1 . 2 .
Comparison of high frequency thresholds between groups as to the right ear.Legends: CG = control group; SG = study group Figure Comparison of high frequency thresholds between groups as to the left ear.

Table 1 .
Audiological findings in kidney transplant recipients Association between age and threshold tonal audiometry results in Staggered Spondaic Word and Random Gap Detection tests for kidney transplant recipients

Table 2 .
Association between time of dialysis treatment and the results of threshold tonal audiometry results in Staggered Spondaic Word and Random Gap Detection tests for kidney transplant recipients

Table 3 .
Association between type of dialysis treatment and threshold tonal audiometry results in Staggered Spondaic Word and Random Gap Detection tests for kidney transplant recipients

Table 4 .
Association between the type of donor and threshold tonal audiometry results in Staggered Spondaic Word and Random Gap Detection tests for kidney transplant recipients Fisher's exact test (p≤0.05).Only two treatment modalities were considered: peritoneal dialysis and hemodialysis (most common ones).Legend: Unilateral = unilateral changes; Bilateral = bilateral changes Fisher's exact test (p≤0.05).Legend: Unilateral = unilateral changes; Bilateral = bilateral changes *Significant values (p≤0.05)-Fisher'sexact test.Legend: Unilateral = unilateral changes; Bilateral = bilateral changes