Objectives: Renal transplant provides a long-term survival. Hearing impairment is a major factor in subjective health status. Status of hearing and the cause of hearing impairment in the pediatric renal transplant group have not been evaluated. Here, we studied to evaluate hearing status in pediatric renal transplant patients and to determine the factors that cause hearing impairment.
Materials and Methods: Twenty-seven pediatric renal transplant recipients were investigated. All patients underwent audiologic assessment by means of pure-tone audiometry. The factors on hearing impairment were performed.
Results: Sensorineural hearing impairment was found in 17 patients. There was marked hearing impairment for the higher frequencies between 4000 and 8000 Hz. Sudden hearing loss developed in 2 patients, 1 of them had tinnitus. Decrease of speech understanding was found in 8 patients. The cyclosporine level was significantly high in patients with hearing impairment compared with group without hearing impairment. Cyclosporine levels also were found to be statistically significantly high when compared with the group with decrease of speech understanding and the group without decrease of speech understanding. Similar relations cannot be found between tacrolimus levels and hearing impairment and speech understanding.
Conclusions: Sensorineural hearing impairment prevalence was high in pediatric renal transplant recipients when compared with the general population of children. Cyclosporine may be responsible for causing hearing impairment after renal transplant. We suggest that this effect is a dose-dependent toxicity.
Key words : Hearing impairment, Speech understanding, Audiometry
One of the major goals of the health care is to offer the best quality of life to patients. Renal transplant allows a more children normal life. Hearing impairment is a major factor in the subjective perception of health status. It may have an important effect on social and academic life. Our knowledge about the effects of renal transplant on hearing impairment is limited.
Hearing impairment among patients with chronic renal failure is a common finding in a study investigating the effects of renal failure on auditory function. Ototoxic, congenital, and genetic hearing impairments were more common.1 In a study, hearing impairment prevalence was 41.3% in children with chronic renal failure.2 Status of hearing and the cause of hearing impairment in pediatric renal transplant group have not been evaluated. The cause of sensorineural hearing impairment is usually the combined result of many factors. Potential ototoxic adverse effects (eg, sensorineural hearing impairment) may be related to immunosuppression with calcineurin inhibitors. It has been reported that after administration of various immunosuppressive drugs, including calcineurin inhibitors.3
We conducted a study to evaluate hearing status in pediatric renal transplant patients and to determine the factors that cause hearing impairment.
Methods and Patients
Eighty-six pediatric renal transplant recipients were included in this study. Demographic characteristics of the patients (eg, age, sex, weight, and blood pressure), cause of renal failure, follow-up time after transplant, renal function parameters, and immuno-suppressive regiment were recorded. Usage of ototoxic drugs (eg, aminoglycoside antibiotics, and loop diuretic agents) and infections were documented. Patients with hearing impairment secondary to acoustic trauma were excluded from the study, including Ménière's disease, congenital and genetic diseases that are onset with hearing impairment, thromboembolic event, insufficient graft function (glomerular filtration rate (GFR < 60 mL/min/1.73m2]), hypertension, infection, and drug ototoxicity Twenty-seven pediatric renal transplant recipients (11 males, 16 females) who had appropriate criteria for study were investigated.
Immunosuppressive regiment of patients included in CycA or tacrolimus. Each patient also received mycophenolate mofetil and oral prednisolone. Serum tacrolimus and trough (CycA0) and second-hour (CycA2) CycA levels were measured.
Characteristics and course of hearing impairment were assessed by the questionnaire. The following problems were asked (1) general hearing problems, (2) sudden hearing loss, (3) chronic hearing loss, (4) speech understanding, (5) tinnitus, (6) middle ear infection, and (7) vertigo. Otoscopy revealed for all patients. All patients underwent audiologic assessment by means of pure-tone audiometry. Patients were examined inside an acoustic cabin using an AC-40 Interacoustics audiometer (Interacoustics AS, Assens, Denmark) to perform pure-tone audiometry. The 125, 250, 500, 1000, 2000, 4000, and 8000 Hz frequencies were tested by air conduction.
Demographic, clinical, and laboratory data of patients with and without hearing impairment were compared. Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 11.0, IBM Corporation, Armonk, NY, USA). The chi-square test, t test, and 1-way ANOVA were used for statistical analysis. Adjusted odds ratios and 95% confidence intervals were calculated. P values < .05 were considered to indicate statistical significance.
Written informed consent was obtained from each individual participating in the study, which was approved by the Local Ethics Committee and there were no conflicts of interest involved. All of the protocols conformed with the ethical guidelines of the 1975 Helsinki Declaration.
Recipients were 14.05 ± 4.11 years old at the time of transplant. Nineteen patients received living-related donor allograft and the remaining 8 were from deceased donors. Mean follow-up time after transplant was 29.8 ± 22.5 months. During long-term follow-up, patients did not have infections like meningococcal or cryptococcal meningitis, mumps, rubeola, and rubella. Blood tests for toxoplasmosis, cytomegalovirus, herpes simplex virus, and human immune deficiency virus were negative. Patients’ arterial blood pressures were in normal ranges. Mean systolic blood pressure was 110.37 ± 9.79 mm Hg, and mean diastolic blood pressure was 72.03 ± 10.58 mm Hg.
Seventeen patients had sensorineural hearing impairment. Only 2 of them developed symptomatic sudden hearing loss after transplant, 1 of them had tinnitus. Pure-tone audiometry is used to evaluate quantitatively the perception of hearing impairment, measuring sound frequencies varying from 250 Hz to 8000 Hz. Hearing impairment occurs when auditory loss is greater than 25 dB in any of the mentioned frequencies. The mean values in patients with hearing impairment for 4000 Hz were 28.5 ± 28.69 dB (left) and 25.73 ± 23.76 dB (right) and for 8000 Hz were 46.17 ± 32.51 dB (left) and 44.11 ± 28.68 dB (right). Mean values in patients without hearing impairment were 8.33 ± 3.06 dB (left) and 11.11 ± 4.69 dB (right) for 4000 Hz, 10.83 ± 7.5 dB (left) and 9.16 ± 5.30 (right) for 8000 Hz. Hearing performance for higher frequencies between the 2 groups was significantly different (P = .001) (Figure 1). Decrease of speech understanding was found in 8 patients (30%).
In the hearing impairment group 9 patients received living related donor allograft and the remaining 8 were from deceased donors, but all patients without hearing impairment received living-related donor allograft. Estimated glomerular filtration rate was low in hearing impairment group (mean, 77.23 ± 25.34 mL/min/1.73m2) when compared without hearing impairment group (mean, 111.40 ± 47.10 mL/min/1.73m2) (P = .02). Blood pressure was not associated with hearing impairment and speech understanding (P > .05). Groups of patients with and without hearing impairment were similar for renal failure cause, duration of dialysis, other immunosuppressive treatments, and lipid values.
Assessment of hearing impairment was performed according to high peak blood levels of calcineurin inhibitors and mean assessment time of hearing impairment was 21.3 ± 12.2 months. Cyclosporine A2 level was significantly high in patients with hearing impairment (mean, 1016.2 ± 558.9 ng/mL) when compared to the group without hearing impairment (mean: 807.7 ± 46.8 ng/mL) (P = .005). Cyclosporine A2 levels also were found significantly high when compared to the group with decrease of speech understanding (mean, 1182.2 ± 742.5 ng/mL) and all the rest (813.6 ± 53.5 ng/mL) (P = .00) (Table 1). The relation between cyclosporine A0 and tacrolimus levels and hearing impairment and speech understanding could not be shown.
After dosage correction of immunosuppressive drugs, pure-tone audiometry showed improvement of hearing loss progression for each patient, but decrease of speech understanding was not reversible.
Renal transplant provides a long-term survival. Therefore, it is important to focus not only biologic outcomes, but also the quality of life after renal transplant. Hearing impairment is a major factor in the subjective perception of health status. The knowledge about hearing status after pediatric renal transplant is limited.
A high incidence of high-frequency hearing impairment was obtained in renal failure that could not be attributed to age, noise exposure, ototoxicity, or hereditary. Hearing impairment was reported in 8.6% of children on renal replacement therapy by the European Dialysis and Transplant Association Registry.4 Renal transplant improves hearing function initially and the best audiometric results are being obtained 21.4 months after transplant, but in the long term, leads to worsening of hearing capacity.5 Our mean assessment time was 21.3 months, and we could perform the pure-tone audiometry when the hearing has not got worse; and when it was the best after transplant. Worsening of hearing capacity has been attributed to vascular changes in the inner ear due to hyperlipidemia, ototoxic treatment, or recurrence of renal disease.6
Sensorineural hearing impairment prevalence in pediatric transplant group was higher than in the chronic renal failure group (47% against 29%) in Mancini’s study, and they found a significant correlation with the administration of ototoxic drugs after transplant (eg, aminoglycosides and furosemide).7 Sensorineural hearing impairment prevalence was 62% in our patient group, and it was high when compared with the general population of children. Our higher prevalence may be related to the assessment that was performed without symptoms.
Patients with hearing impairment related to drug ototoxicity were excluded from our study. The most frequent initial manifestation of drug ototoxicity occurs in the higher tones (acute sounds), progressing thereafter through the median and low range frequencies.8 In our study pure-tone audiometry, we showed bilateral sensorineural hearing impairment in 17 recipients (62%). There was a marked hearing impairment for the higher frequencies between 4000 and 8000 Hz. Despite 17 patients with hearing impairment on audiologic assessment, only 2 of them had sudden hearing loss and tinnitus. Decrease of speech understanding was found in 8 patients. None of the patients was conscious of this problem.
The knowledge about hearing impairment after renal transplant and the effect of immuno-suppressive regimen to this sense is limited. Possible adverse effects of immunosuppression are gaining more clinical significance with long-term survival after renal transplant. One of the major adverse effects seen with the use of calcineurin inhibitors is neurotoxicity. Numerous studies have reported diverse neurotoxic effects ranging from mild symptoms (eg, tremor, headache, altered mental functioning, neuralgia, transient apraxia of speech, agitation, and peripheral neuropathy) to more severe symptoms (eg, psychoses, hallucinations, blindness, seizures, cerebellar ataxia, motor weakness, and leukoencephalopathy). Calcineurin plays such an extensive role in the rapid functioning of neurons. Neurotoxicity is likely due to the inhibition of calcineurin within nerve cells.9 These neurotoxic adverse effects could be involved in developing hearing impairment after transplant. Only few cases and studies reported hearing impairment in adults after organ transplant receiving different immunosuppressant (CycA, tacrolimus, OKT3, and antithymocyte globulin).3,10-13 These studies were conducted almost in adult liver transplant recipients and characteristics, and course of hearing impairment was generally assessed with a written questionnaire. In studies, in adult liver transplanted patients and other in adult renal transplanted patients, status of hearing was evaluated with pure-tone audiometry.13,14 De los Santos and associates showed that despite a normal graft function, hearing impairment prevalence is high after renal transplant.14
To our knowledge, this is the first report status of hearing and the effect of immunosuppressive treatment on hearing in pediatric renal transplant recipients. Recent studies were mostly accused tacrolimus as a cause of hearing impairment.13 Only in few case reports CycA was demonstrated as the cause of hearing impairment after transplant. Our results demonstrate that dose-dependent CycA toxicity is related with hearing impairment, particularly in the higher-frequency tones and is also related with decrease of speech understanding. After dosage correction, pure-tone audiometry showed improvement of hearing loss progression for each patient, but decrease of speech understanding was not reversible. Dose-dependent neurotoxicity may be hypotheses as the probable mechanism.
We found that hearing impairment was frequent in pediatric renal transplant patients. We conclude that dosage-dependent CycA toxicity might a responsible agent that causes hearing impairment after transplant. Awareness of this potential complication may be helpful to early recognition and treatment. Our findings suggest that periodic audiologic assessments may be indicated in transplant patients.
Volume : 13
Issue : 4
Pages : 324 - 328
DOI : 10.6002/ect.2014.0158
From the 1Pediatric Nephrology Department; the 2Otorhinolaryngology
Department; and the 3General Surgery Department, Baskent University,
Acknowledgements: The authors declare that they have no sources of funding for this study, and they have no conflicts of interest to declare.
Corresponding author: Kaan Gulleroglu, MD, Baskent University Pediatric Nephrology Department, 54. Cadde No: 72/3, Bahcelievler, Cankaya, 06490, Ankara, Turkey
Phone: +90 532 647 2268
Fax: +90 312 215 7597
Figure 1. Mean Decibel (dB) for Better Hearing for Each Frequencies (Hz)
Table 1. Demographic Data of Groups With or Without Hearing Impairment