Introduction
Cyclosporine was discovered in 1970, it was isolated from the fungus Tolypocladium
inflatum in Switzerland (1). Soon after, an immunosuppressive property was suggested,
and by 1978, it was used for the first time in human kidney transplantation to treat
organ rejection post-transplant (2). It is now used as a treatment for solid organ,
as well as bone marrow transplantation. Its immunomodulatory capacity has extended
its use to other immune-mediated diseases such as severe forms of rheumatoid arthritis
and psoriasis, steroid-dependent, frequently relapsing or steroid-resistant nephrotic
syndrome, graft vs. host disease, refractory posterior uveitis/Behçet disease and
amyotrophic lateral sclerosis (2, 3).
How Does Cyclosporine Work as an Immunosuppressant?
Cyclosporine suppresses T cell activation, by inhibiting calcineurin, as a result
of binding with cyclophilin A. Consequently, calcineurin cannot dephosphorylate nuclear
factor of activated T cell (NFAT) and therefore inhibits the activation of genes required
for proliferation such as IL-2, IL-4, as well as CD40L (4). It has also been demonstrated
that cyclosporine can also block the activation of JNK and p38 signaling pathways
involved in T cell activation (5, 6). Inhibition of these pathways are the main mechanisms
of cyclosporine's immunosuppressive effects.
Cyclosporine also has an effect on the innate immune cells including dendritic cells,
macrophages and neutrophils. Dendritic cells are essential in linking the innate and
adaptive immune response, and it is believed that cyclosporine can modulate cytokine
production in these cells and lead to altered induction of T cell responses (7).
Cyclosporine is an inhibitor of the P-glycoprotein multidrug efflux pump, also known
as Multidrug Resistance Protein 1 (MDR1). It is a competitive inhibitor of MDR1. As
cyclosporine is lipophilic, not only is it a substrate for MDR1 (8), but it can also
enter cells by passive diffusion (3). MDR1 is expressed in several tissues, primarily
epithelial cells with excretory functions (9). It is widely expressed by innate and
adaptive immune cells; macrophages, dendritic cells, naive B cells, CD8+ T cells,
CD4+ T cells, and NK cells (8).
What Are the Known Side Effects of Cyclosporine?
While cyclosporine is now a commonly used immunosuppressant, its use is not without
side effects. Nephrotoxicity, hypertension, neurotoxicity, hepatotoxicity, hirsutism,
gingival hyperplasia, lymphoproliferative neoplasms, opportunistic infections, hyperuricemia,
hyperkalemia, and hypomagnesemia are some of the adverse effects described (10–12).
The drug is erratically absorbed from the gastrointestinal tract which leads to variability
in blood concentrations and unpredictable pharmacokinetics (10, 13). Cyclosporine
also has a narrow therapeutic window, which means that minimal changes in dosage may
lead to therapeutic failures, or adverse effects (14). Therefore, blood levels must
be carefully monitored during treatments with this drug (13). Cyclosporine neurotoxicity
can occur at normal or elevated drug levels. It has been described that the majority
of neurological side effects involve the central nervous system, however, peripheral
nerves can be affected. Autopsy results have shown ischemic lesions, neuronal loss,
hemorrhagic foci and diffuse neuronal damage (11).
It has been suggested that cyclosporine, in combination with methylprednisolone, can
cause microangiopathy (15) and ischemic lesions by endothelial damage and vasoconstriction
(11).
Why Would Cyclosporine Cause Ototoxicity?
Cyclosporine is a calcineurin inhibitor, and calcineurin has been detected in the
cochlear nerve and inner hair cells of rats (16). We know cyclosporine is an immunosuppressant,
and although the cochlea is not considered an immunological organ, it has been shown
to constitutively express a variety of immune-related molecules involved in multiple
signaling pathways. A better understanding of the functional roles of cochlear immune
cells with regards to cochlear homeostasis and disease formation is needed (17). Cyclosporine
could perhaps impact immune activities within the cochlea.
Hearing loss can result from ischemic events in the cochlea (18), and peripheral vestibulopathy
can also result from vascular processes (19). Also, it is known that cyclosporine
can cause hypomagnesemia, and magnesium appears to be an important cation in the auditory
system. Magnesium deficiency has been linked to noise-induced hearing loss, ototoxicity,
and sudden sensorineural hearing loss (SSNHL) (20, 21). The exact mechanism by which
magnesium deficiency can cause hearing loss is not fully understood (22).
Another possible contributing factor is the fact that cyclosporine is a lipophilic
molecule (23), and lipophilic drugs have greater diffusion through the blood labyrinthine
barrier (BLB) (24). This could be a potential pathway for cyclosporine reaching inner
ear cells. Another point to consider here is that presence of perivascular resident
macrophages and pericytes on the vessels of the stria vascularis. The role of these
pericytes is unknown, but we do know that pericytes in other organs (i.e., kidney,
lung, liver, retina) play a role in regulating capillary blood flow and endothelial
activity. Also, it is believed that the perivascular resident macrophages could play
a role in regulating barrier integrity (25). Hence, these new classes of cells of
the BLB could play a role here.
As a result of these observations, it is therefore reasonable to investigate whether
cyclosporine can in fact cause hearing loss or vestibular symptoms. Hence, microangiopathy,
neurotoxicity and/or hypomagnesemia may play a role in cyclosporine induced hearing
loss or vestibulopathy.
Studies Reporting Hearing and Vestibular Symptoms
Various studies have aimed to assess hearing loss or vestibular symptoms with regards
to cyclosporine treatment (Table 1). Ibrahim et al. performed audiometry testing for
children with idiopathic nephrotic syndrome treated with cyclosporine (26). They observed
that 23.7% (n = 19/80) of the patients had hearing loss, however, 47% had sensorineural
hearing loss (SNHL) and 53% had conductive hearing loss (CHL). Between the children
with and without hearing loss, there was no significant difference in the median cyclosporine
treatment duration. Of note, 31% (n = 25/80) of the patients had also received cyclophosphamide,
and the authors report that cyclophosphamide intake was significantly greater in patients
with CHL vs. SNHL. They suggest this may be due to recurrent ear infections caused
by immunosuppression. It is important to remember that the most common cause of pediatric
CHL is otitis media with effusion, a highly prevalent condition in children which
is generally reversible (33).
Table 1
Studies reporting auditory and/or vestibular symptoms with the use of cyclosporine.
Study
Age
n
CsA treatment
Follow-up
Hearing loss eval. method
Hearing loss
Tinnitus
Vestibular symptoms
*
Other drugs used
Indication
Duration
Dosage
Ibrahim et al. (26)
9.7 ± 3 yrs (5–16)
80
Idiopathic nephrotic syndrome
17 m (2–24)
–
At least 12 m
Pure tone audiometry
23.7% (19/80)
–
–
Cyclophosphamide, methylprednisolone
Kasap-Demir et al. (27)
129.06 ± 63.25 m
16
Nephrotic syndrome (SDNS, FRNS, SRNS)
40.22 ± 35.14 (7–129) m
Cumulative: 4,480.9 ± 3,652.86 (630–13,466) mg/kg
30.44 ± 19.88 m (1–53)
Pure tone audiometry, TEOAE
0%
0%
–
Steroids, rituximab, cyclophosphamide, levamisole, mycophenolate mofetil, angiotensin
converting enzyme inhibitors
Gulleroglu et al. (28)
14.05 ± 4.11 yrs
27
Renal transplant
29.8 ± 22.5 m
–
21.3 ± 12.2 m
Pure tone audiometry, questionnaire
63% (17/27)
4% (1/27)
0%
Mycophenolate mofetil, prednisolone
Fortes et al. (29)
46.2 yrs
18
Liver transplant
–
–
636 days (65–939)
Pure tone audiometry
–
–
–
Prednisone, azathioprine, vancomycin, nystatin, sulfamethoxazole-trimethoprim
Rifai et al. (30)
51 ± 17 yrs
478
Orthotopic liver transplant
–
–
8 ± 5 yrs
Questionnaire
15% (73/478)
11% (54/478)
–
Tacrolimus, mycophenolate mofetil, prednisolone, sirolimus, azathioprine
Groothoff et al. (31)
29.3 yrs (20.7–41.7)
106
Renal transplant
–
–
11.3 yrs (0–29.9)
Questionnaire
8%
–
–
Prednisone, azathioprine, tacrolimus, antihypertensive (various)
Cole et al. (32)
46 yrs
1,097
Renal transplant
18 m
- CsA: 257 ± 97 mg/day - CsA-ME: 248 ± 80 mg/day
18 m
?
Overall: 4.7% (52/1,097)
Prednisone, azathioprine
CsA, cyclosporine; CsA-ME, cyclosporine microemulsion; m, months; yrs, years; eval,
evaluation; SDNS, steroid-dependent nephrotic syndrome; FRNS, frequently-relapsing
nephrotic syndrome; SRNS, steroid-resistant nephrotic syndrome; TEOAE, transient evoked
otoacoustic emissions.
*
dizziness, vertigo. Parenthesis represent range.
Kasap-Demir et al. also evaluated hearing loss in pediatric patients with nephrotic
syndrome treated with cyclosporine for at least 6 months. They report that none of
the patients had hearing loss, conductive or sensorineural (27). The patients were
also exposed to multiple other drugs including cyclophosphamide, steroids, levamisole,
rituximab, mycophenolate mofetil and antihypertensive (angiotensin-converting enzyme
inhibitors).
Gulleroglu et al. evaluated the prevalence of hearing loss in renal transplant patients,
they report that 63% of patients had SNHL, and 1 patient had tinnitus. Interestingly,
they report two cases of SSNHL, an uncommon occurrence in pediatric otolaryngology.
The patients with hearing loss were 17 years old (±4.4). They also observed that second-hour
serum cyclosporine levels were significantly higher in patients with hearing loss
and/or decreased speech understanding when compared to the group without hearing impairment.
No vertigo was reported. They suggest that the hearing impairment following transplantation
may be a dose-dependent cyclosporine toxicity (28).
Fortes et al. evaluated adult patients undergoing liver transplantation with a hearing
test, before and after transplantation. Patients received either cyclosporine or tacrolimus
(FK-506) as part of their immunosuppressive regimen. For the cyclosporine group, the
time elapsed between transplantation and the post-transplant hearing test was 635.83
days (range 65–939). No clinically significant changes were seen on pure tone audiometry.
They do, however, report statistically significant changes with the use of tacrolimus
(29).
Rifai et al. sent out a questionnaire to liver transplantation recipients, with a
mean follow-up period of 8 ± 5 years since the transplant. Excluding patients with
a prior history of hearing loss, they observed that 15% reported hearing loss, and
11%, tinnitus. Of interest, the mean time period from transplantation to onset of
hearing impairment was 4 ± 4 years. Self-reported hearing loss was considered severe
in 62%, and sudden hearing loss was the cause of hearing impairment in 26% of these
patients. Hearing loss was associated with the use of tacrolimus immunosuppression,
but not with cyclosporine (30).
Groothoff et al. performed a cross sectional investigation of patients who underwent
renal transplantation. While their cohort is quite large, with 249 subjects, the cross-sectional
analysis was completed for patients who were alive, with a functioning graft, and
for which health and social status could be obtained. Of 106 patients that answered
the questionnaire, 8% reported hearing problems, and 69.2% have used cyclosporine
as part of their treatment at some point in time. There was no association between
hearing problems and the use of cyclosporine (31).
Finally, Cole et al. compared long-term safety and tolerability of cyclosporine and
cyclosporine microemulsion for adult renal transplant patients. As previously mentioned,
cyclosporine pharmacokinetics can be tricky, and the microemulsion formulation was
created in order to obtain a more consistent drug exposure, showing a significant
increase in the area under the concentration-time curve and maximum plasma concentration.
By 18 months, they observed that overall, 4.7% had hearing loss. This was more common
in the microemulsion group (cyclosporine: 2.8%, n = 10/356; microemulsion: 5.7%, n
= 42/737). Mild and moderate hearing and vestibular disorders were more frequent in
the microemulsion group (32).
Case Reports
To the best of my knowledge, four case reports have been published with regards to
hearing impairment due to cyclosporine treatment. Arinsoy et al. reported the case
of a 22-year-old male patient that underwent a renal transplant. Cyclosporine treatment
began before the surgery and was maintained, he also received methylprednisolone and
azathioprine. On post-op day seven, the patient presented with a unilateral SSNHL,
with a flat curve on the audiogram, and 12% speech discrimination. No dizziness was
described. It was believed to be a vascular event, and was treated with vasodilator
and antiaggregant therapy. Seven days later, he had regained his hearing. Initially,
his blood levels of cyclosporine were at 200 ng/ml, the dosage was decreased, and
by the time he had regained his hearing, blood levels were at 50.8 ng/ml (34). Porges
et al. describe the case of a 22-year-old male patient with severe Crohn's disease
that received treatment with cyclosporine. On the fifth day of treatment, the patient
exhibited neurotoxicity and a gastrointestinal bleed requiring blood transfusions.
His cyclosporine blood level was elevated (1,290 ng/ml). They mention bilateral asymmetric
SNHL detected by audiometry, but no details are provided (35). Marioni et al. reported
the case of a 32-year-old male patient who underwent a renal transplant 7 years prior.
He was treated with cyclosporine, azathioprine and methylprednisolone. He then developed
a progressive bilateral SNHL. No dizziness was described. Cyclosporine dosage was
decreased, and 32-weeks later, hearing loss remained stable, and did not worsen. Interestingly,
this patient was only taking cyclosporine and methylprednisolone at the time of hearing
loss onset (36). Finally, Tafazoli et al. published their experience with a 26-year-old
female patient receiving cyclosporine for graft vs. host disease. An accidental overdose
occurred with the microemulsion formulation, and the patient developed nausea, vomiting,
flushing, chest tightness, tremor and vertigo. The neurological examination revealed
a benign paroxysmal positional vertigo (37).
Discussion
The literature regarding the ototoxic potential of cyclosporine is lacking. The published
studies include patients with nephrotic syndrome (26, 27), renal transplantation (28,
31, 32) and liver transplantation (29, 30). These patients usually receive a variety
of drugs, and their underlying condition is a confounding factor. For instance, Saha
et al. observed that children with idiopathic nephrotic syndrome were at greater risk
for developing hearing loss. They suggest that high cumulative doses of furosemide
and hypocalcemia could be risk factors (38). Also, it is known that patients with
chronic diseases such as renal failure on hemodialysis are at greater risk of hearing
loss (39). These patients could have received furosemide at some point during their
treatment, a loop diuretic, known to be ototoxic (40). Many of the patients described
in the included studies and case reports have received various drugs, including methylprednisolone,
a steroid hormone that can increase cyclosporine blood levels. Many drugs including
certain antibiotics, calcium channel blockers and steroids can increase blood levels
of cyclosporine as they are cytochrome P-450 inhibitors, and cyclosporine is metabolized
in the liver (41).
The opposite is true as well, cyclosporine can alter tissue distribution of P-glycoprotein
substrates. As an example, Saito et al. showed that mice receiving doxorubicin did
not develop hearing loss as it is extruded by the P-glycoprotein multidrug efflux
pump from the inner ear. Yet, when given in combination with cyclosporine, cochlear
damage and dysfunction of the auditory pathway was seen, resulting from a significant
accumulation of doxorubicin in the inner ear (42). On the other hand, Yang et al.
used a transtympanic injection of cyclosporine in a guinea pig model of sterile labyrinthitis
to evaluate whether it suppresses inner ear inflammation and hearing loss. While cyclosporine
was not effective in preventing hearing loss, it did not worsen it either (43).
Cyclosporine presents intra and inter-individual variability in blood concentrations
and unpredictable pharmacokinetics (10, 13). It has a narrow therapeutic window (14)
and can interact with multiple drugs (41). While there are reports of hearing loss
and vertigo relating to its use, too many variables including medical condition treated,
concomitant treatments, electrolyte imbalance, dosage, blood levels, cytochrome P-450
metabolism, duration of treatment and pre-existing hearing impairment limit me in
being able to state that cyclosporine is in fact an ototoxic medication. Further studies
are necessary to determine, with some level of certainty, whether cyclosporine is
ototoxic or not, and to assess if microangiopathy, neurotoxicity or hypomagnesemia
play a role.
Literature is currently lacking with regard to risk factors for developing hearing
loss when receiving a treatment with cyclosporine. For instance, the synergistic effect
of impaired renal function. Most of the patients included in the reviewed studies
had some degree of renal insufficiency, or even underwent renal transplantation. Other
known ototoxic drugs are known to affect the kidney as well, causing nephrotoxicity,
such as cisplatin and aminoglycosides (44, 45). We know that there are similarities
between the kidney and inner ear cells. For instance, the basement membranes of the
stria vascularis and glomerular area are comparable (46), and we also know of various
oto-renal syndromes such as branchio-oto-renal syndrome, Townes-Brocks syndrome, Alport
syndrome, among others (47).
Because of the lack of evidence, I cannot elaborate further on a potential ototoxicity
monitoring program, however, clinicians dealing with patients receiving cyclosporine
as part of their treatment regimen should be alert to the possibility of ototoxicity
and screen their patients for hearing loss accordingly. And also, try to avoid the
use of a combination of ototoxic medications in these patients.
While cyclosporine is not a commonly used drug in all medical specialties, it is an
important drug in transplantation, and in 2019, close to 40,000 patients underwent
organ transplantation in the US (48), and most of the people on the waiting list need
a kidney or liver (49). There are many unknowns that remain to be studied, regarding
cyclosporine pharmacokinetics in the inner ear, whether cells in the BLB play a role
and how other drugs such as methylprednisolone may interact with cyclosporine at the
cochlear level. I hope this article will provide the scientific community with some
enthusiasm to tackle this issue.
Author Contributions
The author confirms being the sole contributor of this work and has approved it for
publication.
Conflict of Interest
The author declares that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.