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CORNEA

Adverse effects of low-dose systemic cyclosporine therapyin high-risk penetrating keratoplasty

Jong Joo Lee1& Mee Kum Kim

2,3& Won Ryang Wee

2,3

Received: 21 August 2014 /Revised: 19 March 2015 /Accepted: 31 March 2015 /Published online: 21 April 2015# Springer-Verlag Berlin Heidelberg 2015

Abstract

 Purpose The purpose of this study was to investigate the ad-verse effects of low-dose oral cyclosporine (CsA) therapy fol-

lowing high-risk corneal transplantation.

 Methods The medical records from 88 subjects who had un-

dergone high-risk penetrating keratoplasties and had been ad-

ministered oral CsA were retrospectively analyzed. High risk 

was defined as a history of graft rejection, three or more quad-

rants of vascularization, or the presence or history of intraoc-

ular inflammation. An initial CsA dose of 3 – 5 mg/kg per day

was given for 3 – 7 days, followed by 2.5 – 3.5 mg/kg per day

for approximately 1 month. The concentration of CsA was

maintained at the target trough level of 120 – 150 ng/ml for at 

least 6 months or until serious complications developed. Therelationship between the cumulative dose and duration of CsA

administration and the adverse systemic effects, including the

frequency of herpes keratitis, was evaluated. The incidence of 

herpes keratitis in the study subjects was compared with the

incidence in 185 patients who had not received CsA therapy

following penetrating keratoplasty.

 Results  The mean survival time of the grafts was 33.6 months.

Adverse effects occurred in 81.8 % of subjects. Hypertension,elevated liver enzyme levels, elevated serum creatinine level,

and decreased absolute neutrophil count (ANC) were ob-

served in 14.8, 6.8, 5.7, and 5.7 % of subjects, respectively.

Simvastatin-induced rhabdomyolysis also developed in one

case. Some patients exhibited minor complications, with gas-

trointestinal problems and hypertrichosis recorded in 5.7 and

3.4 % of subjects, respectively. Hypertension and hepatotox-

icity most frequently occurred after 4 to 8 weeks of medica-

tion, while ANC decrease and nephrotoxicity generally devel-

oped after 24 weeks of treatment, with incidence related to the

cumulative dose. Herpes keratitis occurred more frequently

(31.8 %) in the CsA-treated subjects than in subjects that didnot receive CsA therapy ( p=0.005). Most of the adverse ef-

fects were reversed after discontinuation of CsA therapy.

Conclusion  The results of this study suggest that low-dose

oral CsA therapy may induce various adverse effects, the most 

common of which are herpes keratitis and hypertension.

Keywords  Cornea  . Cyclosporine  . Adverse effects .

Penetrating keratoplasty . Hypertension  . Herpes keratitis

Introduction

Penetrating keratoplasty (PKP) is the most common form of 

solid tissue transplantation, with a rejection rate of less than

10 % within the first 5 years in an avascular low-risk disease

like keratoconus [1 – 3]. In contrast, the rejection rate can be

70 % or greater in high-risk keratoplasty without systemic

immunosuppression, and the 5-year survival rate for the allo-

graft is less than 30 % in such cases [4, 5]. Therefore, if a graft 

is placed into a pre-sensitized host or a vascularized, inflamed

recipient bed at   Bhigh-risk ̂   [6], postoperative long-term

Electronic supplementary material  The online version of this article

(doi:10.1007/s00417-015-3008-0 ) contains supplementary material,

which is available to authorized users.

*  Mee Kum Kimkmk9@snu.ac.kr 

1 Department of Ophthalmology, Chungnam National University

College of Medicine, Daejeon, Korea 

2 Department of Ophthalmology, Seoul National University College of 

Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, Republic of 

Korea 

3 Laboratory of Ocular Regenerative Medicine and Immunology,

Seoul Artificial Eye Center, Seoul National University Hospital

Biomedical Research Institute, Seoul, Korea 

Graefes Arch Clin Exp Ophthalmol (2015) 253:1111 – 1119

DOI 10.1007/s00417-015-3008-0

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CsA was administered for an average of 214 days. The

mean graft survival following CsA discontinuation was

418 days. Of the 51 chronic rejection cases, rejection devel-

oped and became irreversible while CsA was being adminis-

tered in 18 cases (35.3 %). After the occurrence of adverse

events, the administration of CsA was either discontinued

(56.8 %) or the dose was reduced (43.2 %). In the NCAE

group, the mean duration of CsA therapy was 236 days and

the mean cumulative dose was 802.0 mg/kg, while the mean

duration in the CAE group was 190 days and the mean cumu-

lative dose was 617.9 mg/kg. However, the differences in

duration and cumulative dose between the two groups were

not significant. There was also no significant difference in

mean graft survival time as estimated by Kaplan – Meier anal-

ysis (log-rank test, Fig. 1b) between thetwo groups: 30 months

for the NCAE group and 37 months for the CAE group.

Incidence and peak time of adverse effects

Of the 88 patients included in the study, 72 (81.8 %) experi-

enced adverse effects. Table 2  lists all the types of adverse

effects encountered in the patients.

Fig. 1 a Graft survival in high-

risk penetrating keratoplasty

(PKP) in which oral cyclosporine

A (CsA) was administered. The

mean survival was 33.6 months. b

The survival curves of PKP grafts

with no occurrence of CsA

adverse events (NCAE group,

black line) and those with CsA

adverse events (CAE group, graydotted line). There was no

significant difference between the

two groups in mean graft survival

time, as estimated by Kaplan – 

Meier analysis, after 30 months in

the NCAE group and 37 months

in the CAE group (log-rank test).

1114 Graefes Arch Clin Exp Ophthalmol (2015) 253:1111 – 1119

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Systemic adverse events most frequently occurred 4 to8 weeks after CsA therapy had been initiated (36.4 %,

Fig. 2a ). The incidence of adverse events peaked at a cumu-

lative dose between 100 and 200 mg/kg (36.4 %, Fig.  2b).

Duration of therapy and cumulative dose were strongly corre-

lated (Fig. 2c, r 2=0.890, p

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 patients with a history of herpes (n=13). Herpes keratitis oc-

curred in 26.7 % of patients in the CsA group without previ-

ous herpes infection (n=75). When herpes keratitis was cate-

gorized according to the location of the original lesion, herpes

epithelitis accounted for 92.8 % of the postoperative herpes

cases in the CsA group. Postoperative herpes epithelitis devel-

oped more often in the CsA group than in the no-CsA group

regardless of whether there was a history of ocular herpes

(Table 3a and b).

Hypertension was the second most common adverse effect,

occurring in 13 of the 88 cases (14.8 %). Two patients had

hypertension prior to CsA therapy. Temporary BP elevations

higher than systolic 180 mmHg or diastolic 110 mmHg were

recorded in three cases (3.4 %). After discontinuation of CsA,

 blood pressure returned to preoperative levels.

There were five cases (5.7 %) in which serum Cr increased.

These patients were not taking any other systemic drugs at the

time, and their Cr concentration normalized after discontinu-

ation of CsA therapy.

Rhabdomyolysis was diagnosed in a 65-year-old woman

who had received simvastatin for hypercholesterolemia. Sim-

vastatin shares the same metabolic pathway as CsA via the

hepatic cytochrome P-450 3A enzyme system (CYP 3A4).

Simvastatin-induced rhabdomyolysis developed 1 month after 

the start of CsA, an inhibitor of CYP3A4, with a cumulative

dose of 171.5 mg/kg. As a result of rhabdomyolysis, serum

levels of AST and ALT increased markedly, to 309 and

170 IU/L, respectively.

AST and ALT levels were elevated in six cases (6.8 %),

although the CsA concentration was always within the target 

range when the abnormalities were detected. The elevation

was reversed after cessation of CsA therapy. ANC decreased

in five cases (5.7 %). None of these patients had any infectious

disease. One patient showed an ANC less than 1500/mm3 on

day 40, which increased after cessation of CsA therapy.

The most common minor adverse effect reported was gas-

trointestinal (GI) discomfort (heartburn or indigestion), which

occurred transiently in five cases (5.7 %). Three of these pa-

tients developed symptoms within 4 weeks of commencing

oral CsA therapy, while another reported symptoms after 

1 year of CsA therapy. Hypertrichosis was reported in three

cases (3.4 %), most prominently on the face, especially around

the brows and ears. A general feeling of being unwell was

reported by three patients (3.4 %). One case of skin eruption

on the legs was also detected. Among 13 patients with well-

controlled DM, 2 experienced temporary loss of control of 

 blood glucose levels (2.3 %). Cessation of CsA resulted in

complete resolution of these symptoms.

Discussion

In the present study, we examined the various temporary ad-

verse effects (81.8 %) associated with low-dose CsA admin-

istration that can develop even when CsA concentration is

maintained within the target range (120 – 150 ng/ml). Herpes

keratitis was the most common side effect (31.8 %), and hy-

 pertension was the second most common (14.8 %). Elevation

of blood pressure or liver enzyme levels most frequently oc-

curred 4 to 8 weeks after the start of medication, while ANC

reduction and nephrotoxicity were most noticeable after 

24 weeks of therapy.

Corneal herpetic recurrence rates between 29 and 52 %

have been reported after PKP in patients with a history of 

herpetic keratitis [14]. The 1-year recurrence rate has ranged

from 21 to 39 % [15 – 17], and a 2-year rate of 44 % was

Table 3   Comparison of herpes

keratitis occurrence between oral

cyclosporine A administration

group (CsA group) after high-risk 

 penetrating keratoplasty (PKP)

and no-CsA group after normal-

risk PKP

A. No history of herpes

Post-op herpetic occurrence CsA group (n=75) No-CsA group (n=149)

Epithelium 24.0 %** (18) 6.7 %** (10)

Stroma 0 % (0) 0.7 % (1)

Endothelium 2.7 % (2) 0.7 % (1)

Total 26.7 %* (20) 8.1 %* (12)

B. Previous history of herpesRecurrence (post-op/pre-op) CsA group (n=13) No-CsA group (n=36)

Epithelium 88.9 %§ (8 / 9) 50.0 %§ (11 / 22)

Stroma 0 % (0 / 2) 57.1 % (4 / 7)

Endothelium 0 % (0 / 2) 57.1 % (4 / 7)

Total 61.5 % (8 / 13) 52.8 % (19 / 36)

Herpes keratitis occurred more frequently in the CsA group (31.8 %) than in the no-CsA group (16.8 %) ( p=

0.005). A. In cases with no history of herpes-associated eye disease, the frequency was higher in the CsA group

(* p

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reported [17]. Herpetic recurrence is thought to be triggered

 by systemic immunosuppression [14]. CsA-treated patients

can acquire viral infections such as herpes or cytomegalovirus

[18]. Cytotoxic CD8 T cells are known to play an important 

role in the clearance of infectious herpes simplex virus (HSV).

CD4 T helper cells are also involved in the clearance of infec-

tious HSV-1 [19, 20]. A previous study reported herpetic re-

currence in 32.1 % of grafts among 84 high-risk keratoplastiestreated with a postoperative combined systemic therapy of 

acyclovir and immunosuppression with mycophenolate mofe-

til (n=79) or CsA (n=5) [14].

In the present study, herpes keratitis occurred in 31.8 % of 

cases and the herpetic recurrence rate was 61.5 % among

 patients with a history of herpes keratitis (Table 3b). In this

study, newly developed herpes keratitis accounted for 71.4 %

(n=20) of patients with postoperative herpes, while herpetic

recurrence was observed in only eight patients with a previous

history of herpes infection. The mean time to development of 

herpes keratitis after CsA administration was 145 days.

An interesting finding from this study was that, regardlessof patient history, herpetic epithelitis occurred more often in

the low-dose CsA group than in the no-CsA group. This sug-

gests that prophylactic treatment of herpes may be necessary

not only in patients with a previous history of herpes, but also

in patients with no history of infection when CsA therapy is

initiated.

In high-risk keratoplasty, the incidence of systemic compli-

cations associated with CsA has been reported in a range of 13

to 45 % [5,  8 – 11,   14,   21]. Some reports found that kidney

dysfunction was the most common complication (16 – 26 %)

[8, 9], while others found hypertension to be the most frequent 

side effect (10 %) [13].

 New onset or worsening of hypertension is a common side

effect of CsA. The main target tissues considered to mediate

CsA-induced hypertension are the kidneys, vascular smooth

muscle, endothelium, and central nervous system [18, 22 – 24].

In the present study, lowering the dose of CsA reduced blood

 pressure levels, and the use of vasodilators was not necessary.

Since the CsA dose used in our study was low, elevations in

 blood pressure appear to have been caused by CsA sensitiza-

tion of the vascular smooth muscles, endothelium, or central

nervous system rather than by kidney toxicity.

 Nephrotoxicity and hypertension are well-known adverse

effects of CsA following renal transplantation [24]. In stable

renal transplant recipients, CsA is usually maintained at a dose

of 3 to 6 mg/kg/day for more than 12 months, and the recom-

mended blood trough concentration range is 250 – 400 ng/mL

[24], which is higher than that for keratoplasty. The lower 

incidence of renal toxicity in keratoplasty found in our study

appears to be related to the lower dose and shorter exposure to

CsA in our patients.

Even when a low dose is used, sustained administration of 

CsA can cause a significant increase in plasma creatinine

levels. In a prospective study of 41 patients with posterior 

idiopathic uveitis, long-term low-dose CsA treatment resulted

in significantly impaired renal function [25]. The incidence of 

hypertension in patients also increased from 15 % at baseline

to 81 % at 5 years. A higher cumulative dose was associated

with poorer renal function, and the same was true for the

trough level, with higher trough levels associated with de-

creased renal function. The study suggested that loweringthe daily dose to  ≤   3.16 mg/kg might prevent CsA-induced

nephrotoxicity [25]. In this study, the maintenance dose gen-

erally fell below the range of 2.5 to 3.5 mg/kg/day, and neph-

rotoxicity began to appear after 83 days (mean 218 days) of 

CsA administration.

Renal dysfunction can be either acute or chronic. Acute

toxicity usually occurs within weeks and is reversible in most 

cases by dose reduction. The hemodynamic dysfunction was

originally identified as acute toxicity, although tubular 

vacuolization and thrombotic microangiopathy are also recog-

nized in this category. Intrarenal vasoconstriction and en-

hanced vascular reactivity become permanent and irreversibleafter 3 months. The toxic effects of CSA-cyclophilin-

calcineurin complexes on tubular and endothelial cells play a 

role in chronic toxicity. Significant interstitial fibrosis

and glomerular sclerosis is an indicator of irreversible

damage. By 10 years post-kidney transplantation, lesions

suggestive of chronic nephrotoxicity are seen in virtual-

ly all patients [24 – 27,   18,   28]. In the present study,

late-onset chronic nephrotoxicity did not occur, given

the relatively short-term nature of the therapy and low

CsA dose used.

It is possible that concurrent oral medication with CSA

affects the development of renal dysfunction. The patients in

this study took aceclofenac for only 3 days immediately after 

surgery. Short-term use of NSAIDs may result in acute kidney

toxicity and subsequent hypertension over hours to days [29].

In this study, however, no hypertension or serum creatinine

increase was observed within 1 month. As for the effect of oral

acyclovir on renal complication, we performed additional

analysis of the rate of renal complication in patients taking

cyclosporine only versus patients taking both cyclosporine

and acyclovir. Those who had taken acyclovir along with cy-

closporine because of the herpes keratitis (n=33, Table 3; her-

 pes keratitis without a previous history, n =20 + herpes kera-

titis with a previous history,   n=13) did not show a higher 

frequency of renal toxicity than those who had not taken acy-

clovir (n=55). There was no statistical difference in the fre-

quency of serum creatinine increase between patients who had

taken acyclovir (3.0 %, 1/33) and those who had not (7.3 %,

4/55, chi-square test, Supplementary Table   S1). Therefore,

adverse renal effects in the present study appear to be caused

 by CsA.

Hypertrichosis is usually noted 2 months after initiation of 

therapy in a dose-dependent manner [30,   31]. Because the

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activation of nuclear factor of activated T-cells (NFAT) is as-

sociated with follicular keratinocyte differentiation, the inhi-

 bition of NFAT by CsA causes enhanced hair growth [31].

Glucose intolerance may also occur, as calcineurin inhibitors

are toxic to pancreatic islets [24]. In this study, there were only

two patients with increased blood glucose concentration, and

no evidence of neurotoxicity was observed. ALT, a cytosolic

enzyme found predominantly in the liver, is a fairly specificmarker of hepatic injury, although it is also present in several

other organs including muscle. AST, a mitochondrial enzyme

affected by alcohol, is predominantly located in the liver,

heart, and skeletal muscles, in decreasing order of concentra-

tion. In rhabdomyolysis, the increase in AST levels is more

marked than the increase in ALT levels [32]. The elevation of 

ALT and AST levels can be reversed by cessation of CsA

therapy. Because CsA is metabolized in the liver via CYP

3A4, care needs to be taken not to increase the concentrations

of co-administered drugs that share the same metabolic path-

way [33, 34].

In our study, there was no statistically significant differencein graft survival between the NCAE group (the group receiv-

ing oral CsA without adverse effects) and the CAE group (the

group showing adverse effects as a consequence of oral CsA

therapy). There were also no significant differences in the

duration and cumulative dose of CsA administered, regardless

of early cessation or dose reduction of CsA following adverse

events. As for efficacy, on the other hand, graft survival of 

only 34.0 % suggests that CsA is not likely sufficient as a 

single agent for high-risk PKPs, and combination with a sec-

ond agent such as mycophenolate mofetil or azathioprine is

needed [13, 21, 35 – 37].

In summary, reversible systemic adverse effects of CsA

administration can often occur (50 %) under a low-dose target 

level (120 – 150 ng/ml) following keratoplasty. The most com-

mon adverse effects of CsA administration that we observed

were herpes keratitis and hypertension. Therefore, continuous

monitoring is required, especially in the early stages, and pro-

 phylactic herpes treatment may be necessary during adminis-

tration of CsA. In conclusion, the present study indicates that 

the risk of irreversible toxicity of CsA is extremely low in the

concentration used here (serum trough levels of 120 to 150 ng/ 

mL), favoring the safety of CsA therapy, since all adverse

events were reversible with appropriate monitoring and ces-

sation of CsA.

Conflict of interest   All authors certify that they have no affiliations

with or involvement in any organization or entity with any financial

interest (including honoraria; educational grants; participation in

speakers’ bureaus; membership, employment, consultancies, stock own-

ership, or other equity interest; and expert testimony or patent-licensing

arrangements), or non-financial interest (including personal or profes-

sional relationships, affiliations, knowledge or beliefs) in the subject mat-

ter or materials discussed in this manuscript.

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