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Risk factors and rejection frequency in patients undergoing penetrating keratoplasty

How to cite this article: Gittins-Nuñez LO, Díaz del Castillo-Martín E, Huerta-Albañil I, Ríos-Prado R, Soto-Dávila MA. [Risk factors and rejection frequency in patients undergoing penetrating keratoplasty]. Rev Med Inst Mex Seguro Soc. 2016;54(2):190-5.



Received: October 16th /2014

Accepted: September 9th 2015

Risk factors and rejection frequency in patients undergoing penetrating keratoplasty

Luis Othón Gittins-Nuñez,a Ernesto Díaz del Castillo-Martín,a Irma Huerta-Albañil,a Rita Ríos-Prado,a Marco Antonio Soto-Dávilaa

aDivisión de Oftalmología, Hospital de Especialidades

Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguros Social, Ciudad de México, México

Communication with: Luis Othón Gittins-Nuñez

Telephone: (55) 5456 7124


Background: Corneal transplantation is one of the surgical procedures most frequently performed worldwide and with better prognosis. Among its main indications include: keratoconus, bullous keratopathy, previous graft rejection, corneal dystrophy, and infection. The known risk factors for graft rejection are: recipient’s age, presence of vessels in the recipient cornea, intraocular pressure, and retransplantation. The objective of this article is to determine the risk factors and frequency of corneal rejection in patients undergoing penetrant keratoplasty.

Methods: The study’s design was descriptive, observational, transversal, analytical and retrospective. Patients operated of penetrating keratoplasty in cornea clinic with follow up during at least 6 months were studied. A review of the medical records of patients undergoing penetrating keratoplasty at the Hospital de Especialidades del Centro Médico Nacional Siglo XXI was performed.

Results: The 35.3 % of the transplanted patients had corneal transplant rejection. Corneal neovascularization of the recipient cornea previous to transplant was present in 21.3 %.

Conclusions: In our study we found similar results to the reported in the literature, the most important risk factors for rejection was the use of threphine 7.50 mm, older patient with a history with previous corneal neovascularization, keratopathy and herpetic keratitis.

Keywords: Corneal transplantation; Risk factors; Refractive surgical procedures

Corneal transplantation or keratoplasty is a surgical procedure in which damaged or diseased corneal tissue is replaced by healthy corneal tissue.1

It represents one of the surgical procedures performed most often worldwide and with the best prognosis. The main indications include: keratoconus, bullous keratopathy, previous corneal rejection, corneal dystrophy, and infection.1

Corneal transplant success is due to immune privilege of the anterior chamber and cornea. Corneal rejection, first described in 1948 by Louis Paufique, is now considered a specific process in which a graft that has remained transparent at least two weeks, suddenly develops edema accompanied by inflammation of the anterior segment. This process is measured immunologically.2,3

Corneal rejection is an immune process initiated by the recognition and primary response of antigens of the major histocompatibility complex (MHC) to the transplantation. MHC antigens, by themselves, are not a barrier for rejection, as the antigen-presenting cells can initiate an immune response.4,5

The antigen-presenting cells may induce graft failure by two mechanisms:6,7

  • Direct: antigen presentation provided by the graft’s dendritic cells is responsible for directly activating the T-helper lymphocyte (THL) receptor and causes acute rejection.8-10 
  • Indirect: the antigens of the graft’s major histocompatibility complex are processed and presented by the receptor’s dendritic cells, possibly causing chronic rejection.8-10

Corneal rejection is generally considered a result of the TH1-CD4 immune response, which is characterized by the production of proinflammatory cytokines, interferon gamma (IFN-y), and interleukin 2 (IL2).10-12

Corneal rejection may be chronic focal or endothelial, chronic stromal, hyperacute stromal, and epithelial; it occurs most frequently during the first 6 months following surgery; it often occurs in isolation or in combination, so it is not easy to identify which layer is involved in a corneal rejection event.10,11   

Corneal rejection can be of two types:

  • Reversible: this is the condition in which the rejected corneal graft responds to corticosteroid therapy with decreased edema, recovery of transparency, and absence of inflammatory signs.12-14
  • Irreversible: this is when, despite management, endothelial decompensation fails to keep the graft transparent.12-14

This is defined as when an eye with a previously transparent, thin graft presents inflammation with cells and flare in the anterior chamber, posterior keratic precipitates, and graft edema in the form of a rejection line.

It is likely when one eye presents all of the above signs, but no rejection line, and is said to be possible when an eye presents graft edema with no other inflammatory sign.

Risk factors for rejection

Donor factors

  • Age: it has been suggested that the corneas of young donors may have greater immunological load and, therefore, greater theoretical risk of rejection.14-16
  • Conservation: Langerhans cells (LC) play a very important role in the rejection of corneal transplantation. The manipulation of conservation media shows a decreased viability of these cells.17
  • Histocompatibility: it is difficult to draw conclusions from the various publications about HLA typing. There are a large number of prospective and retrospective studies that confer increased graft survival in high-risk patients (presence of two or more quadrants of corneal vascularization, previous rejections in the eye) when there is HLA I compatibility.16-21

Host factors

  • Age: recipient age and donor age are sources of controversy.22-27
  • Vascularization: the presence of vessels in the recipient cornea is a factor of poor prognosis.2,14,15,28-32
  • Eye annexes: chronic inflammation caused by dysfunction of these elements will create a climate conducive for rejection to begin.24,26
  • Corneal epithelium: corneal epithelium regeneration derives from stem cells located in the limbal basal epithelial layer. Damage at this level would cause recurrent epithelial defects in the graft.27,28
  • Intraocular pressure: changes in intraocular pressure cause repeated damage at the endothelial level.15,30,31
  • Activity: disease activity (uveitis, keratitis) worsens the transplant prognosis.15,32-34
  • Retransplantation: the presence of a previously rejected corneal graft has been included as a factor of greater risk.14,32
  • Etiology: the etiology leading to corneal transplantation is a significant factor in graft survival, as there are stimuli that induce LC migration from the periphery to the central area, such as: burns, viral and bacterial infections.4,5,24

Intraoperative factors

  • Graft size: grafts with greater surgical success have a diameter less than 8.5 mm and greater than 6.5 mm.35-37
  • Location: the location of the graft should be central, as regards both the donor and the recipient.9
  • Surgery associated: performing cataract, iris, vitreous, or retinal surgery in the same surgery as the keratoplasty increases the inflammatory component.38-40

Which risk factors or factors are significantly associated with corneal transplant rejection in patients with penetrating keratoplasty performed at the Hospital de Oftalmología del Centro Médico Nacional Siglo XXI, as the association of risk factors with graft rejection in the candidate population in our area is unknown.


A descriptive, observational, retrospective, transversal, and analytical study was developed. The accessible population was patients operated on in the UMAE SXXI Servicio de Oftalmología from December 1st, 2012 to November 12th, 2013. The study included patients undergoing corneal transplant for any disease, with a minimum follow-up of 6 months, with any gender or age. Patients were excluded whose preoperative diagnosis could not be determined to classify them in a risk group.

Age, gender, and previous diagnosis were recorded for each patient, as were rejection at any time of follow-up, type of rejection, state of the cornea during follow-up, and associated factors: sex, vascularization, drill size, previous intraocular surgery, and visual acuity. The variable of study was corneal transplant rejection, defined as the report of rejection in the clinical diagnosis record; it was a qualitative, nominal variable whose unit of measurement was presence or absence. Associated risk factors were identified during the first year in the whole sample and in each risk group; their frequency among patients was compared with and without rejection using Chi-squared. p < 0.05 was considered significant. 

To determine the frequency of corneal rejection, a base sample size was calculated for accurately determining a ratio of 40% in a given population with an accuracy of 90%. The sample size for each of the risk factors was calculated based on difference of proportions (Table I). The calculation was performed in the program Epi info version 3.4.3 - 2010'. Alpha: 0.10, Power 0.80.

Table I Risk factors
P1 P2 Size
Neovascularization 0.35 0.35 150 patients
Previous intraocular surgery 0.35 0.55 150 patients
History of


0.35 0.55 150 patients
Donor > age 55 0.35 0.55 150 patients


A study was performed with 150 patients undergoing penetrating keratoplasty from December 1st, 2012 to November 12th, 2013 in the cornea service of the IMSS Hospital de Oftalmología de Centro Médico Nacional Siglo XXI.  

This study reviewed 150 cases of patients given corneal transplants, of whom 53 (35.3%) had corneal transplant rejection. Rejection was more frequent in the male population, with 31 patients (58.4%), while in the female population 22 patients (41.5%) presented rejection; the right eye was most affected, with 29 (54.7%) compared to 24 cases (45.2%). The distribution by age group is shown in Table II. The distribution of cases of rejection based on preoperative diagnosis is shown in Table III.

Table II Age by group
Frequency Percentage
< 40 16 30.2 %
40-60 years 13 24.5 %
> 60 years 24 45.3 %

Table III Distribution of cases of rejection as a function of diagnosis prior to graft
Keratoconus 12 22.6 %
Bullous keratopathy 17 32.1 %
Herpetic keratopathy 2 3.8 %
Leucomas 3 5.7 %
Corneal ulcer 2 3.8 %
Bacterial keratitis 8 15.1 %
Other ectasias 2 3.8 %
Corneal graft rejection 7 13.2 %
Total 53 100.0 %

Of the patients who had corneal graft rejection, the most frequent was the endothelial type with 31 patients (58.4%), then combined type with 17 patients (32.0%), and finally the epithelial type with 5 patients (9.4%). Study results are summarized in Table IV.

Table IV Summary of 150 patients of protocol
Variable Unit of measurement Frequency Percentage (%)
Sex Male 90 60.0
Female 60 40.0
Age Under age 60 74 49.3
Over age 40 76 50.7
Eye operated on Right 76 50.7
Left 74 49.3
Neovascularization of receptor corona Present 32 21.3
Absent 118 78.7
VA pre-surgery ≥ 20/400 18 12.0
≤ CD 132 88.0
VA 12 months post-surgery ≤ MM 9 6.0
CD 19 12.7
20/400 22 14.7
20/140 27 18.0
20/100 43 28.7
20/80 11 7.3
20/60 14 9.3
20/50 5 3.3
Comparison of VA pre-and post-surgery Worse 9 6
Same 24 16
Better 117 78
Presence of rejection Present 53 64.7
Absent 97 22.7
Time from surgery to rejection 1st  quarter 34 22.7
2nd quarter 8 5.3
3rd quarter 7 4.7
4th quarter 4 2.7
No rejection 97 64.7
Type of rejection Endothelial 31 20.7
Epithelial 5 3.3
Combined 17 11.3
No rejection 97 64.7


This study found a slightly higher frequency of rejection (35.3%) than that reported in the literature; reports vary with different figures, but a range from 28 to 35% chance of rejection can be established.

In terms of age, no statistically significant differences were found in recipient age for rejection (Chi-squared (2) = 3.834, p > 0.05). No statistically significant differences were found either in the proportion of corneal rejection regarding sex (Chi-squared (2) = .011, p > 0.05).

Unlike the reports in the literature, which mention the most common cause of corneal transplantation as keratoconus, the main indication for penetrating keratoplasty in our study population was bullous keratopathy due to the average age of patients who underwent this treatment.

The pathology with the highest percentage of rejection was bullous keratopathy with 32.1%, followed by keratoconus with 22.6% of all rejections. It is important to note that the two cases of herpetic keratitis presented episodes of corneal rejection, representing only 3.8% of all cases, which is assumed to be due to the low incidence of herpetic keratitis, without representing a significant statistical difference.

Most patients (81.3%) achieved improved visual acuity compared to pre-surgery; only 28 patients had counting fingers or worse; half of these (14 cases) had episodes of graft rejection.

Regarding the postoperative time when the episode of corneal rejection was observed, the majority of cases occurred during the first quarter (Chi-squared (2) = .015, p < .05), which was statistically significant, which coincides with reports in the literature, which have already described that episodes of corneal rejection are more frequent within the first 6 months post-surgery. In addition, it was found that 81.3% of patients with previous neovascularization had a rejection episode (Chi-squared (2) = 35,024, p < 0.000). As described in the literature, larger grafts are more prone to rejection, 41 of the 53 rejection cases occurred with donor tissue greater than 8.00 mm (p < 0.000).


The main indication for penetrating keratoplasty in this hospital in this study was bullous keratopathy, followed by keratoconus.

The factor most significantly associated with corneal transplant rejection was anatomical (vascularization), not etiological; it is therefore necessary to standardize the preoperative measurement of this factor to assess its usefulness as a predictive factor and, if so, its predictive value may be high to use it routinely in the assessment of corneal transplant rejection risk, and take steps to reduce the risk.

Cataract surgery is one of the major surgical procedures performed worldwide, bullous keratopathy being one of its main postsurgical complications. In our population, bullous keratopathy, along with keratoconus, was the most common preoperative diagnosis for corneal transplantation. For this reason it is necessary to optimize the cataract surgical technique to reduce cases of bullous keratopathy, and to closely monitor patients after cataract surgery to provide timely care.

Timely identification and treatment of pathologies of the cornea causing visual impairment in economically active patients is vital to achieve a speedy recovery and return them to the productive sector.

The proportion of improvement in visual acuity was significant, although better results could be achieved by protocolizing the choice of patients for the surgical procedure. 

Our study found similar results to those reported in the literature, the most important risk factors for rejection being: the use of drills larger than 7.50 mm, patient history of previous corneal neovascularization, keratopathy, and herpetic keratitis.

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Conflict of interest statement: The authors have completed and submitted the form translated into Spanish for the declaration of potential conflicts of interest of the International Committee of Medical Journal Editors, and none were reported in relation to this article.

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