Abstract
This study was performed to determine whether chronic kidney disease (CKD) is associated with an increased risk of pseudoexfoliation (PEX) syndrome. This is an age-matched case control study evaluating frequency of PEX in patients over age 40 with the diagnosis of stage 1–4 CKD and those undergoing hemodialysis (HD). Subjects over age 40 with hypertension and/or diabetes mellitus (DM) and normal kidney functions were studied as a control group. CKD was diagnosed as decreased glomerular filtration rate (GFR) of less than 60 mL/min/1.73 m2 for at least 3 months. Study groups were arranged as group 1 consisting of HD receiving CKD patients, group 2 consisting of CKD patients who do not need HD and group 3 as a control. Demographic properties and the prevalence of PEX were evaluated and compared between groups. Because of the effect of DM on PEX occurrence, it was also evaluated after exclusion of diabetic patients. A total of 101 cases in group 1, 106 cases in group 2 and 117 cases in group 3 were included in the study. Pseudoexfoliation was found in 7 (6.9%) patients in group 1, 5 (4.7%) patients in group 2 and 7 (5.9%) patients in group 3 (p > 0.05). After exclusion of diabetic patients the prevalence of PEX changed as 4 (5.6%) in group 1, 2 (4.4%) in group 2 and 1 (1.8%) in group 3 (p > 0.05). In conclusion, CKD was not associated with increased prevalence of PEX in this study.
Introduction
Pseudoexfoliation (PEX), an age-related disease, with a reported prevalence of 0–21% is characterized by the deposition of a typical fibrillar material in the ocular tissues.Citation1–3 PEX is not only an ocular disease, but also a generalized disorder that involves the abnormal production and/or turnover of extracellular matrix material.Citation4,Citation5 Recent investigations have shown that the PEX material is found in many parts of the body such as the eyes, skin, heart, lungs, liver, kidney, gall bladder, blood vessels, optic nerves and meninges. Pseudoexfoliative fibers are consistently associated with fibroblasts, collagen and elastic fibers.Citation5,Citation6 Hypoxia was hypothesized as an important contributory factor for the development of PEX, and a possible link between the presence of ocular PEX and vascular disease was studied in detail.Citation4 Elastin is a major part of the extracellular matrix of arterioles and previous studies have shown an association between vascular wall elastosis, endothelial dysfunction and pseudoexfoliative material.Citation7,Citation8 In the iris vessels of PEX patients studied by electron microscopy a gradual degeneration of vascular cells, progressing from adventitial to endothelial cells, associated with the production of excess extracellular material, including pseudoexfoliative fibers was found. Oxygen partial pressure in the anterior chamber of these patients was lower compared to controls. It was concluded that anterior-chamber hypoxia due to iris vasculopathy represent a complication of PEX.Citation9 Systemic endothelial dysfunction in patients with PEX was shown by assessment of the response to flow-mediated dilation of the brachial artery and was attributed to the accumulation of pseudoexfoliative fibrils in arterial wall.Citation8,Citation10
Chronic kidney disease (CKD) is due to a progressive loss of renal function that may lead to complications such as cardiovascular disease or pericarditis. Established CKD and chronic renal failure (CRF) are terms that describe the late stage of kidney damage, when the disease is considered irreversible. CKD leads to altered properties and responses of the endothelium. Endothelial dysfunction is a common event described in renal failure, both chronic and acute, as well as in all end-stage renal diseases.Citation11,Citation12 Given the fact that PEX is associated with a significant endothelial dysfunction, we hypothesize that CKD patients may have increased PEX frequency. To begin testing this hypothesis, we studied PEX prevalence in CKD patients and compared it with age and sex matched controls. To our knowledge no study of PEX prevalence in CKD patients was reported previously.
Materials and methods
The study group was selected from a population of patients aged 40 years or older who attended the nephrology outpatient clinics of Hitit University Corum Education and Research Hospital. The hospital is located in Corum, a middle Black Sea region of Turkey. Relevant details in medical and ocular history were obtained from each patient including; history of systemic arterial hypertension (HT), diabetes mellitus (DM) and intraocular surgery. Parameters such as age, gender, duration of CKD or hemodialysis (HD) were obtained from the medical records of the patients. CKD was diagnosed as decreased glomerular filtration rate (GFR) of less than 60 mL/min/1.73 m2 for 3 or more months. Estimated GFR was measured according to the method of Levey et al.Citation13 Hemodialysis patients were recruited from patients who were routinely treated in the dialysis unit of our hospital for at least 1 year and were receiving standardized HD prescriptions (500 mL/min dialysate flow; 200–250 mL/min blood flow; 4 h of dialysis per session; three sessions per week). Routine serum biochemical variables including glucose, blood urea nitrogen and creatinine were analyzed using standard laboratory methods. Blood samples were obtained in the morning after an overnight fast (before starting a dialysis session in HD patients). All of the diabetic patients were diagnosed with diabetes mellitus type 2. Systolic and diastolic blood pressures of patients and healthy subjects were measured in an upright sitting position after at least 5 min of rest. Patients were divided into two groups as CKD patients undergoing HD (group 1) and stage 1–4 CKD patients that do not need HD (group 2). Subjects over age 40 with hypertension and/or diabetes mellitus and normal kidney functions were studied as a control group (group 3).
All patients underwent complete ocular examination conducted by an experienced ophthalmologist. After undilated slit-lamp biomicroscopy evaluation, the dilation of the pupil was performed using 1% cyclopentolate and examination repeated thereafter. Pseudoexfoliation was diagnosed clinically by the presence of typical PEX material at the pupil edges, iris and/or lens. Anterior and posterior segment findings and intraocular pressure measured by noncontact pneumotonometer were recorded. Eyes with a history of cataract surgery were excluded from this study, because it prevented the accurate evaluation of PEX. This is the reason why the numbers of the eyes are less than doubled numbers of the cases.
The statistical analysis was performed using the Statistical Program for the Social Sciences Version 16.0 (SPSS, Inc, Chicago, IL). Means, standard deviations (SDs) and 95% confidence intervals (CIs) were obtained. A p value of <0.05, measured by Pearson’s chi-square test, was considered to indicate statistical significance. For each study group the sex distribution, mean age and standard deviations (SDs) were calculated.
Informed consent was obtained from each patient. The study was approved by the local ethics committee.
Results
A total of 101 cases in group 1, 106 cases in group 2 and 117 cases in group 3 were included in the study. Clinical characteristics and data of study groups are given in .
Table 1. Clinical characteristics and data of study groups.
Mean age of cases in group 1 was 59.7 ± 11 years, in group 2 it was 60 ± 8 years and in group 3 it was 55 ± 9 years. The age and gender distribution of the control group were similar to that of the study groups (p > 0.05).
In group 1, 192 eyes (97 right, 95 left) of 101 cases were included in the study. Pseudoexfoliation was present in 7 (6.9%) cases (10 eyes – 6 right, 4 left). Out of 7 cases with PEX, 3 had and 4 did not have DM (p = 0.38).
In group 2, 205 eyes (101 right, 104 left) of 106 cases were included in the study. Pseudoexfoliation was present in 5 (4.7%) cases (10 eyes – 5 right, 5 left). Out of 5 cases with PEX, 3 had and 2 did not have DM (p = 0.35).
In group 3, 229 eyes (114 right, 115 left) of 117 cases were included in the study. Pseudoexfoliation was present in 7 (5.9%) cases (11 eyes – 7 right, 4 left). Out of 7 cases with PEX, 6 had DM and 1 did not have DM (p = 0.11).
The difference in PEX rates between the three study groups was statistically insignificant (p > 0.05).
The number of patients with PEX after exclusion of diabetic patients is given in . Pseudoexfoliation was present in 5.6% of patients in group 1, 4.4% in group 2 and 1.8% in group 3. The difference between study groups remained insignificant (p > 0.05).
Table 2. PEX in non-diabetic patients.
Discussion
Pseudoexfoliation syndrome is a disorder with both ocular and systemic manifestations and is related with increased risk of glaucoma, cataract surgery complications and systemic vascular diseases. Zenkel et al. investigated the presence, expression, regulation and functional significance of proinflammatory cytokines in eyes with early and late stages of PEX syndrome/glaucoma in comparison with normal and glaucomatous control eyes using multiplex bead analysis, immunoassays, real-time PCR, Western blotting, immunohistochemistry and cell culture models. The findings suggested that an increased expression of IL-6 and IL-8, which may be induced by chronic stress conditions, such as oxidative stress and hypoxia, may act as a triggering factor for the abnormal PEX material production in the early stages.Citation14 It is accepted that oxidative stress contributes to atherosclerosis and also to kidney injury. Antioxidant mechanisms are inefficient in chronically hemodialyzed patients, which result in increased formation of reactive oxygen species and other free radicals and consequently in oxidative stress. This is related to numerous factors, including a considerable concentration of uremic toxins, activation of inflammatory mediators and elimination of low-molecular antioxidants by hemodialysis.Citation15 We hypothesized that PEX can be increased in patients with CKD because of the increased inflammatory process and oxidative stress. An association between PEX and CKD could allow for earlier detection of PEX and related abnormalities in CKD population, potentially resulting in a better long term prognosis of possible abnormalities. Furthermore, this association may shed light on underlying pathophysiology of PEX and stimulate further researches.
The aim of this study was to determine whether PEX syndrome risk is increased in patients with CKD at any stage. Pseudoexfoliation rate was similar in stage 1–4 CKD, dialysis and control groups. No significant increase or decrease was found between the patients and the control group. The occurrence of DM in cases with PEX syndrome was also neither increased nor decreased. Zakrzewski et al. have examined CKD rate in patients with PEX syndrome, primary open angle glaucoma and in the control group. They found that CKD was higher in the control group. However after adjusting for the differences in the rate of DM, an important risk factor for CKD, none of the study groups was associated with increased risk of CKD.Citation16 Our study was in part the reverse of this study where we evaluated the occurrence of PEX in patients with CKD and HD.
Sollosy reported higher rate of PEX in diabetic patients in contrast to Psilas et al. who observed a decreased incidence of PEX in diabetics.Citation17,18 Because of the DM effect on PEX, we analyzed the rate of PEX after exclusion of diabetic patients. Although the occurrence of PEX was least in the control group, the difference between all study groups was not found to be statistically significant (p = 0.273). The difference between our findings and those, reported previously, may be attributed to different geographical locations and genetic factors of study populations.
In conclusion, the results of our study show that ocular PEX occurrence is not increased in CKD patients. So, the routine screening of PEX in CKD patients seems to be unnecessary.
Declaration of interest
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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