| Abstract|| |
Disorders associated with the hepatitis C virus (HCV) have been reported including cardiovascular, metabolic, and central nervous system diseases. Since chronic HCV infections may be curable, their identification as causal contributors to cardiovascular risk could offer new perspectives in the prevention of cardiovascular disease. The aim of this study is to investigate the association between HCV and aortic arch calcification (AAC) and corneal and conjunctival calcification (CCC) in maintenance hemodialysis (MHD) patients; further, we assessed the correlation of CCC with vascular calcification. A total of 100 patients undergoing hemodialysis (HD) in our hospital were included in this study. Patients underwent a complete ocular examination including intraocular pressure, and CCC was looked for by slit lamp and fundoscopy. CCC was graded according to modified Porter and Crombie classification system described by Tokuyama et al. Helical computerized tomographic chest examination was used to evaluate the grading of AAC. Demographic, hematological, biochemical, and dialysis-related data were obtained. There was significant difference between seropositive (n = 51) and seronegative patients (n = 49) regarding grading of AAC and CCC (P <0.001). Signiﬁcant positive correlation was found between grading of CCC, AAC, age (P <0.001), duration on HD (P <0.001), HCV-antibody positivity (P <0.001), serum calcium level (P <0.001), serum phosphorus level (P <0.001), calcium × phosphorus product (P <0.001), and i-parathormone level (P < 0.001). In addition, CCC grading positively correlated with AAC. Our results suggest that patients undergoing HD infected with the HCV have high degree of CCC, AAC, and mineral metabolism disorder. The strong correlation between CCC and AAC indicates that CCC evaluation is an easy, fast, non-invasive method, and might be used as an indirect indicator to detect vascular calcification in patients undergoing MHD.
|How to cite this article:|
AbouSeif K, Sany D, Elshahawy Y, Seddik A, Rahman K, Gaber M. Association of conjunctival and corneal calcification with vascular calcification among hepatitis-C-seropositive hemodialysis patients. Saudi J Kidney Dis Transpl 2016;27:1168-81
|How to cite this URL:|
AbouSeif K, Sany D, Elshahawy Y, Seddik A, Rahman K, Gaber M. Association of conjunctival and corneal calcification with vascular calcification among hepatitis-C-seropositive hemodialysis patients. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2020 Aug 15];27:1168-81. Available from: http://www.sjkdt.org/text.asp?2016/27/6/1168/194606
| Introduction|| |
Hepatitis C virus (HCV) is a chronic infection which may or may not be associated with atherosclerosis. Possible association between HCV infection and carotid atherosclerosis has been demonstrated among the Japanese general population. , Several studies have been conducted to confirm or disprove, an independent association between HCV infection and atherosclerotic disorders, including coronary artery disease,  ischemic stroke, and  early atherosclerosis, especially among patients without advanced liver cirrhosis. It has been clearly shown that various underlying factors can affect the eye, such as hemodialysis (HD) treatment.  The most important ocular changes seen among HD patients are retinal vascular complications such as hypertensive retinopathy, anterior optic ischemic neuropathy, central retinal artery occlusion, and diabetic retinopathy.  The intraocular pressure has shown a significant rise in the majority of patients on regular HD. , The development of conjunctival and corneal calcification (CCC) in patients with end-stage renal disease (ESRD) is well known. , Usually, a slit-lamp examination is needed for their accurate identification.  They appear as fine white deposits, coarse granular crystals, or flatter plaques confined to the areas of the cornea and conjunctiva exposed at the palpebral aperture. , The exact mechanism underlying CCC remains unclear. Porter and Crombie proposed that a high serum calcium-phosphate product in patients with chronic kidney disease (CKD) failure leads to deposition of calcium salt in the cornea and conjunctiva exposed by the palpebral aperture when pH is increased by CO  loss.  Vascular calciﬁcation (VC), particularly arterial calciﬁcation, is very prevalent in patients with CKD and is associated with high cardiovascular morbidity and mortality in these patients.  The pathophysiology of VC in patients with CKD is recognized to be distinct from atherosclerosis in the general population.  The advanced stage of atherosclerosis usually appears as intimal calciﬁcation, which is focal and is associated with inﬂammation and occlusive lesions in the intimal layer of the vessel wall while the medial layer may remain intact.  In contrast, patients with CKD may develop VC in the intimal layer or the medial layer of the vessel wall. The mechanism underlying the development of VC in CKD is still unknown. Several factors, including mineral metabolism abnormalities, high serum level of parathyroid hormone (PTH), excessive consumption of calcium salts, inﬂammation, malnutrition, and oxidative stress, have been shown to contribute signiﬁcantly to the development of VC in patients with CKD. 
To examine the impact of HCV on vascular calcification and bone metabolism, we analyzed the biochemical parameters in our patients undergoing HD, determined the signiﬁcant risk factors for CCC and VC, and investigated the correlation of CCC with aortic arch calcification (AAC).
| Patients and Methods|| |
One hundred patients with CKD undergoing HD in the dialysis unit of Ain Shams University Hospitals were enrolled in this cross-sectional observational study. Etiology of the primary kidney disease was hypertensive nephrosclerosis in 40 patients (40%), diabetes in 25 (25%), chronic glomerulonephritis in eight (8%), interstitial nephritis in seven (7%), amyloidosis caused by familial Mediterranean fever in three (3%), polycystic kidney disease in two (2%), and uncertain in 15 patients (15%). None of the patients had a history of malignancy or primary hyperparathyroidism. All patients were under treatment with oral calcium carbonate and alphacalcidol administered according to calcium, phosphorus, calcium × phosphorus product (Ca × P), and PTH values. Target values were as follows: calcium, 8.4-9.5 mg/dL (2.10-2.37 mmol/L); phosphorus, 3.5-5.5 mg/dL (1.13-1.78 mmol/ L); Ca × P, <55 mg 2 /dL 2 (4.44 mmol 2 /L 2 ; and PTH, 150-600 pg/dL (ng/L). Active Vitamin D and phosphorus binder treatment at enrollment were recorded, and mean doses were calculated per month. HD was performed using synthetic membranes, and bicarbonate dialysate was used with 1.5 mmol/L of calcium. Weekly HD treatment duration was tailored individually between 10 and 15 h and adjusted to achieve a Kt/V >1.2. The mean ± standard deviation (SD) duration on HD was 4.41 ± 3.44 years. Determination of HCV serology was performed using the third generation enzyme-linked immunosorbent assay method. HCV-positive patients were subclassified according to the Child-TurcottePugh score.  This study was performed according to the Declaration of Helsinki, approved by the Research Ethics Committee of the hospital, and written informed consent was obtained from all the patients.
Grading and classiﬁ cation of CCC
The same observer, who was blinded to clinical data, evaluated CCC in all subjects. There were no other clinically apparent eye diseases that could cause CCC in the study subjects. Examinations were carried out using a slitlamp microscope. Ocular calcifications were scored between 0 and 5 as described by Tokuyama et al:  0 no deposits; 1 conjunctival deposits; 2 conjunctival and strictly limbal deposits; 3 conjunctival deposits and irregular corneal deposits; 4 clear single line of corneal deposits and conjunctival deposits; and 5 more extensive corneal deposits and conjunctival deposits. The date of the eye examination was accepted as the enrollment date to the study. To calculate intra-observer variability, the same ophthalmologist reevaluated 10 randomly selected photographs three months after the first evaluation.
Grading of aortic arch calcification
Spiral chest computerized tomographic (CT) examination was used to assess the presence of vascular calcification. An experienced radiologist, who was blinded to the laboratory and ocular data of the patients, evaluated all radiographic films. The grading of AAC was modified from the categorization proposed in a previous report  and was divided into four grades as follows: grade 0 indicated no calcification in the aortic arch; Grade 1 indicated linear or curvilinear calcification in the aortic arch, and the length of calcification <1 cm and the thickness of calcification <1 mm; Grade 2 indicated length of calcification ≥1 cm and thickness of calcification <1 mm or length of calcification <1 cm, but the thickness of calcification ≥1 mm; and Grade 3 indicated the length of calcification ≥1 cm and the thickness of calcification ≥1 mm, Grade 3 AAC was defined as severe calcification.
Blood specimens were collected within a few days of clinical examination during stable HD sessions to minimize the effect of any acute event. Blood was drawn from the arterial end of the vascular access immediately before midweek HD, centrifuged, and then stored at −70°C until performing the assays. Serum levels of albumin, blood urea nitrogen, creatinine, and transferrin saturation were measured and used as nutritional markers. Highsensitivity C-reactive protein (hsCRP), used as an inflammatory marker, was analyzed by immune-nephelometry (Nanopia CRP; Daiichi, Inc., Tokyo, Japan). The lowest detection limit was <0.15 mg/L. All other data were obtained with standard laboratory procedures using an automatic analyzer (Hitachi 705, Boehringer Ingelheim GmbH, Ingelheim, Germany). Serum levels of calcium, phosphate, and intact PTH (iPTH) were also measured, and the corrected serum calcium level was calculated as: calcium (mg/dL) + 0.8 [4.0 − albumin (g/dL)].
| Statistical Analysis|| |
Data were fed to the computer and analyzed using IBM SPSS software package version 20.  Qualitative data were described using number and percentage. Quantitative data were described using range (minimum and maximum), mean, SD, and median. Comparison between different groups regarding categorical variables was tested using Chi-square test. When more than 20% of the cells had expected count <5, correction for Chi-square was conducted using Fisher's Exact test or Monte Carlo correction. The distributions of quantitative variables were tested for normality using Kolmogorov-Smirnov test, Shapiro-Wilk test, and D'Agstino test, also Histogram and QQ plot were used for vision test. If it revealed normal data distribution, parametric tests were applied. If the data were abnormally distributed, nonparametric tests were used. For normally distributed data, comparison between two independent populations was made using independent t-test. For abnormally distributed data, comparison between two independent populations was performed using Mann-Whitney U-test. Correlations between two quantitative variables were assessed using Spearman coefficient. Binary logistic regression was assessed.
| Results|| |
The demographic and clinical characteristics, calcification, retinal findings, and biochemical variables of HCV-positive and HCV-negative patients are listed in [Table 1]. HCV-positive patients were significantly older, had longer duration on HD, higher body mass index (BMI), as well as higher frequency of smokers, diabetes mellitus, hypertension, history of bilharziasis, cataract, retinopathy, AAC, CCC, cardiovascular disease, peripheral vascular disease, central vascular disease, serum phosphorus, Ca × P, iPTH, hs-CRP, and lipid profile (P <0.001).
|Table 1: Clinical characteristics and laboratory variables of subjects (n = 100) stratified by HCV status.|
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Comparison between patients with and without CCC
We reclassified our patients into two groups based on their CCC grading: patients with CCC Grades 1-3, and those without calcification. We compared the baseline characteristics and biochemical variables of the two groups.
The comparison is shown in [Table 2].
|Table 2: Clinical characteristics and laboratory variables of subjects (n=100) stratified by CCC grading.|
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Comparison between patients with and without AAC
We reclassified our patients into two groups based on their AAC grading: patients with AAC (Grades 1-3) and those without calcification. We compared the baseline characteristics and biochemical variables of the two groups. The results are shown in [Table 3].
|Table 3: Clinical characteristics and laboratory variables of subjects (n=100) stratified by AAC grading.|
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Binary logistic regression analysis of CCC and AAC
Binary logistic regression analysis for the most predictive factors affecting CCC revealed that duration on HD [hazard ratio (HR), 2.20; 95% confidence interval (95% CI) 1.4-3.4;P = 0.001] and iPTH (HR, 1.0; 95% CI 1.0-1.0; P = 0.001) significantly correlated with grading of CCC than other variables. Binary logistic regression analysis for AAC showed that duration on HD (HR, 2.5; 95% CI 1.5-4.1; P = 0.001) and iPTH (HR, 1.0; 95% CI 1.0-1.02; P = 0.002) significantly correlated with AAC grading than other variables.
Correlation of CCC with AAC
Our results from the analysis of the correlation of CCC with AAC demonstrated that CCC grading significantly positively correlated with AAC score in our HCV-positive patients (coefficient = 0.850, P <0.001; [Figure 1]; similar results were seen in the entire studied patient group (coefficient = 0.939, P <0.001) [Figure 1]a and b.
|Figure 1: Correlation between conjunctival and corneal calcification score and aortic arch calcification grading. (a) Conjunctival and corneal calcification grading positively correlated with aortic arch calcification grading in hepatitis C virus-positive patients (r = 0.850, P < 0.001). (b) Conjunctival and corneal calcification grading positively correlated with aortic arch calcification grading in total patients (r = 0.850, P < 0.001).|
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Variables that correlated with CCC grading in MHD patients
In HCV-positive patients, the CCC grading correlated with age (rs = 0.541; P <0.001), duration on HD (rs = 0.392; P <0.001), serum ferritin (rs = 0.408; P = 0.003), serum calcium (rs = 0.456; P <0.001), serum phosphorus (rs = 0.456; P <0.001), Ca × P (r = 0.660, P <0.001), iPTH (rs = 0.668; P <0.001) [Figure 2]a-f. In addition, in the total sample, there was a significant positive correlation with age, HD duration, diabetes duration, serum calcium, serum phosphorus, Ca × P, iPTH, CRP, and alkaline phosphatase.
|Figure 2: Correlations between conjuctival and corneal calcification grading and clinical and biochemical parameters in hepatitis C virus positive patients. Conjuctival and corneal calcification score significantly correlated with (a) serum Ca levels (r = 0.456, P = 0.001), (b) P levels (r = 0.561, P = 0.001), (c) Ca × P product (r = 0.660, P = 0.001), (d) iPTH (r = 0.668, P = 0.001), (e) age (r = 0.541, P = 0.001), (f) duration on dialysis (r = 0.697, P = 0.001).|
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Variables that correlated with AAC grading patients
AAC grading correlated with age in HCVpositive patients (rs = 0.552; P <0.001), duration on HD (rs = 0.772; P <0.001), serum ferritin (rs = 0.389; P = 0.005), serum calcium (rs = 0.405; P = 0.003), serum phosphorus (rs = 0.705; P <0.001), Ca × P (rs = 0.752, P = 0.001), iPTH (rs = 0.728; P <0.001) [Figure 3]a-f. In addition, in the whole sample, there was a significant positive correlation with age, HD duration, diabetes duration, serum calcium, serum phosphorus, Ca × P, iPTH, CRP, and alkaline phosphatase.
|Figure 3: Correlation between aortic arch calcification and clinical and biochemical parameters in hepatitis C virus positive patients. Aortic arch calcification grading significantly correlated with (a) serum Ca levels (r = 0.405, P = 0.003), (b) serum P levels (r = 0.705, P = 0.001), (c) Ca × P product (r = 0.752, P = 0.001), (d) iPTH (r = 0.728, P = 0.001), (e) age (r = 0.552, P = 0.001), (f) duration on dialysis (r = 0.772, P = 0.001).|
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| Discussion|| |
Several cross-sectional studies have linked HCV and insulin resistance. ,,, This goes with our study that showed higher BMI, increased frequency of diabetes and hypertensive patients, higher total cholesterol, and triglyceride levels among HCV-positive patients. A significant portion of the health burden associated with HCV is the consequence of a number of HCV-associated comorbidities.  Among these, type-2 diabetes and atherosclerosis are noteworthy because HCV infection has been linked to their pathogenesis.  In addition, HCV also causes steatosis,  which has been suggested to increase the risk of cardiovascular morbidity.  This study showed significantly more cardiovascular and peripheral vascular disease among HCV-positive patients. The observation that HCV seems to increase the risk of morbidity and mortality for some cardiovascular events and that the atherogenic role of HCV appears independent of classical risk factors raises the issue of the pathogenesis of cardiovascular damage in HCV infection. Although metabolic factors such as steatosis,  may play a role, systemic chronic inflammation seems more likely to be a central factor, ,, together with possible endothelial dysfunction,  and the contribution of genetic and environmental factors. Finally, it is interesting to note that according to a Danish study, some biomarkers predictive of coronary artery disease were more elevated in the 60 HCV-infected patients than among 60 controls: these markers included hsCRP;  this goes with our result which showed significant higher levels CRP in HCVpositive patients. Our study revealed higher frequency of cerebrovascular disease among HCV-positive patients in agreement with a cohort study from Taiwan.  In our study, 49 patients (49%) had AAC detected by CT examination, and CCC was detected by slit lamp examination in 55 patients (55%) with significantly greater frequency of high serum phosphorus, Ca × P, iPTH among HCV-positive patients. AAC has been associated with an increased risk of cardiovascular morbidity and mortality in the general ,, and HD populations,  and aortic calcification has been correlated with calcification in coronary arteries, which in turn predicts all-cause mortality. , Forty-one percent of patients in our study had ischemic heart disease, and 26% had suffered from myocardial infarction. However, the increased frequency of CCC in patients undergoing prolonged HD reﬂ ects the presence of a bone metabolic disorder. Because the course of CCC can be easily followed, its evaluation is very useful for assessing the severity of Ca and P imbalance and bone metabolic disorder in HD patients. We are interested to determine whether the degree of CCC is associated with the development of VC. If so, an increase of CCC may be a sign of more life-threatening diseases elsewhere such as coronary arteries. Our study showed that patients with CCC and AAC had multifactorial mechanisms underlying the development of vascular calcification. Several factors including mineral metabolism abnormalities, high serum level of PTH, excessive consumption of calcium salts, malnutrition, and oxidative stress, have been shown to contribute significantly to development of VC in patients with CKD.  Our study revealed that the average CRP level in patients with CCC and AAC was dramatically higher than that in patients with no AAC or CCC; this indicates that maintenance hemodialysis MHD patients with high level of VC might have higher degree of inflammation than MHD patients with mild VC. Pro-inflammatory stimulators including oxidative stress, CRP, and cytokines can directly induce VC.  Oh et al demonstrated that CRP independently predicts coronary calcification in young adults with ESRD.  Our study showed that the duration on HD and PTH levels were better predictors than other factors for vascular and corneal calcification. Similar to the reports of others, we also observed high levels of iPTH in patients with severe CCC. ,, Nasri et al conducted a study on 24 HD patients and found that the iPTH level positively correlated with corneal calcification.  Khamis et al studied the vascular calcifications in 88 patients on regular HD and discovered that iPTH level is the only predictor for both vascular calcification and CCC.  These results further support that secondary hyperparathyroidism of HD contributes to CCC and VC and emphasize the importance of proper management of hyperparathyroidism in MHD patients. The strong correlation between CCC and AAC might suggest some possible clinical applications of CCC score. Hsiao et al reported that the severity of CCC is an independent predictor for all-cause one-year mortality in MHD patients.  Thus, CCC score might be used as an indirect indicator to predict cardiovascular risks in HD patients. The present study has some limitations. First, it was a single-center study, and consequently, center-specific effects cannot be excluded from the study. Second, the sample size was small. Despite these limitations, our study proposes a new strategy for the detection of vascular calcification.
| Conclusions|| |
Our study demonstrates that HCV-positive MHD patients exhibited higher degree of both ACC and CCC. Grading of calcification positively correlated with age of the patients, duration on dialysis, calcium, phosphorus, and iPTH levels. In addition, strong correlation existed between AAC and CCC; hence, the evaluation of CCC grading is an easy, fast, inexpensive, and noninvasive method, and can be used as a tool to assess the status of extraskeletal calcification in patients with CKD.
Conflict of interest: None declared.
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Division of Nephrology, Ain Shams University, Cairo
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]