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Association of conjunctival and corneal calcification with vascular calcification in dialysis patients
Association of Conjunctival and Corneal Calcification With Vascular Calcification in Dialysis Patients Nurhan Seyahi, MD, Mehmet R. Altiparmak, MD, Arzu Kahveci, MD, Huseyin Yetik, MD, Kaya Kanberoglu, MD, Kamil Serdengecti, MD, Rezzan Ataman, MD, and Ekrem Erek, MD ● Background: Conjunctival and corneal calcification (CCC) is a well-known and easily detectable extraskeletal calcification, but its association with vascular calcification was not investigated previously. The aim of this study is to investigate the relationship of CCC with vascular calcification and bone metabolism parameters in dialysis patients. Methods: We evaluated 63 patients (30 men, 33 women; mean age, 43.5 ⴞ 13.4 years) who were on dialysis therapy for more than 6 months. Forty-four patients were on peritoneal dialysis and 19 patients were on hemodialysis therapy. The same observer evaluated the presence of CCC by using a slit-lamp microscope, and a total CCC score was recorded for each patient. Fifty-two age- and sex-matched healthy controls also were evaluated by using the same method. Biochemical data were collected from patient files. Bone mineral density (BMD) of the lumbar spine and femoral neck was measured, and the presence of vascular calcification was assessed by using x-ray examinations of the pelvis and hands. Results: Mean CCC score in patients was significantly higher than that in controls (6.2 ⴞ 5.1 versus 1.3 ⴞ 1.8; P ⴝ 0.001). CCC score correlated significantly with duration of renal replacement therapy (rs ⴝ 0.392; P ⴝ 0.002), serum phosphorus level (rs ⴝ 0.259; P ⴝ 0.042), and calcium ⴛ phosphorus product (rs ⴝ 0.337; P ⴝ 0.007). However, we did not find a significant correlation with calcium, parathyroid hormone, alkaline phosphatase, albumin, or C-reactive protein level or BMD. The frequency of vascular calcification was significantly greater in patients with a high CCC score (CCC score > 10) compared with a low CCC score (<3; 56.3% versus 5.6%; P ⴝ 0.002). Conclusion: Evaluation of CCC score is an easy, fast, and noninvasive method. It seems that CCC score can be used as an additional tool to assess the status of extraskeletal calcification in dialysis patients. Am J Kidney Dis 45:550-556. © 2005 by the National Kidney Foundation, Inc. INDEX WORDS: Corneal calcification; conjunctival calcification; vascular calcification; dialysis.
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HE DEVELOPMENT OF conjunctival and corneal calcification (CCC) in patients with end-stage renal disease (ESRD) is well known.1-3 Usually, a slit-lamp examination is needed for their accurate identification.2 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.2,3 Sometimes calcifications appear as noncrystalline, and the exact identification of calcification can be made only by histological examination. Histologically, the site of deposition is the subepithelial layers and the epithelium itself.2
From the Departments of Nephrology, Ophthalmology, and Radiology, Istanbul University, Cerrahpasa Medical Faculty, Istanbul, Turkey. Received September 9, 2004; accepted in revised form November 5, 2004. Originally published online as doi:10.1053/j.ajkd.2004.11.002 on January 14, 2005. Address reprint requests to Nurhan Seyahi, MD, Halaskargazi c no 209-211, Huzur ap d 2, Sisli, Istanbul, 34360 Turkey. E-mail: [email protected] © 2005 by the National Kidney Foundation, Inc. 0272-6386/05/4503-0012$30.00/0 doi:10.1053/j.ajkd.2004.11.002 550
Recently, the association of CCC with bone metabolism was investigated systematically in hemodialysis patients; however, such data are missing in peritoneal dialysis patients.4 Furthermore, to the best of our knowledge, their association with vascular calcification was not evaluated previously. Vascular calcifications, especially arterial calcifications, have been recognized as a common complication of ESRD for many years.5 Current data suggest their association with the high cardiovascular morbidity and mortality of patients with ESRD.6-10 Therefore, there is a need for widely available and affordable techniques to evaluate vascular calcifications or, more generally, soft-tissue calcifications in these patients. The aim of this study is to evaluate the relation of CCC with bone metabolism parameters in both hemodialysis and peritoneal dialysis patients and investigate the association of CCC with vascular calcification in these patients. METHODS Sixty-three adult (age ⱖ 18 years) patients with ESRD who were on renal replacement therapy (RRT) for at least 6 months were included in the study. Forty-four patients were on peritoneal dialysis and 19 patients were on hemodialysis therapy. Continuous ambulatory peritoneal dialysis was per-
American Journal of Kidney Diseases, Vol 45, No 3 (March), 2005: pp 550-556
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Fig 1. Conjunctival calcium deposits detected using slit-lamp examination. Circle, area of conjunctival calcification; arrows, fine white deposits.
formed using 4 to 5 daily exchanges with a 2,000-mL volume, aiming at a Kt/V greater than 1.8. Standard solution contained 1.75 mmol/L of calcium. Hemodialysis was performed using synthetic or semisynthetic membranes, and bicarbonate dialysate was used with 1.5 mmol/L of calcium. Weekly hemodialysis treatment duration was tailored individually between 10 and 15 hours and adjusted to achieve a Kt/V greater than 1.2. Calcium- or aluminum-containing phosphorus binders and active vitamin D were administered to all patients according to calcium, phosphorus, calcium ⫻ phosphorus product (Ca ⫻ P), and parathyroid hormone (PTH) values. Target values were as follows: calcium, 8.4 to 9.5 mg/dL (2.10 to 2.37 mmol/L); phosphorus, 3.5 to 5.5 mg/dL (1.13 to 1.78 mmol/L); Ca ⫻ P, less than 55 mg2/dL2 (⬍4.44 mmol2/L2); and PTH, 150 to 250 pg/dL (ng/L). Active vitamin D and phosphorus-binder treatment at enrollment was recorded, and mean doses were calculated for the last 12 months. If the duration of RRT was less than 12 months, average values for the entire RRT period were calculated. Causes of ESRD were chronic glomerulonephritis in 23 patients (36.5%), interstitial nephritis in 7 patients (11.1%), amyloidosis caused by familial Mediterranean fever in 7 patients (11.1%), diabetes in 6 patients (9.5%), polycystic kidney disease in 6 patients (9.5%), hypertensive nephrosclerosis in 3 patients (4.7%), and uncertain in 11 patients (17.5%). The same observer, who was blinded to clinical data, evaluated CCC in all subjects. There were no clinically apparent eye diseases that can cause CCC in the study subjects. Examinations were carried out using a slit-lamp microscope. Ocular calcifications were scored between 0 and 5, as described by Tokuyama et al4: 0 indicates 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 nasal and temporal regions
of both corneas were evaluated, and a total calcification score ranging between 0 and 20 was obtained by adding scores for each region (Fig 1). The date of the eye examination was accepted as the enrollment date to the study. The same observer also assessed calcification scores in 52 healthy volunteers by using the described method. Serum levels of calcium, phosphorus, alkaline phosphatase (ALP), PTH, albumin, and C-reactive protein (CRP) were collected from patients’ files. Average values for the last 12 months were calculated by using 6 measurements of calcium, phosphorus, ALP, and albumin. Average values for PTH and CRP were calculated using 3 measurements. If duration of RRT was less than 12 months, average values for the entire RRT period were calculated. These mean values were used in the study. Biochemical parameters were measured using an autoanalyzer (Olympus AU 800; Olympus Diagnostica GmhH, Hamburg, Germany). PTH levels were determined by means of chemiluminescent immunoassay (Liaison N-tact; DiaSorin Inc, Stillwater, MN), and CRP values were measured using a nephelometer (Behring BN II; Dade Behring, Deerfield, IL). Bone mineral density (BMD) of the lumbar spine at L1 to L4 of the anteroposterior view (lumbar BMD) and also of the femoral neck (femoral BMD) were measured by using a dual-energy radiograph absorptiometry (Hologic QDR4500; Bedford, MA). BMD measurements were performed within 2 weeks of enrollment. Anteroposterior x-ray examination of the pelvis and hands was performed to assess for the presence of vascular calcifications. One single experienced radiologist who was blinded to patient information evaluated all radiographic films. Linear calcifications are defined as uniform railroad-track–type (angiogram-like) opacities. Patchy calcifications are defined as discrete plaques with irregular and patchy distribution. The presence of linear calcifications with or without patchy calcifications was recorded for each film (Fig 2). Isolated patchy calcifications may be confused with other types of extravascular calcifications and therefore were not consid-
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Fig 2. Vascular calcifications in (A) pelvic arteries and (B) hand arteries. Arrows show calcified arteries.
ered. X-ray evaluation was performed within 2 weeks of enrollment. To calculate intraobserver variability, the same radiologist reevaluated 32 randomly selected radiographs 3 months after the first evaluation. Thirty-one of these samples were reclassified correctly ( ⫽ 0.93). Data are expressed as mean ⫾ SD if not stated otherwise. Continuous variables were compared using Student’s t-test or Mann-Whitney U test, when appropriate. Categorical variables were compared using chi-square or Fisher exact test, when appropriate. Associations between CCC scores and study variables were evaluated by means of Spearman’s rank correlation (rs). All tests were performed using SPSS for Windows, version 10.0, software (SPSS Inc, Chicago, IL). P less than 0.05 is considered statistically significant.
RESULTS
Demographic characteristics of patients and healthy controls are listed in Table 1. Age and sex distribution of both groups was similar. At enrollment, 20 patients were administered active vitamin D; 50 patients, calcium-containing phosphorus binders; and 13 patients, aluminumcontaining phosphorus binders. Mean doses of Table 1. Demographic Data and CCC Frequency and Score of Patients and Controls Patients (n ⫽ 63)
Controls (n ⫽ 52)
P
Men/women 30/33 30/22 Not significant Age (y) 43.5 ⫾ 13.4 41.2 ⫾ 11.2 Not significant CCC presence 55 (87.3) 20 (38.5) 0.001 CCC score 6.2 ⫾ 5.1 1.3 ⫾ 1.8 0.001 Median (range) 4 (0-20) 0 (0-6) NOTE. Values expressed as mean ⫾ SD or number (percent) unless otherwise noted.
active vitamin D and phosphorus binders are listed in Table 2. A previous parathyroidectomy was performed in 5 patients. Graphical representation of the frequency table showing the distribution of individual CCC scores in patients and controls is shown in Fig 3. CCC was significantly more frequent in patients than controls (Table 1). Mean CCC score of patients was 6.2 ⫾ 5.1, and this score was significantly higher than that of controls (Table 1). CCC score correlated with age in healthy controls (rs ⫽ 0.404; P ⫽ 0.003). However, in patients, CCC score did not correlate with age (rs ⫽ 0.196; P ⫽ 0.124), but correlated with duration of RRT (rs ⫽ 0.392; P ⫽ 0.002; Fig 4A). Biochemical values for patients are listed in Table 2. CCC score correlated with serum levels of phosphorus (rs ⫽ 0.259; P ⫽ 0.042; Fig 4B) and Ca ⫻ P (rs ⫽ 0.337; P ⫽ 0.007; Fig 4C). However, it did not correlate with calcium (rs ⫽ 0.167; P ⫽ 0.193), ALP (rs ⫽ 0.103; P ⫽ 0.426), PTH (rs ⫽ 0.130; P ⫽ 0.318), albumin (rs ⫽ 0.113; P ⫽ 0.38), or CRP (rs ⫽ 0.024; P ⫽ 0.866) levels. Mean BMD values were 1.01 ⫾0.19 g/cm2 for lumbar BMD and 0.78 ⫾ 0.13 g/cm2 for femoral BMD. Neither lumbar (rs ⫽ ⫺0.14; P ⫽ 0.914) nor femoral (rs ⫽ ⫺0.37; P ⫽ 0.738) BMD correlated with CCC score. Vascular calcifications were present in 21 patients (33.3%; Table 2). In 12 patients (19.0%), calcifications were detected in the pelvis; 4 patients (6.4%), the hands; and 5 patients (7.9%), both regions. CCC score of patients with vascu-
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Table 2. Clinical and Biochemical Data, BMD Results, and Vascular Calcification Frequency of Patients
Men/women Age (y) Peritoneal dialysis/hemodialysis RRT duration (mo) Parathyroidectomy Calcium (mg/dL) Phosphorus (mg/dL) Ca ⫻ P (mg2/dL2) ALP (U/L) PTH (pg/mL) Albumin (g/dL) CRP (mg/dL) Lumbar BMD (g/cm2) Femoral BMD (g/cm2) Active vitamin D (g/d) Elemental calcium (g/d) Elemental aluminum (g/d) Presence of vascular calcification Pelvis Hands
All Patients (N ⫽ 63)
Low CCC Score (n ⫽ 17)
High CCC Score (n ⫽ 16)
P*
30/33 43.5 ⫾ 11.7 44/19 54.5 ⫾ 39.9 5 (7.9) 9.22 ⫾ 0.56 5.38 ⫾ 1.30 48.47 ⫾ 12.41 161.0 ⫾ 116.7 310.8 ⫾ 257.4 3.75 ⫾ 0.46 14.31 ⫾ 22.40 1.01 ⫾ 0.19 0.78 ⫾ 0.13 0.36 ⫾ 0.34 0.84 ⫾ 0.41 0.42 ⫾ 0.32 21 (33.3) 16 (27.0) 9 (14.3)
7/10 37.9 ⫾ 14.8 10/7 21.1 ⫾ 5.1 1 (5.9) 9.08 ⫾ 0.38 5.17 ⫾ 1.04 44.76 ⫾ 10.36 133.1 ⫾ 65.7 292.2 ⫾ 272.5 3.62 ⫾ 0.61 13.09 ⫾ 17.95 1.02 ⫾ 0.19 0.81 ⫾ 0.16 0.37 ⫾ 0.32 0.71 ⫾ 0.42 0.52 ⫾ 0.41 1 (5.6) 1 (5.6) 0 (0.0)
8/8 46.31 ⫾ 14.3 12/4 42.2 ⫾ 10.6 1 (6.3) 9.39 ⫾ 0.69 5.96 ⫾ 1.58 56.11 ⫾ 17.44 156.5 ⫾ 96.5 320.6 ⫾ 243.4 3.88 ⫾ 0.36 13.14 ⫾ 22.71 1.02 ⫾ 0.23 0.79 ⫾ 0.09 0.28 ⫾ 0.20 0.82 ⫾ 0.39 0.47 ⫾ 0.28 9 (56.3) 7 (43.8) 3 (18.8)
NS NS NS 0.003 NS NS NS 0.021 NS NS NS NS NS NS NS NS NS 0.002 0.017 NS
NOTE. Values expressed as mean ⫾ SD or number (percent). To convert calcium in mg/dL to mmol/L, multiply by 0.2495; phosphorus in mg/dL to mmol/L, multiply by 0.3229; PTH in pg/mL to ng/L, multiply by 1; albumin in g/dL to g/L, multiply by 10; and CRP in mg/dL to mg/L, multiply by 10. Abbreviation: NS: not significant. *Comparison of low-CCC-score (CCC score ⱕ 3) and high-CCC-score (CCC score ⱖ 10) groups.
lar calcification was significantly higher than that of patients without vascular calcification (8.6 ⫾ 5.4 versus 5.0 ⫾ 4.5; P ⫽ 0.003). The 25th percentile of the CCC score distribution (cutoff CCC score, 3) was chosen as the low-CCC-score group (n ⫽ 17), and the 75th percentile of CCC score distribution (cutoff CCC score, 10) as the high-CCC-score group (n ⫽ 16). Clinical and laboratory characteristics of these 2 patient groups are listed in Table 2. In the low-CCC-score group, 4 patients were administered active vitamin D; 15 patients, calciumcontaining phosphorus binders; and 2 patients, aluminum-containing phosphorus binders. In the high-CCC-score group, 8 patients were administered active vitamin D; 12 patients, calciumcontaining phosphorus binders; and 4 patients, aluminum-containing phosphorus binders. There were no statistically significant differences between groups regarding vitamin D and phosphorus-binder treatment. Mean doses of active vitamin D and phosphorus binders are listed for both groups in Table 2.
We compared the frequency of vascular calcifications between these 2 groups. The frequency of vascular calcifications was significantly greater in the high-CCC-score than low-CCC-score group (5.6% versus 56.3%; P ⫽ 0.002; Table 2). The frequency of vascular calcifications according to anatomic regions also is listed for both groups in Table 2. In the low-CCC-score group, the single vascular calcification was detected in the pelvis, and there was no vascular calcification in the hands. However, in the high-CCC-score group, vascular calcifications were detected in the pelvis of 7 patients and hands of 3 patients. The frequency of pelvic vascular calcifications was significantly greater in the high-CCC-score than low-CCC-score group (43.8% versus 18.8%; P ⫽ 0.017). Duration of RRT and Ca ⫻ P values also were significantly greater in this group; however, other study parameters were similar in both groups (Table 2). Finally we grouped patients according to RRT type. Age, sex distribution, RRT duration, CCC scores, biochemical parameters, BMD measure-
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Fig 3. Distribution of individual CCC scores in patients and controls.
ments, and vascular calcification frequencies were similar between peritoneal dialysis and hemodialysis patients (data not shown). DISCUSSION
The exact mechanism for CCC in patients with ESRD remains unclear. However, for several decades, it has been considered that the loss of carbon dioxide from the surface of the eye leads to a relative alkalinity, which promotes the development of calcifications.1 Some investigators proposed such local factors as minor tissue injury of the limboconjunctival epithelium as a determinant of CCC.11 The association of CCC with tear calcium levels and impression cytology of the conjunctival epithelium also was investigated, but an association was not found.12,13 In this study, we found increased frequency and severity of CCC in patients with ESRD compared with age- and sex-matched controls. Conjunctival white chalky deposits were found in a considerable number of apparently healthy controls; however, corneal deposits were not detected in any controls. To the best of our knowledge, only 1 other study evaluated the presence of CCC in uremic patients and healthy controls. In that study, CCC was not detected in any subject in the control group, which was
composed of 150 persons.14 However, in that study, age and sex distribution of controls were not described. Moreover, the report did not state whether observers were blinded to clinical data of subjects. Therefore, we think it is not appropriate to compare control-group data from that study with ours. However, there are some limitations in our study, as well. We did not measure renal function of controls; hence, it is possible to speculate about the presence of subjects with impaired renal function in our control group. Additionally, the exact identification of calcifications can be made only by histological examination. Therefore, we cannot exclude the possibility of false identification of atypical conjunctival degenerations as calcification. Severity of CCC in patients correlated with duration of RRT and phosphorus and Ca ⫻ P values. Similar results were obtained in the majority of previous studies of hemodialysis patients.1-3,14-16 Our study validates this correlation in a study group composed of both hemodialysis and peritoneal dialysis patients. However, we could not find a correlation of CCC with the other study variables, including PTH and ALP levels and lumbar and femoral BMD. The role of these factors in the development of extraskeletal calcifications was investigated pre-
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Fig 4. Correlations between CCC score and (A) duration of RRT (rs ⴝ 0.392;P ⴝ 0.002), (B) phosphorus level (rs ⴝ 0.259; P ⴝ 0.042), and (C) Ca ⴛ P value (rs ⴝ 0.337; P ⴝ 0.007). To convert calcium in mg/dL to mmol/L, multiply by 0.2495; phosphorus in mg/dL to mmol/L, multiply by 0.3229.
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viously. A negative correlation between BMD and vascular calcification was reported.17 In a recent study, Tokuyama et al4 reported a positive correlation of CCC with PTH and ALP levels and a negative correlation with radial BMD.4 Their study included 44 patients who were on hemodialysis therapy for more than 2 years; they used mean values of these variables during the entire hemodialysis period. However, we only used data up to the most recent 12 months to calculate mean values. Our BMD data were cross-sectional, and we did not measure radial BMD. Therefore, the difference in data collection might explain the difference in our findings. In any case, the role of PTH in the development of extraskeletal calcifications is not clear. A few studies,18,19 but not the majority, detected an association between calcification and PTH level.9,10,20-23 The association of CRP level with other types of extraskeletal calcifications was reported previously in dialysis patients.6,10 However, we did not find an association between CRP level and CCC, and, to the best of our knowledge, this association was not investigated previously. We evaluated the presence of vascular calcification by using plain x-ray films and showed that mean CCC score was higher in patients with vascular calcification compared to patients without vascular calcification. We also found a 10fold greater vascular calcification frequency in the high-CCC-score group compared with the low-CCC-score group. Therefore, we think CCC score might be used as a marker for the presence of vascular calcifications. However, future studies using more sensitive and quantitative methods to detect vascular calcifications must be performed to confirm our results. The use of plain x-ray films for the detection of vascular calcifications is a weakness of our study. There are more accurate and sensitive methods to detect and quantify vascular calcifications in patients with ESRD, such as electron-beam computed tomography and spiral tomography.20,22,24 These methods are particularly useful for the detection of coronary calcifications; however, cost and availability concerns limit their usefulness as practical tools.25 Two recent studies that showed the association of vascular calcifications with cardiovascular mortality validated the value of plain radiograms for the detection of vascular
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calcifications.9,10 Therefore, we think the use of plain x-ray films is acceptable for the purpose of our study. On the other hand, the use of more sensitive methods allowing the quantification of vascular calcifications would have provided more suitable data to correlate vascular calcification with CCC score. Recently, the need for widely available and relatively inexpensive methods for the assessment of extraskeletal calcification was emphasized.25 Despite the mentioned limitations, evaluation of CCC score is an easy, fast, inexpensive, and noninvasive method. CCC score correlates with duration of dialysis therapy and Ca ⫻ P and phosphorus levels and tends to be higher in patients with vascular calcification. Therefore, we think CCC score can be used as an additional tool to assess the status of extraskeletal calcification in patients with ESRD. Longitudinal studies are needed to evaluate the value of CCC score as a marker of cardiovascular mortality in patients with ESRD. REFERENCES 1. Berlyne GM, Shaw AB: Red eyes in renal failure. Lancet 1:4-7, 1967 2. Berlyne GM: Microcrystalline conjunctival calcification in renal failure. A useful clinical sign. Lancet 2:366-370, 1968 3. Porter R, Crombie AL: Corneal and conjunctival calcification in chronic renal failure. Br J Ophthalmol 57:339343, 1973 4. Tokuyama T, Ikeda T, Sato K, Mimura O, Morita A, Tabata T: Conjunctival and corneal calcification and bone metabolism in hemodialysis patients. Am J Kidney Dis 39:291-296, 2002 5. Ibels LS, Stewart JH, Mahony JF, Neale FC, Sheil AG: Occlusive arterial disease in uraemic and haemodialysis patients and renal transplant recipients. A study of the incidence of arterial disease and of the prevalence of risk factors implicated in the pathogenesis of arteriosclerosis. Q J Med 46:197-214, 1977 (abstr) 6. Blacher J, Guerin AP, Pannier B, Marchais SJ, London GM: Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension 38:938942, 2001 7. London GM: Cardiovascular disease in chronic renal failure: Pathophysiologic aspects. Semin Dial 16:85-94, 2003 8. Salgueira M, del Toro N, Moreno-Alba R, Jimenez E, Areste N, Palma A: Vascular calcification in the uremic patient: A cardiovascular risk? Kidney Int Suppl 85:S119S121, 2003 9. London GM, Guerin AP, Marchais SJ, Metivier F, Pannier B, Adda H: Arterial media calcification in end-stage
renal disease: Impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant 18:1731-1740, 2003 10. Adragao T, Pires A, Lucas C, et al: A simple vascular calcification score predicts cardiovascular risk in haemodialysis patients. Nephrol Dial Transplant 19:1480-1488, 2004 11. Klaassen-Broekema N, van Bijsterveld OP: A local challenger of ocular calciphylaxis in patients with chronic renal failure: A hypothesis. Graefes Arch Clin Exp Ophthalmol 233:717-720, 1995 12. Oto S, Aydin P, Haberal A, Dursun D, Yilmaz A: Is tear calcium an indicator of ocular calcification in patients with chronic renal failure? Eur J Ophthalmol 7:181-184, 1997 13. Dursun D, Demirhan B, Oto S, Aydin P: Impression cytology of the conjunctival epithelium in patients with chronic renal failure. Br J Ophthalmol 84:1225-1227, 2000 14. Klaassen-Broekema N, van Bijsterveld OP: Limbal and corneal calcification in patients with chronic renal failure. Br J Ophthalmol 77:569-571, 1993 15. Caldeira JAF, Sabbaga E, Ianhez LE: Conjunctival and corneal changes in renal failure. Influence of renal transplantation. Br J Ophthalmol 54:339-404, 1970 16. de Graaf P, Polak BC, de Wolff D, Schicht IM, Oosterhuis JA, de Graeff J: Ocular calcification in dialysis patients. Metab Pediatr Ophthalmol 4:73-77, 1980 17. Braun J, Oldendorf M, Moshage W, Heidler R, Zeitler E, Luft FC: Electron beam computed tomography in the evaluation of cardiac calcification in chronic dialysis patients. Am J Kidney Dis 27:394-401, 1996 18. Wang AY, Wang M, Woo J, et al: Cardiac valve calcification as an important predictor for all-cause mortality and cardiovascular mortality in long-term peritoneal dialysis patients: A prospective study: J Am Soc Nephrol 14:159168, 2003 19. Oh J, Wunsch R, Turzer M, et al: Advanced coronary and carotid arteriopathy in young adults with childhoodonset chronic renal failure. Circulation 106:100-105, 2002 20. Braun J, Oldendorf M, Moshage W, Heidler R, Zeitler E, Luft FC: Electron beam computed tomography in the evaluation of cardiac calcification in chronic dialysis patients. Am J Kidney Dis 27:394-401, 1996 21. Arad Y, Spadaro LA, Roth M, et al: Serum concentration of calcium, 1,25 vitamin D and parathyroid hormone are not correlated with coronary calcifications. An electron beam computed tomography study. Coron Artery Dis 9:513518, 1998 22. Goodman WG, Goldin J, Kuizon BD, et al: Coronaryartery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 342:14781483, 2000 23. Okuda K, Kobayashi S, Hayashi H, et al: Casecontrol study of calcification of the hepatic artery in chronic hemodialysis patients: Comparison with the abdominal aorta and splenic artery. J Gastroenterol Hepatol 17:91-95, 2002 24. Moe SM, O’Neill KD, Fineberg N, et al: Assessment of vascular calcification in ESRD patients using spiral CT. Nephrol Dial Transplant 18:1152-1158, 2003 25. Goodman WG, London G, Amann K, et al: Vascular calcification in chronic kidney disease. Am J Kidney Dis 43:572-579, 2004
T
HE DEVELOPMENT OF conjunctival and corneal calcification (CCC) in patients with end-stage renal disease (ESRD) is well known.1-3 Usually, a slit-lamp examination is needed for their accurate identification.2 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.2,3 Sometimes calcifications appear as noncrystalline, and the exact identification of calcification can be made only by histological examination. Histologically, the site of deposition is the subepithelial layers and the epithelium itself.2
From the Departments of Nephrology, Ophthalmology, and Radiology, Istanbul University, Cerrahpasa Medical Faculty, Istanbul, Turkey. Received September 9, 2004; accepted in revised form November 5, 2004. Originally published online as doi:10.1053/j.ajkd.2004.11.002 on January 14, 2005. Address reprint requests to Nurhan Seyahi, MD, Halaskargazi c no 209-211, Huzur ap d 2, Sisli, Istanbul, 34360 Turkey. E-mail: [email protected] © 2005 by the National Kidney Foundation, Inc. 0272-6386/05/4503-0012$30.00/0 doi:10.1053/j.ajkd.2004.11.002 550
Recently, the association of CCC with bone metabolism was investigated systematically in hemodialysis patients; however, such data are missing in peritoneal dialysis patients.4 Furthermore, to the best of our knowledge, their association with vascular calcification was not evaluated previously. Vascular calcifications, especially arterial calcifications, have been recognized as a common complication of ESRD for many years.5 Current data suggest their association with the high cardiovascular morbidity and mortality of patients with ESRD.6-10 Therefore, there is a need for widely available and affordable techniques to evaluate vascular calcifications or, more generally, soft-tissue calcifications in these patients. The aim of this study is to evaluate the relation of CCC with bone metabolism parameters in both hemodialysis and peritoneal dialysis patients and investigate the association of CCC with vascular calcification in these patients. METHODS Sixty-three adult (age ⱖ 18 years) patients with ESRD who were on renal replacement therapy (RRT) for at least 6 months were included in the study. Forty-four patients were on peritoneal dialysis and 19 patients were on hemodialysis therapy. Continuous ambulatory peritoneal dialysis was per-
American Journal of Kidney Diseases, Vol 45, No 3 (March), 2005: pp 550-556
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Fig 1. Conjunctival calcium deposits detected using slit-lamp examination. Circle, area of conjunctival calcification; arrows, fine white deposits.
formed using 4 to 5 daily exchanges with a 2,000-mL volume, aiming at a Kt/V greater than 1.8. Standard solution contained 1.75 mmol/L of calcium. Hemodialysis was performed using synthetic or semisynthetic membranes, and bicarbonate dialysate was used with 1.5 mmol/L of calcium. Weekly hemodialysis treatment duration was tailored individually between 10 and 15 hours and adjusted to achieve a Kt/V greater than 1.2. Calcium- or aluminum-containing phosphorus binders and active vitamin D were administered to all patients according to calcium, phosphorus, calcium ⫻ phosphorus product (Ca ⫻ P), and parathyroid hormone (PTH) values. Target values were as follows: calcium, 8.4 to 9.5 mg/dL (2.10 to 2.37 mmol/L); phosphorus, 3.5 to 5.5 mg/dL (1.13 to 1.78 mmol/L); Ca ⫻ P, less than 55 mg2/dL2 (⬍4.44 mmol2/L2); and PTH, 150 to 250 pg/dL (ng/L). Active vitamin D and phosphorus-binder treatment at enrollment was recorded, and mean doses were calculated for the last 12 months. If the duration of RRT was less than 12 months, average values for the entire RRT period were calculated. Causes of ESRD were chronic glomerulonephritis in 23 patients (36.5%), interstitial nephritis in 7 patients (11.1%), amyloidosis caused by familial Mediterranean fever in 7 patients (11.1%), diabetes in 6 patients (9.5%), polycystic kidney disease in 6 patients (9.5%), hypertensive nephrosclerosis in 3 patients (4.7%), and uncertain in 11 patients (17.5%). The same observer, who was blinded to clinical data, evaluated CCC in all subjects. There were no clinically apparent eye diseases that can cause CCC in the study subjects. Examinations were carried out using a slit-lamp microscope. Ocular calcifications were scored between 0 and 5, as described by Tokuyama et al4: 0 indicates 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 nasal and temporal regions
of both corneas were evaluated, and a total calcification score ranging between 0 and 20 was obtained by adding scores for each region (Fig 1). The date of the eye examination was accepted as the enrollment date to the study. The same observer also assessed calcification scores in 52 healthy volunteers by using the described method. Serum levels of calcium, phosphorus, alkaline phosphatase (ALP), PTH, albumin, and C-reactive protein (CRP) were collected from patients’ files. Average values for the last 12 months were calculated by using 6 measurements of calcium, phosphorus, ALP, and albumin. Average values for PTH and CRP were calculated using 3 measurements. If duration of RRT was less than 12 months, average values for the entire RRT period were calculated. These mean values were used in the study. Biochemical parameters were measured using an autoanalyzer (Olympus AU 800; Olympus Diagnostica GmhH, Hamburg, Germany). PTH levels were determined by means of chemiluminescent immunoassay (Liaison N-tact; DiaSorin Inc, Stillwater, MN), and CRP values were measured using a nephelometer (Behring BN II; Dade Behring, Deerfield, IL). Bone mineral density (BMD) of the lumbar spine at L1 to L4 of the anteroposterior view (lumbar BMD) and also of the femoral neck (femoral BMD) were measured by using a dual-energy radiograph absorptiometry (Hologic QDR4500; Bedford, MA). BMD measurements were performed within 2 weeks of enrollment. Anteroposterior x-ray examination of the pelvis and hands was performed to assess for the presence of vascular calcifications. One single experienced radiologist who was blinded to patient information evaluated all radiographic films. Linear calcifications are defined as uniform railroad-track–type (angiogram-like) opacities. Patchy calcifications are defined as discrete plaques with irregular and patchy distribution. The presence of linear calcifications with or without patchy calcifications was recorded for each film (Fig 2). Isolated patchy calcifications may be confused with other types of extravascular calcifications and therefore were not consid-
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Fig 2. Vascular calcifications in (A) pelvic arteries and (B) hand arteries. Arrows show calcified arteries.
ered. X-ray evaluation was performed within 2 weeks of enrollment. To calculate intraobserver variability, the same radiologist reevaluated 32 randomly selected radiographs 3 months after the first evaluation. Thirty-one of these samples were reclassified correctly ( ⫽ 0.93). Data are expressed as mean ⫾ SD if not stated otherwise. Continuous variables were compared using Student’s t-test or Mann-Whitney U test, when appropriate. Categorical variables were compared using chi-square or Fisher exact test, when appropriate. Associations between CCC scores and study variables were evaluated by means of Spearman’s rank correlation (rs). All tests were performed using SPSS for Windows, version 10.0, software (SPSS Inc, Chicago, IL). P less than 0.05 is considered statistically significant.
RESULTS
Demographic characteristics of patients and healthy controls are listed in Table 1. Age and sex distribution of both groups was similar. At enrollment, 20 patients were administered active vitamin D; 50 patients, calcium-containing phosphorus binders; and 13 patients, aluminumcontaining phosphorus binders. Mean doses of Table 1. Demographic Data and CCC Frequency and Score of Patients and Controls Patients (n ⫽ 63)
Controls (n ⫽ 52)
P
Men/women 30/33 30/22 Not significant Age (y) 43.5 ⫾ 13.4 41.2 ⫾ 11.2 Not significant CCC presence 55 (87.3) 20 (38.5) 0.001 CCC score 6.2 ⫾ 5.1 1.3 ⫾ 1.8 0.001 Median (range) 4 (0-20) 0 (0-6) NOTE. Values expressed as mean ⫾ SD or number (percent) unless otherwise noted.
active vitamin D and phosphorus binders are listed in Table 2. A previous parathyroidectomy was performed in 5 patients. Graphical representation of the frequency table showing the distribution of individual CCC scores in patients and controls is shown in Fig 3. CCC was significantly more frequent in patients than controls (Table 1). Mean CCC score of patients was 6.2 ⫾ 5.1, and this score was significantly higher than that of controls (Table 1). CCC score correlated with age in healthy controls (rs ⫽ 0.404; P ⫽ 0.003). However, in patients, CCC score did not correlate with age (rs ⫽ 0.196; P ⫽ 0.124), but correlated with duration of RRT (rs ⫽ 0.392; P ⫽ 0.002; Fig 4A). Biochemical values for patients are listed in Table 2. CCC score correlated with serum levels of phosphorus (rs ⫽ 0.259; P ⫽ 0.042; Fig 4B) and Ca ⫻ P (rs ⫽ 0.337; P ⫽ 0.007; Fig 4C). However, it did not correlate with calcium (rs ⫽ 0.167; P ⫽ 0.193), ALP (rs ⫽ 0.103; P ⫽ 0.426), PTH (rs ⫽ 0.130; P ⫽ 0.318), albumin (rs ⫽ 0.113; P ⫽ 0.38), or CRP (rs ⫽ 0.024; P ⫽ 0.866) levels. Mean BMD values were 1.01 ⫾0.19 g/cm2 for lumbar BMD and 0.78 ⫾ 0.13 g/cm2 for femoral BMD. Neither lumbar (rs ⫽ ⫺0.14; P ⫽ 0.914) nor femoral (rs ⫽ ⫺0.37; P ⫽ 0.738) BMD correlated with CCC score. Vascular calcifications were present in 21 patients (33.3%; Table 2). In 12 patients (19.0%), calcifications were detected in the pelvis; 4 patients (6.4%), the hands; and 5 patients (7.9%), both regions. CCC score of patients with vascu-
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Table 2. Clinical and Biochemical Data, BMD Results, and Vascular Calcification Frequency of Patients
Men/women Age (y) Peritoneal dialysis/hemodialysis RRT duration (mo) Parathyroidectomy Calcium (mg/dL) Phosphorus (mg/dL) Ca ⫻ P (mg2/dL2) ALP (U/L) PTH (pg/mL) Albumin (g/dL) CRP (mg/dL) Lumbar BMD (g/cm2) Femoral BMD (g/cm2) Active vitamin D (g/d) Elemental calcium (g/d) Elemental aluminum (g/d) Presence of vascular calcification Pelvis Hands
All Patients (N ⫽ 63)
Low CCC Score (n ⫽ 17)
High CCC Score (n ⫽ 16)
P*
30/33 43.5 ⫾ 11.7 44/19 54.5 ⫾ 39.9 5 (7.9) 9.22 ⫾ 0.56 5.38 ⫾ 1.30 48.47 ⫾ 12.41 161.0 ⫾ 116.7 310.8 ⫾ 257.4 3.75 ⫾ 0.46 14.31 ⫾ 22.40 1.01 ⫾ 0.19 0.78 ⫾ 0.13 0.36 ⫾ 0.34 0.84 ⫾ 0.41 0.42 ⫾ 0.32 21 (33.3) 16 (27.0) 9 (14.3)
7/10 37.9 ⫾ 14.8 10/7 21.1 ⫾ 5.1 1 (5.9) 9.08 ⫾ 0.38 5.17 ⫾ 1.04 44.76 ⫾ 10.36 133.1 ⫾ 65.7 292.2 ⫾ 272.5 3.62 ⫾ 0.61 13.09 ⫾ 17.95 1.02 ⫾ 0.19 0.81 ⫾ 0.16 0.37 ⫾ 0.32 0.71 ⫾ 0.42 0.52 ⫾ 0.41 1 (5.6) 1 (5.6) 0 (0.0)
8/8 46.31 ⫾ 14.3 12/4 42.2 ⫾ 10.6 1 (6.3) 9.39 ⫾ 0.69 5.96 ⫾ 1.58 56.11 ⫾ 17.44 156.5 ⫾ 96.5 320.6 ⫾ 243.4 3.88 ⫾ 0.36 13.14 ⫾ 22.71 1.02 ⫾ 0.23 0.79 ⫾ 0.09 0.28 ⫾ 0.20 0.82 ⫾ 0.39 0.47 ⫾ 0.28 9 (56.3) 7 (43.8) 3 (18.8)
NS NS NS 0.003 NS NS NS 0.021 NS NS NS NS NS NS NS NS NS 0.002 0.017 NS
NOTE. Values expressed as mean ⫾ SD or number (percent). To convert calcium in mg/dL to mmol/L, multiply by 0.2495; phosphorus in mg/dL to mmol/L, multiply by 0.3229; PTH in pg/mL to ng/L, multiply by 1; albumin in g/dL to g/L, multiply by 10; and CRP in mg/dL to mg/L, multiply by 10. Abbreviation: NS: not significant. *Comparison of low-CCC-score (CCC score ⱕ 3) and high-CCC-score (CCC score ⱖ 10) groups.
lar calcification was significantly higher than that of patients without vascular calcification (8.6 ⫾ 5.4 versus 5.0 ⫾ 4.5; P ⫽ 0.003). The 25th percentile of the CCC score distribution (cutoff CCC score, 3) was chosen as the low-CCC-score group (n ⫽ 17), and the 75th percentile of CCC score distribution (cutoff CCC score, 10) as the high-CCC-score group (n ⫽ 16). Clinical and laboratory characteristics of these 2 patient groups are listed in Table 2. In the low-CCC-score group, 4 patients were administered active vitamin D; 15 patients, calciumcontaining phosphorus binders; and 2 patients, aluminum-containing phosphorus binders. In the high-CCC-score group, 8 patients were administered active vitamin D; 12 patients, calciumcontaining phosphorus binders; and 4 patients, aluminum-containing phosphorus binders. There were no statistically significant differences between groups regarding vitamin D and phosphorus-binder treatment. Mean doses of active vitamin D and phosphorus binders are listed for both groups in Table 2.
We compared the frequency of vascular calcifications between these 2 groups. The frequency of vascular calcifications was significantly greater in the high-CCC-score than low-CCC-score group (5.6% versus 56.3%; P ⫽ 0.002; Table 2). The frequency of vascular calcifications according to anatomic regions also is listed for both groups in Table 2. In the low-CCC-score group, the single vascular calcification was detected in the pelvis, and there was no vascular calcification in the hands. However, in the high-CCC-score group, vascular calcifications were detected in the pelvis of 7 patients and hands of 3 patients. The frequency of pelvic vascular calcifications was significantly greater in the high-CCC-score than low-CCC-score group (43.8% versus 18.8%; P ⫽ 0.017). Duration of RRT and Ca ⫻ P values also were significantly greater in this group; however, other study parameters were similar in both groups (Table 2). Finally we grouped patients according to RRT type. Age, sex distribution, RRT duration, CCC scores, biochemical parameters, BMD measure-
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Fig 3. Distribution of individual CCC scores in patients and controls.
ments, and vascular calcification frequencies were similar between peritoneal dialysis and hemodialysis patients (data not shown). DISCUSSION
The exact mechanism for CCC in patients with ESRD remains unclear. However, for several decades, it has been considered that the loss of carbon dioxide from the surface of the eye leads to a relative alkalinity, which promotes the development of calcifications.1 Some investigators proposed such local factors as minor tissue injury of the limboconjunctival epithelium as a determinant of CCC.11 The association of CCC with tear calcium levels and impression cytology of the conjunctival epithelium also was investigated, but an association was not found.12,13 In this study, we found increased frequency and severity of CCC in patients with ESRD compared with age- and sex-matched controls. Conjunctival white chalky deposits were found in a considerable number of apparently healthy controls; however, corneal deposits were not detected in any controls. To the best of our knowledge, only 1 other study evaluated the presence of CCC in uremic patients and healthy controls. In that study, CCC was not detected in any subject in the control group, which was
composed of 150 persons.14 However, in that study, age and sex distribution of controls were not described. Moreover, the report did not state whether observers were blinded to clinical data of subjects. Therefore, we think it is not appropriate to compare control-group data from that study with ours. However, there are some limitations in our study, as well. We did not measure renal function of controls; hence, it is possible to speculate about the presence of subjects with impaired renal function in our control group. Additionally, the exact identification of calcifications can be made only by histological examination. Therefore, we cannot exclude the possibility of false identification of atypical conjunctival degenerations as calcification. Severity of CCC in patients correlated with duration of RRT and phosphorus and Ca ⫻ P values. Similar results were obtained in the majority of previous studies of hemodialysis patients.1-3,14-16 Our study validates this correlation in a study group composed of both hemodialysis and peritoneal dialysis patients. However, we could not find a correlation of CCC with the other study variables, including PTH and ALP levels and lumbar and femoral BMD. The role of these factors in the development of extraskeletal calcifications was investigated pre-
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Fig 4. Correlations between CCC score and (A) duration of RRT (rs ⴝ 0.392;P ⴝ 0.002), (B) phosphorus level (rs ⴝ 0.259; P ⴝ 0.042), and (C) Ca ⴛ P value (rs ⴝ 0.337; P ⴝ 0.007). To convert calcium in mg/dL to mmol/L, multiply by 0.2495; phosphorus in mg/dL to mmol/L, multiply by 0.3229.
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viously. A negative correlation between BMD and vascular calcification was reported.17 In a recent study, Tokuyama et al4 reported a positive correlation of CCC with PTH and ALP levels and a negative correlation with radial BMD.4 Their study included 44 patients who were on hemodialysis therapy for more than 2 years; they used mean values of these variables during the entire hemodialysis period. However, we only used data up to the most recent 12 months to calculate mean values. Our BMD data were cross-sectional, and we did not measure radial BMD. Therefore, the difference in data collection might explain the difference in our findings. In any case, the role of PTH in the development of extraskeletal calcifications is not clear. A few studies,18,19 but not the majority, detected an association between calcification and PTH level.9,10,20-23 The association of CRP level with other types of extraskeletal calcifications was reported previously in dialysis patients.6,10 However, we did not find an association between CRP level and CCC, and, to the best of our knowledge, this association was not investigated previously. We evaluated the presence of vascular calcification by using plain x-ray films and showed that mean CCC score was higher in patients with vascular calcification compared to patients without vascular calcification. We also found a 10fold greater vascular calcification frequency in the high-CCC-score group compared with the low-CCC-score group. Therefore, we think CCC score might be used as a marker for the presence of vascular calcifications. However, future studies using more sensitive and quantitative methods to detect vascular calcifications must be performed to confirm our results. The use of plain x-ray films for the detection of vascular calcifications is a weakness of our study. There are more accurate and sensitive methods to detect and quantify vascular calcifications in patients with ESRD, such as electron-beam computed tomography and spiral tomography.20,22,24 These methods are particularly useful for the detection of coronary calcifications; however, cost and availability concerns limit their usefulness as practical tools.25 Two recent studies that showed the association of vascular calcifications with cardiovascular mortality validated the value of plain radiograms for the detection of vascular
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calcifications.9,10 Therefore, we think the use of plain x-ray films is acceptable for the purpose of our study. On the other hand, the use of more sensitive methods allowing the quantification of vascular calcifications would have provided more suitable data to correlate vascular calcification with CCC score. Recently, the need for widely available and relatively inexpensive methods for the assessment of extraskeletal calcification was emphasized.25 Despite the mentioned limitations, evaluation of CCC score is an easy, fast, inexpensive, and noninvasive method. CCC score correlates with duration of dialysis therapy and Ca ⫻ P and phosphorus levels and tends to be higher in patients with vascular calcification. Therefore, we think CCC score can be used as an additional tool to assess the status of extraskeletal calcification in patients with ESRD. Longitudinal studies are needed to evaluate the value of CCC score as a marker of cardiovascular mortality in patients with ESRD. REFERENCES 1. Berlyne GM, Shaw AB: Red eyes in renal failure. Lancet 1:4-7, 1967 2. Berlyne GM: Microcrystalline conjunctival calcification in renal failure. A useful clinical sign. Lancet 2:366-370, 1968 3. Porter R, Crombie AL: Corneal and conjunctival calcification in chronic renal failure. Br J Ophthalmol 57:339343, 1973 4. Tokuyama T, Ikeda T, Sato K, Mimura O, Morita A, Tabata T: Conjunctival and corneal calcification and bone metabolism in hemodialysis patients. Am J Kidney Dis 39:291-296, 2002 5. Ibels LS, Stewart JH, Mahony JF, Neale FC, Sheil AG: Occlusive arterial disease in uraemic and haemodialysis patients and renal transplant recipients. A study of the incidence of arterial disease and of the prevalence of risk factors implicated in the pathogenesis of arteriosclerosis. Q J Med 46:197-214, 1977 (abstr) 6. Blacher J, Guerin AP, Pannier B, Marchais SJ, London GM: Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension 38:938942, 2001 7. London GM: Cardiovascular disease in chronic renal failure: Pathophysiologic aspects. Semin Dial 16:85-94, 2003 8. Salgueira M, del Toro N, Moreno-Alba R, Jimenez E, Areste N, Palma A: Vascular calcification in the uremic patient: A cardiovascular risk? Kidney Int Suppl 85:S119S121, 2003 9. London GM, Guerin AP, Marchais SJ, Metivier F, Pannier B, Adda H: Arterial media calcification in end-stage
renal disease: Impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant 18:1731-1740, 2003 10. Adragao T, Pires A, Lucas C, et al: A simple vascular calcification score predicts cardiovascular risk in haemodialysis patients. Nephrol Dial Transplant 19:1480-1488, 2004 11. Klaassen-Broekema N, van Bijsterveld OP: A local challenger of ocular calciphylaxis in patients with chronic renal failure: A hypothesis. Graefes Arch Clin Exp Ophthalmol 233:717-720, 1995 12. Oto S, Aydin P, Haberal A, Dursun D, Yilmaz A: Is tear calcium an indicator of ocular calcification in patients with chronic renal failure? Eur J Ophthalmol 7:181-184, 1997 13. Dursun D, Demirhan B, Oto S, Aydin P: Impression cytology of the conjunctival epithelium in patients with chronic renal failure. Br J Ophthalmol 84:1225-1227, 2000 14. Klaassen-Broekema N, van Bijsterveld OP: Limbal and corneal calcification in patients with chronic renal failure. Br J Ophthalmol 77:569-571, 1993 15. Caldeira JAF, Sabbaga E, Ianhez LE: Conjunctival and corneal changes in renal failure. Influence of renal transplantation. Br J Ophthalmol 54:339-404, 1970 16. de Graaf P, Polak BC, de Wolff D, Schicht IM, Oosterhuis JA, de Graeff J: Ocular calcification in dialysis patients. Metab Pediatr Ophthalmol 4:73-77, 1980 17. Braun J, Oldendorf M, Moshage W, Heidler R, Zeitler E, Luft FC: Electron beam computed tomography in the evaluation of cardiac calcification in chronic dialysis patients. Am J Kidney Dis 27:394-401, 1996 18. Wang AY, Wang M, Woo J, et al: Cardiac valve calcification as an important predictor for all-cause mortality and cardiovascular mortality in long-term peritoneal dialysis patients: A prospective study: J Am Soc Nephrol 14:159168, 2003 19. Oh J, Wunsch R, Turzer M, et al: Advanced coronary and carotid arteriopathy in young adults with childhoodonset chronic renal failure. Circulation 106:100-105, 2002 20. Braun J, Oldendorf M, Moshage W, Heidler R, Zeitler E, Luft FC: Electron beam computed tomography in the evaluation of cardiac calcification in chronic dialysis patients. Am J Kidney Dis 27:394-401, 1996 21. Arad Y, Spadaro LA, Roth M, et al: Serum concentration of calcium, 1,25 vitamin D and parathyroid hormone are not correlated with coronary calcifications. An electron beam computed tomography study. Coron Artery Dis 9:513518, 1998 22. Goodman WG, Goldin J, Kuizon BD, et al: Coronaryartery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 342:14781483, 2000 23. Okuda K, Kobayashi S, Hayashi H, et al: Casecontrol study of calcification of the hepatic artery in chronic hemodialysis patients: Comparison with the abdominal aorta and splenic artery. J Gastroenterol Hepatol 17:91-95, 2002 24. Moe SM, O’Neill KD, Fineberg N, et al: Assessment of vascular calcification in ESRD patients using spiral CT. Nephrol Dial Transplant 18:1152-1158, 2003 25. Goodman WG, London G, Amann K, et al: Vascular calcification in chronic kidney disease. Am J Kidney Dis 43:572-579, 2004