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Conjunctival and Corneal Calcific Deposits in Uremic Patients
CONJUNCTIVAL AND CORNEAL CALCIFIC DEPOSITS IN UREMIC P A T I E N T S LAURENCE S. HARRIS, M.D.,
K E N N E T H COHN, M.D.,
EDMUND LONERGAN, M.D.,
HIDENAO TOYOFUKU,
AND MILES A.
GALIN,
M.D.,
M.D.
New York, New York
Deposition of calcium crystals in the limbus and conjunctiva of patients with other wise normal eyes has long been recognized to occur with hypercalcemia.1"3 Recently, how ever, conjunctival metastatic calcification has been reported in uremic patients with low or normal serum calcium.4-5 It has been felt that the sine qua non for this phenomenon is an elevated serum calcium and phosphorus product, usually in the neighborhood of 70 mg%. 4 ' 5 The present study was undertaken to ana lyze further the calcium and phosphorus concentrations necessary to induce limbal and conjunctival calcification and to deter mine the effect of chronic hemodialysis on these deposits.
RESULTS
The age and sex distributions of the 18 pa tients included in this study are found in Ta ble 1, which also includes their diagnoses and known duration of disease. Biomicroscopy was essential for the detec tion of the conjunctival microcrystals in all cases examined, but certain limbal deposits were grossly visible. All deposits were in variably located in the palpebral fissure. Conjunctival deposits were found immedi ately beneath the conjunctival epithelium, which was elevated over these areas. Small crystals tended to be white in color, but TABLE 1 PATIENT DATA
MATERIALS AND METHODS
A total of 18 consecutive patients between the ages of 21 and 65 years, who were un dergoing hemodialysis for periods of from two to 33 months, were studied. All had pre viously undergone extensive medical evalua tion and laboratory testing in the Renal Ser vice of the New York Medical College. Each patient was given a complete ocular exami nation, including visual acuity, refraction, biomicroscopy, applanation tonometry, and ophthalmoscopy. In addition, slit lamp pho tography of the conjunctiva and cornea was performed and repeated at periodic intervals. From the Department of Ophthalmology and the Department of Medicine (Dr. Lonergan) of the New York Medical College. This study was sup ported by USPHS Grants NS-07162-04 and P H 43-67-654, by Grant 69-869 from the American Heart Association, and by Grant T-517 from the American Cancer Society, Inc. Reprint requests to Laurence S. Harris, M.D., Department of Ophthalmology, New York Medical College, 1249 Fifth Avenue, New York, New York 10029.
Patient No., Age and Sex 1. 41-M 2. 26-M 3. 65-M 4. 5. 6. 7.
21-M 38-M 50-M 49-M
8. 9. 10. 11. 12. 13. 14. 15. 16. 17.
25-M S7-M 27-M 22-M 21-M 36-F 35-F 54-F 41-F 25-F
18. 32-F
Diagnosis
Malignant hypertension AGN Chronic pyelo nephritis CGN* CGN CGN Polycystic disease CGN CGN CGN CGN CGN CGN CGN Renal failure CGN Polycystic disease Amyloidosis
Duration of Disease
Duration of Hemo dialysis (months)
S months
3
5 months 15 years
4 18
1 2 28 3
year years years years
6 20 7 10
2 6 1 16 6 3 3 2 3 3
years months year years months years months months years years
6 4 9 15 2 14 2 2 8 33
2 years
6
* AGN = acute glomerulonephritis, CGN =■ chronic glomerulonephritis. 130
VOL. 72, NO. 1
CALCIFIC DEPOSITION IN UREMIA
larger depositions were flat and colorless. The deposits were superficial to the episcleral vessels and did not move with blink ing. Most commonly, limbal calcification formed a half-moon-like arc concentric with the limbus. In all instances, these deposits extended from sclera onto cornea without an intervening area of clear cornea. Of the 18 patients studied, calcium crystals were pres ent bilaterally at the corneoscleral limbus in nine patients and unilaterally in three. Conjunctival crystals were noted bilaterally in seven patients and unilaterally in three (Ta ble 2). Four patients had solely conjunctival, and three solely limbal, calcification. In only two cases of this series were the "red eyes of renal failure" seen. In both of these patients, bacteriologic cultures were negative. Clini cally, these patients manifested only con junctival vascular congestion with mild chemosis. Follicles were not present, nor was there a significant degree of follicular hyper trophy of the tarsal conjunctiva. The results of laboratory evaluations are listed in Table 3. From this data, it is appar ent that serum calcium levels were low or
131 TABLE 2
DISTRIBUTION OF LIMBAL AND CONJUNCTIVAL CALCIFIC DEPOSITS IN 1 8 CONSECUTIVE UREMIC PATIENTS Limbus Bilateral Unilateral None
Conjjunctiva
9 3 6
Total patients 18 Limbus and conjunctiva Limbus alone Conjunctiva alone Absent
7 3 8 18 8 4 3 3 18
Total patients
normal in all patients having calcific depos its, whereas the phosphorus level was some what elevated to yield mean abnormal cal cium-phosphorus products. However, no strict correlations were noted between cal cium, phosphorus, or calcium-phosphorus products and the presence of calcific deposits in either the limbus or conjunctiva (Table 3). Furthermore, despite the fact that the calcium-phosphorus product was often re duced and held within normal range by
TABLE 3 CHEMICAL VALUES OF PATIENTS IN THIS STUDY Crystals Patient No.
Limbus
1 2 3 4 S 6* 7 8 9 10 11 12 13 14 15 16 17 18*
_ _ + ++ ++ — — — ++ — ++ ++ + + + + — + + + + + + + — — — — — — — — + + ++ ++ Mean±S.D.
RE
LE
Conjunctiva RE
LE
+ — + + — ++ ++ + — — — — ++ — — — — ++ ++
_ ++ + + + ++ +++ — — — — ++ + — — — ++ ++
Calcium (mg/100 ml) Norm =9-11.5
Phosphorus (mg/100 ml) Norm =3-4.5
Serum CaXP (mg/100 ml) Norm =27-51.75
9.9 9.0 9.5 7.5 8.4 8.7 7.7 8.4 7.2 9.4 8.2 9.0 8.8 6.1 9.5 9.2 9.2 9.0
2.6 9.4 6.6 4.6 6.5 8.9 7.5 8.0 6.2
25.7 84.6 62.7 34.5 54.6 77.4 57.7 67.2 44.6 103.4 78.7 77.4 74.8 67.1 S9.8 84.6 82.8 108.9 69.3±21.5
8.6±1.0
* Indicates patients manifesting "red eyes" of renal failure.
11.0 9.6 8.6 8.5
11.0 6.3 9.2 9.0
12.1 8.1±2.4
BUN Serum Creatinine (mg/100 ml) (mg/100 ml) Norm =11-17 Norm =0.6-1.3 81 141 133 137 75 100 135 120 100 160 95 110 HI 165 94 80 100 74
109.7±28.7
11.8 22.0 15.3 13.6 14.5 15.0 13.0 14.0 9.0
16.0 15.0 16.0 11.8 16.0 8.5
15.0 13.0 14.0— 14.0±2.9
132
AMERICAN JOURNAL OF OPHTHALMOLOGY
JULY, 1971
hydroxyapatite, as in crystals found in metastatic calcification in other locii.8 Limbal calcific deposits in these patients occasionally resembled Vogt's white limbus girdle (Fig. 1), but the limbus girdle is rarely seen in young patients and the deposits are usually not quite this large and coarse. The limbus girdle is most often yellowish-white, whereas the lesions described in the current study are chalk-white in appearance.0 Initially, Berlyne and Shaw4'5 postulated that the "red eyes of renal failure" occurred in those patients with deposits consisting of small crystals. It was felt that in those pa tients who had a shorter duration of renal failure the crystal size was an important fac tor in determining the presence or absence of ocular irritation. In our study, however, "red eyes" were noted in two patients with rather dense, conjunctival and corneal de posits involving large crystals (Fig. 2). Fig. 1 (Harris and associates). Limbal calcific de posits in a 26-year-old man (Patient 2).
chronic hemodialysis, no change in the limbal or conjunctival calcification resulted during the one-year period of this study. In both patients with "red eyes," rather heavy deposits were noted in both limbal and conjunctival locii (Table 3). DISCUSSION
Limbal and conjunctival deposition of cal cium salts is a frequent occurrence in ad vanced, acute and chronic renal failure.1"5 Although there are exceptions, as shown in this study, the calcium-phosphorus product is usually in the neighborhood of 70 mg% in such patients. These findings are not usu ally noted with frequency in normal sub jects or those in whom renal disease is less severe.4-5 Histologically, the site of this calcium de position has been shown to be subepithelial and epithelial.5 It is felt that these crystals consist of a calcium-phosphate salt, probably
Fig. 2 (Harris and associates). A large, con junctival, calcific deposit in a 50-year-old man (Pa tient 6). Extensive limbal crystalline material is also evident.
VOL. 72, NO. 1
CALCIFIC DEPOSITION IN UREMIA
Moreover, the duration of disease in both of these patients was more than two years. These findings would tend to argue against crystal size as being an important determi nant factor in the "red eye" syndrome. Disappearance of ocular calcific deposits has recently been described to have occurred within several days of renal transplantation, despite persistence of elevated calciumphosphorus products in some patients.7 In the current study, calcific deposits were noted in patients undergoing routine, chronic hemodialysis for periods in excess of one year. No change could be detected resulting from or attributable to hemodialysis during this period. The mechanism of deposition of calcium crystals remains unknown. It has been sug gested in the past that the interpalpebral re gion is a site of crystal deposition in the presence of elevated calcium because of loss of carbon dioxide from the exposed con junctiva. The decreased P C 0 2 would be as sociated with a rise in pH, so that in the presence of an elevated calcium-phosphorus product, calcium-phosphate salts might pre cipitate.1 Fifteen of the 18 consecutive severely uremic patients in this series had biomicroscopically definable crystals. However, the three patients without calcific deposits had distinctly abnormal calcium-phosphorus products and were chemically as uremic as the remainder of the patients in this series who did have calcific deposits. Conversely, three patients with normal calcium-phospho rus products had minimal calcific deposits. It would appear that the ophthalmologist can use this observation to make the diagnosis of advanced renal failure in the overwhelming majority of cases.
133
SUMMARY
Examination of a consecutive group of 18 severely uremic patients disclosed an inci dence of over 80% corneal or conjunctival calcific deposits, or both, in the presence of low or normal serum calcium levels. Serum phosphorus was elevated in all patients. The prerequisite for this phenomenon would ap pear to be an elevated serum calcium-phos phorus product in the neighborhood of 70. However, the three patients in this study who had no deposits were in no way distin guishable from other patients in this series with calcific findings on the basis of blood chemistry values or duration of disease. The vast majority of these patients were asymptomatic and unaware of the calcific de posits. Limbal calcifications in uremic pa tients are distinguishable from Vogt's white limbus girdle by their presence in young pa tients and by the considerably larger and coarser crystal size, as well as the absence of a clear area of cornea at the limbus. Chronic hemodialysis appeared to have no influence on the distribution, size, or appearance of these crystals. REFERENCES
1. Cogan, D. G., Albright, F. and Barrter, F. C.: Hypercalcemia and band keratopathy. Arch. Ophth. 40:624, 1948. 2. Duke-Elder, S.: System of Ophthalmology, vol. 8. St. Louis, C. V. Mosby, 1965, part II, p. 898. 3. Gartner, S., and Rubner, K.: Calcified scleral nodules in hypervitaminosis D. Am. J. Ophth. 39: 658, 1955. 4. Berlyne, G. M., and Shaw, A. B.: Red eyes in renal failure. Lancet 1:4, 1967. 5. Berlyne, G. M.: Microcrystalline conjunctival calcification in renal failure. Lancet 2:366, 1968. 6. Duke-Elder, S.: System of Ophthalmology, vol. 8. St. Louis, C. V. Mosby, 1965, part II, p. 869. 7. Caldeira, J. A. F., Sabbaga, E., and Ianhez, L. E.: Conjunctival and corneal changes in renal failure. Brit. J. Ophth. 54:399, 1970.
K E N N E T H COHN, M.D.,
EDMUND LONERGAN, M.D.,
HIDENAO TOYOFUKU,
AND MILES A.
GALIN,
M.D.,
M.D.
New York, New York
Deposition of calcium crystals in the limbus and conjunctiva of patients with other wise normal eyes has long been recognized to occur with hypercalcemia.1"3 Recently, how ever, conjunctival metastatic calcification has been reported in uremic patients with low or normal serum calcium.4-5 It has been felt that the sine qua non for this phenomenon is an elevated serum calcium and phosphorus product, usually in the neighborhood of 70 mg%. 4 ' 5 The present study was undertaken to ana lyze further the calcium and phosphorus concentrations necessary to induce limbal and conjunctival calcification and to deter mine the effect of chronic hemodialysis on these deposits.
RESULTS
The age and sex distributions of the 18 pa tients included in this study are found in Ta ble 1, which also includes their diagnoses and known duration of disease. Biomicroscopy was essential for the detec tion of the conjunctival microcrystals in all cases examined, but certain limbal deposits were grossly visible. All deposits were in variably located in the palpebral fissure. Conjunctival deposits were found immedi ately beneath the conjunctival epithelium, which was elevated over these areas. Small crystals tended to be white in color, but TABLE 1 PATIENT DATA
MATERIALS AND METHODS
A total of 18 consecutive patients between the ages of 21 and 65 years, who were un dergoing hemodialysis for periods of from two to 33 months, were studied. All had pre viously undergone extensive medical evalua tion and laboratory testing in the Renal Ser vice of the New York Medical College. Each patient was given a complete ocular exami nation, including visual acuity, refraction, biomicroscopy, applanation tonometry, and ophthalmoscopy. In addition, slit lamp pho tography of the conjunctiva and cornea was performed and repeated at periodic intervals. From the Department of Ophthalmology and the Department of Medicine (Dr. Lonergan) of the New York Medical College. This study was sup ported by USPHS Grants NS-07162-04 and P H 43-67-654, by Grant 69-869 from the American Heart Association, and by Grant T-517 from the American Cancer Society, Inc. Reprint requests to Laurence S. Harris, M.D., Department of Ophthalmology, New York Medical College, 1249 Fifth Avenue, New York, New York 10029.
Patient No., Age and Sex 1. 41-M 2. 26-M 3. 65-M 4. 5. 6. 7.
21-M 38-M 50-M 49-M
8. 9. 10. 11. 12. 13. 14. 15. 16. 17.
25-M S7-M 27-M 22-M 21-M 36-F 35-F 54-F 41-F 25-F
18. 32-F
Diagnosis
Malignant hypertension AGN Chronic pyelo nephritis CGN* CGN CGN Polycystic disease CGN CGN CGN CGN CGN CGN CGN Renal failure CGN Polycystic disease Amyloidosis
Duration of Disease
Duration of Hemo dialysis (months)
S months
3
5 months 15 years
4 18
1 2 28 3
year years years years
6 20 7 10
2 6 1 16 6 3 3 2 3 3
years months year years months years months months years years
6 4 9 15 2 14 2 2 8 33
2 years
6
* AGN = acute glomerulonephritis, CGN =■ chronic glomerulonephritis. 130
VOL. 72, NO. 1
CALCIFIC DEPOSITION IN UREMIA
larger depositions were flat and colorless. The deposits were superficial to the episcleral vessels and did not move with blink ing. Most commonly, limbal calcification formed a half-moon-like arc concentric with the limbus. In all instances, these deposits extended from sclera onto cornea without an intervening area of clear cornea. Of the 18 patients studied, calcium crystals were pres ent bilaterally at the corneoscleral limbus in nine patients and unilaterally in three. Conjunctival crystals were noted bilaterally in seven patients and unilaterally in three (Ta ble 2). Four patients had solely conjunctival, and three solely limbal, calcification. In only two cases of this series were the "red eyes of renal failure" seen. In both of these patients, bacteriologic cultures were negative. Clini cally, these patients manifested only con junctival vascular congestion with mild chemosis. Follicles were not present, nor was there a significant degree of follicular hyper trophy of the tarsal conjunctiva. The results of laboratory evaluations are listed in Table 3. From this data, it is appar ent that serum calcium levels were low or
131 TABLE 2
DISTRIBUTION OF LIMBAL AND CONJUNCTIVAL CALCIFIC DEPOSITS IN 1 8 CONSECUTIVE UREMIC PATIENTS Limbus Bilateral Unilateral None
Conjjunctiva
9 3 6
Total patients 18 Limbus and conjunctiva Limbus alone Conjunctiva alone Absent
7 3 8 18 8 4 3 3 18
Total patients
normal in all patients having calcific depos its, whereas the phosphorus level was some what elevated to yield mean abnormal cal cium-phosphorus products. However, no strict correlations were noted between cal cium, phosphorus, or calcium-phosphorus products and the presence of calcific deposits in either the limbus or conjunctiva (Table 3). Furthermore, despite the fact that the calcium-phosphorus product was often re duced and held within normal range by
TABLE 3 CHEMICAL VALUES OF PATIENTS IN THIS STUDY Crystals Patient No.
Limbus
1 2 3 4 S 6* 7 8 9 10 11 12 13 14 15 16 17 18*
_ _ + ++ ++ — — — ++ — ++ ++ + + + + — + + + + + + + — — — — — — — — + + ++ ++ Mean±S.D.
RE
LE
Conjunctiva RE
LE
+ — + + — ++ ++ + — — — — ++ — — — — ++ ++
_ ++ + + + ++ +++ — — — — ++ + — — — ++ ++
Calcium (mg/100 ml) Norm =9-11.5
Phosphorus (mg/100 ml) Norm =3-4.5
Serum CaXP (mg/100 ml) Norm =27-51.75
9.9 9.0 9.5 7.5 8.4 8.7 7.7 8.4 7.2 9.4 8.2 9.0 8.8 6.1 9.5 9.2 9.2 9.0
2.6 9.4 6.6 4.6 6.5 8.9 7.5 8.0 6.2
25.7 84.6 62.7 34.5 54.6 77.4 57.7 67.2 44.6 103.4 78.7 77.4 74.8 67.1 S9.8 84.6 82.8 108.9 69.3±21.5
8.6±1.0
* Indicates patients manifesting "red eyes" of renal failure.
11.0 9.6 8.6 8.5
11.0 6.3 9.2 9.0
12.1 8.1±2.4
BUN Serum Creatinine (mg/100 ml) (mg/100 ml) Norm =11-17 Norm =0.6-1.3 81 141 133 137 75 100 135 120 100 160 95 110 HI 165 94 80 100 74
109.7±28.7
11.8 22.0 15.3 13.6 14.5 15.0 13.0 14.0 9.0
16.0 15.0 16.0 11.8 16.0 8.5
15.0 13.0 14.0— 14.0±2.9
132
AMERICAN JOURNAL OF OPHTHALMOLOGY
JULY, 1971
hydroxyapatite, as in crystals found in metastatic calcification in other locii.8 Limbal calcific deposits in these patients occasionally resembled Vogt's white limbus girdle (Fig. 1), but the limbus girdle is rarely seen in young patients and the deposits are usually not quite this large and coarse. The limbus girdle is most often yellowish-white, whereas the lesions described in the current study are chalk-white in appearance.0 Initially, Berlyne and Shaw4'5 postulated that the "red eyes of renal failure" occurred in those patients with deposits consisting of small crystals. It was felt that in those pa tients who had a shorter duration of renal failure the crystal size was an important fac tor in determining the presence or absence of ocular irritation. In our study, however, "red eyes" were noted in two patients with rather dense, conjunctival and corneal de posits involving large crystals (Fig. 2). Fig. 1 (Harris and associates). Limbal calcific de posits in a 26-year-old man (Patient 2).
chronic hemodialysis, no change in the limbal or conjunctival calcification resulted during the one-year period of this study. In both patients with "red eyes," rather heavy deposits were noted in both limbal and conjunctival locii (Table 3). DISCUSSION
Limbal and conjunctival deposition of cal cium salts is a frequent occurrence in ad vanced, acute and chronic renal failure.1"5 Although there are exceptions, as shown in this study, the calcium-phosphorus product is usually in the neighborhood of 70 mg% in such patients. These findings are not usu ally noted with frequency in normal sub jects or those in whom renal disease is less severe.4-5 Histologically, the site of this calcium de position has been shown to be subepithelial and epithelial.5 It is felt that these crystals consist of a calcium-phosphate salt, probably
Fig. 2 (Harris and associates). A large, con junctival, calcific deposit in a 50-year-old man (Pa tient 6). Extensive limbal crystalline material is also evident.
VOL. 72, NO. 1
CALCIFIC DEPOSITION IN UREMIA
Moreover, the duration of disease in both of these patients was more than two years. These findings would tend to argue against crystal size as being an important determi nant factor in the "red eye" syndrome. Disappearance of ocular calcific deposits has recently been described to have occurred within several days of renal transplantation, despite persistence of elevated calciumphosphorus products in some patients.7 In the current study, calcific deposits were noted in patients undergoing routine, chronic hemodialysis for periods in excess of one year. No change could be detected resulting from or attributable to hemodialysis during this period. The mechanism of deposition of calcium crystals remains unknown. It has been sug gested in the past that the interpalpebral re gion is a site of crystal deposition in the presence of elevated calcium because of loss of carbon dioxide from the exposed con junctiva. The decreased P C 0 2 would be as sociated with a rise in pH, so that in the presence of an elevated calcium-phosphorus product, calcium-phosphate salts might pre cipitate.1 Fifteen of the 18 consecutive severely uremic patients in this series had biomicroscopically definable crystals. However, the three patients without calcific deposits had distinctly abnormal calcium-phosphorus products and were chemically as uremic as the remainder of the patients in this series who did have calcific deposits. Conversely, three patients with normal calcium-phospho rus products had minimal calcific deposits. It would appear that the ophthalmologist can use this observation to make the diagnosis of advanced renal failure in the overwhelming majority of cases.
133
SUMMARY
Examination of a consecutive group of 18 severely uremic patients disclosed an inci dence of over 80% corneal or conjunctival calcific deposits, or both, in the presence of low or normal serum calcium levels. Serum phosphorus was elevated in all patients. The prerequisite for this phenomenon would ap pear to be an elevated serum calcium-phos phorus product in the neighborhood of 70. However, the three patients in this study who had no deposits were in no way distin guishable from other patients in this series with calcific findings on the basis of blood chemistry values or duration of disease. The vast majority of these patients were asymptomatic and unaware of the calcific de posits. Limbal calcifications in uremic pa tients are distinguishable from Vogt's white limbus girdle by their presence in young pa tients and by the considerably larger and coarser crystal size, as well as the absence of a clear area of cornea at the limbus. Chronic hemodialysis appeared to have no influence on the distribution, size, or appearance of these crystals. REFERENCES
1. Cogan, D. G., Albright, F. and Barrter, F. C.: Hypercalcemia and band keratopathy. Arch. Ophth. 40:624, 1948. 2. Duke-Elder, S.: System of Ophthalmology, vol. 8. St. Louis, C. V. Mosby, 1965, part II, p. 898. 3. Gartner, S., and Rubner, K.: Calcified scleral nodules in hypervitaminosis D. Am. J. Ophth. 39: 658, 1955. 4. Berlyne, G. M., and Shaw, A. B.: Red eyes in renal failure. Lancet 1:4, 1967. 5. Berlyne, G. M.: Microcrystalline conjunctival calcification in renal failure. Lancet 2:366, 1968. 6. Duke-Elder, S.: System of Ophthalmology, vol. 8. St. Louis, C. V. Mosby, 1965, part II, p. 869. 7. Caldeira, J. A. F., Sabbaga, E., and Ianhez, L. E.: Conjunctival and corneal changes in renal failure. Brit. J. Ophth. 54:399, 1970.