quirements (90 to 100 Cal [380 to 420 kJl/kg .d) are tolerated orally. Peripheral TPN is a safe and relatively simple method. However, failure to deliver calculated energy and fluid needs for several successive days is an indication for insertion of a central venous infusion catheter with sterile technique. Thus, most of the infants in this series were victims of a preventable disease. The incidence of intractable diarrhea, especially among male and prematurely born Inuit infants, is alarmingly high. If the high cost of hospital treatment, which lasted an average of 78 days for the Inuit survivors, could be applied to improving
the health
of the pregnant Inuit
26
woman and encouraging better nutrition of the infant, the deaths and other consequences of the nutritional deprivation in the early months of life might have been avoided. As well, the maternal separation that may result in rejection of even the rehabilitated infant may be prevented. References I. AVERY GB, VILLAVICENCIO 0, LILLY JR, Ct al:
Intractable diarrhea in early infancy. Pediatrics 41: 712, 1968
2. KEATING JP, TERNBERO JL: Amino acidhypertonic glucose treatment for intractable diarrhea in infants. Am J Dix Child 122: 226, 1971 3. HYMAN CJ, REITER J, RODMAN J, et al: Parenteral and oral alimentation in the treatment of the non-specific protracted diarrheal syndrome of infancy. J Pediatr 78: 17, 1971 4. Wu P,
HAMILTON JR, LEBLANC AE:
A
clinical and metabolic study of an intravenous feeding technique using peripheral veins as the initial infusion site. Can Med Assoc J 106: 969, 1972
5. BANISTER
A,
MATIN-SIDDIQI
SA,
HATCHER
GW, et al: Intravenous feeding of young infants with persistent diarrhea. Acta Paediatr Scand 64: 732, 1975 6. MCLAREN DS: Protein energy malnutrition (PEM), in Textbook of Paediatric Nutrition, MCLAREN DS, BURMAN D (eds), Edinburgh & London, Churchill Livingstone, 1976, p 105 7. TEMTAMY SA, MILLER JD: Extending the scope of the VATER association: definition of the VATER syndrome. J Pediatr 85: 345, 1974 8. CAsHORE WJ, SEDAGHATIAN MR, USHER RH:
Nutritional supplements with intravenously administered lipid, protein hydrolysate and glucose in small premature infants. Pediatrics 56: 8, 1975 9. FILLER RM, ERAKLIS AJ, RUBIN VG, et al: Long-term total parenteral nutrition in infants. N Engi J Med 281: 589, 1969 10. RYAN JA, ABEL RM, Aeeorr WM, et al: Catheter complications in total parenteral nutrition. A prospective study of 200 consecutive patients. N Engi I Med 290: 757, 1974 11. NELSON R: Minimizing systemic infection during complete parenteral alimentation of small infants. Arch Dix Child 49: 16, 1974 12. TOULOUKIAN RJ: Isosmolar coma during par-
enteral alimentation with protein hydrolysate in excess of 4 gm/kg/day. I Pediatr 86: 270, 1975 13. LLOYD-STILL JD, SCHWACHMAN H, FILLER RM: Protracted diarrhea of infancy treated
by intravenous alimentation. Am I Dis Child
125: 358, 1973
14. PEDEN VH, WITZLEBEN CL, SKELTON MA: Total parenteral nutrition. J Pediatr 78: 180, 1971 15. HEIRD WC, DRISCOLL JM JR, SCHULLINGER JN, et al: Intravenous alimentation in pediatric patients. J Pediatr 80: 351, 1972 16. RAGER R, FINEGOLD MJ: Cholestasis in immature newborn infants: is parenteral alimentation responsible? J Pediatr 86: 264, 1975 17. ASHWORTH A, BELL R, JAMES WPT, et al: Calorie requirements of children recovering from protein-calorie malnutrition. Lancet 2: 600, 1968 18. SETH V, CHANDRA RK: Opsonic activity, phagocytosis and bactericidal capacity of polymorphs in undernutrition. Arch Dis Child 47: 282, 1972 19. SIRIsINHA 5, Susicn.. R, EDELMAN R, et al: Complement and C3-proactivator levels in children with protein-calorie malnutrition and effect of dietary treatment. Lancet 1: 1016, 1973 20. SMYTHE PM, ScHONLAND M, BRERETON-STILES GG, et al: Thymolymphatic deficiency and depression of cell mediated immunity in protein-calorie malnutrition. Lancet 2: 939, 1971 21. PURTILO DT, CONNOR DH: Fatal infections in protein-calorie malnourished children with thymolymphatic atrophy. Arch Dis Child 50: 149, 1975 22. FERGUSON AC, LAWLOR GJ, NEUMANN CG, et al: Decreased rosette-forming lymphocytes in malnutrition and intrauterine growth retardation. .1 Pediatr 85: 717, 1974 23. SAYED M, SAYED J, HILDES JA, et al: Deficiency of secretory IgA in Eskimo saliva (abstr), Third International Symposium on Circumpolar Health, Yellowknife, NWT, July 8-11, 1974 24. SCHONLAND MM, SHANKLEY BC, LOENING WEK, et al: Plasma-cortisol and immunosuppression in protein-calorie malnutrition. Lan-
cet 2: 435, 1972
25. FAucI AS, DALE DC: The effect of in vivo hydrocortisone on subpopulations of human lymphocytes. I Clin Invest 53: 240, 1974 26. CLOW CL, LABERGE C, SciuvER CR: Neonatal hypertyrosinemia and evidence for deficiency of ascorbic acid in Arctic and subarctic peoples. Can Med Assoc 1 113: 624, 1975
Ocular complications in renal transplant recipients CHARLES R. PAVLIN, MD, FRCS[C]; GEORGE A. DEVEBER, MD, FRCP[C]; G.T. COOK, MD, FRCS[C]; LIONEL D.J. CHISHOLM, MD, FRCS[C]
The occurrence of ocular complications among 62 recipients of functioning renal transplants was reviewed 6 months to 7½ years after transplantation. Posterior subcapsular cataracts were found in 29 (46.70/o). A positive correlation was found between the development of cataracts and the total dose of corticosteroid, the number of days on which the dose exceeded 100 mg, and the number of rejection episodes treated with high doses of corticosteroid. Identification of specific high-risk periods in regard to cataract formation could lead to use of preventive therapy, as yet undetermined, during these periods. Lower doses of corticosteroids should be used to treat rejection episodes.
From the divisions of ophthalmology, nephrology and urology, Toronto Western Hospital, University of Toronto Reprint requests to: Dr. Lionel D.J. Chisholm, 600 Sherbourne St., Ste. 815, Toronto, Ont. M4X 1W4
L'apparition de complications oculaires parmi 62 receveurs de greffes renales fonctionnelles a ete revue entre 6 mois et 71/2 ans apres Ia transplantation. Des cataractes souscapsulaires posterieures ont ete retrouvees cbez 29 d'entre eux (46.70/o). Une correlation positive a ete retrouvee entre le developpement de cataractes et Ia dose totale de corticosteroides, le nombre de jours ou Ia dose a excede 100 mg, et le nombre d'episodes de rejet traites avec de fortes doses de corticosteroides. En ce qui a trait a Ia formation de cataractes, l'identification de periodes de risque eleve pourrait conduire a l'emploi, durant ces periodes, d'un traitement preventif qui reste a .tre determine. Les episodes de rejet devraient .tre traitees avec de plus faibles doses de corticosteroides.
Reported ocular complications in renal transplant recipients have consisted primarily of cataracts,17 corticosteroidinduced glaucoma1'3'8 and retinitis secondary to cytomegalovirus infection.3'9'10
360 CMA JOURNAL/AUGUST 20, 1977/VOL. 117
Some authors have found a significant correlation between the development of cataracts and corticosteroid therapy in terms of duration of treatment,5 total doseSA.U and a high maintenance dose,4 whereas others have found no significant correlation between the development of cataracts and any dosage feature of corticosteroid therapy.1 This report reviews the ocular complications found in 62 recipients of functioning renal transplants. Patients and methods Patients
Sixty-two renal transplant recipients, 16 women and 46 men ranging in age from 17 to 61 years (average, 39 years) were studied 6 months to 7½ years (average, 36 months) after transplantation. Each patient regularly attending the outpatient transplant clinic was studied and none was excluded for medical reasons. All patients had received either long-term hemodialysis or
long-term peritoneal dialysis for various periods prior to transplantation. The original causes of end-stage renal failure are listed in Table I. Methods All patients had received azathioprine, 2 mg/kg .d or less if indicated, throughout the transplantation program. Prednisone, 1.5 mg/kg .d, had been given for 1 week after transplantation, then the dose was reduced gradually to 0.2 mg/kg .d at 6 months and 0.15 mg/kg ed at 12 months, this last dose being maintained indefinitely if the patient's condition remained stable. Additional immunosuppressive therapy with one or more of actinomycin C or D, local graft irradiation, antithymocyte globulin and cyclophosphamide had been given to most patients during various phases of the transplantation program. Treatment of rejection episodes had consisted of initial high-dose therapy with corticosteroids (5 mg/kg .d orally prior to 1969 in 10 patients; 10 mg/kg .d intravenously from 1969 on in 52 patients) for a maximum of 3 or 4 days, with gradual reduction to the baseline dose over the next 2 weeks.
Eye examination in each patient included tests of visual acuity, applanation tonometry, biomicroscopy of the anterior chamber and lens, and ophthalmoscopy with the pupil dilated. Tonography, gonioscopy and visual field examinations were carried out in patients with ocular hypertension. Results The findings on ocular examination are listed in Table II. Subepithelial deposits in cornea and conjunctiva Of the 62 patients 35 displayed pale grey or white clumps of chalk-like material beneath the corneal epithelium along the limbal margin and in the adjacent conjunctiva. These were invariably restricted to the interpalpebral area. Cataract The cataracts found were all of the posterior subcapsular variety, in which opaque deposits lie on the anterior or inner surface of the posterior lens capsule. These varied considerably in density and area. In our statistical calculations we considered only the presence or absence of cataracts and not the severity. Of the 62 patients 29 (46.8%) 21 of the 46 men and 8 of the 16 women - had bilateral, symmetric cataracts. The sex difference was not significant; therefore the findings in the two groups were considered together in subsequent calculations. The prevalence of cataracts was 50% (5 of 10 patients) in the group receiving transplants prior to 1969 and 46.2% (24 of 52 patients) in the group receiving transplants subsequently. Of 13 patients with visual acuity of less than 6/9, 9 had cataracts, and in 7 of the 9 the visual impairment was considered to be a direct result of cataractous opacification. The cataracts
were extracted in five of the seven patients, unilaterally in four and bilaterally in one; in all five, visual acuity in the eyes undergoing operation improved to 6/9 or better. Of the six patients in whom the cataracts did not contribute to decreased visual acuity, three had residual macular damage from severe preoperative hypertensive retinopathy, two had pre-existing unilateral amblyopia, and one had anterior lenticonus in association with Alport's syndrome. The patients were divided into two groups, those with cataracts (29) and those without (33), then compared as to age and various dosage features of prednisone and azathioprine therapy. Statistical comparisons were performed with both the t-test for normal distribution and the Mann-Whitney U-test12 for skewed distribution. The results of these tests agreed in all applications. The mean age of the cataract group was 41.6 years and that of the noncataract group, 37.4 years; this difference was not significant. No significant relation could be found between the development of cataracts and the duration of therapy, the overall mean dose per day or the mean maintenance dose per day of prednisone. However, a high level of significance (P < 0.01) was evident in the correlations of cataract development with total dose and total number of days on which the dose exceeded 100 mg (Table III). In an attempt to relate this finding to rejection episodes, we then compared the development of cataracts with the number of periods of 3 days or more in which the prednisone dose exceeded 100 mg/ d. This relation was also highly significant (P < 0.01); thus cataract development appeared to correlate with the number of rejection episodes treated with high doses of prednisone (Table III). There was no significant difference between the two groups in the total dose or mean daily dose of azathioprine or
:7
CMA JOURNAL/AUGUST 20, 1977/VOL. 117 361
(by a chi-square test) in the numbers of patients who had received cyclophosphamide. Concentrations of serum calcium, measured in all patients at 3-month intervals after transplantation, showed no correlation with the development of cataracts.
Ocular hypertension Four patients had elevated intraocular pressure (TOP), defined as two or more readings greater than 21 mm Hg by applanation tonometry; none had glaucomatous optic atrophy or visual field loss. Two of the patients had cataracts. Two were receiving a low maintenance dose of prednisone and in one the drug had been discontinued 2 weeks previously. In the fourth patient the TOP varied directly with the fluctuating prednisone dose (Fig. 1). Discussion We detected pale grey or white subepithelial deposits in the interpalpebral cornea and conjunctiva of 35 of our 62 patients. This frequency is less than that in Berlyne's group of patients with chronic renal failure, of whom 13 of 16 had such deposits.13 These deposits may be related to a high concentration of plasma inorganic phosphate and the resultant elevation in the calcium x phosphate product, which favours precipitation of calcium and phosphate in tissues having higher alkalinity. Because the interpalpebral cornea and conjunctiva are exposed to the atmosphere, the local Pco2 decreases and the pH increases; this favours the precipitation of calcium and phosphate when tissue fluids are saturated. We believe that these deposits are associated with chronic renal failure and, indeed, may cease to progress or may regress after successful renal transplantation. This may explain the greater frequency of these deposits in Berlyne's patients with chronic renal failure. So-called corticosteroid-induced cataracts have been well described in the medical literature.14-17 In renal transplant recipients the incidence of cataract development has been as high as . IDJ
01301
.
__
i
20 LU
35-
. z O
3025-
U)
a. 20RI 15o U- 104 5-
__
HIGH DOSAGE PERIOD
-.4 HIGH DOSAGE PERIOD
010
20 FEB
0
20 MAR
30
ID 20 APR
FIG. 1-Relation of intraocular pressure to daily dose of prednisone in one renal transplant recipient.
46%. Some workers have found a significant correlation between cataract development and duration of corticosteroid therapy,1'5 total dose3'5'11 and a high maintenance dose,4 while others could establish no significant correlation between cataract development and any dosage feature.1 Rapid progession of cataract opacification during periods of treatment with high doses of corticosteroids have been observed.2'6 In the Hovland and Ellis1 series 2 patients had cataracts prior to renal transplantation, whereas 12 of the 26 displayed lens opacities after transplantation. Berkowitz and colleagues5 found no cataracts among 22 control patients with chronic renal failure. To our knowledge our 62 renal transplant recipients represent the largest adult group yet reviewed for ocular complications. In these patients we found no significant relation between the development of cataracts and corticosteroid therapy with regard to duration of administration, average daily dose and maintenance dose of the drug. However, there was a highly significant relation between the development of cataracts and the total dose of corticosteroid, the number of days on which the dose exceeded 100 mg, and the number of rejection episodes treated with high doses of corticosteroids. The last two factors are directly related to immunosuppression during rejection episodes, and it seems likely that the first factor, the total dose of corticosteroid, is also influenced greatly by immunosuppression. The incidence of cataract development was similar in the group of patients receiving transplants prior to 1969 and those receiving transplants subsequently. The former received a maximum of 5 mg/kg .d orally for rejection episodes and the latter, 10 mg/kg ed intravenously. If cataract formation is related primarily to periods of high-dose therapy with corticosteroids, the two doses appear to have an equally deleterious effect. We found no relation between cataract development and therapy with azathioprine or cyclophosphamide, or abnormalities in serum calcium concentration. Elevated lOP has been demonstrated in patients receiving long-term oral corticosteroid therapy.8 Hovland and Ellis1 found 8 patients with increased TOP among 26 renal transplant recipients, while Berkowitz and colleagues5 found only 1 among 44 patients. Two of our four patients with elevated lOP were receiving a low maintenance dose of prednisone, and in one other the corticosteroid had been discontinued 2 weeks earlier. A fourth patient exhibited a slightly elevated lOP while taking 20 mg/d of prednisone, but the
362 CMA JOURNAL/AUGUST 20, 1977/VOL. 117
lOP increased substantially whenever the prednisone dose was increased, although the dose was never greater than 35 mg/d (Fig. 1). This represents a good example of a positive lOP response to oral corticosteroid therapy. None of our patients had visual field loss secondary to elevated lOP and there was no family history of glaucoma. This report is the first to demonstrate a significant correlation between formation of cataracts and periods of highdose corticosteroid therapy in renal transplant recipients. The exact metabolic factors leading to cataract formation, either de novo or secondary to corticosteroid therapy, are unknown at present. Future knowledge could lead to the development of preventive therapy to be applied during specific highrisk periods such as those surrounding rejection episodes, or during longer periods when high-dose maintenance doses of corticosteroid are required. In addition, recent evidence that rejection episodes may be equally well controlled by much lower doses of corticosteroids than those currently used by most transplant groups18 could have important applications in the prevention of cataract development after transplantation. References 1. HOYLAND KR, ELLIS PP: Ocular changes in renal transplant patients. Am I Ophihalmol 63: 283, 1967 2. KaRN R, ZARUBA K, SCHEIThIN W: Ocular
side-effects of long-term immunosuppressive therapy in recipients of cadaver kidney transplants. Ophthalmol Res 1: 21, 1970
3. PORTER R, CROMBIE AL, GARDNER PS, et al: Incidence of ocular complications in patients
undergoing renal transplantation. Br Med I 3: 133, 1972 4. LEROUX-ROBERT C, Bio.,ou. G, MEYRIER A, et al: Ocular complications in renal transplantation (C). Br Med 1 3: 586, 1972
5. BERKOWITZ JS, DAVID DS, SAICAI 5, et al: Ocular complications in renal transplant recipients. Am I Med 55: 492, 1973 6. MILLET VG, CASADO PgREZ 5, ALvAREZ GRANDE J, et al: Cataracts after renal transplantation (C). Br Med J 4: 47, 1972 7. MANLIcH J, THIEL G, DosRivojEvIc D, et al: Die Cortison Katarakte nach Nierentransplantation. Dtsch Med Wochenschr 97: 860 1972 8. BERSTEIN HN, SCHWARTZ B: Effect of' longterm systemic steroids on ocular pressure and tonographic values. Arch Oph:halmol 68: 742, 1962 9. WALLOW I: Nekrotisierende Retinitis bel schwerer Allgemeinerkrankung. Ber Dtsch
Ophthalmol Ges 70: 55, 1970 et al: Cytomegalic inclusion retinitis in an adult. Arch Ophihalmol 86: 44 1971 FINE RN, WILSON WA, MICKEY MR, et al: Posterior subcapsular cataracts (PSC) in paediatric renal allograft recipients (abstr), International Congress of Nephrology, Florence, June 1975, p 1029 SIEGEL 5: in Non-parametric Statistics, McGraw-Hill Series in Psychology, HARLOW HF (ed), New York, McGraw, 1956, p 116 BERLYNE GM: Microcrystalline conjunctival calcification in renal failure. A useful clinical sign. Lancet 2: 366, 1968 OGLESBY RB, BLACK RL, vor. SALLMANN L,
10. DE VENECIA G, Zu RHEIN GM, PRArr MV,
11.
12. 13. 14.
et al: Cataracts in patients with rheumatic diseases treated with corticosteroids. Arch
Ophthalmol 66: 625, 1961 al: Posterior subcapsular cataracts as a complication of adrenocortical steroid therapy. Can Med Assoc 1 86: 52, 1962 16. SPENCER RW, ANDELMAN SY: Steroid cataracts. Arch Ophthalmol 74: 38, 1965 17. FURST C, SMILEY WK, ANSELL BM: Steroid cataracts. Ann Rheum Dis 25: 364, 1966 18. SALvATIERRAO PD, COCHRUM KR, AMEND WJC, et al: Improved patient survival in renal transplantation. Surgery 79: 166, 1976 15. TOOGOOD JH, DYSON C, THOMPSON CA, et
the health
of the pregnant Inuit
26
woman and encouraging better nutrition of the infant, the deaths and other consequences of the nutritional deprivation in the early months of life might have been avoided. As well, the maternal separation that may result in rejection of even the rehabilitated infant may be prevented. References I. AVERY GB, VILLAVICENCIO 0, LILLY JR, Ct al:
Intractable diarrhea in early infancy. Pediatrics 41: 712, 1968
2. KEATING JP, TERNBERO JL: Amino acidhypertonic glucose treatment for intractable diarrhea in infants. Am J Dix Child 122: 226, 1971 3. HYMAN CJ, REITER J, RODMAN J, et al: Parenteral and oral alimentation in the treatment of the non-specific protracted diarrheal syndrome of infancy. J Pediatr 78: 17, 1971 4. Wu P,
HAMILTON JR, LEBLANC AE:
A
clinical and metabolic study of an intravenous feeding technique using peripheral veins as the initial infusion site. Can Med Assoc J 106: 969, 1972
5. BANISTER
A,
MATIN-SIDDIQI
SA,
HATCHER
GW, et al: Intravenous feeding of young infants with persistent diarrhea. Acta Paediatr Scand 64: 732, 1975 6. MCLAREN DS: Protein energy malnutrition (PEM), in Textbook of Paediatric Nutrition, MCLAREN DS, BURMAN D (eds), Edinburgh & London, Churchill Livingstone, 1976, p 105 7. TEMTAMY SA, MILLER JD: Extending the scope of the VATER association: definition of the VATER syndrome. J Pediatr 85: 345, 1974 8. CAsHORE WJ, SEDAGHATIAN MR, USHER RH:
Nutritional supplements with intravenously administered lipid, protein hydrolysate and glucose in small premature infants. Pediatrics 56: 8, 1975 9. FILLER RM, ERAKLIS AJ, RUBIN VG, et al: Long-term total parenteral nutrition in infants. N Engi J Med 281: 589, 1969 10. RYAN JA, ABEL RM, Aeeorr WM, et al: Catheter complications in total parenteral nutrition. A prospective study of 200 consecutive patients. N Engi I Med 290: 757, 1974 11. NELSON R: Minimizing systemic infection during complete parenteral alimentation of small infants. Arch Dix Child 49: 16, 1974 12. TOULOUKIAN RJ: Isosmolar coma during par-
enteral alimentation with protein hydrolysate in excess of 4 gm/kg/day. I Pediatr 86: 270, 1975 13. LLOYD-STILL JD, SCHWACHMAN H, FILLER RM: Protracted diarrhea of infancy treated
by intravenous alimentation. Am I Dis Child
125: 358, 1973
14. PEDEN VH, WITZLEBEN CL, SKELTON MA: Total parenteral nutrition. J Pediatr 78: 180, 1971 15. HEIRD WC, DRISCOLL JM JR, SCHULLINGER JN, et al: Intravenous alimentation in pediatric patients. J Pediatr 80: 351, 1972 16. RAGER R, FINEGOLD MJ: Cholestasis in immature newborn infants: is parenteral alimentation responsible? J Pediatr 86: 264, 1975 17. ASHWORTH A, BELL R, JAMES WPT, et al: Calorie requirements of children recovering from protein-calorie malnutrition. Lancet 2: 600, 1968 18. SETH V, CHANDRA RK: Opsonic activity, phagocytosis and bactericidal capacity of polymorphs in undernutrition. Arch Dis Child 47: 282, 1972 19. SIRIsINHA 5, Susicn.. R, EDELMAN R, et al: Complement and C3-proactivator levels in children with protein-calorie malnutrition and effect of dietary treatment. Lancet 1: 1016, 1973 20. SMYTHE PM, ScHONLAND M, BRERETON-STILES GG, et al: Thymolymphatic deficiency and depression of cell mediated immunity in protein-calorie malnutrition. Lancet 2: 939, 1971 21. PURTILO DT, CONNOR DH: Fatal infections in protein-calorie malnourished children with thymolymphatic atrophy. Arch Dis Child 50: 149, 1975 22. FERGUSON AC, LAWLOR GJ, NEUMANN CG, et al: Decreased rosette-forming lymphocytes in malnutrition and intrauterine growth retardation. .1 Pediatr 85: 717, 1974 23. SAYED M, SAYED J, HILDES JA, et al: Deficiency of secretory IgA in Eskimo saliva (abstr), Third International Symposium on Circumpolar Health, Yellowknife, NWT, July 8-11, 1974 24. SCHONLAND MM, SHANKLEY BC, LOENING WEK, et al: Plasma-cortisol and immunosuppression in protein-calorie malnutrition. Lan-
cet 2: 435, 1972
25. FAucI AS, DALE DC: The effect of in vivo hydrocortisone on subpopulations of human lymphocytes. I Clin Invest 53: 240, 1974 26. CLOW CL, LABERGE C, SciuvER CR: Neonatal hypertyrosinemia and evidence for deficiency of ascorbic acid in Arctic and subarctic peoples. Can Med Assoc 1 113: 624, 1975
Ocular complications in renal transplant recipients CHARLES R. PAVLIN, MD, FRCS[C]; GEORGE A. DEVEBER, MD, FRCP[C]; G.T. COOK, MD, FRCS[C]; LIONEL D.J. CHISHOLM, MD, FRCS[C]
The occurrence of ocular complications among 62 recipients of functioning renal transplants was reviewed 6 months to 7½ years after transplantation. Posterior subcapsular cataracts were found in 29 (46.70/o). A positive correlation was found between the development of cataracts and the total dose of corticosteroid, the number of days on which the dose exceeded 100 mg, and the number of rejection episodes treated with high doses of corticosteroid. Identification of specific high-risk periods in regard to cataract formation could lead to use of preventive therapy, as yet undetermined, during these periods. Lower doses of corticosteroids should be used to treat rejection episodes.
From the divisions of ophthalmology, nephrology and urology, Toronto Western Hospital, University of Toronto Reprint requests to: Dr. Lionel D.J. Chisholm, 600 Sherbourne St., Ste. 815, Toronto, Ont. M4X 1W4
L'apparition de complications oculaires parmi 62 receveurs de greffes renales fonctionnelles a ete revue entre 6 mois et 71/2 ans apres Ia transplantation. Des cataractes souscapsulaires posterieures ont ete retrouvees cbez 29 d'entre eux (46.70/o). Une correlation positive a ete retrouvee entre le developpement de cataractes et Ia dose totale de corticosteroides, le nombre de jours ou Ia dose a excede 100 mg, et le nombre d'episodes de rejet traites avec de fortes doses de corticosteroides. En ce qui a trait a Ia formation de cataractes, l'identification de periodes de risque eleve pourrait conduire a l'emploi, durant ces periodes, d'un traitement preventif qui reste a .tre determine. Les episodes de rejet devraient .tre traitees avec de plus faibles doses de corticosteroides.
Reported ocular complications in renal transplant recipients have consisted primarily of cataracts,17 corticosteroidinduced glaucoma1'3'8 and retinitis secondary to cytomegalovirus infection.3'9'10
360 CMA JOURNAL/AUGUST 20, 1977/VOL. 117
Some authors have found a significant correlation between the development of cataracts and corticosteroid therapy in terms of duration of treatment,5 total doseSA.U and a high maintenance dose,4 whereas others have found no significant correlation between the development of cataracts and any dosage feature of corticosteroid therapy.1 This report reviews the ocular complications found in 62 recipients of functioning renal transplants. Patients and methods Patients
Sixty-two renal transplant recipients, 16 women and 46 men ranging in age from 17 to 61 years (average, 39 years) were studied 6 months to 7½ years (average, 36 months) after transplantation. Each patient regularly attending the outpatient transplant clinic was studied and none was excluded for medical reasons. All patients had received either long-term hemodialysis or
long-term peritoneal dialysis for various periods prior to transplantation. The original causes of end-stage renal failure are listed in Table I. Methods All patients had received azathioprine, 2 mg/kg .d or less if indicated, throughout the transplantation program. Prednisone, 1.5 mg/kg .d, had been given for 1 week after transplantation, then the dose was reduced gradually to 0.2 mg/kg .d at 6 months and 0.15 mg/kg ed at 12 months, this last dose being maintained indefinitely if the patient's condition remained stable. Additional immunosuppressive therapy with one or more of actinomycin C or D, local graft irradiation, antithymocyte globulin and cyclophosphamide had been given to most patients during various phases of the transplantation program. Treatment of rejection episodes had consisted of initial high-dose therapy with corticosteroids (5 mg/kg .d orally prior to 1969 in 10 patients; 10 mg/kg .d intravenously from 1969 on in 52 patients) for a maximum of 3 or 4 days, with gradual reduction to the baseline dose over the next 2 weeks.
Eye examination in each patient included tests of visual acuity, applanation tonometry, biomicroscopy of the anterior chamber and lens, and ophthalmoscopy with the pupil dilated. Tonography, gonioscopy and visual field examinations were carried out in patients with ocular hypertension. Results The findings on ocular examination are listed in Table II. Subepithelial deposits in cornea and conjunctiva Of the 62 patients 35 displayed pale grey or white clumps of chalk-like material beneath the corneal epithelium along the limbal margin and in the adjacent conjunctiva. These were invariably restricted to the interpalpebral area. Cataract The cataracts found were all of the posterior subcapsular variety, in which opaque deposits lie on the anterior or inner surface of the posterior lens capsule. These varied considerably in density and area. In our statistical calculations we considered only the presence or absence of cataracts and not the severity. Of the 62 patients 29 (46.8%) 21 of the 46 men and 8 of the 16 women - had bilateral, symmetric cataracts. The sex difference was not significant; therefore the findings in the two groups were considered together in subsequent calculations. The prevalence of cataracts was 50% (5 of 10 patients) in the group receiving transplants prior to 1969 and 46.2% (24 of 52 patients) in the group receiving transplants subsequently. Of 13 patients with visual acuity of less than 6/9, 9 had cataracts, and in 7 of the 9 the visual impairment was considered to be a direct result of cataractous opacification. The cataracts
were extracted in five of the seven patients, unilaterally in four and bilaterally in one; in all five, visual acuity in the eyes undergoing operation improved to 6/9 or better. Of the six patients in whom the cataracts did not contribute to decreased visual acuity, three had residual macular damage from severe preoperative hypertensive retinopathy, two had pre-existing unilateral amblyopia, and one had anterior lenticonus in association with Alport's syndrome. The patients were divided into two groups, those with cataracts (29) and those without (33), then compared as to age and various dosage features of prednisone and azathioprine therapy. Statistical comparisons were performed with both the t-test for normal distribution and the Mann-Whitney U-test12 for skewed distribution. The results of these tests agreed in all applications. The mean age of the cataract group was 41.6 years and that of the noncataract group, 37.4 years; this difference was not significant. No significant relation could be found between the development of cataracts and the duration of therapy, the overall mean dose per day or the mean maintenance dose per day of prednisone. However, a high level of significance (P < 0.01) was evident in the correlations of cataract development with total dose and total number of days on which the dose exceeded 100 mg (Table III). In an attempt to relate this finding to rejection episodes, we then compared the development of cataracts with the number of periods of 3 days or more in which the prednisone dose exceeded 100 mg/ d. This relation was also highly significant (P < 0.01); thus cataract development appeared to correlate with the number of rejection episodes treated with high doses of prednisone (Table III). There was no significant difference between the two groups in the total dose or mean daily dose of azathioprine or
:7
CMA JOURNAL/AUGUST 20, 1977/VOL. 117 361
(by a chi-square test) in the numbers of patients who had received cyclophosphamide. Concentrations of serum calcium, measured in all patients at 3-month intervals after transplantation, showed no correlation with the development of cataracts.
Ocular hypertension Four patients had elevated intraocular pressure (TOP), defined as two or more readings greater than 21 mm Hg by applanation tonometry; none had glaucomatous optic atrophy or visual field loss. Two of the patients had cataracts. Two were receiving a low maintenance dose of prednisone and in one the drug had been discontinued 2 weeks previously. In the fourth patient the TOP varied directly with the fluctuating prednisone dose (Fig. 1). Discussion We detected pale grey or white subepithelial deposits in the interpalpebral cornea and conjunctiva of 35 of our 62 patients. This frequency is less than that in Berlyne's group of patients with chronic renal failure, of whom 13 of 16 had such deposits.13 These deposits may be related to a high concentration of plasma inorganic phosphate and the resultant elevation in the calcium x phosphate product, which favours precipitation of calcium and phosphate in tissues having higher alkalinity. Because the interpalpebral cornea and conjunctiva are exposed to the atmosphere, the local Pco2 decreases and the pH increases; this favours the precipitation of calcium and phosphate when tissue fluids are saturated. We believe that these deposits are associated with chronic renal failure and, indeed, may cease to progress or may regress after successful renal transplantation. This may explain the greater frequency of these deposits in Berlyne's patients with chronic renal failure. So-called corticosteroid-induced cataracts have been well described in the medical literature.14-17 In renal transplant recipients the incidence of cataract development has been as high as . IDJ
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FIG. 1-Relation of intraocular pressure to daily dose of prednisone in one renal transplant recipient.
46%. Some workers have found a significant correlation between cataract development and duration of corticosteroid therapy,1'5 total dose3'5'11 and a high maintenance dose,4 while others could establish no significant correlation between cataract development and any dosage feature.1 Rapid progession of cataract opacification during periods of treatment with high doses of corticosteroids have been observed.2'6 In the Hovland and Ellis1 series 2 patients had cataracts prior to renal transplantation, whereas 12 of the 26 displayed lens opacities after transplantation. Berkowitz and colleagues5 found no cataracts among 22 control patients with chronic renal failure. To our knowledge our 62 renal transplant recipients represent the largest adult group yet reviewed for ocular complications. In these patients we found no significant relation between the development of cataracts and corticosteroid therapy with regard to duration of administration, average daily dose and maintenance dose of the drug. However, there was a highly significant relation between the development of cataracts and the total dose of corticosteroid, the number of days on which the dose exceeded 100 mg, and the number of rejection episodes treated with high doses of corticosteroids. The last two factors are directly related to immunosuppression during rejection episodes, and it seems likely that the first factor, the total dose of corticosteroid, is also influenced greatly by immunosuppression. The incidence of cataract development was similar in the group of patients receiving transplants prior to 1969 and those receiving transplants subsequently. The former received a maximum of 5 mg/kg .d orally for rejection episodes and the latter, 10 mg/kg ed intravenously. If cataract formation is related primarily to periods of high-dose therapy with corticosteroids, the two doses appear to have an equally deleterious effect. We found no relation between cataract development and therapy with azathioprine or cyclophosphamide, or abnormalities in serum calcium concentration. Elevated lOP has been demonstrated in patients receiving long-term oral corticosteroid therapy.8 Hovland and Ellis1 found 8 patients with increased TOP among 26 renal transplant recipients, while Berkowitz and colleagues5 found only 1 among 44 patients. Two of our four patients with elevated lOP were receiving a low maintenance dose of prednisone, and in one other the corticosteroid had been discontinued 2 weeks earlier. A fourth patient exhibited a slightly elevated lOP while taking 20 mg/d of prednisone, but the
362 CMA JOURNAL/AUGUST 20, 1977/VOL. 117
lOP increased substantially whenever the prednisone dose was increased, although the dose was never greater than 35 mg/d (Fig. 1). This represents a good example of a positive lOP response to oral corticosteroid therapy. None of our patients had visual field loss secondary to elevated lOP and there was no family history of glaucoma. This report is the first to demonstrate a significant correlation between formation of cataracts and periods of highdose corticosteroid therapy in renal transplant recipients. The exact metabolic factors leading to cataract formation, either de novo or secondary to corticosteroid therapy, are unknown at present. Future knowledge could lead to the development of preventive therapy to be applied during specific highrisk periods such as those surrounding rejection episodes, or during longer periods when high-dose maintenance doses of corticosteroid are required. In addition, recent evidence that rejection episodes may be equally well controlled by much lower doses of corticosteroids than those currently used by most transplant groups18 could have important applications in the prevention of cataract development after transplantation. References 1. HOYLAND KR, ELLIS PP: Ocular changes in renal transplant patients. Am I Ophihalmol 63: 283, 1967 2. KaRN R, ZARUBA K, SCHEIThIN W: Ocular
side-effects of long-term immunosuppressive therapy in recipients of cadaver kidney transplants. Ophthalmol Res 1: 21, 1970
3. PORTER R, CROMBIE AL, GARDNER PS, et al: Incidence of ocular complications in patients
undergoing renal transplantation. Br Med I 3: 133, 1972 4. LEROUX-ROBERT C, Bio.,ou. G, MEYRIER A, et al: Ocular complications in renal transplantation (C). Br Med 1 3: 586, 1972
5. BERKOWITZ JS, DAVID DS, SAICAI 5, et al: Ocular complications in renal transplant recipients. Am I Med 55: 492, 1973 6. MILLET VG, CASADO PgREZ 5, ALvAREZ GRANDE J, et al: Cataracts after renal transplantation (C). Br Med J 4: 47, 1972 7. MANLIcH J, THIEL G, DosRivojEvIc D, et al: Die Cortison Katarakte nach Nierentransplantation. Dtsch Med Wochenschr 97: 860 1972 8. BERSTEIN HN, SCHWARTZ B: Effect of' longterm systemic steroids on ocular pressure and tonographic values. Arch Oph:halmol 68: 742, 1962 9. WALLOW I: Nekrotisierende Retinitis bel schwerer Allgemeinerkrankung. Ber Dtsch
Ophthalmol Ges 70: 55, 1970 et al: Cytomegalic inclusion retinitis in an adult. Arch Ophihalmol 86: 44 1971 FINE RN, WILSON WA, MICKEY MR, et al: Posterior subcapsular cataracts (PSC) in paediatric renal allograft recipients (abstr), International Congress of Nephrology, Florence, June 1975, p 1029 SIEGEL 5: in Non-parametric Statistics, McGraw-Hill Series in Psychology, HARLOW HF (ed), New York, McGraw, 1956, p 116 BERLYNE GM: Microcrystalline conjunctival calcification in renal failure. A useful clinical sign. Lancet 2: 366, 1968 OGLESBY RB, BLACK RL, vor. SALLMANN L,
10. DE VENECIA G, Zu RHEIN GM, PRArr MV,
11.
12. 13. 14.
et al: Cataracts in patients with rheumatic diseases treated with corticosteroids. Arch
Ophthalmol 66: 625, 1961 al: Posterior subcapsular cataracts as a complication of adrenocortical steroid therapy. Can Med Assoc 1 86: 52, 1962 16. SPENCER RW, ANDELMAN SY: Steroid cataracts. Arch Ophthalmol 74: 38, 1965 17. FURST C, SMILEY WK, ANSELL BM: Steroid cataracts. Ann Rheum Dis 25: 364, 1966 18. SALvATIERRAO PD, COCHRUM KR, AMEND WJC, et al: Improved patient survival in renal transplantation. Surgery 79: 166, 1976 15. TOOGOOD JH, DYSON C, THOMPSON CA, et
