Clin Transplantation 1999: 13: 356–362Printed in Ireland. All rights reser6ed

Diabetic retinopathy after combinedkidney–pancreas transplantation

Chow VCC, Pai RP, Chapman JR, O’Connell PJ, Allen RDM,Mitchell P, Nankivell BJ. Diabetic retinopathy after combined kidney–pancreas transplantation.Clin Transplantation 1999: 13: 356–362. © Munksgaard, 1999

Abstract: Diabetic retinopathy (DR) is amenable to good diabetic con-trol; however, only successful pancreas transplantation can achieve sus-tained normoglycaemia. The aim of this long-term study was toexamine the course of DR in insulin-dependent diabetic recipients of asimultaneous kidney and pancreas transplant (SPK). Successful SPKrecipients (n=46) and failed pancreas transplant with a functioningkidney transplant (n=8) were assessed by baseline and regular post-transplant ophthalmic examinations (n=432) for up to 10 yr afterSPK. At the time of SPK (n=108 eyes), the mean duration of diabeteswas 2597 yr, ten eyes were blind, and 79% of eyes had advanced DRthat had panretinal laser (panretinal photocoagulation, PRP). Success-ful SPK recipients had normal glucose control with a mean HBA1C of5.290.6%. DR remained stable in 75% of both the study and controlgroups, with no difference between groups. The DR mostly evolvedtowards inactive proliferative DR. After SPK, 14% of non-blind eyesshowed improvement of DR, 76% remained stable and 10% progressed.Early vitreous haemorrhage occurred in 6.1% of eyes, and was relatedto established DR. Cataract of all types increased after transplantation(pB0.01), which reduced visual acuity (VA) in affected eyes. The meanoverall VA remained unchanged for the study duration. In summary,uremic patients from diabetic nephropathy had a high prevalence ofsevere proliferative DR and blindness at the time of presentation forSPK. This was subsequently stabilised to inactive proliferative DR byappropriate laser therapy followed by metabolic control achieved bySPK.

Vincent CC Chowa, RamiP Paib, Jeremy R Chapmana,Philip J O’Connella, RichardDM Allena, Paul Mitchellb andBrian J Nankivella

a National Pancreas Transplant Unit andb Department of Ophthalmology, Universityof Sydney, Westmead Hospital, Sydney2145, Australia

Key words: diabetic retinopathy – kidney –pancreas – transplantation

Corresponding author: Dr BJ Nankivell, De-partment of Renal Medicine, WestmeadHospital, Westmead, Sydney, NSW 2145,Australia. Tel: +61-2-9845-6962; fax: +61-2-9633-9351; e-mail:bn@renal.wh.usyd.edu.au

Accepted for publication 14 April 1999

Diabetes mellitus is associated with microvascularcomplications, such as diabetic retinopathy (DR),a leading cause of adult blindness (1–3). The sever-ity of DR is strongly associated with duration ofdiabetes (2–7), hypertension (8), renal disease andblood glucose control (4, 9). The Diabetes Controland Complication Trial (DCCT) has shown that ininsulin-dependent diabetes mellitus (IDDM) pa-

tients, tight glucose control with intensive therapyreduced development and progression of microvas-cular complications, including DR (4). Successfulpancreatic transplantation is the only therapy ca-pable of achieving sustained euglycaemia, insulin-independence and complete normalisation ofglycosylated haemoglobin levels in IDDM pa-tients. However, there is little long-term data onthe effects of pancreas transplantation on the pro-gression of DR. Available studies have shown vari-able results, and are often limited by small patientnumbers and short follow-up times.

The aims of this long-term, prospective studywere to determine the natural history and out-comes of DR, and to evaluate risk factors forprogression for up to 10 yr after combined kid-ney–pancreas transplantation.

Abbre6iations: DR, diabetic retinopathy – HBA1C, glycosy-lated haemoglobin – IDDM, insulin-dependent diabetes melli-tus – NPDR, non-proliferative diabetic retinopathy – OGTT,oral glucose tolerance test – PDR, proliferative diabeticretinopathy – PMF, pre-retinal macular fibrosis – PRP, pan-retinal photocoagulation – SPK, simultaneous pancreas andkidney transplant – VA, visual acuity

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Methods and patientsStudy population and surgical technique

Patients (n=54) with IDDM and end-stage renaldisease who received a simultaneous kidney andpancreas transplant (SPK) from June 1987 to April1997 in Westmead Hospital were studied. Patientswere excluded if follow-up examinations were un-available to the Department of OphthalmologyUnit because of geographical reasons, or if theydied within 1 yr of transplantation (n=21). Thestudy group comprised successful SPK with sus-tained euglycaemia (n=46), with a mean follow-up of 4.192.6 yr. A control group of patients(n=8), who again became diabetic after pancreasgraft failure, was formed, with a mean follow-upafter pancreas transplantation of 2.392.2 yr.

Patients received ABO-compatible, cross-matchnegative grafts and were immunosuppressed usingtriple therapy with cyclosporine (CsA, initially 10–12.5 mg/kg/d adjusted according to whole bloodcyclosporine levels), azathioprine (1.5 mg/kg/d)and prednisolone (30 mg tapering to 10 mg/d over6 months). The pancreas and kidney were placed inan intraperitoneal position, the pancreas in theright iliac fossa and under the anterior abdominalwall, and the kidney on the left side, and wereanastomosed to the iliac vessels, with pancreaticduct drainage to the bladder.

Study design and ophthalmic examinations

Regular ophthalmic examinations of SPK recipi-ents and controls were conducted at the WestmeadHospital Eye Clinic for up to 10 yr after surgery.Baseline examinations were performed at a meanof 8.3 months (range 6–24 months) prior tosurgery, and post-operative examinations were per-formed at variable intervals of 6–24 months, de-pending on the severity of the DR. Blind eyes(n=10) were excluded in the assessment ofretinopathy and visual acuity (VA) changes. Toexamine the effects of euglycaemia on the progres-sion of DR, only non-blind eyes from functioningSPK (assessed by oral glucose tolerance test crite-ria) were analysed (n=82), and these were com-pared to the control group of non-blind eyes fromfailed SPK (n=16).

Ophthalmic evaluations included measurementof best corrected VA on a Snellen chart using thedecimal notation (10), slit-lamp examination todetect presence of iris neovascularisation and toevaluate severity and type of cataract, documenta-tion of retinopathy by detailed retinal examina-tions, including slit-lamp biomicroscopy with aVolk 90 diopter double aspheric lens (Volk Optical

Inc, Mentor, OH). Most patients also underwentcolour fundus photography (Topcon TRC 50IAretinal camera, Topcon corporation, Tokyo,Japan), and fluorescein angiography was only per-formed when clinically indicated. The level of DRin individual eyes was classified by a single oph-thalmologist (R.P.P.) based on the clinical data, asshowing evidence of no retinopathy, non-prolifera-tive diabetic retinopathy (NPDR), active prolifera-tive retinopathy (PDR, if retinalneovascularisation or vitreous or preretinal haem-orrhage was present), or stable proliferativeretinopathy (if active proliferation occurred previ-ously, which had regressed either spontaneously orwith treatment). Using these data, it was deter-mined whether the individual eye showed regres-sion, progression or stability. Any surgical or lasertreatment given during the previous observationperiod was recorded.

Other parameters and statistical analysis

Other baseline characteristics recorded includeddemographic data, duration of diabetes, require-ment for dialysis prior to transplantation and in-sulin dosage before transplantation. At regularmedical follow-up, blood pressure, fasting choles-terol, triglycerides, and glycosylated haemoglobinwere measured. Pancreatic function was assessedby a simultaneous oral glucose tolerance test,within a week of the pre-transplant ophthalmologi-cal examination, which included fasting and stimu-lated plasma glucose and serum insulin levels.Renal function was assessed by isotopic glomerularfiltration rate of technetium99m diethylenetriaminepentaacetic acid (Tc99m DTPA).

Categorical comparisons used Pearson’s (r) orSpearman’s correlation tests, as appropriate. Achi-square or conditional binomial test was usedfor categorical data. Multivariate analysis was usedto determine potential factors that may influenceVA. Demographic data are expressed as mean9SD.

ResultsPatient characteristics

Demographic and clinical data of the 54 patientsare described (Table 1). Immunosuppression com-prised a mean CsA dose of 3429108 mg/d, aza-thioprine of 106935 mg/d and prednisolone of13.4911.1 mg/d, yielding CsA trough levels of2239128 ng/mL. Hypertension was present in77.6% of patients at the time of eye examination,which was controlled by use of a dihydropyridinecalcium channel blocker in 47.1%, a b-blocker in

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31.9% and an ACE inhibitor in 23.7% of hyperten-sive patients. Prior to transplantation, mean fast-ing cholesterol was 6.0291.05 and mean fastingtriglyceride was 1.6590.71 mmol/L. Biochemistryafter transplantation showed normalisation of fast-ing and post-prandial glucose (Fig. 1) and satisfac-tory lipid levels (Table 2).

Ophthalmological findings

Baseline characteristics. Of 108 eyes from 54 pa-tients that were examined on 432 occasions, teneyes (9% of patients) were blind at the baselineexamination. Eight eyes were blind from previoussevere PDR, including four due to tractional reti-nal detachment secondary to PDR, and two werephthisical (shrunken and fibrotic) with rubeosis.After excluding the blind eyes from the study, of

Table 2. Summary data of key biochemical and clinical data taken at thetime of ophthalmic examinations in functioning SPK recipients, stratified bytime period after transplantation (mean9SD)

1–2 yrFactor 3–5 yr 6–10 yr

Fasting cholesterol (mmol/ 5.891.3 5.691.2 6.290.9L)

1.490.6 1.791.0Fasting triglycerides 1.390.6(mmol/L)

Glycosylated haemoglobin 5.190.65.290.7 5.390.6(%)

57.2916.8Isotopic DTPA GFR 57.2919.0 52.3926.9a

(mL/min)Trough CsA level (ng/mL) 2469128 2179120c 1729172c

Prednisolone dose (mg/d) 17920 9.792.7b 9.192.6c

Systolic blood pressure 140919 142922 142920Diastolic blood pressure 7999 749127499

a pB0.05.b pB0.01c pB0.001 vs. 1–2 yr group.

Table 1. Pre-transplant demographic characteristics of all transplant recipi-ents (n=54, mean9SD (%))

Mean9SD (%)Characteristic

38.697.6Age (yr)Male sex 29 (53.7%)Duration of diabetes (yr) 25.097.1Insulin dose before SPK (units/d) 47.1930.9Time on dialysis (yr) 1.791.1Past smokers 32 (39%)Current smokers (time adjusted) 3.3 (6.2%)Total HLA mismatch score 4.591.2

the remaining eyes (n=98), five (5.1%) had noDR, 12 (12.3%) had NPDR, 65 (66.3%) had inac-tive PDR and 16 (16.3%) had active PDR. Afterexcluding the 16 control eyes (15%) from 8 pa-tients, the remaining 82 eyes belonging to success-ful SPK patients (n=41) showed a high prevalenceof PDR at baseline (Table 3).

Fig. 1. Sustained euglycaemia demonstrated by oral glucosetolerance test for patients after successful pancreas transplanta-tion, stratified by time after transplantation. Conversion frommmol/L to mg % is ×18.02. Squares: 1–2 yr; circles: 3–5 yr;and triangles: 6–10 yr after SPK. Mean9SEM.

Table 3. Ophthalmic characteristics obtained in 432 examinations of 82non-blind eyes before and after successful pancreas transplantation

Pre-transplant (n (%)) Post-transplant (n (%))

Diabetic retinopathy5 (6)Nil 3 (4)

Non-proliferative (NPDR) 12 (15) 8 (10)64 (78)52 (63)Proliferative inactive (PDR)

Proliferative active (PDR) 13 (16) 7 (8)

(7)Pre-retinal macular fibrosis 8 (10)(PMF)

New traction retinal detach- 0 (0) 1 (1)ment

Eye treatment11 (12)c68 (83)Focal laser and/or PRP

Retinal detachment02 (2)surgery only

Vitrectomy only 2 (2) 0a

Cataract surgery 4 (2) 12 (15)b

0YAG laser therapy 2 (2)a

a pB0.05b pB0.01c pB0.001 vs. pre-transplant values.

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Table 4. The course of diabetic retinopathy assessed over the duration offollow-up between examinations in non-blind eyes in functioning combinedpancreas–renal transplant recipients and control diabetic patients with afailed transplant

All (n (%)) SPK (n (%))Group Control (n (%))

82 (41)98 (49)Number of eyes 16 (8)(patients)

Course of diabetic retinopathy14 (14) 11 (14) 3 (19)Improved

12 (75)62 (75)74 (76)Stable9 (11) 1 (6)Progressed 10 (10)

Table 5. Visual acuity, vitreous haemorrhage and retinal abnormalities in346 examinations of 82 non-blind eyes before and after successful pan-creas transplantation

Post-transplant (n (%))Pre-transplant (n (%))

26482Eye examinations0.6590.420.7090.40Visual acuitya

6 (2)Macular oedema 1 (1)NeovascularisationDisc 3 (4) 9 (3)Elsewhere 3 (4) 4 (1)

2 (1)2 (2)BothVitreous haemor- 6 (7) 8 (3)

rhage

a Mean9SD.

Diabetic retinopathy after SPK. Following trans-plantation, the total group, including controls, hadthree eyes with no DR, eight with NPDR, 79 withinactive PDR and eight with active DR. In thestudy group, the number of eyes with no DR andNPDR was comparable after SPK, 78% had inac-tive PDR and 8% had active PDR (Table 3). In thecontrol group, 94% had inactive PDR and 6% hadactive PDR after SPK, compared with 81% and19%, respectively. Overall, there were no differ-ences between the study group and control groups.

Of the 98 non-blind eyes, the level of DR re-mained stable in 76%, progressed in 10% and im-proved in 14% (Table 4). There was no significantdifference between study and control eyes for evo-lution of level of DR (Table 4, Fig. 2). Of the teneyes that showed progression of DR, three pro-

gressed to NPDR from no retinopathy at baselinelevel. Six eyes showed active proliferation frombaseline NPDR (two eventually stabilised and fourremained with active PDR despite laser treatment).The remaining one eye from a control patient hadinactive PDR that became active after transplanta-tion. Of the 14 eyes that showed improvement, onehad NPDR at baseline, which regressed to no DRwithout treatment. The remaining 13 had activePDR at baseline that became inactive after lasertreatment.

Laser therapy. Most of the patients (83%) hadfocal or panretinal laser (panretinal photocoagula-tion, PRP) for PDR prior to transplantation(Table 3). After transplantation, 11 (10%) eyesneeded further PRP. Six eyes (2%) developed mac-ular oedema after SPK, of which four resolvedspontaneously and two resolved after focal or gridlaser treatment. Pre-retinal macular PMF was al-ready present in 7% of eyes before transplantationand developed in an additional 8.3% of eyes afterSPK. Traction retinal detachment developed inone eye after SPK (Table 3).

Vitreous haemorrhage. Vitreous haemorrhage oc-curred in 19 eyes, seven prior to transplantationand in 11 eyes (on 12 occasions) after SPK, at amean interval of 2.0 yr (Table 5). Nine of these 12eyes required further laser treatment. At the timeof vitreous haemorrhage, the mean systolic bloodpressure was 144916 and the mean diastolic pres-sure was 7596 mmHg.

Of the 82 non-blind eyes, five developed signifi-cant vitreous haemorrhage within 6 months aftertransplantation. Three had active PDR, one hadstable PDR and one had NPDR prior to SPK. Allrequired further laser therapy with stabilisation inthree, although two had persisting active PDR.There was no relationship with level of blood pres-

Fig. 2. Evolution of type of diabetic retinopathy in non-blindeye examinations (n=346) after successful pancreas transplan-tation. Nil retinopathy (open bars), non-proliferative diabeticretinopathy (dotted bar), stable inactive diabetic proliferativeretinopathy (hatched bars), and active diabetic proliferativeretinopathy (solid bars).

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sure control at the time of haemorrhage, use ofaspirin or heparin, current prednisolone dose, re-cent kidney rejection, duration of diabetes or dialy-sis, serum lipids or bicarbonate, fasting orstimulated glucose or insulin, or haemoglobinlevels.

Visual acuity. The mean decimalised VA of non-blind eyes at transplantation was 0.67 (equivalentto 20/30 vision)90.42 (Table 5), and this remainedconstant for up to 10 yr after SPK (Fig. 3). Notsurprisingly, VA was negatively correlated withseverity of DR (r= −0.229, pB0.001, Fig. 4),vitreous or pre-retinal haemorrhage (r= −0.169,pB0.001) and traction retinal detachment (r= −0.284, pB0.001). By multivariate analysis, in-creased grade of cataract (pB0.05) and thepresence of combined nuclear and posterior sub-capsular cataracts (pB0.001) reduced VA. Otherimportant predictors of VA were the presence ofPMF (pB0.001), vitreous haemorrhage (pB0.05)and level of DR (pB0.001).

The prevalence of cataract significantly increasedfrom a baseline of 40–78% of eyes after transplan-tation (pB0.001). After transplantation, 14% ofeyes underwent cataract extraction (pB0.01 vs.pre-transplant). YAG capsulotomy for thickenedposterior capsule was performed in 4% of eyes.Because increased cataract prevalence may haveconfounded the assessment of VA after transplan-

Fig. 4. Effect of diabetic retinopathy level on decimalised vi-sual acuity. Mean9SEM. Non-proliferative diabetic retinopa-thy (NPDR), inactive proliferative diabetic retinopathy(I-PDR), active proliferative diabetic retinopathy (A-PDR),*pB0.05, ***pB0.001 vs. no diabetic retinopathy.

tation, a subset analysis excluding eyes withcataracts was performed, and the effect of timeafter SPK was examined by multivariate analysis.In both analyses, there was no underlying changewith time in the level of adjusted VA after SPK(coefficient of change with time=0.00890.22,p=NS). Cataract extraction improved the meandecimalised VA from 0.28 to 0.43 (pB0.001), butdid not improve it to the non-cataract VA level of0.72.

Discussion

This study has shown that pancreas transplanta-tion of type 1 diabetic patients with appropriatelaser therapy before transplantation results in long-term stabilisation of severe DR, and preservationof VA for up to 10 yr after transplantation. Severeproliferative DR was common at the time of pan-creas transplantation in this and other studies (11–19) and presents a challenge to theophthalmologist and clinician. DR causes a mi-croangiopathy affecting the pre-capillary arterioles,the capillaries and the venules, causing microvas-cular occlusion and leakage. Microaneurysm for-mation due to damaged supporting capillarypericytes and localised dilatation is an early featureof DR (1–3), which is followed by capillary clo-sure, retinal ischaemia, retinal oedema, haemor-rhage and hard exudate formation secondary tovascular leakage. In this study, severe proliferativeDR and blindness was common at baseline, butstabilised with laser therapy and metabolic correc-

Fig. 3. Time-course of decimalised visual acuity in non-blindeyes (n=82) for up to 10 yr after successful pancreas trans-plantation. Mean9SEM.

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tion from transplantation. The risk of progressionof DR may be reduced by optimal anti-hyperten-sive control and by control of blood glucose levels(4, 9, 10). However, it was not possible in ourstudy to separate the effects of normoglycaemiafrom that of laser therapy in the stabilisation ofDR because of small numbers in the failed SPKcontrol group, short follow-up times and by thegrading system of DR, which cannot detect smallimprovements of established proliferative DR.

The results of the studies of DR after pancreastransplantation are difficult to interpret, being con-founded by small patient numbers, short follow-uptimes and differing control groups. This may ex-plain why some studies have failed to show adifference in progression of DR between kidney–pancreas and diabetic kidney recipients at follow-up from 1 to 2.7 yr (11–13). Severe pre-existingDR treated with panretinal laser at the time ofpancreas transplantation may have obscured anypotential benefit of sustained normoglycaemiafrom SPK (20). In contrast, other controlled stud-ies have described stabilisation or clear improve-ment of DR in successful SPK recipients (14, 15),especially in the early stages of DR (less than grade5 on the EDTRS scale of 10) without previouslaser therapy (15). Substantial deterioration oc-curred in the majority of control eyes (14, 15). Ourstudy has also demonstrated comparable long-termstability of DR; however, some activity and pro-gression of DR were still present in those eyeswithout previous laser treatment. Again, this mayreflect pre-existing permanent and irreversible is-chaemia from large zones of capillary closure, the‘early worsening’ observed after euglycaemia (2),or the additional effects of hypertension. Theremay also be a lag period between achieving normo-glycaemia and improvement of the capillary clo-sure and retinal ischaemia responsible forarterio-venous shunts, intra-retinal microvascularanomalies and retinal neovascularisation and vas-cular leakage (2, 3). Although stabilisation ofsevere DR was achieved by pancreas transplanta-tion and PRP in this study, it was not the substan-tial regression seen in other diabetic microvascularcomplications, such as peripheral neuropathy, au-tonomic neuropathy or subcutanoeus microvascu-lar anomalies.

In this study, 87% of eyes received laser therapyprior to SPK, and an additional 10% needed treat-ment after SPK, mostly in the form of PRP. PRPcan stabilise DR and prevent severe visual loss inhigh-risk eyes (21), although the exact mechanismof action remains unknown. PRP may reduce thehypoxic retinal stimulus for vasodilatation, en-dothelial cell proliferation and vasoproliferative

factor production by direct peripheral retinal dam-age, increase diffusive retinal and choriodal oxy-genation or stimulate anti-angiogenic factors fromthe retinal pigment epithelium (17, 18). The currentrecommendation from this and other studies is thatactive proliferative DR be stabilised prior to SPKto reduce the risk of subsequent complications,such as vitreous haemorrhage.

Vitreous haemorrhage, which occurred in theearly post-operative period, was related to activePDR at transplantation, although the majority ofour patients received laser therapy prior to SPK.Vitreous haemorrhage is due to bleeding from reti-nal or optic disc new vessels (22). It is possible thatthe abrupt change of osmolality and sudden nor-moglycaemia from pancreas transplantation, fol-lowing a period of poor diabetic control, couldinduce structural changes within the eye and rup-ture fragile new vessels. Vitreous haemorrhage hasbeen observed, with abrupt improvement of dia-betic control, with initiation of insulin therapy orsubcutaneous minipump therapy (2, 23). In ourstudy, aspirin or heparin use, blood pressure ormaintenance corticosteroid dose were not corre-lated with the early onset of vitreous haemorrhage,suggesting that existing proliferative DR itself wasthe major risk factor (22). In diabetic patientspresenting for SPK, we strongly recommend a cur-rent ophthmalic assessment at the time of initialtransplant evaluation. This would ensure that anyactive PDR is detected and appropriate laser ther-apy undertaken if needed. Because of the possibil-ity of accelerated disease with the onset of renalfailure, regular ophthmalic review should be un-dertaken every 6 months or less while on thepancreas transplant waiting list.

VA remained stable, for up to 10 yr in thisstudy, despite the widespread presence of DR andthe increased prevalence of cataract. Severe visualloss can occur with proliferative DR when compli-cated by vitreous haemorrhage or traction detach-ment of the macula, as was observed in this study.NPDR may result in visual loss when associatedwith macular ischaemia or macular oedema. In ourstudy, determinants of reduced VA included thegrade and type of cataract, pre-retinal macularfibrosis, vitreous haemorrhage and the severity ofDR.

All forms of cataract increased after transplanta-tion and, when present, reduced VA. Long-termcorticosteroid use typically causes posterior sub-capsular cataract or cortical cataract. Nuclearcataract is mostly related to age. The increase in alltypes of cataract after transplantation, despite eug-lycaemia, may reflect the effect of maintenancecorticosteroid therapy in cataract progression.

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In summary, patients with renal failure fromdiabetic nephropathy presenting for combined kid-ney–pancreas transplantation had a high preva-lence of severe proliferative DR and blindness.Vitreous haemorrhage early in the post-transplantperiod appeared related to underlying active prolif-erative retinopathy. In most patients, stabilisationof DR was achieved with pre-transplant laser ther-apy and commonly evolved towards inactive pro-liferative DR with time. Severe pre-existing retinaldamage and a small control group confounded theassessment of any potential benefit conferred bysustained normoglycaemia in this study. VA re-mained unchanged for up to 10 yr after transplan-tation, despite an increased prevalence of cataract.Where possible, we recommend stabilisation of ac-tive DR prior to pancreas transplantation andregular ophthmological evaluation for develop-ment of cataract formation and any residual activeretinopathy.

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