Diabetologia 9 Springer-Verlag 1992

Transcription

1 Diabetlgia (1992) 35: Diabetlgia 9 Springer-Verlag 1992 Cyclsprin A treatment f yung children with newly-diagnsed Type 1 (insulin-dependent) diabetes mellitus M.Jenner 1, G. gradish t, C. Stiller 2, P. Atkisn 1'2 fr the Lndn Diabetes Study Grup 1 Department f Paediatrics, Children's Hspital f Western ntari, University f Western ntari, and 2 Multi-rgan Transplant Service, University Hspital, Lndn, ntari, Canada Summary. Several studies have demnstrated the efficacy f cyclsprin A in mdifying the initial curse f Type 1 (insulin-dependent) diabetes mellitus in lder children and adults but nne have reprted the effects in very yung children. We treated 14 newly-diagnsed Type 1 diabetic patients aged 22 mnths t 95 mnths with cyclsprin A. Mean insulin dse at entry was.7 _+.7 IU- kg-l - day -t. Initial cyclsprina dse was 1mg.kg-l.day -1. Insulin dse reached a nadir f.13 IU. kg- 1. day- z by 18 days. Mean glucagn-stimulated cnnecting peptide levels were maximal at 6 mnths (.75 nml/1) and were maintained while n cyclsprin A. Insulin was discntinued in furpatients fr4,12,15 and 3 mnths respectively. In five ther patients the insulin dse was less than.15 IU. kg-i day-~ fr at least 3 mnths. Glycated haemglbin levels fr all patients were within the nrmal range. Side effects included anrexia, stmach pains, pr weight gain, hypertrichsis, gum hyperplasia, mild anaemia and elevated creatinine. All patients have nw dis- cntinued cyclsprin A and all but ne have been fllwed fr 5 years after discntinuatin. Reasns fr discntinuing cyclsprin A included expsure t chicken px (varicella), nn-reslving titis media, incmplete r n respnse and relapse. All side effects have reslved since the treatment was discntinued. Fllwing discntinuatin f cyclspfin A insulin requirements and glycated hemglbin levels increased while glucagn-stimulated cnnecting peptide levels declined dramatically. In summary, a small number f very yung patients treated with cyclsprin A achieved nninsulin requiring remissins while partial remiss ins ccurred in several ther patients and endgenus insulin prductin was maintained. Side effects t the drug ccurred althugh there have been n lng-term cnsequences. Key wrds: Cyclsprin A, Type i (insulin-dependent) diabetes mellitus, children, side effects. A number f studies, including tw randmized - duble blind placeb cntrlled trials [1, 2] have nw demnstrated the efficacy f cyclsprin A (CsA) in mdifying the initial curse f Type 1 (insulin-dependent) diabetes mellitus. Three recent reprts [3-5] have suggested that CsA may be particularly useful in treating yung, newlydiagnsed patients between the ages f 7-15 years since they shw higher rates f nn-insulin requiring remissins. Significant side effects, particularly nephrtxicity, have limited the use f CsA in these patients. Hwever, nephrtxicity appears t be dse related and des nt ccur, r is reversible, at lwer dses [6]. This pilt study was initiated in 1983 fllwing the encuraging results f ur early studies f CsA treatment f newly-diagnsed adults with Type 1 diabetes [7]. We wanted t assess the ptential benefits fr yung children as extreme variability in activity and diet make cnventinal diabetes management difficult in this age grup. In additin very yung children have nly small amunts f subcutaneus fat which ften restrict the number f injec- tin sites. CsA therapy was successful in sme f these yunger patients aged 22 mnths t 95 mnths. Hwever, difficulties with administratin f CsA, its side effects and variable results, resulted in discntinuatin f CsA therapy in all f these patients. With the exceptin f ne patient these children have nw been fllwed-up fr a minimum f 5 years after discntinuatin f CsA. This reprt summarizes the results f CsA therapy in this age grup and their lng-term fllw-up. Subjects and methds Apprval fr this study was btained frm the Human Ethics Cmmittee at the University f Western ntari. Patients ranged in age frm 22 mnths t 95 mnths. Diagnsis f Type 1 diabetes was established by cnventinal means including classic symptms in assciatin with grss elevatins f bld glucse. Exclusin criteria included: a histry f hepatic, renal r bne marrw disease, a histry f malignancy, evidence f Epstein-Barr virus, cytmegalvirus r ther uncntrlled infectins r ther cntraindicatins t immun-

2 M. Jenner eta].: Cyclspfin A in yung children with recent-nset diabetes b t~ c- 13 =c3 12 E W -, I I ~ I I L i Cyclsprin A therapy 1 12,5 5, , i I i t i Pst-discntinuatin f therapy E e* Fig.la, h. Effects f cyclsprin A (CsA) therapy n haemglbin levels (triangles) and bilirubin (squares). Values are shwn as mean ( + SEM) pst-entry t study while n CsA therapy (a, pen symbls) and after discntinuatin f CsA (b, clsed symbls). The n fr each time pint varied slightly and fr haemglbin was: 13,12, 1, 9, 5, 5, 2 and fr bilirubin: 1, 9, 1, 9, 5, 5, 2 at, 3, 6, 9,12, 15, 18 mnths respectively pst-entry while n CsA. Fllwing discntinuatin f CsA the n : 1, 12,11, 9, 9,1, 9, 6, 8, 3, 6, fr haemglbin and 8, 1,1, 9, 9, 8, 9, 6, 7, 4, 5, fr bilirubin at, 6, 12,18, 24, 3, 36, 42, 48, 54, mad 6 mnths respectively suppressin. All but tw f the patients were entered int the study within 6 weeks f diagnsis f diabetes. The remaining tw patients were started within 7 and 11 weeks fllwing diagnsis. Patients were entered int this study n a case-by-case basis fllwing discussin f ptential side effects f CsA therapy with the families and after btaining infrmed cnsent. The gals f therapy were similar t thse previusly reprted fr the Canadian Eurpean randmized cntrl trial [2]. In brief, we attempted t keep befre meal and befre bedtime glucse levels less than 7.8 mml/1 and glycated haemglbin levels within the nrmal range. At the start f therapy patients were admitted t hspital fr stabilizatin f bld glucse. Cyclsprin A treatment was initiated while in hspital at a dse f 1 rag- kg- 1. day- 1 in tw divided ral dses. The CsA dse was adjusted t maintain serum trugh levels between ng/ml as determined by a plyclnal radiimmunassay. The antibdy was kindly prvided by Sandz (Basel, Switzerland). Bld was btained at the start f the study fr baseline measurements. Patients were seen at frequent intervals fllwing diagnsis at which time labratry studies were repeated, bld pressure, height and weight were recrded. Insulin adjustments were made t minimize the dse f insulin while maintaining target glycaemic cntrl. Endgenus insulin secretin was assessed every 3 mnths with 1 mg glucagn administered i.v. fllwing an vernight fast. Bld samples were cllected fr cnnecting peptide levels at and 6 rain fllwing injectin. Patients were cnsidered t be in remissin if they maintained target glycaemia withut the need fr exgenus insulin r partial remissin if they required less than.15 IU-kg -1.day 1 s.c. fr at least 2 weeks. A diagnsis f relapse was made if there was deteriratin in glycaemic parameters r a necessary increase in insulin requirements beynd.15 IU. kg- 1. day 1 s.c. fr mre than 4 weeks in rder t maintain target glycaemic cntrl r bth in which case cyclsprin A was then discntinued. Patients wh did nt achieve insulin dses f less than.15 IU- kg 1. day- 1 were cnsidered t be nn-respnsive. Results Furteen patients (fur male, ten female) entered the study ranging in age frm 22 mnths t 95 mnths. The mean age at entry was 5.4 _+.6 years. With the exceptin f tw patients, all thers were enrlled in the study within 6 weeks f diagnsis and the remaining tw were entered at 7 and 11 weeks fllwing diagnsis. The mean duratin frm diagnsis t initiatin f CsA in the 12 patients was days. Ninety-three percent f the patients were HLA DR3 psitive, DR4 psitive r bth. ne patient was discntinued frm the study 7 days after initiating CsA therapy due t expsure t chicken px (varicella), this patient was nt included in the data analysis. The remaining 13 patients were cntinued n CsA therapy fr varying lengths f time. CsA was discntinued fr a variety f reasns, ne patientwas discntinued due t expsure t chicken px at 1 days. Three patients discntinued CsA therapy at 3, 8 and 9 mnths respectively, due t nn-reslving titis media. Six patients discntinued CsA at 3, 4, 6,1 (tw patients) and 16 mnths respectively, due t an inability t discntinue exgenus insulin althugh five f these had insulin requirements f less than.15 IU. kg- 1. day- 1 fr mre than 3 mnths. Fur patients wh had undergne a nn-insulin requiring remissin, discntinued CsA therapy at 9, 16, 22 and 36 mnths respectively, due t their lss f a nn-insulin-requiring state. There were n bvius differences in the achieved degree f glycaemic cntrl during the initial (1 t 14 days) treatment perid with CsA t accunt fr the respnse t CsA. f the fur patients wh discntinued insulin three were female. All started CsA within 4 weeks f diagnsis. Their ages at the start f CsA therapy were 39, 77, 78 and 95 mnths. Thus, they tended t be lder and had a shrt duratin f diabetes. Neither patient wh started CsA therapy beynd 6 weeks after diagnsis achieved even a partial remissin (less than.15 IU. kg -1. day-1 f insufin). f the*13 patients n CsA five were lst t fllw-up at varius times after discntinuing CsA. Side effects f CsA therapy Bth minr and majr side effects t CsA therapy were seen in these patients. Minr side effects included gingival hyperplasia (mst patients), hypertrichsis (mst patients), anrexia (ccasinal) and abdminal pains (cca-

3 886 M. Jenner et al.: Cyclsprin A in yung children with recent-nset diabetes.e 7 --z ~ " 6 -~ 55 1 E 75 Q c 1.. "~ , ~ = i i i i i i i Cyclsprin A therapy 1.5 7E 1. 5C!/!q/!'! 2, Pst-discntinuatin f therapy 1.5 r m "6 1. "= Fig.2a, b. Effects fcyclsprin A (CsA) n diastlic bld pressure (triangles), creatinine (squares) and creatinine clearance (circles). Values are shwn as the mean ( + SEM) by the pen symbls pst-entry int study while n CsA therapy (a) and fllwing discntinuatin f CsA therapy by the clsed symbls (b). The n fr each time pint varied slightly and fr diastlic bld pressure was: 7, 8, 9, 8, 5, 5, 2 while creatinine was: 13,12, 1, 9, 5, 5, 2 and creatinine clearance was: 1, 12, 1, 9, 5, 5, 2, at, 3, 6,9, 12, 15 and 18 mnths respectively pst-entry while n CsA. Fllwing discntinuatin f CsA: the n fr diastlic bld pressure was: 8,12, 11, 9, 6, 9, 7, 8, 7, 3, 7, fr creatinine: 9, 13,12, 8, 9, 9, 8, 6, 8, 4, 7 and fr creatinine clearance: 1,11,11, 9, 8, 1, 8, 6, 8,4, 7, at, 6,12,18, 24, 3, 36, 42, 48, 54 and 6 mnths respectively sinal). As shwn in Figure 1, haemglbin decreased n CsA therapy. Haemglbin decreased frm a mean f g/1 at the start f CsA therapy t g/1 at 18 mnths. The decline in haemglbin was nt serius enugh t discntinue CsA. There was little, if any, effect n serum bilirubin measurements. As shwn in Figure 2, diastlic bld pressure tended t increase n CsA therapy althugh there was cnsiderable variability. Serum creatinine levels increased n CsA frm a mean f 42.1 _+ 3.3 gml/1 t a high f gml/1 at 18 mnths in the remaining tw patients. Calculated creatinine clearance (Cckrft-Gault frmula) declined in patients n CsA frm a mean value at the start f therapy f ml/s t a nadir f ml/s at 18 mnths. Grwth was generally unaffected by CsA therapy in bth male and female patients with a minr decrease in the linear grwth f ne male and ne female patient. This was nt cnsidered significant and CsA was nt discntinued. In additin, diminished appetite ccurred in sme patients, and clse dietary supervisin was necessary t maintain adequate calric intake. Metablic effecs f CsA therapy Nn-insulin requiring remissins were achieved in fur patients, wh at the start f therapy were 39, 77, 94 and 78 mnths f age. The duratin f the nn-insulin requiring remissins were 4, 12, 15 and 3 mnths, respectively. The ne patient wh remained insulin-free fr 1 year had a brief (2 week) relapse at 6 mnths fllwed by a secnd nn-insulin requiring remissin which lasted 4 mnths befre anther relapse ccurred. In an additinal five patients, the insulin requirements declined t less than.15 IU. kg- 1. day- 1 fr mre than 3 mnths. As shwn in Figure 3 the mean dse f insulin declined t a lw at 6 mnths f.13 IU. kg-l-day -1. The tw patients still n CsA therapy at 18 mnths did nt require insulin. The mean values f glucagn-stimulated cnnecting peptide (GSCP; Fig.3) were maximal at 6mnths (.75 nml/1) and remained stable until discntinuatin f CsA. Finally, glycated haemglbin levels declined t a minimum f 8.9 % at 3 mnths and then remained cnstant while n CsA therapy. The nrmal range fr the clrimetric glycated haemglbin in ur labratry was %. Side effects f pst-discntinuatin f CsA All CsA-related side effects reslved shrtly after discntinuing CsA. These included the csmetic (gingival hyperplasia, hypertrichsis) as well as ther minr side effects such as abdminal cramps and decreased appetite. Mre significant side effects nted during CsA therapy imprved fllwing discntinuatin. Haemglbin prgressively increased and returned t nrmal values while bilirubin cncentratins did nt shw any significant change (Fig. 1). Diastlic bld pressure decreased slightly fllwing discntinuatin f CsA therapy while creatinine decreased and creatinine clearance increased (Fig. 2). Grwth has been nrmal (data nt shwn). Metablic parameters pst-discntinuatin f CsA (Fig. 3) Insulin requirements increased steadily fllwing discntinuatin f CsA therapy. This was accmpanied by a decline in GSCP levels. By 24 mnths fllwing discntinuatin there was n measurable GSCP in any patient. Glycated haemglbin levels increased t a maximum f 14.5 %, 54 mnths fllwing discntinuatin f CsA therapy. Discussin Stiller and clleagues [8] initially suggested a pssible therapeutic rle fr CsA therapy in treating individuals with Type i diabetes. Their initial studies n diabetesprne BB/W rats indicated that CsA therapy culd prevent diabetes and insulitis in these animals. Subsequently, they reprted that CsA therapy in newly-diagnsed individuals with Type i diabetes resulted in nn-insulin re-

4 M. Jenner et al.: Cyclsprin A in yung children with recent-nset diabetes ~, 1.25 e 1. ~..~ I=: * ~.75 ~r.e r -~.5 m ~ Cyclsprin A therapy l SIt,,#yl /,,. ' L I i Pst-discntinuatin f therapy 12.5 " E "1" >, Fig.3a, b. Metablic effects fcyclsprin A (CsA) therapy. The mean ( + SEM) fr glycated haemglbin (circles), daily insulin dse (triangles) and glucagn-stimulated cnnecting peptide (squares) are shwn pstentry int study while n CsA therapy (a) and fllwing discntinuatin f CsA therapy (b). The number f children included at each time pint were similar and are as fllws: 13, 13, 1, 9, 5, 5,2, at, 3, 6, 9, 12, 15 and 18 mnths pst-entry while n CsA and 12, 11, 1, 9, 8, 1, 9, 8, 6 and 8 at, 6, 12, 18, 24, 3, 36, 42, 48, 54 and 6 mnths respectively after CsA was discntinued. Glucagn-stimulated cnnecting peptide (GSCP) levels were measured nly until the values fell belw the sensitivity f the assay quiring remissins in sme f these patients [7]. A number f additinal studies have cnfirmed the efficacy f CsA in inducing nn-insulin requiring remissins [1-5, 7, 9-11]. Tw randmized cntrl trials reprted 3 %-4 % f patients remained in nn-insulin requiring remissin at 9 mnths and 1 year f therapy, respectively [2, 3]. Additinally, endgenus insulin secretin was preserved and GSCP levels were near-nrmal [1]. Patients mst likely t enter a nn-insulin requiring remissin were thse wh had symptms fr le, ss than 6 weeks, less than 3 weeks f insulin therapy, r bth. Bugnhres et al. [2] reprted that CsA therapy in children between the ages f 7 and 15 years f age, was assciated with a nn-insulin requiring remissin in apprximately 5 % f patients fr up t 1 year f treatment. Results frm the Canadian pen Study f CsA therapy in newly-diagnsed Type I diabetes suggested that the pssibility fr remissin is greater in lder patients [1]. Given the encuraging results in lder patients this study was initiated t examine the ptential benefit f CsA therapy in children with newly-diagnsed diabetes. The results f this study indicate that CsA therapy des have an effect in inducing remissins in sme yung children. Fur f 14 (29 %) patients were able t achieve nninsulin requiring remissins including three with remissins ranging frm 1 t 2.5 years. Five ther patients (36 % ) were able t reduce their insulin requirements t less than.15 IU-kg-l-day -~ fr mre than 3 mnths. Given the small number f patients it is nt pssible t assess which, if any, factrs determined the respnse t CsA. In general hwever, they were lder with a shrt duratin between diagnsis and initiatin f CsA (fr three patients, less than 2 weeks). There were n differences in the initial GSCP r glycaemic cntrl. As nted abve, this is similar t the findings f the Canadian Eurpean Randmized Trial [2] which reprted that a nn-insulin requiring remissin was mre likely in shrt-duratin diabetes. Side effects frm CsA, in particular renal txicity, frequently nece, ssitated a decrease in the CsA dse. This was assciated with an increase in insulin requirements in the majrity f these patients. The small number f children in this study wh were able t discntinue insulin may suggest that Type 1 diabetes is mre advanced r mre aggressive by the time the diagnsis is made in this yunger grup f patients. Endgenus insulin secretry activity as measured by GSCP was maintained n CsA even thugh patients in remissin eventually relapsed. This is supprted by the results f Bugn6res et al. [12] wh fund that children 7 t 15 years f age in remissin eventually relapsed while being treated with CsA despite maintained GSCP levels. They speculated that the reduced Beta-cell mass at diagnsis may have been incapable f maintaining nrmal insulin sensitivity. Similar evidence has been reprted recently by Finegd et al. [13]. Thus, CsA therapy may prevent additinal Beta-cell Iss but the residual mass may be t little by the time f diagnsis and initiatin f CsA therapy. Side effects frm CsA therapy have been cnsistent thrugh varius studies t date and include hypertrichsis, gum hyperplasia, nrmcytic, nrmchrnic anaemia, headache, tremr, peripheral paraesthesias and gastrintestinal upset. We bserved similar side effects in this study. In additin, anrexia was a prblem in several patients and required careful mnitring f dietary intake, t avid significant weight lss r lack f weight gain. Mre serius side effects frm CsA include serius infectin, lymphprliferative disease and nephrtxicity. In all studies f CsA therapy in Type 1 diabetes there have been n reprted life-threatening infectins [14,15]. Similarly in this study there appeared t be n increase in rates f infectin, hwever, in three children titis media appeared t be mre difficult t cntrl and eventually resuited in discntinuatin f CsA therapy. There have been n reprts t date f lymphprliferative disease in patients underging CsA therapy fr diabetes. Epstein-Barr virus is assciated with increased risk f lymphprliferative disease in immunsuppressed patients [16-18]. Therefre, mnitring f Epstein-Barr virus infectin is

5 888 essential in treating individuals with CsA althugh n patients in this study became infected while n CsA therapy. Finally, nephrtxicity is a frequent cmplicatin f CsA therapy. It has been nted in all studies t date and appears t be dse-dependent [1, 2, 9]. Histlgical evidence f dse-dependent CsA txicity has been reprted in patients with Type 1 diabetes and CsA therapy [6]. In dses less than 5 mg. kg-1. day-1, with whle bld trugh levels less than 3 ng/ml in adults r 6 ng/ml in children r bth, there des nt appear t be any histlgical renal txicity. In this study calculated creatinine clearance declined while n CsA therapy. Fllwing discntinuatin f CsA creatinine clearance increased and returned t nrmal values. A decline in creatinine clearance f greater than 3 % prmpted a decrease in CsA therapy which frequently resulted in a decline in endgenus insulin secretin in additin t an increase in insulin requirements. Mre sensitive indicatrs f renal txicity may have demnstrated minr changes in renal functin. Hwever, as discussed abve the bld levels f CsA in these patients have nt been assciated with histlgical renal txicity [6]. In the eight patients still being fllwed-up in ur clinic all but ne have micralbuminuria less than 3 gg/min mre than 6 years after discntinuing CsA. The ther patient is a 16-year-ld male wh had a nn-insulin requiring remissin fr 15 mnths. Eighty-nine mnths after discntinuing CsA he had micralbuminuria f 52.3 gg/min. It is difficult t determine whether this is due t CsA nephrtxicity, diabetes r bth. All side effects frm CsA therapy disappeared fllwing its discntinuatin. Fr the perid f pst-csa bservatin, which is nw 5 years fr all but ne patient, there have been n significant side effects. Grwth and renal functin have been nrmal, and nrmal grwth has als been reprted in children wh have received a renal transplant and are n CsA therapy [19, 2]. In summary, CsA had limited efficacy in mdifying the initial curse f Type i diabetes in this very yung age grup. Althugh several side effects f CsA were nted all f these were reversible fllwing discntinuatin f CsA and there have been n lng-term effects. The efficacy f CsA in newly-diagnsed patients with Type 1 diabetes suggest a rle fr immunmdulatin nce a safe therapy is available. Hwever, the results f this study indicate that treating very yung children at the time f diagnsis may be t late fr mst t achieve a nn-insulin requiring remissin. Future interventin studies shuld be directed at treating the pre-clinical state such as that recently reprted by Ellitt and Chase [21], using nictinamide. Acknwledgements. We gratefully acknwledge Dr. G. Murphy and Sandz Canada fr supplying cyclsprin A. We als thank Ms. H. Sim and Mr. G. Ryan fr data analysis and Ms. E. Allisn fr the preparatin f this manuscript. M. Jenner et al.: Cyclsprin A in yung children with recent-nset diabetes 2. Canadian-Eurpean randmized cntrl trial grup (1988) Cyclsprine-induced remissin f IDDM after early interventin. Assciatin f ne year f cyclsprine with enhanced insulin secretin. Diabetes 37: Stiller CR, Dupr6 J, Gent Met al. (1987) Effects f cyclsprine in recent-nset juvenile Type i diabetes: impact f age and duratin f disease. J Pediatr 111: Bugneres PF, Carel JC, Castan Let al. (1988) Factrs determining early remissin f Type 1 diabetes in children treated with cyclsprin A. N Engl J Med 38:663%7 5. Bach JF (1987) Cyclsprine in insulin-dependent diabetes mellitus. J Pediatr 111: Feutren G (1988) Functinal cnsequences and risk factrs f chrnic cyclsprin A nephrtxicity in Type I diabetes trials. Transplant Prc 2: Stiller CR, Dupr6 J, Gent Met al. (1984) Effects f cyclsprine immunsuppressin in insulin-dependent diabetes mellitus f recent nset. Science 223: Laupacis A, Stiller CR, Gardell C et al. (1983) Cyclsprin prevents diabetes in BB Wistar rats. Lancet I: Assan R, Sachs MD, Labrie C et al. (1985) Metablic and immunlgic effect f cyclsprine in recently diagnsed Type 1 diabetes mellitus. Lancet I: Dupr6 J, Stiller CR, Gent Met al. (1988) Effects f immunsuppressin with cyclsprine in insulin dependent diabetes mellitus f recent nset: the Canadian pen study f 44 mnths. Transplant Prc 2: Stiller CR, Kewn PA (1984) Cyclsprine therapy in perspective: In Mrris PJ, Tilney NL (eds) Prgress in transplantatin. Churchill Livingstne, Edinburgh, pp Bugnbres PF, Landais R Bissn C et al. (199) Limited duratin f remissin f insulin dependency in children with recent vert type l diabetes treated with lw-dse cyclsprin. Diabetes 39: Finegd D, Hramiak IM, Dupr6 J (199) Relatinship between stimulated C-peptide respnses and insulin sensitivity in insulindependent diabetics treated with cyclsprin. Diabetlgia 33 [Suppl]: A28 (Abstract) 14. Bach JF (1988) The risk/benefit rati in immuninterventin fr autimmune diseases. J Autimmun 1: Bach JF (1992) Immuninterventin in autimmune diseases frm cellular selectivity t autantigen specificity. J Autimmun 5 [Suppl]: A Editrial (1984) Lymphma in rgan transplant recipients. Lancet I: Hant DW, Frizzera G, Gajl-Peczalska K J, Simmns RL (1985) Epstein-B arr virus, immundeficiency and B cell lymphprliferatin. Transplantatin 39: H M, Jaffe R, Miller Get al. (1988) The frequency f Epstein- Barr virus infectin and assciated lymphprliferative syndrme after transplantatin and its manifestatins in children. Transplantatin 45: Ettenger RB, Rsenthal JT, Marik J et al. (1991) Lng-term results with cyclsprine immune suppressin in pediatric cadaver renal transplantatin. Transplant Prc 23: Klre B, Strm TM, Hahn H et al. (1991) Remarkable lng-term prgnsis and excellent grwth in kidney-transplant children under cyclsprine mntherapy. Transplant Prc 23: Ellitt RB, Chase HP (1991) Preventin f delay f Type i (insulin dependent) diabetes mellitus in children using nictinamide. Diabetlgia 34: Received: 19 March 1992 and in revised frm: 25 May 1992 References 1. Feutren G, Papz L, Assan R, Vialettes et al. (1986) Cyclsprin increases the rate and length f remissin in insulin-dependent diabetes f recent nset. Lancet II: Dr. P. R. Atkisn University Hspital 339 Windermere Rad Lndn, ntari N6A 5A5 Canada