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Diabetes & Metabolism
Vol 24, N° 3  - juin 1998
p. 195
Doi : DM-06-1998-24-3-1262-3636-101019-ART98
Reviews

PANCREAS TRANSPLANTATION : RESULTS AND INDICATIONS
 

J.M. DUBERNARD (1), L.C.F. TAJRA (1), N. LEFRANÇOIS(1), M. DAWAHRA (1), C. MARTIN (2), C. THIVOLET (3), X. MARTIN (1)
Abstract

International Pancreas Transplant Registry, Minneapolis. 1997, 09, 1-12.


Pancreatic transplantation is the best method of replacing the endocrinefunction of the gland in Type 1 insulin-dependent diabetic patients.At the end of 1996, 9,000 pancreas transplants had been reported tothe International Pancreas Transplant Registry. For 1994-1996, one-yearpancreas survival rates were 81 % for simultaneous pancreas and kidneytransplantation (n = 1,516), 71 % for pancreas after kidney(n = 141) and 64 % for pancreas alone (n = 64).In patients with a functional graft, glycosylated haemoglobin, fasting bloodsugar, and 24-h metabolic profiles are normal. The effect of pancreatictransplantation on secondary complications often appears after several yearsof normal pancreatic function. Successful transplantation is associatedwith an improvement in different aspects of the quality of life. The decisionto perform pancreatic transplantation depends on the balance between therisks of transplantation, mainly surgical or related to immunosuppression,and those of diabetes development. The advantages and drawbacks of pancreatictransplantation and insulin therapy need to be honestly and carefully analysedfor specific populations of diabetic patients as well as for each individual.At present, simultaneous pancreaticorenal transplantation is the best treatmentfor diabetic patients with chronic renal failure. Transplantation of thepancreas alone in non-uraemic patients may also be considered in carefullyselected subjects.

Key-words : pancreas transplantation, results, indications, secondarycomplications.

La transplantation pancréatique : résultats et indications.

La transplantation pancréatique est la meilleure méthodede remplacement de la fonction endocrine du pancréas chez les patientsdiabétiques insulino-dependants de type I. A la fin de 1996, 9 000 transplantationspancréatiques etaient rapportées au Registre Internationalde Transplantation Pancréatique. Pour la période 1994-1996,la survie du greffon pancréatique était de 81 % àun an pour la transplantation rein-pancréas simultanées (n = 1 516),de 71 % pour le pancréas après rein (n = 141)et de 64 % pour la transplantation de pancréas seul (n = 64).Chez les receveurs porteurs d'un greffon fonctionnel, l'hémoglobineglycosylée, la glycémie et les profils métaboliquessont normaux. L'effet de la transplantation pancréatique sur lescomplications secondaires apparaissent après plusieurs annéesd'une fonction pancréatique normale. Le succès de la transplantationest associé à une amélioration dans differents aspectsde la qualité de vie. La décision de réaliser une transplantationpancréatique dépend de la balance entre les risques opératoiresou de l'immunosuppresion, et les risques évolutifs du diabète.Les avantages et les inconvénients de la transplantation pancréatiqueet de l'insulinotherapie doivent être honnêtement et attentivementanalysés pour une population diabétique spécifiqueet sur le plan individuel. Actuellement, la transplantation simultanéeerénale et pancréatique est le traitement le plus adaptépour les diabétiques avec insuffisance rénale chronique. Latransplantation du pancréas isolé chez les patients non urémiquesest une option qui s'adresse à certains patients sélectionnés.

Mots-clés : transplantation pancréatique, résultats,indications, complications secondaires.

J.M. Dubernard, Service d'Urologie et Chirurgie de la Transplantation,Hôpital Edouard Herriot, Place d'Arsonval, Lyon, 69743 France.Tél : (33) 472110581. Fax (33) 472110582.

(1) Service d'Urologie et Chirurgie de la Transplantation, HôpitalEdouard Herriot. (2) Service de Médecine Interne, Centre HospitalierLyon-Sud. (3) Service d'Endocrinologie, Hôpital Edouard Herriot. Lyon,France.

ancreatic transplantation has become the best method of replacing theendocrine function of the gland in Type 1 insulin-dependent diabeticpatients. Since the first attempts at the end of the 1960s, more than 10,000 transplantshave been performed, half during the past decade. Results have considerablyimproved, reaching the patient and graft survival rates observed after transplantationof other solid organs such as kidney, liver, or heart. Simultaneously, themorbidity and mortality of the surgical procedure have decreased, whileprogress in immunosuppression has led to greater efficacy and less toxicity.As a result of these improvements, the indications for pancreatic transplantationare gradually moving towards transplantation earlier in the course of thediabetic disease.

RESULTS

The International Pancreatic Transplant Registry offers a unique sourceof information. The registry summarises large numbers of grafts. However,data need to be analysed with due caution since they are collected in numerouscentres. Individual centres usually publish more homogeneous and often betterresults.

At the end of 1996, 9,000 pancreas transplants had been reportedto the International Pancreas Transplant Registry [1], although this numberwas probably an underestimation since only 2,100 cases (104 in1996) were reported from European countries. Bladder drainage for duct managementwas used in the majority of cases (92 % of U.S. cases). However, morephysiological enteric drainage of exocrine secretion has recently regainedpopularity. When 1987/96 U.S. data for bladder drainage were analysedaccording to the three major recipient categories -- simultaneous pancreasand kidney transplantation (SPK) in diabetic patients with chronic renalfailure (n = 3,989), pancreas after kidney (PAK) in diabetic patientswith a functional renal graft (n = 375), and pancreas alone (PTA)in non-uraemic diabetic patients (n = 229) -- patient survivalrates at one year were respectively 92 %, 92 % and 91 %.Graft survival rate was 79 % in the SPK group and thus significantlyhigher (P = 0.001) than for PAK (60 %) and PTA (57 %)groups. In the SPK group, kidney survival at one year was 88 %. Animprovement in graft survival rates was demonstrated for all categories.For 1994-1996, one-year pancreas survival rates were 81 % for SPK (n = 1,516),71 % for PAK (n = 141) and 64 % for PTA (n = 64).

For all categories of transplants, minimisation of HLA mismatches wasassociated with a significantly lower risk of graft loss. The positive impactof HLA-matching was best seen in the group of recipients who died with afunctioning graft. For SPK cases, the risk of graft loss at one year for0, 1, 2-3 and 4-6 mismaches was 0 %, 9 %, 4 % and 5 %respectively. For PAK, it was 0 %, 12 %, 19 % and 26 %.Although the number of patients was small (n = 35), it was strikingthat no immunological loss was observed before one year in any categoryfor all pancreas recipents with 0 mismatch grafts.

Progress in immunosuppression has been associated with improved results.In the SPK and PTA categories, anti-T-cell therapy (antilymphocyte globulins,antithymocyte globulins, OKT3 monoclonal antibodies) has significantly loweredthe risk of graft loss. In the SPK category, the graft survival rate was81 % with OKT3 (n = 1,600), 78 % with ALG or ATG (n = 1,715)and 75 % with neither (n = 457 ; P < 0.001).In the PTA category, one-year survival was 59 % when ALG or ATG wasused (n = 132), 57 % with OKT3 (n = 76) and 26 %(n = 13) when neither was used. When Ciclosporin and Tacrolimuswere compared in PTA, no differences were observed in one-year graft survivalrates, although the number of immunological losses was higher with Ciclosporinthan Tacrolimus (9 % and 0 % respectively ; p > 0.2).

INDICATIONS

Unlike heart, lung or liver transplantation, pancreatic transplantationis not a lifesaving procedure. Patients have to be carefully selected inorder to reduce morbidity and mortality. Investigations of myocardial andcerebral vascularisation are mandatory. Coronary arteriography has to beperformed when thalium scintigraphy is not normal, and angiography of thecerebral arteries when the carotid Doppler is not normal. Severe vascularabnormalities need to be corrected prior to transplantation. Cancer anda developing viral or bacterial infection, as well as other contraindicationsto organ transplantation, must be respected.

Indications should be discussed on the basis of the results of pancreatictransplantation in terms of normalisation of glucose metabolism, the effecton secondary complications and quality of life.

Normalisation of glucose metabolism after pancreatic transplantationhas been well-demonstrated. In patients with a functional graft, glycosylatedhaemoglobin, fasting blood sugar, and 24-h metabolic profiles are normal[2, 3]. In the absence of rejection, the quality of the function ismaintained at long term. However, total pancreatic grafts show a betterresponse to intravenous or oral glucose tolerance tests than do segmentalgrafts [4].

For two main reasons, the effects on secondary complications are moredifficult to demonstrate. Firstly, most pancreatic transplantations areperformed at a late stage of the diabetic disease in patients with severesecondary lesions. The effect of pancreatic transplantation often appearsafter several years of normal pancreatic function [5-8]. Secondly, the capacityof pancreatic transplantation to reverse nephropathy has been demonstratedby studies in patients receiving a pancreas several years after a kidneygraft. Renal biopsies taken at the time of pancreatic transplantation andthen several years later have shown improvement of glomerular lesions [9].

The decision to perform pancreatic transplantation depends on a balancebetween the risks of transplantation, mainly surgical or related to immunosuppression,and the risks of diabetes development.

Insulin-dependent diabetic patients with chronic renal failure -

Inthis category of patients, the choice is between dialysis (continuous ambulatoryperitoneal dialysis, haemodialysis), renal transplantation alone, or pancreaticorenaltransplantation.

Data on the course of diabetic patients on dialysis are difficult tofind in the literature. In France, according to the 1995 UREMIDIAB study[10], the prevalence of diabetic patients in the dialysed population was14.2 %, and the incidence was 17.7 %. Thirteen percent of thepopulation had Type 1 diabetes. Four years after starting dialysis,only 10 % of diabetic patients (Type 1 and 2 combined) werealive. In Europe, according to the 1994 report on management of renal failure[11], patient survival after renal replacement (dialysis and renal transplantation)in diabetic patients (Type 1 and 2 combined) was between 50 %and 55 % at 2 years, but only 25 % five years after the startof treatment. In 1995, dialysis accounted for 80 % as the first modeof treatment for new non-paediatric patients [12]. Survival curves for patientsstarting treatment in 1981, 1984 or 1988 showed virtually no differences.Restriction of the overall survival analysis to patients reported to havediabetic nephropathy as the primary renal disease and who were 15 to34 years of age at the start of treatment led to only a slight increasein survival (55 % at 3 years). Forty percent of these patientswere supported by a functional graft. Thus, there is a clear need for morecomplete and more precise studies. However, directly or indirectly, thesedata demonstrate that the results of dialysis in diabetic patients are poor.The main causes of failure are related to difficulties of vascular access,infectious complications, myocardial and cerebrovascular complications andthe development of secondary diabetic complications.

For many years, kidney transplantation alone has been the treatment ofchoice for uraemia in diabetic patients, mainly because of the greater lifeexpectancy and better quality of life that it provides. However, a patientwith a successful renal graft is not in the same condition as a diabeticpatient without renal failure since the risks of surgery and immunosuppressionare to be added to those of diabetes. Although it can enhance the qualityof life, simultaneous pancreas transplantation is not performed in manycentres because it may cause complications not encountered when only a kidneyis transplanted. At present, the additional risks of mortality and morbiditywith pancreas transplantation are respectively estimated to be 1 %to 2 % and 10 to 15 % [13, 14]. Are these risks worthtaking to achieve a potential additional improvement in the quality of lifeby becoming non-diabetic as well as dialysis-free ? In the literature,only incomplete answers have been given to this question up to the 1990s.

The 1992 annual report of the USRDS (United States Renal Data System)is a landmark [15]. Patient and kidney survival were compared in two groupsof patients receiving an SPK or a renal transplantation alone. No statisticallysignificant differences were observed in patient survival in this largeseries (n = 3,168) of patients 18 to 45 years of agewho received a cadaveric kidney between 1986 and 1989. Nine point sevenpercent of SPK patients and 9.8 % of KTA patients died during the studyperiod up to the end of 1990. Kidney graft survival was significantly higherfor SPK patients than for KTA patients. During the first year followingtransplantation, 16.8 % of SPK grafts and 25.2 % of KTA kidneygrafts failed. This study indicated that the risk of death associated withSPK was not greater than with KTA. Furthermore, the risk of kidney graftfailure was lower among SPK transplants than KTA up to 29 months aftertransplantatation and possibly longer. From this report, as well as frommany publications from individual centres [16-18], simultaneous pancreas-kidneytransplantation now appears to be the best treatment for uraemic diabeticpatients. However, careful selection of recipients is necessary, and thisselection may influence the interpretation of results.

Non-uraemic diabetic patients -

Diabetic patientswith a functional kidney graft are a particular category of non-uraemicsubjects. They have a long history of diabetes, and the risk of secondarycomplications is high. They receive immunosuppressive treatment to maintainrenal graft function. Theoretically, they are excellent candidates for PAK.However, the results of PAK are not as good as those of SPK, probably becauseof genetic differences between the kidney donor and pancreas donors. Inthese patients, the indication of pancreatic transplantation depends onthe course of secondary complications and the day-to-day problems of insulintherapy. Because of their immunosuppressed condition, they might be thebest candidates for islet transplantation, especially when they belong tothe group of SPK in which a pancreatic graft has failed for technical reasonsand pancreatic retransplantation represents a risk related to local or generalconditions.

Pancreatic transplantation has many advantages : secretion by thegraft of C peptide and amylin, the other hormone of ß cells ;normalisation of glucose metabolism with (systemic venous drainage) or withouthyperinsulinaemia (portal venous drainage) ; and improved metabolicprofiles. Immunosuppressants are given

per os,

and monitoring ofthe graft is simple (usually one blood sample per month after one year).There are no diet restrictions. When performed before secondary complicationsoccur, or when they are not serious, pancreatic transplantation may cureor improve neuropathy, retinopathy, nephropathy and macroangiopathy. Resultsin terms of quality of life are excellent.

The drawbacks of pancreatic transplantation are related to surgical risksand long-term risks and side effects of immunosuppression.

The main advantages of exogenous insulin are the relative simplicityof treatment and monitoring, which however require multiple daily injectionsand capillary glycaemia, possibly influencing the quality of life of thepatient. Intensive therapy delays the onset and slows the progression ofdiabetic retinopathy, nephropathy and neuropathy. In the Diabetes Controland Complications Trial study [19], the risk of retinopathy was reducedby 76 % as compared to conventional therapy, and the progression ofretinopathy was reduced by 54 %. However, intensive therapy did notreduce the incidence of ketoacidosis but increased (threefold) that of severehypoglycaemic coma and weight gain. There was no change in the quality oflife. Exogenous insulin has its drawbacks because of the absence of amylinand C-peptide secretion that may protect against secondary complications.Daily injections and monitoring as well as diet may represent a psychologicalburden. Insulin concentrations are unphysiological in the absence of a feedbackmechanism. The balance between hypoinsulinaemia and hyperinsulinaemia andhyperglycaemia and hypoglycaemia is difficult to adjust. Lipodystrophy atinjection sites and allergy may be a problem in some patients.

Ideally, pancreatic transplantation should be performed earlier in thecourse of the disease, before the appearence of secondary complicationsincluding nephropathy. As results have improved considerably during thepast 5 years, the indication of pancreatic transplantation alone hasbecome the main subject of controversy in pancreatic transplantation.

As a preliminary consideration, the respective advantages and drawbacksof pancreatic transplantation and insulin therapy need to be honestly andcarefully analysed for specific populations of diabetics as well as foreach individual.

In diabetic patients without renal failure, the choice of pancreatictransplantation should be determined by the balance between the risks ofsurgery and immunosuppression on the one hand and the risks of secondarydiabetic complications and complications of insulinotherapy on the other.

The three key questions are :

Will pancreas transplantation have a positive, neutral or negative effecton patient survival ?

Will the benefits of insulin independence offset the side effects ofantirejection drugs ?

Will the management of immunosuppression be less, more or equally difficultthan/as management of diabetes ?

The cooperation of diabetologists and transplant surgeons is mandatoryin order to select patients for whom pancreatic transplantation will reducethe risks of severe complications of diabetes while offering a better qualityof life.

The population of diabetic patients is not homogeneous. At the presenttime, candidates for pancreatic transplantation can be selected among variouscategories of diabetic subjects. In some patients with labile diabetes,immunosuppression could be an acceptable alternative, and some patientswith frequent hypoglycaemic episodes requiring constant family attentioncould also benefit from pancreatic transplantation, especially when HbA

1

Cis high. Some patients with poor compliance with insulin injections andmonitoring might prefer immunosuppressive drugs.

Trials comparing insulin therapy with transplantation of the pancreasalone could be performed at the onset of diabetics or after a delay, forexample, of 10 years of microalbuminuria. However, before consideringthese types of studies, results of pancreatic transplantation alone needto be improved, and immunosuppression must progress.

CONCLUSION

The results of pancreatic transplantation have improved considerablyduring the past decade. Normalisation of glucose metabolism is regularlyobtained in successful pancreatic transplantation. The effects on secondarydiabetic complications still need to be confirmed. However, improvementsof neuropathy and stabilisation of retinopathy have been demonstrated inseveral studies after a few years of graft function. Successful transplantationis associated with an improvement in different aspects of the quality oflife.

At the present time, simultaneous pancreaticorenal transplantation isthe best treatment for diabetes with chronic renail failure.

Improvements in surgical techniques and better handling of immunosuppression,including the use of new immunosuppressive agents, should make PTA morefeasible in non-uraemic diabetes. Candidates could be chosen among subjectswith advanced autonomic and peripheral neuropathy, or oscillating ketoacidosisand hypoglycaemia, or rapidly developing retinopathy and loss of visualacuity.

In the future, pancreatic transplantation could also be used prophylacticallyto prevent secondary complications. This possibility will be based on thestudy of genetic susceptibility to complications. At the present time, geneticmarkers are lacking, although microalbuminuria has been shown to be an earlymarker of nephropathy in some patients. Elevated Na/Li countertransportmay prove to be an interesting marker if its capacity to predict the developmentof nephropathy is confirmed.

Candidates for pancreatic transplantation alone could also be selectedfrom the prepubertal diabetic population : the younger the onset ofdiabetes, the greater the risk of complications. However, well-controlledinsulin treatment during childhood and adolescence is not without psychologicalconsequences. Transplantation could be considered when patients reach theirmajority and can participate in the choice of the most suitable treatment.

Only well-conducted, prospective, randomised studies can compare thepotential advantages of transplantation (implying the use of immunosuppression)over those of remaining diabetic for many years.

These new indications open up exciting prospects for pancreatic transplantation.Diabetologists and transplant surgeons need to cooperate to select the patientswho will benefit the most from pancreatic transplantation.

© Masson, Paris, 1998

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