Bjo~~teddl Phffrtn~cother( I99t ) 46.7 1-78
71
0 Elsevie;, Paris
lDQSSiW
J Timsit’, C Legendre’,
L Chatenoud’,
C Boitard’
‘Service d’llnl~utlo~ogie Cl~nique~ INSERT U2S. U~pitQ~ Neeker: ‘Service de Tr~?lsp~~ntaion~H~p~t~l Nerker. 16f rue de SC;vres, 75743 Paris, France (Received 6 April 1992; accepted 21 April 1992)
- The results of pancreas transplantation have greatly improved, the overall patient and graft l-year survival rates now being 89 and 62%. respectively. A technically successful graft ensures a near-normal glucose metabolism in most cases, and improves the patient’s quality of life. However, pancreas transplantation is uot a life-saving procedure and because of the necessary permanent immunosuppression it is usually performed in patients in whom a kidney transplant is needed or has been previously established. In such patients the other diabetic chronic complications are often advanced and limit the potential benefit of pancreas transplantation, but it seems premature to extend the indications to early stage diabetes. Islet transplantation has many potential advantages, mainly the possibilities of immune aiteration and immune protection of the transplant that could allow transplantation to be performed without immunosuppression and the use of xenogenic tissue. Major Iimiting factors are the high numbers of islets necessary to ensure insulin independence and the low yield of islet isolation from adult pancreas. Encouraging, albeit preliminary results have been recently reported in man.
Summary
pancreas I islet I transplantation
R&urn6 - Transplantation du pan&as et d’flots chez I’homme. Lps re’sultats de la greffe de pnncr& son? en canstante amPlioration avec des w-vies actua.rielles ri un an de 89% pour les patients et de 62% pour les greflims. Une greffe techniquement re’ussie assure un me’tabolisme du glucose pratiquement normal dans lu plupart des cas et une otne’lioration de la qualit& de vie des patients. la greffe de pancrPas n’est cependnnt pas un geste vital et, du fait de la n&essiti d’une immunosuppression permanente, elle est habituellement rPulisPe the: des sujets justifiant une greffe r&aie. Ces patients on? souvelZt des complications dt$Wrativecl .sCvPr~s ce qui limite le bMfice de la gre#e de pancrt%s mais il semble pr&maturt! d’Ptendre ses indications d des strides plus p&oces du dinb2te. La grzffe d’ilots a de nombreux awntages potentiels, en particuiier les possibilittis d’imtnrcnoaltL;mtinti au d’immunoprotection du grezon, re qui permettrait de greffpr stms itn~l~nu.~uppression et d’uti&er des i&s .~~tio~~n~ques. Les fucteurs limitants tiennent, entre uurres. nu nornltre &VP d’iiots n~cess~ire.~ pour assurer l~insulino-independence et RU faible rellde~~ent des techniques d’iso~ett~ent des flats. Des r&&ats encour~ge~nts. mais encore pr~liminuires, ont &*n r~~e~nn~entr~pport~.~ the: ~‘hot?t~ne. pancri?as I Hots / transplantation
Introduction Insulin-dependent diabetes mellitus (IDDM) is a chronic metabolic disease due in most cases to the aut~immune destruction of the Langherans islet p-cells. The main consequences of IDDM are macro- and microangiopathy and neuropathies which are responsible for increased morbidity and mortality. Due to the fact that the incidence of the disease peaks between 10 and 15 years of age, the severe complications mainly affect young individuals. Treatment of IDDM currently associ-
ates diet, physical exercise and the subcutaneous administration of insulin, the doses of which are adjusted from the results of blood glucose selfmonitoring. The aim of such therapy is to correct metabolic disturbances in order to prevent comptications connected with IDDM. which are mainly due to chronic hyperglycemia. However, in most patients the state of Ned-no~og~ycemia is far from being consistently achieved, and such a glycemic target requires major efforts and implies particular risks, notably that of severe or frequent hypoglycemia [54].
From a theoretical point of view the transplantation of insulin-secreting cells constitutes a potentia1 treatment for Insulin deficiency. Such therapy should fulfil several criteria: islet P-cell function must be adequately restored both quantitatively (critical islet cell mass) and qualitatively (dynamics of insulin secretion): rejection of the grafted tissue and the potential relapse of the autoimmune disease must be prevented. The procedure should be at least as efficient as insulin therapy in restoring normal metabolic control, and should offer a good quality of life to the patient without increased risk. Lastly it should be performed early in diabetic patients since there is probably a “point of no return” in the progression of some complications of the disease. Several procedures have been envisaged to restore normal insulin secretion, including transplantation of whole or segmental pancreas, islet or purified &cell transplantation, or even the transplantation of engineered insulin-secreting non-#%cel]s. Pancreas transplantation and to a lesser extent islet transplantation have already been performed in man, allowing a review of the results.
Pancreas transplantation
in man
Since 1966, more than 3000 pancreas transplantations (PT) have been performed in man and considerable progress has been made in the last few years 1461. PT is the only method to transfer a sufficient islet mass from one donor so that diabetes can be cured in the recipient. However, there are still limitations to its wide use in diabetic patients. The mortality associated with the surgical procedure is still significant. although it has now fallen to under 10% in experienced centers [33]. The graft of the exocrine part of the organ (which is in fact unnecessary) leads to a specific morbidity which includes thrombosis, necrosis of the graft, infections and fistulas [ 111. Obviously continuous immunosuppression is needed 1461, with its inherent risks. Moreover, the limited number of available donors still constitutcs a problem.
Technical aspects Whole gland grafts as well as segmental grafts taken from cadaveric donors have been per-
formed. In the large majority of cases a simultaneous pancreas and kidney transplantation (SPK) is pe~ormed, but some centers also transplant pancreas in patients with an established kidney graft (PAK), and transplantations of the pancreas only (PA) have been carried out in subjects not requiring a kidney graft [44]. Segmental grafts from a living related donor have also been performed in a few centers but it has been shown that the procedure is associated with a significant morbidity in the donor including the long-term occurrence of abnormal glucose tolerance tests in 25% of the tested donors [18]. Management of the exocrine secretion of the grafted pancreas has been resolved by 2 main approaches: drainage of the pancreatic duct, mostly into the bladder or in some cases into the stomach or the small bowel, and duct obstruction by in situ injection of a synthetic polymer leading to secondary fibrosis of the exocrine tissue [lo]. The latter technique has been associated with low morbidity, but urinary drainage has been advocated to allow early diagnosis of graft rejection by monitoring urinary amylase; the latter procedure is currently in widespread use [41]. Prevention diagnosis and treatment of rejection episodes remain a major problem, as rejection is still the main cause of the failure of technically successful grafts [49]. Given the scarcity of donors, PT has been performed without previous HLA-matching. lmmunosuppression regimens comprise azathioprine, steroids and cyclosporin. The introduction of cyclosporin has greatly improved the results, but the associated nephrotoxicity limits its use for PA in patients with subnormal renal function [7]. It is generally admitted that the diagnosis of rejection cannot be based on the resumption of hyperglycemia which is a late phenomenon, but amylase decrease in the pancreatic secretion may be a helpful indicator, since it precedes rejection of the endocrine tissue, To date, there is no other reliable rejection marker, thus making urinary drainage the method of choice in pancreas transplantation. In pancreas-kidney transplantations the problem is simplified by the simultaneous occurrence of kidney graft rejection which can be detected early on. Antilymphocytic globulin (ATG) or monoclonal antibodies have been used in association with ‘conventional’ immunosuppressive drugs to prevent or to treat graft rejection. It should be emphasized that even in the rare cases of totally histocompatible grafts, such as those performed between monozygotic twins, immunosuppression
73 is still necessary as demonstrated by the resumption of the autoimmune process and the relapse of IDDM within a few weeks of transplantation in non-immunosuppressed recipients 1381. Pancreas transplantation is usually performed in IDDM patients requiring a kidney graft; hence the use of immunosuppressive agents. However, in such patients other chronic complications of IDDM are often severe, particularly macroangiopathy. and the procedure is at risk. Moreover, it is difficult to evaluate the potential benefit of PT in such patients due to the advanced stage of retinopathy and neuropathy.
Patients and graft survival By March 1991, 3082 PT had been reported to the rnternational Pancreas Transplant Registry f45J. Analysis by era shows a continuous improvement in both patient and graft survival. Considering the 2087 cases treated between 1986 and 1990, the overall l-year patient, graft, and technically successful graft survival rates were 89, 62 and 74%, respectively. A 50% graft survival rate at 4-5 years has been reported by several groups 1331. Several factors which influence patient and graft survival have been identified. Interestingly a significant difference in outcome was found by univariate analysis according to duct management techniques, the l-year graft survival being 6.5, 56 and 52% for bladder drainage, duct obstruction, and intestinal drainage respectively. However, the difference was not more significant by multivariate analysis, probably due to the fact that in most cases (over 75%) an SPK transplantation was performed and the kidney ailowed early detection of rejection. In the same respect the l-year pancreas graft survival was better in the case of SPK (68%) than in PAK (45%) and in PA (370/o), and the recipient category is probably still the main factor affecting graft survival. By contrast patient survival rates were higher in PAK than in SPK recipients (94 and 88%, respectively). The use of UW solution allowed a cold preservation time of up to 24 h without increasing the rate of technical failure. Immunosuppression now systematically includes cyclosporine and the prophylactic use of OKT3 or ATG is associated with a better graft survival rate. An~ysis of the results according to HLA-DR matching provided convicting results. Graft survival rate was lower in cases of mismatch for 1 or 2 DR antigens than in cases
matched for 2 DR antigens but this effect was only significant in the overall analysis and not in the technically successful cases, possibly due to the fact that some ‘technical failures’ were actually cases of acute rejection. In the univariate analysis the benefit of HLA-matching was observed in the PA recipients. The analysis also demonstrated that overall graft survival was better in North America than in Europe. At the University of Minnesota, where the largest series has been performed, the best results (l-year graft survival rate of over 70%) were observed in recipients of either SPK, PAK, or PA with the bladder-drainage technique, use of ATG in the initial immunosuppressive regimen, and HLAmatching [46]. Lastly, it should be emphasized that the l-year kidney graft survival rate is about 80% in patients receiving SPK transplantation 1451.
Metabolic effects The long-term metabolic effects of pancreas transplantation have now been assessed by several groups. A technically successful graft ensures a biphasic insulin secretion and normal fasting blood glucose values. Basal and stimulated insulin and C peptide plasma levels are increased, probably due to the combined effects of systemic (vcrsus portal) delivery of insulin and of insulin resistance, the latter being observed in other organ transplantations 18, 351. Some abnormalities of oral and intravenous glucose tolerance tests have been demonstrated in 20-50% of the patients, with glucose intolerance or diabetes, according to WHO criteria, and decreased glucose disappearance rate 15. 12, 171. There is some indication that such alterations may be due to insufFicient P-cell mass in the case of segmental graft IS], although this has not been consistently observed [4]. However, their clinical consequences are probably limited since glycemic profiles are usually normal and glycosylated hemoglobin is normal in 50-60% of recipients and mildly elevated in the others. Moreover, metabolic results are maintained or even improved in the long term [34], up to 3-7 years [4, 241 even in the case of polymer-injected segmental grafts [37]. Plasma lipid profiles are normalized and the secretion of ~ounterregulatory hormones is improved f91. It is obvious from these results that pancreas transplantation is to date the only means of ob-
taining a near-normal restoration of glucose metabolism and metabolic control in the long term. This is associated with a dramatic improvement in the quaI@ of fife, even when compared with what is achieved in patients with a functional kidney graft but who remain diabetic 1261,
Elects
on diabetic co~pli~~tio~s
The effects of a successful pancreas transplantation on chronic diabetic complications are difficult to document. First, in most cases patients who receive a pancreas transpi~tation already have advanced diabetic ~~mpl~~ations, including in most cases end-stage renal failure which is often associated with severe retinopathy and neuropathy. Second, in most patients a kidney transplantation was performed concurrently with a pancreas t~nsplantation and may have its own effects on some complications. Lastly, the potential benefit of good metabolic control requires longterm follow-up to be adequately assessed. In fact, the course of retinopathy did not seem to improve after pancreas transplantation due to the late p~liferative stage of this complication. While some authors reported that stabilization of retinal lesions was more frequent in patients with a successful graft than in those in which pancreas transplantation failed 1203, others were unable to document any effect of pancreas transplantation [30]. Improvement of retinal status occurred very rarely in such patients. Peripheral neuropathy stabilizes or improves in patients with functional pancreas graft. In patients who received combined pancreas-kidney grafts it has been shown that the improvement could be ascribed to pancreas and not solely to kidney transplantation_ Subjective improvement in autonomic neuropathy symptoms has also beera reported but quantitative assessment has usually failed to demonstrate a clear improvement in antonomi~ function (19, 401. Mortality rate associated with autonomic dysfunction decreased in patients with successful pancreas transplant but increased in patients whose pancreas graft failed, compared to non-transplanted patients [27], The most encouraging results concern nephropathy. Cross-sectional and prospective studies have established that pancreas transplant Aon prevents or even reverses the renal histological alterations associated with diabetes such as mesailgial expansion and glomerular hyper-
throphy, which occurred in kidney grafts of diabetic patients but not in those from patients having an associated functional pancreas graft 12, 31. This patent&l benefit should be counterbalanced against the nephrotoxicity associated with the necessary use of cy~iosporin. However, from a theoretical point of view these observations are significant, since they demonstrate the efficiency of pancreas ~nsplantation in preventing a major diabetic complication in susceptible patients.
In patients requiring kidney transplantation or with an established renal graft, pancreas transplantation can provide an improvement in quality of life and well-being, particularly in the case of brittle diabetes and hypoglycemia unawereness, but there is probabl:! little benefit of clinical reE evance with regard to diabetic complications [43]. In such patients careful pre-operative assessment is mandatory, particularly concerning coronary disease, and effective treatment should be performed before transplantation can be considered 161. Patients must be informed about the potential risks of the procedure and of its long-term efficacy 1281. It should be noted that these patients constitute only a small fraction of IDDhrl patients and that their number will probably decrease if one refers to the existing epidemiological data concerning diabetic nephropathy 1211. In pre-uremic patients, because of cyclosporin nephrotoxicity, pancreas transplantation cannot be Performed alone when creatinine clearance is below 50-40 nl/min. The potential benefit of PT alone in patients with mild to moderate renal insufficiency should be balanced with the relatively low graft survival rate of PT alone in the longterm. Moreover, several medical approaches, particularly ‘aggressive’ treatment of hype~ension, have shown good efficacy in postponing the need for dialysis. This points to the need for controlled trials of PT Iterssus medical treatment of diabetes, which have not yet been performed 1281. Brittle diabetes in itself does not appear as an indication for transplantation. Some surgeons have suggested that IDDM patients who have early symptoms of severe diabetic complications such as increased urinary albumin excretion could be eiigible for pancreas transplantation f47]. Such an extension of present indications should be
75 viewed with caution if one considers the need for immunosu~pressio~ and the risks associated with this therapy? and the coatin~o~s progress in the medical treatment of diabetes @S, 33f.
I?roma theoretical point of view* islet tranS#mtation offers many advantages, which have all been successfully exploited in animal models. Islets are isolated from the paacreas by enzymatic digestion and mechanical dispersion, and purified on a density gradient. Due to the smalf volume of endocrine tissue, purified islets can be intphmted in various sites via a procedure that is both simple and safe [15]. Islets can be tested before transplantation with regard to purity, insulin content, insulin secretion i~ virrr, and bacteriological and vi~logical co~t~mi~ation~ which r~&ts in increased safety and allows objective interpretation of the results fSl& Several sources of insulin-secreting cells have been envisaged, including allogeneic and even xcnogeneic (pig) adult pancreas, fetal islets, purified p-cells, and benign insul~~oma ceifs. islets from rnulti~l~ donors can be utilized, the more so Since cryopreservation of islets does not alter their functionality and allows the setting up of a tissue bank [29], Various approaches have been tested to eliminate the need for continuous immunosuppressio~. Besides the a~ernF~s to induce immune tolerance in the reGpient, ulceration of the graft to diminish its immunogenicity has been achieved by culturing the islets prior to transplantation in order to remove ‘passenger leucocytes’ [22], or by usirtg monoclonal antibodies directed against target m#~ecules of rejection I13]. Another promising way to overcome immunological problems has been the isolation of isletts by artificial membranes with setactive permeability (‘bioartificial pancreas’) in capsules or fibers [23, 251, or even in vascularized systems [42], allawing the diffu&on of nutrients and insulin but not that of cells and an~b~es. In various animaf mode&, in which IDDM is induced by ~a~c~eatectomy~ by the administration of a toxin (streptozotocin in most cases), or occurs as the result of autoimmune disease, it has been shown that islet transplantation can cure diabetes and prevent or even reverse drastic com~li~~~ions 1141. In man until recently, results of islet and fetal pancreas transplantation have been disappointing,
with no clearly documented reversal of insulindependency or even long-lasting partial recovery of endo~~aeous insulin secretion [If& A number of reasm’ts have been identified to explain these failures. Besides ethical issues, fetal pancreas transplantation poses several problems, part&larly that of the functional immaturity of the tissue. Failures concerning adult pancreatic islets, have been mainly attributed to rejection and to inadequate islet mass Islet preparations were very often impure and although islets are probably highly immunogenic, in most cases “islet’ transplantation has been performed alone, with no accurate marker to monitor rejection, or even without i~~nosu~~~Ssion_ The o~~rn~ site for engraf~ent has not been defined in man, and it has been suggested that it might vary from one species to another [l]. hleovascularization of the islets may be impaired by the pre-exist@ microangiopathy in the recipient and by poor gXycemic control da~ng the ~stu~e~tive confse. In fact it has been clearly demonstrated that the main limiting factor is the grafted islet mass. The number of islets necessary to enSure insulin-independence has previously been largely underestimated. It now appears that 5000 isletslIcg body weight are required for dog auto~ans~~anta~u~ E!%] and there are ~rel~rn~n~ indications that the number must be increased to 10 000 islets/kg (expressed as the number of islet equivalent, ie islets with an average diameter of 190 pm) for allotransplantation in man [53]. The yieId of islet isolation from adult large m~aIian pancreas has been very low, thus preventing tmns~la~t~tio~ in one recipient of the pancreas from one donor until reccntlyr when advances were made in the procedures used for isiet isolation and purification, which include the early distension of pancreatic duct with collagenase sofution and the use of Semi-automated devices for the digestion step E3l]; reproducible isolation of about 250 000 islets from one pancreas has been achieved by some investigators [39]. Utilizisg such technirlues and ettsuring adequate ~mmunosuppression* several groups have naw report& e~~o~~~i~g results in p&%tS With c peptide-negative type 1 diabetes. Nine patients who received an intraportal islet allograft Corn--Ð bined with liver transplantation after abdominal exenteration demonstrated partial recovery of endog~~eous insulin secretion, one being totally ins~~ia~i~de~ndent~ and 4 requiring inSuhn thera spy only during parenteral hype~lim~nta~on [48]. in a further analysis of 22 consecutive trans-
76
+-;a-& by the same plantations performed in 2! pa,~: group, 6 out of 10 patients with islet-liver graft after exe~teration remained insulin-independent for 5 to > 16 months. By contrast, no patient became insulin-independent among 3 subjects with islet-liver transplantation for associated cirrhosis and 7 with islet-kidney graft (end-stage renal diabetic renal disease), while the average numbers of injected islets (625 000 and 597 000 equivalent islets, respectively} were higher than in patients with exenteration. These failures were interpreted as being due to the combined effects of rejection, the use of steroids, and impaired function or vascularization of the graft due to long-standing iDDM [32f. However, in another study, insulin independence was obtained in 2 patients (for up to 1 year in one subject) who received intraportal fresh and cryopreserved islets together with a !Gdney graft, and partial recovery of basal and stimulated insulin secretion was noted in 2 other patients who only received fresh islets. It should be noted that more than 10 000 equivalent islets/kg were transplanted in the 2 patients who could stop insulin [52, 531. Similarly, among 7 type 1 iDDM patients with established kidney transplant who underwent intraportal islet transplantation, 2 out of the 3 who received over 12 000 equivalent islets/kg achieved insulin-independence 1361. Although these results do not match those of pancreas transplantation, thL;; demonstrate the feasibility of islet transplantation in man.
Conclusion To date pancreas
transplantation is the only method to cure insulin-dependent diabetes mellitus, and its results are now in the range of those for other organ solid transplants. However, the need for continuous immunosuppression limits its indications to a small number of patients, ie mainly those in whom kidney transplantation is also necessary. By contrast, the results of islet transplantation in man are still preliminary. Recent conceptual and technical improvements have been made in this field, but many problems, mairily immunological, still have to be resolved before this method can be applied to large numbers of patients prior to the onset of the chronic complications of IDDM.
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46
and immunohistochemical analysis of four cases. Lab Invest 53, 132 Socci C, Falqui L, Davalli AM, Ricordi C, Braghi S, Bertuzzi F, Maffi P, Secchi A, Gavazzi F, Freschi M, Magistretti P, Socci S, Vignafi A, Di Carlo V, Pozza G (199 1) Fresh human islet ~ansplanta~on to replace pancreatic endocrine function in type 1 diabetic patients. Acre Din&& 28, 151 Solders 6, Wilczek H, Gunnarsson R, Tyden G, Persson A, Groth CG (1987) Effects of combined pancreatic and renal transplantation on diabetic neuropathy: a two year follow-up study. Lancet ii, 1231 Sollinger HW. Stratta RJ, Kalayoglu M, Pirsch JD, Belzer FO (1987) Pancreas transplantation wifh pancreaticocystostomy and quadruple immunosuppression. Srrgev 102, 674 Sullivan Sf. Maki T, Borland KM, Mahoney MD, Solomon BA, Muller TE, Monaco AP, Chick WL ( 199 1) Biohyb~d artificial pancreas: long-term implantation studies in diabetic, pancreatectomized dogs. Science 252, 718 Sutherland DER (1988) Who should get a pancreas transplant? Diabetes Core 11, 68 1 Sutherland DER, Kendall DM, Moudry KC, Navxrro X, Kennedy WR, Ramsay RC, Steffes MW, Mauer SM, Goetz FC. Dunn DL, Najarian JS (1988) Pancreas transplantation in nonuremic, typ; t diabetic recipients. Surgery 104, 453 Sutherland DER (1991) Report from the International Transplant registry. ~jffbetologi~ 34 fsuppl 11, 28 Sutherland DER f 1991) Clinical Review 25. Current status of pancreas transplantation. J Clin Endocrinol Metab 73, 461
47 The University of Michigan Pancreas Transplant Evaluation Commitee (1988) Pancreatic transplantation as treatment for IDDM. Proposed candidate criteria before end-stage diabetic nephropathy. LX&&es Care 11, 669 48 Tzakis AG, Ricordi C, Alejandro R, Zeng X Fung JJ, Todo S, Demetris AI, Mintz DH, Starzl TE (1990) Pancreatic islet transplantation after upper abdominal exenteration and liver replacement. Lancet ii, 402 49 Viste A, Moudry-Munns K, Sutherland DER (1990) Prognostic risk factors for graft failure following pancreas transplantation: results of multivariate analysis of data from the International Pancreas Transplant Registry. Transplant Int 3, 98 50 Warnock GL, Cattral MS, Rajotte RV (1988) Normoglycemia after implantation of purified islet cells in dog. Can J Surg 3 I, 421 51 Warn&c GL, Dwayne E, Rajotte RV, Dawidson I, Baekkeskov S, Egebjery J (1988) Studies of the isolation and viability of human islets of Langerhans. Transplantation 35, 957 52 Warnock CL, Kneteman NM, Ryan EA. Seelis REA, Rabinovitch A, Rajotte RV (1991) Normoglycemia after transplantation of freshly isolated and cryopreserved pancreatic islets in type 1 (insulin-dependent) dlabei;; mellitus. Diubetologia 34, 5.5 53 Warnock GL, Kneteman NM, Ryan EA, Rabinovitch A, Rajotte RV (1992) Long-term follow-up after transpl~nt~~t~on of ;~~~l~n-prod~~cing pancreatic islets into patients with type 1 (insulin-dependent) diabetes meltitus. ~iubeto~ogia 35, 89 54 Zinman (1989) The physiologic replacement of insulin. An elusive goal. N Engl .I hfed 321, 363
71
0 Elsevie;, Paris
lDQSSiW
J Timsit’, C Legendre’,
L Chatenoud’,
C Boitard’
‘Service d’llnl~utlo~ogie Cl~nique~ INSERT U2S. U~pitQ~ Neeker: ‘Service de Tr~?lsp~~ntaion~H~p~t~l Nerker. 16f rue de SC;vres, 75743 Paris, France (Received 6 April 1992; accepted 21 April 1992)
- The results of pancreas transplantation have greatly improved, the overall patient and graft l-year survival rates now being 89 and 62%. respectively. A technically successful graft ensures a near-normal glucose metabolism in most cases, and improves the patient’s quality of life. However, pancreas transplantation is uot a life-saving procedure and because of the necessary permanent immunosuppression it is usually performed in patients in whom a kidney transplant is needed or has been previously established. In such patients the other diabetic chronic complications are often advanced and limit the potential benefit of pancreas transplantation, but it seems premature to extend the indications to early stage diabetes. Islet transplantation has many potential advantages, mainly the possibilities of immune aiteration and immune protection of the transplant that could allow transplantation to be performed without immunosuppression and the use of xenogenic tissue. Major Iimiting factors are the high numbers of islets necessary to ensure insulin independence and the low yield of islet isolation from adult pancreas. Encouraging, albeit preliminary results have been recently reported in man.
Summary
pancreas I islet I transplantation
R&urn6 - Transplantation du pan&as et d’flots chez I’homme. Lps re’sultats de la greffe de pnncr& son? en canstante amPlioration avec des w-vies actua.rielles ri un an de 89% pour les patients et de 62% pour les greflims. Une greffe techniquement re’ussie assure un me’tabolisme du glucose pratiquement normal dans lu plupart des cas et une otne’lioration de la qualit& de vie des patients. la greffe de pancrPas n’est cependnnt pas un geste vital et, du fait de la n&essiti d’une immunosuppression permanente, elle est habituellement rPulisPe the: des sujets justifiant une greffe r&aie. Ces patients on? souvelZt des complications dt$Wrativecl .sCvPr~s ce qui limite le bMfice de la gre#e de pancrt%s mais il semble pr&maturt! d’Ptendre ses indications d des strides plus p&oces du dinb2te. La grzffe d’ilots a de nombreux awntages potentiels, en particuiier les possibilittis d’imtnrcnoaltL;mtinti au d’immunoprotection du grezon, re qui permettrait de greffpr stms itn~l~nu.~uppression et d’uti&er des i&s .~~tio~~n~ques. Les fucteurs limitants tiennent, entre uurres. nu nornltre &VP d’iiots n~cess~ire.~ pour assurer l~insulino-independence et RU faible rellde~~ent des techniques d’iso~ett~ent des flats. Des r&&ats encour~ge~nts. mais encore pr~liminuires, ont &*n r~~e~nn~entr~pport~.~ the: ~‘hot?t~ne. pancri?as I Hots / transplantation
Introduction Insulin-dependent diabetes mellitus (IDDM) is a chronic metabolic disease due in most cases to the aut~immune destruction of the Langherans islet p-cells. The main consequences of IDDM are macro- and microangiopathy and neuropathies which are responsible for increased morbidity and mortality. Due to the fact that the incidence of the disease peaks between 10 and 15 years of age, the severe complications mainly affect young individuals. Treatment of IDDM currently associ-
ates diet, physical exercise and the subcutaneous administration of insulin, the doses of which are adjusted from the results of blood glucose selfmonitoring. The aim of such therapy is to correct metabolic disturbances in order to prevent comptications connected with IDDM. which are mainly due to chronic hyperglycemia. However, in most patients the state of Ned-no~og~ycemia is far from being consistently achieved, and such a glycemic target requires major efforts and implies particular risks, notably that of severe or frequent hypoglycemia [54].
From a theoretical point of view the transplantation of insulin-secreting cells constitutes a potentia1 treatment for Insulin deficiency. Such therapy should fulfil several criteria: islet P-cell function must be adequately restored both quantitatively (critical islet cell mass) and qualitatively (dynamics of insulin secretion): rejection of the grafted tissue and the potential relapse of the autoimmune disease must be prevented. The procedure should be at least as efficient as insulin therapy in restoring normal metabolic control, and should offer a good quality of life to the patient without increased risk. Lastly it should be performed early in diabetic patients since there is probably a “point of no return” in the progression of some complications of the disease. Several procedures have been envisaged to restore normal insulin secretion, including transplantation of whole or segmental pancreas, islet or purified &cell transplantation, or even the transplantation of engineered insulin-secreting non-#%cel]s. Pancreas transplantation and to a lesser extent islet transplantation have already been performed in man, allowing a review of the results.
Pancreas transplantation
in man
Since 1966, more than 3000 pancreas transplantations (PT) have been performed in man and considerable progress has been made in the last few years 1461. PT is the only method to transfer a sufficient islet mass from one donor so that diabetes can be cured in the recipient. However, there are still limitations to its wide use in diabetic patients. The mortality associated with the surgical procedure is still significant. although it has now fallen to under 10% in experienced centers [33]. The graft of the exocrine part of the organ (which is in fact unnecessary) leads to a specific morbidity which includes thrombosis, necrosis of the graft, infections and fistulas [ 111. Obviously continuous immunosuppression is needed 1461, with its inherent risks. Moreover, the limited number of available donors still constitutcs a problem.
Technical aspects Whole gland grafts as well as segmental grafts taken from cadaveric donors have been per-
formed. In the large majority of cases a simultaneous pancreas and kidney transplantation (SPK) is pe~ormed, but some centers also transplant pancreas in patients with an established kidney graft (PAK), and transplantations of the pancreas only (PA) have been carried out in subjects not requiring a kidney graft [44]. Segmental grafts from a living related donor have also been performed in a few centers but it has been shown that the procedure is associated with a significant morbidity in the donor including the long-term occurrence of abnormal glucose tolerance tests in 25% of the tested donors [18]. Management of the exocrine secretion of the grafted pancreas has been resolved by 2 main approaches: drainage of the pancreatic duct, mostly into the bladder or in some cases into the stomach or the small bowel, and duct obstruction by in situ injection of a synthetic polymer leading to secondary fibrosis of the exocrine tissue [lo]. The latter technique has been associated with low morbidity, but urinary drainage has been advocated to allow early diagnosis of graft rejection by monitoring urinary amylase; the latter procedure is currently in widespread use [41]. Prevention diagnosis and treatment of rejection episodes remain a major problem, as rejection is still the main cause of the failure of technically successful grafts [49]. Given the scarcity of donors, PT has been performed without previous HLA-matching. lmmunosuppression regimens comprise azathioprine, steroids and cyclosporin. The introduction of cyclosporin has greatly improved the results, but the associated nephrotoxicity limits its use for PA in patients with subnormal renal function [7]. It is generally admitted that the diagnosis of rejection cannot be based on the resumption of hyperglycemia which is a late phenomenon, but amylase decrease in the pancreatic secretion may be a helpful indicator, since it precedes rejection of the endocrine tissue, To date, there is no other reliable rejection marker, thus making urinary drainage the method of choice in pancreas transplantation. In pancreas-kidney transplantations the problem is simplified by the simultaneous occurrence of kidney graft rejection which can be detected early on. Antilymphocytic globulin (ATG) or monoclonal antibodies have been used in association with ‘conventional’ immunosuppressive drugs to prevent or to treat graft rejection. It should be emphasized that even in the rare cases of totally histocompatible grafts, such as those performed between monozygotic twins, immunosuppression
73 is still necessary as demonstrated by the resumption of the autoimmune process and the relapse of IDDM within a few weeks of transplantation in non-immunosuppressed recipients 1381. Pancreas transplantation is usually performed in IDDM patients requiring a kidney graft; hence the use of immunosuppressive agents. However, in such patients other chronic complications of IDDM are often severe, particularly macroangiopathy. and the procedure is at risk. Moreover, it is difficult to evaluate the potential benefit of PT in such patients due to the advanced stage of retinopathy and neuropathy.
Patients and graft survival By March 1991, 3082 PT had been reported to the rnternational Pancreas Transplant Registry f45J. Analysis by era shows a continuous improvement in both patient and graft survival. Considering the 2087 cases treated between 1986 and 1990, the overall l-year patient, graft, and technically successful graft survival rates were 89, 62 and 74%, respectively. A 50% graft survival rate at 4-5 years has been reported by several groups 1331. Several factors which influence patient and graft survival have been identified. Interestingly a significant difference in outcome was found by univariate analysis according to duct management techniques, the l-year graft survival being 6.5, 56 and 52% for bladder drainage, duct obstruction, and intestinal drainage respectively. However, the difference was not more significant by multivariate analysis, probably due to the fact that in most cases (over 75%) an SPK transplantation was performed and the kidney ailowed early detection of rejection. In the same respect the l-year pancreas graft survival was better in the case of SPK (68%) than in PAK (45%) and in PA (370/o), and the recipient category is probably still the main factor affecting graft survival. By contrast patient survival rates were higher in PAK than in SPK recipients (94 and 88%, respectively). The use of UW solution allowed a cold preservation time of up to 24 h without increasing the rate of technical failure. Immunosuppression now systematically includes cyclosporine and the prophylactic use of OKT3 or ATG is associated with a better graft survival rate. An~ysis of the results according to HLA-DR matching provided convicting results. Graft survival rate was lower in cases of mismatch for 1 or 2 DR antigens than in cases
matched for 2 DR antigens but this effect was only significant in the overall analysis and not in the technically successful cases, possibly due to the fact that some ‘technical failures’ were actually cases of acute rejection. In the univariate analysis the benefit of HLA-matching was observed in the PA recipients. The analysis also demonstrated that overall graft survival was better in North America than in Europe. At the University of Minnesota, where the largest series has been performed, the best results (l-year graft survival rate of over 70%) were observed in recipients of either SPK, PAK, or PA with the bladder-drainage technique, use of ATG in the initial immunosuppressive regimen, and HLAmatching [46]. Lastly, it should be emphasized that the l-year kidney graft survival rate is about 80% in patients receiving SPK transplantation 1451.
Metabolic effects The long-term metabolic effects of pancreas transplantation have now been assessed by several groups. A technically successful graft ensures a biphasic insulin secretion and normal fasting blood glucose values. Basal and stimulated insulin and C peptide plasma levels are increased, probably due to the combined effects of systemic (vcrsus portal) delivery of insulin and of insulin resistance, the latter being observed in other organ transplantations 18, 351. Some abnormalities of oral and intravenous glucose tolerance tests have been demonstrated in 20-50% of the patients, with glucose intolerance or diabetes, according to WHO criteria, and decreased glucose disappearance rate 15. 12, 171. There is some indication that such alterations may be due to insufFicient P-cell mass in the case of segmental graft IS], although this has not been consistently observed [4]. However, their clinical consequences are probably limited since glycemic profiles are usually normal and glycosylated hemoglobin is normal in 50-60% of recipients and mildly elevated in the others. Moreover, metabolic results are maintained or even improved in the long term [34], up to 3-7 years [4, 241 even in the case of polymer-injected segmental grafts [37]. Plasma lipid profiles are normalized and the secretion of ~ounterregulatory hormones is improved f91. It is obvious from these results that pancreas transplantation is to date the only means of ob-
taining a near-normal restoration of glucose metabolism and metabolic control in the long term. This is associated with a dramatic improvement in the quaI@ of fife, even when compared with what is achieved in patients with a functional kidney graft but who remain diabetic 1261,
Elects
on diabetic co~pli~~tio~s
The effects of a successful pancreas transplantation on chronic diabetic complications are difficult to document. First, in most cases patients who receive a pancreas transpi~tation already have advanced diabetic ~~mpl~~ations, including in most cases end-stage renal failure which is often associated with severe retinopathy and neuropathy. Second, in most patients a kidney transplantation was performed concurrently with a pancreas t~nsplantation and may have its own effects on some complications. Lastly, the potential benefit of good metabolic control requires longterm follow-up to be adequately assessed. In fact, the course of retinopathy did not seem to improve after pancreas transplantation due to the late p~liferative stage of this complication. While some authors reported that stabilization of retinal lesions was more frequent in patients with a successful graft than in those in which pancreas transplantation failed 1203, others were unable to document any effect of pancreas transplantation [30]. Improvement of retinal status occurred very rarely in such patients. Peripheral neuropathy stabilizes or improves in patients with functional pancreas graft. In patients who received combined pancreas-kidney grafts it has been shown that the improvement could be ascribed to pancreas and not solely to kidney transplantation_ Subjective improvement in autonomic neuropathy symptoms has also beera reported but quantitative assessment has usually failed to demonstrate a clear improvement in antonomi~ function (19, 401. Mortality rate associated with autonomic dysfunction decreased in patients with successful pancreas transplant but increased in patients whose pancreas graft failed, compared to non-transplanted patients [27], The most encouraging results concern nephropathy. Cross-sectional and prospective studies have established that pancreas transplant Aon prevents or even reverses the renal histological alterations associated with diabetes such as mesailgial expansion and glomerular hyper-
throphy, which occurred in kidney grafts of diabetic patients but not in those from patients having an associated functional pancreas graft 12, 31. This patent&l benefit should be counterbalanced against the nephrotoxicity associated with the necessary use of cy~iosporin. However, from a theoretical point of view these observations are significant, since they demonstrate the efficiency of pancreas ~nsplantation in preventing a major diabetic complication in susceptible patients.
In patients requiring kidney transplantation or with an established renal graft, pancreas transplantation can provide an improvement in quality of life and well-being, particularly in the case of brittle diabetes and hypoglycemia unawereness, but there is probabl:! little benefit of clinical reE evance with regard to diabetic complications [43]. In such patients careful pre-operative assessment is mandatory, particularly concerning coronary disease, and effective treatment should be performed before transplantation can be considered 161. Patients must be informed about the potential risks of the procedure and of its long-term efficacy 1281. It should be noted that these patients constitute only a small fraction of IDDhrl patients and that their number will probably decrease if one refers to the existing epidemiological data concerning diabetic nephropathy 1211. In pre-uremic patients, because of cyclosporin nephrotoxicity, pancreas transplantation cannot be Performed alone when creatinine clearance is below 50-40 nl/min. The potential benefit of PT alone in patients with mild to moderate renal insufficiency should be balanced with the relatively low graft survival rate of PT alone in the longterm. Moreover, several medical approaches, particularly ‘aggressive’ treatment of hype~ension, have shown good efficacy in postponing the need for dialysis. This points to the need for controlled trials of PT Iterssus medical treatment of diabetes, which have not yet been performed 1281. Brittle diabetes in itself does not appear as an indication for transplantation. Some surgeons have suggested that IDDM patients who have early symptoms of severe diabetic complications such as increased urinary albumin excretion could be eiigible for pancreas transplantation f47]. Such an extension of present indications should be
75 viewed with caution if one considers the need for immunosu~pressio~ and the risks associated with this therapy? and the coatin~o~s progress in the medical treatment of diabetes @S, 33f.
I?roma theoretical point of view* islet tranS#mtation offers many advantages, which have all been successfully exploited in animal models. Islets are isolated from the paacreas by enzymatic digestion and mechanical dispersion, and purified on a density gradient. Due to the smalf volume of endocrine tissue, purified islets can be intphmted in various sites via a procedure that is both simple and safe [15]. Islets can be tested before transplantation with regard to purity, insulin content, insulin secretion i~ virrr, and bacteriological and vi~logical co~t~mi~ation~ which r~&ts in increased safety and allows objective interpretation of the results fSl& Several sources of insulin-secreting cells have been envisaged, including allogeneic and even xcnogeneic (pig) adult pancreas, fetal islets, purified p-cells, and benign insul~~oma ceifs. islets from rnulti~l~ donors can be utilized, the more so Since cryopreservation of islets does not alter their functionality and allows the setting up of a tissue bank [29], Various approaches have been tested to eliminate the need for continuous immunosuppressio~. Besides the a~ernF~s to induce immune tolerance in the reGpient, ulceration of the graft to diminish its immunogenicity has been achieved by culturing the islets prior to transplantation in order to remove ‘passenger leucocytes’ [22], or by usirtg monoclonal antibodies directed against target m#~ecules of rejection I13]. Another promising way to overcome immunological problems has been the isolation of isletts by artificial membranes with setactive permeability (‘bioartificial pancreas’) in capsules or fibers [23, 251, or even in vascularized systems [42], allawing the diffu&on of nutrients and insulin but not that of cells and an~b~es. In various animaf mode&, in which IDDM is induced by ~a~c~eatectomy~ by the administration of a toxin (streptozotocin in most cases), or occurs as the result of autoimmune disease, it has been shown that islet transplantation can cure diabetes and prevent or even reverse drastic com~li~~~ions 1141. In man until recently, results of islet and fetal pancreas transplantation have been disappointing,
with no clearly documented reversal of insulindependency or even long-lasting partial recovery of endo~~aeous insulin secretion [If& A number of reasm’ts have been identified to explain these failures. Besides ethical issues, fetal pancreas transplantation poses several problems, part&larly that of the functional immaturity of the tissue. Failures concerning adult pancreatic islets, have been mainly attributed to rejection and to inadequate islet mass Islet preparations were very often impure and although islets are probably highly immunogenic, in most cases “islet’ transplantation has been performed alone, with no accurate marker to monitor rejection, or even without i~~nosu~~~Ssion_ The o~~rn~ site for engraf~ent has not been defined in man, and it has been suggested that it might vary from one species to another [l]. hleovascularization of the islets may be impaired by the pre-exist@ microangiopathy in the recipient and by poor gXycemic control da~ng the ~stu~e~tive confse. In fact it has been clearly demonstrated that the main limiting factor is the grafted islet mass. The number of islets necessary to enSure insulin-independence has previously been largely underestimated. It now appears that 5000 isletslIcg body weight are required for dog auto~ans~~anta~u~ E!%] and there are ~rel~rn~n~ indications that the number must be increased to 10 000 islets/kg (expressed as the number of islet equivalent, ie islets with an average diameter of 190 pm) for allotransplantation in man [53]. The yieId of islet isolation from adult large m~aIian pancreas has been very low, thus preventing tmns~la~t~tio~ in one recipient of the pancreas from one donor until reccntlyr when advances were made in the procedures used for isiet isolation and purification, which include the early distension of pancreatic duct with collagenase sofution and the use of Semi-automated devices for the digestion step E3l]; reproducible isolation of about 250 000 islets from one pancreas has been achieved by some investigators [39]. Utilizisg such technirlues and ettsuring adequate ~mmunosuppression* several groups have naw report& e~~o~~~i~g results in p&%tS With c peptide-negative type 1 diabetes. Nine patients who received an intraportal islet allograft Corn--Ð bined with liver transplantation after abdominal exenteration demonstrated partial recovery of endog~~eous insulin secretion, one being totally ins~~ia~i~de~ndent~ and 4 requiring inSuhn thera spy only during parenteral hype~lim~nta~on [48]. in a further analysis of 22 consecutive trans-
76
+-;a-& by the same plantations performed in 2! pa,~: group, 6 out of 10 patients with islet-liver graft after exe~teration remained insulin-independent for 5 to > 16 months. By contrast, no patient became insulin-independent among 3 subjects with islet-liver transplantation for associated cirrhosis and 7 with islet-kidney graft (end-stage renal diabetic renal disease), while the average numbers of injected islets (625 000 and 597 000 equivalent islets, respectively} were higher than in patients with exenteration. These failures were interpreted as being due to the combined effects of rejection, the use of steroids, and impaired function or vascularization of the graft due to long-standing iDDM [32f. However, in another study, insulin independence was obtained in 2 patients (for up to 1 year in one subject) who received intraportal fresh and cryopreserved islets together with a !Gdney graft, and partial recovery of basal and stimulated insulin secretion was noted in 2 other patients who only received fresh islets. It should be noted that more than 10 000 equivalent islets/kg were transplanted in the 2 patients who could stop insulin [52, 531. Similarly, among 7 type 1 iDDM patients with established kidney transplant who underwent intraportal islet transplantation, 2 out of the 3 who received over 12 000 equivalent islets/kg achieved insulin-independence 1361. Although these results do not match those of pancreas transplantation, thL;; demonstrate the feasibility of islet transplantation in man.
Conclusion To date pancreas
transplantation is the only method to cure insulin-dependent diabetes mellitus, and its results are now in the range of those for other organ solid transplants. However, the need for continuous immunosuppression limits its indications to a small number of patients, ie mainly those in whom kidney transplantation is also necessary. By contrast, the results of islet transplantation in man are still preliminary. Recent conceptual and technical improvements have been made in this field, but many problems, mairily immunological, still have to be resolved before this method can be applied to large numbers of patients prior to the onset of the chronic complications of IDDM.
References 1
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