Pancreas Transplantation: Solid Organ and Isletperspectivesinmedicine.cshlp.org/content/4/4/a015610.full.pdfisletafterkidney(IAK)transplantation(Gerber et al. 2008). Diabetes and Hypoglycemia

Pancreas Transplantation: Solid Organ and Islet

Shruti Mittal, Paul Johnson, and Peter Friend

Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 9DU, United Kingdom

Correspondence: [email protected]

Transplantation of the pancreas, either as a solid organ or as isolated islets of Langerhans, isindicated in a small proportion of patients with insulin-dependent diabetes in whom severecomplications develop, particularly severe glycemic instability and progressive secondarycomplications (usually renal failure). The potential to reverse diabetes has to be balancedagainst the morbidity of long-term immunosuppression. For a patient with renal failure, thetreatment of choice is often a simultaneous transplant of the pancreas and kidney (SPK),whereas for a patient with glycemic instability, specifically hypoglycemic unawareness, thechoice between a solid organ and an islet transplant has to be individual to the patient.Results of SPK transplantation are comparable to other solid-organ transplants (kidney, liver,heart) and there is evidence of improved quality of life and life expectancy, but the results ofsolitary pancreas transplantation and islets are inferior with respect to graft survival. There issome evidence of benefit with respect to the progression of secondary diabetic complica-tions in patients with functioning transplants for several years.

Effective medical therapy with exogenous in-sulin has been available for patients with di-

abetes since 1922, and the majority of patientsare well managed on this basis. However, a pro-portion of patients develop life-threateningcomplications of diabetes that fail to respondto the most careful insulin regimes. These pa-tients, in whom there is a failure of effectivemedical therapy, fall broadly into two categories:progression of diabetes renal failure and compli-cations and instability of glycemic control.

Progression of Diabetes-Related Renal Failureand Other Secondary Complications

An unequivocal body of evidence shows thatclose glycemic control is beneficial to the patientin relation to the onset and progression of sec-

ondary complications (nephropathy, neuropa-thy, and retinopathy) (The Diabetes Control andComplications Trial Research Group 1993).However, tight glycemic control using exoge-nous insulin is associated with a higher inci-dence of severe hypoglycemic episodes, makingperfect glycemic control unachievable.

Life-Threatening Instability of GlycemicControl

Some patients with difficult-to-manage diabe-tes experience hypoglycemic unawareness; notonly are these patients liable to hypoglycemicevents, but they also have no warning of suchan episode and are therefore unable to react intime to prevent hypoglycemic coma. Patientswith frequent hypoglycemic unawareness re-

Editors: Laurence A. Turka and Kathryn J. Wood

Additional Perspectives on Transplantation available at www.perspectivesinmedicine.org

Copyright # 2014 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a015610

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quire constant supervision, and many cannotlive independently or maintain employment.

It is reasonable to hypothesize that b-celltransplantation should be the most effectiveway to maintain physiological glycemic controland also prevent hypoglycemia and hypoglyce-mic unawareness. However, if transplantation isto be considered the treatment of choice in suchpatients, then two essential prerequisites mustbe fulfilled. The first is evidence that transplan-tation is more effective than other means tomaintain stable glycemic control in brittle dia-betic patients. The second is evidence thatb-celltransplantation is beneficial with respect to lifeexpectancy, quality of life, or disease progres-sion in patients with renal failure and other sec-ondary complications.

The potential benefit of pancreas transplan-tationwas recognized from the early days of solidorgan allografting. Following failed initial at-tempts at xenotransplantation of fragmentedpancreases (Pybus 1924) and the developmentof immunosuppressive therapies, the first trans-planted pancreas was reported by Kelly et al.(1967). The morbidity and mortality associatedwith these early transplants were extremely high:In a publication in 1970, only two patients out ofa series of 10 were alive (Lillehei et al. 1970). Inthe decades that followed, the morbidity andmortality of solid organ transplantation havedecreased greatly, and the rate of success has im-proved to a level now comparable to kidney andliver transplantation. However, much of thecomplexity and morbidity of pancreas trans-plantation still relates to the exocrine compo-nent of the gland, and the concept of transplant-ing only the 2%–3% of cells within the pancreasthat produce insulin is clearly attractive. In 1974,Paul Lacy performed the first clinical allotrans-plant using isolated islets of Langerhans; al-though initially insulin independent, the recipi-ent subsequently died from sepsis (Karl et al.1977). It was not until isolation and transplan-tation of viable islets were first shown to be con-sistently successful in a report from Edmontonthat islet cell transplantation became widespread(Shapiro et al. 2000). In the current era, there-fore, there are two therapeutic options for pa-tients with diabetes who require transplantation.

CURRENT PRACTICE AND INDICATIONSFOR TRANSPLANTATION

Diabetes and Renal Failure

The large majority of patients undergoing solid-organ pancreas transplantation are those withchronic renal failure secondary to diabetes.These patients, on or approaching the need fordialysis, are candidates for kidney transplanta-tion even in the absence of a pancreas transplant.Kidney transplantation alone for diabetic renalfailure has a relatively poor prognosis comparedwith other indications for this procedure (Cosioet al. 2008; Kuo et al. 2010; Taber et al. 2013);although never subjected to a randomized study,there is increasing evidence that, in patients suit-ably assessed for the larger procedure, simulta-neous pancreas and kidney (SPK) transplanta-tion is associated with improved quality of life(Speight et al. 2010) and life expectancy (vanDellen et al. 2013). The decision as to whethersuch patients are better advised to undergokidney transplantation alone, and possible sub-sequent pancreas after kidney (PAK) transplan-tation, instead of the combined operation de-pends on several factors. These include theavailability of a potential living donor, the ur-gency to avoid/come off dialysis, and the likelywaiting time for an SPK. There are marked na-tional differences: for example, in the UnitedKingdom, the majority of patients are listed foran SPK—this reflects the relatively high prioritygiven to such patients in the organ allocationsystem and the shorter waiting time that results.Currently, SPK and PAK are offered to peoplewith insulin-dependent diabetes (type 1 ortype 2) with chronic renal failure. Good resultshave also been achieved in selected patients fol-lowing both simultaneous islet kidney (SIK) andislet after kidney (IAK) transplantation (Gerberet al. 2008).

Diabetes and Hypoglycemia

In patients in whom the primary indication fortransplantation is unstable glycemic control,particularly hypoglycemic unawareness, thechoice is between solid-organ pancreas trans-plantation alone (PTA) or islet transplantation.

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This is, essentially, a choice between a muchhigher-morbidity procedure with a higher like-lihood of insulin independence (solid-organtransplantation) versus a much lower-morbidi-ty procedure with a lower chance of long-termfunction or insulin independence. As is dis-cussed below, insulin independence is lessessential if resolution of life-threatening hypo-glycemia is the primary indication for trans-plantation. Indeed, resolution of hypoglycemiaunawareness is increasingly seen as the metricof success in islet transplantation rather thaninsulin independence. This interface betweensolid-organ and islet transplantation is dynam-ic, and, with recent improvements in the out-come of islet transplantation in the best centers,the 1-yr and 5-yr graft survival data are muchcloser between the two modalities. Patients be-ing offered transplantation for hypoglycemicunawareness should be considered for bothtreatment options. These should be consideredas complementary rather than competing treat-ments, and the decision as to which procedureto perform should be tailored to individual pa-tient needs and preferences.

Diabetes and Other Complications

The role of PTA in the management of patientswho have neither established renal failure (yet)nor hypoglycemic unawareness remains contro-versial. Offering pancreas transplantation tosuch a patient is at least partly based on theassumption that benefits will accrue with re-spect to the progression of secondary diabeticcomplications and that this benefit will out-weigh the complications of long-term immuno-suppression. There is evidence (see below) that asuccessful pancreas transplant may, in the me-dium term, lead to stabilization or improve-ment of retinopathy, neuropathy, and cardio-vascular disease. However, in a patient whodoes not require a kidney transplant, this neces-sitates the patient exchanging the complicationsof diabetes (metabolic instability, quality of life,life expectancy, secondary complications) withthose of the procedure and long-term immuno-suppression (operative risk, graft failure, oppor-tunistic infection, cardiovascular disease, can-

cer). In the case of a patient with renal failurewho would otherwise be receiving a kidneytransplant, this balance does not apply becausethe patient is already committed to the long-term risks of immunosuppression. This is theprimary reason that solid-organ pancreas trans-plantation in the absence of a kidney transplantis much less commonly performed than thecombined operation.

This is an area where better evidence is need-ed; registry analysis is limited by the range andcompleteness of the recorded data and is unlike-ly to contribute more than graft and patient sur-vival. Any beneficial effects on secondary com-plications are likely to require several years tobecome manifest, necessitating close and repeat-ed measurements of (for example) retinal dis-ease/visual acuity, cardiovascular status, neuro-logical function, and renal function (after PTA).The relatively small numbers of transplants per-formed by most centers would require this lon-gitudinal study to be performed on a multicen-ter basis over 5–10 yr.

SECONDARY COMPLICATIONSOF DIABETES

A crucial question that has not yet been an-swered definitively is whether successful b-celltransplantation leads to stabilization or im-provement of the secondary complications ofdiabetes. Many small studies have addressedthis issue in both solid-organ and islet trans-plantation, but the general quality of evidenceis relatively poor, and there is a need for largerclinical trials.

Diabetic neuropathy can have a significantimpact on the quality of life of patients withdiabetes. Autonomic neuropathy causes debili-tating gastrointestinal problems that are verydifficult to manage, and peripheral neuropathymay cause problems with mobility, pain, or un-recognized injuries that may lead to amputa-tions. Improvements in diabetic neuropathyhave been observed with good glycemic control(Callaghan et al. 2012); however, evidence in thecontext of solid-organ pancreas transplanta-tion is limited. Kennedy et al. (1990) showedimprovements in neurological function after

Pancreas Transplantation

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24 mo of stable transplant pancreatic function.These improvements were seen in motor, sen-sory, and autonomic neurology and persisted to10 yr posttransplant, although improvementsin autonomic neuropathy were comparativelymodest (Navarro et al. 1990). The Edmontongroup were unable to show a statistically signifi-cant difference in neuropathy between an islettransplant and the best medical therapy groupin a crossover trial (Thompson et al. 2011). Oneobstacle to research in this area is the lack of agold standard outcome measure. The recent es-tablishment of confocal corneal microscopy as areliable, noninvasive, readily repeatable investi-gation for detecting new nerve growth may ad-dress this, and early evidence after pancreastransplantation is promising (Shtein and Calla-ghan 2013; Tavakoli et al. 2013).

Diabetic retinopathy is the leading cause ofblindness in young people, and impairment invision can severely limit independence and op-portunities for employment. Giannarelli et al.(2006) studied 33 Type 1 diabetic patients whounderwent PTA, matched with 35 controls andfollowed for a mean of 30 mo, and found signifi-cant improvement in the incidence of prolifera-tive retinopathy and the need for laser treatment,and also in nonproliferative retinopathy. How-ever, a high proportion of patients have ad-vanced retinopathy at the time of pancreas trans-plantation, making stabilization rather thanimprovement a more realistic goal. Stabilizationof disease progression has been observed in sev-eral studies (Chow et al. 1999), although theabsence of a large comparative study meansthat it remains unclear whether this is a devia-tion from the natural progression of advancedretinopathy (Sosna et al. 1998). Data from islettransplantation are similarly sparse; Lee et al.(2005) examined eight patients and found im-provement in one and stabilization in seven pa-tients with diabetic retinopathy. Data from thecross-over study performed by the Edmontongroup showed significant differences in progres-sion between an islet transplant and best medicaltherapy (Thompson et al. 2008). However, inorder to establish the real effect of transplanta-tion on vision, a large prospective study involv-ing longitudinal retinal images and a relevant

control group will be necessary. It has been sug-gested that rejection episodes may have a dele-terious effect on retinopathy, causing suddendeterioration (Scheider et al. 1991). In addition,the increased risk of cataracts following trans-plantation must also be considered. However,the indications for transplantation would ex-pand significantly if it were proven definitivelythat transplantation is effective in preventing theprogression of diabetic retinopathy.

The effect of pancreas transplantation onrenal function is highly relevant to clinical prac-tice but is confounded by the nephrotoxic effectof calcineurin inhibitor drugs, with which mostpancreas transplant patients are treated. In pa-tients with already significant diabetic nephrop-athy (glomerular filtration rates ,40 mL/min),the drug-induced detriment in renal functionmay advance the need for dialysis. PTA trans-plantation is therefore contraindicated, but suchpatients are some years away from dialysis andnot yet eligible for a kidney under current allo-cation systems. There is currently no satisfactoryroute for the management of this group of pa-tients, but if there were evidence that pancreastransplantation prevents the progression of di-abetic renal disease, this may justify much ear-lier transplantation in such patients. In addi-tion, these patients may benefit from the useof calcineurin-inhibitor-avoiding immunosup-pression, although there is little published liter-ature in this area. In a much-cited study, Fio-retto et al. (1998) followed eight nonuremicpatients who underwent PTA. Although the glo-merular filtration rate declined by 5 yr (108 to74 mL/min), it remained stable at 10 yr. Proto-col biopsies at 5 and 10 yr showed a decrease inthe glomerular and tubular basement mem-brane thickness at 10 yr, with the mesangialfractional volume increased at 5 yr but de-creased by 10 yr. In islet recipients, the Edmon-ton group showed a slower decline in GFR aftertransplantation compared with best medicaltherapy (Thompson et al. 2011).

Cardiac disease is the leading cause of deathin patients with diabetic renal failure. There isevidence that pancreas–kidney transplantationreduces the cardiovascular death rate (La Roccaet al. 2001), and functional studies have shown

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improvement in blood pressure and dyslipide-mia compared with kidney transplantationalone (Luan et al. 2007). Benefits have alsobeen shown with respect to systolic and diastolicventricular function (Fiorina et al. 2000; LaRocca et al. 2001) and endothelial dysfunction(Fiorina et al. 2003; Stadler et al. 2009). Howev-er, low cardiac-event rates after transplantationmay also reflect stringent cardiac screening andpreoperative optimization. Long-term studieslinking postoperative functional investigationsand clinical end points are needed; current re-search is addressing cardiac screening tech-niques and markers of cardiac risk. Fiorinaet al. (2003) compared 21 patients with success-ful islet–kidney transplantation with 13 pa-tients in whom the islet transplant failed, show-ing benefits with respect to survival andcardiovascular and endothelial function.

BENEFITS OF PANCREAS AND ISLETTRANSPLANTATION

Although there have been no large-scale ran-domized controlled trials to establish eitherwhether transplant therapies are more effectivethan other means of maintaining stable glyce-mic control, or whether replacement of b-cellmass is beneficial in patients with secondarycomplications, ultimately, the object of bothsolid pancreas and islet transplantation is to en-hance quality of life and life expectancy.

For a patient with hypoglycemic unaware-ness, both quality of life and life expectancy arelikely to be improved by resolution of hypogly-cemic unawareness, even if they are not renderedinsulin independent. Although life-expectancydata are not yet available, emerging quality-of-life data do, indeed, suggest a significant benefitfrom successful islet transplantation (Bassi andFiorina 2011) and solid-organ transplantation(Speight et al. 2010).

For patients undergoing transplantation be-cause of secondary diabetic complications (par-ticularly kidney damage), any benefit is likely torequire longer-term function (several years) andinsulin independence (probably). There is con-siderable evidence (although not from random-ized trials) that successful solid-organ trans-

plantation increases life expectancy. Tydenet al. (1999) showed that, in a reasonably homo-geneous group of patients with diabetic renalfailure, those who achieve stable function of acombined pancreas and kidney transplant hadsubstantially improved 10-yr survival comparedwith the group with stable kidney transplantfunction alone. Registry analyses confirm thebenefit of SPK transplantation versus kidneytransplantation alone (and of kidney transplan-tation versus dialysis). Ojo et al. (2001) showedan almost doubling of life expectancy in patientsundergoing the combined operation comparedwith those who underwent deceased-donor kid-ney transplantation alone for diabetic renal fail-ure. Clearly, however, these groups were notmatched for age or morbidity, although all pa-tients were selected as suitable for transplanta-tion of one or both organs.

SUCCESS OF PANCREAS AND ISLETTRANSPLANTATION

The outcomes of both solid pancreas and islettransplantation have improved progressively.One- and 5-yr results of SPK transplantationare now close to those of kidney, liver, and hearttransplantation (Kandaswamy et al. 2013). Suc-cess, however, requires definition. Convention-ally, a successful solid-organ pancreas transplantis defined by insulin independence. This is arational policy based on the assumption thatonly perfect glycemic control is likely to achievethe benefits in relation to life expectancy andsecondary complications. However, as dis-cussed above, in the case of patients with unsta-ble glycemic control undergoing islet transplan-tation, the primary objective is the resolution ofhypoglycemia awareness, and not the restora-tion of normoglycemia. There is now good ev-idence that this does not require insulin inde-pendence but rather the consistent productionof C peptide (Ryan et al. 2004). For this reason,lack of hypoglycemia unawareness is the gener-ally accepted definition of success in islet trans-plantation.

Current pancreas graft survival in patientsundergoing SPK is 85% at 1 yr and 73% at 5 yr(Figs. 1–3) ( Kandaswamyet al. 2013). Nearly all



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the improvement in graft outcome in recentdecades has been achieved during the first 12 mopostoperatively with much less in subsequent

years (in line with other solid-organ transplantoutcomes). In solid-organ transplantation, SPKoutcomes are consistentlysuperior to those fromPTA or PAK transplantation (Gruessner et al.2012). Patients undergoing PTA can expect 1-and 5-yr pancreas graft survival of 80% and58%, and those undergoing PAK can expect77% and 56% (Kandaswamy et al. 2013). It isgenerally assumed that the main reason for thediscrepancy between SPK and PTA/PAK out-comes is the presence of a kidney from thesame donor in the former. This allows renalfunction to be used as a surrogate biomarkerfor rejection; not only is it possible to measurerenal function in a more sensitive manner, butalso the kidney is amenable to biopsy. The great-est risk of graft loss still occurs within the firstyear posttransplant, and, in particular, withinthe first 3 mo, when failure is often associatedwith reperfusion pancreatitis and sepsis due toischemia-reperfusion injury, a potentially fatalcomplication. Pancreas transplantation, withor without kidney transplantation, has a patientsurvival rate of 95% at 1 yr and 85% at 5 yr.

Figure 1. Back-table preparation of pancreas graft forimplantation. The segment of donor duodenum isshortened, the donor spleen is removed, and retro-peritoneal tissue is removed/ligated. The arterialsupply via the superior mesenteric and splenic arter-ies is attached to a Y graft, usually from the bifurca-tion of the donor common iliac artery in order toprovide a single arterial inflow. Venous outflow viaportal vein (shown). (Photograph courtesy of JamesGilbert, Oxford Transplant Centre.)

0 12 24 36 48 60 72 84 96 108

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Figure 2. Pancreas graft survival (defined by insulin independence) and patient survival after transplantation atthe Oxford Transplant Centre. SPK, Simultaneous pancreas kidney transplant; PTA, pancreas transplant alone;PAK, pancreas after kidney.

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The results of islet transplantation have im-proved greatly over the past decade, in termsboth of resolution of hypoglycemic unawarenessand achievement of insulin independence. Inthe 1990s, the Islet Transplant Registry reportedan insulin-independence rate of only 11% inalmost 500 islet transplant recipients. However,the introduction of the steroid-free, repeat infu-sion Edmonton Protocol significantly improvedoutcomes (Shapiro et al. 2000), which were con-firmed by the multicenter Immune ToleranceNetwork (ITN) trial results of 58% 1-yr insulinindependence in 36 patients (Shapiro et al.2006). Longer-term results of the original Ed-monton Protocol showed a high rate of attrition,with only �10% of 65 patients remaining insu-lin independent 5 yr later (Ryan et al. 2005a),although �80% of patients remained C-peptidepositive with well-controlled HbA1c. In recent

years, the results of islet transplantation haveimproved. The Islet Transplant Registry report-ed a 3-yr graft function of only 19% in 2001,whereas in 2009, the Collaborative Islet Trans-plant Registry (CITR), with data from islettransplant centers of variable experience, re-ported that this had risen to 45%.

Islet transplantation has been seen to be evenmore successful in some centers of excellence.The Minneapolis team achieved 5-yr insulin-in-dependence rates of 50% in 25 patients usingsingle islet infusions (Ryan et al. 2005a), albeitin recipients with low body-mass indices. TheLille group reported 57% insulin independenceat 3.3 yr posttransplantation in 14 patients(Campbell et al. 2007). The Edmonton teamrecently presented excellent 5-yroutcomes usingalemtuzumab as the induction agent. Althoughthe longer-term results of islet transplantation

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Figure 3. Continuous glucose monitoring before and after islet transplantation performed within the OxfordIslet Transplant Programme, showing improved glycemic control.



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Table 1. b-Cell transplantation indications, contraindications, risks, and benefits

Procedure SPK PTA PAK Islet

Indication Insulin-treateddiabetes

Chronic renalfailure withGFR ,

20 mL/min oron dialysis

Insulin-treated diabetes

Significant diabeticcomplications

Severe diabeticcomplications butnormal or near-normal renal function

Frequent and severeepisodes ofhypoglycemia (morethan two severehypoglycemicepisodes within last24 mo); assessed bydiabetologist to havedisablinghypoglycemia orhypogylcemicunawareness orsignificantimpairment of qualityof life due to diabetes

Insulin-treateddiabetes

Stable function ofprevious renalallograft

Meet criteria forPTA

Insulin-treated diabetes

Frequent and severeepisodes ofhypoglycemia (morethan two severehypoglycemicepisodes within last24 mo); assessed bydiabetologist to havedisablinghypoglycemia orhypogylcemicunawareness orsignificantimpairment of qualityof life due to diabetes

Contraindications Relative:Cerebrovascular accident with long-term

impairmentActive infection hepatitis B or C virusBody mass index .30 kg/m2

Insulin requirements .1.5 units/kg per dayExtensive aorta/iliac and/or peripheral

vascular diseaseContinued abuse of alcohol or drugs

Absolute:Excessive cardiovascular risk (significant

noncorrectable coronary artery disease;left ventricular ejection fraction ,50%;myocardial infarction within 6 mo)

Uncurable malignancy (excluding localizedskin cancer)

Active sepsis or peptic ulcerMajor psychiatric history likely to result in

nonadherenceInability to withstand surgery and

immunosuppressionBenefits Insulin

independenceGood pancreas

and kidneygraft outcomes

Insulin independence

Cure of hypoglycemia

Insulinindependence

Early dialysisindependence

Cure of hypoglycemia

Less invasive

Risks Operativemorbidity andmortality

Risk of graft failure

Higher morbidityprocedure

Sensitization

Poorer pancreasgraft outcomes

Less likely to achieveinsulin independence

Often need more thanone infusion

SPK, Simultaneous pancreas kidney transplant; PTA, pancreas transplant alone; PAK, pancreas after kidney.

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are inferior to those of solid-organ transplanta-tion, the much lower morbidityof islet transplan-tation does enable the possibility of repeat trans-plantation. However, this carries the risk ofsensitizing the recipient to HLA antigens (Camp-bell et al. 2007; Naziruddin et al. 2012), whichmay disadvantage any patient who requires kid-ney transplantation at a subsequent stage.

b-CELL TRANSPLANTATION—THE PROCESS

Organ Donation

Donor selection for pancreas transplantation ismore stringent than for other organs, thus lim-iting the number of potential donors available.Conservative acceptance practices mean that of-fered pancreases are often declined; indeed, or-gans may be declined on the basis of donor al-cohol use, family history of diabetes, or serumamylase, none of which has been found to beassociated with graft outcome (Axelrod et al.2010). Many donor organs are found to be ab-normal at the time of retrieval with fibrosis or fatdeposition within the gland. Although steatoticorgans often provide good immediate functionif transplanted, these organs are liable to severereperfusion pancreatitis with associated mor-bidity, and fatty organs are therefore usually dis-carded. Similarly, donors with a body mass in-dex (BMI) .30 are usually declined for solid-organ donation although the evidence base fordoing so is limited (Humar et al. 2004; Axelrodet al. 2010). Organ donors up to the age of 60 yrare considered for solid-organ transplantation,but, because donor age has frequently beenidentified as predictive of graft outcome, pan-creases from younger donors are preferred (Pro-neth et al. 2013). The pancreas is very vulnerableto injury sustained during retrieval, which leadsto a higher discard rate of retrieved organs thanis seen in other transplant types. For all thesereasons, the conversion rate from potential do-nor to transplant is very low; data from the Sci-entific Registry of Transplant Recipients showthat as little as 20% of potential donor pancre-ases are actually retrieved, and of these a further30% are discarded after retrieval (Kandaswamyet al. 2013).

Although historically older and higher-BMIdonors were preferred for islet transplantation,this was based on isolation rates rather than isletphysiology (Lakey et al. 1996; Nano et al. 2005).It is now clear that the optimal donor for islets isyounger (Niclauss et al. 2011); this is supportedby “in vitro” data of human islets (Lakey et al.1996; Ihm et al. 2007). Fibrosis and fatty infil-tration of the pancreatic parenchyma can pre-vent pancreas digestion during islet isolation,but fat overlying the pancreas is not in itself acontraindication because this can be removedbefore digestion.

Cold ischemia is deleterious in both solidorgan and islet transplantation, although therecommended limit is shorter (8 h) in the caseof islet transplantation (Lakey et al. 1995; Axel-rod et al. 2010). Organs donated after circula-tory death (DCD) are used in increasing num-bers in solid organ transplantation and havebeen shown to produce results that are compa-rable in quality to organs removed from brain-dead donors (Muthusamy et al. 2012). Howev-er, this is achieved by a more selective approach,particularly in terms of donor age and BMI. Anobjective analysis of donor risk factors has beenperformed, leading to a donor risk index (Ax-elrod et al. 2010). The factors associated with thegreatest risk (hazard ratio) are as follows: donorage (1.56), DCD status (1.39), black race (1.27),cerebrovascular cause of donor death (1.23), se-rum creatinine .2.5 mg/dL (1.22). Both do-nor and recipient risk factors need to be incor-porated into new organ allocation schemes tooptimize the usage of the limited supply of do-nor pancreases, as well as clinical outcomes forpatients undergoing either form of transplanta-tion (Berney and Johnson 2010).

Organ preservation for both solid-organand islet transplants is performed by staticcold storage, most commonly with Universityof Wisconsin solution, although some units useCelsior or HTK. Despite several trials, no con-sistent evidence of benefit has been shown, al-though some studies found a higher incidenceof graft pancreatitis, a decreased rate of insulinindependence at hospital discharge, and a high-er rate of graft loss in HTK-stored pancreases(Stewart et al. 2009). The potential benefits of



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oxygen carriage using the two-layer techniquefor islet transplantation (Kawamura et al. 1992)did not to translate from the small animal mod-els to clinical evidence (Kin et al. 2008).

Living Donation and PancreasTransplantation

Sutherland et al. (2012) reported 163 living-donor pancreas transplants using segmental(body and tail of pancreas) organs; these weremainly solid organ, but a small number of islettransplants have been performed. The majorityof these were performed at the University ofMinnesota; others were performed in countrieswhere deceased donors are rarely available,particularly Japan. There is little evidence ofany long-term advantage over deceased-do-nor transplantation, and subsequent metabolicstudies in donors detected significant and con-cerning metabolic abnormalities (Robertsonet al. 2003). This procedure is very rarely per-formed now.

Solid-Organ Implantation

The surgical techniques of solid-organ trans-plantation have changed substantially over theyears. The majority of transplant units aroundthe world now transplant the solid pancreas to-gether with a segment of duodenum. The arte-rial supply via the superior mesenteric andsplenic arteries is attached to a Y graft usuallyfrom the bifurcation of the donor common iliacartery in order to provide a single arterial inflow.Most units transplant the pancreas with venousdrainage to the common iliac vein or inferiorvena cava and arterial inflow from the commoniliac artery. A much smaller proportion of unitsadvocate venous drainage into the portal venoussystem. Although associated with more physio-logical systemic levels of insulin (lower), there isno evidence of substantial benefit with respect tograft or patient survival orother parameters (Ba-zerbachi et al. 2012).

Drainage of the exocrine excretions of thepancreas has historically been the Achilles heelof pancreas transplantation. Numerous techni-cal modifications have included (1) transplan-

tation of the body and tail of the gland (segmen-tal) with occlusion of the pancreatic duct, ordrainage into the bladder, the jejunum or thestomach; and (2) transplantation of the wholeorgan with a “button” of duodenum or duode-nal segment, drained into the bladder, jejunum,or duodenum. The expansion of clinical trans-plantation in the 1990s was based largely onanastomosis of the donor duodenum to thebladder (Sollinger et al. 2009), which had ad-vantages for monitoring (as explained below).In recent years, bladder drainage has been large-ly supplanted by enteric drainage in which thedonor duodenum is anastomosed to the prox-imal jejunum either directly or via a roux loop.This is clearly a more physiological techniquebut one that renders the pancreas less easilymonitored.

Islet Cell Isolation and Implantation

The most challenging part of islet transplanta-tion remains the islet isolation. This is a two-stage procedure involving pancreas digestion us-ing a combination of enzymatic and mechanicaldissociation, and islet purification using densi-ty-gradient separation (Ricordi et al. 1989).Although refined in recent decades, this remainsa relatively nonspecific, unpredictable methodwith only �30% of pancreases resulting intransplantable yields even in leading centers.Current research efforts are investigating theultrastructure of the pancreatic exocrine–isletinterface in different donor types, so that noveltargeted enzyme blends can be developed(Hughes et al. 2006). Islet isolation requires spe-cialized expertise, and, in order to focus skills,many programs are based on a hub-and-spokemodel, in which each isolation laboratory pro-vides islets for several implanting centers(Kempf et al. 2005).

Although the original Edmonton Protocolinvolved the transplantation of “fresh” islets im-mediately following islet isolation, most centershave now adopted a period of at least 24 h of isletculture before transplantation (Shapiro et al.2000). This not only improves the logistics ofthe transplant, but also enables additional pre-transplant islet assessment to be undertaken and

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enables the islets to “recover” following isola-tion. This is particularly useful for preparationsinvolving larger islets, where central necrosis canbe monitored during culture.

Although a few cases of intramuscular isletautotransplants have been reported (Dardenneet al. 2012), the majority of clinical islet allo-transplants are performed via the portal veininto the liver sinusoids. This is performed eitherby a percutaneous, radiologically guided trans-hepatic approach, or via cannulation of a mes-enteric vessel approached laparoscopicallyor viaa mini-laparotomy. Recipients are anticoagu-lated, and heparin is added to the islet infusionto reduce the immediate inflammatory re-sponse, which is believed to be responsible forearly islet loss (Cabric et al. 2007). If performedtrans-hepatically, embolization of the puncturesite in the liver is performed to prevent bleeding(Owen et al. 2003).

Immunosuppression

Immunosuppression in pancreas transplanta-tion follows a similar pattern to other solid-organ transplants. The majority of units usebiological induction (thymoglobulin, alemtu-zumab, or basiliximab) followed by a combina-tion of tacrolimus and mycophenolate, and theuse of steroids is advocated by some but not allunits. There is no conclusive evidence regardingoptimal induction therapy; single center studiesare small, and of the two multicenter trials, thelargest examined an agent (daclizumab) that isno longer available, and the other used variableinduction agents (Niederhaus et al. 2013). Theuse of non-nephrotoxic medication is attractive,but experience in the use of sirolimus followingpancreas transplantation remains limited (Kan-dula et al. 2012).

Similarly, various immunosuppressive re-gimes have been used for islet transplantation.A feature of the successful Edmonton Protocolwas a steroid-free regime, using tacrolimus andsirolimus as maintenance (Shapiro et al. 2000).Since then, many centers have replaced siroli-mus with mycophenolate. The use of alemtuzu-mab-induction therapy is associated with en-couraging longer-term function.

In the future, the application of currentlyexperimental methods of immunomodula-tion are likely to change the practice of pancreastransplantation not only by reducing the mor-bidity of immunosuppression but also by re-ducing the adverse effects of unrecognized re-jection. Treatment with T-regulatory cells and/or mesenchymal stem cells may substantiallyalter the practice of pancreas transplantation.

Graft Monitoring

Monitoring of both solid-organ and islet trans-plants is a major challenge. The lack of any sim-ple marker of early graft injury is problematic,with no equivalent to the glomerular filtrationrate in kidney transplantation. Hyperglycemiais a relatively late event and often signifies sub-stantial and irreversible graft injury. Glycemicstability is closely monitored and graft functionis measured by basal and stimulated C-peptidelevels. In islet transplantation, several usefulmetabolic scores have been introduced to assessgraft function objectively. These include the b-score, a composite of fasting glucose, HbA(1c),stimulated C-peptide, and insulin requirement(Ryan et al. 2005b); the HYPO score, whichprimarily assesses resolution of hypoglycemia;and the liability index (Ryan et al. 2004).

Surrogate measures, including those that re-late to the transplanted exocrine tissue, are usedin the monitoring of solid organ grafts. Rises inserum amylase and lipase are commonly as-sociated with pancreatitis, but the relevance ofchanges in the context of graft rejection is un-certain. In combined pancreas–kidney trans-plantation, kidney graft function (and rejection)is used as a surrogate for changes presumed to beoccurring within the pancreas also (although itis recognized that discordant rejection can oc-cur) (Troxell et al. 2010). When the pancreasis transplanted alone, monitoring of pancreasfunction is problematic. This may explain thediscrepancy in outcomes—unrecognized rejec-tion may account for poorer graft survival in thisgroup.

Bladder drainage of exocrine secretions en-ables amylase production to be used as a mea-sure of transplant function and also allows bi-



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opsy of the donor duodenum via cystoscopy.Alterations in levels of urinary amylase are asso-ciated with impairment in pancreas graft func-tion (Prieto et al. 1987), but this must be ba-lanced against the substantial complications ofbladder drainage, both urological (cystitis) andbiochemical (bicarbonate loss and dehydra-tion). Percutaneous, radiologically guided pan-creatic transplant biopsy of enterically drainedtransplants is increasingly advocated and (de-spite earlier concerns) appears to be safe (Klas-sen et al. 2002). However, this provides themeans of diagnosis of rejection but does notsolve the problem of monitoring; the challengeof detecting the early manifestations of rejectionremains (see review in Margreiter et al. 2013).The development of donor-specific antibodiesposttransplant is associated with rejection andgraft failure in the pancreas, as in other solid-organ transplants, and monitoring is advocated.

Radiological and radioisotopic methods tomeasureb-cell mass and monitor graft functionare of experimental interest but not in clinicaluse. Metabolic tests indicate graft function andreserve but are unwieldy for the purpose of fre-quent monitoring. Immunological blood mon-itoring may give advance warning of an im-mune reaction, but such methods are not yetin routine clinical use.

Morbidity

Solid-organ and islet transplantation share sim-ilar long-term risks with respect to immuno-suppression–opportunistic infections, specificdrug side effects, and malignancy. Solid-organpancreas transplantation is associated withmuch higher procedure-specific morbidity andmortality with many complications requiringreoperation, including hemorrhage, thrombo-sis, pancreatitis, and sepsis. Venous thrombosis,once a major cause of morbidity (Stocklandet al. 2009), has been partially overcome by care-ful monitoring of coagulation using thrombo-elastography or other methods—many patientsundergoing SPK are relatively hypercoagulable(Muthusamy et al. 2010). Ischemia-reperfusioninjury is manifest by reperfusion pancreatitisleading to sepsis and, sometimes, exocrine leak-

age. Subsequent complications include mycoticaneurysm formation due to infection of vascularanastomoses—this appears to be a greater risk inpancreas transplantation, possibly because ofcontamination by enteric organisms at thetime of organ retrieval or at the time of entericanastomosis.

In contrast, islet transplantation is a safeprocedure. The two most serious (but rare) pro-cedure-related complications are portal veinthrombosis and bleeding. Although thrombosisof the main portal vein has been reported afterislet transplantation using unpurified islets, therisk of this complication is now reduced sub-stantially owing to more rigorous approachesto purification (reducing the volume of cells in-fused), anticoagulation, and portal pressuremonitoring during infusion (Kawahara et al.2011). However, segmental thrombosis hasbeen reported in up to 5% of patients (Owenet al. 2003). This risk has been reduced by addingheparin to the islet preparation and by systemicanticoagulation posttransplantation. Hemor-rhage from the hepatic puncture site was report-ed in up to 8% of cases (Owen et al. 2003), butthis complication has been reduced with the in-troduction of techniques to embolize the cath-eter tract following islet infusion.

Challenges in b-Cell Transplantation

Currently, the morbidity of solid-organ pancre-as transplantation restricts pancreas transplan-tation to relatively younger and fitter patients(very few patients older than 60 yr are acceptedfor solid-organ pancreas transplantation). Ac-cess to islet transplantation is restricted by dif-ferent parameters, including body mass indexand renal function. As the mortality and mor-bidity of solid pancreas transplantation dimin-ish and the longer-term outcomes of both solid-organ and islet transplantation improve, theappropriate indications for both procedureswill expand, particularly with the increasing in-cidence of diabetes as well as evidence thattransplantation is suitable not only for type 1diabetics but also for selected insulin-depen-dent patients with type 2 diabetes (nonobese,non-insulin resistant).

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There is a clear challenge to improve theutilization of potential donor organs to the levelcurrently achieved in kidney and liver transplan-tation. This will require new approaches to or-gan retrieval, preservation, assessment, and themanagement of ischemia-reperfusion injury.

The process of islet isolation and culture stillresults in more than 30% of donor organs notproducing a transplantable islet yield, and this iscompounded by the fact that many patients stillrequire two infusions to achieve optimal func-tion. In the future, novel enzyme blends willspecifically target the pancreatic matrix of thefull range of different donor types.

Developments in immunosuppression willreduce the morbidity of transplantation and ex-pand the criteria for transplantation. Tolerancestrategies, including T-regulatory cells, will re-duce the long-term risks and further shift therisk–benefit threshold of pancreatic transplan-tation. Novel methods are needed for graft mon-itoring by immunological or biochemical bio-markers.

It is widely assumed that the development ofstem cell therapy will displace allotransplanta-tion in the management of diabetes. Althoughthis is a reasonable long-term vision, the devel-opment of insulin-producing cells is not yetclose to the point at which clinical implemen-tation is feasible.

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Effector Mechanisms of Rejection

al.Aurélie Moreau, Emilie Varey, Ignacio Anegon, et

Immunosuppression?Coming to the Limits of−−Opportunistic Infections

Jay A. Fishman

The Innate Immune System and Transplantation

Steven H. SacksConrad A. Farrar, Jerzy W. Kupiec-Weglinski and

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Documents

Pancreas Transplantation: Solid Organ and Isletperspectivesinmedicine.cshlp.org/content/4/4/a015610.full.pdfisletafterkidney(IAK)transplantation(Gerber et al. 2008). Diabetes and Hypoglycemia