Vascularized pancreas allotransplantation – clinical indications and outcome

Vascularized pancreas allotransplantation ± clinicalindications and outcome

S. A. White, M. L. Nicholson and N. J. M. London

Abstract

Aims This review examines the status of vascularized pancreas transplantation

as a treatment for Type 1 diabetes mellitus (DM).

Methods The world literature, with a particular emphasis on data from the

International Pancreas Transplant Registry (IPTR), is reviewed and interpreted

particularly for clinical indications and outcome.

Results Over 9000 cases of vascularized pancreas transplant (VPT) have been

registered, with insulin dependence approaching 82% at 1 year with 94%

patient survival. The majority of transplants are simultaneous pancreas and

kidney (SPK) transplants, with far fewer pancreas after kidney (PAK) or

pancreas transplants alone (PTA). The success rates differ between the

procedures but are generally improving as technical advances, improvements

in immunosupression and greater experience are gained. The most obvious

advantage is an improved quality of life (QoL) but there are risks associated

with the procedure and with the immunosuppression. There is some evidence

coming to light of a very slow bene®cial effect on microvascular

complications.

Conclusions VPT is an attractive option to offer Type 1 DM patients who need

or already have a renal allograft. Patients have to decide between the increased

surgical risk and the risks of long-term immunosuppression and the bene®ts of

improved QoL. In the absense of end-stage renal failure (ESRF) there is no

justi®cation for PTA, except where the diabetes itself poses a greater risk to life

than the transplantation procedure.

Diabet. Med. 16. 533±543 (1999)

Keywords diabetes mellitus, nephropathy, neuropathy, pancreas transplant,

retinopathy

Abbreviations ALS, anti-lymphocyte serum; BD, bladder drainage; ED, en-

teric drainage; ESRF, end-stage renal failure; GFR, glomerular ®ltration rate;

HLA, human lymphocyte antigen; IPTR, International Pancreas Transplant

Registry; IRx, intensi®ed insulin treatment; KTA, kidney transplant alone;

MMF, mycophenolate mofetil; PAK, pancreas after kidney transplant; PTA,

pancreas transplant alone; QoL, quality of life; SPK, simulataneous pancreas

and kidney transplant; VPT, vascularized pancreas transplant

R

Department of Surgery, University of Leicester, UK

Received 19 October 1998; revised 22 February

1999; accepted 26 February 1999

Correspondence to: Mr Steve White, Department of Surgery, University of

Leicester, LeicesterGeneral Hospital, GwendolenRoad, Leicester, LE5 4PW, UK.

ã 1999 British Diabetic Association. Diabetic Medicine, 16, 533±543 533

Introduction

With the publication of the Diabetes Control and

Complications Trial [1] it has now been widely

accepted that intensi®ed insulin regimens can reduce

the risk of developing the complications of diabetes

mellitus (DM). However, intensi®ed insulin regimens

(IPx) increase the risk of developing severe hypogly-

caemia and will never be able to mimic the minute by

minute variation of insulin secretion in vivo. Currently,

the only realistic way of achieving near normoglycae-

mia is to perform either a vascularized pancreas

transplant (VPT) or to transplant isolated islets of

Langerhans. The aim of this review is to address the

current status of VPT.

Over 9000 cases of VPT have been reported to the

International Pancreas Transplant Registry (IPTR) and

over 170 centres worldwide have now performed a VPT

[2]. Insulin independence now approaches 82% at 1 year

with a 94% patient survival [3]. There are various

strategies for performing a VPT; either simultaneous

pancreas and kidney (SPK), pancreas after kidney (PAK)

and pancreas transplant alone (PTA) (vide infra). The

majority are SPK transplants (90%), 4% are PAK and less

than 6% are PTA [4]. Despite the increasing popularity of

VPT, it must not be forgotten that the procedure is still only

applicable to a minority of the diabetic population. Only

50% of patients with diabetes of 20 years or more duration

will develop severe neuropathy, retinopathy or nephro-

pathy with 30% progressing to end-stage renal failure

(ESRF) [2]. In view of the dif®culty in predicting those

patients who will develop chronic diabetic complications,

VPT is currently performed in those patients with

established complications. In comparison, the theoretical

concept of islet transplantation, with its lower morbidity

and mortality, is to perform the procedure suf®ciently early

in the course of the disease to prevent diabetic complica-

tions before they have become established. However, many

problems have thwarted successful clinical islet transplan-

tation. Most of these relate to the techniques of islet

isolation and prevention of acute rejection. The current

problems associated with islet transplantation will be

reviewed in more detail in a later review.

Rationale

Unlike liver, lung and heart transplantation, VPT is

not a life-saving procedure and its value must be

balanced against the risks of the operative procedure

and inevitable long-term immunosuppressive therapy.

The potential bene®t of VPT is an improved quality of

life (QoL). VPT should be restricted to patients with

established, or at considerable risk of developing,

diabetic complications that are considered to be more

severe than the complications of life-long immunosup-

pression and perceived to be more harmful than the

risks of the surgical procedure.

Patient selection

The technical advances of VPT have opened the way for a

variety of recipient categories to be considered. One of the

more contentious issues is who should receive a VPT [5]?

All recipients should have Type 1 DM as it is dif®cult to

show conclusively any bene®t in hyperinsulinaemic Type

2 DM patients because of the peripheral insulin resistance

and pre-existing C-peptide secretion.

VPT is a formidable operation and to achieve good

results it is crucial that patients are in good general

health. For the best results, patients are carefully

selected and stringent consideration is given to any

pre-existing comorbidity. This applies in particular to

coronary artery disease and, if suspected, it is best to

diagnose and treat early by coronary bypass grafting

before proceding to VPT [6]. In addition, there is no

agreement as to whether the extent of ESRF in¯uences

outcome. It has been argued that those with a

glomerular ®ltration rate (GFR) of < »45 ml/min

(normal values in males 131 6 21; in females

117 6 15.6 ml/min) may have an advantage over those

patients near to long-term dialysis (e.g. GFR < 10 ml/

min). Few studies to date have demonstrated any

signi®cant advantage between different patient groups,

with the exception of those patients who have an

existing functioning renal allograft. These patients have

a tendency to do better with less risk of developing

postoperative surgical complications.

The optimum age of potential recipients also needs to be

addressed. Current evidence suggests that patients who are

over 50 years of age with a long duration of diabetes and

more advanced diabetic complications have little chance of

VPT being able to reverse or stabilize retinopathy,

nephropathy or neuropathy. The situation is very different

in younger recipients (< 50 years) whose disease is perhaps

less advanced and the amelioration of diabetic complica-

tions may be possible [7]. There is also good evidence that

patients approaching 50 years of age represent a high risk

group in terms of graft and patient survival [7±9].

Surgical aspects

Pancreas donation

One of the problems associated with a successful VPT

programmeintheUKisthedesirabilityofretrievingboththe

liver and the pancreas at the same time for patients involved

in a combined liver±pancreas transplant programme. A

combined procurement is quicker because there is less

dissection of the blood vessels and cold in situ vascular

L534 Vascularized pancreas allotransplantation · S. A. White et al.

ã 1999 British Diabetic Association. Diabetic Medicine, 16, 533±543

perfusion is optimized. The application of hypothermic in

situ vascular perfusion and cold storage in an organ

preservation solution (e.g. University of Wisconsin solu-

tion) has allowed experimental success after 72 h [10] but

this is not advisable in the clinical situation. For pancreata

with a cold storage time of less than 11 h, graft survival at

1 year is 78% in comparison to 76% for those preserved for

longerthan23 h[3].However,fewcentresintheUKpractice

VPT,andforthoseundertakingarenalandVPTprogramme

there is much competition for organ retrieval, as the liver is

given priority at the expense of the pancreas. The pancreas

maybedamagedandaninadequatelengthofportalveinwill

make subsequent revascularization dif®cult.

The Minneapolis group have strongly emphasized the

need for younger organ donors because of improved

recipient graft survival. They recommend donors should

be< 45 yearsofage,asolderorgandonorsincreasetheriskof

poorergraftandpatientsurvivalrates. Incontrast, thelower

agelimitismoreconjecturalwithno®xedcriteria.Asensible

approach adopted by Nghiem et al. [11] is that donors

shouldbeat least5 yearsofagewithabodymass indexequal

to or greater than 20 kg/m2. Lean donors are preferable

(BMI < 30 kg/m2) as obesity predisposes towards heavy

in®ltration of the pancreas with adipose tissue. A sensible

approachalsoneedstobeadoptedregardingtherelativesize

of the kidney and pancreas compared to the recipient, as

substantial discrepancies in size will cause technical

dif®culties, thereby prolonging the procedure for the

recipient and increasing the risk of postoperative complica-

tions [6].

Donorhyperglycaemiaat thetimeoforganretrieval isnot

a contra-indication to VPT. With the metabolic response to

trauma and the use of steroids or intravenous glucose

solutions, hyperglycaemia is a normal physiological and

metabolic response to injury. However, an HbA1c level that

excludes previously undiagnosed diabetes mellitus may be

useful in a minority [7]. Likewise, hyperamylasaemia is

frequently observed in traumatized patients and should not

be regarded as an absolute contra-indication to pancreas

donation. However, it would be unwise to retrieve a

pancreas with petechial haemorrhage or peripancreatic

oedema because of the risk of pancreatitis.

Tissuematchingandbloodcompatibilityneedconsidera-

tion.SeveralauthorsindicatethatonlyABOcompatibilityis

necessary, as routine human lymphocyte antigen (HLA)

matching only appears to in¯uence graft outcome in PTA

[12] and living related donor pancreatic transplants.

Although some centres would prefer HLA matching, with

thesmallpopulationwhoaresuitableforaVPT®ndingafull

donor±recipient match would result in longer waiting lists.

Recipient operation

Although it is not within the scope of this review to detail

all the technical aspects of VPT, a brief outline of the

important advances in this area will be discussed. Over 40

techniques for VPT have been described in 170 centres

worldwide [13].

Recently, the whole pancreas rather than a segment of

distal pancreas has been grafted, with the presumption of

increasing islet cell mass [14] and reducing blood loss and

exocrine leakage. The pancreas is revascularized to the

recipient's iliac vessels and the graft is placed within the

peritoneal cavity. Insulin is secreted into the systemic

venous system. This relative hyperinsulinaemia is com-

pounded by insulin resistance from the additional steroid

immunosuppression, which at least in theory may potenti-

ate the risk of macrovascular diabetic complications

[15,16]. Pancreatic grafts can be anastomosed to the portal

vein [17] but the technical aspects of this operation and the

risks of portal venous thrombosis make this option less

attractive [18,19].

The management of the pancreatic exocrine secretions

has always been problematic [20] and many different

variations of ductal reconstructions have been tried. The

®rst pancreas transplant by Kelly et al. [21] entailed a duct-

ligated graft. This method precipitated pancreatitis be-

cause of obstruction to exocrine secretions. The most

appropriate and logical manoeuvre for diverting physio-

logical exocrine secretion, was to establish drainage

directly into the bowel by a pancreaticoenterostomy

(pancreatic drainage or enteric drainage (ED)). This is

usually undertaken by keeping the pancreas attached to its

duodenal segment as early attempts at external drainage

via cutaneous graft jejunostomies failed [22,23]. Another

technique involves obliterating the pancreatic duct by

intraductal administration of synthetic polymers [24].

Some centres in Europe now have up to 10 years experience

of duct occlusion techniques [25] and, although it is still

more popular in France, it has up to a 70% local

complication rate (e.g. collections or ®stulas) [26].

One of the more in¯uential developments of VPT

was the idea of anastomosis of the pancreatic graft to

the urinary tract. Gleidman et al. [27] ®rst reported a

ureteropancreatic duct anastomosis, though most of

the credit for urinary exocrine diversion should be

given to Sollinger and colleagues [28,29] who have

reported their experience of over 300 simultaneous

pancreas and kidney grafts with bladder drainage

(BD). One of the advantages of performing a duodenal

to bladder anastomosis is the earlier identi®cation of

graft rejection because the early decline in urinary

amylase can be particularly useful for commencing

treatment for acute rejection [30]. The technique used

today has been slightly modi®ed by forming the

anastomosis between a button of duodenum or by

using a short duodenal segment as a conduit between

the pancreatic graft and bladder [31].

Although both BD and ED remain popular (50% BD vs.

23% ED) [32], both are subject to complications. Urinary

RReview article 535


tract complications are a major source of morbidity after

BD, including dysuria and urinary tract infections (50%),

haematuria, strictures, bladder mucosal dysplasia and

re¯ux pancreatitis [28,33]. Other inconveniences have also

emerged including chronic metabolic acidosis, especially

during dehydration, and consequently more groups now

prefer pancreaticoduodenal grafts with ED. The largest,

most recently reported series of ED procedures, demon-

strates that with experience and re®nements in technique,

complications can be as low as 10% [34].

Immunosuppression

In the USA the favoured immunosuppression regimens

are based on quadruple therapy (cyclosporine A,

azathioprine, prednisolone) in conjunction with induc-

tion anti-lymphocyte serum (ALS) preparations. In

Europe, ALS induction is less popular as it is more

immunosuppressive than standard drugs, increasing the

risk of postoperative infections. The advantage of ALS

is that it reduces the incidence of early acute rejection,

however, it does not appear to have any in¯uence

upon overall outcome compared to kidney transplant

alone (KTA) where ALS induction is not often used.

The addition of a pancreas increases the morbidity of

postoperative infection. Acute rejection is much more

common than after KTA. After SPK, acute rejection

occurs in 50% of recipients with ALS induction and in

80% of those without [7,35]. In the recent report

from Sollinger et al. [29] of 500 VPT the overall rate

of acute rejection was 75% at 1 year compared to

47% after KTA. It is also interesting that recipients of

SPK appear to have increasing episodes of renal

rejection compared to pancreas rejection [35,36], thus

perhaps increasing the risk of renal graft loss through

chronic rejection. Nevertheless, the IPTR suggests that

patient and kidney survival after SPK are at least

equivalent to KTA in diabetic patients [4] and it is

likely that these discrepancies relate to the easier

diagnosis of acute rejection of renal allografts com-

pared to pancreas allografts (vide supra). This is

supported by the improved rates of graft survival after

SPK compared to PAK, where pancreas graft rejection

in SPK is suspected by an early rise in creatinine. This

does not occur for PAK where the pancreas and

kidney are from different donors or for PTA.

With the recent introduction of microemulsions (e.g.

Neorallq, Novartis, UK) rates of acute rejection may

be less because of their improved rates of absorption

but this has not been conclusively shown [37,38].

Results with Tacrolimus are superior to cyclosporine

with better rates of graft salvage [39] and lower rates

of acute rejection [40]. For SPK, rates of graft survival

are not different for Tacrolimus vs. cyclosporine

(» 80%) but for PAK the difference is more signi®cant

(65% vs. 84%) [41]. Nevertheless, it must be

remembered that neither drug is ideal as they are

both diabetogenic, especially Tacrolimus [42]. Any

advantage of Tacrolimus over cyclosporine has not

been con®rmed by a randomized controlled trial, yet

more centres are now using Tacrolimus as their

primary immunosuppressive drug [43] with or without

newer agents such as mycophenolate mofetil (MMF)

[12,44]. There is good evidence to indicate that MMF

can signi®cantly reduce the rate of acute allograft

rejection by 50% compared to azathioprine [45±47],

especially when used in combination with Tacrolimus

[44,48,49] but little is known of its potential long-

term side-effects. A multicentre European trial is

currently underway to assess the bene®ts of some of

these newer immunosuppressive agents.

Autoimmune recurrence

Type 1 DM is an autoimmune disease with selective

destruction of the beta cells within islets of Langerhans.

One of the biggest worries in the early days of VPT was the

recurrence of autoimmunity and subsequent diabetes in the

new transplant recipient. Although, this has not been as

problematic as anticipated, isolated cases of autoimmune

recurrence have been described. In practice the immuno-

suppression is usually suf®cient to prevent autoimmune

recurrence. Twin studies [50], indicate that if one twin

suffers with diabetes and receives a segmental pancreatic

isografts from the nondiabetic twin, immunosuppression is

still required to help prevent the rapid onset of autoimmune

reoccurrence. However, even therapeutic levels of immu-

nosuppression still cannot guarantee the absolute preven-

tion of autoimmune recurrence [51,52]. Therefore for a

twin who receives a segmental pancreas isograft there has

to be a trade-off with the risks associated with the

immunosuppression vs. the improvement in QoL through

normoglycaemia.

Recipient groups

Simultaneous pancreas and kidney (SPK) transplant

SPK is the preferred procedure in Type 1 diabetics and

uraemic patients (creatinine 300±400 mmol/l) with

proteinuria and hypertension. The advantage of SPK

is that any rejection can be treated early, based on the

preceding rise in creatinine that indicates renal

allograft rejection. This is important as any anti-

rejection treatment commenced at the time of the later

rise in blood glucose is less worthwhile.

Some would advocate that immunosuppressive regi-

mens for SPK pose no additional risk to outcome as

the patient already needs a renal allograft. However,

there is a growing awareness that SPK does carry an



appreciable excess morbidity and mortality compared

to KTA [53]. SPK seems to be associated with higher

rates of infection, acute rejection (three-fold greater

and more steroid resistant) [35,54], hospital admission,

surgical complications, and a 12% increase in malig-

nancy [55] compared to KTA [28,56,57]. A reasonable

viewpoint is that a young, ®t patient with stable

diabetes receiving a renal transplant should be offered

a pancreas simultaneously, with the proviso that they

understand the increased morbidity and mortality

associated with a SPK transplant [58].

Pancreas after kidney (PAK) transplant

In Minneapolis the favoured technique is PAK,

advocating a living related renal donation ®rst, to

correct uraemia, followed by cadaver VPT 12 months

later. This sequence maximizes the availability of

cadaver kidneys to other nondiabetic cohorts of

patient and improves the recipient's wellbeing, but its

limitation is the lower rate of pancreas graft survival.

More recently, this disadvantage is becoming less

important as graft survival rates have improved [59]

from 50% in 1987 to 70% in the 1990s. It is hoped

that with future advances in immunosuppression (e.g.

MMF or rapamycin) this still appreciable difference

will be further reduced.

Pancreas transplant alone (PTA)

A more contentious area is the role of PTA. Should a

nonuraemic diabetic patient receive a VPT [60]? In a

few American centres, including Minneapolis and

Omaha [12,61], this approach has been reserved for

those patients with very unstable diabetes or a

hypoglycaemic unawareness that is life-threatening.

Other potential indications include aggressive neuro-

pathy or early nephropathy but some would argue that

the latter indications should be treated by the safer

option of intensi®ed insulin regimens, particularly if

commenced early.

The current argument for PTA concerns the ad-

vantages of an improved quality of life (QoL) balanced

against morbidity and mortality associated with the

life-long immunosuppression and the surgical proce-

dure itself. In the 1980s this application was very

controversial but in the 1990s there have been many

improvements in VPT, perhaps making PTA a more

viable alternative for those with labile diabetes. With

this in mind the recent series (n = 225) documented

from Minneapolis [12] shows a very acceptable 1 year

graft survival of 80% with FK 506 immunosuppression

and patient survival rates of 90%. These results have

improved because of better patient selection, careful

evaluation of pre-transplant function (e.g. creatinine

clearance of at least 80 ml/min) and native renal

biopsies to establish disease severity. Yet, despite the

technical improvements, it is still questionable whether

the improvement in QoL balances the 10% risk of

death at 1 year. The 3% risk of immunosuppression-

related malignancy also needs consideration, and the

nephrotoxic effect of cyclosporin (which can be as

high as 27%), the severe myelosuppression and the

associated problems of severe infection and hyperten-

sion. There is also a theoretical increased risk of

macroangiopathy because of hyperinsulinaemia. In

summary, PTA is only appropriate in nonuraemia

patients where the problems of the diabetes itself are

perceived to be more serious than the potential

problems of immunosuppression. Currently, the evi-

dence is unconvincing, but for the diabetic patient

whose metabolic control is so fragile that their life is

chaotic, VPT may be their only hope for a tolerable

lifestyle [62].

Effect on diabetic complications

Quality of life

Evidence for VPT in reducing diabetic complications is

variable. This is arguably because of the transplanta-

tion being undertaken in those with chronic, incapa-

citating diabetic complications that may prove to be

irreversible [2]. For any useful interpretations in

outcome, it must also be remembered that SPK is

reserved for ®tter and younger patients than those

having KTA who are generally in a poorer state of

health. This makes direct comparisons more dif®cult to

interpret.

Up to 90% of VPT recipients report a healthier

lifestyle and most remain insulin-independent if rejec-

tion can be prevented [63±65]. Detailed studies of

QoL analyses [63,66] indicate that patients having SPK

transplants have a signi®cantly better QoL than those

having a KTA. One problem with the majority of

these studies are that many are retrospective and

conclusions can only be drawn for the 94% that

survive the procedure at 1 year. Nevertheless most

investigators involved in VPT state that a successful

pancreas transplant accompanied by cessation of

exogenous insulin therapy and liberalization of diet

decrease the impact and worry of diabetes with an

overall improvement in QoL [63].

Most would agree that successful VPT normalizes

glucose homeostasis in patients with Type 1 DM

[14,67±72]. VPT lowers glycosylated haemoglobin

levels to within normal limits [73], even after 10 years

[74]. In a nonrandomized prospective study Tyden

et al. [75] con®rmed these ®ndings where recipients of

SPK, compared to KTA, had improved glucose control,

RReview article 537


QoL and improved autonomic and somatic nerve

function after 10 years of follow-up. It is likely that

this bene®t is attributable to the minute by minute

variation in insulin secretion from the VPT, avoiding

the hyperglycaemic ¯uctuations observed with exogen-

ous insulin therapy [67]. In general, VPT leads to

hyperinsulinaemia with improved glucose responses

during hypoglycaemia [76], normalizes hepatic glucose

production [77], improves lipid pro®les [78] and

insulin-mediated protein kinetics [79]. However,

although VPT couples glucose sensing with insulin

secretion, hypoglycaemia is not completely avoided.

There are reports of patients with recurrent hypogly-

caemia having improved counter-regulatory responses

after VPT [80] but the evidence is con¯icting [81].

More recent studies suggest that compared to exogen-

ous insulin treatment in Type 1 DM, VPT improves

but cannot completely eliminate hypoglycaemia

[82,83].

Retinopathy

Patients who have had successful kidney±pancreas trans-

plants, when compared to those whose grafts have been

rejected, gain no additional bene®t in terms of improve-

ment in retinopathy, despite their euglycaemic status [84].

There have been some reports of an amelioration of

retinopathy but these studies have been poorly controlled

[67]. Any lack of improvement is probably due to late

restoration of beta cell function when the proliferative

changes of retinopathy are already too far advanced.

Furthermore, it is dif®cult to demonstrate any differences

between pancreas/kidney vs. KTA. Similar observations

have occurred in studies claiming no discernible improve-

ment of diabetic retinopathy after SPK [85], where

retinopathy bene®ts by correction of uraemia alone. These

disconcerting ®ndings have been substantiated by others

[86±88]. In contrast, Wang et al. [89], comparing several

parameters of diabetic retinopathy documented regression

in 43% of SPK recipients, compared with 23% with KTA.

However, 50% of both groups gained no bene®t but only

7% of the SPK recipients deteriorated, as opposed to 27%

after KTA who had progressive disease. Between 20 and

35% of patients who have proliferative changes of

retinopathy at the time of VPT will paradoxically show a

deterioration of retinopathy [84,90] despite normoglycae-

mia.

In conclusion, these data suggest that retinopathy

does not necessarily bene®t from VPT. In the short

term, retinopathy may even deteriorate but after

3 years of normoglycaemia the bene®ts begin to appear

[84]. It must also be kept in mind that most recipients

of a sole pancreatic graft have advanced retinal disease

previously treated by photocoagulation which is

known to stabilize disease progression, thus confound-

ing any advantage in those having had such a

procedure [91]. As photocoagulation has become an

established treatment for retinopathy, VPT should not

be offered as a substitute [62].

Nephropathy

Current immunosuppressive regimens that prevent allo-

graft rejection are nephrotoxic; because of this, renal

function can deteriorate more rapidly after solitary PTA

[92] than in diabetic patients with overt nephropathy

treated with insulin. The decline in creatinine clearance is

approximately three-fold faster [92,93]. Moreover, VPT

was previously thought to be unable to reverse residual

renal disease [62]. This assumption is commensurate with

studies where patients with established glomerular lesions

within native kidneys, receiving a successful VPT, have

failed to show any amelioration of nephropathy after

5 years of normoglycaemia [94]. Nonetheless long-term

follow-up, now at 10 years, does show some indication

that VPT can reverse established lesions of diabetic

nephropathy in native kidneys. The Stockholm Group

with 8 years of follow-up also demonstrated a signi®cant

difference in basement membrane thickness in SPK

transplants as opposed to KTA.

The overall conclusions from these studies suggest

that VPT, with subsequent normalization of blood

glucose, can prevent and reduce the progression of the

earliest signs of diabetic nephropathy in kidney

allografts [62]. With respect to VPT after renal

allotransplantation, a prospective trial has demon-

strated less glomerular hypertrophy and mesangial

proliferation when kidney recipients were given an

additional pancreatic graft [95]. This suggests that

VPT is advantageous in patients with an established

renal allograft and can reverse established lesions in

native kidneys in those having PTA, providing that the

patients life-expectancy is considered to be beyond

10 years [96]. However, many diabetic patients receiv-

ing KTA fail to develop any further lesions in the ®rst

6±14 years after correction of uraemia and in those

that do severe renal impairment is still unlikely after

10 years [97].

Neuropathy

There have been several studies that have demonstrated

subtle bene®ts for patients with neuropathy after kidney±

pancreas transplants when compared to those patients

with failed grafts or those who had no transplant [98,99].

There have been reports of milder peripheral neuropathy,

paraesthesia [85,100,101], autonomic neuropathy [102]

and slightly better sensory amplitudes [103,104]. Improve-

ment is relatively mild but can reduce the risk of death if

patients have dysautonomia, particularly with abnormal



cardiovascular re¯exes [99]. Although, the duration of

follow-up in some of these studies was short, bene®t was

detectable after only 2 years. However, as similar results

can be demonstrated after KTA, it would be dif®cult to

ascertain whether the improvement was due to the

correction of the diabetes or the uraemia. A recent

prospective study does not support these ®ndings and

showed less improvement in patients in an advanced stage

of diabetic polyneuropathy [105] after a SPK, but it is

plausible that the results may have been better if the

polyneuropathy had been less advanced.

Atherogenic risks

To date there have been no controlled trials evaluating

the effect of VPT upon the multisystemic macrovas-

cular complications of diabetes. Only those relevant to

lipid pro®les have been reported. Those patients

receiving a whole pancreas, in contrast to those

receiving a segment, have a near-normalization of

lipid and lipoprotein pro®les [14]. Nevertheless, very

low density lipoproteins (LDL), high density lipopro-

teins, and the triglyceride content of LDL are still

higher than in healthy subjects [106]. This may be

exacerbated by the relative peripheral hyperinsulinae-

mia caused by the vascular reconstruction [16].

Recipients are therefore unlikely to have any regression

of atheroma owing to their atherogenic pro®les.

Morbidity and mortality

It cannot be denied that the technical failure rate of

VPT is high in inexperienced hands. For cases

performed in Europe there is an 18% technical failure

rate in contrast to 12% for those performed in

America. Figures range between 11 and 39% for all

variations of pancreatic transplantation (SPK, PTA,

and PAK) performed throughout the world. Patient

survival rates at 1 year for SPK allografts (1994±1997)

are now 94% with 82% insulin-independent, this

compares to 90% and 74%, respectively, during the

1987±1989 era. At 5 years, the actuarial function rate

is 65% [41,107]. Nonetheless Manske et al. [53] report

increasing mortality after 3 years for SPK (68%)

compared to KTA (90%).

The propensity to lose grafts from rejection is more

frequent after PTA than SPK and generally, grafts with BD

are currently preferred in some centres because of the better

patient survival rates. Some groups would dispute this,

preferring ED to BD [34,108,109] because of the higher

rates of urological complications and enzyme leaks in the

latter and the need to convert up to 25% to ED

[29,110,111].

In a recent series of 200 cases of VPT with BD reported

by Sollinger et al. [28], patients receiving a SPK transplant

had a 90% re-admission rate (77% within 6 months), 85%

rejection rate, 84% infection rate and a 27% re-operation

rate. Mortality rates vary between centres but Stratta [8]

reports an overall 12% mortality rate in a series of 196

patients; overwhelming infection and cardiac-related

deaths appearing to be the most common cause of

mortality in the early postoperative period. Late graft loss

can be attributable to chronic graft rejection in 38% of SPK

transplants [112]. Despite this, SPK transplants fare better

than PTA where there may be graft failure in up to 69% at 1

year [41,107]. Nevertheless, results of solitary pancreas

transplants (PTA and PAK) are now approaching that of

other solid organs, largely owing to the introduction of

Tacrolimus [59].

Recent reports from participating centres in the UK and

Ireland are also encouraging. The largest series is reported

by the Liverpool group (n = 40; 35 segmental, 5 total), with

5 year graft and patient survival rates of 78% and 93%,

respectively [113]. A series from St Mary's, London [114]

(n = 34) has reported a 77% pancreas survival rate at 1 year

(SPK) but 63% for PTA at 6 month follow-up. More

importantly, in this series, 20% had a vascular graft

thrombosis, two required enteric conversion and there was

a 60% acute rejection rate, emphasizing the technical

dif®culties of the procedure. Two smaller series have been

reported from Cardiff [115] (SPK n = 10, PAK n = 7) and

Dublin [116] (SPK n = 23, PAK n = 2) where graft survival

rates are 63% at 1 year and 88% at 2 years, respectively. In

the Cardiff series, 58% developed a surgical complication.

Some would argue that perhaps centres in the UK with a

small KTA program should not perform SPK transplants

because of the risk of high morbidity and mortality rates

[2]. With this in mind, a recent analysis from the IPTR has

compared the results of centres in the USA performing 20

or more VPT annually vs. those performing < 19. Although

both patient (91% vs. 87%) and pancreas (78% vs. 67%)

survival rates at 1 year were signi®cantly better in high

volume centres compared to those with limited experience,

the difference was small. It is widely accepted that there is a

learning curve for VPT [2,58], but with the BD technique

good results can be obtained even in small centres.

However, it is vital that centres with limited experience

appreciate the extra risks involved with PTA in nonur-

aemic patients, suggesting that these patients should be left

to the high volume centres with greater expertise.

Cost

There are no reports emphasizing the cost of a VPT

program in the UK but much can be gained from the

experience in the USA. VPT is covered by a number of

insurance companies in the USA. The bene®ts of VPT must

be weighed against the cost. For uraemic diabetic patients

having SPK, the additional cost of a pancreas is US$40 000

($16 000 for the organ retrieval and $24 000 for post-

RReview article 539


operative care). For PTA the average total cost is $65 000

[51]. On balance a VPT is certainly more expensive than

exogenous insulin but patients would probably say that it is

worth the expense for the improved QoL, even after PTA

with the addition of the immunosuppressive risks.

Conclusion

In conclusion, VPT offers an attractive alternative to

exogenous insulin therapy for those patients with Type 1

DM, who need or already have a renal allograft. The IPTR

clearly shows that VPT is a reasonably safe procedure with

patient survival in the region of 90% in experienced

centres, and 82% are insulin-independent at 1 year

[28,107]. Similarly, it cannot be denied that long-term

metabolic control is impressive [117]. In patients under-

going SPK the decision they have to take is between the

increased surgical risks of VPT and immunosuppression vs.

the bene®ts of improved QoL. Finally, there is at present no

justi®cation for PTA other than in patients with extremely

labile diabetes that is in itself life-threatening or incapaci-

tating.

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Vascularized pancreas allotransplantation – clinical indications and outcome