Long-term outcome of pancreas transplantation

Long-Term Outcome of Pancreas Transplantation W.O. Bechstein

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ONG-TERM CONTROL of glucose metabolism has only been achieved by pancreas transplantation (Ptx). PTx can reverse the morphological and functional changes of diabetic nephropathy.1 The vast majority of PTx, however, are performed as simultaneous pancreas-kidney transplantations (SPK) or pancreas-after-kidney transplantation (PAK), pancreas transplantation alone (PTA) is an exception. Thus, candidates for PTx usually present with late complications of diabetes mellitus (DM). When assessing the long-term outcome after pancreas transplantation a number of different aspects need to be considered: ● the long-term prognosis of Ptx with regard to graft and patient survival, ● the influence of PTx on late complications of diabetes, ● the long-term prognosis of PTx according to surgical technique, and ● the long-term adverse effects of immunosuppression including risk of de novo malignancy. In our own limited experience with the first 100 pancreas transplant (SPK n ⫽ 99, PAK n ⫽ 1) performed between 1995 and July 2000, actuarial patient survival at 1, 3, and 5 years was estimated at 97%. Pancreas graft survival measured as freedom from exogenous insulin therapy at 1, 3, and 5 years was 93%, 88%, and 85% (Fig 1). Due to short follow-up, results such as these are likely to be overestimated. Nevertheless, recent registry data have also consistently shown 1-year patient survival exceeding 90% and pancreas graft survival at 1 year exceeding 80%. Moreover,

Tyden et al reported in a recent single-center analysis from Huddinge, Sweden that already after 6 years, a significantly improved patient survival of a group of diabetic recipients after SPK was observed when compared to a group of diabetic recipients who received a kidney only or who lost their pancreatic graft but had a functioning kidney graft.2 In a retrospective study from the Netherlands, Smets et al compared two cohorts of diabetic patients with end-stage renal disease (ESDR)—a cohort of 56 patients treated in the Leiden area with a cohort of 158 patients treated in the rest of the Netherlands. The Leiden cohort was treated preferentially with SPK while the non-Leiden cohort received preferentially a kidney transplant alone (KTA). At 10 years, a significantly improved survival for the Leiden cohort could be observed.3 Thus SPK may be considered a life-saving procedure. Does Ptx alter the natural course of late complications of DM in recipients whose diabetes has already led to ESDR? Or have these complications progressed to a point of no From the Department of Surgery, Charite´, Campus VirchowKlinikum, Humboldt University, Berlin, Germany. Supported by an unrestricted grant from Fujisawa GmbH, Germany. Address reprint requests to Professor W.O. Bechstein, Department of Surgery, Ruhr University Bochum, Knappschaftskrankenhaus Bochum—Langendreer, In der Schornau 23-25, 44892 Bochum, Germany.

Fig 1. Survival after pancreas transplantation, Charite´, Campus Virchow, Berlin (1995 to July 2000).

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Transplantation Proceedings, 33, 1652–1654 (2001)

LONG-TERM OUTCOME

return where even optimal blood glucose control provided by a pancreas transplant does not prevent further progression? The most important manifestations of late complications such as macro- and microangiopathy, retinopathy, nephropathy, and neuropathy including autonomic neuropathy have to assessed separately. Furthermore, there is no uniform reporting of late complications after PTx, which makes comparison of different studies difficult. Clinically relevant end points of late complications of DM would seem to be the incidences of myocardial infarction, stroke, and limb amputation for macroangiopathy; the progression to complete blindness for diabetic retinopathy (DR); the development of microalbuminuria as early sign of nephropathy; and 24-hour heart rate variability and gastrointestinal transit time as measurements of autonomic neuropathy. The influence of optimal blood glucose control on the renal graft is difficult to assess after SPK. Renal graft dysfunction may be caused by rejection, both acute and chronic, nonallogeneic causes (such as donor age, brain death induced changes, or ischemia/reperfusion damage), or drug-induced nephrotoxicity (often associated with use of calcineurin inhibitors). Whatever the reasons, kidney graft survival after SPK seems to be improved compared to KTA in diabetic recipients. Does combined kidney-pancreas transplantation (KPT) alter the prognosis of peripheral vascular disease? Morrissey et al from Boston compared a group of 39 KPT recipients with 65 KTA diabetic recipients with at least 6 months graft function who had received their grafts between 1988 and 1995. Prior to the transplant a comparable number of peripheral vascular complications (PVC) was recorded. PVCs were classified as limb amputations (AMP), ulcers defined as any ischemic ulcer requiring treatment, and lower extremity bypass procedures (LEBP) consisting either of peripheral vascular bypass surgery or angioplasty. After transplantation new PVCs were observed in 18/39 KPT recipients (46%) and consisted of 9 AMP, 11 ulcers, and 15 LEBP. Surprisingly only 20/65 KTA recipients (31%) developed new PVCs including 10 AMP, 8 ulcers, and 14 LEBP even though this group had a higher incidence of concomitant atherogenic risk factors.4 DR may ultimately lead to complete blindness and is thus a particularly disabilitating late complication of DM. The further development of DR after pancreas transplantation is difficult to predict. Improvement has been reported in 14% to 32% of cases; most patients showed a stabilized course of DR (46% to 75%), while in 10% to 22% of cases eyesight worsened despite a functioning pancreas graft.5–7 In the most recent of these studies, Chow et al closely followed 46 patients with successful SPK and compared them to eight patients with failed PTx but functioning KTx. The initial status of 108 eyes at the time of SKP was complete blindness in 10 eyes, while 79% of eyes had advanced DR with the previous need for panretinal laser therapy. Mean duration of diabetes was 25 ⫾ 7 years. After SPK 432 ophthalmological examinations were carried out with a follow-up of up to 10 years. DR remained stable in

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75% of eyes in both groups. In the SPK group 14% nonblind eyes improved, 76% remained stable, while 10% showed progression of DR. Cataract increased after Tx in both groups.5 Improvements in autonomic neuropathy and gastric function were reported several years ago by the Memphis group. Hathaway et al compared a cohort of 23 KPT recipients with 10 KTA, uremic type 1 diabetics. A broad range of parameters of neuropathy was investigated including vasomotor function (total capillary pulse amplitude, capillary vasoconstriction response to cold, capillary response to postural adjustments), cardiac function (R-R interval variation, Valsalva ratio), and gastric function (cutaneos electrogastrography, gastric emptying, total GI symptoms score). KPT recipients showed significant improvements at 1 year in postural adjustment score, Valsalva ratio, electrogastrography, and total symptom score.8 The recovery of diabetic neuropathy was also demonstrated by the Sydney group. Allen et al reported results of 219 electrophysiological studies in 44 patients up to 8 years following SPK. The control group consisted of 35 studies in nine diabetic recipients with a functioning kidney graft. A gradual, sustained improvement of nerve action potential amplitudes was observed after SPK: recovery of neuropathy was negatively affected by obesity, pre-TX dialysis, and poor kidney graft function.9 From these results it would follow that SPK should be performed before the need for dialysis with the aim of optimal kidney graft function to achieve the best possible recovery of neuropathy. Not only DM but also uremia leads to autonomic neuropathy. Cashion et al from the Memphis group carried out 24-hour Holter monitoring pre-Tx, at 6 months, and at 12 months in 90 nondiabetic KT and 30 diabetic KPT during the same time period. Both KT and KPT recipients showed improvement in indices of heart-rate variability over time; however, KPT recipients had significantly poorer values at each time point compared to KT. Thus, cardiac autonomic neuropathy occurs both in ESRD and as a late complication of DM.10 Is the long term-prognosis after PTx related to surgical technique? This question has been addressed in a multitude of single-center analyses. One of the pioneer groups of pancreas transplantation, the group of Dubernard in Lyon, reported their experience over time with different surgical techniques. The respective 3-year survival rates for the PTx graft were 47% for segmental grafts with duct obstruction, 60% for whole grafts with bladder drainage (BD), and 65% for whole grafts with enteric drainage (ED). It was concluded that grafting of the whole pancreas with enteric drainage yields the best results and should be the preferred technique.11 However, studies such as these reflect not only advances in surgical technique and personal experience but also other advances in fields such as organ preservation, infectious disease management, and immunosuppression. Whole organ transplantation is certainly the preferred approach today; on the other hand, the debate about the best technique of exocrine drainage does not seem to be closed. United States registry data show equivalent 1-year

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pancreatic graft survival rates exceeding 80% for enteric and bladder drainage alike for the PTx performed during the period from 1994 until 1998, yet ⬎70% of PTx performed during that time were carried out with BD. Technical Tx graft loss was recorded significantly more often due to anastomotic leaks and bleeding in the group of PTx with ED compared to BD. Overall, technical graft loss was recorded in 8% of 2352 BD cases compared to 11% of 908 ED cases. This difference reached statistical significance with P ⫽ .0338%.12 Despite the apparent technical ease and safety of BD in PTx, long-term problems with haemorrhagic cystitis, urethritis, balanitis in males, dehydration, bicarbonate loss, and recurrent urinary tract infections are responsible for later conversion to enteral drainage of exocrine pancreatic secretions. The cumulative incidence of conversion to enteric drainage after PTx with primary bladder drainage has been reported between 18.7% to 32.1%.13–15 Another area of controversy with regard to surgical technique and in view of long-term results concerns the best management of endocrine secretion, ie, the anastomosis of the venous outflow of the graft. The theoretical advantage of the more physiologic portal-venous (PV) drainage over the long-established systemic venous (SV) drainage remains to be empirically demonstrated. In a recently published randomized study, Martin et al from Lyon compared 16 PTx recipients with PV with 14 PTx recipients with SV. Exocrine drainage was ED in all cases. One-year patient survival was 96% vs 92%, and 1-year PTx graft survival was 82% vs 78%. After 1 year no significant differences with regard to fasting glucose, fasting insulin, oGTT, HbA1c, cholesterol, or triglycerides could be detected.16 Thus, the controversies over the best surgical technique for whole organ PTx are not yet resolved. With regard to the effects of PTX on long-term complications of DM, the following conclusions are currently supported by sound data: ● KPT in uremic diabetic recipients is a live-saving procedure compared to KTA. ● Autonomic neuropathy is improved after KPT. ● Diabetic retinopathy is rarely improved.

BECHSTEIN

Peripheral vascular complications may occur more often after KPT compared to KTA. Current challenges for the immediate future are long-term adverse effects of immunosuppression including risk of de novo malignancy. Nevertheless, today KPT is the preferred treatment for type 1 diabetics with ESRD. ●

ACKNOWLEDGMENTS The help of Igor Sauer, MD, and Michael Heppler-Benscheidt with data analysis is gratefully acknowledged.

REFERENCES 1. Fioretto P, Steffes MW, Sutherland DE, et al: New Engl J Med 339:69, 1998 2. Tyden G, Bolinder J, Solders G, et al: Transplantation 67:645, 1999 3. Smets YFC, Westendorp RG, van der Pijl JW, et al: Lancet 353:1915, 1999 4. Morrissey PE, Shaffer D, Monaco AP, et al: Arch Surg 132:358, 1997 5. Chow VC, Pai RP, Chapman JR, et al: Clin Transplant 13:356, 1999 6. Sosna T, Saudek F, Dominek Z: Acta Univ Palacki Olomuc Fac Med 141:75, 1998 7. Ulbig M, Kampik A, Thurau S, et al: Graefes Arch Clin Exp Opthalm 229:242, 1991 8. Hathaway DK, Abell T, Cardoso S, et al: Transplantation 57:816, 1994 9. Allen RD, Al-Harbi IS, Morris JG, et al: Transplantation 63:830, 1997 10. Cashion AK, Hathaway DK, Milstead EJ, et al: Transplantation 68:1846, 1999 11. Feitosa-Tajra LC, Dawhara M, Benchaib M, et al: Transplant Int 11:295, 1998 12. IPTR/Unos data quoted from http://www.insulin-free.org/. 13. Bloom RP, Olivares M, Rehman L, et al: Transplantation 64:1689, 1997 14. Sollinger HW, Odonco JS, Kinchette SJ, et al: Ann Surg 228:284, 1998 15. Kaplan AJ, Valente JF, First MR, et al: World J Surg 22:890, 1998 16. Martin X, Petruzzo P, Dawahra M, et al: Transplant Int 64:13, 2000