Successful pancreas transplantation has been demonstrated to be efficacious in significantly improving the quality of life of people with diabetes, primarily by eliminating the need for exogenous insulin, frequent daily blood glucose measurements, and many of the dietary restrictions imposed by this disorder . It is recommended by the American Diabetes Association that pancreas transplantation should be considered an acceptable therapeutic alternative to continued insulin therapy in diabetic patients with imminent or established end stage renal disease, who have had or plan to have a kidney transplant . Successful addition of a pancreas does not put the patient at additional risk concerning patient survival, and may even improve kidney survival. On the contrary, the usefulness of pancreas transplantation in type 1 diabetic patients without advanced nephropathy is more debated [3▪,4▪▪]. Such patients have not only to meet the medical indications and criteria for kidney transplantation but importantly exclusion of excessive surgical risk is a prerequisite to qualify for the dual transplant procedure. In the absence of indications for kidney transplantation, pancreas transplantation should be only considered a therapy option in patients who exhibit following criteria: a history of frequent, acute and severe metabolic complications (hypoglycemia, hyperglycemia, ketoacidosis) requiring medical attention; in addition, clinical and emotional problems with exogenous insulin therapy, and finally consistent failure of insulin-based management to prevent acute complications . In some instances, advanced diabetic retinopathy has been considered as an indication for pancreas transplantation .
Diabetic patients undergoing dialysis have a mean survival of 8 years, whereas the mean survival of diabetic patients who receive a kidney transplant increases to 22 years [6,7]. Similarly, those diabetic patients who are eligible for a simultaneous kidney and pancreas transplant ((SPK) likely a slightly healthier population due to acceptance criteria) but remain on dialysis have an estimated mortality of 40% at 4 years, whereas those who receive SPK transplants have a mortality of 10% . The timing of kidney transplantation is also a critical determinant to outcomes. If performed before the need of dialysis (preemptive transplant), kidney transplantation results in a 43% reduction in risk of death compared with transplantation after the onset of dialysis. Pre-emptive kidney transplants from a deceased donor are associated with a 12% reduction in risk of death . Given these dramatic differences in outcomes, patients with DM1 and estimated glomerular filtration rate (GFR) of 30 ml/min per m2 should be referred to a transplant center for pretransplant evaluation and counseling regarding potential transplant options.
However, differently from heart, lung and liver transplantation, pancreas transplantation cannot be considered a life-saving procedure and advantages in the long term should be carefully considered and balanced with morbidity and mortality associated with the surgical procedure itself as well as side-effects of immunosuppression .
Simultaneous pancreas–kidney transplantation is probably the best option for most candidates needing a pancreas transplant. Due to a world-wide shortage of deceased donors, however, living-kidney donation should be encouraged for all end-stage renal disease patients irrespective of the need for a pancreas. When the waiting time for SPK is long, a preemptive kidney transplant from a living donor should be followed by a pancreas transplant from a deceased donor to avoid the high risk of mortality and the need for dialysis . However, SPK is the most cost-effective option .
EVALUATION BEFORE TRANSPLANTATION
The pretransplant evaluation determines whether a patient is an appropriate candidate for transplantation. Contraindications for pancreas transplantation include the general contraindications for any transplantation which comprises the presence of a recent malignancy, morbid obesity (BMI > 40), psychiatric disease, active alcoholism and/or drug dependency, and of course most importantly severe cardiovascular disease, which is also stated by the European Renal Best Practice Guidelines . The nature of the complications of type1 diabetes gives a straightforward regimen for risk evaluation. This includes mainly complications related to macrovascular disease including coronary artery disease, peripheral vascular disease and stroke.
Evaluation of cardiovascular risk
It is well known that the burden of cardiovascular risk is disproportionably high in patients with advanced chronic kidney disease (CKD) and end stage renal disease (ESRD) compared with the general population . Especially in patients with diabetes, the major causes of death relate to cardiovascular events – predominantly myocardial infarction and cerebrovascular events . Approximately 40% of ESRD patients have angiographic evidence of significant coronary artery stenosis (>70%) and thus have increased risk of acute myocardial infarction and death . Accordingly, eligibility protocols for SPK focus on the preoperative cardiovascular assessment to select patients who might maximally benefit from transplantation. Various management algorithms have been suggested to optimize investigations, for example, coronary angiography for those older than 45 years because the probability of coronary artery disease is high ; or all candidates older than 30 years or those with the disease for more than 20 years should undergo stress testing, and in those not able to perform those test adequately, coronary angiography . It would therefore seem logical that careful cardiac screening before transplantation would improve survival after transplantation. But this is still a subject of debate as shown by a recent article of Patel et al.. The authors challenged in their study the premise that cardiovascular testing before renal transplantation improves cardiovascular mortality outcome after transplantation . Their study noted a similar risk for cardiovascular complications after transplantation despite cardiovascular testing and interventions in high-risk patients before transplantation was performed. A recent study even proposed a randomized controlled trial on patients on the waiting list for a kidney transplant [17▪▪]. Nevertheless, intense cardiovascular evaluation in the diabetic population is considered mandatory before transplantation , and in our opinion, coronary angiography is necessary in most of the transplant candidates.
Impairment of left ventricular function is frequent in patients with type 1 diabetes in the absence of ischemia, hypertension, or valvular heart disease (reviewed in ). Possible mechanisms for diabetic cardiomyopathy include abnormalities of small intramural coronary vessels, deposition of collagen, and lipid and metabolic derangements. Therefore, we would suggest performing the cornerstones of cardiac evaluation including ECG, echocardiography and coronary angiography. The latter has the best predictive value, at least in renal transplant patients for cardiac events . Furthermore, in the presence of diabetes, coronary angiography is recommended in the presence of more than one of the following risk factors: age greater than 45 years, nicotine abuse, dyslipidemia, hypertension, history of cerebrovascular or peripheral vascular disease . The exception of the rule for not performing coronary angiography in diabetic patients would be a coronary computed tomography (CT) with electron beam CT scan showing no sign of coronary calcification (Agatson Score <100) .
Signs of peripheral arterial occlusive disease that may reflect compromised arterial inflow into the graft require pretransplant vascular evaluation, such as CT angiography, magnetic resonance angiography (if not dialysis-dependent) or even intraarterial angiography . In all patients, a thoroughly evaluation of the peripheral vessels and carotid arteries with ultrasound is mandatory.
Common pretransplant patient evaluation like in other solid organ transplant programs comprises gastrointestinal, urological and gynecological, metabolic, neurological, ophthalmological, dermatological, pulmonary and psychiatric evaluations. Together with the above extensively described pretransplant evaluation all examinations are summarized as follows:
3. coronary angiography,
4. peripheral vascular status and imaging oft eh peripheral vessels,
5. carotis duplex sonography,
6. chest radiograph,
7. abdomen sonography,
8. renal sonography,
9. mammography (> 40a),
11. stool sample on occult blood,
12. coloscopy (> 50a),
13. urological council,
14. gynaecological council including cervical swab,
15. dermatological council,
16. ophthalmological council,
17. council of a ear, nose and through specialist,
18. dentist's council,
a. dental panorama X-ray
In addition, several special issues on the influence of other conditions as described above are added:
Age is not a contraindication for pancreas transplantation based on the prerequisite that the patient is healthy enough to survive surgery [4▪▪]. Improvements in the physician's armamentarium to reduce the development of diabetic complications have led to the emergence of a healthier aging population of type 1 diabetics in need of pancreas transplantation [22,23]. Progress in surgical techniques, critical care, and immunosuppressive medications has also expanded the pool of transplant candidates to include a significant proportion of patients over the age of 50 years . Pancreas transplantation has the highest morbidity of all routinely performed abdominal solid organ transplantation procedures [23,25]. Thus, weighing the risk of pancreas transplantation procedure against the benefit of insulin independence has been debatable [26,27].
The mean age of pancreas transplant recipients continues to increase; however data on older pancreas transplant recipients remains limited. Salvalaggio et al. demonstrated a lower mortality in patients receiving pancreas transplants, regardless of age, than those remaining on the waiting list, even with older (45 years or older) donors. Many institutions have placed age limitations on potential pancreas transplant recipients, considering age a risk factor for inferior outcome. In one study patients 50 years of age or older had a higher incidence of graft thrombosis and bleeding requiring re-exploration, as well as higher incidence of pulmonary infections . Other studies have shown a lower patient survival for older patients (45 years or older) undergoing pancreas transplantation [29,30]. Additionally, Gruessner and Sutherland found that patients older than 45 years of age had lower graft survival; however, immunological graft loss decreased with increasing age [29,30]. The rejection rate is lower in older than in younger recipients , but those older than 50 years have an increased rate of postoperative complications that should be taken into account when the benefits and risks are assessed . Interestingly, recent data from New York compared pancreas recipients older than 50 years of age with younger and found comparable major and minor surgical complications. The older group had a lower 1-year and overall acute rejection rate. The incidence of nonsurgical infections and overall-patient survival was similar between the groups. The authors concluded that older patients with type 1 diabetes are feasible suitable candidates for pancreas transplantation .
Overweight and Obesity
The prevalence of overweight (BMI 25–29.9 kg/m2) and obesity (BMI>30 kg/m2) has increased in dialysis patients and kidney transplant candidates with 60% overweight or obesity at the time of transplantation in the USA in 2001 . In kidney transplantation the majority of studies showed inferior outcome for obese patients in kidney transplant alone [34–36]. Data on impact of obesity on SPK transplant outcome are limited and most of them derived from single center analyses. Obesity was associated with increased posttransplant complications in two of four studies [37–40], but in only one of the studies obesity was associated with worse survival outcome . In a recent investigation from the OPTN/UNOS database, Sampaio et al. identified 33 and 11% in a cohort of 5725 pancreas recipients to be overweight or obese, respectively. Obese recipients were older, and had more severe coronary disease. Overall posttransplant complications were higher in the obese group when compared with the normal BMI group. Complications comprised delayed kidney graft function, episodes of acute rejection within the first posttransplant year and vascular thrombosis of the pancreatic graft. Obesity was associated with patient death and kidney graft loss after 3 years. The higher rates of death and graft failure in the first 30 days posttransplant mostly accounted for the 3-year survival differences . The authors concluded that obesity in SPK recipients is associated with increased risk of posttransplant complications, pancreas and kidney graft loss, and patient death.
Should SPK in obese candidates be avoided? The benefits of kidney transplantation in diabetics are well defined . Studies have shown that despite the higher risk of death in the first 90 days after SPK, along the further posttransplant course an increased survival was seen in SPK recipients compared with patients who remained on the waiting list [7,42]. Similar respective outcome data for obese patients after SPK do not exist. However, in obese ESRD patients (excluding BMI >41 kg/m2) waitlisted for a kidney transplant, a significant lower mortality was seen when they were transplanted compared with those who remained on the list . In this context data for SPK are needed .
Preoperative risk evaluation procedures in recipients of a pancreatic graft do not differ greatly compared with kidney transplant recipients only. Because of the nature of the underlying disease, namely type I diabetes, the patients are at an extremely high risk for cardiovascular disease. Therefore, intensive cardiovascular risk stratification and evaluation is mandatory in those cohorts of patients. Recent discussion on the necessity of extensive cardiovascular evaluation as well as pretransplant evaluation of tumor risk (e.g., prostate cancer) in the general population does not influence procedures in most transplant centers, so far. In any case, an extensive education of the patients and its relatives is necessary before the patient is accepted for the transplant list. Future studies should be undertaken to evaluate the effectiveness of pretransplant evaluation in pancreas transplant recipients.
Conflicts of interest
Disclosure information: there are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 125).
1. Fioretto P, Steffes MW, Sutherland DE, et al. Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med 1998; 339:69–75.
2. Robertson RP, Davis C, Larsen J, et al. Pancreas and islet transplantation in type 1 diabetes. Diabetes Care 2006; 29:935.
3▪. Gruessner AC, Sutherland DE, Gruessner RW. Pancreas transplantation in the United States: a review. Curr Opin Organ Transplant 2010; 15:93–101.
Overview on the current status of pancreas transplantation in the USA.
4▪▪. White SA, Shaw JA, Sutherland DE. Pancreas transplantation. Lancet 2009; 373:1808–1817.
Extensive overview on the issue of pancreas transplantation including surgical aspects as well as the issue of immunosuppression and patient eligibility.
5. Giannarelli R, Coppelli A, Sartini MS, et al. Pancreas transplant alone has beneficial effects on retinopathy in type 1 diabetic patients. Diabetologia 2006; 49:2977–2982.
6. Wolfe RA, Ashby VB, Milford EL, et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 1999; 341:1725–1730.
7. Gruessner RW, Sutherland DE, Gruessner AC. Mortality assessment for pancreas transplants. Am J Transplant 2004; 4:2018–2026.
8. Becker BN, Rush SH, Dykstra DM, et al. Preemptive transplantation for patients with diabetes-related kidney disease. Arch Intern Med 2006; 166:44–48.
9. Wiseman AC. Simultaneous pancreas kidney transplantation: a critical appraisal of the risks and benefits compared with other treatment alternatives. Adv Chronic Kidney Dis 2009; 16:278–287.
10. Douzdjian V, Escobar F, Kupin WL, et al. Cost-utility analysis of living-donor kidney transplantation followed by pancreas transplantation versus simultaneous pancreas-kidney transplantation. Clin Transplant 1999; 13:51–58.
11. Transplantation EEGoR. European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV.5.1. Cardiovascular risks. Cardiovascular disease after renal transplantation. Nephrol Dial Transplant 2002; 17 (Suppl 4):24–25.
12. Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004; 351:1296–1305.
13. Diabetes mellitus: a major risk factor for cardiovascular disease. A joint editorial statement by the American Diabetes Association; The National Heart, Lung, and Blood Institute; The Juvenile Diabetes Foundation International; The National Institute of Diabetes and Digestive and Kidney Diseases; and The American Heart Association. Circulation 1999, 100:1132–1133.
14. Collins AJ, Li S, Ma JZ, Herzog C. Cardiovascular disease in end-stage renal disease patients. Am J Kidney Dis 2001; 38:S26–29.
15. Manske CL, Thomas W, Wang Y, Wilson RF. Screening diabetic transplant candidates for coronary artery disease: identification of a low risk subgroup. Kidney Int 1993; 44:617–621.
16. Patel RK, Mark PB, Johnston N, et al. Prognostic value of cardiovascular screening in potential renal transplant recipients: a single-center prospective observational study. Am J Transplant 2008; 8:1673–1683.
17▪▪. Kasiske BL, Israni AK, Snyder JJ, et al. Design considerations and feasibility for a clinical trial to examine coronary screening before kidney transplantation (COST). Am J Kidney Dis 2011; 57:908–916.
This study nicely discusses that invasive coronary screening before transplantation is still on debate and proposes a randomized controlled trial.
18. Zaman F, Abreo KD, Levine S, et al. Pancreatic transplantation: evaluation and management. J Intensive Care Med 2004; 19:127–139.
19. De Lima JJ, Sabbaga E, Vieira ML, et al. Coronary angiography is the best predictor of events in renal transplant candidates compared with noninvasive testing. Hypertension 2003; 42:263–268.
20. Kasiske BL, Malik MA, Herzog CA. Risk-stratified screening for ischemic heart disease in kidney transplant candidates. Transplantation 2005; 80:815–820.
21. Sharples EJ, Pereira D, Summers S, et al. Coronary artery calcification measured with electron-beam computerized tomography correlates poorly with coronary artery angiography in dialysis patients. Am J Kidney Dis 2004; 43:313–319.
22. Hovind P, Tarnow L, Rossing K, et al. Decreasing incidence of severe diabetic microangiopathy in type 1 diabetes. Diabetes Care 2003; 26:1258–1264.
23. Schenker P, Vonend O, Kruger B, et al. Long-term results of pancreas transplantation in patients older than 50 years. Transpl Int 2011; 24:136–142.
24. Gruessner AC, Sutherland DE. Pancreas transplant outcomes for United States (US) cases as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR). Clin Transpl 2005; 19:433–455.
25. Humar A, Kandaswamy R, Granger D, et al. Decreased surgical risks of pancreas transplantation in the modern era. Ann Surg 2000; 231:269–275.
26. Ablorsu E, Ghazanfar A, Mehra S, et al. Outcome of pancreas transplantation in recipients older than 50 years: a single-centre experience. Transplantation 2008; 86:1511–1514.
27. Sinclair AJ, Alexander CM, Davies MJ, et al. Factors associated with initiation of antihyperglycaemic medication in UK patients with newly diagnosed type 2 diabetes. BMC Endocr Disord 2012; 12:1.
28. Salvalaggio PR, Schnitzler MA, Abbott KC, et al. Patient and graft survival implications of simultaneous pancreas kidney transplantation from old donors. Am J Transplant 2007; 7:1561–1571.
29. Gruessner AC, Sutherland DE. Pancreas transplant outcomes for United States (US) and non-US cases as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR) as of June 2004. Clin Transplant 2005; 19:433–455.
30. Sutherland DE, Gruessner RW, Dunn DL, et al. Lessons learned from more than 1,000 pancreas transplants at a single institution. Ann Surg 2001; 233:463–501.
31. Stratta RJ. Mortality after vascularized pancreas transplantation. Surgery 1998; 124:823–830.
32. Afaneh C, Rich BS, Aull MJ, et al. Pancreas transplantation: does age increase morbidity? J Transplant 2011; 2011:596801.
33. Friedman AN, Miskulin DC, Rosenberg IH, Levey AS. Demographics and trends in overweight and obesity in patients at time of kidney transplantation. Am J Kidney Dis 2003; 41:480–487.
34. Chang SH, Coates PT, McDonald SP. Effects of body mass index at transplant on outcomes of kidney transplantation. Transplantation 2007; 84:981–987.
35. Gore JL, Pham PT, Danovitch GM, et al. Obesity and outcome following renal transplantation. Am J Transplant 2006; 6:357–363.
36. Meier-Kriesche HU, Arndorfer JA, Kaplan B. The impact of body mass index on renal transplant outcomes: a significant independent risk factor for graft failure and patient death. Transplantation 2002; 73:70–74.
37. Bumgardner GL, Henry ML, Elkhammas E, et al. Obesity as a risk factor after combined pancreas/kidney transplantation. Transplantation 1995; 60:1426–1430.
38. Hanish SI, Petersen RP, Collins BH, et al. Obesity predicts increased overall complications following pancreas transplantation. Transplant Proc 2005; 37:3564–3566.
39. Humar A, Ramcharan T, Kandaswamy R, et al. Technical failures after pancreas transplants: why grafts fail and the risk factors – a multivariate analysis. Transplantation 2004; 78:1188–1192.
40. Rogers J, Chavin KD, Baliga PK, et al. Influence of mild obesity on outcome of simultaneous pancreas and kidney transplantation. J Gastrointest Surg 2003; 7:1096–1101.
41. Sampaio MS, Reddy PN, Kuo HT, et al. Obesity was associated with inferior outcomes in simultaneous pancreas kidney transplant. Transplantation 2010; 89:1117–1125.
42. Venstrom JM, McBride MA, Rother KI, et al. Survival after pancreas transplantation in patients with diabetes and preserved kidney function. JAMA 2003; 290:2817–2823.
43. Glanton CW, Kao TC, Cruess D, et al. Impact of renal transplantation on survival in end-stage renal disease patients with elevated body mass index. Kidney Int 2003; 63:647–653.