Pancreas transplant for diabetes mellitus

SURGICAL COMPLICATIONS

Surgical complications have long been considered a limiting factor in the growth of pancreas transplant. Technical failure or loss of the graft within 90 days is most commonly due to graft thrombosis, leakage of the enteric anastomosis, or severe peripancreatic infection. The rate of technical failure has declined across all recipient categories and is currently about 9%.⁸

DO RECIPIENT FACTORS AFFECT OUTCOMES?

As mentioned above, the PDRI identifies donor factors that influence the 1-year graft survival rate. Recipient factors are also thought to play a role, although the influence of these factors has not been consistently demonstrated.

Humar et al¹⁵ found that recipient obesity (defined in this study as BMI > 25 kg/m²) and donor age over 40 were risk factors for early laparotomy after pancreas transplant.¹⁵ Moreover, patients undergoing early laparotomy had poorer graft survival outcomes.

This finding was reinforced by an analysis of 5,725 primary simultaneous pancreas-kidney recipients between 2000 and 2007. Obesity (BMI 30 ≥ kg/m²) was associated with increased rates of patient death, pancreas graft loss, and kidney graft loss at 3 years.¹⁶

More recently, Finger et al¹⁷ did not find a statistically significant association between recipient BMI and technical failure, but they did notice a trend toward increased graft loss with a BMI greater than 25 kg/m². Similarly, others have not found a clear adverse association between recipient BMI and pancreas graft survival.

Intuitively, obesity and other recipient factors such as age, vascular disease, duration of diabetes, and dialysis should influence pancreas graft survival but have not been shown in analyses to carry an adverse effect.¹⁸ The inability to consistently find adverse effects of recipient characteristics is most likely due to the relative similarity between the vast majority of pancreas transplant recipients and the relatively small numbers of adverse events. In 98 consecutive pancreas transplants at our center between 2009 and 2014, the technical loss rate was 1.8% (unpublished data).

Acute rejection most commonly occurs during the first year and is usually reversible. More than 1 year after transplant, graft loss is due to chronic rejection, and death is usually from underlying cardiovascular disease.

The immunosuppressive regimens used in pancreas transplant are similar to those in kidney transplant. Since the pancreas is considered to be more immunogenic than other organs, most centers employ a strategy of induction immunosuppression with T-cell–depleting or interleukin 2-receptor antibodies. Maintenance immunosuppression consists of a calcineurin inhibitor (tacrolimus or cyclosporine), an antimetabolite (mycophenolate), and a corticosteroid.⁸

Immunosuppressive complications occur at a rate similar to that seen in other solid-organ transplants and include an increased risk of opportunistic infection and malignancy. The risk of these complications must be balanced against the patient’s risk of health decline with dialysis and insulin-based therapies.

OVERALL OUTCOMES ARE GOOD

The success rate of pancreas transplant is currently at its highest since the inception of the procedure. The unadjusted patient survival rate for all groups is over 96% at 1 year, and over 80% at 5 years.⁸ One-year patient survival after pancreas transplant alone, at better than 96%, is the highest of all organ transplant procedures.⁹

Patient survival 1 year after pancreas-alone transplant is > 96%

Several recently published single-center reviews of pancreas transplant since 2000 report patient survival rates of 96% to 100% at 1 year and 88% to 100% at 5 years.^19–22 This variability is likely closely linked to donor and recipient selection, as centers performing smaller numbers of transplants tend to be more selective and, in turn, report higher patient survival rates.^19,21

Long-term patient survival outcomes can be gathered from larger, registry-based reviews, accepting limitations in assessing causes of patient death. Siskind et al²³ analyzed the outcomes of 20,854 US pancreas transplants done between 1996 and 2012 and found the 10-year patient survival rate ranged from 43% to 77% and was highly dependent on patient age at the time of the procedure.²³ Patient survival after transplant must be balanced against the generally poor long-term survival prospects of diabetic patients on dialysis.

By type of transplant, pancreas graft survival rates at 1 year are 89% for simultaneous pancreas-kidney transplant, 86% for pancreas-after-kidney transplant, and 84% for pancreas-alone transplant. Graft survival rates at 5 years are 71% for simultaneous pancreas-kidney transplant, 65% for pancreas-after-kidney transplant, and 58% for pancreas-alone transplant.^8,9

Simultaneous pancreas-kidney transplant has been shown to improve the survival rate compared with cadaveric kidney transplant alone in patients with type 1 diabetes and chronic kidney disease.^24,25 The survival benefit of isolated pancreas transplant (after kidney transplant and alone) is not evident at 4-year follow-up compared with patients on the waiting list. However, the benefit for the individual patient must be considered by weighing the incapacities experienced with insulin-based treatments against the risks of surgery and immunosuppression.^26,27 For patients who have experienced frequent and significant hypoglycemic episodes, particularly those requiring third-party assistance, pancreas transplant can be a lifesaving procedure.

Effects on secondary diabetic complications

Notwithstanding the effect on the patient’s life span, data from several studies of long-term pancreas transplant recipients suggest that secondary diabetic complications can be halted or even improved. Most of these studies examined the effect of restoring euglycemia in nephropathy and the subsequent influence on renal function.

Effect on renal function. Kleinclauss et al²⁸ examined renal allograft function in type 1 diabetic recipients of living-donor kidney transplants. Comparing kidney allograft survival and function in patients who received a subsequent pancreas-after-kidney transplant vs those who did not, graft survival was superior after 5 years, and the estimated glomerular filtration rate was 10 mL/min higher in pancreas-after-kidney recipients.²⁸ This improvement in renal function was not seen immediately after the pancreas transplant but became evident more than 4 years after establishment of normoglycemia. Somewhat similarly, reversal of diabetic changes in native kidney biopsies has been seen 10 years after pancreas transplant.²⁹

Effect on neuropathy. In other studies, reversal of autonomic neuropathy and hypoglycemic unawareness and improvements in peripheral sensory-motor neuropathy have also been observed.^30–32

Effect on retinopathy. Improvements in early-stage nonproliferative diabetic retinopathy and laser-treated proliferative lesions have been seen, even within short periods of follow-up.³³ Other groups have shown a significantly higher proportion of improvement or stability of advanced diabetic retinopathy at 3 years after simultaneous pancreas-kidney transplant, compared with kidney transplant alone in patients with type 1 diabetes.³⁴

Effect on heart disease. Salutary effects on cardiovascular risk factors and amelioration of cardiac morphology and functional cardiac indices have been seen within the first posttransplant year.³⁵ Moreover, with longer follow-up (nearly 4 years), simultaneous pancreas-kidney recipients with functioning pancreas grafts were found to have less progression of coronary atherosclerosis than simultaneous pancreas-kidney recipients with early pancreas graft loss.³⁶ These data provide a potential pathophysiologic mechanism for the long-term survival advantage seen in uremic type 1 diabetic patients undergoing simultaneous pancreas-kidney transplant.

In the aggregate, these findings suggest that, in the absence of surgical and immunosuppression-related complications, a functioning pancreas allograft can alter the progress of diabetic complications. As an extension of these results, pancreas transplant done earlier in the course of diabetes may have an even greater impact.