Title: Pancreas Transplantation Alone: Radical or Rationale?
Abstract: Originally developed as a therapeutic modality to reestablish endogenous insulin secretion responsive to normal feedback controls, vascularized whole organ pancreas transplantation (PTx) has evolved into a method of complete β-cell replacement that frees the patient with diabetes mellitus (DM) from the need to monitor serum glucose and from dependence on exogenous insulin administration.1 Unfortunately, PTx entails a major surgical procedure and the necessity for long-term immunosuppression, which means that despite the high likelihood of rendering patients ex-diabetic, it is considered a treatment rather than a cure. For these reasons, PTx is usually reserved for those patients with insulin-requiring DM who will already be committed to long-term immunosuppression for another reason, most commonly a kidney transplant for end-stage diabetic nephropathy performed either simultaneously or sequentially, both of which became Medicare-approved procedures in July 1999. Additionally, candidates with potentially life-threatening metabolic complications from hyperlabile diabetes such as hypoglycemia unawareness, recurrent episodes of ketoacidosis, or progressive nonrenal complications may benefit from PTx alone (PTA) in the absence of a kidney transplant.1-4 Apancreatic patients following total pancreatectomy for benign disease are particularly brittle diabetics, lack pancreatic exocrine function, and would also benefit from PTA.5 Rarely, insulin allergy, extreme insulin sensitivity, or erratic insulin absorption may result in true failures of exogenous insulin therapy irrespective of compliance.6 Consequently, PTA also became a Medicare-approved procedure in April 2006. A successful PTx is currently the only definitive long-term treatment that restores normal glucose homeostasis and may prevent, stabilize, or even reverse progressive diabetic complications.1-4 Consequently, is PTx the ultimate form of endogenous insulin delivery or an extreme surgical approach to a metabolic disease? It is interesting to note that, with the evolution of bariatric surgery, DM is no longer considered exclusively a medical disease. With steadily improving outcomes, PTx has been successfully performed for >60 y, yet it is neither universally recognized nor accepted by frontline practitioners who manage diabetes. Improvements in diabetes management, education, and awareness; better insulin analogs and glucose sensors; sophisticated and more patient-friendly insulin pumps; and the promise of the artificial or bionic pancreas have all contributed to the diversion of interest away from transplantation as a treatment for DM. Because PTA is one of many treatment options available, it stands in direct competition with conventional medical therapies and islet transplantation (ITx). It is considered by many diabetes care professionals to be a “radical” therapy requiring major surgery and lifelong immunosuppression for a “benign” yet life-shortening disease. Other available treatment options are less invasive and, for that reason alone, are more appealing to providers. The situation for potential candidates interested in pursuing PTA is made even more difficult because many patients have to circumvent their diabetes care providers to gain access to PTA. According to Registry data (from January 2015 to December 2019), the rate of early graft loss secondary to technical failure following PTA was 6.9%, whereas the incidence of early (1 y) immunologic graft loss was 4.9%.7 The 1-y patient and pancreas graft survival (defined as complete insulin independence) rates were 98% and 86%, respectively. The 5- and 10-y patient survival rates were 90% and 75%, respectively. For patients with a functioning allograft at 1 y, the half-life of the pancreas is in excess of 10 y! In fact, the current expectation is that most patients will do extremely well for a long term following PTA. Surprisingly, PTA and ITx are usually (and inappropriately) linked together as equivalent β-cell replacement strategies for patients with diabetes in the absence of chronic kidney disease (CKD), both of which are subsequently grouped together as investigational therapies despite the fact that PTA is recognized as a standard of care. For comparison, in a study of 10-y outcomes following ITx (n = 28), only 28% of patients were insulin free at 10 y.8 In the previous century, Dr David Sutherland and the group at the University of Minnesota were the original torchbearers for PTx in general and PTA in particular.4 In the new millennium, the torch has been passed to others, such as Dr Ugo Boggi and the group at the University of Pisa. In this issue of Transplantation, Boggi et al report 10-y outcomes following PTA in patients with type 1 DM and low BMI (<30 kg/m2). This single-center, retrospective study represents the current state of the art in PTA.9 Strengths of the article include the long-term follow-up, the relatively large cohort size (n = 66), the excellent overall outcomes (no early technical graft losses and a relaparotomy rate of only 13%), and the detailed analysis of the trajectory of native renal function. At 10-y follow-up, overall mortality was low (7.6%), good or excellent pancreas allograft function (death-censored) was 60% (57% insulin free), and the incidence of progression to stage 4/5 CKD was <10%. One of the major concerns in nonrenal transplantation in general and PTA in particular is the risk of CKD progression as a result of either diabetic nephropathy or nephrotoxicity related to immunosuppression. Previous studies have suggested that the risk of end-stage renal disease following PTA may be as high as 10%–15% at 5 y and 20%–50% at 10 y.10-12 However, with appropriate candidate selection (estimated glomerular filtration rate [eGFR] >60 mL/min/1.73 m2 and absence of macroalbuminuria), the authors clearly demonstrate that this risk can be minimized. Although most patients experience an absolute 15% decline in eGFR in the first year following PTA (probably related to the introduction of calcineurin inhibitors), many subsequently exhibit relative stability in native renal function thereafter contingent upon duration of pretransplant DM and absence of hyperfiltration. In fact, the authors suggest that the subsequent decline in eGFR is similar to what is expected in patients with longstanding type 1 DM in the absence of transplantation. Areas for future investigation include the effect of PTA on quality of life, functional status, and progressive nonrenal diabetic macrovascular and microvascular complications. However, the marked improvement in outcomes reported in this study confirms that PTA should not be considered a radical but rather a rational therapy for appropriately selected patients with type 1 DM who are failing conventional therapies.