Pancreas Transplant Alone in Uremia and Non-uremia Patients

1. Introduction Pancreas transplant remains a highly effective option for achieving long-term physiological euglycemia in patients with labile diabetes mellitus (DM). This procedure is most commonly applied to diabetic patients with end-stage kidney disease (ESKD), either through simultaneous pancreas-kidney transplant (SPK), pancreas after kidney transplant (PAK), or pancreas transplant alone (PTA) for patients with labile DM but without ESKD[1, 2]. According to the Scientific Registry of Transplant Recipients (SRTR), most pancreas transplants in the United States are SPK procedures (79% to 84%), followed by PTA (9% to 11%) and PAK (7% to 9%)[2-4]. SPK is often preferred because it allows diabetic patients with uremia to achieve both insulin and dialysis independence in a single operation[5-10]. Additionally, SPK is reported to have the best long-term outcomes for pancreas graft survival compared to PTA and PAK[11, 12]. However, the availability of pancreas and kidney grafts may not always coincide, making PAK a viable alternative for patients who receive a kidney transplant first[3, 13, 14]. Theoretically, pancreatic transplant alone in uremia (PTAu) or pancreas before kidney transplant (PBK) could also be considered for those waiting for both pancreas and kidney grafts[1], in addition to the options of SPK and PAK.

   This study evaluates the outcomes of PTAu in terms of endocrine function, immunological response, graft survival, and surgical outcomes compared to pancreas transplant alone in non-uremic patients (PTAn).

2. Materials and Methods Patient characteristics and pancreas transplant types A total of 184 cases of pancreas transplants performed between September 2003 and August 2024 were included in this study. Perioperative and follow-up data for each patient were prospectively collected and stored in a computer database. Ethical approval for this study (IRB-TPEVGH No.: 2024-12-003BC) was provided by the Institutional Review Board of Taipei Veterans General Hospital, Taipei, Taiwan on 20 December 2024. The research adhered to IRB regulations and guidelines. Informed consent requirements were waived due to the anonymized and retrospective nature of the study. Indications for pancreas transplant include: (1) Type 1 diabetes mellitus (T1DM) with complications such as nephropathy, retinopathy, neuropathy, and cardio-cerebral vasculopathy; (2) T1DM with frequent life-threatening hypoglycemia or hyperglycemia; (3) T1DM causing severe disability in daily activities, including education and employment; and (4) Type 2 diabetes mellitus (T2DM) with kidney disease leading to end-stage kidney disease (ESKD), requiring insulin at less than 1.5 units/kg/day. Based on the patient's condition, pancreas transplants were categorized into 4 subgroups at our institute: 1. Pancreas transplant alone in uremia (PTAu) or pancreas before kidney transplant (PBK); 2. Pancreas transplant alone in non-uremia (PTAn); 3. Simultaneous pancreas-kidney transplant (SPK); 4. Pancreas after kidney transplant (PAK). In Taiwan, the waiting lists for pancreas and kidney grafts are separate, according to the regulations of Taiwan Organ Registry and Sharing Center. There are always more than 8,000 uremic patients waiting for a kidney graft, but only about 70 diabetic patients waiting for a pancreas graft (as of September 4, 2024, at https://www.torsc.org.tw). Consequently, it has been always very competitive to have a kidney graft from a deceased donor in our country. As a result, some diabetic patients with uremia, who would ideally receive SPK, opt for PTAu after thorough counseling and explanation.

Demographic data, surgical outcomes including early (before discharge) and late (after discharge) complications, surgical mortality, acute and chronic rejections, graft loss, and immunological outcomes including fasting blood sugar, serum hemoglobin A1c (HbA1c), serum C-peptide were evaluated. Pancreas graft and patient survival rates were compared between the PTAu and PTAn groups. Surgical mortality was defined as death occurring either before discharge or within 90 days post-operation. Any return to insulin therapy was considered pancreas graft failure. Pancreas graft survival was assessed using two criteria: 1. Graft loss due to patient death with functioning graft was considered as "censor" (indicating a functioning graft); 2. Graft loss, including patient death with a functioning graft, was considered as an "event" (indicating graft failure).

Study endpoints The primary endpoint of this study was to assess the justification for PTAu or PBK by comparing the endocrine function, immunological responses, and graft survival outcomes with those of the PTAn group. The secondary endpoint focused on evaluating the feasibility of PTAu or PBK by comparing surgical outcomes and patient survival rates between the PTAu and PTAn groups.

Pancreas transplant techniques and immunosuppressant protocols Pancreas transplant techniques and immunosuppressant protocols have been detailed in our previous article [1]. In brief, pancreas grafts were procured in a "'no touch" technique en bloc with the duodenum. The spleen was routinely separated from the pancreas before aorta cross-clamping. For in situ perfusion, 4,000 to 6,000 c.c. of Histidine-Tryptophan-Ketoglutarate solution was used via the aorta, and 2,000 to 4,000 c.c. via the inferior mesenteric vein. During back-table preparation, the peripancreatic fat was removed, and arterial Y-graft reconstruction was performed. The graft's portal vein was anastomosed end-to-side to the recipient's distal inferior vena cava, with the pancreas placed in a head-up position. The superior mesenteric and splenic arteries, reconstructed using a donor iliac arterial Y-graft, were anastomosed to the recipient's right common or external iliac artery. Exocrine drainage was achieved by a hand-sewn, side-to-side duodenojejunostomy placed 30-50 cm beyond the Treitz ligament using a Roux-en-Y technique, with retroperitoneal placement.

The immunosuppressant protocol included quadruple therapy for all recipients. Induction therapy used basiliximab (Simulect, Novartis Pharmaceuticals Corp., East Hanover, NJ), 20 mg on postoperative days 0 to 4, or anti-thymocyte globulin (Thymoglobulin®; Genzyme, Cambridge, Mass., USA) for high rejection risk cases, such as positive panel-reactive antibody (PRA) or retransplant, with 1 mg/kg daily from days 1 to 7. Maintenance therapy consisted of tacrolimus (Prograf; Astellas Pharma US, Inc., Deerfield, IL), enteric-coated mycophenolic acid (Myfortic; Novartis Pharmaceuticals Corp., East Hanover, NJ), and prednisolone. Prednisolone was gradually tapered and discontinued within six months post-transplant. Tacrolimus target trough levels were 8-12 ng/mL in the first year and 6-8 ng/mL thereafter. Tacrolimus target trough levels were 8-12 ng/mL in the first year and 6-8 ng/mL thereafter.

Statistics Statistical analyses were performed using Statistical Product and Service Solutions (SPSS) version 26.0 software (SPSS Inc., IBM, Armonk, NY, USA). Categorical data were presented as numbers (%). Categorical data were compared by Pearson's χ2 test or Fisher's exact test contingency tables. Continuous data were presented as medians, ranges, and mean ± standard deviation (SD), and the mean values were compared using a two-tailed Student's t-test. Nonparametric tests were applied if the data did not follow a normal distribution. Actuarial graft survival rates were estimated using the Kaplan-Meier method, excluding the primary graft failure and surgical mortality. Survival curves were compared using the log-rank test. A p-value of \<0.05 was considered statistically significant in all analyses.