Outcomes following simultaneous pancreas-kidney transplantation: Single center experience in Korea

Purpose: Among organ transplantation, simultaneous pancreas-kidney (SPK) transplantation is becoming increasingly common in patients with type I and II diabetes mellitus (DM). The purpose of this study is to review SPK transplantation cases and learn the lessons from the experience performed at out institution. Methods: We retrospectively reviewed and the analyzed the medical records of 25 SPK transplantation recipients performed from January 2003 to June 2016 in Korea. Results: 25 cases of SPK transplantation were type I DM patients. Twenty-four patients (seven males and 18 females) underwent SPK transplantation from deceased donors, and one female patient received living kidney transplantation. Enteric exocrine drainage via pancreas graft drainage was done in all cases. There were 10 acute rejection cases; all were relieved by steroid pulse therapy. Kidney graft loss occurred in four patients and two pancreatectomy graft surgeries were performed due to one graft necrosis and the other graft rejection. Insulin injection or oral hypoglycemic agents were used for three patients. With the exception of five mortality cases, 20 patients stopped insulin and oral hypoglycemic agents after transplantation. Blood glucose level was maintained within normal range without medication in 16 patients. Conclusion: SPK transplantation is a multiple organ transplantation that requires careful treatment to avoid complications in the postoperative period. SPK transplantation can render insulin dependent type I DM patients with end stage renal disease (ESRD) free from insulin use and produce proper graft functions. Correspondence to: Sung Joo Kim, Department of Surgery, Samsung Medical Center, Sunkyunkwan University School of Medicine, 81 Irwon-ro, Gangnamgu, Seoul, 06351, Republic of Korea, Tel: +82-2-3410-3476; Fax: +82-2-34100040; E-mail: kmhyj.kim@samsung.com


Introduction
Diabetes mellitus (DM) underlies many micro-and macrovascular diseases, such as retinopathy, neuropathy, nephropathy, cerebrovascular, and coronary and peripheral vascular systems. Hyperglycemia attributed to these complications can be fatal; the mortality rate is 13% after 20 years of type 1 DM (T1DM) [1]. Many people with DM require insulin injections. Exogenous insulin does compare to the physiologic insulin produced by a functional pancreas. Simultaneous pancreas-kidney (SPK) transplantation has been the ultimate treatment of DM and end-stage renal disease (ESRD) for a half-century [2]. SPK transplantation yields better graft survival than pancreas or kidney transplantation alone [3]. The benefit of SPK transplantation comes with the risks of higher morbidity and longer hospital stay [4]. Complications of pancreatic transplantation can be divided into early and late stages. Infection and vascular complications are more common in the early stage [5]. Thrombosis, leaks and infections are technical reasons that lead to graft lost. These technical failures occur more often in SPK transplantation than in pancreas after kidney (PAK) and pancreas transplant only (PTA); in SPK, thrombosis accounts for more than half of all technical failures followed by infection [6].
Efforts to reduce these technical failures may reduce the risks of SPK transplantation.
This study retrospectively reviews SPK transplantation cases conducted at single center in Korea.

Materials and methods
The present retrospective study of medical records and radiological examinations involved 25 patients underwent SPK transplantation from January 2003 to June 2016. All the cases were performed by one transplantation team. All data were recorded on a computerized database. All patients were followed-up in our center for a minimum 5 months post-transplantation.
The bench work was done with the donor iliac artery Y-graft. Implantations of both the pancreas and kidney were done intraperitoneally with the pancreas for the right iliac fossa and the kidney for the left iliac fossa. Anastomosis of the artery and vein of the graft was performed to internal or external iliac artery and external vein, with the pancreas to the right side and kidney to the left side. The gastoduodenal artery of the pancreas graft was anastomosed to the right internal iliac artery. For enteric drainage, the duodenum of the graft was anastomosed to the recipient's jejunum by hand-sewing. The ureter of the graft was anastomosed to the recipient's bladder using the Liche's technique.
The patients received anti-thymocyte globulin (ATG), basiliximab, alemtuzumab, or ATG+rituximab as an induction therapy. Maintenance immunosuppression consisted of calcineurin inhibitor, mycophenolate mofetil (MMF), steroids. Calcineurin inhibitor was started twice a day for a serum trough level of 8-12 ng/mL. MMF was given at an oral dose of 540 mg twice a day. Methylprednisolone 500 mg was administrated intravenously during surgery and then rapidly tapered, with an effort made to stop completely. All recipients received infection prophylaxis consisting of antibiotics (cefotaxime 1 g tid for 5 days and ampicillin/ sulbactam 1.5 g tid for 5 days) and antifungal agent (sulfamethoxazole/ trimethoprim for 6 months and itraconazole 100 mg bid for 1 month). Anticoagulation therapy was routinely performed. Heparin was started intravenously after absence of postoperative bleeding was confirmed. After starting oral intake, hepatin was replaced by warfarin, which was continued for 6 months with treatment adjusted to a serum INR level 1.8-2.0. Delayed graft function of the kidney was defined as the need of hemodialysis for the first week after transplant.
After discharge, the patients were regularly followed-up at the outpatients clinic. When creatinine was elevated or hypo-or hyperglycemia was detected, evaluation of the kidney or the pancreas was performed by Doppler sonography and a biopsy of the kidney was performed. Biopsy-proven acute cellular rejections were treated using steroid pulse therapy with methylprednisolone 500 mg for 3 days and continuously tapering steroid. A postoperative complication was defined as the need for re-operation, medication (anticoagulation or antibiotics) or intervention. Pancreas graft failure was defined as the permanent requirement for exogenous insulin after transplantation. Kidney graft failure was defined as the permanent requirement for dialysis after transplantation. Graft survival was censored for patient death with a functional graft, and patients with no record of death or graft failure were censored at the date of last follow-up. Patient survival was determined as time from first transplant to time of patient death, censoring at last follow-up where no death was reported.
All data was summarized as the median with the range, and categorical data was summarized as proportions and percentages. The Kaplan-Meier method was used to calculate graft and patient survival rates. Statistical analysis was performed using SPSS for Windows, version 22.0 software package (SPSS Inc, Chicago, IL, USA) and p values less than 0.05 was considered to be statistically significant.

Results
Twenty-five patients underwent SPK transplantation in our institution from January 2003 to June 2016. The baseline characteristics of donors and recipients are summarized in Table 1. Median age was 37 years (range, 23-58 years). It consists of seven male and 18 female patients. All the patients were diagnosed with T1DM. Median duration following diagnosis was 19 years (range 5-28 years). Nineteen patients had hypertension. No patients had a history of coronary artery disease or cerebrovascular disease. The median duration of dialysis was 58 months (range, 3-120 months). Twenty-one patients were maintained on hemodialysis and the other four patients were on peritoneal dialysis.
The median age of the donors was 29 years (range, 15-45 years). There were 15 male and 10 female donors. The causes of death were trauma in nine, hypoxic brain damage in four, and cerebrovascular accident in 12 donors. The median body mass index of the donors was 22.0 kg/m 2 (range, 15.6-38.1 kg/m 2 ). The median level of final serum creatinine was 1.02 mg/dL (range, 0.31-2.61 mg/dL).
The operation-related characteristics are presented in Table 2. Seventeen patients were 0% panel reactive antibody (PRA) matching, two patients displayed < 50% PRA match, and four patients had were more than ≥50% PRA match. Median number of HLA mismatches was three in Class I (range, 1-3) and one in Class II (range, 0-2). Induction therapy was decided based on the risk of the patients. Eighteen patients received ATG, one patient received basiliximab, two patients received alemtuzumab, and four patients received ATG and rituximab as an induction therapy. The latter four patients were high-risk: one had received a kidney transplant, one was HLA Class I positive and B cell positive, and the remaining two were HLA Class I/II positive and DSA positive. Systemic venous drainage was performed for all pancreas transplantation cases. Pancreas exocrine drainage was performed by enteric drainage in all patients.

Discussion
SPK transplantation is the ultimate cure for insulin-dependent DM and ESRD. SPK transplantation outcomes and survival rates are better than pancreas or kidney transplantation alone [7]. This study shows long-term results from our initial to the present time at our center, although the number of patients is small. The graft survival rate of kidney and pancreas is similar to that of other institution [8].
Five patients died. One had received a graftectomy after 15 days due to graft necrosis. Another patient had been diagnosed as rejection due to deterioration of graft function; the graft was removed 3 months after transplantation to control an infection. Four of the other patients received experienced insulin injections or oral diabetes medication due to graft failure. The remaining 16 patients were successfully weaned off insulin.
Of the five patients who died, one died of hypoxic brain damage due to hypoglycemia. The other four deaths were due to infection. One patient underwent emergent surgery for acute cholecystitis and empyema 15 days after SPK transplantation and died 2 months after transplantation of an uncontrolled Candida peritonitis infection. One patient died of intraabdominal bleeding and sepsis due to intestinal perforation 4 months after the SPK transplantation. One patient died within 41 months of an intraperitoneal infection due to duodenal perforation at 39 months after transplantation. One patient died of peritoneal infection due to small bowel perforation during treatment with graft versus host disease (GVHD) 1.5 months after SPK transplantation. In addition to these patients, one patient had undergone a graftectomy for uncontrolled infection due to graft failure as well as rejection. Transplant patients are known to be at risk of infection because of the use of immunosuppressants. In addition, intraabdominal infections after SPK transplantation are directly related to death; this risk is more pronounced than flowing solid organ transplantation.
The early postoperative period is still considered a high-risk period for a relaparotomy [9]. This suggests that surgical complications are associated with strong non-immunologic complications after transplantation in the early postoperative period [10]. Anticoagulation therapy after SPK transplantation is also involved. Anticoagulation therapy begins immediately without any evidence of bleeding after transplantation. Therefore, the risk of recurrent bleeding is high. Even if the re-bleeding is stopped, intraabdominal hematoma can cause the infection and the complication of relaparotomy cannot be overlooked if reoperation is done to remove hematoma or to prevent bleeding. However, restriction of the coagulation to prevent bleeding can cause intravenous thrombosis resulting in graft loss. Fine control between bleeding and thrombosis after SPK transplantation is very important.
Duodenal leakage is also a potential complication after pancreas transplantation. Graftectomy should be considered as a life-saving measure when duodenal segment leakage with abdominal sepsis occurs or upon prolonged morbidity with non-healing leakage [11]. Duodenal leakage has not occurred in any cases at our center, and it seems to be influenced by the supply of blood flow to the inferior pancreaticoduodenal arcade of the graft by connecting the gastroduodenal artery with internal iliac artery.
It is not easy to find a suitable deceased donor because the SPK transplantation basically requires a healthy donor without underlying disease under the age of 45 years. In Korea, there are a few large transplant centers, but there are not many other SPK transplantation experienced teams. In addition, SPK transplantation is difficult to perform in small institution because it requires a collaborative teamwork with a diverse team including transplant physicians, radiologist, endocrinologists, nutritionists and pharmacists. Although the results of the present study are not inferior to those of large overseas institutions, the results could be further improved through surgical complication improvement, infection control and accurate anticoagulation therapy system.