Shiraz, Iran: the Largest Center for Pancreas Transplantation in the Middle East

INTRODUCTION Subsequent to the first successful procedure in 1966,1 pancreas transplantations (PTs) either as simultaneous pancreas kidney (SPK), pancreas after kidney (PAK), or pancreas transplant alone (PTA) have been established for patients with end-stage renal disease and diabetes (predominantly type I) and in some cases for patients with a labile diabetes in the absence of end-stage renal disease. More than 56 000 PTs have been recorded with the majority of these procedures being performed in the United States compared to other regions in the world (32 000 versus 24 000) according to the report from the International Pancreas Transplant Registry.2,3 Improvements in surgical techniques, immunosuppressive regimens, and patient care have led to significant improvements in patient survival and quality of life in pancreas transplant recipients.4,5 PANCREAS TRANSPLANTATIONS IN THE MIDDLE EAST AND IRAN The Middle East is a geographic region with a very high prevalence and incidence for diabetes type 1. Saudi Arabia (33.5 per 100 000) and Kuwait (44.5 per 100 000) are among the top 10 countries worldwide for the incidence of diabetes type 1 among those younger than 20 y.6 A recent report from the International Diabetes Federation (2017)7 showed Iran to be among the 3 countries with the highest number of adults with diabetes in the Middle East, reflective of a prevalence of 5 (3.9–6.6) million. It has been shown that the Middle East and North Africa have one of the highest mortality rates attributed to diabetes in those younger than 60 y (43%).8 Although effective treatments are available, high nonadherence rates (up to 38.3%) compound the problem.9 Waiting lists for PT in emerging countries are in general small as candidacy of patients with diabetes type 1 is frequently limited with a poor nutritional status, poor lifestyle habits, limited exercise capacities, elevated body mass indexes in addition to an augmented cardiovascular risk.10 Thus, rates of PTs have been low in the Middle East. A global report (2016) has listed 1 PT in Kuwait, 6 in Turkey, 11 in Saudi Arabia, and 30 cases in Iran.11 The Shiraz Transplant Center at Abu Ali Sina Hospital, which is affiliated to Shiraz University of Medical Sciences, Shiraz, Iran, is the main center for organ transplantations in Iran and one of the largest transplantation centers in the world.12,13 The first PT (in the form of SPK) in the Middle East has been performed by S.N. at the Shiraz Organ Transplantation Center and since then PT has become a routine practice in our center. PANCREAS TRANSPLANTATION AT THE SHIRAZ TRANSPLANT CENTER Until March 2020 and before the global COVID-19 pandemic, a median of 17.50 (11.75, 26.75) PTs have been performed at the Shiraz Organ Transplantation Center annually resulting into a total of 268 procedures. The highest number of PTs in our center has been performed between March 20, 2012, and March 20, 2013 (n = 33). After the outbreak of coronavirus disease 2019, from March 2020, up to August 2020, only 2 SPK transplantations have been performed as nonemergent surgeries had to be limited. Volumes of pancreas transplants in Shiraz are shown in Figure 1.Figure 1.: Trends in pancreas transplantation from 2006 to 2020.During recent years, the volume of SPK transplants increased at our center relative to PTAs. The youngest patient to receive a PT in our center was 16 y and the oldest 61 y old. It should be noted that there are 2 additional pancreas transplant centers in Iran, at Imam Khomeini Hospital in Tehran and Montaserieh Transplant Hospital in Mashhad; both centers have started PTs during the past 2 y with <5 PTs annually. PROCEDURAL AND TREATMENT DETAILS In our center in Shiraz, we have used both portal and systemic draining techniques. With either venous drainage, the graft is anastomosed to the right common iliac artery. We use an enteric drainage, in most cases to the jejunum and in few patients to either stomach or ileum. Kidneys are implanted to the left retroperitoneum using a single midline incision. As an induction treatment, we use methylprednisolone and thymoglobulin. Maintenance immunosuppression includes mycophenolate mofetil, tacrolimus and prednisolone. Starting on postoperative day 7, we add everolimus to the immunosuppressive regimen. Prednisolone is tapered over a 3- to 6-mo period in SPK patients. A low dose of corticosteroids is maintained in patients with PTA. Cotrimoxazole is continued for 1 y for the prevention of Pneumocystis jiroveci-related infections. CMV prophylaxis with valcyte is continued for 6 mo in SPK patient, fluconazole is continued for a period of 1 mo as a prophylaxis for fungal infections; patients are kept on Aspirin (81 mg/d) long term. Intraoperative anticoagulation for patients undergoing SPK transplantations is guided by thromboelastogram data for the administration and dosage of heparin. All patients receiving PTA receive intraoperative heparin that is continued for 48 h postoperatively. PAK transplantations are rarely performed in Iran compared to other regions in the world and this is mainly due to the short wait times among our kidney and pancreas recipients with the availability of deceased donors. A deceased donor policy for PT has been implemented after the first successful transplant in 2006; with available deceased donors, there has not been a need for living donor PTs in Iran. OUTCOMES SPK Transplants Among a total of 174 patients who received SPKs, 67 (38%) developed complications. Acute rejections have been seen in 37 patients (55.2%), postoperative bleeding and infections have been seen in 23.4% and 6%, respectively. In-hospital pancreas graft survival was 97.8% and only 4 cases had an immediate graft failure. In this group, the in-hospital kidney graft survival was 95.5% and 8 patients had acute kidney rejection during hospitalization. One-, 5-, and 15-y patient survival was 87.9%, 83.9%, and 82.7%, respectively (Figure 2). The most common causes of death in this group were sepsis (63%) and acute graft rejection (22.2%) (Table 1). Mean duration of follow-up in the SPK group was 134.14 mo. TABLE 1. - Baseline characteristics and clinical of patients with pancreas transplantationa Variables Simultaneous pancreas/kidney (n = 174) Isolated pancreas (n = 90) Total (n = 264) Age, y 33.60 ± 8.01 31.67 ± 8.98 32.95 ± 8.39 Sex, No. (%) Male 117 (67.2) 60 (66.7) 177 (67) Female 57 (32.8) 30 (33.3) 87 (33) BMI, kg/m2 21.36 ± 4.11 21.60 ± 3.88 21.46 ± 4.00 Cause of pancreatic disease, No. (%) Unconscious unawareness 0 57 (83.8) 67 (36.4) Diabetes and nephropathy 115 (99.1) 8 (11.8) 113 (61.4) Neuroendocrine tumor 0 1 (1.5) 1 (0.5) Rejection 1 (0.9) 2 (2.9) 3 (1.6) In-hospital and follow-up complications, No. (%) Yes 67 (38) 34 (37.8) 101 (37.8) Rejection 37 (55.2) 24 (70.6) 61 (60) Bleeding 16 (23.9) 5 (14.7) 21 (21) Infection 4 (6) 5 (14.7) 9 (9) Vascular 4 (6) 0 4 (4) Renal 3 (4.5) 0 3 (3) Gastrointestinal 2 (3) 0 2 (2) Neurological 1 (1.5) 0 1 (1) No 107 (62) 56 (62.2) 164 (62.2) Follow-up duration, mo Mean ± SD 62.87 ± 49.57 79.68 ± 47.19 68.60 ± 49.33 Median (IQR) 56 (18.75, 100) 84 (46, 119.50) 67 (24, 103) Mortality, No. (%) Alive 129 (77.7) 64 (71.1) 201 (76.1) Dead 34 (20.5) 20 (22.2) 54 (20.5) Unknown 3 (1.8) 6 (6.7) 9 (3.4) Mortality, No. (%) 1 y No 153 (87.9) 80 (88.8) 233 (88.2) Yes 21 (12.1) 10 (11.2) 31 (11.8) 5 y No 146 (83.9) 76 (84.4) 222 (84) Yes 28 (16.1) 14 (15.6) 42 (16) 10 y No 146 (83.9) 74 (82.2) 220 (83.3) Yes 28 (16.1) 16 (17.8) 44 (16.7) 15 y No 144 (82.7) 74 (82.2) 218 (82.5) Yes 30 (17.3) 16 (17.8) 46 (17.5) Graft survival, No. (%) 1 y No 34 (19.5) 16 (17.8) 50 (18.9) Yes 140 (80.5) 74 (82.2) 214 (81.1) 5 y No 35 (20.1) 19 (21.1) 54 (20.5) Yes 139 (79.9) 71 (78.9) 210 (79.5) 10 y No 37 (21.3) 20 (22.2) 57 (21.6) Yes 137 (78.7) 70 (77.8) 207 (78.4) 15 y No 38 (21.8) 20 (22.2) 58 (22) Yes 136 (78.2) 70 (77.8) 206 (78) Cause of death, No. (%) Sepsis 17 (63) 4 (28.6) 21 (51.2) Rejection 6 (22.2) 5 (35.7) 11 (26.8) Gastrointestinal leak 2 (7.4) 2 (14.3) 4 (9.8) Bleeding 1 (3.7) 1 (7.1) 2 (4.9) Vascular thrombosis 1 (3.7) 1 (7.1) 2 (4.9) Renal failure 0 1 (7.1) 1 (2.4) aAll plus-minus values are means and SD.BMI, body mass index. Figure 2.: Patient survival and graft survival for pancreas transplantation. SPK, simultaneous pancreas-kidney; Tx, transplantation.One-, 5-, and 15-y graft survival was 80.5%, 79.9%, and 78.2%, respectively (Table 1; Figure 2). Pancreas Transplant Alone Thirty-four (37.8%) out of 90 patients that received PTA in our center, developed complications with rejections (70.6%), bleeding (14.7%), and infections (14.7%) being the most common. In-hospital pancreas graft survival was 96.7% in the PTA group. One-, 5-, and 15-y patient survival was 88.8%, 84.4%, and 82.2%, respectively (Figure 2). The most common causes of death in the PTA group were sepsis (48.6%) and acute graft rejection (35.7%). Mean duration of follow-up in the PTA group was 126.88 mo. One-, 5-, and 15-y graft survival in this group was 82.2%, 78.9%, and 77.8%, respectively (Table 1; Figure 2). In total, 6 patients required the retransplantation of the kidney alone and 4 patients were in need of pancreas retransplantation (2 of which were SPK). SUMMARY The transplant center in Shiraz performs one of the world’s largest volume of pancreas transplants and is the largest program outside the United States. Outcomes meet international standards. Our center provides fellowships and training for postgraduate surgeons worldwide and aims to expand its volume furthermore. PT is a technically challenging procedure requiring accurate teamwork and coordination between many specialists in endocrinology, nephrology, intensive care, and surgery. As PT is based on the availability of deceased donors, it is only performed in few centers in the Middle East. ACKNOWLEDGMENTS The authors would like to thank all the personnel at the Shiraz transplant data registration center for their continuous efforts in gathering patients’ data, especially Zahra Ebrahimi Fam.