Study Population
Medical data from patients with insulin dependent diabetes mellitus (type 1 or 2) and end-stage renal diseases (ESRD) who received simultaneous pancreas-kidney transplantation (SPKT) at the University Hospital of Leipzig between 2000 and 2016 were retrospectively analyzed. Our data source comprised a prospectively collected electronic database. Approval for this analysis was granted by the local ethics committee [AZ: Nr: 111–16–14032016]. Patients undergoing pre-emptive transplantation, re-transplants, living donor kidney transplantation, younger than 18 years, and those with missing data were excluded from the study.
Outcome measures
Special emphasis was placed on the outcome of dialysis modality before transplantation (hemodialysis (HD) versus peritoneal dialysis (PD)), recipient and donor characteristics, intra- and postoperative variables and complications, such as patient, graft as well as health-related quality of life outcomes before (during dialysis) and after transplantation.
Characteristics included age, gender, body mass index (BMI, weight in kg/height in m2), duration of insulin dependent diabetes mellitus, duration of dialysis, time on the waiting list. Cardiovascular disease included information about peripheral arterial obstructive disease and coronary heart disease (coronary artery bypass graft or stent). Peri- and post-transplant data included information on cold ischemia time of kidney/pancreas, immunosuppressive therapy as well as patient and organ graft function.
Furthermore, complications occurring during the first three months after transplantation were analyzed. Surgical complications were defined as the need for relaparotomy within the first 3 months after transplantation. Intraabdominal infections were defined as the development of infected fluid collection that required an intervention and/or antibiotic drug therapy. Gastrointestinal bleedings were defined as bleedings requiring relaparotomy or endoscopy, or patients suffering from sudden anemia combined with either melena or hematemesis. Other bleedings, consisting of intra-abdominal hemorrhages, were diagnosed by CT scan or relaparotomy performed due to acute anemia.
Health-related Quality of Life (HRQoL)
For measuring the HRQoL in this study, the mostly used and internationally validated Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) questionnaire was used. Patients were asked to evaluate their HRQoL before transplantation (undergoing dialysis (HD versus PD)), such as one year after transplantation.
The SF-36 survey is suitable to compare the health status of chronically ill patients with the general population in terms of functional status and well-being.
In this study, HRQoL was evaluated in a second assessment through written HRQoL questionnaires (SF-36) sent to all patients with invitation to complete a quality of life survey retrospectively.
The SF-36 survey was sent by mail to patients’ home addresses. Additionally, patients were interviewed via telephone or during clinical visit, as indicated. Return envelopes were included free of charge. A period of two weeks was envisaged for questionnaire return. All patients who had not returned the questionnaire after two weeks were contacted a second time via mail or telephone within another 14 days. Altogether, patients had four weeks for their responses. Prior to the study, informed consent of all patients and the consent of the local ethics committee [AZ: Nr: 111–16–14032016] were obtained. Because the HRQoL assessment was performed separately, it was not possible to correlate HRQoL scores with all clinical data. The average time span between SPKT and completion of the questionnaires was 8.6 ± 2.9 years.
The SF-36 has thirty-six questions (without specific for renal failure or diabetes) which assess ability to perform vigorous activities and activities for daily living and participate in social, family and occupational activities. Eight scales/dimensions describe domains of physical functions (PF, 10 items), role limitations due to physical problems (PR, 4 items), bodily pain (BP, 2 items), a general perception of health (GH, 5 items), energy and vitality (VIT, 4 items), social functions (SF, 2 items), role limitations due to emotional problems (RE, 3 items), and mental health (MH, 5 items). The subscales can be combined into two summation scales measuring the overall physical and mental HRQoL: a physical component summary (PCS = PF + PR + BP + GH) and a mental component summary (MCS = VIT + SF + RE + MH). Subscale scores were transformed to a 0–100 scale, with 0 representing the least well-being to 100 representing the greatest well-being.
Surgical Techniques
As described previously, pancreas and kidney grafts were procured following the international standards and guidelines provided by the Deutsche Stiftung für Organtransplantation (DSO) [14, 15]. In short, the pancreas was explanted in a no-touch technique en-bloc with the spleen and duodenum. Back table preparation included removal of the spleen and peripancreatic fat. Reconstruction of the superior mesenteric and the lineal artery was performed using the donor iliac Y-graft.
The pancreas was transplanted into the right iliac fossa using a standard technique with an intraperitoneal location in the right iliac fossa. The Y-graft was anastomosed to the recipient's common iliac artery using 6 − 0 Prolene running sutures. The portal vein was connected to the inferior vena cava of the recipient [16]. Exocrine drainage was carried out with a hand-sutured side-to-side duodenojejunostomy 40 cm beyond the flexure of Treitz [3, 17]. At the end of pancreas implantation, PD catheters were removed in all recipients, and catheter tip culture was routinely performed.
All Kidneys were transplanted into the contralateral iliacal fossa. Vascular anastomoses were performed to the external iliac artery and vein. The ureter was implanted into the bladder according to the Lich-Gregoir technique using a double J catheter as an intraureteral splint [16]. Splint removal was performed 3–4 weeks after successful transplantation. The peritoneal catheter was removed during surgery.
Immunosuppression
The immunosuppressive protocol consisted of an induction therapy followed by triple maintenance therapy.
For induction, antithymocyte globulin with a dose of 4 mg/kg body weight was applied as a single dose before transplantation and followed by a 1 mg/kg body weight infusion on postoperative days 1–3. As an alternative, the interleukin-2 receptor antagonist basiliximab (Simulect ®, 20 mg before transplantation and 20 mg on post-operative day 4) was used in patients with contraindications for ATG therapy. Main contraindications comprised Leukocytopenia, Thrombocytopenia or prevalent urinary tract infections.
Maintenance therapy included calcineurin inhibitors (Cyclosporin (Sandimmun Neoral ® or Tacrolimus (Prograf ®), and/or antimetabolites (Sirolimus (Rapamune ®), Mycofenolate Mofetil (MMF); (Cell Cept ®, Myfortic ®) and tapered steroids (Prednisolone ®). Whole blood levels of Tacrolimus were adjusted to 10–12 ng/ml for the first 3 months and 8–10 ng/ml for month 4 to 12. One year after transplantation levels were reduced to 6 to 8 ng/ml. In parallel, MMF was given at an oral dose of 1 g (Cell Cept ®) or 720 mg (Myfortic ®) twice daily.
A rapid steroid-tapering regimen was applied in all our patients, starting with 500 mg methylprednisolone intraoperatively to reach a dose of 25 mg prednisolone at the end of the first week after transplantation. Further reduction intended a daily maintenance dose of 5 mg. Whenever possible, steroids were rapidly withdrawn and discontinued at the end of the first year.
Statistical analysis
Baseline data are presented as mean values with standard deviation (SD), minimum or maximum range such as proportion percentage (%). Baseline data were compared with appropriate statistical significance test including Student´s t–test, χ2, analysis of variance (ANOVA), Kruskal-Wallis and Wilcoxon–Mann–Whitney test. Comparing HRQoL measurements between PD, HD and the entire SPKT group ANOVA and post-hoc NIR test were used. Survival rates were calculated using the Kaplan-Meier analysis and the log-rank test was applied to test statistical significance. Multivariate Cox proportional hazards analysis was applied to assess independent predictors of patient death and pancreas graft failure, including clinically relevant variables and/or those presenting P ≤ 0.15 in univariate analysis: recipient gender, BMI and age, dialysis modality (HD versus PD), time on dialysis, years of diabetes mellitus, concomitant cardiovascular disease and surgical complications. All data were analysed by using SPSS software (SPSS Inc., Chicago, Illinois, USA, version 21.0). A P value < 0.05 was considered statistically significant.