Simultaneous pancreas-kidney transplantation for end-stage renal failure in type 1 diabetes mellitus: Current perspectives

Type 1 diabetes mellitus(T1DM)is one of the important causes of chronic kidney disease(CKD)and end-stage renal failure(ESRF).Even with the best available treatment options,management of T1DM poses significant challenges for clinicians across the world,especially when associated with CKD and ESRF.Substantial increases in morbidity and mortality along with marked rise in treatment costs and marked reduction of quality of life are the usual consequences of onset of CKD and progression to ESRF in patients with T1DM.Simultaneous pancreas-kidney transplant(SPK)is an attractive and promising treatment option for patients with advanced CKD/ESRF and T1DM for potential cure of these diseases and possibly several complications.However,limited availability of the organs for transplantation,the need for long-term immunosuppression to prevent rejection,peri-and post-operative complications of SPK,lack of resources and the expertise for the procedure in many centers,and the cost implications related to the surgery and postoperative care of these patients are major issues faced by clinicians across the globe.This clinical update review compiles the latest evidence and current recommendations of SPK for patients with T1DM and advanced CKD/ESRF to enable clinicians to care for these diseases.

PREVENTION AND TREATMENT OF REJECTION AFTER SIMULTANEOUS PANCREAS-KIDNEY TRANSPLANTATION

Objective To explore methods of preventing and reversing rejection after simultaneous pancreas-kidney （SPK） transplantation. Methods Seventeen patients underwent SPK transplantation from September 1999 to September 2003 were reviewed retrospectively. Immunosuppression was achieved by a triple drug regimen consisting of cyclosporine, mycophenolate mofleil （MMF）, and steroids. Three patients were treated with anti-CD3 monoclone antibody （OKT3, 5 mg·d^-1） for induction therapy for a mean period of 5-7 days. One patients received IL-2 receptor antibodies （daclizumab） in a dose of I mg·kg^-1 on the day of transplant and the 5th day posttransplant. One patient was treated with both OKT3 and daclizumab for induction. Results No primary non-functionality of either kidney or pancreas occurred in this series of transplantations. Function of all the kidney grafts recovered within 2 to 4 days after transplantation. The level of serum creatinine was 94 ± 11 μmol/L on the 7th day posttransplant. One patient experienced the accelerated rejection, resulting in the resection of the pancreas and kidney grafts because of the failure of conservative therapy. The incidence of the first rejection episodes at 3 months was 47.1% （8/17）. Only the kidney was involved in 35.3% （6/17）; and both the pancreas and kidney were involved in 11.8% （2/17）. All these patients received a high-dose pulse of methylprednisone （0.5 g·d^-1） for 3 days. OKT3 （0.5 mg·d^-1） was administered for 7-10 days in two patients with both renal and pancreas rejection. All the grafts were successfully rescued. Conclusion Rejection, particularly acute rejection, is the major cause influencing graft function in SPK transplantation. Monitoring renal function and pancreas exocrine secretion, and reasonable application of immunosuppressants play important roles in the diagnosis and treatment of rejection.

The Current State of Pancreas-kidney Transplantation in China:The Indications,Surgical Techniques and Outcome

It is currently estimated that 50 million Chinese have diabetic mellitus （DM） with more than 90% of these being afflicted with type 2 DM. Concomitantly, the socio-economic improvements in China are supporting the adoption of pancreas-kidney transplantations as a treatment option for these patients. Recipient candidate pool has yet to be expanded and the final effect to be improved in clinical practice. To date, more than 250 pancreas-kidney transplants have been performed on patients with type 1 and type 2 DM. To improve the outcome, a new surgical technique that involves anastomosis of the graft duodenum to recipient jejunum side-to-side but not Roux-en-Y, has been devised for enteric drainage. Furthermore, the systemic venous drainage （SVD） has been used as the method of choice for endocrine secretions. Graft and recipient long-term survival in China was similar to that in America and Europe. Three-year survival rate of pancreas and kidney grafts was 92.2% and 90.2%, respectively, in our center. No difference in survival and graft function between type 1 and type 2 DM recipients was noted. It is concluded that pancreas-kidney transplantation is an effective way for the treatment of type 1 DM and some type 2 DM complicated with uremia.

A mathematical model for shortening waiting time in pancreas-kidney transplantation

AIM: To simulate a hypothetical increase of 50% in the number of pancreas-kidney (PK) transplantations using less-than-ideal donors by a mathematical model. METHODS: We projected the size of the waiting list by taking into account the incidence of new patients per year, the number of PK transplantations carried out in the year and the number of patients who died on the waiting list or were removed from the list for other reasons. These variables were treated using a model developed elsewhere. RESULTS: We found that the waiting list demand will meet the number of PK transplantation by the year 2022. CONCLUSION: In future years, it is perfectly possible to minimize the waiting list time for pancreas transplantation through expansion of the donor pool using less-than-ideal donors.

Mycophenolic Acid Absorption Profiles in Patients with Kidney or Combined Pancreas-Kidney Transplantation

Background: Mycophenolate Mofetil (MMF) is widely used in organ transplant patients to avoid calcineurine inhibittor-associated side effects. Therapeutic monitoring of MMF is up to now perform by using trough level measurements (measurements before drug administration). The present study was designed to characterize potential differences in MMF absorption kinetics between patients with allogenic kidney transplantation [kidney Tx] and simultaneous pancreas kidney transplantation [PK Tx], which might for example occur due to diabetic gastrointestinal atony. Methods: A total of 64 pharmacokinetic profiles were prospectively studied in 44 adult kidney Tx and 20 PK Tx patients. To calculate AUC by the trapezoidal rule, mycophenolic acid (MPA) levels were measured in EDTA-plasma by an EMIT assay at 0, 0.5, 1, 2, 3, 4 6, and 12h after oral MMF administration between postoperative day 14 to 28 instable patients. Results: Substantial differences between kidney Tx and PK Tx patients were evident concerning: donor age, recipient age, number of mismatches, and kidney function (serum creatinine). Despite these dissimilarities pharmacokinetic absorption profiles did not significantly differ between patient groups as measured by AUC, C2, maximum MPA concentration (Cmax), and time until maximum absorption (Tmax). Astonishingly, concomitant cyclosporine and tacrolimus medication did not influence adsorption profiles. Only MPA concentrations 6h post administration correlated closely with AUC in both patient groups, whereas trough levels failed to be predictive for AUC. Conclusions: In our study population, MMF absorption kinetics did not differ between kidney and PK Tx patients and did not seem influenced by concomitant immunosuppressive medication. Therefore, MPA measurements during the absorption phase could be useful to better estimate AUC in patients with kidney Tx and PK Tx.

Simultaneous pancreas-kidney transplantation with enteric drainage of exocrine secretions

s To simplify the enteric drainage (ED) procedure and to decrease surgical and metabolic complications in simultaneous pancreas-kidney transplantation (SPK) patients Methods Between June 2000 and June 2002, nine patients with insulin-dependent diabetes mellitus (IDDM) and uremia underwent simultaneous pancreas-kidney transplantati on The arterial inflow of the pancreas was based upon the right external iliac artery, while venous drainage was systemic via the external iliac vein The allografts’ exocrine secretions were drained into the proximal jejunum via a two-layer hand sewn, side-to-side donor duodenum to proximal small bowel anastomosis after reperfusion No Roux-en-Y an astomosis of the jejunum was performed The kidney graft was placed in the left iliac fossa Quadruple immunosuppressive therapy with antilymphocyte globulin or anti-CD25 monoclonal antibody (Zenapax ), tacrolimus, mycophenolate mofetil and steroids was standard treatment in all patients Results This procedure was successfully applied in all 9 patients without complication referable to the technique All patients had achieved euglycemia and excellent renal function, and stopped being dependent on an external insulin source Fasting serum glucose fell from 9 5 preoperatively to 4 8 mmol/L and remained stable thereafter At the time this paper was written, the grafts from eight patients were functioning well Conclusions Our primary experience suggests that SPK with ED without Roux-en-Y anastomosis represents a more physiologic milieu, and a viable alternation to replace the bladder (BD) as the primary route of drainage for exocrine secretions of the pancreas It is a feasible and safer procedure

Simultaneous pancreas-kidney transplantation in a single center： 10-year retrospective analysis

Background Simultaneous pancreas-kidney transplantation （SPKT） is the best treatment option for diabetic patients with advanced chronic renal failure. The current study aimed to analyze the surgical indications, treatments and prognosis of SPKT.Methods We retrospectively analyzed 40 cases of SPKT performed between December 1999 and January 2010 in our center, including the survival rate, complications and the reasons of reoperation.Results Of all the 40 SPKT cases, the one-year survival rates of the recipients, kidney and pancreas transplant graft were 97.6%, 97.6% and 92.7%, while 97.6%, 91.1%, 92.7% at 3 years and 83.6%, 78.0%, 79.4% at 5 years, respectively. After SPKT, 10 patients need reoperation because of surgical complications （14 operations）. The reoperation rate was 25%, including 2 patients （4 operations） with hematuria, 4 patients with abdominal hemorrhage, 2 patients （3 operations） with abdominal infection, 1 patient with pancreatic venous thrombosis, 1 patient with anastomotic leakage, and 1 patient with fistula.Conclusion Although SPKT provides a successful and effective treatment for diabetics with end-stage renal disease, how to reduce the complications of this treatment still need further effort.

Mortality assessment for pancreas transplants in the United States over the decade 2008-2018

BACKGROUND Pancreas transplant is the only treatment that establishes normal glucose levels for patients diagnosed with diabetes.However,since 2005,no comprehensive analysis has compared survival outcomes of:(1)Simultaneous pancreas-kidney(SPK)transplant;(2)Pancreas after kidney(PAK)transplant;and(3)Pancreas transplant alone(PTA)to waitlist survival.AIM To explore the outcomes of pancreas transplants in the United States during the decade 2008-2018.METHODS Our study utilized the United Network for Organ Sharing Standard Transplant Analysis and Research file.Pre-and post-transplant recipient and waitlist characteristics and the most recent recipient transplant and mortality status were used.We included all patients with type I diabetes listed for pancreas or kidneypancreas transplant between May 31,2008 and May 31,2018.Patients were grouped into one of three transplant types:SPK,PAK,or PTA.RESULTS The adjusted Cox proportional hazards models comparing survival between transplanted and non-transplanted patients in each transplant type group showed that patients who underwent an SPK transplant exhibited a significantly reduced hazard of mortality[hazard ratio(HR)=0.21,95%confidence intervals(CI):0.19-0.25]compared to those not transplanted.Neither PAK transplanted patients(HR=1.68,95%CI:0.99-2.87)nor PTA patients(HR=1.01,95%CI:0.53-1.95)experienced significantly different hazards of mortality compared to patients who did not receive a transplant.CONCLUSION When assessing each of the three transplant types,only SPK transplant offered a survival advantage compared to patients on the waiting list.PKA and PTA transplanted patients demonstrated no significant differences compared to patients who did not receive a transplant.

Pancreas transplantation in type Ⅱ diabetes mellitus

Although the diagnosis of type 2 diabetes mellitus was once considered a contraindication to simultaneous pancreas-kidney transplantation, a growing body of evidence has revealed that similar graft and patient survival can be achieved when compared to type 1 diabetes mellitus recipients. A cautious strategy regarding candidate selection may limit appropriate candidates from additional benefits in terms of quality of life and potential amelioration of secondary side effects of the disease process. Although our current understanding of the disease has changed, uniform listing characteristics to better define and study this population have limited available data and must be established.

Exocrine drainage in vascularized pancreas transplantation in the new millennium

The history of vascularized pancreas transplantation largely parallels developments in immunosuppression and technical refinements in transplant surgery. From the late-1980 s to 1995, most pancreas transplants were whole organ pancreatic grafts with insulin delivery to the iliac vein and diversion of the pancreatic ductal secretions to the urinary bladder(systemic-bladder technique). The advent of bladder drainage revolutionized the safety and improved the success of pancreas transplantation. However, starting in 1995, a seismic change occurred from bladder to bowel exocrine drainage coincident with improvements in immunosuppression, preservation techniques, diagnostic monitoring, general medical care, and the success and frequency of enteric conversion. In the new millennium, pancreas transplants are performed predominantly as pancreatico-duodenal grafts with enteric diversion of the pancreatic ductal secretions coupled with iliac vein provision of insulin(systemic-enteric technique) although the systemic-bladder technique endures as a preferred alternative in selected cases. In the early 1990 s, a novel technique of venous drainage into the superior mesenteric vein combined with bowel exocrine diversion(portal-enteric technique) was designed and subsequently refined over the next ≥ 20 years to recreate the natural physiology of the pancreas with firstpass hepatic processing of insulin. Enteric drainage usually refers to jejunal or ileal diversion of the exocrine secretions either with a primary enteric anastomosis or with an additional Roux limb. The portal-enteric technique has spawned a number of newer and revisited techniques of enteric exocrine drainage including duodenal or gastric diversion. Reports in the literature suggest no differences in pancreas transplant outcomes irrespective of type of either venous or exocrine diversion. The purpose of this review is to examine theliterature on exocrine drainage in the new millennium(the purported "enteric drainage" era) with special attention to technical variations and nuances in vascularized pancreas transplantation that have been proposed and studied in this time period.