|Year : 2018 | Volume
| Issue : 2 | Page : 27-33
Pancreatic transplantation for diabetic patients with end-stage renal failure: a brief review
Fakhriya Alalawi1, Ajay Sharma2, Ahmed Halawa3
1 Department of Nephrology, Dubai Hospital, Dubai Health Authority, Dubai, UAE; University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool, UK
2 University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool; Department of Nephrology, Royal Liverpool University Hospitals, Liverpool, UK
3 University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool; Department of Nephrology and Transplantation, Sheffield Teaching Hospitals, Herries Road, Sheffield, UK
|Date of Submission||30-Apr-2018|
|Date of Acceptance||27-May-2018|
|Date of Web Publication||4-Sep-2018|
Department of Transplant Surgeon, Sheffield Teaching Hospital, Herries Road, Sheffield S5 7AU
Source of Support: None, Conflict of Interest: None
Renal transplant, undoubtedly, is the most physiological renal replacement therapy for patients with end-stage kidney disease (ESRD). It enhances patient’s quality of life and improves expectancy when compared with dialysis therapy. However, diabetic kidney transplant recipients can have progressive diabetic nephropathy in renal allograft and other complications of diabetes resulting in relatively inferior patient and graft survival in comparison with nondiabetic patients with ESRD. Currently, the pancreatic-kidney transplant has proven to be a very good option in selected patients with ESRD with type-1 diabetes mellitus, that is, insulin-dependent diabetes mellitus, and further smaller number of patients with ESRD with type-2 diabetes mellitus, that is, noninsulin-dependent diabetes mellitus. The aim of pancreatic transplantation is to enhance the quality of life, improve allograft and patient survival and to reverse some of the microvascular complications associated with diabetes.
Keywords: chronic kidney disease, diabetes mellitus, end-stage renal disease, kidney transplant alone, pancreas after kidney transplants, pancreas transplant alone, simultaneous pancreatic-kidney transplant
|How to cite this article:|
Alalawi F, Sharma A, Halawa A. Pancreatic transplantation for diabetic patients with end-stage renal failure: a brief review. J Egypt Soc Nephrol Transplant 2018;18:27-33
|How to cite this URL:|
Alalawi F, Sharma A, Halawa A. Pancreatic transplantation for diabetic patients with end-stage renal failure: a brief review. J Egypt Soc Nephrol Transplant [serial online] 2018 [cited 2019 Jan 20];18:27-33. Available from: http://www.jesnt.eg.net/text.asp?2018/18/2/27/240587
| Background|| |
The incidence of end-stage kidney disease (ESRD) continues to grow. This global trend is in parallel with the higher prevalence of diabetes mellitus and hypertension. Renal transplant is the preferred modality of renal replacement therapy for patients with ESRD as it provides superior quality of life and enhances patient’s survival when compared with patients who are on waiting list for renal transplantation. In diabetic patients, there is a risk of recurrence of diabetic nephropathy in the renal allograft. Life-threatening microvascular and metabolic complications are the reasons for the relatively worse patient and graft survival in patients having ESRD with diabetes. There is good evidence that combined kidney and pancreas transplant (either at the same time from same donor or pancreas transplant sometime after renal transplant) can ameliorate some microvascular pathology in diabetic patients with uraemia. Quality of life in these patients is much better than diabetics who get a kidney transplant alone (KTA) . We need to appreciate that in pancreas transplant, 99% of the organ (i.e. exocrine part) is not only not necessary but is potentially dangerous. Most peroperative complications in pancreas transplantation are related to this part of pancreas allograft.
Management options for end-stage kidney disease in diabetics
Patients with ESRD secondary to diabetic nephropathy should be educated about all forms of renal replacement therapy, including dialysis and transplantation. Before transplantation, patient’s general condition should be optimized, including blood sugar control, blood pressure management and correction of anaemia. The insulin pump is useful in blood sugar control by delivering frequent and small doses of daily basal insulin, which are essential to control glucose levels for the 24-h period, simulating the natural islets insulin production. Basal insulin dosage can be adjusted, thereafter, as needed. A combination of the insulin pump with continuous glucose monitoring system is an excellent modality for diabetes control. Continuous glucose monitoring system apparatus consists of alarms that warn too low and too high blood sugar levels, which help in adjusting insulin bolus doses and limit variability in blood glucose . Although an insulin pump is a good alternative for diabetics, yet, in the long term, it is not as effective as pancreatic transplantation in preventing long-term complications.
Per the European Renal Best Practice guidelines, there is no superiority of haemodialysis over the peritoneal dialysis in diabetics with ESRD. The optimum timing to create dialysis access is determined by the rapidity of deteriorating kidney functions, the likelihood of working dialysis access, patient’s choice and patient’s life plans .
Timely referral for transplantation
Live kidney donation, when available, remains preferred treatment option over cadaveric renal allograft . Diabetic patients with advanced nephropathy need to be referred earlier to the transplant team when the glomerular filtration rate (GFR) ranges between 25 and 30 ml/min. Early referral facilitates detailed evaluation of transplant candidate and prospective donors. The unidentified coronary artery disease poses a serious threat to these patients, and the battery of tests might include invasive investigations such as coronary angiography. Furthermore, a timely referral facilitates selection of most appropriate donor for pre-emptive transplantation, and in the instances of immunologically incompatible donors (such as ABO incompatible or HLA incompatible), it is possible to work towards successful pooled (or paired) renal donation ,.
Transplant options for diabetics end-stage kidney disease
- KTA: although renal transplant offers reasonable survival advantages for diabetics with ESRD and decreases mortality by nearly 73% in comparison with patients still listed on the waiting list , yet diabetic patients’ graft and patient survivals are inferior to nondiabetic transplants candidates. This is related to advanced cardiovascular diseases, which result in poorer outcomes ,. Strikingly, most episodes of morbidity and mortality are related to cardiovascular events that manifest in the first 3 months after renal transplantation.
- Simultaneous pancreatic-kidney transplant (SPK): when a living donation is not feasible, then a combined surgery of cadaveric kidney and pancreatic transplant is the next preferred option. A segmental pancreatic transplant from a living donor is used in a very limited number of transplant centres, but most transplant centres do not offer this opportunity because of complex surgery and potential life-threatening postoperative complications in donor .
Till recently, pancreatic transplantation was considered as a relative contraindication for diabetic patients with type-2 diabetes mellitus. However, the latest evidence suggests that SPK can be offered to carefully selected group of patients with ESRD with noninsulin-dependent diabetes mellitus (NIDDM). In most of those studies, the transplanted patients are young with no obesity and minimal cardiovascular risk, somewhat uncommon among the vast majority of patients having NIDDM with ESRD.
The patients with frequent hypoglycaemic unawareness episodes are ideal candidates for SPK. All possible advantages of transplantation ought to be balanced carefully against the possible complications of surgical techniques and the adverse effects of immunosuppression. Pros and cons of SPK should be deliberated with the transplant candidate. The prospective recipients should be explained that SPK is surgically more challenging when compared with KTA . United Network for Organ Sharing has defined the following criteria for SPK: (a) insulin therapy and C-peptide level less than 2 ng/ml or (b) insulin therapy with C-peptide level greater than 2 ng/ml and BMI less than 28 kg/m2 . Although there is an inherent risk of additional morbidity following combined kidney-pancreatic transplantation, yet their benefits are substantial, which include enhanced patient and kidney allograft survival, steadiness of diabetic neuropathy and improved quality of life .
Islet cell transplantation
Islet cell transplantation involves percutaneous infusion of pancreatic islets into the portal vein, harvested from one or more deceased donors, and is not a standard surgical procedure. Currently, only a few centres are experienced in using this technique. To achieve insulin independence, most patients require multiple islet transfusions. The long-term success rate is less than 10% as the immunosuppressive protocols are potentially nephrotoxic and failed islet grafts pose a risk alloimmunization (sensitization) of recipients in 10.8–31% .
Pancreas after kidney transplant
In PAK, a kidney from a living donor is followed by pancreatic transplantation from a deceased donor. Pancreatic graft survival in patients with PAK ranges from 78 to 83% at 1 year .
Pancreas transplants alone
PTA patients have 1-year pancreatic allograft survival rate that is similar to PAK transplantation. However, PTA is rarely performed owing to the higher surgical complications rate in addition to other immunological complications .
Patients ought to be considered for pancreatic transplant only when the benefits of operation outweigh the morbidity and mortality risk associated with surgery and immunosuppression. It is suggested that islet cell transplantation can be reserved for diabetics with a low insulin requirement, whereas pancreatic transplant might be ideal for patients with a high insulin requirement or insulin resistance .
Complications of pancreatic transplant surgery
Besides the well-known complications associated with kidney transplantation, pancreatic transplant surgery is associated with a range of perioperative complications that are mainly related to surgical technique, and these are specifically related to the drainage of the exocrine secretions.
Pancreatic graft duct is drained using different surgical methods such as intraperitoneal drainage, cutaneous graft duodenostomy, urinary bladder drainage (BD) and enteric drainage (ED). Currently, only ED and BD are used .
BD is accompanied with chronic complications, for example, dehydration, hyperchloremic metabolic acidosis, recurrent urinary tract infections, intermittent haematuria, chemical cystitis, bladder stones, urethritis, urethral stricture, recurrent pancreatitis, duodenocystostomy leak and perineal excoriations. ED, though much more used over the past decade, is associated with potentially devastating intestinal leakage and duodenal necrosis .
Vascular complications are the most significant threat. Allograft vascular thrombosis (3–10%) is related to numerous vascular anastomoses, twisting and kinking during arterial reconstruction, iliac artery intimal damage and mishandling of arteries and veins.
Other surgical complications include intra-abdominal bleeding, anastomotic leakage (mainly from duodenal anastomosis), pancreatitis, pancreatic necrosis, pancreatic fistula, pancreatic ascites, abscess formation, wound infection, dehiscence, atelectasis and deep vein thrombosis. PAK transplant is an independent risk factor for allograft vascular thrombosis .
Other complications in patients with pancreatic transplant are similar to patients with other form of solid transplanted organs, such as Infectious complications, primary non-functioning graft, delayed allograft function and acute rejection. The probability of immunological failure of pancreas allograft owing to acute rejection is much higher in PTA and PAK than in SPK. Similarly the rate of chronic rejection is higher in PAK (11.6%) and PTA (11.3%) than in SPK (3.7%) ,. This difference is because the acute rejection of kidney allograft in SPK acts as a surrogate marker of pancreatic allograft rejection as both these allografts come from the same donor. Unfortunately, this ‘luxury’ is not available in PAK and PTA as allograft dysfunction is not detected until and unless 90% of endocrine function is knocked off.
Long-term outcomes of pancreatic transplantation
SPK has shown a dramatic improvement in both allograft and patient survival, owing to the advances in immunosuppression and surgical practices ,. Nath et al.  had reported 1-year graft survival rates of 94%, whereas his long-term follow-up (4.3 years) showed patient survival rate of 71% and a pancreas survival rate of 63%. Gruessner & Sutherland (2005) reported improvement of 1-year pancreatic survival rate from 75% in 1998 to 85% in 2003 for SPK and from 55 to 77% for PAK and from 45 to 77% in PTA for United States (US) and non-US cases as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR) . Similarly, Wai & Sollinger (2011) reported 5-year, 10-year, and 20-year patient survival for SPK recipients at 89%, 80% and 58%, correspondingly .
Moreover, quality of life improved in 95% of SPK recipients compared with KTA patients, probably owing to the reduction of the frequent pricking needed for glucose monitoring and stoppage of insulin injections . Besides, better glycaemic control is associated with pancreatic transplantation, and an improvement is noted in lipid profile, and peripheral and autonomic neuropathy. However, diabetic retinopathy and cardiac and macrovascular complications remain irreversible following SPK. PAK recipients can have similar effects as SPK whereas KTA diabetic recipients can develop progressive diabetic nephropathy resulting in inferior allograft survival .
Despite the enhanced allograft survival, cardiovascular mortality in recipients with a functioning graft remains the leading cause of death .
Transplant workup for prospective diabetic recipients
The aim of pretransplant workup ([Figure 1]) is to exclude those who can be harmed by transplantation. Cardiovascular co-morbidities are the most significant threat, and in diabetics, these can remain ‘silent’ because the patients may not challenge themselves enough to manifest symptoms. Patient selection is guided by a comprehensive multidisciplinary pretransplant evaluation, with additional workup as indicated by the particular issues of each patient .
The pretransplant evaluation aims to decide whether the potential candidate is eligible for transplantation or not. Contraindications for transplant surgery include the presence of active infection, morbid obesity, drug or alcohol dependence, psychiatric illness, end organ damage, advanced cardiovascular diseases and the presence of malignancy. Age is not an absolute contraindication for renal transplantation, though most transplant centres do not accept diabetic patients older than 50 years for SPK, yet a few reports of SPK transplant in patients exceeding this age do come to fore .
Obesity with BMI greater than 30–35 kg/m2 is associated with inferior outcomes for both renal transplant and SPK; hence, it is viewed as a relative contraindication for transplantation mostly because of surgical complications. Nevertheless, morbid obesity with BMI greater than 40 kg/m2 is deliberated as an absolute contraindication. However, advances in laparoscopic bariatric surgery can make morbidly obese diabetics ‘earn’ transplant surgery . The expression ‘earning obesity operation and then transplantation’ is emphasized here because the most significant step to weight loss is demonstrable commitment to change in lifestyle.
Basic workup for the transplant candidate ([Figure 1])
Diabetic patients with ESRD represent an elevated cardiovascular morbidity and mortality risks; hence a pretransplant assessment must concentrate on the existence and severity of coronaries and peripheral arteries diseases. There is no international agreement with respect to optimum practice for cardiovascular risks stratification; however, most centres refer the transplant candidates for a cardiac stress test and/or coronary angiography. Moreover, history of dyslipidaemia, smoking and history of cerebrovascular or peripheral vascular diseases represent high cardiovascular risk factors .
Evaluation of carotid arteries stenosis and peripheral arterial disease should start with a duplex examination. Further tests such as computed tomography/MR angiography might be indicated in high-risk patients ,. Patients with extensive arterial calcification noted on their pelvic radiography will make transplanting kidney on either side technically challenging.
Recipient follow-up plan
In clinically stable patients, the usual outpatient clinic visit scheduling is as illustrated in [Table 1] and can be modified as needed .
Common laboratory assessment incorporates blood urea, creatinine, electrolytes, full blood count, glucose, serum amylase/lipase (in cases of SPK/PAK) and immunosuppression blood levels (cyclosporine or tacrolimus) .
Immunosuppression protocols for diabetic recipients are almost similar to other transplant regimens; however, there is a trend for using steroid-free or steroid-tapering (over 4–12 weeks) or steroid minimization regimens ,. Pancreatic recipients are thought to require higher immunosuppressive levels, probably to correlate with increased pancreatic immunogenicity .
Suggested calcineurin inhibitors (CNI) levels in adult’s kidney transplant alone/combined kidney-pancreatic transplant
Mycophenolate mofetil is given in the usual dose of 0.75–1 g twice a day for adult kidney and kidney-pancreatic transplant recipients. Unexplained hyperglycaemia should trigger a prompt evaluation of allograft vasculature with duplex sonography. Moreover, further tests include serum amylase/lipase, C-peptides, haemoglobin A1C, and urinary amylase (unreliable test in cases of BD) and protocol-guided biopsies guided by ultrasound or computed tomography scan ([Table 2] and [Table 3]) .
|Table 2 Target cyclosporine blood concentrations for adult kidney and kidney-pancreas transplant recipients |
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|Table 3 Target tacrolimus blood concentrations for adult kidney and kidney-pancreas transplant recipients |
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For urinary bladder drainage (BD) pancreas transplants and Reduced urinary amylase and lipase levels are the best markers for pancreatic transplant acute rejection, which often herald hyperglycaemia. Currently, protocol pancreatic biopsies are the standard strategy in most transplant units and can diagnose pancreatic acute rejection much before the appearance of clinical manifestations  ([Figure 2]).
|Figure 2 Proposed algorithm by University of Wisconsin for Diagnosis and Treatment of Pancreatic Graft Rejection. ACMR, acute cell-mediated rejection; aAMR, acute antibody-mediated rejection; ATG, antithymocyte globulin; cAMR, chronic antibody-mediated rejection; DSA, donor-specific antibody; IVIg, intravenous immunoglobulin; PP, plasmapheresis .|
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| Conclusion|| |
Renal transplant, undoubtedly, is the best available modality for renal replacement therapy in diabetic patients with ESRD. It enhances patient’s quality of life and improves life expectancy when compared with dialysis. Therefore, any diabetic patients who are suitable for renal transplant surgery and chronic immunosuppression therapy should have an extensive assessment to identify any factors that may hinder their suitability for any forms of pancreatic transplantation. Currently, combined kidney/pancreas transplant became the best treatment option for selected patients with ESRD with insulin-dependent diabetes mellitus (IDDM) and much smaller number of patients with ESRD with NIDDM. These would provide satisfactory glycaemic control, possibly reverse early diabetic complications and improve quality of life. However, pros and cons of SPK and PAK transplantation should be deliberated carefully, and it must be emphasized that such surgery is much more challenging when compared with KTA. Islet cell transplantation is a reasonable option if whole organ transplantation is not feasible provided that expertise and resources are available or as a part of an investigative trial.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]