The primary targets of islet transpla in DM are to: o Provide insulin independence, o Improve quality of life, & o Limit secondary sequelae.
Islet transplant
Abbreviations
o AB: antibodies
o Ac Rj: Acute rejection.
o ADA: American Diabetes Association.
o AE: adverse events.
o BMI: body mass index.
o CITR: Collaborative Islet Transplant Registry.
o CT: computed tomography.
o CyA: Cyclosporine.
o Dc Np diabetic nephropathy
o Dc Nr diabetic neuropathy
o DCCT: Diabetes Control and Complications Trial.
o EPITA: the European Pancreas and Islet Transplant Association
o ESKD: end-stage kidney disease.
o FBS: fasting blood glucose.
o GC: glucocorticoids
o HDL: serum high-density lipoprotein.
o HG: hypoglycaemia.
o HLA: human leukocyte antigen.
o im/m: immunosuppressive therapy
o IPITA: International Pancreas and Islet Transplant Association
o KTx: kidney transplantation.
o LDL: low-density lipoprotein.
o Mgcp: magnetoencapsulation/magnetocapsules.
o Mic: Microencapsulation.
o MMF mycophenolate mofetil.
o MR: mortality rates.
o MRI: Magnetic resonance imaging.
o NEPECs: nonendocrine pancreatic epithelial cells.
o PAK: Pancreas after kidney.
o PET: positron-emission tomography.
o PTA: pancreas transplant alone.
o PV: Portal vein.
o SPK: simultaneous pancreas-kidney.
o SRL Sirolimus.
o Tac: tacrolimus.
o Tac: Tacrolimus.
o TNFa: Tumour necrosis factor-alpha.
o TPIAT: total pancreatectomy and islet auto transplantation.
o TR: Transplant recipients.
o Tx: transplantation.
o UB: urinary bladder.
o UNOS: United Network for Organ Sharing.
The primary targets of Tx in DM are to:
o Provide insulin independence,
o Improve quality of life, &
o Limit secondary sequelae.
Pancreas Tx is usually performed with simultaneous KTx in selected ptns with DM + ESKD who’re already requiring im/m for the kidney allograft. PAK & PTA are proceeded less commonly. Islet cell Tx is still under development. We will go through the history, technique, and clinical outcomes of pancreas & pancreatic islet Tx in hyperglycaemic ptns with longstanding DM type 1, focusing on islet Tx or pancreatic tissue alone. Both pancreas & islet Tx needs lifelong im/m to impede allograft rejection. ESKD ptns receiving SPK or PAK Tx are already maintained on im/m therapy for the kidney allograft, so, the impact of im/m therapy on quality of life is minimal. However, ptns may receive PTA with no Dc Np, the benefit of impeding the progression of secondary complications must be weight for the untoward effects of the im/m medications after Tx (e.g., diarrhoea, cytopenia, anaemia, fatigue, HT, osteoporosis, variable infections & secondary malignancies).
ADA criteria for Tx:
· SPK or PAK: ptns with type 1 DM & ESRD having had or plan to get KTx are candidates also for pancreas Tx. Successfully performed pancreatic Tx will help better glycemic control with better kidney survival. Pancreatic Tx usually proceeded in DM + ESKD. TR mostly receive SPK rather than PAK.
· PTA: considered only in ptns with intolerable diabetic sequelae where the quality of life is awfully difficult with complications like:
o Persistent, frequent & severe metabolic sequelae (HG, severe hyperglycaemia, ketoacidosis)
o Incapacity with clinical/emotional feelings related to exogenous insulin injection.
o Persistent resistance to insulin-based regimen to hold acute complications
· Islet: Islet Tx considered an evolving technique that is usually confined only to the controlled research work-up. Pre- Tx screening for CVS disease in PTA is similar to that in combined kidney-pancreas Tx.
Pancreas vs islet Tx:
There’re no direct, RCT comparing outcome of SOT vs islet Tx. Few observational studies compared pancreas & islet Tx. Report: single centre performed 33 PTA & 33 islet Tx, ptns undergoing PTA showed a higher rate of insulin independence after one-y. follow-up. Long-term side effects (timing/frequency of hospitalization, re-intervention for acute surgical/immunologic sequelae, infection) was higher with pancreas Tx. Retrospective study: compared 15 PTA & 10 islet Tx, the rate of insulin independence at 3 ys was similar. Database from pancreas & islet Tx showed elevated rate of insulin independence with pancreas Tx, but also a higher morbidity related to general surgery. However, islet Tx is less invasive, so, it associated with lowered morbidity. However, the rate of long-term success (= insulin independence) is lesser.
PANCREATIC TX
It was the year 1966, when pancreas Tx was 1st used to treat DM in humans. The reported rates of graft & ptn survival were low; consequently, very few operations were implemented in the early/mid-1970s. With subsequent advent of better im/m plans (especially CyA & anti-T-cell AB), new surgical approaches, & selection of healthier TR resulted in a greatly better outcome. So, the number of pancreatic Tx were rising each year in the US, up to its peak at 1484 in 2004. In the US within 2016, 791 SPK, 73 PAK, and 73 PTA) Tx were implemented. The decline in frequency of pancreas Tx probably related to improved therapies of insulin-based protocols since the DCCT results and the subsequent lower rates of secondary sequelae of chronic hyperglycaemia.
Outcomes: MR/morbidity, and results of Tx vary with team experience & TR selection.
TR survival
● Considering 2004-2015 data, ptn survival for SPK, PAK, or PTA = 96-99 % at postoperative one y, 89-91 % at 5 ys, and 70-80 % at 10 ys. Most deaths in the 1st 3 mo post-Tx & subsequently were related to CVS or cerebrovascular disorder.
● Few data on survival benefits for TR as compared to waitlisted ptns. The following findings rely on the retrospective analysis of Tx registries from 1995-2003:
o Survival rates for SPK TR was much better than waitlisted ptns maintained on DX. The lowered MR is partly related to the documented survival benefit offered by KTx alone (KTA; even with no pancreatic Tx) as compared to DX.
o Among PTA or PAK TRs, survival at 4 ys was equivalent to that on waiting list.
o Retrospective study: 11,572 Dcs with preserved renal function on waiting list for pancreatic Tx, survival (4 ys): significant worsened with PTA as compared to waitlist ptns on conventional plans. However, there could be clear variables between the PTA g. and the waitlisted ptns. This repetition could induce bias on the outcome of this report favouring ptns on the waiting list.
Graft survival: Based on 2004-2015 data, early graft loss (on 90 d.s) seen in about 8-9.4 % of TR. 5-y pancreatic graft survival for SPK, PAK, & PTA was: 73, 65, & 53 %, resp. Pancreatic graft survival is inversely related to many donor factors, i.e., age, BMI, and CVS death. TR of pancreas Tx alone with organs coming from donors with poor donor indices showed declined rate of graft survival as compared to SPK TR.
Definition of pancreatic graft survival has variable definition in Tx centres (e.g., persistent entire insulin independence, persistent C-peptide production). Consensus in definition may strengthen future outcome trials. In the US, the UNOS has admitted a new definition of graft failure (2018) that includes using of insulin ≥0.5 units/kg/d for 90 consecutives d.s. In 2018, a classified graft function was admitted by the IPITA & EPITA. They are based primarily on glycated HB (A1C), severity of HG episodes, insulin requirement, & C-peptide. Graft function could be:
o Optimal function: Near-normal glycemic control (A1C ≤6.5 %) + No severe HG or insulin/other antihyperglycemic agents + raised C-peptide as compared to pre-Tx.
o Good function: A1C <7 % + no severe HG + significant decline in insulin needs (>50 % decline = <0.5 units/kg/d) + raised C-peptide compared with pre-Tx.
o Marginal function: A1C ≥7 %, + severe HG, or < 50 % decline in insulin needs, when there’s rise in C-peptide compared to pre-Tx.
o Failed graft: Lack of any evidence for clinically significant C-peptide availability.
Metabolic effects: pancreatic Tx can induce independence from exogenous insulin + improved glucose metabolism, A1C, acute insulin response to IV glucose, & counterregulatory s. glucagon & glucose to insulin-induced HG. These benefits can be attributed to resuming islet function that can be maintained for ys. (15 ys in some centres).
Ptn with functioning graft showed normal insulin response to oral & IV glucose triggering and to IV arginine & IV secretin. However, considering the systemic (rather than portal) venous drainage of the allograft basal and stimulated peripheral insulin concentrations are 2-3 times higher than normal. So, the hepatic 1st-pass uptake & degradation of insulin secretion into the PV are bypassed; normally, 50-90 % of insulin in PV blood undergoes 1st -pass hepatic metabolism. Post-Tx hyperinsulinemia has no impact on CVS risk. S. triglyceride & LDL tend to drop while s. HDL tend to rise.
Glucose counter-regulating hormones after HG can be corrected by pancreas Tx. This is beneficial as ptns with DM for years prior to Tx typically show abnormal glucose counter regulating system due to lowered s. glucagon & epinephrine response to HG. The improved glucose counter regulation in TR of pancreatic Tx is due normalizing the glucagon & improving the epinephrine counterregulatory responses. Awareness of HG Sms also improved. HG due to pancreas Tx has been reported, but it is usually mild. Many studies conducted ptns with combined kidney-pancreas Tx.