Orlando, G: Transplantation, Bioengineering, and Regeneratio

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TRANSPLANTATION,
BIOENGINEERING,
AND
REGENERATION
OF THE ENDOCRINE
PANCREAS,
VOLUME 1
Copyright
Dedication
Contributors
Preface
Part A: Whole pancreas allo-transplantation
Section I: Introduction
1 History of pancreas transplantation
	The first attempt at transplantation of pancreatic tissue
	The nature of the pancreas
	Discoveries about the pancreas
	Discoveries about the relationship between pancreas and diabetes
	Discoveries about insulin and diabetes etiology
	Early animal models of diabetes and pancreas transplantation
	Modern animal models of pancreas transplantation and surgical techniques
	Modern animal models of pancreas transplant immunology
	History of pancreas transplantation in humans
	Acknowledgments
	References
2
How to build a pancreas transplant program
	Introduction
	Leadership commitment to growth in pancreas transplantation
	Growing the pancreas transplant waitlist through reevaluation of diabetic kidney waitlist patients
	Growing the pancreas transplant waitlist through expanded recipient eligibility criteria
	Modification of kidney transplant evaluation of new patients
	Promotion of pancreas transplant for diabetic kidney transplant recipients (PAK)
	Promotion of solitary pancreas transplants for hypoglycemic unawareness
	Modification of clinical outreach to promote pancreas transplantation
	Modification of donor call to promote pancreas transplant
	Modification of donor pancreas acceptance rates
	Simplifying pancreas transplant management through use of protocols
	Conclusions
	References
3
Pathophysiology of diabetes
	Introduction
	Insulin structure, secretion, and action
		Structure
		Secretion
		Action
			Effects of insulin on glucose and lipid metabolism
			Vascular actions of insulin
		Pathogenesis of diabetes
			Genetic factors
			Environmental factors
	Type 1 diabetes
		Autoimmunity and cellular immunity
	Type 2 diabetes
		Insulin resistance
			Adipokines and insulin resistance
		Peripheral glucose uptake
		Hepatic glucose production
		β -Cell dysfunction
			Glucotoxicity
			Lipotoxicity
	References
4
Epidemiology of diabetes mellitus
	History/classic definitions
	Special populations
	Descriptive epidemiology
	Risk factors
	Diabetes complications
	Treatment
	References
Section II: The donor
5
Pancreas donor selection
	Introduction
	The ideal pancreas donor
		Extending the age range of viable pancreas donors
		Donor body mass index
		Abnormal laboratory values
		Infection
		Local vs imported organs
		Donation after cardiac death donors
		Pancreas donor quality assessment scales
		Graft selection
	Logistical aspects to optimize organ viability
	Conclusion
	References
6
Deceased donor pancreas procurement
	Donor selection
	Assessment of the potential pancreas donor
	Evolution of practice
	Preoperative preparation
	Surgical technique
		Warm phase dissection
		Cross clamping and initiation of cold perfusion
		Cold phase dissection
	Pancreas preservation
	En bloc technique for pancreas-liver procurement
	DCD procurement
	Arterial variations in combined pancreas and liver procurement
	Procurement with small bowel
	Procurement without liver
	Summary
	References
7
Surgical techniques for living donor pancreas transplantation
	Introduction
	Selection criteria for donors
	Donor operation
		Open standard procurement of the distal pancreas from a living donor
		Open simultaneous procurement of left kidney/distal pancreas
		Laparoscopic/robotic procurement of the distal pancreas from a living donor
		Variations
			Laparoscopic/robotic procurement of the distal pancreas with the left kidney
			Laparoscopic/robotic procurement of the distal pancreas with the right kidney
	Postoperative management
	Donor complications
	Recipient operation
		Bladder drainage
		Enteric drainage
	Variations in operative technique
		Diversion of exocrine pancreatic secretions
		Positional variations
		Posttransplant management
			Anticoagulation
			Immunosuppression
			Blood glucose control and octreotide
		Complications
		Outcomes
	Conclusions
	References
8
Pancreas preservation
	Introduction
	Organ damage after death
	Cold storage and its effects
		Development of UW
		Clinical results
		Pancreas preservation going forward
	References
9
Pancreas graft back-table surgery technique
	Introduction
		Anatomical variations
	Classical technique with sutures/ties
		Vascular reconstruction
		Gastroduodenal reconstruction
		Dorsal pancreatic artery
		Venous reconstruction
	Tieless technique with bipolar device
	Methods (description of technique)
	Conclusion
	References
	Further reading
Section III: The recipient
10
Pancreas transplant alone
	Introduction
	Indications
	Pretransplant evaluation
		Cardiovascular assessment
		Peripheral vascular disease
		Assessment of insulin requirements, C-peptide, and autoimmunity
		Assessment of hypoglycemia
		Assessment of complications related to hyperglycemia
		Kidney function evaluation
	Donor selection: Avenues to increase pancreas utilization
	Preoperative transplant assessment
	Recipient operation
	Immunosuppression
	Postoperative management
	Complications
	Rejection
	Outcomes
	Summary
	References
11
Pancreas after kidney transplantation
	Introduction
	Indications and options for uremic diabetes
		General indications for PAK
		Availability of a living donor kidney and avoiding dialysis
		Determining appropriateness for PAK
		Timing of PAK
		Deciding between SPK and PAK
	Operative concerns and immunologic challenges for PAK
	Outcomes: Graft and patient survival
		Patient-reported outcomes
	Future directions and challenges
	References
12
Simultaneous pancreas-kidney transplantation
	Introduction
	History
	Epidemiology
	Indications
		IDDM patients with renal failure: Treatment options (SPK, KTA, PAK, and re-transplantation)
	Recipient selection
	Donor characteristics
		Donor/recipient compatibility
	Outcomes
		Patient survival
		Pancreas graft survival
		Kidney graft survival
		Effects on long-term diabetes complications
	Immunosuppression
		Induction
		Biological agents
		Corticosteroids
	Maintenance
		Calcineurin-inhibitors (CNI)
		Rapamycin inhibitors
	Antiproliferative agents
		Corticosteroids
	Surgical techniques
		Back-table surgery
	Implantation
		Exocrine drainage
		Endocrine drainage
	Complications
		Early technical failure
	Medical postoperative complications
		Cardiovascular complications
	Immunological complications
		Rejection
		Recurrent autoimmune disease
	Infections
		Cancer
	Surgical late complications
	SPK and pregnancy
	References
	Further reading
13
Surgical techniques for deceased donor pancreas transplantation
	Introduction
	Management of exocrine pancreatic secretions: Bladder vs enteric drainage
		Surgical procedure: Intraoperative management
		Surgical procedure: Recipient operation (1)
			Enteric drainage
			Bladder drainage
		Surgical procedure: Recipient operation (2)
	Venous outflow: Systemic vs portal drainage
	Graft size: Whole organ vs segmental transplants
	Graft placement: Intraperitoneal vs extraperitoneal implantation
	Surgical variations and technical modifications
		Systemic vein and bladder exocrine drainage
			Whole organ pancreaticoduodenal transplants with systemic vein and bladder exocrine drainage on the right side
			Whole organ pancreaticoduodenal transplants with systemic vein and bladder exocrine drainage on the left side
			Segmental pancreas transplant with systemic vein and bladder drainage
		Systemic vein and enteric drainage
			Whole organ pancreaticoduodenal transplant with systemic vein and enteric drainage: Right side
				Caudad position
				Cephalad position
			Whole organ pancreaticoduodenal transplant with systemic vein and enteric drainage: Left side
			Segmental pancreas transplants with systemic vein and enteric drainage
		Portal vein and enteric drainage
			Whole organ pancreaticoduodenal transplant with portal vein and enteric drainage
			Segmental pancreas transplants with portal vein and enteric drainage
		Other drainage options
	Other types of pancreas transplants
	Robotic techniques
		Surgical technique
	Conclusion
	References
14
Robotic pancreas transplantation
	Introduction
		Why to pursue robotic PTx
		Practical issues with robotic PTx
			Graft rewarming/cooling
			Pneumoperitoneum
			Graft bleeding at the time of reperfusion
		What is needed to perform robotic PTx
			Operative team
			Operating room
	Donor procedure
		Recipient procedure
	Other techniques for robotic PTx
	Conclusions
	References
15
Pancreas transplantation in the setting of multivisceral transplantation
	Introduction
	Indications and types of grafts
	Contraindications
	Donor selection
	Donor surgery
	Recipient surgery
	Immunosuppression
	Postoperative management
	Monitoring of the pancreas graft
	Outcomes and complications
		Ischemia-reperfusion injury
		Technical complications
		Pancreaticobiliary complications
	Infections
	Rejection
		Mechanisms of allograft rejection
		Acute rejection
		Chronic rejection
	Gvhd
	Chronic kidney disease
	References
16
Imaging in pancreas transplantation
	Preoperative planning: Imaging of potential recipient
	Preoperative planning: Imaging of donor
	Postoperative imaging
	Sonography
	Computed tomography and magnetic resonance imaging
	Interventional imaging
	Complications
		Vascular complications
		Nonvascular complications
			Postoperative hematoma
			Postoperative abscess
			Pancreatitis
			Rejection
		Bowel complications
		Posttransplant lymphoid proliferative disorders
	Conclusion
	References
17
Postoperative care of the pancreas transplant patient
	Introduction
	Perioperative care
	General postoperative care
		Antibioprophylaxis
		Glycemic control
		DVT prophylaxis
	Nutrition
	Somatostatin and analogues
	Immunosuppression
	Prevention of vascular graft vein thrombosis
	Other specific surveillance
	Conclusion
	References
18
Immunosuppression for pancreas allo-transplantation
	Introduction
	Induction therapy
		Induction immunosuppression agents
		Evidence for induction therapy
	Maintenance therapy
		Maintenance immunosuppression agents
		Evidence for maintenance regimens
	Antirejection treatment
	Infections and immunosuppression
	Immunosuppression and malignancy in PTX
	Immunosuppressive therapy and pregnancy
	Conclusion
	References
Section IV: Complications after pancreas allo-transplantation
19
Infectious complications after pancreas allotransplantation
	Introduction
	Evaluation for infection before transplantation
	Perioperative prophylaxis
	Surgical site infections
	Urinary tract infections
	Bacteremia
	Cytomegalovirus infection
	BK virus infection
	Donor-derived infections
	Pancreas transplantation in HIV-infected individuals
	Conclusions
	References
	Further reading
20
Medical complications after pancreas transplantation
	Hyperglycemia
		Early posttransplant hyperglycemia
			Primary nonfunction
			Delayed endocrine graft function
		Late posttransplant hyperglycemia
	Hypoglycemia
		Early posttransplant hypoglycemia
		Late posttransplant hypoglycemia
	Pancreatitis
		Pancreatitis in enteric-drained and bladder-drained grafts
		Pancreatitis specific to bladder-drained grafts
	Gastrointestinal bleeding
		Gastrointestinal bleeding in enteric-drained pancreas graft recipients
		Gastrointestinal bleeding in bladder-drained pancreas graft recipients
	Loss of native kidney function (pancreas transplant alone recipients only)
	Other medical complications specific to bladder-drained grafts
		Urinary tract infection
		Urethral complications and dysuria
		Hematuria
		Metabolic acidosis and dehydration
	References
21
Technical complications of pancreas allotransplantation
	Introduction
	Surgical techniques/considerations
		Current pancreas transplant procedure
		Exocrine drainage
		Endocrine drainage
	Pretransplant complications
	Intraoperative complications
	Posttransplant complications
		Early posttransplant pancreas graft thrombosis
		Late posttransplant pancreas graft thrombosis
		Posttransplant bleeding
			Intra-abdominal bleeding
			Gastrointestinal (GI) bleeding
			Genitourinary (GU) bleeding
			Other potential causes of bleeding and vascular compromise
		Intra-abdominal infection
		Anastomotic leak
		Graft pancreatitis
		Transplant pancreatic pseudocysts and fistulas
		Urologic complications of bladder-drained grafts
		Kidney vascular torsion
	Conclusion
	References
22
Pancreas transplantation, bioengineering, and regeneration
	Introduction: Clinical presentation of pancreas rejection through the evolution of surgical techniques and immunosuppressiv ...
		The early segmental pancreas transplant period
		Return to the whole organ technique for transplantation
	Epidemiology and risk factors for pancreas rejection
		The early beneficial role of HLA matching in pancreas transplantation
		Recurrence of autoimmunity in pancreas recipients
	Evaluation means of diagnosing rejection
		Clinical manifestations
		Laboratory monitoring for rejection
			Urinary markers
				Urine markers of exocrine rejection
					Urine amylase
					Other urine markers
				Urine markers of endocrine rejection
			Serum markers
				Serum markers of exocrine rejection
					Serum amylase and serum lipase
					Other serum markers of exocrine rejection
				Serum markers of endocrine rejection
					Plasma glucose
					Glucose disappearance rate
					First-phase insulin release
			Immunological markers
		Imaging techniques
			US, CT, and magnetic resonance imaging
			Other imaging techniques
		Cell and tissue diagnosis of allograft rejection
			Fine-needle aspiration biopsy
			Cytology
			Needle core biopsy
				Graft biopsy: Cystoscopic transduodenal
				Graft biopsy: Percutaneous
				Graft biopsy: Laparoscopic
				Graft biopsy: Endoscopic gastroduodenal and enteric biopsies
				Biopsy algorithm
	Clinical presentation of pancreas graft dysfunction and rejection
		Recipients of a solitary pancreas transplant (PAK or PTA)
		Recipients of a SPK transplant
	Confirming the diagnosis of pancreas allograft rejection
		Acute cellular rejection
		Antibody-mediated rejection
		Mixed AR
	Treatment of pancreas transplant rejection
	Summary and recommendations
	References
Section V: Natural history
23
Reversal of secondary complications of type 1 diabetes (nephropathy, neuropathy, retinopathy, and cardiopathy)
	Introduction
	Nephropathy
		Effect of PTx alone on native kidney function
		Effect of simultaneous pancreas-kidney or pancreas after kidney on preservation of kidney graft
		Impact of immunosuppression
	Neuropathy
		Effect of PT on peripheral DN
		Effect of PT on autonomic DN
		Impact of immunosuppression
	Retinopathy
		Effect of PTx on DR
	Cardiopathy
		Effect of PTx on diabetic cardiopathy
		Effect of PTx cardiovascular risk factors and ischemic heart disease
	Summary
	References
24
Recurrence of type 1 diabetes following simultaneous pancreas-kidney transplantation
	Preamble
	Introduction
		Diagnosis of T1D recurrence (T1DR)
			Remodeling/transdifferentiation in pancreas transplant of T1DR
			Treatment of T1DR: Evidence for return of memory T cells in T1DR
			Cell-mediated responses in T1DR
				Autoreactive T cell-mediated beta cell destruction experimentally in vivo
				A possible case of incipient T1DR
			Re-transplantation of the pancreas for T1DR
		Longitudinal study of T1DR at the University of Miami
		Therapy for T1D
		T1DR therapy at the Miami Transplant Institute
		Theoretical considerations
			CXCR3 as a potential target in T1DR
			CXCR3 in alopecia areata and AA as a model of T1DR
		Combination therapies
	Future considerations
	Network for the pancreas organ donors with diabetes
	Conclusions
	Acknowledgment
	References
25
Pathological evaluation of whole pancreas transplants
	Introduction
		Types of Biopsies for Evaluation of WPnTx
		Pathological guidelines for processing pancreas allograft biopsies
		Concordance between the pancreas and kidney rejection in SPK
		Surveillance (protocol) biopsies
	Acute rejection in the duodenal cuff
		Features of acute rejection
		Concordance of rejection in the duodenal cuff and the pancreas
		Enteroscopic duodenal cuff biopsies
	Histological diagnosis and grading of acute allograft rejection—Banff schema
		Diagnostic categories specific considerations
		Mixed ACMR and ABMR
	Other (nonrejection) histological diagnoses
		Graft thrombosis
		Posttransplantation (ischemic) pancreatitis
		Posttransplant infectious pancreatitis/peripancreatitis/fluid collection/peripancreatic abscess
		Anastomotic leak
		Viral infections
			Cytomegalovirus infection
			EBV-related posttransplant lymphoproliferative disorder
	Correlation between pathological findings and time and type of WPnTx dysfunction
	References
26
Failure of the pancreas allograft
	Definition of pancreas allograft failure
	Epidemiology of pancreas allograft failure
	Causes of pancreas allograft failure
		Histological findings
		Causes of pancreas allograft failure
			Early graft failure
			Late graft failure
		Diagnostic strategy
	Risk factors of pancreas allograft failure
		Risk factors of early pancreas allograft failure
		Risk factors of long-term allograft failure
	Evaluation of glucose homeostasis to predict long-term allograft failure
	Therapeutic issues
		Indications of transplantectomy
	Conclusions and prospects
	References
27
Pancreas retransplantation
	Introduction
	Historical perspective
	Indications and considerations
	Retransplant type and outcomes
	Recipient evaluation
	Donor selection
	Timing
	Surgical approaches
	Postoperative care
	Summary
	References
Section VI: State of the art of pancreas transplantation
28
The current state of pancreas transplantation in the United States—A registry report
	Introduction
	Statistical methods
		Patient population
		Recipient characteristics
		Donor characteristics
		Transplant characteristics
		Transplant outcomes
	Discussion
	References
29
Trends in pancreas transplantation in the United States
	Introduction
	Number of pancreas transplant recipients
	Demographic characteristics of pancreas transplant recipients and donors over time
	Transplant volume by center
	Outcomes following transplantation
	Summary
	References
30
Experimental pancreas transplantation
	Introduction
	Small animal models
		Surgical techniques
		Immunogenicity
		Organ preservation
		Xenotransplantation
		Rejection
		Pharmacology
		Summary
	Large animal models
		Surgical techniques
			Canine model
			Swine model
		Systemic vs portal venous drainage
		Graft pancreatitis
		Preservation
		Rejection
		Summary
	References
31
Pancreas transplantation: Current issues, unmet needs, and future perspectives
	Introduction
	Improving outcomes in the setting of fewer transplants being performed
	Donor, recovery, and preservation issues
	Pancreas allocation and donor risk indices
	Surgical techniques
	Recipient selection and waiting list considerations
	Immunosuppression and immunological outcomes
	Pancreas vs islet transplantation
	Summary and conclusions
	References
Part B: Islet allo-transplantation
Section I: Introduction and indications
32
Treatment of type 1 diabetes complicated by problematic hypoglycemia
	Introduction
		What is problematic hypoglycemia?
	How common is problematic hypoglycemia in type 1 diabetes?
	Risk factors for problematic hypoglycemia
		Patient-related factors
		Secondary causes
	Approach to a patient with problematic hypoglycemia
		Identifying patients with problematic hypoglycemia or at high risk of SH
		Review risk factors for hypoglycemia
		Structured education
		Psychologically based educational interventions
	Hypoglycemia and the role of different insulins
		The balance between basal and bolus insulin
			Basal Insulins
			Prandial Insulins
	Use of technology
		Bolus advisors
		Continuous subcutaneous insulin infusion
		Continuous glucose monitoring
		SAP therapy
		Closed loop
		Continuous intraperitoneal insulin infusion
		Transplantation
	Summary
	References
33
Eligibility of patients with type 1 diabetes for islet transplantation alone
	Introduction: Current status of islet transplantation alone
	Indications for beta-cell replacement in the absence of renal insufficiency
	Assessment of “problematic hypoglycemia” as an indication for ITA
	Management of problematic hypoglycemia
	Clinical efficacy of ITA in problematic hypoglycemia
	Eligibility criteria for ITA
		Age
		Metabolic demand
		HLA sensitization
		Autoimmunity
		Coagulation disorders
		Hepatic disorders
		Retinopathy
		HbA1c
		Nephropathy
	Inclusion and exclusion criteria in recent multicenter clinical trials
	Selection for PTA vs ITA
	A word on IAK transplantation
	Perspectives
	References
34
Islet vs pancreas transplantation in nonuremic patients with type 1 diabetes
	Introduction
	β -Cell replacement
	Solid organ pancreas transplant
	Islet transplantation
	Recommendations for pancreas vs islet transplantation
	References
35
Simultaneous islet-kidney and islet-after-kidney transplantation
	Introduction
	Treatment strategy in patients with end-stage kidney disease with and without a history of severe hypoglycemia
	Treatment algorithm for beta-cell replacement therapy depends on kidney function
	Indications and exclusion criteria for islet or pancreas transplantation (for SIK/SPK, IAK/PAK, or ITA/PTA)
	Conclusions
	References
36
Pancreatic islet transplantation in cystic fibrosis: Lung and islet transplantation
	Introduction
	Techniques
		Combined islet-lung transplantation
		Islet after lung transplantation
	Immunosuppression
	Indications
	Results
	Complications
	Perspectives
	Acknowledgments
	References
37
Combined liver and islet transplantation in hepatogenous diabetes, cluster exenteration, and cirrhosis with type 1 diabetes
	Introduction
	Epidemiology, diagnosis, and prognosis of HD
	Pathophysiology of HD
	Treatment of HD
	Liver transplantation
	Combined liver and islet transplantation after upper abdominal exenteration
	Combined liver and islet transplantation in patients with HD/T2DM
	Combined liver and islet transplantation in patients with cirrhosis and T1DM
	Combined liver and pancreas transplantation in cirrhotic patients with T1DM or HD/T2DM
	Concluding remarks
	References
Section II: Donor selection
38
Evolving approaches to organ allocation for the whole pancreas vs islet transplantation
	Introduction
	Indications and definition of success after β -replacement
	Edmonton protocol
	Donor risk stratification
	Impact of donor age
	Impact of donor obesity
	Allocation scheme in the United Kingdom
	Allocation scheme in the United States
	Cost and reimbursement implications
	Forging ahead toward insulin-independence
	References
39
Living donors
	Introduction
	Background of living donor islet transplantation
	First report of living donor islet transplantation
	Can we expand living donor islet transplantation?
		Possible disadvantage to be concerned
			Donor safety
			Efficacy to ameliorate diabetes mellitus
			Ethical considerations of donors
		Possible advantages
	Conclusion
	Conflicts of interest
	References
40
Pancreatic islet isolation from donation after circulatory death pancreas
	Introduction
	History
	Donation after brain death
	Donation after circulatory death
	Ischemic time intervals
	Controlled DCD perfusion technique
	Prevalence of DCD
	Graft outcomes in DCD kidney and liver transplantation
	DCD vascularized pancreas transplantation
	Donor selection for pancreas retrieval in DCD donors
	Clinical outcome of vascularized DCD pancreas transplantation
	Donor selection for DCD pancreatic islet isolation
	Pancreatic islet isolation from DCD pancreas
	Islet in vitro function after islet isolation from DCD pancreas
	Clinical outcome of islet transplantation using DCD pancreas
	Future perspectives
	Conclusion
	References
Section III: Islet isolation
41
Factors related to successful clinical islet isolation
	Introduction
	Clean rooms, equipment, and essentials for islet isolation
	Donor and pancreas impacts
	Donor retrieval and perfusion of the pancreas
	Donor factor effects
	Processing effects
	Receipt and pancreas preparation
	Minimization of potential contaminants
	Distension and digestion of the pancreas
	Density separation
	Postisolation culture and quality assurance
	Discussion
	Acknowledgments
	References
42
Pancreas and islet preservation
	Introduction
	Key determinants of islet yield, function and viability during preservation
		Impact of ischemia time during pancreas procurement, storage and transportation on transplantation outcomes
		Ischemia/reperfusion injury
			Hypoxia/cold ischemia
			Ionic disturbances
			ROS-mediated injury
		Effects of hypoxia during islet isolation, culture and distribution
	Pancreas preservation prior to islet isolation
		Static methods/pancreas immersion
			Static cold storage
				Preservation solutions
				Perfluorocarbons (PFCs)
				Additives
		Dynamic methods/pancreas perfusion
			Liquid perfusion
				Hypothermic machine perfusion
				Normothermic machine perfusion
			Gaseous perfusion
				Persufflation
	Islet preservation during isolation and purification
		Isolation of human islets
		Pancreas distension, tissue dissociation, and islet collection
		Islet purification
	Islet preservation during culture and distribution
		Culture ware and culture methods
		Islet culture supplements
		Cryopreservation
	Outlook
	References
43
Collagenases in pancreatic islet isolation
	Introduction
	Basic structure
		Collagenases
		Neutral proteases
		Clostripain
	ECM of the pancreas with emphasis on the peri-insular region
	Role of different enzyme fractions in pancreatic digestion
	Pancreatic dissociation enzymes in clinical islet isolation: Evolution, safety, and overview of commercial products
	Exogenous parameters affecting collagenase digestion
	Tailored approach to islet isolation
	Conclusions
	References
44
Predicting the function of islets after transplantation
	Introduction
	Glucose tolerance and stimulation tests
		Oral glucose tolerance test
		Glucose clamp techniques
		Intravenous glucose tolerance test
		Mixed-meal tolerance test
	Indices for solitary transplantation
		HYPO score and lability index
		MAGE index
		SUITO index
		Clarke score
		C-peptide-to-glucose ratio
		β -Score
		Transplant estimated function
		Transplanted functional islet mass
	Biomarkers of graft failure
		Measurements of alloimmune response
		Soluble CD30
		Cytotoxic lymphocyte genes
		Microparticles in peripheral blood
		Autoimmune recurrence
	Proteins
		C-peptide
		Gad65
		Doublecortin
		Ppp1r1a
		Uch-L1
		Hmgb1
		Cxcl10
		Ccl2
	Nucleic acids
		Circulating cell-free DNA
		Ratio of unmethylated to methylated insulin DNA
		Micro RNAs
		Long noncoding RNAs
		Circular RNAs
	Current noninvasive imaging techniques for pancreatic islet transplantation
		Bioluminescence imaging
		Fluorescence imaging
		Ultrasonography
		Positron emission tomography
		Single-photon emission computed tomography
		Magnetic resonance imaging
	Summary
	References
Section IV: Outcomes after allogeneic pancreatic islet transplantation
45
Metabolic and endocrine evaluation of islet transplant function
	Introduction
	Glycemic control
	Glucose tolerance
	β -Cell function
	β -Cell secretory capacity
	β -Cell stress
	Insulin-dependent glucose disposal (insulin sensitivity)
	Insulin-independent glucose disposal (glucose effectiveness)
	α -Cell function and glucose counterregulation
	Conclusion
	Acknowledgments
	References
46
Procedure-related and medical complications in and after intraportal islet transplantation
	Introduction
	General overview of complication incidence related to intraportal ICT
	Differences in complication rates between allogeneic and autologous islet cell transplantation
	Complications related to percutaneous islet cell transplantation
		Bleeding
			Risk factors for bleeding complications
				Antiplatelet therapy and anticoagulation
				Portal venous pressure
				Coagulopathy
				Technical aspects of procedure
			Diagnosis of bleeding complications
			Preventative measures against bleeding complications
			Treatment of bleeding complications related to islet cell transplantation
		Portal vein thrombosis
			Risk factors for portal vein thrombosis related to islet cell transplantation
				Purity of islet preparations
				Infusion volume
				Increased portal venous pressure
				Thrombophilic disorders
			Diagnosis of portal vein thrombosis after islet cell transplantation
			Preventative measures against PVT Complications
			Treatment of PVT complications
				Noninvasive management
				Invasive management
		Rare procedure-related complications associated with percutaneous transhepatic islet cell transplantation
		Procedure-related complications pertaining to the percutaneous transjugular approach
		Procedure-related complications pertaining to the surgical (transmesenteric) approach to islet cell transplantation
	Medical complications of islet cell transplantation
		Hepatic steatosis
			Risk factors for hepatic steatosis
			Diagnosis of hepatic steatosis
			Management of hepatic steatosis
		Chronic portal hypertension
		Complications related to immunosuppression
	Closing remarks
	References
47
Secondary complications of diabetes
	Introduction
	Nephropathy
	Retinopathy
	Neuropathy
	Cardiovascular disease
	Conclusion
	References
Section V: Current clinical results
48
Treating diabetes with islet transplantation: Lessons learnt from the Nordic network for clinical islet transplantation
	Introduction
	The development of networks
	How can we better serve our patients by working in networks?
	The islet isolation facilities within the NNCIT
	Standard operational procedures
	CoE for type 1 diabetes
	Allocation of pancreas
		Patient selection and allocation
	Our current practice in islet transplantation in brief
		Concomitant medication
	Follow-up
		Metabolic and functional follow-up post-islet transplantation
		Safety
	A selection of NNCIT studies or reports
		Visualizing islets with positron-emission tomography combined with computed tomography
		Amyloid deposition in transplanted human pancreatic islets
		Clinical and experimental pancreatic islet transplantation to striated muscle, an establishment of a vascular system simila ...
		Encapsulation of the insulin-producing cells with the bioartificial pancreas β Air
		Inhibition of IBMIR with heparin or low molecular weight sulfated dextran in clinical islet transplantation
		Insulin independence after conversion from tacrolimus to cyclosporine in islet transplantation
		Predict patient outcome in IAK
		Islet graft function 1 year after pregnancy
		Cost and clinical outcome of clinical islet transplantation in Norway 2010–2015
	Conclusion
	Acknowledgments
	References
49
UK’s nationally funded integrated islet transplant program
	Demonstration of successful steroid-free islet transplantation in the UK
	Validation of islet transport protocol
	National Institute for Health and Care Excellence assessment
	National Health Service funding of an integrated program
	Listing criteria/recipient assessment
	Product release and transplantation
	Posttransplant follow-up
	Attainment of metabolic goals within the integrated UK program with locally isolated and transported islets
	The UK Pancreas Allocation Scheme for whole organ and islet transplantation
	Islet graft survival and metabolic outcomes within the integrated Pancreas Allocation Scheme
	UKITC biomedical and psychosocial outcomes of islet transplant research
		To determine and implement congruent protocols for rigorous clinical, metabolic, and psychosocial assessment and follow-up ...
		To determine and implement congruent protocols for rigorous recording of donor pancreas quality in addition to islet number ...
		To validate a new approach to transplantation across UK incorporating separate isolation and transplant centers ensuring co ...
		To develop/validate two new instruments for psychosocial evaluation enabling robust assessment of satisfaction/impact on qu ...
		To establish an external quality assurance (QA) system and UK database for collation of all patient, islet, transplantation ...
	Next steps for the UKITC/NHS program
	Concluding comments
	References
50
Type 1 diabetes transplanted with allogenic islets within the Swiss-French GRAGIL network
	Introduction
		Rationale for the Swiss-French GRAGIL network
		Cost analysis of islet transplantation in the GRAGIL network
	Organisation of the GRAGIL network
		Patient wait-listing and pancreas allocation
		Logistics and coordination
	Islet processing and transplantation
	Evolution of islet transplantation protocols in the GRAGIL network and outcomes
		The initial Geneva experience
		GRAGIL-1 clinical trial and the initial GRAGIL experience
		GRAGIL-1b clinical trial
		GRAGIL-1c clinical trial
		GRAGIL-2 clinical trial
		TRIMECO clinical trial
		STABILOT clinical trial
		Current ITA protocol
		Current IAK/SIK protocol
	Activity in the GRAGIL network
		QoL after islet transplantation in the GRAGIL network
	Islet transplantation in diabetic patients with cystic fibrosis within the GRAGIL network
	Lessons learned from 20 years of the GRAGIL network—Conclusion
	Acknowledgments
	References
51
Optimizing primary graft function in islet allotransplantation: T he Lille experience
	Introduction
	Methods
		Patients
		Transplantation
		Sequential multiple infusions in Lille
	Results
		Patient and graft characteristics
		Primary graft function
	Discussion and perspectives
	References
52
Treating diabetes with islet transplantation: Lessons from the Milan experience
	Introduction
	Indication for beta-cell replacement in Italy
	Pancreas transplantation activity in Italy
	Pancreas transplantation cost
	Islet transplantation in Italy
		Pancreas allocation system
		Islet isolation and transplantation activity in Italy
	Islet transplantation cost
		The Milan pioneering activity during the early 1990s
	Major achievement of Milan experience
	Main ongoing projects
	Future plans
	References
53
Treating diabetes with islet transplantation: Lessons from the University of Miami
	Introduction
	Clinical islet transplantation experience at the University of Miami
	Adjuvant therapies
	Patient management
	Psychosocial outcomes
	Potential risks and complications
	Conclusion
	Acknowledgment
	References
54
Treating diabetes with islet cell transplantation: Lessons from the Edmonton experience
	Introduction
	The history of islet transplantation
	The Edmonton protocol
	Indication for islet transplantation
	Islet isolation and transplantation
		Donor selection
		Pancreas procurement
		Islet isolation
		Intraportal infusion
		Risks of islet transplantation
	Immunosuppresion
		Induction immunosuppression
		Maintenance immunosuppression
		Adjunct peri-transplant anti-inflammatory agents
	Outcomes
	Future directions
	References
Section VI: Monitoring of allogeneic islet grafts
55
Immune monitoring of allogeneic islets
	Introduction
	Mechanism of rejection of pancreatic islet grafts
		Innate immunity
		Humoral immunity
		Cell-mediated immunity
	Nonimmune monitoring of pancreatic islet grafts
		Clinical monitoring
		Urine markers
		Serum markers
		Imaging modalities
	Immune monitoring of pancreatic islet grafts ( Table 1)
		Islet graft biopsy
		Innate response
		Humoral response
		Cellular response
	Conclusion
	References
56
Markers for beta-cell loss
	Introduction
	Beta-cell loss after islet transplantation
	Indirect markers of beta-cell loss
		Imaging techniques
		Functional beta-cell mass
			Choice of the function marker
			Choice of the stimulation test
			Hyperglycemic clamp test
				Validation in (a)symptomatic type 1 diabetes
				Validation in islet transplantation
	Direct markers of beta-cell loss
		Protein markers
			The 65 kDa isoform of glutamate decarboxylase (GAD65)
				Validation in vitro and in animal models
				Validation in islet transplantation
			Other candidate protein markers
				Validation in vitro and in animal models
		Nucleic acid markers
			Differentially methylated DNA
				Validation in vitro, in animal models and in type 1 diabetes
				Validation in islet transplantation
			Differentially expressed RNA
			Coding RNA
			Noncoding RNA: The example of miR-375
				Validation in vitro, in animal models and in type 1 diabetes
				Validation in islet transplantation
		Comparison of protein- and nucleic acid markers in islet transplantation
	Conclusions and perspectives
	References
57
In vivo quality control of human islets in the immunodeficient mouse to predict islet function in man: A retrospec
	Introduction
	Methods
		Islet isolation, transplantation, and quality controls
		Animal follow-up
		Transplant morphology
		Statistical analysis
	Results
		Our in vivo model is potentially a good model to predict islet function in man after transplantation
		Involvement of transplant aspect, purity, and vascularization in transplanted islet function
		Determining the functional islet mass required in 1–3 transplants to achieve optimal long-term islet function (beta score  ...
	Discussion
	Conclusion
	Perspectives
	Acknowledgments
	References
	Further reading
Section VII: Immunomodulatory technologies applied to islet transplantation
58 Progress toward islet transplantation tolerance
	Introduction—Rationale for tolerance in islet transplantation
	History of tolerance in solid organ transplantation
	Tolerance strategies for islet transplantation
		T-cell-focused immune tolerance strategies
		B cell-focused immune tolerance strategies
		Dendritic cells and myeloid-derived suppressor cells in tolerance
		Nonimmune and stromal cell-mediated tolerance
	Advanced islet transplantation technologies and immune tolerance
	Conclusion and future directions
	References
59
Filling the gap to improve islet engraftment and survival using anti-inflammatory approaches
	Introduction
	Inflammation prior islet isolation
		The pancreas donor
		The cold ischemia injury
	Inflammation and isolation procedure
		Inflammatory status during islet culture
	Peri-transplant inflammation
		The ischemia–reperfusion injury
		The instant blood-mediated inflammatory reaction
	Posttransplant inflammation
		Hypoxia
		Innate immune reaction
	Conclusion
	References
60
Islet immunoisolation by macroencapsulation
	Introduction
	Key aspects in islet macroencapsulation
		Structural approaches
		Encapsulation materials
		Protection from immune rejection and inflammation
		Oxygen requirements
		Kinetics of glucose and insulin release
		Transplantation site
	Recent and current clinical trials
	Future perspectives
	Conclusions
	References
61
Islet immunoisolation by microencapsulation
	Introduction
	Brief pre-insulin history of diabetes
	Brief review of medical treatment for diabetes
	Brief history of pancreas research
	Human islet transplants
	Decline of pancreas transplants
	Limitations with islet transplant
		Alternative therapies
		Newer glucose-lowering agents
	Gene therapy with attempts at modifying gene expression utilizing gene vectors or gene vaccines
	Regenerative therapy of pancreatic β cells
	Induction of graft tolerance by utilizing bone marrow transplantation or foreign antigen recognition blocking agents
	Xenotransplantation
	Genetic modification of porcine cells
	Islet immunoisolation
		Extravascular diffusion devices
		Sheet- and pouch-type macroencapsulation devices
		Polymer scaffolds
		Various implantation sites have been evaluated
		Intravascular diffusion devices
	Extravascular micro-devices
		Microencapsulation
		Oxygen supply to immunoisolated islets
	Other factors that affect pancreatic islet function and viability
		Alginate-based microcapsules
	Conformal coatings
		Alternative micro-coating techniques
			Nanoencapsulation or layer-by-layer approaches
		Other nanotechniques
	Professional opinion
	References
62
Recurrence of type 1 diabetes after beta-cell replacement
	Introduction
	The persistence of autoreactive memory T cells and B cells after the onset of T1D
	The presence of autoreactive memory T cells and autoantibodies before islet transplant
	Autoimmunity recurrence after islet or pancreas transplantation
		Pancreas transplantation
		Islet transplantation
	References
Section VIII: Cellular therapies in preclinical and clinical islet transplantation
63
T regulatory cell therapy in preclinical and clinical pancreatic islet transplantation
	Introduction
	Types of regulatory T cells and mechanisms of suppression
		CD4 + regulatory T cells
			tTreg
			iTreg
			Tfr
			Tr1
		CD8 + regulatory T cells
		CD4 − CD8 − regulatory T cells
		NKT cells
	γ δ T cells
		Non-T regulatory cells
			Breg
			Tolerogenic DCs
			Regulatory macrophages
			MSCs
			MAPCs
			MDSCs
			ILCs
	Treg isolation and expansion protocols
	Treg stability and how to improve it
	Treg cell dose to meet the therapeutic target
	Approaches to generate (allo)antigen-specific Tregs
		FOXP3 Tregs
		Tr1 cells
	Location of Treg infusion and function
	Tregs alone or in combination with immunotherapy?
	Timing of Treg infusion
	Safety and survival in vivo
	Ongoing Treg therapies in solid organ transplantation
	Barriers and other logistics
	Conclusions
	References
64
Cellular therapies in preclinical and clinical islet transplantation: Mesenchymal stem cells
	Introduction
		Clinical islet transplantation
		Mesenchymal stem cells (MSCs)
	Understanding the mechanisms of MSCs
		MSCs mediator secretion, immunogenicity, and immunomodulation
		MSCs administration in vivo
		MSCs in chronic clinical settings
		Treating type 1 diabetes with MSC-based therapy
		Ex vivo processing of MSCs. How to minimize the confounding artefacts?
			Donor variability
			Manufacturing of clinical grade MSCs
	MSCs and islets
		Co-culture of MSCs and islets
		Co-transplantation of MSCs and islets
		Systemic administration of MSCs to restore or repair islet damage
		The use of MSCs in clinical islet transplantation
		The potential of MSCs for islet transplantation
	Conclusion
	References
65
Alternative transplantation sites for islet transplantation
	Introduction
	The pancreas
	The spleen
	The kidney
	The adrenal glands
	Immunoprivileged sites
		The brain
		The testis
		The thymus
		The anterior chamber of the eye
	The bone marrow
	The gastrointestinal tract
		The gastric submucosa
		The duodenal submucosa
		The small bowel
	The urinary tract
	The muscle
	The subcutaneous space
	The peritoneum
	The omentum
	Conclusions
	References
Index
	A
	B
	C
	D
	E
	F
	G
	H
	I
	J
	K
	L
	M
	N
	O
	P
	Q
	R
	S
	T
	U
	V
	W
	X
	Z
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