Pediatric Solid Organ Transplantation: A Practical Handbook

Foreword
Contents
About the Editors
Part I: Renal Transplant
1: Pediatric Kidney Transplantation: A Historic View
1.1 The Triangulation Technique
1.2 An Immunologic Barrier
1.3 “Science Fiction”: The Beginnings of Human Transplantation
1.4 Breaking the Barrier
1.5 Youthful Rebellion and Tissue Typing
1.6 “It Seemed Too Good to be True”: Pharmacologic Immunosuppression
1.7 A Framework for Allocation
1.8 “The Greatest Application”: Pediatric Transplantation
References
2: Transplant Immunobiology
2.1 Introduction
2.2 EC Activation Starts before Transplant
2.3 The Grafted Organ Comes from an Ischemic Period: Role of the Hypoxic Phase and of Reperfusion
2.4 Endothelial Cells Talk with the Immunological System
2.5 T and B Cells Are the Main Effectors of Acute Rejection
2.6 The Pathways of T Cell Allorecognition
2.7 T Cell-Mediated Cytotoxicity
2.8 The Costimulatory System
2.8.1 The CD28:B7 Family
2.8.2 The TNF-Related Family
2.9 Adhesion Molecules
2.10 B Cells’ Role in Transplantation
2.11 Plasma Cells
2.12 Cells Participating in the Immune Response: Not Only T and B Cells
2.13 Dendritic Cells in Allograft Rejection
2.13.1 Which DC: From the Donor’s or the Recipient’s?
2.14 Innate Immune Response
2.15 Memory Can be Present Also in Non-lymphoid Cells
2.16 Tubular Epithelial Cells as Immunoregulator
2.17 Extracellular Vesicles Mediate Cellular Cross Talk between Immune System and Graft
2.18 Role of Antibodies
2.18.1 How Antibodies Damage the Graft
2.18.2 Clinical Effects
2.19 Role of Complement
References
3: Deceased Donor Allocation Policy and Kidney Allocation System on Young Pediatric Recipients
3.1 Kidney Transplant’s Impact on Young Pediatric Recipients
3.2 Deceased Donors for Pediatric Recipients
3.2.1 Ethical Arguments for Pediatric Priority for Deceased Donor Kidney Transplantation
3.3 The “Old” and “New” Allocation Systems
3.3.1 Share 35
3.3.2 Changes in Pediatric Priority under KAS
3.4 The KAS Effect on Young Recipients
3.5 Eliminating Donation Service Area
3.6 Conclusion
References
4: Donor-Recipient Size Mismatch in Pediatric Renal Transplantation
4.1 Cause of Donor-Recipient Size Mismatch
4.2 Overcoming Hemodynamic Imbalance
4.3 Surgical Techniques
4.4 Graft Survival and Adaptation
References
5: Medical Evaluation of the Living Donor for Pediatric Kidney Transplantation
5.1 Introduction
5.2 Donor Age
5.3 Kidney Function
5.4 Hypertension
5.5 Diabetes and Glucose Abnormalities
5.6 Obesity
5.7 Proteinuria
5.8 Hematuria
5.9 Kidney Stones
5.10 Malignancy
5.11 Screening for Transmissible Infections
5.12 Psychological Issues
5.13 Conclusion
References
6: Surgical Management of the Pediatric Renal Transplant Patient
6.1 Introduction
6.2 Timing of Transplantation
6.3 Donor Selection
6.4 The Operation
6.5 Incision and Graft Placement
6.6 Vessels
6.7 Native Nephrectomy
6.8 Ureteral Implantation
6.9 Postoperative Management
6.10 Conclusions
References
7: Management of the Pediatric Renal Transplant with Posterior Urethral Valves for Successful Transplantation
7.1 Introduction, Epidemiology, and Clinical Presentation
7.2 Pathophysiology of Renal Dysfunction in ESRD
7.3 Risk Factors for End-Stage Renal Disease in PUV
7.4 Preoperative Workup/Evaluation
References
8: RISE to Transition: A Structured Transition Protocol for Renal Transplant Recipient
8.1 Introduction
8.2 Problems of Transition and Consequences of Non-adherence to Transition
8.3 Transition Process in Various Studies and Challenges of Transition
8.4 Survey of Pediatric Nephrologists and Concern for Transition Process
8.5 RISE Protocol
8.5.1 Importance of RISE Protocol
8.5.2 Transition Age
8.5.3 Elements of the RISE Protocol
8.5.4 Transition Clinic
8.5.5 Transition Team
8.5.6 Transition Tools
8.5.7 Transition Stages
8.5.8 Limitations of RISE Protocol
8.5.9 Implementation of RISE Protocol
8.6 Conclusion
References
9: Induction Therapy in Pediatric Renal Transplant Recipients
9.1 Introduction
9.2 Aims of Induction Therapy
9.3 Historical Induction Agents
9.4 Currently Utilized Induction Agents
9.4.1 Lymphocyte-Depleting Agents
9.4.2 Non-lymphocyte-Depleting Agents
9.4.3 Comparison of Antibody Induction Agents
9.4.4 Chemical Agents (CNI, Corticosteroids)
9.5 Induction Strategies Based on Patient Risk
9.5.1 Induction Therapy in Standard-Risk Group
9.5.2 Induction Therapy with Steroid Avoidance
9.5.3 Induction Therapy in Diseases with a High Risk of Recurrence
9.5.3.1 Focal Segmental Glomerulosclerosis (FSGS)
9.5.3.2 Atypical Hemolytic Uremic Syndrome (aHUS)
9.5.3.3 C3 Glomerulopathy (C3GN)
9.5.4 Induction Therapy in Immunologically High-Risk (HLA-Sensitized) Patients
9.5.4.1 Intravenous Immunoglobulin: IVIg
9.5.4.2 Alemtuzumab
9.5.4.3 Antithymocyte Globulin
9.5.4.4 Rituximab
9.5.4.5 Eculizumab
9.5.4.6 C1-INH (Berinert; CSL Behring, King of Prussia, Penn)
9.5.4.7 Bortezomib
9.5.4.8 Imlifidase
9.6 Current Practices in the USA
9.7 Conclusions
References
10: Maintenance Immunosuppression in Kidney Transplantation
10.1 Introduction
10.2 Corticosteroids
10.3 Calcineurin Inhibitors (CNIs)
10.4 Antimetabolite Agents
10.5 Mammalian Target of Rapamycin (mTOR) Inhibitor: Sirolimus
10.6 Costimulation Blocker: Belatacept
References
11: Pediatric ABO-Incompatible Renal Transplant
11.1 History of ABOi Renal Transplants
11.2 Blood Group Antigens and Blood Group Compatibility
11.3 Anti-Blood Group Antibodies and Methods of Determination
11.4 Preconditioning Protocol
11.5 Accommodation
11.6 Significance of Antibody Titer
11.7 Outcomes in Children
11.8 Unanswered Questions
11.9 Conclusions
Suggested Readings
12: Overview of Biomarkers of Rejection in Pediatric Renal Transplantation
12.1 Invasive Molecular Markers
12.2 Noninvasive Biomarkers
12.3 Current Challenges
References
13: Adherence in Pediatric Transplant Recipients
13.1 Introduction
13.2 Components of Adherence
13.3 Unintentional Vs. Intentional Poor Adherence
13.4 Determinants of Adherence
13.5 Transfer to Adult-Oriented Care and Adherence
13.6 Pretransplant Adherence as a Predictor of Posttransplant Adherence
13.7 Methods of Measuring Adherence
13.8 Improving Adherence for all Patients
13.9 Targeted Intervention
13.10 Conclusions
References
14: Recent Advances in the Diagnosis and Treatment of Antibody-Mediated Rejection in Pediatric Kidney Transplants
14.1 Diagnosis
14.2 Detection of Donor-Specific Antibodies
14.3 Surveillance DSA Monitoring
14.4 Histology
14.4.1 Detection of C4d by Immunostaining
14.5 Histologic Changes of Tissue Injury
14.6 On the Horizon
14.7 Treatment of Antibody-Mediated Injury
14.8 Removal/Neutralization of Antibody
14.9 B-Cell Depletion
14.10 Depletion of Plasma Cells
14.11 Complement Inhibition
14.12 Summary
References
15: Acute Vascular Rejection
15.1 Terminology and Evolution
15.2 Pathogenesis
15.3 Clinical Presentation and Diagnosis
15.4 Treatment
15.5 Prognosis
References
16: Infectious Complications in Pediatric Renal Transplantation
16.1 Predisposing Factors
16.2 Timing of Infections After KTx
16.2.1 Early Post-KTx Period (the First Months After KTx)
16.2.1.1 Surgical Site Infections (SSIs) [5]
16.2.1.2 Urinary Tract Infections [7]
16.2.1.3 Respiratory Tract Infections
16.2.1.4 Clinical Sepsis
16.2.1.5 Viral Infections
16.2.2 Intermediate Time Period (1–6 Months After KTx)
16.2.2.1 Viral Infections
Cytomegalovirus
Epstein-Barr Virus [14, 15]
BK Polyomavirus [21]
16.2.2.2 Fungal Infections
Endemic Fungal Infections
16.2.3 Late Post-KTx Period
16.3 Management
16.3.1 Pre-transplant Evaluation
16.3.2 Post-KTx Immunization [25]
References
17: Post-Kidney Transplant Hypertension in Children
17.1 Introduction
17.2 Hypertension Epidemiology Post-Renal Transplant
17.3 Consequences of Hypertension in Post-Transplant Patients
17.4 Diagnosis of Hypertension and Importance of ABPM
17.5 Pathophysiology
17.6 Pre-Transplant Factors
17.7 Immediate and Early Post-Transplant Period
17.8 Late Post-Transplant Factors
17.9 Management
17.10 Targeted Blood Pressure in Post-Transplant Patients
17.11 Non-pharmacological Interventions
17.12 Pharmacotherapy
17.13 Management in the Immediate Post-Transplant Period
17.14 Long-Term Management
17.15 Summary
References
18: Recurrent Renal Disease After Transplantation
18.1 Introduction
18.2 Focal Segmental Glomerulosclerosis
18.2.1 Incidence
18.2.2 Risk Factors
18.2.3 Diagnosis and Treatment
18.2.4 Prognosis
18.3 IgA Nephropathy
18.3.1 Incidence
18.3.2 Risk Factors
18.3.3 Diagnosis and Treatment
18.3.4 Prognosis
18.4 Membranoproliferative Glomerulonephritis
18.5 Immune Complex-Mediated MPGN
18.5.1 Incidence
18.5.2 Risk Factors
18.5.3 Diagnosis and Treatment
18.5.4 Prognosis
18.6 Complement-Mediated MPGN (C3GN/Dense Deposit Disease)
18.6.1 Incidence
18.6.2 Risk Factors
18.6.3 Diagnosis and Treatment
18.6.4 Prognosis
18.7 Anti-neutrophil Cytoplasmic Antibody-Associated Vasculitis
18.7.1 Incidence
18.7.2 Risk Factors
18.7.3 Diagnosis and Treatment
18.7.4 Prognosis
18.8 Lupus Nephritis
18.8.1 Incidence
18.8.2 Risk Factors
18.8.3 Diagnosis and Treatment
18.8.4 Prognosis
18.9 Idiopathic Membranous Nephropathy
18.9.1 Incidence
18.9.2 Risk Factors
18.9.3 Diagnosis and Treatment
18.9.4 Prognosis
18.10 Conclusion
References
19: Post-Transplant Lymphoproliferative Disorders
19.1 Introduction
19.2 Pathogenesis
19.3 Risk Factors
19.4 Clinical Features
19.5 Pathology
19.6 Prevention and Preemptive Strategies
19.7 Treatment
19.8 Prognosis
References
20: How to Manage Children with Chronic Kidney Allograft Dysfunction
20.1 Introduction
20.2 Evaluation of Kidney Allograft Function
20.2.1 Serum Creatinine
20.2.2 Proteinuria
20.2.3 Ultrasound
20.2.4 Histopathology
20.2.5 Outcomes
20.3 Treatment
20.3.1 Immunosuppressive Therapy
20.3.2 Nephrectomies
20.4 Chronic Kidney Disease (CKD) Management
20.5 Conclusion
References
Part II: Intestinal Transplant
21: Indications for and Management of Pediatric Intestinal Transplant Patients
21.1 Introduction
21.2 Intestinal Transplantation in the Management of Intestinal Failure
21.3 Indications for Intestinal Transplantation
21.3.1 Intestinal Failure-Associated Liver Disease (IFALD)
21.3.2 Loss of Central Venous Access
21.3.3 Recurring, Life-Threatening Bloodstream, or Metastatic Infection
21.3.4 Intra-Abdominal Neoplastic Disease
21.4 Evaluation for Transplant
21.4.1 Confirmation of an Indication for Intestinal Transplant
21.4.2 Isolated Intestinal vs. Combined Liver and Intestinal Transplantation
21.4.3 Inclusion of Additional Organs in the Transplant
21.4.4 Venous Access
21.4.5 Assessment of Co-Morbid Disorders
21.5 Intestinal Transplant Allograft Types
21.5.1 Isolated Intestinal Transplantation
21.5.2 Combined Liver-Intestinal-Pancreas Transplantation
21.5.3 Multivisceral Transplantation
21.6 Management Following Intestinal Transplantation
21.6.1 Post-Operative Management
21.6.2 Enteral Nutrition
21.6.3 Immunosuppressive Therapy
21.6.4 Surveillance of the Allograft
21.6.5 Growth and Development After Intestinal Transplantation
21.6.6 Quality of Life After Intestinal Transplantation
21.6.7 Coordination of Care After Intestinal Transplantation
21.6.8 Allograft Loss and Long-Term Outcomes of Intestinal Transplantation
21.7 Conclusion
References
22: Intestinal and Multivesicular Transplantation in Children: Outcomes and Complications
22.1 Indications for Visceral Transplantation
22.2 Global Trends
22.3 Immunosuppressive Management
22.4 DSA and Liver’s Immunological Protective Effect
22.5 Complications
22.5.1 Acute Rejection
22.5.2 Viral Infections
22.5.3 Graft-Versus-Host Disease (GVHD)
22.5.4 Posttransplant Lymphoproliferative Disorder
22.6 Outcomes
22.6.1 Patient and Graft Survivals
22.6.2 Growth and Nutrition
22.6.3 Quality of Life
References
23: Long-Term Management of Intestinal Transplant Patients
23.1 Nutrition
23.2 Infections
23.3 Monitoring Allograft Function and Surveillance for Rejection
23.4 Immunosuppression and Management of Rejection
23.5 Renal Dysfunction and Hypertension
23.6 Graft vs Host Disease
23.7 Malignancy
23.8 Long-Term Development and Quality of Life
References
Part III: Pancreatic Transplant
24: Pediatric Pancreas Transplantation
24.1 Introduction
24.2 Incidence of Diabetes in the Young
24.3 Incidence of Diabetes Mellitus and End-Stage Renal Disease (ESRD) in the Young
24.4 Pancreas Transplantation for Pediatric Recipients
24.5 Reason for Pediatric Pancreas Transplantation
24.6 Transplantation of Pediatric Donor Organs
24.7 Summary
References
25: Total Pancreatectomy and Islet Auto-Transplantation for Chronic Pancreatitis Children: Pre-Surgical Evaluation, Patient Selection, the Surgical Procedures, Islet Isolation Procedure, and the Early Inpatient Management
25.1 Introduction
25.2 Selection of Patients for TP-IAT
25.3 Surgical Considerations in Pediatric Patients [21]
25.4 Islet Isolation and Infusion
25.5 Islet Cell Infusion
25.6 Post-Operative Care
25.7 Pain Management
25.8 Splenectomy Management
25.9 Surgical Morbidity and Mortality
25.10 Narcotic Use and Pain After TP-IAT
25.11 Islet Function After TP-IAT
25.12 Factors Predicting Insulin Independence
25.13 How Young Is Too Young for TP-IAT
25.14 Conclusions
References
26: Total Pancreatectomy with Islet Autotransplantation (TPIAT): Postoperative Management and Outcomes
26.1 Introduction to TPIAT in Children
26.2 Diabetes Management in the Outpatient Setting after TPIAT
26.3 Pain Management in the Outpatient Setting after TPIAT
26.4 Management of Exocrine Pancreatic Insufficiency after TPIAT
26.5 Nutrition Management after TPIAT
26.6 Other Considerations
26.7 Outcomes of Pediatric TPIAT
26.7.1 Opioid Use and Pain Relief
26.7.2 Insulin Independence
26.7.3 Quality of Life
26.8 Conclusions
References
Part IV: Heart Transplant
27: Indications and Outcomes of Heart Transplantation in Children
27.1 Indications of Heart Transplant in Pediatrics and in Adults with Congenital Heart Disease
27.2 Cardiomyopathies
27.3 Unrepaired Congenital Heart Disease
27.4 Repaired Congenital Heart Disease
27.5 Retransplantation
27.6 Changing Indications in Current Era
27.7 Outcomes
27.8 Cardiomyopathies
27.9 Retransplantation
27.10 ABO-Incompatible (ABOi) Heart Transplant Outcomes
27.11 Mechanical Cardiac Support and Outcomes Post-Transplant
27.12 Morbidity
27.12.1 Rejection
27.12.2 Coronary Allograft Vasculopathy (CAV)
27.12.3 Infections
27.12.4 Renal Dysfunction
27.12.5 Hypertension and Hyperlipidemia
27.12.6 Diabetes
27.12.7 Post-Transplant Lymphoproliferative Disease (PTLD) and Other Cancers
27.12.8 Functional Status, Exercise Capacity, and Limitations
27.12.9 Quality of Life
References
28: Pediatric Heart Transplant Immunosuppression
28.1 Introduction
28.2 Peri-Transplant Immunosuppression
28.2.1 Induction Therapy
28.2.2 Polyclonal Anti-Thymocyte Globulin
28.2.3 Monoclonal Interleukin-2 Receptor Antagonists
28.2.4 Basiliximab Vs Anti-Thymocyte Globulin
28.2.5 Perioperative Steroids
28.3 Maintenance Immunosuppression
28.3.1 Calcineurin Inhibitors: Cyclosporine and Tacrolimus
28.3.2 Antiproliferative Agents: Azathioprine and Mycophenolate Mofetil
28.3.3 Proliferation Signal Inhibitors: Sirolimus and Everolimus
28.3.4 Corticosteroids
28.4 Side Effects of Immunosuppression
28.4.1 Gastrointestinal Symptoms
28.4.2 Myelosuppression
28.4.3 Diabetes Mellitus
28.4.4 Impaired Wound Healing
28.4.5 Hyperlipidemia
28.4.6 Chronic Kidney Disease (CKD)
28.4.7 Post-Transplant Lymphoproliferative Disorder (PTLD)
28.5 Conclusions
References
Part V: Liver Transplant
29: Pediatric Liver Transplantation
29.1 Introduction
29.2 Indications for Liver Transplantation in Children
29.2.1 Cholestatic Liver Disease
29.2.2 Metabolic Liver Diseases
29.2.3 Primary Liver Malignancy
29.3 Recipient Evaluation and Contraindications to Transplantation
29.4 Donor Assessment
29.5 Recipient Operation
29.6 Immunosuppression
29.7 Postoperative Surgical Complications
29.7.1 Primary Non-function
29.7.2 Biliary Complications
29.7.3 Vascular Complications
29.8 Post-Transplant Medical Complications
29.8.1 Acute and Chronic Rejection
29.8.2 Infections
29.9 Long-Term Outcomes
References
30: Perioperative Management after Liver Transplantation
30.1 Pre-Transplant Assessment
30.2 Liver Function and Associated Complications
30.2.1 Cardiopulmonary Assessment
30.2.2 Pre-Transplant: Admission
30.2.3 Intraoperative Care
30.2.4 Postoperative Care
30.3 Airway and Ventilation
30.4 Fluids and Nutrition
30.5 Inotropes
30.6 Immunosuppression
30.7 Renal Dysfunction
30.8 Radio Imaging
30.9 Infection Control
30.10 Anticoagulation
30.11 Immediate Post-Transplant Complications
30.11.1 Primary Non-function (PNF) of the Liver Graft
30.11.2 Vascular Complications
30.11.3 Complications Due to a Large Graft
30.11.4 Functional Small for Size Syndrome
30.11.5 Bleeding
30.11.6 Abdominal Drain Fluid
30.12 Conclusion
References
31: Immunosuppression after Liver Transplantation in Pediatric Population
31.1 Introduction
31.2 Background
31.3 Immunosuppressive Agents
31.3.1 Corticosteroids
31.3.2 Calcineurin Inhibitors
31.3.3 Mycophenolate Mofetil (MMF)
31.3.4 mTOR Inhibitors
31.3.4.1 Sirolimus
31.3.4.2 Everolimus
31.3.5 IL2 Receptor Blockers
31.4 Immunosuppression Withdrawal and Tolerance
31.5 Problems with Teenagers: Adherence
31.6 Transition to Adulthood
31.7 Summary
References
32: Combined Liver-Kidney Transplantation for Primary Hyperoxaluria Type 1
32.1 Introduction
32.2 Genetics and Pathophysiology
32.3 Clinical Presentation
32.4 Diagnosis
32.5 Treatment
32.6 Transplantation
32.7 Postoperative Management
32.8 Conclusion
References
33: Human Hepatocyte Transplantation
33.1 Introduction
33.2 Hepatocyte Processing and Transplantation Protocols
33.2.1 Source of Hepatocytes
33.2.2 Hepatocyte Isolation
33.2.3 Quality Control of Hepatocytes
33.2.4 Hepatocyte Infusion
33.2.5 Immunosuppression
33.3 Clinical Indications for HT
33.3.1 Liver-Based Metabolic Diseases (LBMD)
33.3.2 Acute Liver Failure (ALF)
33.4 Optimizing and Advancing HT
33.4.1 Alternative Source of Hepatocytes
33.4.2 In Vitro Expansion of Human Hepatocytes
33.4.3 Generation of Hepatocyte-like Cells from Stem Cells
33.4.4 Hepatocyte Co-Culture with Mesenchymal Stromal Cells
33.4.5 Strategies to Enhance Primary Hepatocyte Engraftment
33.4.5.1 Liver Preconditioning
33.4.5.2 Alpha-1 Antitrypsin Co-Administration
33.4.6 Cell Encapsulation to Evade Immune System
33.5 Conclusions
References
34: Split Liver Transplantation
34.1 Introduction
34.2 Donor Selection
34.2.1 Graft Allocation
34.2.2 Donor Criteria
34.3 Liver Procurement
34.3.1 In Situ Split
34.3.2 Ex Situ Split
34.4 Split
34.4.1 Before Starting
34.4.2 First Step: Dissection
34.4.3 Second Step: Hilar Vessel’s Section
34.4.4 Third Step: Parenchymal Transection
34.4.5 Final Step: Hepatic Vein
34.4.6 Alternative Split
34.5 Hepatectomy
34.6 Transplantation
34.6.1 Before Starting
34.6.2 First Step: Hepatic Vein Anastomosis
34.6.3 Second Step: Portal Vein Anastomosis
34.6.4 Third Step: Hepatic Artery Anastomosis
34.6.5 Fourth Step: Biliary Anastomosis
34.6.6 Final Step: Closing
34.7 Results
34.8 Complications
References
Part VI: Lung Transplant
35: Pediatric Lung Transplantation: Indications and Outcomes
35.1 Introduction
35.2 Transplant Evaluation
35.3 ECMO as Bridge to Transplant
35.4 Donor Acceptability Criteria and Graft Size Reduction
35.5 Management of Pediatric Patients Receiving a Lung Transplantation
35.6 Conclusion
References
36: Paediatric Lung Transplantation
36.1 Introduction
36.2 Indications for Lung Transplantation
36.3 Referrals and Candidate Selection
36.4 Contraindications and Exclusion Criteria
36.5 Donor Criteria
36.6 Perioperative Management and Surgery
36.6.1 The Donor
36.6.2 The Recipient
36.7 Surgical Approach
36.8 Early Complications
36.8.1 Surgical Complications
36.8.2 Primary Graft Dysfunction
36.8.3 Hyperacute Rejection
36.9 Immune Suppression
36.10 Home Monitoring
36.11 Following the Transplantation
36.11.1 Acute Rejection: Cellular and Antibody Mediated
36.11.2 Acute Cellular Rejection (ACR)
36.11.3 Antibody-Mediated Rejection (AMR)
36.11.4 Infection
36.12 Post-Transplantation Lymphoproliferative Disorder (PTLD)
36.13 Chronic Lung Allograft Syndrome (CLAD)
36.14 Summary
References