Kidney and Pancreas Transplantation (eBook)

Preface 6
Contents 8
Contributors 10
Chapter 1: The Immune Response to Transplanted Organs 13
Introduction 13
Ischemia-Reperfusion Injury 13
Induction of the Donor-Specific T-Cell Response 15
The Functional Development of T Cells during Activation 17
T-Cell-Mediated Cytolysis of Target Cells 19
Phenotypic Changes During TCR-Mediated Activation 20
T-Cell-Mediated Rejection 23
Memory Cells 24
B Cells and Antibody in Transplant Rejection 25
The Problem of Chronic Rejection 29
Summary 29
References 30
Chapter 2: The Histocompatibility Laboratory in Clinical Transplantation 35
Our History 35
Where We Are Now 41
Our Future 55
References 56
Chapter 3: Immunosuppressive Therapy in Kidney and Pancreas Transplantation 60
Introduction 60
Trends in Immunosuppression 60
Immunosuppressive Drugs Versus Regimens 61
Sites and Mechanisms of Actionof Immunosuppressive Agents 62
Induction Therapy 66
Depleting Antibodies 67
Polyclonal Antibodies 67
Mechanism of Action 67
Dosing and Administration 67
Side Effects 68
Monoclonal Antibodies 68
Mechanism of Action 68
Efficacy 68
Dosing and Administration 68
Side Effects 68
Nondepleting Antibodies 69
Anti-CD25 Monoclonal Antibodies/IL-2 Receptor Antibodies 69
Mechanism of Action 69
Dosing and Administration 69
Side Effects 69
Newer Agents for Induction Therapy 69
Mechanism of Action 69
Dosing and Administration 70
Side Effects 70
Maintenance Therapy 70
Calcineurin Inhibitors 70
Dosing and Monitoring 72
Side Effects 72
Antimetabolites 74
Dosing, Formulations, and Side Effects 75
Mammalian Target of Rapamycin (m-TOR) Inhibitors 76
Corticosteroids 77
Dosing and Side Effects 77
Intravenous Immune Globulin 78
Dosing and Side Effects 78
Emerging Immunosuppressive Agents 78
Small Molecules 78
Janus Kinase Inhibitors/CP-690,550 79
PKC Inhibition/AEB071 (Sotrastaurin) 79
FTY 720 79
Biologic Agents 79
Belatacept/Costimulation Blockade 79
Targeting B Cells and Plasma Cells 80
Rituximab 80
Bortezomib (Velcade) 80
Currently Used Combination Immunosuppressive Regimens and Outcomes 80
Choice of Induction Regimen 81
Choice of Calcineurin Inhibitors 81
Choice of Antiproliferative Agent 82
Mycophenolate Mofetil Versus Azathioprine 82
Mycophenolate Mofetil Compared to Sirolimus in Cyclosporine-Based Regimens 82
Mycophenolate Mofetil Versus Sirolimus with Tacrolimus 83
Calcineurin Inhibitor and Steroid Avoidance Regimens 83
Rationale and Impetus for Use 83
Calcineurin Inhibitor Avoidance: De Novo Studies 84
Mycophenolate Mofetil with Sirolimus 84
Calcineurin Inhibitor Withdrawal with Mycophenolate Mofetil 84
Patients with Stable Graft Function 84
Patients with Deteriorating Graft Function 86
Calcineurin Inhibitor Withdrawal or Substitution Using Sirolimus 86
Cyclosporine Withdrawal 86
Cyclosporine Substitution with Sirolimus 87
Corticosteroid Avoidance Regimens 87
Treatment of Acute Rejection 87
Global Considerations 87
Acute Cellular Rejection 88
Pulse Corticosteroids 88
Anti-T-Cell Antibody Therapy 88
Treatment-Resistant Rejections and Late Rejections 89
Treatment of Antibody-Mediated Rejection 89
Immunosuppression Management in Chronic Allograft Failure 90
Immunosuppression for Pancreas Transplantation 90
Using Immunosuppression in the Clinic 90
Conclusion 92
References 92
Chapter 4: Clinical Pharmacologic Principles and Immunosuppression 98
Introduction 98
Pharmacology 98
Corticosteroids 98
Calcineurin Inhibitors 99
Mycophenolic Acid 99
M-TOR Inhibitors 99
General Pharmacokinetic Principles 100
Bioavailability 100
Calcineurin Inhibitors (Cyclosporine and Tacrolimus CNI )101
Mycophenolate Mofetil (MMF) 102
Corticosteroids 102
Apparent Volume of Distribution (Vd) 102
Binding 103
Clearance 103
Restrictive Clearance and Protein Binding 105
Pharmacogenetics 106
Interactions 107
Therapeutic Drug Monitoring 108
C2 Monitoring 108
Everolimus 113
Conclusion 113
References 113
Chapter 5: Pathology of Kidney and Pancreas Transplants 121
Introduction 121
General 121
Immunology 121
Allograft Biopsy Processing 122
Early Allograft Biopsies from Zero-Time to the Early Posttransplant Period 123
Donor Biopsies 123
Immediate Posttransplantation Biopsies 124
Early Posttransplant Graft Dysfunction 126
Early Transplant Interval 128
General 128
Acute Tubular Injury 128
Acute Rejection 129
Acute Tubulointerstitial Rejection 129
Rejection in the Vasculature 129
Infection 133
Recurrent Disease 134
Intermediate and Late Transplant Period 135
Posttransplant Proteinuria 137
Banff Schema and Rejection Classification 139
Pancreas Transplant Pathology 141
General 141
Acute Rejection 142
Chronic Rejection 145
Pancreatitis 145
Lesions in the Islets of Langerhans 146
References 146
Chapter 6: Design, Conduct, and Report of Clinical Trials of Immunosuppressive Regimens in Solid Organ Transplantation 149
Introduction 149
Designing a Clinical Study 149
What Is the Question? 149
How to Choose the Study Design? 149
Randomized Control (Placebo or Active) Studies 150
Observational Studies 152
Systematic Reviews and Metaanalysis 153
Registry Analyses 153
How to Determine the Experimental Group? 154
How to Select the Control Group? 154
What Are the Endpoints? 155
How Do We Define the Study Population? 156
How Many Study Subjects Do We Need? 157
Conducting a Clinical Study 157
How Do We Write the Protocol? 157
How Do We Manage the Data? 158
How Do We Analyze the Data? 159
What Are the Regulatory Considerations? 159
Reporting Clinical Trials 160
How Do We Report Clinical Trials Results? 160
Clinical Research Collaboration 161
Postapproval Company-Sponsored Clinical Studies 161
Post approval Clinical Studies Safety Monitoring 161
Summary 162
References 162
Chapter 7: Outcomes of Kidney and Pancreas Transplantation 164
Introduction 164
Understanding Survival Models 165
Transplantation Confers a Durable Survival Advantage Over Dialysis 167
Donor Source and Quality 167
Patient and Graft Survival in Kidney Transplantation 167
Patient and Graft Survival in Pancreas Transplantation 168
Long-Term Outcomes in Renal Transplantation 170
Factors Affecting Renal Allograft Survival 172
Donor–Recipient Factors 172
Delayed Graft Function 172
HLA Matching 172
Waiting Time and Preemptive Transplantation 173
Center Effect 174
Year of Transplant (Era Effects) 174
Donor Factors 175
Donor Source: Deceased Versus Living Donor 175
Donor Age 175
Cold Ischemia Time 176
Donor Race 176
Donor Gender 176
Donor Nephron Mass 176
Expanded Criteria Donors 176
Recipient Factors 177
Recipient Age 177
Recipient Race 178
Recipient Gender 178
Recipient Sensitization: Before or after Transplantation 179
Acute Rejection 179
Recipient Hepatitis C Virus Antibody and Hepatitis B Virus Surface Antigen Positivity 179
Recipient Immunosuppression 179
Tacrolimus in Combination with MMF 180
MMF Compared to Sirolimus in Cyclosporine-Based Regimens 180
MMF Versus Sirolimus with Tacrolimus 181
MMF with Sirolimus 181
Corticosteroid Avoidance Regimens 181
Recipient Compliance 182
Obesity 182
Hypertension in the Recipient 183
Recipient Dyslipidemia 183
Recurrence of Primary Disease in the Allograft 183
Proteinuria 184
Applying Outcomes Data in Practice 184
References 186
Chapter 8: Medical and Surgical Evaluation of the Adult Kidney Transplant Candidate 191
Introduction 191
Who Is a Kidney Transplant Candidate? 191
Preemptive Transplantation is Preferable When Feasible 192
Who Is Not Eligible for a Transplant? 192
Referral for Transplantation 193
Process of Evaluation 193
Education and Consent 193
Education 194
Consent 194
Medical Evaluation 195
Cardiovascular Disease 195
Pulmonary Disease 196
Cerebrovascular and Peripheral Vascular Disease 197
Evaluation of the Abdomen and Gastrointestinal Tract 197
Infections 197
Malignancy 198
The Elderly Transplant Recipient 199
Financial Considerations 200
Patients with Prior Transplants 200
Coagulopathy 201
The Highly Sensitized Patient 201
Waitlist Management 201
Native Kidney Disease and Recurrence 202
Focal and Segmental Glomerulosclerosis 202
IgA Glomerulonephritis 203
Obesity 203
Indications for Nephrectomy 203
Multiorgan Transplants 204
Management of Lower Urinary Tract Disease 204
Summary and Recommendations 204
Conclusions 205
References 205
Chapter 9: Selection and Preparation of the Pancreas Transplant Recipient 208
Introduction 208
Patient Selection for Pancreas Transplantation 208
Categories of Pancreas Transplantation 209
Medical Evaluation and Preparation 211
Summary and Conclusions 213
References 214
Chapter 10: Kidney Transplant Recipient Surgery 217
Implant Location 217
Preparation of Donor Kidney 217
Venous Preparation 218
Arterial Preparation 218
Ureteral Preparation 219
Final Preparation 220
Recipient Surgery 221
Pediatric En Bloc Transplant 222
Chapter 11: Issues and Surgical Techniques to Expand the Pool of Kidneys Available for Transplantation 224
Introduction 224
The Expanded Criteria Donor 224
The Recipient of an Expanded Criteria Donor Kidney: Selection Criteria 225
Clinical Evaluation of the Potential Deceased Donor 226
The Role of the Allograft Kidney Biopsy in Renal Transplantation 227
Organ Preservation and Pulsatile Perfusion 227
The Donor Kidney with Reduced Renal Function 229
The Donor Kidney with Prolonged Preservation times 229
The Non-Heart Beating Donor (Donation After Cardiac Death) 229
The Elderly Deceased Donor Allograft and Dual Renal Transplantation 230
The Pediatric Deceased Donor Kidney 232
Single-Unit Pediatric Deceased Donor Transplantation 232
Pediatric En Bloc Deceased Renal Transplantation 232
The Anencephalic Infant Donor Kidney 233
The Deceased Donor with Hypertension 235
The Living Donor with Hypertension 235
Contaminated Donor Kidneys and the Donor with Systemic Infection 235
The Donor with Hepatitis 237
The Donor with History of Malignancy 238
The Donor with Diabetes 238
Glomerulonephritis, Lupus, Membranous Nephropathy, and Preexisting Lesions in the Donor Kidney 238
ABO Incompatible and the Positive Cross-Match Renal Transplant 239
The Anatomically Abnormal Allograft 240
The Horseshoe Deceased Kidney Donor 240
The Polycystic Deceased Donor Kidney 240
The Donor with Multiple Arteries and Vascular Abnormalities 241
Bench Table Vascular Reconstruction of the Deceased Kidney 243
The Donor Allograft with Ureteral Abnormalities 243
Expanded Criteria Living (Old Living) Renal Donor Transplantation 243
Elderly Living Donor 243
Living Unrelated Renal Transplantation, Altruistic Living Renal Transplantation, and Paired Living Donor Exchange Transplantation 245
Living Kidney Donor with Stones 245
The Radiographically Abnormal Live Donor Kidney 245
The Obese Living Donor 245
Immunosuppression Issues and the Expanded Criteria Donor 245
Summary 246
References 246
Chapter 12: Pancreas Transplantation: Surgical Techniques 254
Background 254
Surgical Technique 254
Incision and Exposure 255
Bench Preparation 255
Inspection of the Pancreas Allograft 255
Splenectomy 255
Portal Vein Mobilization 256
Reinforcement of the Mesenteric Root 256
Preparation of the Duodenal Segment 256
Arterial Reconstruction 256
Revascularization of the Pancreas Allograft 258
Venous Drainage 258
Portal Venous Drainage 258
Systemic Venous Drainage 259
Arterial Revascularization 259
Duct Management 259
Summary 261
References 262
Chapter 13: Laparoscopic Living Kidney Donation 264
Introduction 264
Preoperative Evaluation 265
Operative Technique 266
Summary 275
References 275
Chapter 14: Perioperative and Anesthetic Management in Kidney and Pancreas Transplantation Management 277
Introduction 277
Kidney Transplantation 277
Preoperative Assessment 277
Anesthetic Management 278
Deceased Donor Kidney Management 278
Living Donor Management 278
Recipient Anesthetic Management 279
Renal Preservation in Transplantation 279
Perioperative Fluid Management 279
Pharmacologic Therapies 280
Other Considerations 280
Management in the Recovery Room 280
Conclusion 281
Pancreas Transplantation 281
Perioperative Considerations 281
Anesthetic Management 282
References 283
Chapter 15: Surgical Complications after Kidney Transplantation 285
Surgical Complications 285
The Transplant Wound 285
The Incision 285
Hernias 286
The Infected Transplant Wound 288
Lymphocele 288
Vascular Problems 291
Hemorrhage 291
Renal Artery Thrombosis 291
Renal Vein Thrombosis 292
Renal Artery Stenosis 292
Renal Artery Pseudoaneurysm 293
Allograft Rupture 294
Urologic Problems 294
Ureteral Fistulae 294
Calyceal Fistulae 297
Bladder Fistulae 298
Ureteral Obstruction 298
Hydrocele 300
References 300
Chapter 16: Urologic Complications After Kidney Transplantation 303
Urologic Complications after Kidney Transplantation 303
Ureteral Complications 303
Ureteral Leak 304
Ureteral Stenosis 307
Prophylactic Ureteral Stents 309
Urinary Calculi in Transplant Recipients 309
Urinary Retention 310
Erectile Dysfunction 311
References 312
Chapter 17: Medical Management of Kidney Transplant Recipients 314
Introduction 314
Cardiovascular Disease 314
Hypertension 315
Epidemiology and Clinical Importance 315
Risk Factors and Pathogenesis 315
Diagnosis and Management 316
Treatment 316
Management of TRAS 318
Diabetes 318
Epidemiology and Clinical Importance 318
Risk Factors and Pathogenesis 319
Diagnosis and Management 319
Hyperlipidemia 322
Epidemiology and Clinical Importance 322
Risk Factors and Pathogenesis 322
Diagnosis and Monitoring 322
Cancer 324
Nonmelanomatous Skin and Lip Cancers 324
Malignant Melanoma 325
Cancers Associated with Viral Infections 325
Colorectal Cancer 325
Breast Cancer 325
Prostate Cancer 326
Bone Disease 326
Epidemiology and Pathogenesis 326
Treatment in Early Posttransplant Period 327
Treatment in the Late Posttransplant Period 327
Anemia 327
Epidemiology and Background 327
Risk Factors and Pathogenesis 328
Diagnosis and Management 328
Posttransplant Erythrocytosis (PTE) 329
Pregnancy 329
Introduction 329
Infertility and Sexual Dysfunction 329
Optimal Timing and Contraception 330
Antenatal Period 330
Risks of Pregnancy to the Mother 330
Risks to Fetus 332
Miscellaneous 334
Hypophosphatemia 334
Hypomagnesemia 334
Hyperkalemia 334
References 334
Chapter 18: Infectious Complications: Prevention and Management 336
Introduction 336
Pretransplant Screening of Donor and Recipient, and Donor-Derived Infections 336
Posttransplant Infections: Overview 337
Posttransplant Infections: Surgical Site and Intraabdominal Infections 338
Postoperative Infections: Bloodstream Infections 340
Postoperative Infections: Urinary Tract Infections 340
Viral Infections: CMV, EBV, and Other Herpesviruses 341
Practical Management of CMV Infection and Viremia 343
Epstein-Barr Virus 344
BK Virus and Polyomavirus Allograft Nephropathy 344
Practical Management of BK Virus Infection 345
Hepatitis Viruses in Renal and Pancreatic Transplantation 346
Practical Approach to Hepatitis C in the Transplant Candidate and Recipient 347
Other Viral Infections 348
Pneumocystis and Fungal Infections 349
Practical Approach to Fungal Infections 351
Other Bacterial Infections: Clostridium difficile, Mycobacterium, Legionella, Nocardia, Listeria, Rhodococcus spp. 351
A Practical Approach to the Febrile Transplant Recipient 352
Preventing Infections in the Transplant Population: Exposures, Immunizations 354
Conclusion 354
References 354
Chapter 19: Living Kidney Donation: Pre- and Postdonation Evaluation and Management 360
Introduction 360
Donor Evaluation 361
Donor Age 361
Cardiovascular and Pulmonary Evaluation 364
Hypertension 365
Metabolic Derangements 366
Dyslipidemia 366
Impaired Fasting Glucose 366
Increased Body Mass Index and Obesity 367
Nephrolithiasis 367
Hematuria 368
Renal Mass and Function 368
Potential Risks Associated with Donor Nephrectomy 369
Immediate Complications 369
Late-Term Complications 370
Maternal and Fetal Complications following Donation 370
Late-Term Outcomes and Implications for Subsequent Kidney Disease and Overall Survival 370
Conclusion 371
References 372
Chapter 20: Psychology, Quality of Life, and Rehabilitation After Kidney and Pancreas Transplantation 375
Introduction 375
Psychological Aspects of ESRD 375
Psychological Adjustment to Dialysis 375
Quality of Life in ESRD and Transplantation 376
Psychiatric Referral in Patients with ESRD 376
Nonadherence with the Medical Regimen 377
Selection for Transplantation 377
Rehabilitation Posttransplantation 378
Psychiatric Symptoms and Disorders in Kidney–Pancreas Recipients, and Adaptation to Transplantation 378
Pretransplant Psychological Issues 378
Posttransplant Psychological Issues 379
Posttransplant Adherence to the Medication Regimen 380
Psychiatric Disorders in Kidney and Pancreas Transplant Recipients 380
Alcohol and Substance Abuse in Kidney and Pancreas Transplant Patients 381
Sleep Disorders 381
Pain 381
Antidepressant and Antipsychotic Drugs in ESRD 382
Summary and Conclusions 384
References 384
Chapter 21: Kidney Allocation System for Deceased Donor Kidneys in the United States 387
Introduction 387
What Is the National Infrastructure for Organ Allocation? 387
Ethical Issues in Organ Allocation 387
The Current Organ Allocation System 388
Wait Time 388
HLA Matching 389
Zero Mismatch (0MM) Sharing 389
Degree of Sensitization 389
Younger Age 389
Prior Organ Donation 390
Strengths and Weaknesses of the Current Kidney Allocation System 390
Additional Considerations for a New Allocation System 390
Life Years from Transplant 391
Donor Profile Index 391
Dialysis Time 391
Sensitization 392
Summary 392
References 392
Chapter 22: Ethics of Transplantation 393
Introduction 393
Brain Death 393
Consent for Brain Dead Donors 394
Donation After Cardiac Death 394
Criteria 395
Donors 395
Withdrawal of Life-Sustaining Measures 396
Medicolegal Challenges 396
Living Donor Issues 396
Transplant Commercialism and Tourism 398
Summary and Conclusions 399
References 399
Chapter 23: World-Wide Long-Term (20–40 Years) Renal Transplant Outcomes and Classification of Long-Term Patient and Allograft Survivals 401
Introduction 401
Overall Outcomes of Long-Term(20 Years or More) Renal Transplants 402
Subsets of Long-Term (20 Years or More) Renal Transplant Recipients 406
Pediatric Recipients 406
Protocol 20-Year Transplant Biopsy 407
23-Year Successes despite Long Cold Ischemia times 407
Effect of Viral Hepatitis on 20-Year Outcomes 407
Malignancy at 20–25 Years 407
Recurrent Glomerulonephritis at 20 Years 408
20-Year Outcomes with ABO Incompatibility 408
Effect of HLA Matching on 20-Year Outcomes 408
Chimerism Beyond 20 Years 408
Urinary Cytolytic Moleculesin Recipients with Allografts Functioning More than 20 Years 408
Acute Cellular Rejection and Antibody-Mediated Rejection after 20 Years 409
Individual Long-Term Renal Transplant Successes (25 Years to More than 40 Years) 409
Summary 409
References 409
Chapter 24: Quantitative Aspects of Clinical Reasoning: Measuring Endpoints and Performance 412
Introduction 412
Data Sources: Strengths and Weaknesses 412
Clinical Trials 413
Single-Center Observational Studies 414
Multicenter Observational Studies 414
National Registries 414
Endpoints in Kidney Transplantation 416
Acute Rejection 416
Delayed Graft Function 416
Infections 416
Graft Loss 417
Patient Death 417
Renal Function 418
Costs and Resource Utilization 418
Provider Quality of Care 418
Patient Satisfaction and Quality of Life 419
Novel Endpoints 419
Statistical Models Utilized to Assess Endpoints 420
Transplant Center Quality Assurance 420
Summary 421
References 421
Chapter 25: The Business of Transplantation 423
Introduction 423
The Organ Transplant Network 424
Setting Up a Transplant Program 425
Administering a Program 425
Personnel 425
Finance 426
Compliance 429
Organ Procurement 430
Marketing 430
Internal and External Liaison 430
Tracking Outcomes 430
Conclusion 431
References 431
Index 432