Kidney Transplantation: A Guide to the Care of Kidney Transplant Recipients (eBook)

Preface 8
Contents 10
Contributors 12
1 Ten Things Not to Do 16
Introduction 16
2 The Transplant Procedure: Surgical Techniquesand Complications 29
Renal Transplantation 29
Introduction 29
History 30
Living Donors 31
Cadaver Kidneys 31
Organ Implantation 32
Preparation 32
Exposure 33
Vascular Anastomoses 34
Ureteral Anastomosis 34
Closing 35
Complications 35
Summary 36
References 37
3 What Is Transplant Immunology and Why Are Allografts Rejected? 38
Chapter Overview 38
Donor Harvest 38
The Donor Kidney Is Comprised of Immune Cells That Are Activated by Ischemia 38
Ischemia/Anoxia-Induced Death of Kidney Cells Results in the Release of Intracellular Contents and Activation of Donor Innate Immune Cells 40
Anastomosis of Donor and Recipient Vessels 41
Activation of the Recipient's Adaptive Immune Response Begins with Anastomosis of the Donor and Recipient Vessels 41
Interaction of Donor Dendritic Cells with T Cells 0 How the Recipient Becomes Aware of the Foreign Donor Kidney 42
Recipient Immune Response to Transplanted Organ 43
Formation of the Immunologic Synapse -- Target of Costimulatory and Adhesion Molecule Blockers (Belatacept and Alefacept) 43
T-Cell Receptor-Mediated Signaling Events -- Target of Calcineurin Inhibitors (Cyclosporine and Tacrolimus) 44
T-Cell Activation: Cytokine Production ® Target of Anti-IL-2 Receptor Blockers [Daclizumab (Zenapax ® ) and Basiliximab (Simulect ® )] and the JAK3 Inhibitor CP-690 550 45
T-Cell Division: Target of Azathioprine, Mycophenolate, and Sirolimus 45
Effectors of Rejection The Adaptive Immune System 46
T cells 46
B Cells 48
Donor-Specific Antibodies (DSAs) 48
Acute Cellular vs. Humoral Rejection 48
After Transplantation: The Later Phase Months to Years Later 49
Chronic Allograft Dysfunction, Chronic Allograft Nephropathy 49
The Concept of Immunological Tolerance 49
References 50
4 What Is Histocompatibility Testing and How Is It Done? 53
Introduction 53
HLA Antigens 53
Genetics of the HLA Region 53
Classes of HLA: Class I 54
Classes of HLA: Class II 55
Role of HLA Molecules in Normal Immunity 55
HLA Molecules as Antigens 56
Serologic Definition of HLA Antigens 57
Serologic Typing for HLA 57
Phenotyping, Genotyping, and Haplotyping 58
Crossmatch 59
Autoantibody 62
IgM and IgG Antibody in Crossmatch 62
Screening of Recipient Serum 63
HLA-Specific Screening Using Purified Antigen Targets 64
Post-transplant Monitoring 65
Emerging Field of Non-HLA Antigens and Antibodies 65
References 66
5 Kidney Allocation: Role of UNOS and OPOs 68
Part 1: What Is UNOS and How Are Kidneys Allocated? Patricia L. Adams and Walter K. Graham 68
Part 2: What Is an OPO and How Does It Work? 77
Glossary 82
References 83
6 Live Donors: How to Optimally Protect the Donor 84
What Normal Donors Face 84
The Medical Evaluation and Operative Risk of Prospective Donors 85
Surgical Risks 87
Medical Testing of the Potential Donor 87
Donor Glomerular Filtration Rate (GFR) 87
Risks of Donation for Those with Specific Medical Conditions 88
Diabetes Mellitus (DM) 88
Obesity 89
Hypertension 90
Proteinuria 90
Intrinsic Renal Disease 91
Recurrent and Familial Renal Disease 91
Nephrolithiasis 92
Microhematuria 92
Malignancy 93
Counseling Donors with Isolated Medical Abnormalities (IMAs) 93
Estimating Risks Associated with Donation and the Example of Hypertension in Donor Candidates 94
The Effect of Nephrectomy on Long-Term Kidney Function 94
Testing Donors Knowledge and Reasoning 96
Assuring Confidentiality 99
Ethical Issues 100
References 101
7 Laparoscopic Donor Nephrectomy: Essentialsfor the Nephrologist 105
History of Live donation 105
First Laparoscopic Nephrectomy 106
First Laparoscopic Donor Nephrectomy (LDN) 106
Current Number of Donors 106
Selection Criteria 107
Expanding Donors 107
Contraindications to Laparoscopic Donor Nephrectomy 107
Approaches 108
How I Do It 108
Surgical Complications of Laparoscopic Donor Nephrectomies 110
Delayed Graft Function (DGF) and Acute Tubular Necrosis (ATN) with Laparoscopic Donor Nephrectomies 110
References 111
8 New Sources in Living Kidney Donation 113
History 113
New England Implementation 114
Kidney List Donation 114
Kidney Paired Donation 115
Benefits of KPD 117
Computer Optimization 117
Types of KPD Programs 119
Multiregional Application 119
Candidacy for Kidney List Donation 120
Kidney List Donation Allocation 120
Candidacy for Kidney Paired Donation 121
Donor Candidacy for KPD and KLD 121
Alloantibody Screening 122
Consent for Participation 122
Exchange Process 122
Ethical and Legal Issues in Kidney Paired Donation and Kidney List Donation 123
National Pilot Program 124
Proposed Operational Guidelines 124
Optimization and Prioritization 124
Options for Individual Patients and Transplant Programs 124
Crossmatching 125
Living Donor Evaluation 126
Program Evaluation 126
References 126
9 What Are Immunosuppressive Medications? How Do They Work? What Are Their Side Effects? 128
Introduction 128
Antibodies Used for Induction Therapy 128
Lymphocyte Depleting Antibodies 129
Polyclonal Depleting Antibodies 129
Monoclonal Depleting Antibodies 130
Non-depleting Antibodies 131
Maintenance Immunosuppressants 131
Corticosteroids 131
Mechanisms of Action 131
Dosing 132
Side Effects 133
Calcineurin Inhibitors 133
Mechanisms of Action 133
Dosing 133
Drug Interactions 134
Side Effects 135
Antiproliferative Agents 137
Azathioprine 137
Mechanisms of Action 137
Dosing 137
Drug Interactions 138
Side Effects 138
Mycophenolic Acid Derivatives 138
Mechanisms of Action 138
Dosing 139
Drug Interactions 139
Side Effects 139
TOR Inhibitors 140
Mechanisms of Action 140
Dosing 140
Drug Interactions 140
Side Effects 141
Maintenance Drug Combinations 141
Treatment of Acute Rejection 141
References 142
10 Optimizing Immunosuppression 145
Rationale for Optimizing Current Immunosuppressant Strategies 145
Current State of Transplant Immunosuppression 146
Corticosteroid Minimization 147
Late Steroid Withdrawal 147
Early Steroid Withdrawal and Steroid Avoidance 150
Corticosteroid Minimization: Summary 151
Calcineurin Inhibitor Minimization 152
Early Calcineurin Inhibitor Withdrawal/Conversion 152
Later Calcineurin Inhibitor Withdrawal/Conversion 155
Calcineurin Inhibitor Avoidance 156
Calcineurin Inhibitor Minimization: Summary 156
Optimizing Immunosuppression - Conclusions 157
References 157
11 Evaluation of Renal Allograft Dysfunction 161
Introduction 161
Determinants of Allograft Function 161
Intercept: Establishing Baseline GFR 161
Slope: The Rate of Change of GFR 163
Proteinuria 163
Measuring Renal Allograft Function 164
Surveillance Biopsy 165
Evaluating Changes in Renal Allograft Function 165
Causes of Kidney Allograft Dysfunction 166
Delayed Graft Function 167
Acute Rejection 168
Impact of Immunosuppressant Drugs on Renal Function 170
Recurrent and De Novo Renal Disease 171
BK Virus Nephropathy 171
Chronic Allograft Nephropathy (CAN) 172
Conclusion 172
References 173
12 The Kidney Transplant Biopsy 177
Introduction 177
Kidney Transplant Biopsy: Specimen Adequacy 178
Utility of the Kidney Biopsy in the Assessment of Donor Quality and Transplant Outcomes 178
Pathology of the Kidney Allograft 179
Antibody-Mediated Rejection 181
Hyperacute Rejection 181
Acute Humoral Rejection (AHR) 183
Chronic Humoral Rejection 184
Accommodation 186
T-Cell-Mediated Rejection 186
Acute T-Cell-Mediated Rejection 186
Chronic T-Cell-Mediated Rejection 188
Calcineurin Inhibitor Nephrotoxicity 188
BK Virus Nephritis 189
Acute Tubular Necrosis 189
Recurrent Glomerular Diseases 191
De Novo Glomerular Disease 193
Protocol Biopsies in Kidney Allografts 193
References 194
13 Evaluation of the Kidney Transplant Candidate and Follow-Up of the Listed Patient 199
The Pre-transplant Evaluation and Follow-Up of the Listed Patient 199
Introduction 199
The Evaluation Phase 201
Education of the Kidney Transplant Candidate 201
Medical Evaluation 202
Special Situations 203
Psychosocial Evaluation 208
Financial Evaluation 209
Dietary Evaluation 209
The Waitlist Phase 209
How Does Kidney Listing Work? 209
Waitlist Status 210
Management of the Patient on the Waiting List (Wait List Maintenance Phase) 211
Strategies to Reduce Waiting Time for Listed Patients 211
Conclusions 212
References 213
14 The Acute Care of the Transplant Recipient 215
Introduction 215
Immediate Postoperative Period 215
The First Postoperative Week 216
Patients with Immediate Graft Function 217
Patients with Slow Recovery of Graft Function 218
Patients with Delayed Graft Function 218
Prerenal Causes of DGF 220
Intravascular Volume Depletion and Nephrotoxic Drugs 220
Vascular Complications 220
Graft Thrombosis 221
Renal Artery Stenosis 221
Intrinsic Renal Causes of DGF 222
Acute Tubular Necrosis 222
Management of Delayed Graft Function 223
Diagnostic Studies in Persistent Oliguria or Anuria 224
Acute Rejection 225
Thrombotic Microangiopathy 225
Recurrence of Glomerular Disease of the Native Kidneys 226
Recurrent Focal Segmental Glomerulosclerosis (FSGS) 226
Postrenal Causes of DGF 227
The First Three Post-transplant Months 228
Acute Allograft Dysfunction 228
Acute Allograft Rejection 229
Treatment of Acute Cellular Rejection 229
Pulse Corticosteroid 230
Antilymphocyte Antibody Therapy 230
Acute Antibody-Mediated Rejection 231
Urological Complications 231
Ureteral Obstruction 231
Perinephric Fluid Collections 232
Common Laboratory Abnormalities 233
Hematologic Abnormalities 233
Anemia 233
Leukopenia and Thrombocytopenia 234
Erythrocytosis 234
Hyperkalemia 235
Hypokalemia 235
Hypophosphatemia 236
Hypercalcemia 237
Hypomagnesemia 238
Transaminitis 238
Outpatient Care 240
References 240
15 Post-transplant Cardiovascular Disease 244
Introduction 244
Post-transplant Cardiovascular Disease Risk Factors 245
Conventional CVD Risk Factors 246
Post-transplant Hypertension 246
Post-transplant Dyslipidemia 249
Cigarette Smoking 254
Obesity 254
Unconventional CVD Risk Factors 255
Hyperhomocysteinemia 255
Proteinuria 256
Anemia 256
Coronary Artery Calcification (CAC) 257
Post-transplant Screening for Cardiovascular Disease 257
Summary 258
References 259
16 Diabetes Mellitus and Transplantation: Risks for Post-transplant Diabetes 262
Introduction 262
Definition and Diagnosis of New Onset Diabetes After Transplantation 262
Incidence 263
Risk Factors for NODAT 264
Non-modifiable Risk Factors 264
Age 265
Race/Ethnicity 266
Family History of Diabetes Mellitus 266
Miscellaneous 266
Modifiable Risk Factors 266
Corticosteroid-Associated NODAT 267
Calcineurin Inhibitor-Associated NODAT: Cyclosporine vs. Tacrolimus 268
Effects of Sirolimus on Glucose Metabolism 269
Obesity 270
Hypertriglyceridemia/Hypertension 270
Proteinuria 271
Potentially Modifiable Risk Factors 271
Impaired Glucose Tolerance Before Transplantation 271
HCV-Associated NODAT 271
Cytomegalovirus-Associated NODAT 272
Impact of NODAT on Patient and Allograft Outcomes 272
Detection and Management of Diabetes Mellitus in Recipients of Solid Organ Transplants 273
Pre-transplant Baseline Evaluation 273
Early Detection of NODAT After Transplantation 274
Management of Established NODAT 275
Modifiable Risk Factor Management Strategy 275
Diet and Physical Activity 276
Modification of Immunosuppression 276
Renin-Angiotensin Inhibition 276
Pharmacologic Treatment for Diabetes Mellitus 277
Oral Hypoglycemic Agents 277
Summary 279
References 280
17 Infections in Kidney Transplant Recipients 284
Introduction 284
Preventing Infectious Diseases in Kidney Transplant Recipients 284
Pre-transplant Evaluation -- Detection of Infections Before Transplantation 284
Prevention of Donor-Related Infectious Disease 285
Preventing Infectious Disease After Transplantation 287
Travel 289
Recognition and Treatment of Infectious Diseases 290
Evaluation of Fever in the Kidney Transplant Recipient 290
Specific Conditions Causing Fever in the Transplant Recipient 291
Bacterial Infections 291
Viral Infections 293
Fungal Infections 304
Parasitic Infections 311
Summary 312
References 313
18 Malignancies Before and After Transplantation 317
Introduction 317
Epidemiology, Etiology, and Risk Factors 317
The Role of Immunosuppression 319
The Role of Infection in Post-transplant Malignancy 320
Cancer Screening Pre-transplantation 320
Prevention and Screening 322
Donor Cancer Transmission 322
Skin Cancers 323
Post-transplant Lymphoproliferative Disorder 325
Renal Cell and Hepatobiliary Carcinomas 327
Other Solid Organ Tumors 327
Anal and Genitourinary Cancers 328
Summary Recommendations 328
References 329
19 Bone Disease in Renal Transplantation 333
Transplant Patients Are at Increased Risk for Fracture 333
CKD: Setting the Stage for Post-transplant Bone Disorders 335
Non-immunosuppressive Post-transplant Factors 336
Immunosuppression 337
Measuring Bone Health 339
Bone Mineral Density 339
Biomarkers 339
Bone Biopsy 340
Treatment 340
Vitamin D 341
Bisphosphonates 341
PTH-Cinacalcet and Parathyroidectomy 341
Teriparatide 342
Summary 342
References 343
20 Sexuality and Pregnancy Before and After KidneyTransplantation 348
Sexuality 348
Fertility 349
Contraception 349
Timing of Pregnancy 350
Pregnancy 350
Risks of Pregnancy to the Mother and the Fetus 351
Maternal Risks 351
Hypertension 351
Preeclampsia 352
Graft Rejection 352
Graft Loss 353
Additional Risks 353
Fetal Risks 354
Delivery and Breastfeeding 354
References 356
21 Socioeconomic Issues and the Transplant Recipient 360
Introduction 360
Widely Accepted Socioeconomic Issues: Age, Gender, Education, and Ethnicity 360
Access to Health Care and Its Impact on the Transplant Recipient 361
Insurance, Co-pays, Deductibles, and Premiums 364
The Importance of Fundraising 364
Transportation, Lodging, and Food 365
Making It Work (Employment Maintenance or Initiation) 365
Ease of Communication Between Patient and Healthcare Provider 366
Medication Side Effects 367
Living Donation 367
Relationship of Donor to Recipient 367
Social Status of Donors 368
Costs Related to Living Donation 368
Specialty Focus 369
International Perspective 369
Provider and Patient Factors: Culture and Ethnicity 370
High-Risk Behaviors 370
Lifestyle Choices and Impact on the Transplant Recipient 371
Emotional and Cognitive Status and Its Relationship to Socioeconomic Status 371
Summary 372
References 372
22 Adherence to the Immunosuppressive Regimen in Adult and Pediatric Kidney Transplant Recipients 375
Introduction 375
Prevalence of Non-adherence to the Immunosuppressive Regimen 375
Consequences of Non-adherence to the Immunosuppressive Regimen 377
Factors Associated with Non-adherence to the Immunosuppressive Regimen 378
Interventions to Improve Adherence 381
Recommendations for Future Research 383
References 383
23 Transitioning Between Pediatric and Adult Clinics 387
Introduction 387
Planning for Transition with a Multidisciplinary Approach 388
Components of the Transition Process 389
Knowledge and Self-Advocacy 389
Independent Behaviors 390
Sexual Health 390
Pregnancy and Contraception 391
Sexually Transmitted Infections 393
HPV Infection 394
Educational/Vocational/Financial Planning 395
Health and Lifestyle 395
Conclusion 395
References 396
Index 399

"Chapter 10 Optimizing Immunosuppression (p. 137-138)

Alexander C. Wiseman and James E. Cooper

Rationale for Optimizing Current Immunosuppressant Strategies

While short-term outcomes in kidney transplantation have improved significantly over the last decades, questions remain regarding long-term improvements in graft survival. Whereas long-term graft survival was reported to improve significantly from the mid-1980s to the mid-1990s,1 a more recent analysis has shown an equivalent relative risk of graft failure for those transplanted in 1995 through 2000 despite a reduction in acute rejection rates of nearly 50% during that time.

Thus, attention has shifted to medication regimens that not only prevent early acute rejection but also take into consideration drug side-effect profiles, ease of use, and effect on long-term graft function. One potentially modifiable factor in improving long-term graft function is the avoidance of nephrotoxicity caused by calcineurin inhibitors (CNIs). CNI nephrotoxicity may be present in 33% of protocol biopsies at 1 year and nearly 100% of all biopsies at 10 years.

Recipients of non-kidney solid organ transplants are not exempt from CNI nephrotoxicity, as over 90% of liver, heart, and lung transplant patients remain on CNI at 1 year,4 with rates of chronic kidney disease (GFR < 30ml/min) of 10–20% over the long term.5 In addition to their nephrotoxic effects, CNIs are associated with post-transplant diabetes, hypertension, hyperlipidemia, hirsutism, neurotoxicity, and alopecia. With the development of newer agents, considerable effort has been devoted to safely reducing exposure of kidney transplant recipients to CNIs over the last decade.

While steroids have not been implicated in chronic graft loss, they are associated with numerous complications that have significant effects on patient morbidity and dissatisfaction. As with CNIs, steroid use causes hypertension and hyperlipidemia, but can also result in obesity, glucose intolerance, osteonecrosis, avascular necrosis, glaucoma, cataracts, myopathy, cushingoid features, and neuropsychiatric complications. An economic analysis of chronic steroid therapy in kidney transplant recipients estimated a $5,300 cost per patient year in 1996,6 concluding that elimination of steroids from immunosuppressive regimens would be cost equivalent even if associated with an 11% increase in acute rejection rates.

Importantly, patients perceive steroids to be less desirable than CNIs and if given an option to discontinue one medication, 65% would prefer steroid elimination vs. 19% that would prefer CNI elimination.7 The metabolic, cardiovascular, and cosmetic side effects associated with chronic corticosteroid use have inspired numerous trials to limit their use. Figure 10.2 illustrates common side effects encountered with chronic steroid and CNI use."