Complement and Kidney Disease (eBook)

Contents 6
Abbreviations 8
List of contributors 9
Preface 13
The complement system in renal diseases 15
Introduction 15
Hypocomplementemia in GN 15
Complement activation fragments in circulation 16
Complement deposits in glomeruli 17
Immune complex diseases and complement 17
Deficiencies of complement components and GN 18
Antibodies against complement components 19
Complement in SLE and lupus nephritis 22
IgA nephropathy and anti-mesangial cell proliferation 23
GN associated with infection 23
Membranous nephropathy 24
Tubulointerstitial disease and complement system 25
Complement, renal transplant and ischemia/reperfusion injury 26
Complement activation in cholesterol crystal emboli disease 27
References 27
Complement in renal transplantation 33
Introduction 33
Complement and renal transplantation 33
Role of complement in renal I/R injury 34
Complement in hyperacute rejection 36
Complement in allograft rejection 37
Locally synthesized C3 in allograft rejection 38
Complement regulates the immune response in allograft rejection 39
C4d in allograft rejection 40
Clinical implications 41
Conclusions 42
References 42
C1q and the glomerulonephritides: therapeutic approaches for the treatment of complement- mediated kidney diseases 50
Introduction 50
C1q deposition patterns in human glomerulonephritis 51
Complement-mediated damage in animal models of glomerulonephritis 51
C1q in glomerulonephritis 53
Anti-C1q antibodies 54
Therapeutic options 55
References 57
Complement deficient mice as model systems for kidney diseases 61
Introduction 61
Mouse strains with targeted deletion of complement components 61
Phenotypes of complement-deficient mice 63
Models of renal disease in which complement-deficient mice have been utilized 64
Conclusions 69
References 70
Non-Shiga toxin-associated hemolytic uremic syndrome 76
Definition 76
Pathology 76
Non-Stx-HUS 79
References 89
Role of complement and Factor H in hemolytic uremic syndrome 95
Introduction 95
HUS: the disease 99
Complement and aHUS 99
aHUS-associated Factor H gene mutations 100
Structure and function of Factor H 102
Autoantibodies to Factor H in aHUS patients 109
Mutations in other complement regulatory proteins: Factor I and MCP ( CD46) 110
Conclusions 110
References 113
Genetic testing in atypical HUS and the role of membrane cofactor protein ( MCP CD46) and Factor I
Introduction 120
Atypical HUS 120
Membrane cofactor protein 121
Function of MCP 121
MCP and HUS 123
Factor I 125
Implications of the association between MCP, Factor I and HUS 126
Clinical evaluation of the patient with aHUS 128
Molecular evaluation of Factor H, MCP and Factor I 129
Summary 131
References 132
Towards a new classification of hemolytic uremic syndrome 137
Introduction 137
Clinical features 137
Pathogenesis 139
HUS-associated mutations 141
Remarks to genetics and phenotype 146
References 150
Therapeutic strategies for atypical and recurrent hemolytic uremic syndromes ( HUS) 157
Introduction 157
Alternative hypothesis of Factor H involvement 159
Recommendations for therapy of recurrent/aHUS 160
Recommendations for mode of plasma therapy 162
Recommendations for plasma volume 162
Choice of plasma 164
Risk of pathogen transmission due to plasma therapy 164
Risks of plasma infusion 164
Risks of plasma exchange 165
Blood pressure control 165
High viscosity 165
Coagulation 166
Transplantation 166
CD46-associated HUS 166
Transplantation of liver and combined simultaneous liver and kidney transplantation 166
Complement inhibitors 167
Conclusions 168
References 168
Complement defects in children which result in kidney diseases: diagnosis and therapy 172
Introduction 172
The complement system 173
Kidney diseases as result of complement defects in children 177
Appendix 183
Diagnosis and therapy 187
Summary 193
References 196
The role of complement in membranoproliferative glomerulonephritis 205
Introduction 205
Membranoproliferative glomerulonephritis: the disease 205
Type I membranoproliferative (mesangiocapillary) glomerulonephritis 206
Type II membranoproliferative glomerulonephritis 206
The alternative pathway as an essential part of complement 207
Regulation and regulators 209
Site of action and regulation 209
Expression of complement regulators on kidney cells and surfaces 211
Dysregulation of the alternative pathway results in membranoproliferative glomerulonephritis 214
Defective Factor H expression or deregulated function of Factor H 214
Factor H gene mutations observed in patients with defective secretion 215
Mutations that result in a secreted but functionally defective protein 216
Autoantibodies that inactivate the regulatory function of Factor H 217
Animal models 217
C3 nephritic factor, an autoantibody that inactivates the alternative complement pathway convertase C3bBb 219
Pathomechanisms 220
Outlook: diagnosis, treatment and prognosis for transplanted kidneys 221
Conclusions 222
References 222
The experience of a patient advocacy group 228
Introduction 228
The Foundation for Children with Atypical HUS 228
Advocacy, education and support 228
Our world 229
Support system rationale 231
The child’s/adolescent’s reality 232
Support system 233
The parent speaks 234
To raise a resilient child 234
Professional lifeline 235
In conclusion 236
Index 237