Textbook of Nephro-Endocrinology (eBook)

Front Cover 1
Textbook of Nephro-Endocrinology 4
Copyright Page 5
Contents 6
List of Contributors 8
Preface 12
PART I: THE KIDNEY AS AN ENDOCRINE ORGAN 13
Section I: Erythropoietin 13
Chapter 1 Erythropoietin: An Historical Overview of Physiology, Molecular Biology and Gene Regulation 15
I. Introduction 15
II. Hormonal regulation of erythropoiesis 16
III. Identification of the site of erythropoietin production 17
IV. Assays of erythropoietin 17
V. Isolation and characterization of erythropoietin 17
VI. Erythropoietin effector mechanisms 18
VII. Regulation of erythropoiesis by hypoxia 18
VIII. Regulatory elements of erythropoietin (EPO) gene 19
IX. Erythropoietin – the paradigm for gene regulation by hypoxia 20
X. Hypoxia inducible-factor (HIF) 22
XI. The elusive nature of the oxygen sensor 22
XII. Degradation of HIF by the ubiquitin-proteosomal pathway 24
XIII. Disruption of the oxygen-sensing pathway in cancer 26
XIV. Disruption of the oxygen-sensing pathway in hereditary polycythemia 27
XV. Pharmacological manipulation of HIF 28
XVI. Summary 28
References 28
Chapter 2 Erythropoiesis: The Roles of Erythropoietin and Iron 31
I. Erythropoiesis: an overview 31
II. Role of erythropoietin in erythropoiesis 33
III. Role of iron in erythropoiesis 34
References 36
Chapter 3 Extra-Hematopoietic Action of Erythropoietin 39
I. Introduction 39
II. The EPO receptor (EPOR) 39
III. Regulation of EPOR expression 40
IV. Action of EPO 41
V. Mechanisms of EPO action 42
VI. Summary 43
References 43
Chapter 4 Development of Recombinant Erythropoietin and Erythropoietin Analogs 47
I. Introduction 47
II. History of recombinant human erythropoietin 47
III. Biosimilar EPOs 48
IV. Potential strategies for modifying erythropoietin to create new EPO analogs 49
V. Darbepoetin alfa 50
VI. Continuous erythropoietin receptor activator (C.E.R.A.) 53
VII. Small molecule ESAs 55
VIII. Other strategies for stimulating erythropoiesis 56
IX. Conclusions 56
References 56
Chapter 5 Erythropoietin Anemia and Kidney Disease 61
I. Introduction 61
II. Erythropoietin pathophysiology in CKD patients 61
III. Anemia of chronic kidney disease 63
IV. Anemia and erythropoietin treatment in children with CKD 67
V. Conclusions 68
References 68
Section II: Vitamin D, PTH and Novel Regulators of Phosphate 73
Chapter 6 Vitamin D and the Kidney: Introduction and Historical Perspective 75
I. Introduction 75
II. Vitamin D 75
III. Cinacalcet 77
References 78
Chapter 7 Vitamin D: Molecular Biology and Gene Regulation 81
I. Vitamin D 81
II. The 1,25-dihydroxyvitamin D/vitamin D receptor complex 82
III. Relevance of 1,25-dihydroxyvitamin D/VDR actions in health and in kidney disease 92
IV. Concluding remarks 97
References 98
Chapter 8 Molecular Biology of Parathyroid Hormone 107
I. Introduction 107
II. Biosynthesis and metabolism 107
III. PTH receptors 109
IV. Isoforms 110
V. Physiological actions of PTH 111
References 114
Chapter 9 Endocrine Regulation of Phosphate Homeostasis 117
I. Introduction 117
II. Phosphate homeostasis 118
III. Renal phosphate transport 119
IV. Role of phosphate in the regulation of renalvitamin D metabolism 124
V. Mouse models with renal defects of phosphatetransport 125
VI. Disorders with an abnormal regulation of renalphosphate transport 125
References 131
Section III: Renin–Angiotensin 139
Chapter 10 The History of the Renin–Angiotensin System 141
I. Introduction 141
II. The 20th century 141
III. The 21st century 143
IV. The dream to be normotensive and drug free 144
V. Conclusion 144
References 145
Chapter 11 Molecular Biology of Renin and Regulation of its Gene 147
I. Introduction 147
II. Production and activation of renin 147
III. Renin gene structure and regulation 150
IV. Renin gene mutation and disease 153
V. Future perspectives 154
References 154
Chapter 12 Physiology and Regulation of the Renin–Angiotensin–Aldosterone System 159
I. Introduction 159
II. The classical circulating renin–angiotensin system (RAS) 159
III. Renin biosynthesis and secretion 160
IV. The renin receptor 161
V. Angiotensin-converting enzyme (ACE) 162
VI. The ACE-2/angiotensin (1–7)/mas receptor pathway 163
VII. AT1 receptors 163
VIII. AT2 receptors 164
IX. Angiotensin receptor heterodimerization 165
X. Tissue renin–angiotensin systems 165
XI. Intrarenal renin–angiotensin system 165
XII. Brain renin–angiotensin system 167
XIII. Vascular tissue renin–angiotensin system 168
XIV. Cardiac renin–angiotensin system 169
XV. Aldosterone and mineralocorticoid receptors 169
XVI. Clinical effects of the renin–angiotensin–aldosterone system (RAAS) 171
XVII. Summary 173
References 173
Chapter 13 The Renin–Angiotensin–Aldosterone System and the Kidney 179
I. Introduction 179
II. Historical background 179
III. Overview of the RAS pathway 180
IV. Physiologic effects of RAS 181
V. Renin inhibitors 186
VI. Conclusion 187
References 187
Chapter 14 The Renin–Angiotensin System and the Heart 193
I. Introduction 193
II. Cardiac RAS: local versus endocrine origin 193
III. RAS actions at the cellular level 194
IV. RAS and the coronary circulation 196
V. Significance of the RAS on cardiac function 196
VI. Conclusions 197
References 197
Chapter 15 Renin–Angiotensin Blockade: Therapeutic Agents 201
I. Introduction 201
II. Therapeutic classes 201
III. Pharmacology 201
IV. ACE inhibitors and angiotensin receptor blockers with other agents 208
V. Select side-effects of ACE inhibitors and angiotensin-receptor blockers 209
VI. Summary 210
References 210
PART II: THE KIDNEY AS A HORMONAL TARGET 215
Section IV: Antidiuretic Hormone 215
Chapter 16 Vasopressin in the Kidney: Historical Aspects 217
I. Introduction 217
II. Hypothalamus 217
III. Vasopressin receptors 218
IV. Vasopressin regulated urea transport 222
V. Aquaporins 224
VI. Nephrogenic diabetes insipidus 227
VII. Vaptans 228
References 229
Chapter 17 Molecular Biology and Gene Regulation of Vasopressin 237
I. Introduction 237
II. The antidiuretic hormone, vasopressin 237
III. Vasopressin receptors 240
IV. Cellular regulation of water, electrolyte and mineral reabsorption 246
V. Vasopressin, renal hemodynamics and blood pressure 252
References 254
Chapter 18 Vasopressin Antagonists in Physiology and Disease 261
I. Introduction 261
II. Physiologic antagonists 261
III. Vasopressin antagonists and their role in the treatment of water-retaining disorders 263
IV. Are vasopressin antagonists safe? 268
V. Summary and unanswered questions 269
References 269
Chapter 19 Diabetes Insipidus and SIADH 273
I. Introduction 273
II. Diabetes insipidus and SIADH 273
III. Hyponatremic encephalopathy 289
References 292
Section V: The Atrial Natriuretic Peptides 299
Chapter 20 ANP, BNP and CNP: Physiology and Pharmacology of the Cardiorenal Axis 301
I. Introduction 301
II. The natriuretic peptides production, processing and release 301
III. Natriuretic peptide particulate guanylyl cyclase receptors and physiological actions 302
IV. Natriuretic peptide receptor and enzymatic pathways for clearance and metabolism 304
V. Pathophysiologic implications in cardiorenal regulation 305
VI. Pharmacology and therapeutics of native peptides 307
VII. Novel delivery systems 311
VIII. Novel chimeric and synthetic natriuretic peptides 311
IX. Future directions 313
References 313
Section VI: Aldosterone 321
Chapter 21 Aldosterone: History and Introduction 323
I. Early history of aldosterone 323
II. Post-discovery progress to approximately 1970 330
III. Blockers of aldosterone action 334
References 336
Chapter 22 Aldosterone Receptors and Their Renal Effects: Molecular Biology and Gene Regulation 341
I. Introduction 341
II. Aldosterone-binding sites and the mineralocorticoid receptor (MR) 341
III. Molecular biology of the MR 342
IV. Distribution of the mineralocorticoid receptor in the nephron 349
V. Proteins induced by aldosterone in transport epithelia 349
VI. Non-genomic effects of aldosterone in the kidney 352
References 354
Chapter 23 Aldosterone and its Cardiovascular Effects 361
I. Introduction 361
II. Aldosterone and the heart 361
III. Aldosterone and stroke 363
IV. Aldosterone and renal disease 363
V. Potential mechanisms mediating the adverse cardiovascular effects of aldosterone (Figure 23.1) 364
VI. Therapeutic considerations 367
VII. Conclusions 367
References 368
Chapter 24 Regulation of Aldosterone Production 373
I. Introduction 373
II. Aldosterone biosynthesis 373
III. Factors regulating aldosterone production 374
IV. Diseases of aldosterone production 383
V. Summary 387
References 387
Section VII: Endocrine Disorders in Renal Failure 395
Chapter 25 Insulin Resistance and Diabetes in Chronic Renal Disease 397
I. Introduction 397
II. Historical perspective 397
III. Cellular mechanisms of insulin secretion and action 398
IV. Clinical physiology of insulin resistance 399
V. Measurement of insulin resistance 400
VI. Metabolic syndrome 401
VII. Pathogenesis of insulin resistance in chronic kidney disease 410
VIII. Regulation of renal glucose production 411
IX. Syndromes of severe insulin resistance 411
X. Treatment 412
XI. Management of diabetes in chronic kidney disease 414
XII. Hyperglycemia associated with renal transplantation 415
XIII. Conclusions 415
References 416
Chapter 26 Growth Hormone 423
I. Growth hormone and insulin-like growth factor-1 in renal failure 423
II. Pediatric implications: growth failure and the GH/IGF-I axis 428
III. Adult Implications: myriad effects of disturbed GH/IGF-I axis in CKD 430
IV. Effects of recombinant growth hormone treatment in renal failure 431
V. The horizon for improving growth and anabolism in renal failure 435
VI. Summary 436
References 436
Chapter 27 Sexual Dysfunction in Men and Women with Chronic Kidney Disease 441
I. Introduction 441
II. Sexual dysfunction in uremic men 441
III. Evaluation of sexual dysfunction in the uremic man 444
IV. Treatment of sexual dysfunction in the uremic man 445
V. Outcomes associated with hypogonadism and treatment 447
VI. Sexual dysfunction in uremic women 449
VII. Treatment 449
References 451
Chapter 28 Thyroid Status in Chronic Renal Failure Patients – a Non-Thyroidal Illness Syndrome 453
I. Introduction 453
II. Circulating thyroid hormone profile 453
III. Thyroid hormone kinetics 455
IV. Tissue T3 content and T4 uptake 457
V. The hypothalamo-pituitary thyroid axis 460
VI. Iodide retention, goiter, hypo- and hyperthyroidism 462
VII. Effects of dialysis and transplantation 462
VIII. Thyroid biology in chronic renal failure and other non-thyroidal illnesses 464
IX. Should thyroid hormone be replaced in CRF and other non-thyroidal illness patients? 465
X. Summary 466
References 466
Chapter 29 Metabolic Acidosis of Chronic Kidney Disease 469
I. Introduction 469
II. Regulation of acid–base balance with normal renal function and chronic kidney disease 469
III. Acid–base production 469
IV. Renal bicarbonate generation 471
V. Cellular buffering 472
VI. Renal tubular bicarbonate reabsorption 472
VII. Hormonal regulation of acid–base balance with normal renal function and with CKD 473
VIII. Clinical characteristics of the metabolic acidosis of chronic kidney disease 477
IX. Clinical characteristics of acid–base parameters in dialysis patients 480
X. Effects of metabolic acidosis of CKD on cellular function 482
XI. Treatment of the metabolic acidosis of CKD 486
References 487
Chapter 30 Pregnancy and the Kidney 495
I. Introduction 495
II. Normal pregnancy 495
III. Pre-eclampsia and HELLP syndrome 497
IV. Other hypertensive disorders of pregnancy 508
V. Renal failure in pregnancy 510
References 514
INDEX 527