Diabetes and Kidney Disease

Contents
Contributors
Chapter 1: Historical Background of Diabetic Kidney Disease
Introduction
The Discovery of Diabetic Kidney Disease
The Pathology of Diabetic Renal Disease
Initial Studies of Renal Biopsies
Radioimmunoassay and the Concept of Microalbuminuria
The Renin–Angiotensin–Aldosterone System and Diabetic Kidney Disease
Value of Glycemic Control
Treatment of Hyperglycemia
Intensive Glycemic Control
The Impact of Glucose-Lowering Drugs on Diabetic Kidney Disease Progression
Sodium Glucose Transporter Inhibitors (SGLT2i)
Glucagon-like Peptide-1 Receptor (GLP-1R) Agonists
Bardoxolone
Recent Updates
Conclusion
References
Chapter 2: Diabetes and Kidney Disease: A Review of the Clinical Practice Guidelines
Introduction
Glycemic Management
Glycemic Monitoring and Targets
Medical Therapy for Hyperglycemia
Older Agents
Newer Agents
Sodium-Glucose Cotransporter 2 Inhibitors (SGLT2i)
Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RA)
Insulin Use in Type 2 DM
Hypertension Control in DKD
Hypertension Management
Albuminuria Management
Lifestyle Management
Tobacco Cessation
Dietary Modifications
Physical Activity and Exercise
Self-management Programs and Team-Based Care
References
Part I: Natural Course, Pathogenesis, Morphology and Genetics
Chapter 3: Diabetic Kidney Disease: Scope of the Problem
Epidemiology of Diabetic Kidney Disease
Obesity, Metabolic Syndrome, and Diabetic Nephropathy
Geriatrics and Diabetic Nephropathy
References
Chapter 4: Natural Course (Stages/Evidence-Based Discussion)
Introduction
Natural History of DKD in T1DM
Stage 1: Hypertrophy-Hyperfiltration
Stage 2: The Silent Stage
Stage 3: Microalbuminuria or Incipient Diabetic Nephropathy (IDN)
Stage 4: Macroalbuminuria
Stage 5: Uremia
Natural History of Diabetic Kidney Disease in T2DM
Stage 1: Initial Stage in T2DM
Stage 2: Normoalbuminuria
Stage 3: Microalbuminuria or Incipient Diabetic Nephropathy
Stage 4: ODN
Stage 5: ESRD
Non-albuminuric DKD
References
Chapter 5: Pathogenesis: Hemodynamic Alterations
Introduction
Single Nephron GFR Versus Total GFR
Renin-Angiotensin-Aldosterone System
Angiotensinogen
ACE-Ang II-AT-1R Axis
ACE2-Ang (1–7)-Mas Axis
Ang (1–9)
Renin/Prorenin
Aldosterone
Neprilysin
Prolyl Oligopeptidase
How Hyperglycemia Affects Single Nephron GFR
Hemodynamics as an Upstream Pathomechanism in Diabetic Nephropathy
References
Chapter 6: Pathogenesis: Structural Changes in the Kidneys in Type 1 and Type 2 Diabetes
Introduction
A Bit of History
Morphologic Findings in Diabetic Nephropathy and Related Physiopathology
Comparison of Diabetic Nephropathy in Type 1 and 2 Diabetic Patients
Pathologic Classification of Diabetic Nephropathy
Understanding the Pathology in Diabetic Kidney Disease: From the Research Laboratory to the Evaluation of Kidney Samples
Reversibility of Structural and Functional Damage in Advanced Diabetic Kidney Disease
Microalbuminuria: The Gold Standard for Diagnosis of Diabetic Kidney Disease
Other Urinary Biomarkers of Diabetic Kidney Disease
Other Biomarkers of Diabetic Kidney Disease Under Study
Differential Diagnosis of Diabetic Kidney Disease
Superimposed Pathology (Nondiabetic Lesions) That Can Alter Structural Alterations in Diabetic Nephropathy Cases
Conclusions
References
Chapter 7: Diabetes in Children and Adolescents
Introduction
Epidemiology of DM
Etiology of DM
Pathophysiology of DM
Development of the Pancreas
Developmental Programming of DM
Clinical Manifestations of DM
Acute Complications of DM
Diagnosis
Monogenic DM
Genetic Defects of β-Cell Function
Other Causes of Familial DM
Treatment of DM
Treatment of T1DM
Insulin
Insulin Regimens
Monitoring
Treatment of T2DM
Treatment of DKA and HHS
Treatment of Monogenic DM
Chronic Complications and Comorbidities of DM
Diabetic Kidney Disease
Diabetic Kidney Disease
Hyperfiltration
Inflammation
ESRD
Screening and Prevention of DM
Transition of Adolescents with DM to Adult Healthcare Service
References
Part II: Clinical Presentation and Associated Conditions
Chapter 8: Screening, Early Diagnosis, Genetic Markers and Predictors of Progression
Introduction
Screening
Albuminuria
Glomerular Filtration Rate
Diagnosis
Other Clinical Predictors of Diabetic Kidney Disease
Age
Hypertension
Hyperglycemia
Diabetic Retinopathy
Novel Biomarkers
Proteomics
Genetic Markers
Conclusion
References
Chapter 9: Atypical Presentations
Overview of Traditional and Nontraditional Concepts in Diabetic Kidney Disease
Hyperfiltration and Increased GFR Herald the Onset of Diabetic Kidney Disease
The Roles of Glucotoxicity, Oxidative Stress (OS), and Inflammation in Diabetic Kidney Disease
AGEs, Oxidative Stress and the Impact on the Diabetic Kidney
Endogenous AGEs
Exogenous AGEs
Role of Polyclonal Free Light Chains (pcFLCs) in Diabetic Nephropathy
Antioxidants and Inhibition of Inflammation
Treatment with RAAS Inhibitors
Aldosterone Blockade and Protection Against Diabetic Nephropathy
Allopurinol
Conclusion
References
Chapter 10: Albuminuria and Proteinuria
Definitions of Proteinuric States in Diabetic Kidney Disease
Justification of the Term “Albuminuria-Proteinuria”
Measurement of Urinary Albumin
Significance of Albuminuria in Type 1 Diabetic Patients
Significance of Albuminuria in Type 2 Diabetic Patients
Mechanisms of Albuminuria in Diabetes
Extrarenal Manifestations of Albuminuria
Albuminuria and Cardiovascular Disease
Albuminuria and Hypertension
Determinants of Albuminuria
Screening for Albuminuria
Proteinuria of Nondiabetic Origin
Treatment of Albuminuria-Proteinuria
Podocyte-Specific Drugs
Conclusions
References
Chapter 11: Hypertension and Diabetes
Introduction
Pathophysiology of Hypertension in Diabetics
Hypertension and Type 1 Diabetes Mellitus
Hypertension and Type 2 Diabetes
Cardiovascular Outcomes in Hypertensive Diabetics vs. Hypertensive Non-Diabetics
Renal Outcomes in Hypertensive Diabetics
Hypertension Treatment Strategies in Diabetics
Lifestyle Modifications
Effects of Antihypertensive Drugs on Incident Diabetes
Pharmacological Treatment of Hypertension in Diabetes
Overview
ARBs
ACE-Inhibitors
Renin Inhibitor(s)
Calcium Antagonists
Beta-Blockers
Diuretics
Other Drug Classes
Blood Pressure Treatment Targets for All Diabetics?
References
Chapter 12: Obesity and Metabolic Syndrome
The Role of Visceral Adiposity
Renal Alterations in Obesity
Increased Sympathetic Nervous System Activity
The Role of Adipose Tissue and Kidney Disease
Metabolic Syndrome
Quantification of Adipose Tissue in Chronic Kidney Disease
Treatment
Lifestyle Modifications
Drug Therapy
Bariatric Surgery
Management Obesity in Patients with ESKD
Conclusion
References
Chapter 13: Anemia and Diabetes
Definition and Prevalence of Anemia in CKD
Causes of Anemia
Iron Deficiency
Erythropoietin Deficiency and Hypo Responsiveness
Nephrotic Syndrome
ACE Inhibitors and Angiotensin Receptor Antagonists
Consequences of Anemia
Quality of Life
Progression of Kidney Disease
Cardiovascular Disease
Clinical Trials of Erythropoietin-Stimulating Agents
Kidney Outcomes
Cardiovascular Outcomes
Cardiovascular Events
Clinical Practice Guidelines for Evaluation of Anemia
Recommendations for Treatment of Anemia
KDIGO and NKF Clinical Practice Guidelines
Food and Drug Administration
Anemia Management
Monitoring Response to Treatment
Adverse Side Effects of Therapy
Economic Burden of Anemia
Areas of Uncertainty
Hypoxia Inducible Factor-Prolyl Hydroxylase Inhibitor (HIF-PHI): A New Beginning?
Summary
References
Chapter 14: Cardiovascular Disease and Diabetic Kidney Disease
Cardiovascular Disease in Patients with Diabetes
Heart Failure and Type 2 Diabetes
Cardiovascular Disease in Chronic Kidney Disease
Cardiovascular Disease and Diabetic Kidney Disease
Sodium-Glucose Cotransporter-2 Inhibitors
Conclusion
References
Chapter 15: Dyslipidemia and Diabetes
Introduction
DKD: Definition and Diagnosis
Lipid Disturbances in Diabetes, CKD, and DKD
Management of CKD
Guidelines
Conclusions
References
Chapter 16: Bone Disease and Diabetes
Introduction
Epidemiology: Fracture Risk
Bone Density in Diabetes
Underlying Mechanisms of Bone Fragility
Insulin
AGEs
Vitamin D and Calcium
Bone Microarchitecture
Sarcopenia
HbA1c
Adiposity-Related Factors
Therapy
Diabetic Kidney Disease
Assessment
Treatment
References
Chapter 17: Diabetic Retinopathy
Hyperglycemia
Hypertension
Hyperlipidemia
Pregnancy
Kidney Disease
Other Risk Factors
Classification of Diabetic Retinopathy
Non-proliferative Diabetic Retinopathy
Diabetic Macular Edema
Proliferative Diabetic Retinopathy
Screening for Diabetic Retinopathy
Treatment of Diabetic Retinopathy
Other Ocular Manifestations
References
Chapter 18: Pregnancy and Diabetes
Introduction
Maternal Pregnancy Outcomes
Fetal Pregnancy Outcomes
Gestational Diabetes Mellitus
Treatment of Diabetes and CKD from Diabetic Kidney Disease During Pregnancy
Preeclampsia Prevention
Antihyperglycemic Treatment
Hypertension Treatment
Anemia of Chronic Kidney Disease
Mineral Bone Disease of CKD
Postpartum Treatment
Preconception Counseling
Special Considerations: Kidney Biopsy During Pregnancy
Conclusion
References
Chapter 19: Kidney Transplantation and Kidney Pancreas Transplantation
Introduction
Transplant Options for Patients with Diabetic Kidney Disease
Patient Selection and Kidney Transplant
Pancreas Transplantation
Indications for Pancreas Transplants
Pancreatic Islet Cell Transplantation
Posttransplant Diabetes Mellitus (PTDM)
Summary and Conclusions
References
Chapter 20: Diabetic Kidney Disease and Covid-19
Introduction
Diabetic Kidney Disease and SARS-CoV-2: An Immunological Approach
Diabetic Kidney Disease and SARS-CoV-2: A Therapeutics Approach
Metformin and DPP-4 Inhibitors
Sodium-Glucose co-Transporter-2 (SGLT2) Inhibitors
Glucagon-like Peptide 1 Receptor Agonists (GLP-1RAs)
Statins and Vitamin D: Common Drugs Used in Diabetic Patients
Conclusions
References
Part III: Treatment and Prognosis
Chapter 21: Glycemic Control
Introduction
Assessment
Estimation of Kidney Function and Staging of Diabetic Kidney Disease
Glycemic Target
UKPDS, DCCT, and Kumamoto
ACCORD, ADVANCE, and VADT
Management
Non-insulin Medications
Oral
Biguanides
Sulfonylureas
Meglitinides
Thiazolidinediones
Dipeptidyl Peptidase-4 Inhibitors
Alpha-Glucosidase Inhibitors
Sodium-Glucose Co-transporter-2 Inhibitors
Parenteral
Glucagon-Like Peptide 1 Receptor Agonists
Amylin Analogues
Others
Dopamine Agonists
Bile Acid Sequestrants
Insulin
Recommendation for Type 2 Diabetes Management in Chronic Kidney Disease
Recommendation for Management of Diabetic Ketoacidosis in End-Stage Kidney Disease
Monitoring
Measuring Glycemic Control
Hypoglycemia
References
Chapter 22: Computerized Clinical Decision Support
Scope of the Problem
Epidemiology
Early Recognition
Proven Interventions
Under-Recognition of CKD
Under-Treatment of CKD
Introduction to CDS
Clinically Relevant CDS
Future Directions with CDS
Existing CDS Systems for Diabetes, Hypertension, and CKD
Preventing Adverse Drug Events in CKD
CDS to Prompt Recognition of CKD
CDS Systems to Improve Blood Pressure Control
CDS Systems to Improve Diabetes Management
CDS to Treat CKD
Optimal CDS for Diabetes and CKD
Identifying High-Risk Patients
Preventing Drug Adverse Events
Identifying Patients Not Meeting Treatment Goals
Recommendations to Help Providers Reach Treatment Goals
Engaging Patients
Ensuring Success
Monitoring Outcomes
References
Chapter 23: Antihypertensive Therapies
Introduction
Interventions for Early Diabetic Kidney Disease
Glycemic Control
Inhibitors of the Renin-Angiotensin System
Angiotensin-Converting Enzyme Inhibitors
Angiotensin II Receptor Blockers
Direct Renin Inhibitor(s)
Aldosterone Antagonists
Other Combinations of RAS Blockers
Blood Pressure Lowering
Dietary Protein Restriction
Dietary Sodium Restriction
Sodium-Glucose Linked Transporter-2 (SGLT-2) Inhibitors
Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists
Summary
References
Chapter 24: Diabetes and Kidney disease: metformin
Metformin: Mechanisms of Action (Fig. 24.1)
Metformin-Positive Effects in the Diabetic Kidney
Experimental Work
Clinical Studies
Metformin and Lactic Acidosis in Patients with Diabetes: The Role of Kidney Function
Guidelines on the Use of Metformin in Patients with Kidney Disease (Fig. 24.2)
Conclusions
References
Chapter 25: Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors
Introduction
Basic Pharmacology of SGLT2i
Cardiorenal Benefits of SGLT2i in Patients with Type 2 Diabetes
Adverse Effects
Urogenital Infections
Diabetic Ketoacidosis (DKA)
Acute Kidney Injury (AKI) and Volume Depletion
Amputations
Use in Kidney Transplant Recipients
Approved Uses and Pharmacological Properties of Individual SGLT2i
Practical Considerations
References
Chapter 26: Glucagon-like Peptide-1 Receptor Agonists (GLP1-RA)
Introduction
Glucagon-like Peptide-1 Physiology and Natural Functions
Natural Roles of GLP-1
Glucose Homeostasis
Immunity
Currently Available GLP-1 Receptor Agonist Therapies
Kidney Disease Outcome Data
Lixisenatide
Liraglutide
Semaglutide
Dulaglutide
Exenatide
Putative Mechanisms of Kidney Protection by GLP-1 Receptor Agonists
Guideline Recommendations on GLP-1 Receptor Agonist Use in DKD
Conclusion
References
Chapter 27: Dipeptidyl Peptidase-4 (DPP4) Inhibitors
Introduction
Mechanism of Action
DPP-4 Enzyme
Antiglycemic Effects of DPP-4 Inhibitors (DPP-4i)
Potential Effects of DPP-4i on the Mechanisms of Diabetic Kidney Disease
Benefits of DPP-4i in Patients with Type 2 Diabetes Mellitus
Adverse Events (AEs)
Pancreatitis
Hospitalization for Heart Failure (hHF)
Arthralgias
Application of DPP-4i in Special Populations
Kidney Transplant Recipients
Dialysis
Practice Considerations
References
Chapter 28: Novel Treatments and the Future of DKD: What Is on the Horizon?
Introduction
The Role of Immune System and Prospects of Immunotherapy in Type 1 Diabetes
The Immune System and Type 2 Diabetes
Epithelial-to-Mesenchymal Transition and Kidney Fibrosis: Potential for Reversibility
The Promise of Metabolomics and Proteomics
Genes, Epigenetics, and MicroRNAs
Nanotechnology in Diabetes Research and Treatment
In Pursuit of Futuristic Therapies
Concluding Remarks
References
Chapter 29: Putting it All Together: Practical Approach to the Patient with Diabetic Kidney Disease
Scope of the Problem
Risk Factors for Development of Type 2 Diabetes
Population Considerations
Additional Risk Factors
Screening for Diabetes
Screening for and Diagnosis of Diabetic Kidney Disease
Management
Lifestyle Management
Cardiovascular and Renal Protection
RAAS (Renin-Angiotensin-Aldosterone System) Inhibition
Angiotensin 2 Inhibition
Mineralocorticoid Inhibition
SGLT2 Inhibitors
Newer Therapies
GLP-1RA
Selective Mineralocorticoid Receptor Antagonists
Glycemic Control
Monitoring
Choice of Agents
Metformin
Hypertension Control
Cholesterol Management
Resources
Summary
References
Index