Kidney Disease in Diabetes

Moro O. Salifu, Samy I. McFarlane, Moro O. Salifu, Samy I. McFarlane

• Publisher: Bentham Science Publishers
• Year: 2020
• Print ISBN: 9789811421990
• eBook ISBN: 9789811422003
• Topic: Medicine
• Subtopic: Nephrology

This reference work provides comprehensive information about diabetic nephropathy. Chapters in the book introduce the reader to the link between diabetes, obesity and chronic kidney disease (CKD) and delve into many topics relevant to treating kidney disease in diabetic patients. These topics include CKD epidemiology, diagnosis, treatment considerations for the elderly patient, post-transplant diabetes, pathophysiology, biomarkers and much more. Special topics such as the incidence of cardiovascular disease in diabetic CKD, nutrition for obese CKD patients and the clinical use of biomarkers for evaluating cases are also included. The broad spectrum coverage of informative topics about diabetic kidney disease make this an essential reference for medical students and clinical residents/healthcare professionals in nephrology, endocrinology, geriatrics, internal medicine and general surgery. Researchers interested in the clinical biochemistry of diabetes and associated disorders will also benefit from the information presented.

Pathogenesis of Diabetic Kidney Disease

Navneet Sharma¹, Justin Lee², Isabel M. McFarlane^{2, *}

¹ Department of Medicine, Division of Cardiology, State University of New York at Stony Brook, Stony Brook, NY, United States

² Department of Medicine, Division of Cardiology, State University of New York, Downstate Medical Center, Brooklyn, NY, United States

Abstract

Diabetic kidney disease (DKD) is a growing health burden globally. Obesity levels continue to increase in developed and developing nations. Obesity represents a chronic inflammatory state that alters glucose metabolism and insulin function, leading to Diabetes Mellitus. Diabetes mellitus initiates a cascade of metabolic and hemodynamic changes in the nephron. Interaction of metabolic and hemodynamic pathways lead to inflammation and fibrosis of the glomerus, a hallmark of DKD. Early control of hyperglycemia and the use of angiotensin converting enzymes inhibitors (ACEi) or angiotensin receptor blockers (ARB) are the cornerstone of management, aiming to slow down the progression of DKD. Better understanding of the pathogenesis involved in development of DKD, has resulted in an exploration for novel therapeutic modalities. These new modalities promise to not only slow down progression of DKD, but also potentially reverse DKD.

Keywords: Adhesion molecules, Advanced glycation end products, Chemokines, Diabetes, Diabetic kidney disease, Endothelial injury, Extracellular matrix, Fibrosis, Glomerulus, Glomerulosclerosis, Hemodynamic pathways, Hyperglycemia, Inflammatory pathways, Inflammation, Metabolic pathways, Mesangium, Mediators of diabetic nephropathy, Pathogenesis, Podocyte damage, Renoprotection.

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^* Corresponding Author Isabel M. McFarlane: Department of Medicine, Division of Cardiology, SUNY Downstate Medical Center, Brooklyn, NY, USA; Tel: [phone]; E-mail: [email protected]

INTRODUCTION

Obesity is a worldwide pandemic that affects two-thirds of the American population [1, 2]. Obesity carries great health and economic burden on societies; it is estimated the obesity and its related health complication cost the US almost $250 billion in health care expenditure each year [3^-5].

Obesity-related chronic inflammation is crucial in the pathogenesis of insulin

resistance and Diabetes Mellitus. Obesity leads to accumulation of free fatty acid in the skeletal muscle, adipose tissue, and liver. The release of cytokines and chemokines causes macrophage activation resulting in localized inflammation. Therefore, insulin resistance and diabetes occur as a consequence of localized inflammation [7]. Additionally in animal models, high fat diets induce endoplasmic reticulum stress and increased beta cell apoptosis [8, 9]. Thus, there are multiple genetic, epigenetic, and environmental risk factors contributing to diabetes. Risk factors (see Table 1) involved in the pathogenesis of diabetes and chronic kidney disease (CKD) include ethnicity, hypertension, central obesity and family history of diabetes/CKD. The rising obesity epidemic has also led to greater diabetes burden; an estimated 387 million people are affected with diabetes worldwide and this number is expected to rise to 592 million by 2030 [10].

Diabetic kidney disease (DKD) is one of the most important types of end organ damage resulting from of obesity and diabetes. Based on National Health and Nutrition Examination Survey data, 38.5% of diabetic population has DKD [11]. Therefore, roughly 30 million people are afflicted by DKD in the US [12]. Of all the DKD cases each year, 44% progress to end-stage renal disease [11]. The 5-year adjusted survival for a patient who begins hemodialysis due to DKD is 31% [11, 12] and the 10-year survival as low at 9% [13].

Table 1 Risk Factors for Type 2 Diabetes [14].

• Age > 45 years • Overweight/obesity particularly central obesity • Lifestyle (physical inactivity, high-caloric, high-fat intake) • Family history of type 2 diabetes (parents or siblings) • Ethnicity (African-Americans, Hispanic-Americans, Asian-Americans, and Pacific Islanders) • Gestational diabetes • Hypertension • Dyslipidemia (low HDL cholesterol, high triglycerides) • Impaired fasting glucose (≥100 to ≤125 mg/dL) • Impaired glucose tolerance 2 hr plasma glucose ≥140 mg/dL • Sleep disorders

The interrelated nature of obesity, diabetes mellitus, and DKD carries a poor prognosis for patients and high economic burden on society. Therefore, it is of utmost importance to understand the pathogenesis involved in the development of DKD, so novel therapeutic strategies can be formulated to combat DKD early and effectively.

PATHOGENESIS OF KIDNEY DISEASE

Pathogenesis of DKD involves a series of complex and interconnected steps that are categorized as the metabolic and hemodynamic pathways. These altered pathways, triggered by hyperglycemia, act independently as well as in concert with each other, via second messenger systems, leading to the distinct structural and functional glomerular damage associated with DKD via three main mechanisms:

• Endothelial damage [15] and increased vascular permeability.
• Mesangial hypertrophy [15], podocyte loss [15^-17], and renal vascular sclerosis.
• Activation of inflammatory pathways via downstream mediators such Extracellular Regulated Protein Kinase (ERK), p38 Mitogen-Activated Protein Kinase (p38 MAPK), Nuclear Factor κB (NF-κB) and Activator Protein-1 (AP1) [17, 18].

METABOLIC PATHWAYS

The metabolic pathway starts with hyperglycemia-induced production of advanced glycation end products (AGE), protein kinase C (PKC) activations, and reactive oxygen species (ROS) generation. Furthermore, AGEs, PKC, and ROS are capable of inducing each other independent of hyperglycemia [17, 19]. Hence, the production of either one of the components, can still lead to production of the other, amplifying the progression to DKD.

Accumulation of Advanced Glycation End Products

Hyperglycemia causes non-enzymatic reduction of sugars by free reactive amino groups of proteins yielding a Schiff base and biochemical reactions (Amadori rearrangement) result in the production of a heterogeneous group of non-reversible products k...

Table of contents

• Welcome
• Table of Content
• Title
• BENTHAM SCIENCE PUBLISHERS LTD.
• FOREWORD
• PREFACE
• ACKNOWLEDGEMENTS
• DEDICATION
• List of Contributors
• Obesity, Diabetes and Chronic Kidney Disease: Insights into an Evolving Epidemic
• Diabetic Kidney Disease: Ethnic and Gender Disparities and Implications for Diagnosis and Treatment
• Chronic Kidney Disease in the Elderly: Special Considerations and Therapeutic Strategies
• Post-Transplant Diabetes Mellitus: Evaluation and Management
• Cardiovascular Disease in Diabetic Chronic Kidney Disease: Evaluation and Therapeutic Implications
• Pathogenesis of Diabetic Kidney Disease
• Proteinuria and Albuminuria as CVD Markers in Diabetes and Chronic Kidney Disease: Evaluation and Management
• Biomarkers as Clinical Tools for Evaluation of Kidney Disease in Diabetes
• Glycemic Control and CKD: Evaluation of the Risk/Benefit Ratio: Optimal Therapeutic Strategies
• Nutrition in CKD Patients Who are Obese
• The Role of RAAS Inhibitors in the Prevention and Treatment of Chronic Kidney Disease in the Diabetic Population
• Diabetic Kidney Disease: Future Directions