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Aldosterone and Its Cardiovascular Effects

Key Points Aldosterone and mineralocorticoid receptor activation exert cardiovascular effects above and beyond effects on blood pressure Several large clinical trials have shown that mineralocorticoid receptor antagonists, in addition to usual therapy that includes angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers, improve clinical outcomes in heart failure Accumulating data also suggest potential beneficial effects of mineralocorticoid receptor antagonists in vascular conditions related to diabetes mellitus…

Regulation of Aldosterone Production

1 Introduction Aldosterone represents the primary mineralocorticoid produced by the adrenal gland and specifically within the outer adrenocortical cells of the glomerulosa. The need for the structural zonation of the adrenal cortex as a mechanism to control aldosterone production is apparent when one considers that the amount of aldosterone needed to control salt balance is 100- to 1000-fold less than the amount of cortisol needed to…

Extrahematopoietic Actions of Erythropoietin

Key Points EPO is a member of the type I cytokine family and a multifunctional protein EPO is synthesized primarily by the kidney as a circulating hormone for erythropoiesis and locally for paracrine/autocrine tissue protection and repair EPO activates multiple cell types in both its hematopoietic and extrahematopoietic roles Cross talk between the hormonal and paracrine/autocrine systems is prevented by existence of receptor isoforms having different…

Vitamin D and the Kidney: Introduction and Historical Perspective

1 Introduction The discovery of vitamin D, the elucidation of the associated pathophysiology and then, more recently, the discovery and application of drugs that modulate the parathyroid hormone (PTH)–vitamin D–mineral physiology have their origins in a fascinating series of scientific experiments that led to the cure for rickets. The pleotropic effects of vitamin D have been elucidated more recently. Vitamin D is now known to play…

Molecular Biology of Renin and Regulation of Its Gene

Acknowledgments The authors would like to thank Chantal Mercure for the gift of previously unpublished images presented in Figs. 21.1 and 21.2 . This work was supported by an unrestricted grant from Merck-Frosst Canada Ltd. to TLR. 1 Introduction Renin, a member of the aspartyl protease family of enzymes, is released into the circulation from the juxtaglomerular (JG) cells of the kidney where it cleaves angiotensinogen…

Clinical Syndromes of Vitamin D and Phosphate Dysregulation

Key Points Vitamin D plays an important role in health. As earlier thought, clinical manifestations of vitamin D abnormalities are not limited to skeletal health. Osteomalacia and rickets are instances of abnormalities in bone metabolism related to vitamin D insufficiency. Vitamin D’s association with cancer, cardiovascular disease, and immune system has displayed an important role for vitamin D in preventive health. Supplementation of vitamin D is…

Vitamin D: Molecular Biology and Gene Regulation

Acknowledgments This work was supported in part by grants DK62713 from the National Institutes of Health (to ASD) and CeDAR (Center for vitamin D receptor Activator Research) grant (to ASD) from Massachusetts General Hospital. 1 Vitamin D Vitamin D is essential for bone health, as has been recognized since the 1930s when vitamin D fortification of milk eradicated rickets, a skeletal disorder characterized by undermineralized bone.…

Pregnancy and the Kidney

1 Normal Pregnancy 1.1 Renal Adaptation Normal pregnancy is associated with increases in glomerular filtration rate (GFR) of 40%–65% and renal plasma flow (RPF) of 50%–85% above nonpregnant levels during the first half of gestation. These increases are a result of reductions in both afferent and efferent arteriolar resistances without glomerular pressure change that have been demonstrated in micropuncture studies. Creatinine clearance has been found to…

Metabolic Acidosis of Chronic Kidney Disease

1 Introduction Approximately, 1 mEq/kg body weight of net endogenous acid is produced in adults and 2–3 mEq/kg body weight in normal children each day. In addition, ∼4500 mEq/day (180L × 25 mEq/L) bicarbonate is filtered by the glomerulus. This filtered bicarbonate must be reabsorbed by the renal tubules and a quantity of bicarbonate equivalent to the acid produced by metabolism must be generated by the…

Sexual Dysfunction in Men and Women With Chronic Kidney Disease

1 Introduction Disturbances in sexual function are common in patients with chronic kidney disease. Such disturbances include erectile dysfunction, decreased libido, and marked declines in the frequency of intercourse. Sexual dysfunction is multifactorial and primarily organic in origin. In addition to the uremic milieu, peripheral neuropathy, autonomic insufficiency, peripheral vascular disease and pharmacologic therapy all play an important role in the genesis of these problems. In…

Growth Hormone

The discovery of growth hormone (GH) has taken a protracted course. Li and Papkoff in California and Raben in Massachusetts first isolated GH in 1956 from the human pituitary. In 1958, Raben reported the results of the first trial to show the effects of human GH extracted from the pituitary gland on growth, and 2 years later its benefits for human growth were demonstrated. The GH…

Insulin Resistance and the Metabolic Syndrome in Chronic Renal Disease

1 Introduction Insulin resistance can broadly be defined as an impairment or defect in the ability of insulin to produce its normal biological, physiological, or clinical effects. Despite the simplicity of this concept and the relatively ease with which it can be demonstrated in vitro and in vivo, the true complexity and multiple clinical manifestations of insulin resistance have only recently been appreciated. Although the effects of insulin…

Development of Recombinant Erythropoietin and Erythropoietin Analogs

1 Introduction The ability to stimulate erythropoiesis with therapeutic agents has probably had the greatest impact in the field of nephrology. Ever since it was recognized that red cell production was controlled by the hormone erythropoietin (EPO), and that this hormone was produced de novo in the kidney in response to hypoxia, there was a clear rationale for administering EPO replacement therapy. When this dream became…

Erythropoiesis: The Roles of Erythropoietin and Iron

Acknowledgments The author acknowledges and thanks Dr. Herbert Lin and Dr. Jody Babbit for an earlier version of this chapter. 1 Erythropoiesis: An Overview 1.1 Hematopoiesis The cellular and cell-derived components of the blood are generated in the process called hematopoiesis. In the adult, hematopoiesis occurs in the medulla of the bone marrow, while some hematopoiesis occurs during early embryonic development in the yolk sac and…

Erythropoietin: An Historical Overview of Physiology, Molecular Biology, and Gene Regulation

Conflict of interest statement P.J. Ratcliffe is a founding scientist of the company ReOx Ltd. 1 Introduction Although generally ascribed to the 19th-century physicians, Richard Bright, Robert Christison, and Pierre Rayer, the link between kidney disease and anemia was first described 18 centuries earlier by the Greek physician Aretaeus, the Cappadocian, who noted: “In all the species there are present paleness, difficulty of breathing, occasional cough;…

Aldosterone’s Mechanism of Action: Genomic and Nongenomic Signaling

1 Introduction Adrenal hormones from the cortex, such as cortisol and aldosterone, are essential for human life and evolved with a complex regulatory system to play a crucial role in metabolism homeostasis, stress response, and blood pressure (BP) regulation. Despite their importance in human physiology for millions of years, the history of the renin–angiotensin–aldosterone system (RAAS) only starts by the end of the 19th century with…

The Cardiac Natriuretic Peptide System: Linking the Heart and Kidney in Cardiorenal Homeostasis and Therapeutics

Acknowledgments Funding for this manuscript was provided by the NHLBI PO1 HL76611 and RO1 HL36634. In 1981, the concept of the heart as an endocrine organ emerged with the discovery of the atrial natriuretic peptide (ANP) by de Bold in 1981. This initial report was followed later by the discovery of B-type natriuretic peptide (BNP) as an additional cardiac hormone which was structurally similar but genetically…

Diabetes Insipidus and Syndrome of Inappropriate Antidiuretic Hormone

1 Introduction Disorders in sodium and water homeostasis primarily result from perturbation in the release or response to arginine vasopressin (AVP). Impaired AVP secretion or response results in impaired renal concentration and is termed diabetes insipidus (DI). Hyponatremia that results from AVP production in the absence of an osmotic or hemodynamic stimulus is termed syndrome of inappropriate antidiuretic hormone secretion (SIADH). The goals of this chapter…

Vasopressin Antagonists in Physiology and Disease

1 Introduction Hyponatremia is the most common electrolyte abnormality in hospitalized patients occurring in as many as 15%–30% of patients. It can present acutely or chronically. The treatment of hyponatremia has been reviewed elsewhere extensively but includes simple strategies such as free water restriction as well as more emergent measures such as the administration of hypertonic (3%) saline. In the last decade a new class of…

Molecular Biology and Gene Regulation

1 Introduction Vasopressin, or in humans and rodents, arginine vasopressin (AVP), is the most important hormone in the regulation of urine concentration. Without the ability to concentrate our urine, we would excrete as much as 170–180 L of urine per day (given an average glomerular filtration rate (GFR) of about 120 mL/min). Other factors have some role, such as the renal sympathetic nervous system and possibly,…