Target Organ Toxicity

Volume 2

Gerald M. Cohen

• Publisher: CRC Press
• Year: 2020
• ISBN:
  9781000697384
• Edition: 1
• Topic: Medicine
• Subtopic: Toxicology

First published in 1986: This two-volume set provides essential information on the general princi-ples of target organ toxicity. Pharmacokinetics, metabolic activation and key defense mechanisms, excretion, species variation, and tissue-specific biochemistry are explored comprehensively. These general principles are then illustrated using specific examples of toxicity to different target organs and systems. DNA modifi-cation and repair in tumor induction, and specificity in tumor initiation are also examined. Of primary interest to toxicologist, pharma-cologists, biochemists, and environmental toxicologists.

Chapter 1

THE KIDNEY AS A TARGET ORGAN FOR TOXICITY

F. Rush and Jerry B. Hook

TABLE OF CONTENTS

I. Introduction

A. Anatomy

B. Unique Susceptibility of the Kidney to Toxicants

II. Susceptibility of the Glomerulus to Toxicants

A. Introduction

B. The Glomerulus as a Target for Toxicity

1. Immune-Mediated Glomerular Nephritis Involving Soluble Antigens

2. Aminoglycoside-Induced Glomerular Toxicity

III. Susceptibility of the Proximal Tubule to Toxicants

A. Introduction

B. The Proximal Tubule as a Target for Toxicity

1. Cephalosporin Nephrotoxicity

2. Aminoglycoside-induced Proximal Tubular Damage

3. Proximal Tubular Damage from Cysteine Conjugates of Halogenated Hydrocarbons

4. Cadmium Nephropathy

IV. Susceptibility of the Renal Medulla to Toxicants

A. Introduction

B. The Renal Medulla as a Target for Toxicity

1. Fluoride Nephropathy

2. 2-Bromoethylamine Hydrobromide-Induced Papillary Necrosis

V. Susceptibility of the Distal Nephron to Toxicants

A. Introduction

B. The Distal Nephron as a Target for Nephrotoxicants

1. Tetracycline Nephrotoxicity

References

I. INTRODUCTION

The mammalian kidney is an extremely complex organ, both anatomically and functionally. Although the primary function of the kidney is excretion of wastes, the kidney also plays an important role in the regulation of total body homeostasis. The kidney is the predominant organ involved in regulation of extracellular volume and in control of electrolyte and acid base balance. This organ is also the major site of formation of hormones that influence systemic metabolic functions such as erythropoietin and 1,25-dihydroxy-vitamin D₃. Any or all of these functions could become targets for toxicants. The kidney is often the main site for excretion of many drugs and drug metabolites and is therefore exposed to a variety of potential toxicants. However, despite this extensive exposure, few chemicals are actually nephrotoxic.

Chemicals may act as general or specific nephrotoxicants. General nephrotoxicants are chemicals whose actions are not limited to the kidney and may act as metabolic poisons or their action may be pre-renal causing systemic hypotension or nutritional or hydration defects. Specific nephrotoxicants are organ specific and their specificity often reflects some unique structural, functional, or biochemical aspect of the kidney. The purpose of this chapter is to discuss aspects of the kidney and chemicals that lead to specific renal damage. Aspects of biochemistry, physiology, and toxicology are left to more general reviews.¹,²

A. Anatomy

Gross examination of a sagittal section of the kidney clearly demonstrates the demarcation between the two major anatomical areas, the cortex and the medulla (Figure 1). The cortex constitutes the major portion of the kidney and consequently receives the greatest fraction of renal blood flow. The basic anatomical unit of the kidney, the nephron, may be considered in three portions: the vascular element including the afferent and efferent arterioles, the glomerulus, and the tubular element. All nephrons have their primary vascular elements and glomeruli in the cortex. The proximal tubule extends from the glomerulus and is localized in the cortex, the later portion of which (the pars recta or straight portion), along with the loops of Henle, extends toward the medulla and papilla. Those glomeruli close to the medulla (juxtamedullary glomeruli) are associated with nephrons that send their loops of Henle deep into the medulla whereas glomeruli closer to the surface of the kidney are often associated with nephrons whose loops of Henle are contained within the cortex.

B. Unique Susceptiblity of the Kidney to Toxicants

Blood flow to the kidney is very high compared to most other organs. The two kidneys together comprise less than 1% of the body weight yet they receive about 25% of the cardiac output. Approximately one third of the plasma water reaching the kidney is filtered, and from this material approximately 98 to 99% of the salt and water are reabsorbed. Maintenance of normal function requires delivery of large amounts of metabolic substrates and oxygen to the kidney and because of the high blood flow, any drug or chemical in the systemic circulation will be delivered in relatively high amounts to this organ. As salt and water are reabsorbed from the glomerular filtrate, the materials remaining, including a potential toxicant, may be concentrated in the tubular urine. Thus, a nontoxic concentration of a chemical in the plasma may become toxic subsequent to concentration within the urine. Furthermore, a chemical reaching the kidney may be concentrated in tubular cells in one or more of the following ways. The chemical may be actively secreted into the tubular fluid, after first being accumulated within the cells of the proximal tubule. This process will expose these cells to high concentrations of the chemical which potentially could result in toxicity. Similarly, a chemical that is reabsorbed, either passively or actively, may expose cells of the proximal tubule to high chemical concentrations, possibly resulting in toxicity.

FIGURE 1. (A) Sagittal section of a mammalian (human) kidney is illustrated in the lower left. A and V refer to renal artery and vein, respectively; (1) minor calix; (2) fat in sinus; (3) renal column of Bertini; (4) medullary ray; (5) cortex; (6) pelvis; (7) interlobar artery; (8) major calix; (9) ureter. Insert (a) from the upper pole of the kidney is enlarged to illustrate the relationships between the nephrons and the vasculature. (B) Anatomy of a juxtamedullary nephron. Note the demarcation between cortex and medulla; (1) glomerulus; (2) proximal convoluted tubule; (3) proximal straight tubule (pars recta); (4) descending limb of the loop of Henle; (6) thick ascending limb of the loop of Henle; (7) distal convoluted tubule; (8) collecting duct. (From Tischer, C. C., in The Kidney, Bremer, B. M. and Rector, F. C., Eds., W. B. Saunders, Philadelphia, 1981, and Gottschalk, C. W., Am. J. Med., 36, 670, 1964. With permission.)

The renal medulla offers unique problems concerning nephrotoxicity. Because of the low blood flow to the medulla, relatively less potential toxicant might enter this region via the bloodstream than in the cortex. However, chemicals in the tubular urine may pass through the loop of Henle and/or medullary collecting duct and be concentrated within the medulla due to normal countercurrent mechanisms.

II. SUSCEPTIBILITY OF THE GLOMERULUS TO TOXICANTS

A. Introduction

The formation of urine begins at the glomerulus where an ultrafiltrate of plasma is formed (glomerular filtrate). The glomerulus consists of a network of capillaries, a visceral layer surrounding these capillaries, a parietal layer (Bowman’s capsule), and interstitial, mesangial cells that are localized within the capillary network. The process of filtration is governed by the same physical properties that determine fluid movement across any other capillary bed, i.e., by the balance between transcapillary hydraulic pressure and colloid osmotic pressure. Glomerular filtration rate (GFR) can be mathema...