TOXIC EXPOSURE OF THE URINARY TRACT - Free Executive Summary

Many environmental and industrial pollutants that appear to be well tolerated at low doses can produce renal damage at high doses; and some nephrotoxic agents that are poorly tolerated at any dose are used injudiciously or otherwise find their way into the environment. In addition, a growing list of therapeutic and diagnostic agents are capable of causing renal injury, and the problem of renal disease due to recreational drug use is growing.

The extent to which those and other agents result in clinical renal insufficiency and the nature of the population at risk are incompletely defined. However, many forms of acute and chronic renal failure occur for unknown reasons, and the incidence of end-stage renal disease (ESRD) has marked racial and regional differences, so nephrotoxicants might well present a serious health hazard. It has been estimated that one in five patients hospitalized with acute renal failure has been exposed to one or more nephrotoxic agents (Rasmussen and Ibels, 1982).

The identification of agents with nephrotoxic potential is hampered by several obstacles. Foremost is a constantly changing environment of chemical hazards. In addition, variations in diagnostic criteria make it difficult to identify conditions due to prolonged exposure to nephrotoxicants.

The lack of availability of simple and reliable tests for early renal injury and the long period between exposure to environmental nephrotoxicants and the onset of definable disease seriously limit the ability to define a cause-effect relationship. Standard indexes of renal function are rather insensitive markers of injury. Each human kidney contains some 800,000–1,000,000 nephrons, and a nephron can have an average filtration rate of 50 µ1/min. The total glomerular filtration rate of both kidneys (1,600,000–2,000,000 nephrons) exceeds 100 ml/

min. After acute or chronic exposure to a nephrotoxicant, hypertrophy of less severely damaged nephrons tends to counterbalance the atrophy of the most severely damaged nephrons. It is conceivable that one-third of the nephrons of the two kidneys could be lost without a noticeable reduction in the whole glomerular filtration rate if

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the remaining 1,330,000 nephrons (assuming a normal total of 2,000,000) hypertrophied so that their filtration rate increased by 50%. Such fine adjustment rarely occurs; the presence of a substantial amount of structural and functional damage might be impossible to determine precisely with standard tests of renal function.

Finally, there are almost no epidemiologic data on the number of people who develop ESRD as a result of acute or chronic exposure to environmental nephrotoxicants. All the estimates depend on inferences drawn from inconclusive sources, such as surveys of patients entering dialysis and transplantation programs. The results of several of the surveys indicate that substantial gaps exist in the ability to identify the primary abnormality leading to ESRD (Burton and Hirschman, 1979; Easterling, 1977; Evans et al., 1981; NIH, 1990; Rostand et al., 1982). For example, data compiled by the U.S. Renal Data System (USRDS) for the years 1987–1990 indicate that disease of unknown cause made up 6.6% of the cases of ESRD (NIH, 1993). Patients with interstitial nephritis not due to analgesics abuse were 3.4% of the total. Because those groups of patients include some who have been exposed to xenobiotics, such as heavy metals, it is possible that for 10.0% of the patients with ESRD, environmental and occupational nephrotoxicants might be of primary importance in the etiology of the disease.

Even in other persons with ESRD, exposure to environmental pollutants might have been a factor in the onset or progression of the disease. Information on occupational history or other factors that would implicate a patient's environment in his or her potentially catastrophic illness is rarely available.

On the basis of the available social and demographic data, several notable groupings might be relevant to the incidence of renal diseases. ESRD is found in a disproportionately high percentage of minority, ethnic, and racial groups in the United States. Native Americans, blacks, and Hispanics, especially Mexican Americans, have overall ESRD rates about 3–4 times greater than the rate in whites (USRDS, 1991). Although the reasons for the increased susceptibility of minority groups to developing ESRD are unknown (Rostand, 1992), several possibilities have been suggested (Feldman et al., 1992). They can be separated into two broad categories:

differences in the access to preventive health care and renal-replacement therapy, and physiologic heterogeneity among racial groups that might increase renal sensitivity to toxic exposures.

A study of 9,390 black and white New York state residents who began treatment between 1982 and 1988 sought to determine whether the incidence of ESRD due to the three most frequent causes (diabetic glomerulosclerosis, hypertensive nephrosclerosis, and glomerulonephritis) was related to socioeconomic status (Byrne et al., 1994). A clear effect of socioeconomic status on the incidence of ESRD due to diabetes or hypertension was demonstrated in whites, but, perhaps because of overriding factors, no such effect was seen in

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blacks. It was suggested that vigorous pursuit of other epidemiologic factors in the development of the progression of renal disease in blacks and of the possible relevance of the different structural, physiologic, and vascular renal responses between blacks and whites is indicated.

The hypothesis that treated ESRD is associated with socioeconomic status—independently of the known associations with race, age, and sex—and the hypothesis that the higher incidence of treated ESRD among blacks could be explained by differences in socioeconomic status have been examined in a study that linked the information from the USRDS and the Bureau of Health Professions Area Resource File (Young et al., 1994). An inverse association between the incidence of treated ESRD and socioeconomic status, as estimated by average income of county of residence, was found after adjustment for race, sex, and age. Differences in socioeconomic status appeared to explain some of the difference between blacks and whites in the incidence of treated ESRD.

That many patients who develop ESRD do so for unknown reasons, are proportionately more likely to be members of minority groups, and come from economically marginal backgrounds is consistent with the possibility that environmental factors influence the development of such disease.

In the United States in 1990, 165,000 people with irreversible renal failure received renal therapy for ESRD with the aid of chronic dialysis, and 9,800 renal transplantations were performed (NIH, 1993). In that year, total medical payments to provide maintenance dialysis, kidney transplantation, and all related health services to ESRD patients were in excess of $6.39 billion. In view of the limited rehabilitation achieved by dialysis, the complications associated with transplantation, and the tremendous costs involved in each, substantial efforts are required to identify the specific causes of renal disease and the factors that determine progressive and irreversible decline in renal function.

THE URINARY TRACT

To understand the inherent limitations in the detection of early renal injury, we consider here several elements of normal renal function. In the sections that follow, we treat the mechanisms that lead to renal toxicity once exposure to a nephrotoxic substance occurs, the host factors that modify the response and the nature and extent of the physiologic adjustments to injury; it is presumably the responses to injury that give rise to the various markers described in later chapters.

Renal Blood Flow

The kidneys are highly vascular organs with a blood flow of about 1,000 and 1,200 ml/min in women and men, respectively, of average height and weight. That flow is about one-fifth of the resting cardiac output.

Within the

kidney, 85–90% of blood flows through the cortex and only 10–15% through the medulla.

Glomerular Filtration

The initial step in the formation of urine is the production of an ultrafiltrate of plasma (filtration under pressure results in the retention of colloids but permits the passage of crystalloids). The unique interposition of the glomerular capillaries between the afferent and efferent arterioles is fundamental to the formation of an ultrafiltrate. Each minute, the kidneys produce 100–140 ml of glomerular filtrate with an osmolality of 280–290 mOsmol/L. In 24 hours, this amounts to 150–200 L of filtrate and over 40,000 mOsmol of solute. The amount and characteristics of the filtrate are influenced by the area available for filtration and the electric charges on the glomerular capillaries.

Tubular Reabsorption and Secretion

Once the glomerular filtrate is formed, it passes through a complex series of tubular structures where it is modified in such a fashion that waste products are excreted in the urine, critical body constituents are conserved, and the body's fluid volume is regulated. More than 99% of the filtered solute and water is reabsorbed. The principal oxygen-consuming work performed by the kidney is electrolyte reabsorption. Urine volume depends on the dietary intake of water, endogenous water production, insensible water losses, and the ability to concentrate or dilute the urine. The final osmolality of the urine can be as high as 1,400 mOsmol/L or as low as 40 mOsmol/

L. The mechanisms by which the kidneys adjust the final composition of the urine are varied. Some substances, which are protein-bound, escape filtration only to be added to the urine by the process of tubular secretion. Other substances that are freely filtered—such as amino acids and glucose—are in normal circumstances completely reabsorbed by the tubules. These processes generally require the expenditure of energy and are particularly vulnerable to the effects of toxicants.

Hormonal Action

Renal function is modified by several extrarenal and intrarenal hormones. The major extrarenal hormones—

aldosterone, vasopressin, and parathyroid hormone—modulate the excretion of sodium, water, and phosphorus, respectively. Intrarenal hormones—such as renin, prostaglandins, and kallikreins—affect renal blood flow, glomerular filtration, and tubular function. The kidneys also produce erythropoietin, which stimulates red-cell production; synthesize vitamin D from its precursor; and participate in the metabolism of several hormones, such as insulin. A complex group of peptide mediators, cytokines, influence cell growth and function;

these are produced locally or systemically and have the potential to influence the response to injury.

MECHANISMS OF RENAL TOXICITY

Susceptibility to Injury

The susceptibility of the kidney to toxic damage is related to various aspects of renal function. First, because blood flow to the kidney per gram of tissue is greater than that to most other organs, the total amount of toxicant delivered can be disproportionately high. Second, the processes of glomerular filtration, tubular reabsorption, and secretion tend to concentrate a toxicant that reaches the kidney. Third, the high metabolic rate of tubular epithelial cells leaves the kidney vulnerable to the actions of metabolic inhibitors. Fourth, the kidney can metabolically alter various endogenous and exogenous chemicals; this generally produces compounds with reduced biologic activity, but occasionally compounds with increased biologic activity are formed. Fifth, the mechanism of countercurrent exchange, which allows the kidney to form a concentrated urine, can prolong the residence time of a toxicant in the kidney.

Direct Toxic Effects

The nephrotoxicity of environmental pollutants is determined by their particular chemical properties, the duration and extent of exposure, and the nature of the host response. Manifestations of toxicity are related to the site of action in the kidney, the degree of damage produced, and the ability of the kidney to compensate for the loss of function or to repair injury.

Renal Vascular Injury

Involvement of the renal vasculature leads to changes in renal vascular resistance with a redistribution of blood flow in the kidney, a decrease in total blood flow, or both. The kidney can also lose its ability to autoregulate its blood flow. To the extent that renal plasma flow determines the rate of glomerular filtration, a decrease in the clearance of a number of substances can be expected to accompany changes in renal vascular resistance. Those effects might be mediated by anatomic changes in the renal vasculature, by changes in the sensitivity to systemic or local vasoactive substances, or by changes in muscular reflexes within the vascular walls themselves.

Glomerular Capillary Injury

The primary effect of a toxicant might be to change the ultrafiltration coefficient of the glomerular capillary membranes. That coefficient is a product of the glomerular capillary surface area and hydraulic conductivity. A decrease in either results in a proportional decrease in the filtration rate. Changes

in pore size or configuration and neutralization of the fixed negative charges can have generalized or selective effects on the ability of various substances to pass the glomerular barrier.

Renal Tubular-Cell Injury

The most firmly established effects of nephrotoxicants are on renal tubular epithelial cells, in particular those of the proximal tubule. Indeed, toxicity might be limited to a specific cell type or to a particular organelle in the cell. For example, some compounds have their major effect on tubular epithelial cell membranes, and others selectively alter the function of lysosomes, mitochondria, nuclei, or the endoplasmic reticulum (Fowler, 1982). Disruption of some organelles—particularly those which provide energy for cellular respiration—can lead to cell death.

The medullary countercurrent multiplication system provides an efficient mechanism for eliminating waste products and minimizing body-water losses. The system is such that drugs and their metabolites can accumulate in the medullary interstitium. Their chemical properties determine whether the accumulated substances initiate an inflammatory response.

The proximal tubule's organic acid and base transport systems provide an important route of elimination of molecular species that, as a result of their charge or size, do not undergo glomerular filtration but still require urinary elimination. Chemicals that interact with the organic ion-transport system can accumulate in cells or achieve high concentrations in the urine.

Other tubular mechanisms that can be impaired include those involved in electrolyte excretion and water metabolism. In addition, the mechanism of pinocytosis—whereby high molecular-weight molecules, if filtered, are recaptured from the proximal tubule fluid—can be disrupted. Finally, mechanisms of tubular epithelial cell regeneration can be compromised by nephro-toxicants.

Indirect Toxic Effects

Immunopathologic Mechanisms

Evidence has accumulated that the toxicity of environmental agents can in part be mediated by immunologic mechanisms that result in glomerular or tubulointerstitial disease (Wilson, 1982). There are four major categories of immunologic mechanisms. In Type I, or immediate hypersensitivity, damage results from the binding of antigen to IgE antibodies fixed to mast cells and basophils. In Type II, or cytotoxic reaction, damage results from the reaction of antibodies with cell-bound antigens and leads to activation of the complement cascade and cell death. Type III, or immune-complex reaction, stems from the formation of immune complexes in situ or in the circulation and leads to tissue damage. Type IV, or delayed hypersensitivity, is mediated primarily by T lymphocytes.

Data are insufficient to implicate a Type I response in mediating the effects of nephrotoxicants. But, various agents, including xenobiotics, might alter glomerular or tubular basement-membrane structures so that autoantigens are produced, autoantibodies or sensitized lymphocytes are formed and come to rest in the glomerulus through the process of filtration arrest, and a Type II response occurs. The Type III response is likely to be more important and might involve either the deposition of immune complexes formed in the intravascular compartment producing a serum-sickness-like reaction, or an antibody-antigen reaction in the extravascular compartment that results in inflammation produced by antigen-reactive cells, rather than antibodies—the so- called Arthus reaction. In either Type III case, the toxicant can act either as a full antigen or as a hapten. The haptens are small antigenic determinants that are covalently coupled to larger carrier molecules. Alternatively, various antibody-antigen complexes can be formed in situ. Once bound to tissue, the complexes fix complement, activating the complement cascade and triggering an in situ inflammatory response. In this situation, material previously trapped or planted in renal structures serves as the antigen; this material can be cationic proteins that are sequestered in the glomerulus or in vascular cells, where they become planted antigens. Later, a circulating antibody can attach to such antigens and result in in situ immune-complex formation. In addition, when structural damage is produced as a result of direct toxic effects, local auto-antigens can be produced.

Environmental agents can also have a primary effect on other antibody-antigen interactions, favoring the formation of complexes of such a size or composition that nephritogenic immune reactions occur.

Apart from those considerations is the possibility that the Type IV mechanism, once thought to be of little importance in the development of renal injury, plays a role in some forms of interstitial disease. In the Type IV, macrophages, either leukocytes or monocytes, invade glomeruli and initiate a local inflammatory response mediated by cytokines, thromboxanes, and leukotriene prostaglandins.

Nephrotoxicants might also produce novel antigens that are capable of stimulating an autoimmune response in keeping with any or all of the four mechanisms.

Xenobiotic Metabolism

Under most circumstances, foreign substances (xenobiotics), once absorbed, are distributed to various tissues where they undergo biotransformation with the production of innocuous metabolites, which are then eliminated. The enzymes responsible for biotransformation include various mixed-function oxidases in microsomes. Nonmicrosomal biotransformation can also occur. At times, these reactions result in the augmentation of toxicity. Although activity of these enzymes in the kidney as a whole is at a low level, certain specific

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