SYMPOSIUM

TOXICOLOGIC PATtIOLOCiY ISSN.0192-6233 Volume 14, Number 1, 1986 Copyright 0 1986 by the Society of Toxicologic Pathologists

Renal Pathology and Toxicity

Renal Function and Laboratory Evaluation* KENNETHC. BOVEE School of Veterinary Medicine. University of Pennsylvania, Philade~hia,Pennsylrania 19104 ABSTRACT This paper reviews the normal renal function in relation to common functional tests helpful to detect nephrotoxicity. The measurement o f renal blood flow, intrarenal distribution of blood flow, and glomerular filtration rate remain thc basic parameters of nephrotoxicity. Renal tubular function is accurately measured by standard clearance tests for solutes including electrolytes, glucose and amino acids. The renal concentrating capacity serves as a sensitive but non-specific measure of renal integrity. The measurement of plasma concentration of some solutes is helpful to identify nephrotoxicity, but is most effective when a profile of solutes is measured over a time period. Urinary protein excretion and particularly the excretion o f enzymes may localizc the nephrotoxicity in certain tubular segments. Due to the multiple functions of the kidney, no single test or group of tests can be relied upon to detect nephrotoxicity. A battery of tcsts inchding screening tests and specific tests to measure glomerular or tubular function must bc selected to match the pattern of nephrotoxicity.

ment resulting in the disruption of a variety of biochemical processes. The kidney must be regarded as a highly heterogeneous tissue from anatomic, physiologic, and biochemical considerations. The interpretation of biochemical data derived from whole organ studies may bc complicated and misleading. The kidney performs dozens of metabolic activities simultaneously with a variety of cell types and complicated interrelationships. Any approach to understand the complex functions that occur in the kidney must recognize this complexity and attempt to investigate abnormal function using a variety of tests. The kidney has tremendous capacity for compensatory hypertrophy after an insult, which may make the value of a functional test of transient importance. A relationship between structural and functional abnormalities may not exist due to this compensation. kinally, a variety of species of animals are used to study renal function, each with its own subtle variations in renal function and sensitivities to renal insult. For example, susceptibility to a glomerular injury in a specific strain of rats may be of minor importance to another strain of rat or have no deleterious effect in another species. Therefore, one must know of the normal renal function of the strain or species of animal, the functional response to a given insult in that animal, and then study these changes in relation to duration, acute or chronic renal injury, and correlate these t0 morphologic changes over time.

INTRODUCTION The kidney has the ability to perform many complex and diverse functions, such as filtration, reabsorption and secretion of solutes, and production of concentrated urine, to fulfill the purpose of maintaining homeostasis. It is important that normal renal physiology and biochemistry be understood by the pathologist and toxicologist to recognize functionalmorphologic alterations that may occur due to disease. The purpose of this paper is to review normal renal function and stress the common functional tests helpful to detect injury due to toxins. Detailed reviews on renal function should be consulted as needed (3,5). In addition, two recent books on nephrotoxicity review a number of renal function tests in a thorough manner (2, 14). The maintenance of normal renal function rcquires a dynamic biochemical status which requires a high renal blood flow and oxygen uptake. Therefore, it is not surprising that the kidney is a common target organ for toxic chemicals. A potentially toxic agent is delivered in high concentration by the circulation, and due to the filtration and concentrating capacity of the kidney may accumulate to critical cellular concentrations. The kidneys are also sensitive to extrarcnal factors such as changes in blood flow, neural activity, and immunologic bombardPresented at the Fourth International Symposium of the Society of Toxicologic Pathologists, June 5 4 , 1 9 8 5 in Washington, D.C.

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Val. 14, NO. 1, 1986

RENAL FUNCTION EVALUATION

RENAL BLOOD FLOW

The intrarenal position of the nephron and its related blood supply are closely tied to the function of various portions of the nephron. While all nephrons have their glomeruli, proximal tubules, and distal tubules in the cortex, only the loops of Henle of the juxtamedullary nephrons course deeply into the medulla. The intrarenal distribution of blood flow is nonuniform. The cortical region receives the largest portion of blood supply, with lesser amounts distributed to the medulla and papilla. Studies on renal circulation have been done with either inert gas washout technique or localization of radioactive microspheres. With both techniques, comparable data are obtained, although the inert gas technique highlights nutrient blood flow and microspheres indicate glomerular blood flow. An example of the nonuniform distribution of blood flow in the dog using radioactive xenon is shown in Fig. 1 (6). This method also provides an accurate measurement of total renal blood flow. Approximately 85% of total renal blood flow can be associated with cortical regions; approximately 14% perfuses the outer medulla, and the remainder is distributed to the inner medulla and papilla. The microsphere method can be used to measure regional cortical blood flow. The outer zones of the cortex, as measured by microsphere method, correspond to component 1using the inert gas method (19). Many factors have k e n shown to influence the distribution of blood flow in the kidney. A reduction in blood pressure results in reduced perfusion to the outer cortical region and increased perfusion to the inner cortical region. Renal vasodilators cause a decrease in flow to the outer cortex and an increase in flow to the inner cortex. Such redistribution of flow to inner cortical nephrons may be associated with the natriuresis of renal vasodilation. Redistribution of the blood supply within these various compartments may be a potential site and mechanism of action of various chemical nephrotoxins. The normal intrarenal distribution of blood is consistent with what is known about intrarcnal metabolism. Cortical regions are much better oxygenated than are medullary regions and the type of metabolism, that is oxidative versus glycolytic, are appropriately distributed. Most of the energy production in the renal cortex comes from oxidative processes; whereas, in the medullary regions, glycolytic processes appear to be more important. A number of suggestions have been made about renal metabolic processes that might be inhibited by diuretics such as ethacrynic acid (1). Such effects are

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FIG.I.-Compartmental distributionofrcnal blood flow in a normal dog. The heavy curve was obtained by external monitoring after a single injection of "JXe in the renal artery. The curve was analyzed graphically as the sum of the four exponcntial components represented by the fine line. Reprinted from (6). thought to be reversible and may underlie diuretic action. It is likely that similar sites of action could be associated with the effects of nephrotoxins. Total renal blood flow may bc measured by direct or indirect methods. Direct methods include the use of an electromagnetic flowmeter or an ultrasonic flow transducer. These last two methods are most useful in long term serial studies in unanesthetized dogs. In small rodents, blood flow can be estimated indirectly from renal plasma flow using the renal clearance or renal extraction of para-aminohippurate (PAH). There are some limitations to the use of PAH clearance with potential nephrotoxic agents. A decrease of PAH clearance may result from an actual reduction in renal plasma flow, an inhibition of PAH transport in tubules due to the toxin, or an alteration in intrarenal blood flow distribution (1 1). The maximal tubular excretion of PAH (TM) may be used to differentiate between a toxic effect with PAH transport and a real reduction in renal plasma flow. The TmpAII is independent of blood flow and reflects the total tubular mass involved in PAH extraction from the blood. It should be kept in mind that many factors can potentially influence renal blood flow or the distribution of blood flow within the kidney secondary to the effect of a nephrotoxin, which influences neural control or a vasoactive effect. For example, a nephrotoxin which alters the availability of catecholamines, dopamine, bradykinin and angiotensin 11, antidiuretic hormone, or prostaglandins may alter renal blood flow. A specilk example is the reduction in renal blood flow and failure to autoregu-

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80 HYOROSTATIC PRESSURE IN GLOMERULAR CAPILLARY

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