lar and molecular studies are presented in light of their potential to provide new markers of effect that will be more sensitive to early nephrotoxicity and can be applied widely to at-risk populations. The conventional markers also can play an important role in validating new markers, particularly in people with compromised renal function who are exposed to additional potentially damaging events. The loss of a small number of tubular cells in a person with only minimal residual kidney function can lead to large changes in conventional markers whereas the same loss in a normal person would be undetectable. Such a change, now easily detectable in a compromised person, can be used to validate new markers against conventional markers.

EXTERNAL VISUALIZATION

Several techniques permit external visualization of the kidney and delineation of functional changes. Radiopaque contrast media and ultrasonic agents permit imaging of changes in blood or urine flow or in renal solute accumulation and secretion. Similar results are routinely obtained with gamma-emitting radioisotopes. In addition to the risks associated with radiation exposure, these tests do not reflect subtle changes in renal function and are therefore limited in their applicability to population screening.

A visualization technique that might hold promise and that has been applied to small animals is magnetic resonance imaging (MRI). Acara et al. (1991) observed conspicuously hyperintense regions in renal papillae in rats and related them to early hydronephrotic changes. Further improvements in MRI might make the technique more useful for screening human populations, but it is still time-consuming and expensive.

URINARY CLEARANCE MEASUREMENTS

Direct

Measurement of urinary clearances is not convenient for use in large populations at risk, but it continues to constitute a basic approach to evaluating renal function. Indeed, the introduction of the clearance concept into renal physiology by Moller et al. in 1929 provided for the first time a relatively simple and informative measure of renal function and was a critical contribution to the study of the kidney. Urinary clearance (C) is the virtual volume of plasma that is cleared per unit time by excretion into urine; it is expressed as Cx = Ux V/Px, where Ux V is the amount of substance x excreted per unit time and Px is the plasma concentration of substance x. Depending on the solute chosen, clearances can provide information on glomerular and tubular function; they are useful under many conditions for evaluating functional integrity of the kidney in humans or animals.

The direct measurement of clearance, however, has disadvantages, especially for the study of large populations. It is clear from the formula Cx = Ux V/Px that it is essential to keep Px constant during the clearance period or at least to be able



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