PRINCIPLES OF TOXICOLOGY - Biology East Borneo

136 NEPHROTOXICITY: TOXIC RESPONSES OF THE KIDNEYThus,V = 1.2 mL/minP in = 0.30 mg/mL(31 mg / ml) × (1.2 ml / min)= 124 ml / min.0.30 mg / mlThe normal human glomerular filtration rate in adult humans is about 125 mL/min and inulinclearance is routinely used as a measure of glomerular function. The GFR is not only a measure of thefunctional capacity of the glomeruli but also indicates the kidney’s ability to concentrate urine byremoval of water. By comparing the amount (milliliters) of urine voided in one minute to the amount(milliliters) of plasma cleared, information can be gained about the amount of water reabsorbed duringpassage through the tubules.Diseases or nephrotoxicants that affect the glomerulus or those that produce renal vascular diseasehave a profound effect on the glomerular filtration rate. Indeed, any significant renal disease ornephrotoxic compromise can reduce the glomerular filtration rate. It should also be realized that anyagent inducing severe hypotension or shock will likewise reduce the glomerular filtration rate.Measurement of certain natural endogenous substances in the blood can be used to assessglomerular function as well. The measurement of blood urea nitrogen (BUN) and plasma creatinineare two endogenous compounds routinely measured for the clinical assessment of glomerular function.As glomerular filtration decreases, BUN and plasma creatinine become more elevated. Normal BUNranges from 5 to 25 mg/100 mL, while serum creatinine ranges from 0.5 to 0.95 mg/mL of serum.Nephrotoxicants may also disrupt the selective permeability of the glomerular apparatus. Normally,the result is an increase in porosity in the glomerulus; protein enters the glomerular filtrate andsubsequently the urine. Therefore, if a compound causes excretion of large amounts of protein into theurine it must be suspected as a nephrotoxicant, and measurement of protein in urine, particularly thoseof high molecular weight, is used to determine which chemicals produce toxic changes to theglomerulus. The normal excretion of protein in humans is no more than 150 mg in 24 h.Renal Plasma FlowSome organic acids, such as p-aminohippuric acid (PAH), can be used in clearance studies to obtaininformation about the total amount of plasma flowing through the kidneys. PAH is transported soeffectively that it is almost completely removed from the plasma in a single passage through the kidney(i.e., 80–90 percent). Any chemically induced reduction in the PAH clearance may be caused by eithera disruption of the active secretory process or by an alteration of the renal blood flow.In a clinical setting, measurements can be made of the concentration of PAH per milliliter of plasma(P PAH), of the concentration of PAH per milliliter of urine (U PAH), and of the volume of urine excretedper minute (V). Using the formula that was previously discussed, the clearance of PAH in mL/min canbe calculated. This calculation represents the rate of plasma flow through the kidneys (average renalplasma flow in the normal, healthy adult male is about 650 mL/min).Excretion RatioAnother useful calculation for evaluating kidney injury is the excretion ratio:Excretion ratio =Renal plasma clearance of drugs (ml / min)Normal GFR (ml / min)If the ratio is less than 1.0, it indicates that a drug has been partially filtered, perhaps also secreted, andthen partially reabsorbed. A value greater than 1.0 indicates that secretion, in addition to filtration, is involvedin the excretion. A substance that is completely reabsorbed, such as glucose, would have an excretion ratioof 0, and a substance such as PAH that is completely cleared can have a ratio of about 5.