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Role of Transport in Chemically-Induced Nephrotoxicity *
Published in Robin S. Goldstein, Mechanisms of Injury in Renal Disease and Toxicity, 2020
Renal physiologists and pharmacologists have used p-aminohippurate (PAH) to measure renal plasma flow for decades. If a nephrotoxicant were to compromise PAH clearance, it would not mean necessarily that PAH transport into tubular cells was affected directly. Indeed, a nephrotoxicant effect on blood flow could equally well compromise PAH clearance, since both the transport and the blood flow are essential for this process to achieve its normal physiological importance. In mammalian species, the transport of organic anions such as PAH occurs primarily on the basolateral side of the proximal tubular cell with its delivery into the tubular fluid resulting either from passive movement of the anion or by an anion exchange process. Chemicals such as probenecid or penicillin block the transport of PAH by a competitive mechanism. These compounds never alter the transport of organic cations. PAH transport in the intact animal or its accumulation by isolated renal slices can be compromised by dinitrophenol (DNP). These data indicate that both an interference with transport (competitive) and an effect of the DNP on energy metabolism result in the inhibition of secretion (Berndt and Grote, 1968).
Renal Effects
Published in Lars Friberg, Tord Kjellström, Carl-Gustaf Elinder, Gunnar F. Nordberg, Cadmium and Health: A Toxicological and Epidemiological Appraisal, 2019
PAH clearance is often used as an indicator of effective renal plasma flow and the decrease was matched by the histological findings of ischemic changes in glomerular capillaries.108 Histological sections of the tubules showed damage (Section IV.A.4). PAH clearance is not a good indicator of renal plasma flow when tubular damage has occurred. The decrease of inulin clearance shows an effect on the glomeruli as well. In the groups with significant functional change the average renal cadmium concentrations were 91 and 112 mg Cd per kilogram wet weight.108 In the publication these concentrations are reported on a dry weight basis but this is a misprint (Itokawa, personal communication).
The Nature of Renal Function
Published in Anthony R. Mundy, John M. Fitzpatrick, David E. Neal, Nicholas J. R. George, The Scientific Basis of Urology, 2010
Many organic substances, anionic at physiological pH, are actively secreted by the proximal tubule. These include endogenous substances such as hippurate and exogenous substances such as penicillin, probenecid, and derivatives of hippuric acid such as orthoaminohippurate (hippuran) and paraaminohippurate (PAH). The renal clearance of these compounds exceeds GFR, and in the case of hippuran and PAH extraction is almost complete. The secretory site is the proximal convoluted tubule, especially the middle and late segments. The small amount of PAH that escapes secretion is accounted for by blood perfusing the deepest (juxtamedullary) nephrons, in which the postglomerular blood flows directly into the medullary vasa recta system without passing through the cortical peritubular capillary plexus, bypassing the secretory site for PAH. In the adult, only about 10% of nephrons are of this type, so the underestimation of renal plasma flow by PAH clearance is small. In the newborn infant, in contrast, the superficial cortical nephrons (the last to be formed) function little or not at all, and the juxtamedullary nephrons provide the lion’s share of renal function. Clearance of PAH and similar substances is, therefore, an unreliable measure of renal plasma flow in babies and newborn animals. PAH secretion is saturable and Tm-limited; below the renal threshold, excretion increases in parallel with rising plasma concentration, while above this value, there is no further rise in excretion. A similar, but separate, transport system exists for the secretion of organic cations.
Kidney physiology and pathophysiology during heat stress and the modification by exercise, dehydration, heat acclimation and aging
Published in Temperature, 2021
Christopher L. Chapman, Blair D. Johnson, Mark D. Parker, David Hostler, Riana R. Pryor, Zachary Schlader
Renal blood flow broadly describes blood flow in the renal artery to the kidneys and regional blood flow within the kidneys (e.g., cortical, medullary). Classically, renal blood flow is measured using clearance techniques that measure renal plasma flow, such as para-aminohippurate (PAH) clearance (Table 3). These techniques are founded on the basis that kidney function is the net action of input (i.e., renal artery blood flow) and output, which is comprised of renal venous blood flow and urinary excretion [121]. In this sense, clearance is defined as the “volume of plasma per unit time from which all of a specific substance is removed (pg. 36)” and is defined as Ux·V/Px, where Ux and Px are the concentration of substance ‘x’ in the urine and plasma, respectively, and V is urine flow rate [149]. Renal blood flow is related to renal plasma flow by the hematocrit, such that renal blood flow is equal to renal plasma flow divided by (1-hematocrit) [RBF=RPF/(1-Hct)]. PAH clearance has traditionally been used as the gold standard measure for renal artery plasma flow. Approximately 90% of PAH, which is filtered at the glomeruli and secreted by the tubules, is extracted from the blood by the kidneys [150], with several factors precluding the complete extraction of PAH from the blood, including periglomerular shunts and limitations in secretion of PAH in cortical areas and in regions of reduced perfusion such as the proximal tubules in the medulla [151]. For these reasons, PAH clearance is often referred to in the literature as ‘effective’ renal plasma flow because it provides an approximation of renal plasma flow without requiring a renal venous blood sample [152]. Determination of PAH clearance is an invasive technique that requires a priming dose and sustained infusion to maintain constant PAH concentration in the plasma [152-154]. Classic methods of measuring PAH clearance use the bladder clearance technique, which requires the collection of urine either through spontaneous voiding or catheterization in order to determine the concentration of PAH in the urine [154]. The alternative constant-infusion technique eliminates the need to collect urine, which was often a source of error (e.g., contaminated urine during spontaneous voiding) [155], and assumes that, for substances such as PAH that are neither metabolized nor stored by the body, when plasma PAH is constant, the rate of excretion of Ux·V must be the same as (and therefore can be substituted by) the rate of infusion. However, this requires equilibrium between rate of infusion and rate of excretion of PAH that may not be possible in shorter duration studies [156]. To overcome this limitation, investigators typically correct for changes in plasma concentration of PAH by accounting for plasma concentrations at the beginning and end of the clearance period [157-160].