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PubMed1997

Effect of dosing vehicle on the hepatotoxicity of CCl4 and nephrotoxicity of CHCl3 in rats.

There are conflicting results in the literature concerning the effect of gavage vehicle, corn oil (CO) versus aqueous suspension, on the toxicity of haloalkanes. The purpose of our study was to assess the influence of oral dosing vehicle on the acute hepatotoxicity of CCl4 and nephrotoxicity of CHCl3. Male Sprague-Dawley rats, fed ad libitum, were treated (po) with single doses of CCl4 or CHCl3 using corn oil (CO), or an aqueous preparation (5%) of Emulphor (EL620) or Tween-85 (Tw-85) as vehicle (10 ml/kg). Rats were killed 48 h after treatment. Blood was collected for plasma alanine aminotransferase (ALT) determination and renal cortical slices were prepared for p-aminohippuric acid (PAH) incorporation. The comparison, between gavage vehicles, of the slopes and ED50 of the dose-response curves, although not significantly different, indicated clear trends for enhanced potency with CO for CHCl3 nephrotoxicity but not for CCl4 hepatotoxicity. However, ALT values, a measure of the severity of effect for CCl4, also indicated that CO, when compared to EL620 and Tw-85, tended to enhance CCl4 hepatotoxicity at low toxicity incidence. Furthermore, CO clearly enhanced the severity of effect for CHCl3 nephrotoxicity, as measured by the slice-to-medium PAH ratios, at high dosage. The greater severity of the lesion produced by exposure to these chemicals, when administered in CO, is consistent with the trends observed for their potency (dose-response curves). Our results agree with an increased toxicity of haloalkanes by the gavage vehicle CO reported in the literature. Thus, CO should be considered a potential confounder in hepato- and nephrotoxicity assays.

Administration, Oral↗
PubMed1981

Response to rapid volume expansion during the postnatal period.

This study was designed to test the hypothesis that the postnatal diuresis observed in healthy neonates during the second hour of life is due to an expansion of their extracellular volume as a result of a purposeful or spontaneous placental blood transfusion. Seven healthy infants were given infusions of a 5% glucose solution, 0.3 to 2.5 ml/kg/min, over a period of 14 to 70 minutes during the third or fourth hour of life. Plasma and urine were analyzed for osmolality, inulin, and p-aminohippuric acid in order to estimate osmolal and free water clearances as well as glomerular filtration rate and renal plasma flow. Despite individual variation in initial values and in response, glucose infusion caused a prompt two- to fourfold increase in urine output with a similar increase in glomerular filtration rate and renal plasma flow but no consistent change in urine osmolality. The response was of short duration, subsiding within less than 30 minutes following the end of infusion. The fraction of exogenous fluid load excreted was less than 5% in five of seven infants. This study indicates that during the first few hours of postnatal life, the kidney of the newborn infant is capable of responding to a water load in a fashion similar to the kidney of the neonate aged a few days. It can also be concluded that the transient postnatal diuresis observed in these infants could, in part, be due to the expansion of extracellular volume by placental blood transfusion.

Blood Volume↗
PubMed1992

Effect of water deprivation on absorption (oral, intramuscular) and disposition of ampicillin in sheep.

The effects of a 72 h water deprivation on the absorption--intramuscular (i.m.) and oral and disposition of ampicillin, inulin and para-aminohippuric acid (PAH) were investigated in six sheep. After intravenous (i.v.) administration of ampicillin sodium (10 mg/kg), the water deprivation decreased slightly the initial volume of distribution (0.082 +/- 0.033 vs. 0.055 +/- 0.030 l/kg) but not the steady state volume of distribution. The plasma clearance was significantly decreased (6.21 +/- 1.94 vs. 3.90 +/- 1.92 ml/min/kg) and the mean residence time (MRT) was increased from 22.25 +/- 4.91 to 33.36 +/- 8.16 min. After i.m. administration of ampicillin sodium (20 mg/kg), ampicillin concentrations were systematically higher after a 3-day period of water deprivation than during the control period but the muscular absorption rate was not modified. After oral administration of ampicillin trihydrate (1 g in toto) plasma concentrations were much lower and more persistent than after an i.m. administration and the systemic availability remained low whatever the hydration status. Influences of water deprivation on ampicillin disposition were linked to adaptation of renal function as assessed by inulin and PAH clearances. The therapeutic relevance of the results are discussed for a better definition of dosage regimens for sheep reared in arid environments.

Absorption↗
PubMedDate not supplied

Kinetic studies on the competition between famotidine and cimetidine in rats. Evidence of multiple renal secretory systems for organic cations.

The H2-receptor antagonists famotidine and cimetidine are both basic drugs that are predominantly eliminated by the kidneys. Cimetidine has been shown to inhibit the renal secretion of tetraethyl-ammonium bromide (TEAB) but not p-aminohippuric acid (PAH), suggesting that cimetidine is secreted by an organic cation transport system [Weiner and Roth: J. Pharmacol. Exp. Ther. 216: 516 (1981)]. The present study shows that famotidine behaves like cimetidine in that it also inhibits TEAB but not PAH excretion. Where a high concentration of cimetidine in plasma has an inhibitory effect on the renal excretion of famotidine, the reverse is not true, i.e. high plasma levels of famotidine have no effect on the excretion of cimetidine. Further evidence that additional transport systems are involved in the renal tubular secretion of cimetidine is as follows. Quinine, a potent competitor of the organic cation transport system, inhibits the secretory component of famotidine renal clearance but not that of cimetidine. Probenecid, a classic competitor for the organic anion transport system, inhibits the renal excretion of cimetidine but not famotidine. However, the effect of probenecid is minor and not sufficient to account for other components of cimetidine secretion not affected by famotidine and quinine.

Animals↗
PubMed1980

Renin uptake by the right kidney in the rat following partial clamping of the left renal artery.

Renin secretion from both kidneys was studied in eleven Wistar rats for 40 min after partial clamping of the left renal artery. 14C Inulin and 3H para aminohippuric acid clearance and the arterial and venous plasma renin concentrations were measured in each kidney during control and experimental procedures. After clamping, the arterial plasma renin concentration increased and correlated positively with the plasma renin concentration in both renal veins. However, the plasma renin concentration of the right renal vein was lower than the arterial concentration (P < 0.01). The slope correlating the two variables is significantly lower than unity (P < 0.05, n = 19). As the left kidney secreted a large amount of renin, calculation of secretion by the right kidney decreased to negative values, implying renin uptake by this kidney. These data suggest the existence of a balance between the two kidneys. Renin secretion appears to maintain an equilibrium between release by the juxtaglomerular apparatus and removal from the blood into interstitial space. Release seems to predominate in the hypoperfused kidney, and removal in the contralateral kidney. This may result from the increase of the circulating angiotensin II, since we observed a direct correlation between renin uptake and the arterial plasma renin concentration.

Animals↗
PubMedDate not supplied

Effects of inorganic divalent cations on the renal basolateral transport system for organic anions.

Recent work demonstrated that the heavy metal ion Cd2+ increases the transport of p-aminohippuric acid (PAH) across the basolateral membrane of microdissected non-perfused rabbit kidney S2 proximal tubule segments. Usually, such ions induce damage of various renal transport systems, therefore the effects of divalent metal ions Zn2+, Co2+ and Ni2+ on this transporter were investigated. Addition of Ni2+ or Zn2+ to the bathing solution leads to a significant reduction of basolateral PAH transport, with IC50 values of 2 x 10(-5) and 10(-6) M, respectively, whereas Co2+ failed to inhibit PAH accumulation. Simultaneous incubation with thrombin (10(-9)M), which is known to increase [Ca2+]i, abolished the effects of the divalent ions. Our results indicate that Ni2+ and Zn2+ reduce cellular PAH uptake. Because Ni2+ and Zn2+ are calcium channel blockers, these effects are probably due to a reduction of [Ca2+]i by an interaction of these metals with binding sites in the calcium channel, whereas Co2+ does not affect these binding sites. This finding is supported by the fact that thrombin abolished the cation effects.

Animals↗
PubMed1998

Basolateral uptake of mercuric conjugates of N-acetylcysteine and cysteine in the kidney involves the organic anion transport system.

Renal uptake and disposition of administered inorganic mercury were studied in rats that had undergone an acute bilateral ureteral ligation shortly before being injected intravenously with a nontoxic 0.5 micromol/kg dose of inorganic mercury with or without 2 micromol/kg N-acetylcysteine or cysteine. Bilateral ureteral ligation was performed in an attempt to reduce glomerular filtration to negligible levels, which in turn permitted the study of the basolateral uptake of inorganic mercury. The disposition of mercury was studied in the kidneys, liver, and blood 1 h after treatment. In rats given only mercuric chloride, the renal burden of mercury was approximately 20% of the administered dose of mercury. This confirms previous observations implicating a basolateral mechanism in the renal uptake of inorganic mercury. Coadministration of inorganic mercury with either N-acetylcysteine or cysteine caused a significant increase in the renal uptake of mercury 1 h after treatment, particularly in the rats treated with inorganic mercury plus N-acetylcysteine. The enhanced uptake of mercury in the kidneys was due to increased uptake of mercury in the renal cortex and outer stripe of the outer medulla. Interestingly, the rate of uptake of mercury was so great in the rats treated with inorganic mercury plus N-acetylcysteine that the renal burden of mercury was virtually equivalent to that generally detected in normal animals administered the same dose of inorganic mercury as mercuric chloride. Pretreatment with para-aminohippuric acid (PAH) (which is a potent inhibitor of the organic anion transport system) caused significant reductions in the renal uptake and burden of inorganic mercury in all the rats administered inorganic mercury, regardless of whether the inorganic mercury was coadministered with N-acetylcysteine or cysteine. Overall, the findings from the present study provide additional evidence that there is basolateral uptake of inorganic mercury in the kidneys, and that the primary or sole mechanism is dependent on the activity of the organic anion transporter. The present findings also show that cysteine and N-acetylcysteine enhance the basolateral uptake of mercuric ions in the kidney when they are coadministered with inorganic mercury, presumably in the form of mercuric conjugates. Moreover, it appears that mercuric conjugates of N-acetylcysteine are taken up more avidly at the basolateral membrane than mercuric conjugates of cysteine. Furthermore, the basolateral uptake of mercuric conjugates of N-acetylcysteine or cysteine in the kidney is due primarily to a mechanism involving the organic anion transport system.

Acetylcysteine↗
PubMed1995

Color Doppler ultrasonography for the assessment of renal blood flow in heart failure.

To validate color Doppler ultrasonography of renal arteries for the assessment of renal blood flow (RBF), we compared left and right RBF estimates and their sum (total RBF) by echo-Doppler with data obtained by iodine 123-123I-p-aminohippuric acid (PAH) scintigraphy in 19 patients with heart failure and 7 normal control subjects. Single-side and total RBF estimates by echo-Doppler ranged, respectively, between 179 and 428 mL/min/m2 and from 378 to 835 mL/min/m2 in patients with heart failure and between 265 and 601 mL/min/m2 and from 564 to 1,182 mL/min/m2 in normal control subjects. Single-side and total RBF estimates by echo-Doppler correlated well with measurements obtained by scintigraphy (r = 0.74 and 0.76, respectively, in patients with heart failure; both: p < 0.001). At Bland and Altman's analysis of correspondence between the 2 techniques, there were 17 disagreements (33.7%) for single-side RBF and 8 disagreements (31.8%) for total RBF. However, the two techniques disagreed markedly in only two single-side and one total RBF estimates. Thus, in patients with heart failure, RBF assessed noninvasively by color Doppler ultrasonography has a good correlation with 123I-PAH renal scintigraphy data over a wide range of blood flow.

Adult↗
PubMed1975

Pharmacodynamic analysis of substrate stimulation of p-aminohippurate transport by newborn rabbit kidney.

Penicillin pretreatment of 2-week-old New Zealand White rabbits significantly increased the ability of renal cortical slices to transport p-aminohippuric acid (PAH). The PAH slice/medium ratio increased with dose to a maximum at 90,000 I.U. of procaine penicillin G. Sodium penicillin G (180,000 I.U.) produced no greater increase. Stimulation was maximal after four penicillin injections at 12-hour intervals. The maximal response was observed 24 hours after the final injection, whereas after 72 hours the capacity of slices from treated animals to transport PAH was no different than control. To determine the effect of a maximal substrate challenge on the development of transport capacity, pregnant does were treated with 90,000 I.U. of procaine penicillin i.m. twice daily through the last half of gestation. Young animals received four penicillin injections before sacrifice. The PAH slice/medium ratio from pups 3 days, 1 and 2 weeks old were not significantly different from that normally observed at 4 weeks. Animals 4 weeks old did not respond to penicillin treatment. Thus, intrinsic transport capacity for PAH is mature at 4 weeks of age. Only before this age may transport be enhanced by substrate. Maximal enhancement of PAH transport capacity occurs when four injections of 90,000 I.U. of procaine penicillin G are administered at 12-hour intervals followed by sacrifice 24 hours after the final injection.

Aging↗
PubMed2006

Efflux of drugs and solutes from brain: the interactive roles of diffusional transcapillary transport, bulk flow and capillary transporters.

We examined the roles of diffusion, convection and capillary transporters in solute removal from extracellular space (ECS) of the brain. Radiolabeled solutes (eight with passive distribution and four with capillary or cell transporters) were injected into the brains of rats (n=497) and multiple-time point experiments measured the amount remaining in brain as a function of time. For passively distributed compounds, there was a relationship between lipid:water solubility and total brain efflux:diffusional efflux, which dominated when k(p), the transcapillary efflux rate constant, was >10(0) h(-1); when 10(-1)<k(p)<10(-2) h(-1) both diffusion and convection contributed, and when k(p)<10(-3) h(-1), convective efflux dominated. Para-aminohippuric acid (PAH) experiments (n=112) showed that PAH entered the brain passively, but had efflux transporters. The total efflux rate constant, k(eff), was the sum of a passive component (k(p)=0.0018 h(-1)), a convective component (k(csf)=0.2 h(-1)), and a variable, concentration-dependent component (k(x)=0 to 0.45 h(-1)). Compounds with cell membrane transporters had longer clearance half times as did an oligonucleotide, which interacted with cell surface receptors. Manipulation of physiologic state (n=35) did not affect efflux, but sucrose efflux half time was longer with pentobarbital anesthesia (24 h) than with no anesthesia or ketamine-xylazine anesthesia (2 to 3 h). These results show that solute clearance from normal brain ECS may involve multiple physiologic pathways, may be affected by anesthesia, and suggests that convection-mediated efflux may be manipulated to increase or decrease drug clearance from brain.

Algorithms↗
PubMed1993

Renal hemodynamics and cardiovascular reactivity in the prehypertensive stage.

To examine whether sympathetic nervous activation has an impact on renal circulation in subjects at risk for high blood pressure, we assessed renal hemodynamics and cardiovascular response to mental stress in 40 healthy young white males, 12 normotensive subjects without and 14 with familial hypertension, and 14 with borderline hypertension. The response of systolic and diastolic blood pressure to mental stress was assessed while each patient performed a mental arithmetic task; this was taken as the parameter for the activation of the sympathetic nervous system. Renal plasma flow was measured by para-aminohippuric acid clearance under steady-state conditions. In parallel, glomerular filtration rate as a parameter for functional impairment of the kidneys was determined by creatinine clearance, and filtration fraction was also calculated. Patients with borderline hypertension were characterized by a reduced renal blood flow and increased filtration fraction in comparison with both normotensive groups. The increase in systolic blood pressure during mental stress was more pronounced in borderline hypertensives. We observed no significant difference in renal hemodynamics and cardiovascular response to mental stress between normotensives with and without a family history of hypertension. In the total population, cardiovascular response to mental stress was correlated with renal hemodynamics: The greater the increase in systolic blood pressure during mental stress, the lower was the renal plasma flow and the greater the filtration fraction. Thus, renal plasma flow was found to be already reduced and filtration fraction increased before sustained hypertension developed. Because this pattern in renal hemodynamics was related to cardiovascular response to mental stress, our data suggest that sympathetic activation already appeared to affect renal hemodynamics at the onset of essential hypertension.

Adult↗
PubMed1993

Quantitative analysis of drug handling by the kidney using a physiological model of renal drug clearance.

Published data on the renal clearance of creatinine, p-aminohippuric acid (PAH) and kanamycin in relation to glomerular filtration rate (GFR) in patients with various renal diseases were analysed by a physiological model of renal clearance. Fitting of the data by the general linear equation representing the model proposed by Levy [10] resulted in insignificant intercepts with the ordinate, indicating the unsuitability of the model for the detection of tubular secretory activity. Use of this model also did not lead to significant improvement in goodness of fit compared to simple proportionality of renal clearance and GFR. On the other hand, parameter estimates of the physiological model obtained from the data by nonlinear regression analysis revealed statistically significant tubular secretion both of PAH and creatinine. The much lower tubular secretory activity estimated from the kanamycin data did not reach statistical significance. For compounds exhibiting statistically significant tubular secretion, use of the physiologically based relationship between renal clearance and GFR significantly improved the goodness of fit to the data as compared to simple proportionality of both variables. It is concluded that analysis of the relationship between renal clearance of drugs and GFR using the physiological model of renal clearance can contribute to our knowledge of drug handling by the kidney, and may facilitate drug classification according to total extraction by this organ.

Aminohippuric Acids↗
PubMed1999

Role of organic anion transporter 1 (OAT1) in cephaloridine (CER)-induced nephrotoxicity.

UNLABELLED: Role of organic anion transporter 1 (OAT1) in cephaloridine (CER)-induced nephrotoxicity. BACKGROUND: Cephaloridine (CER) has been used to elucidate the mechanisms of cephalosporin antibiotic-induced nephrotoxicity. Organic anion transporters have been thought to mediate CER uptake by the proximal tubule. The purpose of this study was to elucidate the possible involvement of organic anion transporter 1 (OAT1) in CER-induced nephrotoxicity. METHODS: A mouse terminal proximal straight tubule (S3) cell line stably expressing rat OAT1 (S3 rOAT1) was established and used in this study. The cellular uptake of [14C]-para-aminohippuric acid (PAH), a prototype organic anion, and that of [14C]-CER were measured. The effects of CER on the viability of the cells and the amount of lipid peroxidation were estimated. RESULTS: S3 rOAT1 expressed a functional organic anion transporter in the cytoplasmic membrane, and exhibited CER uptake activity. CER treatment resulted in a more significant decrease in the viability and a more significant increase in the amount of lipid peroxidation in S3 rOAT1 than in S3 cells transfected with an expression vector lacking the rOAT1 insert. Probenecid, an inhibitor of organic anion transport, and probucol, an antioxidant, significantly suppressed the decrease in viability and increase in the amount of lipid peroxidation in S3 rOAT1 treated with CER. The effects of various cephalosporin antibiotics on the uptake of [14C]PAH were correlated significantly with the effects of these drugs on cell viability. CONCLUSIONS: These results suggest that rOAT1 is, at least in part, responsible for the cellular uptake of CER and therefore CER-induced nephrotoxicity.

Animals↗
PubMed2005

Characterization of secretory intestinal transport of phenolsulfonphthalein.

It is known that secretory transport limits the oral bioavailability of certain drugs. However, there is little information on the secretion of anionic compounds in the intestine. Phenolsulfonphthalein (PSP) and p-aminohippuric acid (PAH) have been used widely as substrates for organic anion transport systems. PAH is transported in the secretory direction in the intestine. It is possible that PSP and PAH share the same transport system at the mucosal membrane. The purpose of this study was to characterize the transport system for PSP in the intestine. In the jejunum, the serosal-to-mucosal permeation rate of PSP was significantly reduced in an ATP-depleted condition, whereas a significant difference was not observed in the ileum. Some multidrug resistance-associated protein 2 (Mrp2) inhibitors inhibited PSP permeation in the jejunum. However, pravastatin, a substrate of Mrp2, did not inhibit the PSP permeation. The jejunal secretory transport of pravastatin was significantly reduced in an ATP-depleted condition and by addition of probenecid, but PSP did not affect the jejunal permeation of pravastatin. These results suggest that PSP is secreted into the intestinal lumen by Mrp2-like transporter and that two Mrp2 substrates, PSP and pravastatin, are likely to be transported by different transport systems at the mucosal membrane.

Adenosine Triphosphate↗
PubMed1989

Oxygen consumption by portal vein-drained organs and by whole animal in conscious growing swine.

A method was developed to measure simultaneously the O2 consumption (VO) by the whole animal and by the hepatic portal vein-drained organs (PVDO), including the gastrointestinal tract, spleen, and pancreas in conscious 3.5- to 4-month-old swine. The method was used to determine (i) the effect of feeding on hepatic portal vein blood flow rate (Qpv) and VO by PVDO and by the whole animal, and (ii) the significance of PVDO on the oxidative demand in the pig. Chronic cannulas were placed in the hepatic portal vein, carotid artery, and ileal vein. The Qpv was determined by an indicator dilution technique employing continuous constant infusion of 1% p-aminohippuric acid into the ileal vein. The VO2 by PVDO was estimated by multiplying Qpv by arterial-portal vein O2 difference measured with an arterial-venous O2 difference analyzer connected to the carotid artery and portal vein cannulas. Whole animal VO2 was measured with an open circuit indirect calorimeter. In seven pigs (3.5- to 4-month-old, 37.4 +/- 0.8 kg) trained to be fed once daily, feeding (1.2 kg of feed mixed with 1.2 liter of H2O) caused postprandial (6 hr) Qpv to increase more than 34 +/- 15% above the preprandial value of 34.5 +/- 4.2 ml.min-1.kg-1 body wt. The postprandial VO2 by PVDO was elevated more than 46 +/- 12% above the value of 1.52 +/- 0.20 ml.min-1.kg-1 body wt observed during the preprandial period. Whole animal VO2 increased 45 +/- 9 and 33 +/- 7% above the preprandial value of 6.23 +/- 0.57 ml.min-1.kg-1 body wt for the first 6 hr and the 7 to 12 hr after feeding, respectively. Although PVDO represent only 5% of body weight, they used 25% of whole body VO2. The study clearly illustrates the significance of PVDO on the whole animal oxidative demand in conscious growing swine.

Animals↗
PubMed1989

The inhibition of thromboxane synthesis has no influence on HgCl2-induced acute renal failure in the rat.

Renal function parameters and urinary thromboxane B2-excretion were studied in the rat in HgCl2-induced acute renal failure. Studies were performed before and 3 h after the inhibition of thromboxane synthesis alone, after HgCl2 alone, or after the combination of HgCl2 and thromboxane-synthesis inhibition. Thromboxane-synthesis inhibition alone by indomethacin (5 mg/kg i.v.), imidazole (25 and 50 mumol/kg per min i.v.) and dazoxiben (5 mg/kg i.v.) had no effect on glomerular filtration rate (GFR) or para-aminohippuric acid clearance (CPAH), whereas urinary thromboxane excretion was suppressed. Only the administration of the selective blockers imidazole and dazoxiben resulted in a marked increase in urinary volume (V) and fractional sodium excretion (FENa). HgCl2 alone (2 mg/kg i.v.) caused a decrease in GFR and CPAH with -38% (P less than 0.01), and urinary thromboxane B2 excretion increased from 20.3 +/- 1.5 to 30.6 +/- 2.6 pg/min. (P less than 0.01). The administration of indomethacin, imidazole (50 mumol/kg per min) and dazoxiben prevented the increase in thromboxane B2 excretion 3 h after HgCl2 to values of 3.3 +/- 1.2, 6.9 +/- 0.6 and 13.0 +/- 1.6 pg/min respectively (P less than 0.01 versus control for all values). Despite this, the decrease in GFR and CPAH after HgCl2 could not be prevented. A decrease of GFR with -44, -54, -57 and -32% and of CPAH with -37, -49, -57 and -27% were observed for indomethacin, imidazole 25 and 50 mumol/kg per min and dazoxiben respectively. This evolution was not significantly different from what was observed with mercury alone. Selective thromboxane synthesis inhibition resulted in a decrease of serum free ionised calcium.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗
PubMed1977

Concentrative transport in human renal biopsy specimens.

In vitro concentrative transport to tritiated p-aminohippuric acid (3H-PAH) was evaluated in renal biopsy specimens from human subjects by section freeze-dry autoradiography. Renal cortical tissue obtained by percutaneous needle biopsy (23 of 27 tissue specimens) was incubated in vitro using a modified renal cortical slice technic. Following incubation in medium containing 3H-PAH, the biopsy fragment was snap-frozen, and section freeze-dry autoradiographs were prepared. The autoradiographs demonstrated cellular accumulation of 3H-PAH by proximal tubules of human kidney in vitro and suggest that PAH transport is uphill across the luminal as well as the antiluminal membrane. The number of proximal tubules which accumulate 3H-PAH in vitro diminishes as renal failure progresses. Cellular accumulation of PAH, however, was not impaired by heavy proteinuria, and appeared not to be related to the underlying glomerular histologic diagnosis. The frequency of proximal tubules showing 3H-PAH uptake in the cortex varied directly with the glomerular filtration rate and inversely with the degree of interstitial involvement. Proximal tubules which maintain the ability to accumulate 3H-PAH are clustered in fewer regions of the cortex in patients with reduced glomerular filtration rates. This observation is consistent with the view that residual renal function is renal failure arises from a few relatively normal nephrons rather than from a more uniformly damaged population of nephrons.

Adolescent↗
PubMed1993

Increase in skeletal muscle blood flow but not in renal blood flow during euglycemic hyperinsulinemia in man.

In order to investigate the effect of euglycemic hyperinsulinemia on skeletal muscle blood flow and renal blood flow, catheters were inserted into both femoral arteries, one femoral vein and one renal vein of 7 healthy men. Constant infusions of indocyanine-green dye (intraarterial) and of p-aminohippuric acid (intra-venous) were used to estimate leg plasma flow (ELPF) and renal blood flow (ERPF), respectively, prior to and during a euglycemic, hyperinsulinemic clamp (1.0 mU/kg.min of human insulin, serum concentrations of insulin before and during the clamp: 4.6 +/- 0.9 microU/ml and 65.5 +/- 20.6 microU/ml, respectively, t = 120 min). ERPF (basal: 1220 +/- 320 ml/min) remained unchanged throughout the period of induced hyperinsulinemia in each volunteer (mean: 1135 +/- 490 ml/min), whereas mean leg plasma flow (ELPF) rose from basal 206 +/- 99 ml/min up to 275 ml/min 90 minutes after the beginning of the euglycemic clamp study (p < 0.01). This was due to the marked rise in ELPF from 149 +/- 24 ml/min up to 243 +/- 25 ml/min (p < 0.01) seen in 5 subjects. In two men, who presented a markedly higher basal ELPF (332 and 365 ml/min, respectively), no further rise in ELPF was seen during induced hyperinsulinemia. Fractional renal extraction of insulin was unchanged during induced hyperinsulinemia (28 +/- 5%; basal: 22 +/- 18%), as was fractional extraction of insulin by the leg (10 +/- 5%; basal: 13 +/- 11%). The observed dissociation of ERPF and ELPF suggests a differential response to insulin in renal vs. leg vasculature which possibly is due to increased peripheral glucose metabolism.

Adult↗