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A C Schoolwerth

Publications and source records attributed to A C Schoolwerth.

At least 37 records · Page 2Linked to original sources
PubMed1992

Remnant kidney oxygen consumption: hypermetabolism or hyperbole?

On the basis of observations in surgically created remnant kidneys of rat and dog, a novel hypothesis for progressive injury in the setting of reduced renal mass has been put forth. Both rat and dog remnant kidneys exhibit significant hypertrophy that is accompanied by an increased rate of oxygen consumption (QO2) per remaining nephron but not per gram of tissue. This putative "hypermetabolism" is seen in the face of progressive scarring of the tubulointerstitial compartment of the remnant kidney, and interventions that reduce QO2 in these models have been associated with reduced tissue injury in previous studies. The proposed pathway by which an increase in QO2 leads to cellular damage is via the production of oxygen-reactive species or free radicals. In this article, the available data upon which this "hypermetabolism" hypothesis is based are reviewed and the constructs within which these data have been analyzed are examined. From these considerations, a set of questions not yet answered that may serve to direct more fruitful query into this intriguing problem

Ammonia↗
PubMed1991

Acute glomerulonephritis in a patient with Rocky Mountain spotted fever.

It is generally assumed that acute tubular necrosis is the etiology of renal failure that can occur during the course of Rocky Mountain spotted fever (RMSF). However, histologic examination of kidneys has been mainly limited to autopsy cases of fulminant infections. Acute glomerulonephritis due to glomerular immune complex deposition has not been reported in RMSF. We describe a case of acute oliguric renal failure that developed more than 2 weeks following the onset of RMSF. Renal biopsy showed acute glomerulonephritis with inflammatory cell infiltration and subendothelial immune deposits. Thus, acute glomerulonephritis should be in the differential diagnosis of acute renal failure that occurs in RMSF.

Acute Kidney Injury↗
PubMed1991

Insulin increases Na(+)-H+ exchange activity in proximal tubules from normotensive and hypertensive rats.

The effects of insulin on Na(+)-H+ exchange were examined in isolated proximal segments from normotensive Sprague-Dawley (SD) and Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR), with monitoring of rates of intracellular pH change (delta pHi/min) and ethylisopropyl amiloride (EIPA)-suppressible 22Na+ uptakes. A 12-min insulin preincubation was necessary for steady-state 22Na+ uptake and rate of pHi change. Insulin responses were similar for 4-wk (prehypertensive) SHR and WKY tubules; 8- (rising hypertension) and 16-wk (established hypertension) SHR responses were increased (P less than 0.05) 23 and 36% with 10(-6) M insulin, respectively. Insulin-like growth factors (IGF-I, IGF-II; 10(-10)-10(-7) M) had no effect on Na(+)-H+ exchange activity. Incubation with physiological concentrations of insulin in combination with hormones that stimulate Na(+)-H+ exchange (angiotensin II; alpha-adrenoceptor agonists) demonstrated no synergistic increases in SHR or WKY tubules; incubation with hormones that inhibit Na(+)-H+ exchange [parathyroid hormone (PTH), dopamine (DA)] indicated that insulin stimulation was decreased with PTH or DA in WKY segments, but PTH or DA reduction of insulin stimulation was lacking in SHR tubules. In summary, these data indicate a direct stimulation by insulin of Na(+)-H+ exchange in the proximal nephron, indicate an increased responsiveness in SHR compared with WKY tubules, and suggest a modulatory role of insulin with other hormones in regulating proximal nephron Na(+)-H+ exchange.

Adrenergic alpha-Agonists↗
PubMed1991

Hormone responses of proximal Na(+)-H+ exchanger in spontaneously hypertensive rats.

Na(+)-H+ exchange activity is increased in hypertensive rat strains and could be a predisposing factor in the pathogenesis of essential hypertension. Previously we demonstrated that proximal nephron Na(+)-H+ exchange is stimulated by alpha-adrenergic agonists and angiotensin II (ANG II) and inhibited by parathyroid hormone (PTH) and dopamine (DA). To test the hypothesis that hormonal regulation of proximal nephron Na(+)-H+ exchange could differ with hypertension, alterations in Na(+)-H+ exchange were determined by 1) amiloride analogue-suppressible 22Na+ uptake and 2) change in intracellular pH (pHi) as monitored with the fluorescent probe 2',7'-bis(carboxyethyl)-5(6)carboxyfluorscein acetoxymethyl ester. Spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats had similar tail-cuff pressures at 4 wk, but SHR blood pressure was significantly elevated at 8 and 16 wk compared with WKY. No significant differences were observed between SHR and WKY basal ethylisopropyl amiloride-suppressible 22Na+ uptakes or rates of pHi change. alpha-Adrenergic agents and ANG II significantly increased (P less than 0.05) Na(+)-H+ exchange, but, in contrast, 8- and 16-wk-old SHR tubules lacked responsiveness to PTH (10(-8) M) and DA (10(-6) M) observed in WKY. A significant reduction (57-79%, P less than 0.05) in norepinephrine and ANG II stimulation was observed with 8- and 16-wk-old WKY tubules incubated in combination with PTH or DA, but only a 3-33% reduction was produced in 8- and 16-wk-old SHR tubules. PTH- and DA-stimulated adenosine 3',5'-cyclic monophosphate accumulation was significantly reduced in SHR compared with WKY tubules at 4 and 8 wk. It appears that proximal nephron Na(+)-H+ exchange activity is a balance between ANG II and NE activation and PTH and DA inhibition. The data suggest SHR proximal hormone responses are different from WKY and may alter the balance of net Na(+)-H+ exchange activity, possibly contributing to the development or maintenance of hypertension in the SHR.

1-Methyl-3-isobutylxanthine↗
PubMed1991

Evidence that high dose cortisol-induced Na+ retention in man is not mediated by the mineralocorticoid receptor.

We have previously shown that high dose cortisol (F; 240 mg/day)-induced Na+ retention and systolic blood pressure (BP) increases are not inhibited by the glucocorticoid (type II) receptor antagonist RU486. Adequacy of type II receptor blockade with RU486 was clearly demonstrated, indicating that the Na+ retention was not mediated through the glucocorticoid receptor. Spironolactone (Sp: 400 mg/day), in a preliminary assessment, also did not inhibit F-induced Na+ retention. The purpose of this study was to determine whether the Na+ retention produced by F administration is mediated by the type I receptor by comparing the effects of F to a potent type I agonist [9 alpha-fludrohydrocortisone (9 alpha FF)] with and without Sp administration. The effects of the two agonists and Sp on urinary K excretion and BP were also compared. Normal male volunteers, on a constant daily diet for 10 days, received either F (240 mg/day) or 9 alpha FF (3.0 mg/day) with or without Sp (400 mg/day) for the last 5 days. The mean cumulative reductions in Na+ excretion during the 5 days compared to baseline values before hormone administration were 255 +/- 38 and 494 +/- 81 mmol/5 days for F (n = 9) and 9 alpha FF (n = 5), respectively (P = 0.01). Sp (n = 5) completely inhibited 9 alpha FF-induced Na+ retention (494 +/- 81 vs. -37 +/- 130 mmol/5 days; P less than 0.01), but had no effect (n = 5) on F-induced Na+ retention (255 +/- 38 vs. 193 +/- 50 mmol/5 days; P = NS). After the expected first day kaliuresis, the effects of both steroids on net cumulative urinary K+ excretion were minimal. Systolic BP was increased by F, but not 9 alpha FF, and Sp did not inhibit this increase. A 2-fold greater Sp-inhibitable Na(+)-retaining effect of the mineralocorticoid demonstrates that the failure of Sp to block F-induced Na+ retention is not due to inadequate type I receptor blockade. Based on these findings and earlier studies, we conclude that high dose (stress level) F-induced Na+ retention and systolic BP increase are not mediated by either the mineralo- or glucocorticoid receptor in normal man.

Adult↗
PubMed1991

Aluminum-citrate interaction in end-stage renal disease.

The influence of a sodium citrate/citric acid mixture on the gastrointestinal (GI) absorption of aluminum (Al) from an Al(OH)3 preparation was evaluated in six stable maintenance hemodialysis patients. Plasma Al concentrations were determined serially after each of the following treatment sequences (I) Al(OH)3; (II) Al(OH)3 + sodium citrate/citric acid; (III) sodium citrate/citric acid; (IV) Al(OH)3 + NaHCO3. AUC0-8 for plasma Al from 0 to 8 hours was significantly greater (p less than 0.05) for Al(OH)3 + sodium citrate/citric acid (73 +/- 23 micrograms.hr/l; mean +/- SEM) than Al(OH)3 (16 +/- 30 micrograms.hr/l); sodium citrate/citric acid (-27 +/- 14 micrograms.hr/l); or Al(OH)3 + NaHCO3 (6 +/- 22 micrograms.hr/l). The 24 hour Al level remained above baseline (p less than 0.03) following Al(OH)3 + sodium citrate/citric acid (31 +/- 12 (pre) vs 54 +/- 14 micrograms/l (post), in contradistinction to study limb: l (34 +/- 14 vs 30 +/- 12 micrograms/l); III (79 +/- 40 vs 65 +/- 35 micrograms/l); and IV (71 +/- 37 vs 66 +/- 42 micrograms/l). We conclude that the GI absorption of Al from Al(OH)3 is enhanced by citrate in patients undergoing hemodialysis and that elevations of plasma Al persist longer. The concomitant administration of citrate and Al-containing phosphate (PO4) binders should be avoided in patients with end-stage renal disease (ESRD). NaHCO3 may serve as an alternative therapy for metabolic acidosis with less risk of enhancing Al absorption.

Adult↗
PubMed1990

Hormonal interactions with the proximal Na(+)-H+ exchanger.

Various types of catecholamine and peptide hormone receptors have been localized to the renal cortex, with the majority of these binding sites located on the proximal tubule. Both subtypes of alpha-adrenergic receptors, angiotensin II (ANG II), parathyroid hormone (PTH), and dopamine (DA) DA-1 receptors have all demonstrated binding sites on this nephron segment. One- to two-thirds of Na+ transport in the proximal nephron is proposed to be mediated by a Na(+)-H+ exchanger. Each of these hormones has been shown to alter Na(+)-H+ exchange activity. The purpose of this study was to examine the interactions of these various hormones on proximal nephron Na(+)-H+ exchange at both physiological and pharmacological concentrations. Na(+)-H+ exchange activity was determined in isolated rat proximal segments by assessing the uptake of 22Na+ that was suppressible by the Na(+)-H+ exchange inhibitor, ethylisopropylamiloride (EIPA). Time course studies indicated that a 1-min preincubation with the hormones followed by a 1-min exposure to 22Na+ was necessary to achieve a steady-state EIPA-suppressible 22Na+ uptake. Selective alpha-adrenergic agonists produced a maximum stimulation of 22Na+ uptake at approximately 10(-6) M final concentration (less than or equal to 192% above the control level of uptake); ANG II produced a maximum increase at 10(-12) M (an 82% increase above the control level). In contrast, PTH and DA inhibited 22Na+ uptake most effectively at 10(-8) M and 10(-6) M, respectively. When submaximal (10(-9) M) concentrations of alpha-agonists were incubated in combination with ANG II, a synergistic effect was observed only with selective alpha 2-agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1990

Measurement of intracellular pH in suspensions of renal tubules from potassium-depleted rats.

Intracellular pH was estimated from the fluorescence of 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein (BCECF) in isolated renal cortical tubules from control, potassium-depleted (KD) and NH4Cl-induced metabolic acidosis (MA) rats. While pHi was not different among control, short- and long-term KD, and NH4Cl MA rats, in vitro rates of ammonium production were increased in rats with metabolic acidosis and both short- and long-term potassium depletion. Mitochondrial matrix pH, and the pH gradient across the mitochondrial membrane were not different in tubules from KD rats compared to those from controls. These results are interpreted to indicate that a signal other than intracellular acidosis maintains the high rate of renal ammoniagenesis seen in KD.

Acidosis↗
PubMed1990

Intramitochondrial pH and ammonium production in rat and dog kidney cortex.

The focus of this investigation was to compare data from isolated tubules and mitochondria of rat and dog kidneys subjected to altered medium pH (pHe) in vitro and to determine the effects of pH on ammonium production. Cytosolic pH (pHi) was determined using the fluoroprobe BCECF-AM; mitochondrial matrix pH (pHm) was estimated from the distribution of a labeled weak acid. The data indicate differences between rat and dog. pHi was consistently lower in rat than dog proximal tubules. In rat, pHm decreased in parallel with pHe and phi, accounting, at least in part, for the accelerated alpha-ketoglutarate dehydrogenase (alpha KGDH) flux, which is important in triggering increased ammoniagenesis. In dog, pHm varied to only a small extent with pHe and pHi changes. The results suggest that changes in pHm are unlikely to explain an increase in alpha KGDH flux in acute acidosis in the dog. However, pHe and pHi could conceivably lead to alterations in other factors than pHm, i.e. matrix Ca2+, which may facilitate accelerated ammonium production.

Acidosis, Renal Tubular↗
PubMed1989

Regulation of rat kidney mitochondrial metabolism in acute acidosis.

Proximal tubular ammoniagenesis is amplified under conditions of acute and chronic metabolic acidosis. Current hypotheses postulate that alterations in intracellular pH (pHi) or in the pH gradient across the inner mitochondrial membrane (delta pHm) influence mitochondrial glutamine metabolism. Enhanced glutamine transport across the inner mitochondrial membrane might constitute a key regulatory factor in acidosis. To examine changes in delta pHm, a technique was used to determine pHi and intramitochondrial pH (pHm) simultaneously. Regulation of the enzyme alpha ketoglutarate dehydrogenase (alpha KGDH) was assessed by evaluating enzyme activity at varied levels of medium pH, Ca++, and adenosine diphosphate (ADP). The results indicate that pHi decreased with an acid external pH. A fall in pHi correlated to increase activity of alpha KGDH associated with increased affinity for the substrate, alpha KG. Increments in either buffer Ca++ or ADP concentration increased enzyme affinity for alpha KG at pH 7.6 but not at pH 6.8. These results, compatible with previous reports, indicate that pH, Ca++, and ADP are effectors of the enzyme alpha KGDH. Alterations in pH across the inner mitochondrial membrane might augment flux through alpha KG by accelerating glutamine metabolism. Increased alpha KG oxidation over the range of 10 to 500 mumol/L Ca++ concentration is compatable with data for Ca++ regulation reported for the solubilized enzyme. These studies provide evidence that the above factors, through enhancing alpha KGDH activity, participate in regulation of ammoniagenesis during states of acidosis.

Acidosis↗
PubMed1989

Acute aluminum toxicity associated with oral citrate and aluminum-containing antacids.

The authors report the development of a rapidly progressive encephalopathy marked by confusion, myoclonus, seizures, coma, and death in a group of women with renal failure who received an oral solution of citrate and aluminum hydroxide gel concurrently. Two patients were documented as having marked hyperaluminemia far exceeding blood aluminum levels encountered in the chronic state of aluminum intoxication. We ascribe the toxicity to enhanced gastrointestinal absorption of aluminum when complexed with citrate.

Acute Kidney Injury↗
PubMed1989

Proton compartmentation in rat renal cortical tubules.

To study the control of renal ammoniagenesis, a technique was developed to estimate simultaneously intracellular (pHi) and intramitochondrial (pHm) pH in suspensions of rat renal cortical tubules. pHi was estimated with the fluorescent probe 2',7'biscarboxyethyl-5(6)-carboxy-fluorescein (BCECF). The intracellular distribution of the weak acid 5,5-dimethyloxazolidine-2,4-dione (DMO) allowed calculation of pHm with the use of values of pHi obtained with BCECF and tubule mitochondrial content. At medium pH (pHe) 7.4, pHi was 7.08 +/- 0.02. Over the pHe range 7.0-7.7, pHi was linearly related to pHe, but the pH gradient across the cell membrane decreased as pHe was lowered. No difference in the relationship between pHe and pHi was obtained when tubules were incubated in the presence of a nonbicarbonate or bicarbonate-buffered medium. Changes in pHe with bicarbonate-buffered media resulted in identical pHi values, whether the changes were induced by altered bicarbonate or CO2 content. At pHe 7.4, pHm was 7.78 +/- 0.6 in bicarbonate-buffered medium but was higher (0.2-0.3 pH units) when tubules were bathed in nonbicarbonate-buffered medium. pHm was linearly related to pHi in either buffer. The pH gradient across the inner mitochondrial membrane was also positively correlated with pHe. The present studies indicate the suitability of the techniques for estimating pHi and pHm simultaneously in suspensions of rat renal cortical tubules. Parallel changes occur in both intracellular compartments when pHe is altered. pHm, which is approximately 0.7 pH units greater than pHi, decreases in acute acidosis. This decrease may be important in stimulating renal ammoniagenesis, possibly by activation of alpha-ketoglutarate dehydrogenase.

Animals↗
PubMed1989

Effects of alpha-adrenergic agonists on intracellular and intramitochondrial pH in rat proximal nephrons.

Rat proximal tubular segments were used to examine alpha-adrenoceptor alterations in Na+-H+ exchange by monitoring intracellular pH (pHi) and mitochondrial matrix pH (pHm). To obtain pHi, tubules were incubated with the cell-permeant fluorescent probe, 2',7'-bis(2-carboxyethyl)-5(6) carboxyfluorescein acetoxymethyl ester in a HCO3--free Na+ buffer. The intracellular distribution of the weak acid [2-14C] 5,5-dimethyloxazolidine-2,4-dione was used to calculate pHm, using values of medium pH, pHi, cell volume, and matrix content. Several selective alpha 1- and alpha 2-adrenoceptor agonists and the endogenous mixed agonist, norepinephrine, all produced dose-related increases in pHi. With each of the agonists tested, a maximum increase in pHi was observed at 1 microM final concentrations, with peak effects occurring in less than 1 min. Pretreatment with ethylisopropyl amiloride (EIPA, 10 microM), a specific inhibitor of proximal Na+-H+ exchange, blocked receptor-stimulated increases in pHi, as well as stimulation of Na+-H+ exchange by phorbol ester (PMA, 0.1 microM). Similarly, selective alpha 1- (prazosin, 0.1 microM) and alpha 2-(idazoxan, 0.1 microM) adrenoceptor antagonists inhibited alterations in agonist-induced pHi changes, whereas PMA-stimulated increases in pHi remained unaffected. Neither alpha 1- nor alpha 2-adrenoceptor agonists produced differences in pHm. Adrenoceptor agonist-induced pHi changes were also assessed at various concentrations of external Na+ (0-135 mM). It was observed that 0 and 10 mM external Na+ concentrations significantly reduced alpha 1- and alpha 2-adrenoceptor-stimulated pHi changes; Km values for the alpha 1-agonist phenylephrine and the alpha 2-agonist B-HT 933 were 18.0 +/- 2.1 and 22.7 +/- 2.6, respectively. In summary, stimulation by alpha-adrenergic agonists may be blocked at the receptor level with specific alpha-antagonists or at the exchanger with EIPA. The increase in cellular pH induced by these agonists is sensitive to external Na+ and reflects alpha-adrenoceptor activation of the Na+-H+ exchanger.

Adrenergic alpha-Agonists↗
PubMed1989

Hyperaluminaemia associated with oral citrate and aluminium hydroxide.

1. A hospitalized patient with renal failure receiving oral aluminium hydroxide was found to have a blood aluminium level of 3124 micrograms/l (116 mumol/l). 2. The extremely high aluminium concentration was attributed to the concurrent use of an oral citrate solution which converted the aluminium to a more soluble and absorbable form. 3. The combination of oral aluminium and citrate should be avoided in patients with poor renal function.

Administration, Oral↗