Role of urinary concentrating ability in the generation of toxic papillary necrosis

Role of urinary concentrating ability in the generation of toxic papillary necrosis. We studied the pathogenesis of chemically induced papillary necrosis in six groups of rats. Papillary necrosis was produced by a single injection of 2-bromoethylamine hydrobromide (BEA), 50 mg, i.v.; the animals were followed for 7 to 10 days after the administration of the compound. Following BEA, heterozygous Brattleboro rats developed all the functional and morphologic lesions of papillary necrosis that we previously described in Sprague-Dawley rats. They were unable to maintain sodium balance when dietary sodium was withdrawn. Homozygous Brattleboro rats, on the other hand, developed none of the manifestations of papillary necrosis (that is, animals with central diabetes insipidus were protected completely from the nephrotoxic effects of BEA). They adapted normally to a zero sodium diet. Chronic administration of vasopressin to homozygous Brattleboro rats fully restored the toxic effects of BEA. Lowering urinary concentrating ability by inducing a water diuresis in Sprague-Dawley rats completely protected against BEA-induced papillary necrosis. Decreasing papillary solute concentration by furosemide or increasing urine flow after abrupt withdrawal of vasopressin to homozygous Brattleboro rats did not protect against BEA-induced papillary necrosis. We conclude that the combination, but not either alone, of increased urine flow and decreased papillary solute concentration protects against the development of BEA-induced papillary necrosis.Rôle du pouvoir de concentration urinaire sur l'apparition d'une nécrose papillaire toxique. Nous avons étudié la physiopathologie d'une nécrose papillaire induite chimiquement chez six groupes de rats. La nécrose papillaire était produite par une injection unique de 2-bromoéthylamine hydrobromide (BEA), 50 mg, i.v.; les animaux étaient suivis pendant 7 à 10 jours après administration du produit. Après le BEA, des rats Brattleboro hétérozygotes ont développé toutes les lésions fonctionnelles et morphologiques d'une nécrose papillaire telles que nous les avions déjà décrites chez des rats Sprague-Dawley. Ils n'étaient pas capables d'assurer l'équilibre de la balance sodée lorsque le sodium alimentaire était supprimé. Par ailleurs, des rats Brattleboro homozygotes n'ont développé aucune des manifestations de nécrose papillaire (c'est-à-dire que les animaux ayant un diabète insipide central étaient complètement protégés des effets néphrotoxiques du BEA). Ils s'adaptaient normalement à un régime sans sodium. L'administration chronique de vasopressine à des rats Brattleboro homozygotes a totalement restauré l'effet toxique du BEA. Le fait d'abaisser la capacité de concentration des urines en induisant une diurèse aqueuse dans les rats Sprague-Dawley a complètement protégé contre la nécrose papillaire induite par le BEA. La diminution de la concentration de solutés papillaires par le furosémide ou l'augmentation du débit urinaire après arrêt brutal de la vasopressine chez des rats Brattleboro homozygotes ne protégeait pas contre la nécrose papillaire induite par le BEA. Nous concluons que la combinaison, mais non chaque facteur séparément, d'une augmentation du débit urinaire et d'une diminution de la concentration de solutés papillaires protègent contre le développement d'une nécrose papillaire induite par le BEA

Clinical and pathophysiologic spectrum of acquired distal renal tubular acidosis

Clinical and pathophysiologic spectrum of acquired distal renal tubular acidosis. Urinary acidification was studied in nine patients with hyper-chloremic metabolic acidosis. The aim of this study was to investigate the mechanism(s) of impaired distal acidification by the systematic administration of sodium sulfate and neutral phosphate. No impairment of proximal acidification was apparent because all patients had a fractional bicarbonate excretion below 5% at plasma bicarbonate concentrations above 22 mEq/liter. All patients except two were unable to lower urine pH below 5.5 despite systemic metabolic acidosis. The two patients who lowered urine pH normally were hyperkalemic and had selective aldosterone deficiency. Six patients failed to lower the urine pH below 5.5 with sodium sulfate (6.04 ± 0.16) and were unable to achieve a normal urine minus blood (U-B) Pco2 gradient with neutral phosphate (2.8 ± 3.5mm Hg). Control subjects, the two patients with selective aldosterone deficiency, and the remaining patient lowered the urine pH below 5.5 and increased the U-B Pco2 gradient above 25mm Hg in response to sodium sulfate and neutral phosphate infusion, respectively. The abnormal response to these agents exhibited by six patients strongly suggests that the mechanism of impaired distal acidification was that of secretory failure of the proton pump. The normal response of the remaining three patients indicates that the proton pump was able to secrete hydrogen ions normally under maximal stimulation. This pattern is totally predictable in patients with isolated selective aldosterone deficiency who are also capable of lowering the urine pH normally in the presence of systemic metabolic acidosis. The distinctive acidification pattern of the remaining patient who was also hyperkalemic can be explained on the basis of a voltage-dependent type of distal renal tubular acidosis. This type may be disclosed by the findings of impairment of both hydrogen ion and potassium secretion.Aspects clinique et physiopathologique de l'acidose tubulaire distale acquise. L'acidification urinaire a été étudiée chez neuf malades ayant une acidose métabolique hyperchlorémique. Le but de ce travail était d'étudier le mécanisme de l'altération de l'acidification distale par l'administration de sulfate de sodium et de phosphate neutre. Il n'est pas apparu d'altération de l'acidication proximale puisque tous les malades avaient une excrétion fractionnelle de bicarbonate inférieure à 5% à des concentrations de bicarbonate plasmatique supérieures à 22 mEq/litre. Tous les malades sauf deux étaient incapables d'abaisser leur pH urinaire au dessous de 5,5 malgré l'acidose métabolique. Les deux malades qui abaissaient le pH de l'urine à des valeurs normales étaient hyperkaliémiques et avaient un déficit sélectif d'aldostérone. Six malades n'ont pu abaisser leur pH urinaire en dessous de 5,5 avec le sulfate de sodium (6,04 ± 0,16) et ont été incapables de réaliser un gradient de Pco2 normal urine-sang sous phosphate neutre (2,8 ± 3,5mm Hg). Les sujets contrôles, les deux malades ayant un déficit d'aldostérone et le dernier malade ont abaissé le pH de l'urine au dessous de 5,5 et augmenté le gradient de Pco2 à plus de 25mm Hg en réponse aux administrations de sulfate de sodium et de phosphate neutre, respectivement. La résponse anormale des six malades suggère fortement que le mécanisme de l'altération de l'acidification distale est un défaut de fonctionnement de la pompe à protons. La réponse normale des trois derniers malades indique que la pompe était capable de sécréter des ions hydrogène dans des conditions de stimulation maximales. Cette modalité est prévisible chez les malades qui ont un déficit sélectif et isolé d'aldostérone et qui sont aussi capables d'abaisser le pH de leur urine en présence d'une acidose métabolique systémique. La modalité d'acidification particulière du dernier malade qui était en même temps hyperkaliémique peut être expliquée par un mécanisme dépendant de la différence de potentiel. Cette situation peut être reconnue par la constatation d'un désordre portant à la fois sur la sécrétion de ions hydrogène et celle de potassium

Effect of Parathyroid Hormone Fragments on Calcium Transport in Toad Bladder1

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Studies on the mechanism of trimethoprim-induced hyperkalemia. Kidney Int

Studies on the mechanism of trimethoprim-induced hyperkalemia. We examined the effects of trimethoprim (TMP) on metabolic parameters and renal ATPases in rats after a 90 minute infusion (9.6 mg/hr/kg body wt, i.v.) and after 14 days (20 mg/kg body wt/day, i.p.). After one dose of TMP, plasma electrolytes, arterial pH and aldosterone levels were normal, but a natriuresis, bicarbonaturia, and decreased urinary potassium excretion occurred. Na-K-ATPase activity in microdissected segments from these animals was decreased by 36 0.9% in proximal convoluted tubule (PCT) (P < 0.005); decreases of 50 2.1% and 40 1.1% were seen in cortical and medullary collecting tubules (CCT and MCT), respectively (P < 0.005). Na-K-ATPase activity was unaffected in medullary thick ascending limb (MTAL). H-ATPase (in PCT and collecting duct) and H-K-ATPase (in CCT and MCT) activities were not changed. Following chronic TMP administration, plasma potassium increased as compared to control (5.16 0.05 mEq/liter vs. 3.97 0.05 mEq/liter, P < 0.05), however, acid-base status and plasma aldosterone levels were normal. Na-K-ATPase activity was decreased by 45 2.6% in PCT (P < 0.005), 73 2.0% in CCT (P < 0.001), and 53 2.5% in MCT (P < 0.005). Na-K-ATPase activity in MTAL and H-K-ATPase activity in CCT and MCT were unchanged. H-ATPase activity in PCT and MTAL was normal, but in the collecting tubule (CCT and MCT) it was decreased by approximately 25% (P < 0.05). TMP inhibited Na-K-ATPase activity in a dose-dependent fashion in PCT, CCT, and MCT when tubules from normal animals were incubated in vitro with the drug; TMP in vitro did not affect H-ATPase or H-K-ATPase activity. These results suggest that TMP-induced hyperkalemia may result from decreased urinary potassium excretion caused by inhibition of distal Na-K-ATPase in the face of intact H-K-ATPase activity. The drug trimethoprim-sulfamethoxazole (Bactrim®) is widely used as an antimicrobial agent, being effective against both gram-positive and gram-negative organisms Methods Male Sprague-Dawley rats weighing 100 to 200 g were used in this study. All animals had free access to the usual laboratory diet and were given tap water to drink ad libitum, unless otherwise noted. In vivo studies A. Acute study (single dose intravenous infusion). Animal preparation. Animals were first anesthetized with sodium pentobarbital and ketamine. The femoral vein was then catheterized with PE-50 tubing for continuous infusion; the femoral artery was cannulated for blood sample

Internephron Heterogeneity for Carbonic Anhydrase-independent Bicarbonate Reabsorption in the Rat

Abstract. The present experiments were designed to localize the sites of carbonic anhydrase-independent bicarbonate reabsorption in the rat kidney and to examine some of its mechanisms. Young Munich-Wistar rats were studied using standard cortical and papillary free-flow micropuncture techniques. Total CO2 (tCO2) was determined using microcalorimetry. In control rats both superficial and juxtamedullary proximal nephrons reabsorbed-95 % ofthe filtered load ofbicarbonate. The administration of acetazolamide (20 mg/kg body weight [bw]/h) decreased proximal reabsorption to 65.6% of the filtered load in superficial nephrons (32 % was reabsorbed by the proximal convoluted tubule while 31.7% was reabsorbed by the loop segment), and to 38.4 % in juxtamedullary nephrons. Absolute reabsorption of bicarbonat