Effects of dexamethasone on renal and systemic acid-base metabolism.
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Acid-Base Equilibrium↗
Biomedical subjects
A Sebastian
Publications and source records attributed to A Sebastian.
Mineralocorticoid-resistant renal hyperkalemia without salt wasting (type II pseudohypoaldosteronism): role of increased renal chloride reabsorption.
A rare syndrome has been described in which mineralocorticoid-resistant hyperkalemia of renal origin occurs in the absence of glomerular insufficiency and renal sodium wasting and in which hyperchloremic acidosis, hypertension, and hyporeninemia coexist. The primary abnormality has been postulated to be a defect of the potassium secretory mechanism of the distal nephron. The present studies were carried out to investigate the mechanism of impaired renal potassium secretion in a patient with this syndrome. When dietary intake of sodium chloride was normal, renal clearance of potassium was subnormal (CK/GFR = 3.6 +/- 0.2%; normal subjects, 9.0 +/- 0.9%, N = 4) despite high normal or supernormal levels of plasma and urinary aldosterone. The fractional clearance of potassium remained subnormal (CK/GFR = 5.1 +/- 0.2%) during superimposed chronic administration of superphysiologic doses of mineralocorticoid hormone. Little increase in renal potassium clearance occurred when the delivery of sodium to distal nephron segments was increased further by the i.v. infusion of sodium chloride, despite experimentally sustained hypermineralocorticoidism. But potassium clearance increased greatly when delivery of sodium to the distal nephron was increased by infusion of nonchloride anions: sulfate (sodium sulfate infusion, low sodium chloride diet; CK/GFR = 63.7 +/- 0.4%) or bicarbonate (sodium bicarbonate plus acetazolamide infusion; CK/GFR = 81.7 +/- 1.7%). These findings indicate that mineralocorticoid-resistant renal hyperkalemia in this patient cannot be attributed to the absence of a renal potassium secretory capability or to diminished delivery of sodium to distal nephron segments; instead it may be dependent on chloride delivery to the distal nephron. We suggest that the primary abnormality in this syndrome increases the reabsorptive avidity of the distal nephron for chloride, which (1) limits the sodium and mineralocorticoid-dependent voltage driving force for potassium and hydrogen ion secretion, resulting in hyperkalemia and acidosis and (2) augments distal sodium chloride reabsorption resulting in hyperchloremia, volume expansion, hyporeninemia, and hypertension.
Adult↗
Renal and systemic acid-base effects of chronic spironolactone administration.
Studies in dogs were carried out to investigate the effects of chronic administration of the mineralcorticoid antagonist spironolactone (15 mg/kg orally) on renal and systemic acid-base metabolism. In adrenalectomized dogs administered fixed mineralocorticoid and glucocorticoid replacement, spironolactone resulted in a definite renal antimineralocorticoid effect, as evidenced by natriuresis and chloruresis, and sustained metabolic acidosis and hyperkalemia due in part to impaired renal secretion of hydrogen and potassium. In adrenalectomized dogs receiving physiological glucocorticoid without mineralocorticoid, metabolic acidosis also occurred, but a marked stimulatory effect of spironolactone on net acid excretion occurred in association with increased urinary SO4-2 and total nitrogen excretion. Accordingly, spironolactone results in sustained renal tubular acidosis when administered in the presence of constant physiological levels of mineralocorticoid and glucocorticoid steroids. When administered under conditions of complete lack of mineralocorticoid activity, spironolactone exerts systemic and renal acid-base effects similar to those of a glucocorticoid steroid, namely, increased protein catabolism and sulfuric acid production with resultant extrarenal metabolic acidosis associated with increased net acid excretion.
Acid-Base Equilibrium↗
Renal and systemic acid-base effects of chronic hypoparathyroidism in dogs.
MEtabolic alkalosis has been reported in patients with chronic hypoparathyroidism under conditions of uncontrolled diet and medication intake. Hypoparathyroidism has also been reported to result in increased renal bicarbonate reabsorptive capacity in acutely bicarbonate-loaded dogs. However, the acid-base effects of experimentally induced chronic hypoparathyroidism have not been investigated in any species. Accordingly, we investigated the chronic effects of hypoparathyroidism by thyroparathyroidectomy (TPTX) plus thyroxine replacement on renal regulation of plasma acid-base composition under metabolic balance conditions of normal dietary acid load (group I) and alkali load (group II, 9.0 meq/kg HCO3(-) daily) in dogs ingesting a normal Cl-, high Ca2+ diet throughout study. For groups I and II pre-TPTX: [HCO3(-)]p, 19.7 +/- 1.0, 20.1 +/- 0.9 meq/liter. Plasma acid-base composition (days 5-10) was unchanged by TPTX: delta [HCO3(-)]p, -0.7 +/- 0.4, 0.0 +/- 0.2 meq/liter; delta [H+]p, 0 +/- 1, -1 +/- 0 neq/liter, NS from control. A reduction in plasma total calcium concentration ([CaT]p) occurred and persisted (group I: [CaT]p, -1.6 +/- 0.2 mg/100 ml, P less than 0.01, day 1 and -1.2 +/- 0.9, days 5-10; group II: -1.4 +/- 0.3 mg/100 ml, P less than 0.01, day 1 and -2.3 +/- 0.4, days 5-10). No significant change in net acid or Cl- excretion occurred following TPTX. Thus, chronic hypoparathyroidism characterized by a chronic reduction in [CaT]p does not result in significant alterations in renal regulation of plasma acid-base composition in the dog.
Acid-Base Imbalance↗
Renal and systemic acid-base effects of chronic dichloroacetate administration in dogs.
Dichloroacetate (DCA) increases metabolic disposal of lactic acid secondary to activation of pyruvate dehydrogenase and consequent acceleration of pyruvate oxidation. DCA has thus been proposed as a therapeutic agent for clinical states of lactic acidosis. Yet, DCA has a potential metabolic acidosis-producing effect by virtue of reported effects of (A) increasing blood ketoacid concentration, (B) decreasing tubular reabsorption of filtered ketoacid anions, and (C) decreasing renal NH3 production. In the present study chronic administration of DCA, 50 mg/kg p.o. daily for 6-8 days, resulted in a cumulative increase in renal net acid excretion (NAE) (sigma delta NAE, +61 meq, p < 0.05). The increase in NAE was accounted for entirely by increased NH4+ excretion. Production of ammonia by the kidney appeared to be increased since the increased excretion of NH4+ was accompanied by an increase in urine pH (delta UpH, +0.18 +/- 0.07, p < 0.05). The increase in NAE was accompanied by a nearly identical increase in urinary anion gap (UAG) (UAG = [NH4+ + Na+ + K+] - [Cl- + HCO3- + HPO4(2-) + H2PO4-]). The increase in UAG was caused by increased urinary total organic anions, accounted for at least in part by a significant increase in urinary acetoacetate. No significant increase in urinary potassium or sodium excretion occurred. A change in plasma acid-base composition occurred that was consistent with a mild respiratory acidosis without associated primary metabolic acidosis or alkalosis. These findings indicate that chronic DCA administration results in (1) increased steady state endogenous noncarbonic organic acid production, and (2) retention of carbonic acid. Further investigation of the potential metabolic and respiratory acidosis-producing effects of DCA is required to determine its clinical efficacy in the treatment of clinical lactic acidosis.
Acetates↗
Prevalence, pathogenesis, and functional significance of aldosterone deficiency in hyperkalemic patients with chronic renal insufficiency.
Our findings indicate that hypoaldosteronism occurs commonly (23/31 patients) in hyperkalemic patients with chronic renal insufficiency and that the deficiency of aldosterone contributes to the pathogenesis of the hyperkalemia. In most patients (83%), hypoaldosteronism could be accounted for by deficient renal secretion of renin, but in some patients (17%) overt renin deficiency did not appear to be present, and therefore other (unidentified) causes of aldosterone deficiency must be invoked. The results also indicate that the urinary excretion rate of aldosterone secretion rate in this group of patients.
Adult↗
Effect of mineralocorticoid replacement therapy on renal acid-base homeostasis in adrenalectomized patients.
Chronic balance studies were performed in six adrenalectomized patients to investigate the renal and systemic acid-base consequences of mineralocorticoid deficiency in the absence of either glucocorticoid deficiency or parenchymal renal disease. Constant glucocorticoid replacement was provided with dexamethasone, 750 to 875 micrograms/day, administered orally. Creatinine clearance averaged 98 +/- 8 ml/min/1.73 m2. Following a control period, mineralocorticoid replacement with fludrocortisone (100 to 200 micrograms/day) was either discontinued (N = 3) or initiated (N = 2). In an additional patient, mineralocorticoid replacement was initiated and sustained (5 days) by continuous i.v. infusion of aldosterone, at a dose approximating the normal secretion rate (120 micrograms/day). Net acid excretion (NAE) and plasma total carbon dioxide decreased in each patient in whom mineralocorticoid was discontinued and increased in each patient in whom mineralocorticoid was initiated. The cumulative change in NAE (sigma delta NAE) independent of direction averaged 66 +/- 20 mEq (P less than 0.05) by the fifth experimental day in the six patients, and the corresponding change in plasma total CO2 averaged 1.2 +/- 0.3 mmoles/liter (P less than 0.02). The magnitude of sigma delta NAE correlated with the basal rate of NAE (r = 0.87, P less than 0.05), which averaged 0.9 +/- 0.1 mEq/kg body wt per day. The change in plasma total CO2 correlated with sigma delta NAE (r = 0.83, P less than 0.05). The changes in NAE correlated positively with the corresponding changes in sodium balance and negatively with the corresponding changes in potassium balance. These findings provide the first evidence that renal acidification is under tonic stimulation by mineralocorticoid at levels not exceeding those in normal subjects ingesting acid-producing diets of normal sodium and potassium content. The extent to which the tonic stimulation of renal acidification is mediated by a direct effect of mineralocorticoid on renal hydrogen ion transport or by an indirect effect dependent on altered renal sodium and/or potassium transport requires further investigation. The findings implicate mineralocorticoid deficiency as a significant renal acidosis-producing condition not dependent on the presence of renal disease or glucocorticoid deficiency, and potentially amplified when endogenous acid production is increased by diet or disease.
Acid-Base Equilibrium↗
Pathogenesis of renal hyperchloremic acidosis resulting from dietary potassium restriction in the dog: role of aldosterone.
In dogs dietary K+ restriction (16 days) results in diminished urinary net acid excretion (NAE) and systemic hyperchloremic metabolic acidosis (sigma delta NAE, -200 meq; delta[HCO3-]p, -2.9 +/- 0.3 meq/liter, P less than 0.05). Urinary aldosterone (aldo) excretion decreased by 34 +/- 3% (P less than 0.001) and metabolic clearance rate of aldo increased by 80 +/- 17% (P less than 0.02) during K+ restriction. Daily subcutaneous injection of a small amount of exogenous aldo (20 micrograms) during K+ restriction significantly attenuated the reduction in NAE (sigma delta NAE -51 vs. -200 meq, P less than 0.05) without raising plasma aldo concentrations to levels greater than control. These findings suggest that hypoaldosteronism induced by potassium depletion is at least in part the cause of the observed renal tubular acidosis. In adrenalectomized (ADX) dogs maintained on fixed mineralocorticoid and glucocorticoid replacement (aldo dose 60 micrograms/day), K+ restriction resulted in a significant degree of renal metabolic acidosis (delta[HCO3-]p, -1.4 +/- 0.3 meq/liter, P less than 0.01). In these ADX dogs, the exogenous supply of aldo was fixed but hypoaldosteronism may have developed owing to increased metabolic clearance rate of aldo caused by dietary K+ depletion. When mineralocorticoid replacement was withheld in ADX dogs, the steady-state degree of renal metabolic acidosis was no more severe in animals with preexisting dietary K+ depletion (16 days) than in the same animals when mineralocorticoid was withheld without preexisting K+ depletion. Thus, when neither endogenous nor exogenous aldo is present, K+ depletion does not result in a renal acidosis-producing effect that exacerbates that of aldo deficiency. The results of these studies suggest that the reduction in NAE and consequent metabolic acidosis induced by dietary K+ depletion is at least in part a consequence of aldo deficiency, and provide no evidence of an additional defect in acidification not caused by aldo deficiency.
Acidosis, Renal Tubular↗
Effects of glucocorticoid steroids on renal and systemic acid-base metabolism.
Clinical states of hyperglucocorticoidism are associated with renal metabolic alkalosis, yet the systemic and renal acid-base response to chronic administration of glucocorticoid steroids (dexamethasone, triamcinolone) possessing little or no mineralocorticoid activity has not been investigated. In balance studies studies in dogs administration of triamcinolone (Tcn), 1.0 mg . kg-1 . day-1 for 6-9 days (group I, n = 5), resulted in a persistent reduction in urine pH and increase in net acid excretion (NAE), and in the excretion of urinary unmeasured anions (C+NH4,Na;K minus A-Cl,HCO3,Pi), which were identified as organic anions and sulfate. A significant degree of metabolic acidosis occurred initially (delta [HCO3-]p, -3.4 meq/liter, P less than 0.05, day 1). As Tcn administration was continued, the cumulative increment in net acid excreted exceeded the cumulative increment in urinary unmeasured anion excreted and [HCO-3]p returned to pre-Tcn control values and remained stable thereafter. In the steady state of Tcn administration plasma potassium concentration and renal potassium clearance were not significantly different from pre-Tcn control, in contrast to the findings of hypokalemia and increased renal potassium clearance during chronic administration of deoxycorticosterone (DOC). Triamcinolone did not result in antinatriuresis or antichloruresis. Chronic administration of a 10-fold smaller dose of Tcn (0.1 mg . kg-1 . day-1) in an additional group (group III) also resulted in a persisting reduction in urine pH and an increase in net acid excretion that exceeded unmeasured anion excretion and resulted in a small increase in steady-state plasma bicarbonate concentration. These results suggest that chronic administration of potent glucocorticoid steroids results in 1) a persisting increase in endogenous acid production, and 2) stimulation of renal hydrogen ion secretion that was of greater degree than accounted for by the increment in endogenous acid production and that was not accompanied by renal mineralocorticoid effects on sodium and potassium transport.
Acid-Base Equilibrium↗
The use of dragonfly nymphs in the control of Aedes aegypti.
The predatory rates of the dragonfly nymphs on Aedes aegypti were studied in the laboratory and under field conditons. Labellulid nymphs were found to predate on Ae. aegypti larvae and pupae readily. The rate of consumption was found to be 133 +/- 21 all stages of larvae per medium size nymph per 24 hours. In container habitats complete elimination of all larvae and pupae were achieved between day 4 and 9 depending on density of aquatic stages. The dragonfly nymphs as predators could be used in biological control of Aedes mosquitoes.
Aedes↗
Pathophysiology of chronic renal tubular acidosis induced by administration of amiloride.
Amiloride is a "potassium-sparing" diuretic agent of moderate natriuretic potency with site of action in postmacula densa segments of the distal nephron. In isolated segments of mammalian cortical distal nephron, amiloride diminishes sodium reabsorption and transtubular electrical PD and inhibits potassium secretion. We investigated the effects of long-term administration of a demonstrably maximal dose of amiloride (1.0 mg/kg b.i.d.) on plasma and urine acid-base and electrolyte composition in fixed steroid-replaced ADX dogs. Amiloride administration resulted in potassium retention and hyperkalemia and reduced net acid excretion and caused chronic hyperchloremic metabolic acidosis. The cumulative reduction in net acid excretion and severity of systemic acidosis were not significantly different in additional groups in which potassium retention was prevented by restriction of dietary potassium during amiloride administration or in which amiloride was administered to animals with pre-existing dietary potassium depletion. The response of urine pH and ammonium excretion, however, differed among groups. In the steady state of chronic acidosis, urine pH and ammonium concentration were lowest in the hyperkalemic group and highest in the hypokalemic group, and among the three groups pH and ammonium were positively correlated (r = 0.67, p less than 0.001). Ammonium concentration varied inversely with plasma potassium concentration. Net acid excretion rates returned to control levels during the steady state of chronic amiloride-induced acidosis in the three groups. During continued amiloride administration, sustained correction of acidosis by long-term oral administration of sodium bicarbonate did not result in negative values of net acid excretion; that is, amiloride did not cause net wasting of base at normal plasma bicarbonate concentration. The results of these studies suggest that chronic amiloride administration results in a sustained impairment of renal hydrogen ion secretion restricted to the distal nephron and not dependent on alterations in potassium balance. Differences in potassium balance (positive or negative) appeared to influence only the availability of ammonia for diffusion into urine and steady-state urine pH, but not the steady-state net rate of renal hydrogen ion secretion during amiloride. These studies identify an experimental model of chronic distal renal tubular acidosis in which external hydrogen ion balance is re-established during chronic acidosis even when the availability of ammonia for excretion is decreased.
Acidosis, Renal Tubular↗
K+ deprivation potentiates the renal acid excretory effect of mineralocorticoid: obliteration by amiloride.
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Acid-Base Equilibrium↗
Renal acidosis in mineralocorticoid deficiency is not dependent on NaCl depletion or hyperkalemia.
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Acid-Base Equilibrium↗
Hyporeninemic hypoaldosteronism.
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Acidosis↗
K+ deprivation potentiates the renal alkalosis-producing effect of mineralocorticoid.
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Adrenalectomy↗
Correction of metabolic acidosis by the kidney during isometric expansion of extracellular fluid volume.
In dogs with chronic hypochloremic metabolic alkalosis associated with ECFV contraction, plasma [HCO-3] ([HCO-3]p) normalizes during expansion of ECFV with a solution containing Cl- and HCO-3 in concentrations duplicating those in the plasma before expansion (isometric expansion). The kidney selectively rejects administered HCO-3 and retains Cl-. If this preferential Cl- less than HCO-3 reabsorptive selectivity were a characteristic renal response to ECFV expansion, isometric expansion during hyperchloremic acidosis would exacerbate the acid-base disturbance rather than correct it as it does in alkalosis. We examined the effect of isometric expansion in dogs with chronic hyperchloremic metabolic acidosis induced by HCl feeding or mineralocorticoid hormone deficiency. During expansion, as the expected decrease occurred in the fractional reabsorption of Na+, a lesser decrease occurred in fractional reabsorption of HCO-3, whereas a greater decrease occurred in fractional reabsorption of Cl-. The kidney selectively retained administered HCO3 and rejected Cl-. [HCO-3]p normalized. The shift to bicarbonate-selective from chloride-selective anion reabsorption during ECFV expansion in metabolic acidosis vs. metabolic alkalosis indicates that in response to ECFV expansion- the kidney selectively alters the ratio of bicarbonate to chloride concentration in the tubular reabsorbate in the direction that tends to normalize plasma acid-base composition, irrespective of the direction of deviation of the initial plasma bicarbonate concentration. The signal that initiates the shift in anion reabsorptive selectivity remains to be identified.
Acidosis↗
Amelioration of metabolic acidosis with fludrocortisone therapy in hyporeninemic hypoaldosteronism.
In four patients with renal hyperchloremic acidosis and hyperkalemia, hyporeninemic hypoaldosteronism and chronic renal insufficiency (glomerular filtration rates of 13, 31, 35 and 44 ml per minute per 1.73 m2), prolonged administration of fludrocortisone increased urinary potassium and net acid excretion, corrected hyperkalemia and substantially ameliorated acidosis. Except in the patient with the lowest glomerular filtration rate, the increased net acid excretion was due mostly to increased ammonium excretion. Urine pH decreased initially in each patient, but in the three patients with the highest filtration rates, it increased subsequently as ammonium excretion increased, indicating that renal ammonia production increased. Urinary ammonium excretion correlated inversely with serum potassium concentration and did not decrease on discontinuation of therapy if hyperkalemia was prevented from recurring. In patients with renal acidosis and hyporeninemic hypoaldosteronism, administration of mineralocorticoid hormone can augment both renal hydrogen-ion secretion and, by correction of hyperkalemia, renal ammonia production, and thereby ameliorate metabolic acidosis.
Acidosis, Renal Tubular↗
Impaired renal H+ secretion and NH3 production in mineralocorticoid-deficient glucocorticoid-replete dogs.
When the administration of exogenous mineralocorticoid hormones was discontinued in adrenalectomized dogs maintained on glucocorticoid, net acid excretion decreased due largely to a reduction in urinary ammonium excretion (UNH4+V), and hyperchloremic hyperkalemic metabolic acidosis occurred and persisted. The reduction in UNH4+V was not associated with an increase in urine pH (UpH) or a decrease in urine flow, but correlated with the severity of hyperkalemia and was mitigated by dietary potassium restriction. UpH decreased to values as low as 5.3. During acidosis, UpH varied directly with UNH4+V, but in relation to UNH4+V, UpH exceeded that in acid-fed mineralocorticoid-replete dogs. Extrapolated to UNH4+V=0, however, UpH was not significantly different in the two groups (5.27 vs. 5.44). When distal delivery of sodium was increased by infusion of sodium phosphate, titratable acid excretion increased in both groups but pateaued at lower rates in the mineralocorticoid-deficient dogs. These results suggest that in mineralocorticoid-deficient dogs, renal ammonia production is diminished, in part due to potassium retention and hyperkalemia; renal hydrogen ion secretory capacity is reduced even when sodium and buffer delivery to the distal nephron is not reduced; and the ability of the kidney to generate normally steep urine-to-blood hydrogen ion concentration gradients is unimpaired.
Acidosis↗