Familiar hyperkalaemic acidosis.

We evaluated a 26-year-old man with hyperkalaemic acidosis, apparently inherited as an autosomal dominant trait. Type II pseudohypoaldosteronism was suggested by normal aldosterone production and renal sodium conservation. The cause of acidosis in this syndrome is unknown. Both urinary ammonium excretion and bicarbonate threshold were low during hyperkalaemia. After correcting the hyperkalaemia ammonium excretion was normal, but bicarbonate threshold remained low. Maximum bicarbonate reabsorption, urine to blood pCO2 gradients, and minimum urine pH were normal. These findings suggest that hyperkalaemia might contribute to the acidosis by limiting urinary buffer, but that the primary defect is reduced mineralocorticoid effect on hydrogen ion secretion. When the poorly reabsorbed anion, sulphate, was infused, hydrogen ion and potassium secretion were normal. When the relatively reabsorbable anion, chloride, was infused, potassium secretion was decreased. These findings suggest that the attenuated mineralocorticoid effect on hydrogen ion secretion is due to increased reabsorptive avidity for chloride in the distal nephron. To determine if this defect caused resistance to mineralocorticoid we increased mineralocorticoid by dietary sodium restriction and later administered desoxycorticosterone and fludrocortisone. Both endogenous and exogenous mineralocorticoid caused increased net acid excretion and corrected the acidosis, indicating no resistance to mineralocorticoid. Hydrochlorothiazide 50 mg daily promptly corrected the acidosis and the hyperkalaemia by increased urinary potassium excretion. We conclude that the acidosis of type II pseudohypoaldosteronism is due in part to attenuation of the voltage-dependent moiety of mineralocorticoid-driven acidification caused by enhanced distal chloride reabsorption. Suppression of ammoniagenesis by hyperkalaemia exaggerates the acidosis. The acidosis and hyperkalemia are corrected by hydrochlorothiazide.

Effects of dietary potassium depletion and mineralocorticoid excess on renal Cl-conservation in the dog.

Preexisting dietary K+ depletion (KD) in dogs exaggerates the renal acid excretory response to mineralocorticoid hormone (MCH) and attenuates the renal Cl- reabsorptive response without altering the Na+ reabsorptive response. The exaggerated acid excretory response has been postulated to be an electrophysiological consequence of a defect in renal Cl- reabsorption caused by KD. To investigate the specific effects of KD on renal Cl- transport in dogs, we assessed renal Cl- conservation during dietary Cl- restriction in KD adrenalectomized dogs maintained on physiological replacement doses of MCH. After a 16-day period of dietary K+ restriction and physiological MCH replacement, reduction of dietary NaCl from 5.0 to 0.25 mmol X kg-1 X 24 h-1 was attended by reduction in urinary Cl- excretion to values less than intake and to significantly lower values than in K+ -replete controls. In a subsequent experimental period of continued Cl- restriction and administration of DOC (15 mg/24 h, i.m.), urinary Cl- excretion decreased further in both groups to stable values, but the values were significantly greater in KD (2.7 +/- 0.4 vs. 1.1 +/- 0.1 meq/24 h, P less than 0.05) and the cumulative retention of urinary Cl- was significantly less (10.3 +/- 1.4 vs. 29.5 +/- 6.7 meq, P less than 0.05). These findings demonstrate that preexisting dietary KD accelerates chronic renal Cl- conservation in response to dietary Cl- restriction under conditions in which MCH supply is normal and fixed but that it impairs maximal renal Cl- -conserving ability in response to MCH excess.

Diuretic regimens in essential hypertension. A comparison of hypokalemic effects, BP control, and cost.

Intolerable side effects and hypokalemia during thiazide treatment of hypertension frequently necessitate a change in diuretic regimen. The hypokalemic effects, effectiveness in controlling BP, and cost of several alternate diuretic regimens were evaluated. Prevalences of serum K+ values less than 3.5 mEq/L were as follows for the various regimens: hydrochlorothiazide, 50 mg daily, 11.0% (n = 500); chlorthalidone, 25 mg daily, 8.1% (n = 37); triamterene, 100 mg, plus hydrochlorothiazide, 50 mg daily, 5.3% (n = 357); hydrochlorothiazide, 25 mg daily, 2.2% (n = 183); and furosemide, 40 mg daily, 3.5% (n = 284). In paired studies comparing hydrochlorothiazide with alternate diuretic regimens, potassium conservation was comparable with furosemide, the triamterene/hydrochlorothiazide combination, the spironolactone/hydrochlorothiazide combination, and adding potassium, 37 mEq daily. All alternate diuretic regimens were as effective as hydrochlorothiazide in controlling BP. Furosemide reduced serum glucose and calcium levels compared with hydrochlorothiazide. When these factors and costs are considered, furosemide appears to be the most cost-effective alternative in patients with hypertension in whom intolerable side effects or hypokalemia develops while taking hydrochlorothiazide.

Dose-related influence of indomethacin on parathyroid hormone-stimulated adenosine 3',5'-monophosphate release from the perfused rat hindlimb.

We examined the effect of indomethacin (INDO) on PTH-stimulated cAMP release from the perfused rat hindlimb. Since this preparation has not been used previously to study the effects of PTH, we first determined the dose-response curve for cAMP release in response to the 1-34 fragment of synthetic bovine PTH. cAMP release peaked 3-6 min after the PTH bolus and declined gradually toward baseline, even with sustained PTH infusion. The rate of cAMP release was directly related to the PTH dose. The lowest PTH priming dose that provoked a significant increase in cAMP release was 0.6 IU. Maximal cAMP release, occurring in response to a PTH priming dose of 30 IU, was 3- to 4-fold greater than baseline. PTH caused no increase in cAMP release from or the cAMP content of isolated skeletal muscle in vitro, suggesting that cAMP released from the hindlimb in response to PTH is derived solely from bone. PTH-stimulated cAMP release was unaltered by pretreatment of the intact rat with 2 mg/kg INDO, a dose that blocks prostaglandin synthesis. In contrast, PTH-stimulated cAMP release was significantly attenuated by pretreatment with 75 mg/kg INDO. The effect was not dependent on the addition of drug to the perfusate and was not altered by thyroparathyroidectomy at the time of INDO administration. We conclude that 1) the perfused rat hindlimb can be used to examine PTH effects on bone; 2) 2 mg/kg INDO has no effect on PTH-stimulated cAMP release from the perfused rat hindlimb; and 3) INDO in high doses blunts PTH activation of adenylate cyclase.

Parathyroid-hormone-induced metabolic alkalosis in dogs.

We examined the effect of parathyroid hormone (PTH), administrated for 24-48 h, on acid-base homeostasis in dogs. Parathyroid extract (PTH), 15 IU/kg/day, given subcutaneously, caused metabolic alkalosis (control vs. experimental; mean +/- SEM): plasma HCO3, 21.3 +/- 0.3 vs. 24.2 +/- 0.5 mEq/l (p less than 0.001); plasma H+, 37.7 +/- 1.1 vs. 35.7 +/- 1.4 nEq/l (p less than 0.05), and net acid excretion, 48.6 +/- 2.0 vs. 65.1 +/- 4.0 mmol/day (p less than 0.01). PTH administered by continuous intravenous infusion had similar effects (control vs. experimental): plasma HCO3, 21.4 +/- 0.4 vs. 23.6 +/- 0.7 mEq/l (p less than 0.001) and net acid excretion, 54.0 +/- 3.5 vs. 68.3 +/- 5.7 mmol/day (p less than 0.05). PTH, 8 IU/kg/day, had qualitatively similar but quantitatively less profound consequences. Bicarbonaturia was not observed in any group. The effects of PTH were similar in adrenalectomized dogs maintained on hormone replacement. Indomethacin (150 mg/day) prevented the renal effects of PTH so that no increase in net acid secretion occurred. However, metabolic alkalosis still developed: control vs. experimental plasma HCO3, 21.8 +/- 0.5 vs. 23.9 +/- 0.5 mEq/l (p less than 0.001). Dichloromethanediphosphonate blunted both the renal and nonrenal effects of PTH, such that hypercalcemia, metabolic alkalosis and increased net acid excretion were quantitatively less and delayed in onset. In summary, PTH administration for 24-48 h causes metabolic alkalosis in dogs, the result of renal and nonrenal mechanisms.

Perimolysis: unveiling the surreptitious vomiter.

Perimolysis is a dental condition linked to chronic regurgitation. When perimolysis is found in the patient who denies vomiting, one must suspect anorexia nervosa, a disorder with a high rate of morbidity and mortality. The dental literature has not provided guidelines for confirming the suspicion of surreptitious vomiting. The purpose of this case report is to describe our approach, using simple blood and urine studies, which establishes whether a patient who has perimolysis but denies vomiting is a surreptitious vomiter.

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.

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.

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.

Penicillinase-resistant penicillin/gentamicin synergism. Effect in patients with Staphylococcus aureus bacteremia.

Gentamicin sulfate has been shown to enhance the effects of penicillinase-resistant penicillins against clinical isolates of Staphylococcus aureus in vitro, but the relevance of this observation to bacteremic patients is unclear. Therefore, serum samples from 14 patients with staphylococcal bacteremia were tested for growth inhibitory and bactericidal effects against the patients' own pathogen while they received a penicillinase-resistant penicillin alone, and again when gentamicin was added to the therapeutic regimen. Addition of gentamicin in vivo was associated with slight improvement in growth inhibitory activity but it caused profound increases in serum bactericidal activity. This effect could not be attributed to higher serum levels of penicillinase-resistant penicillin during gentamicin administration. Addition of gentamicin to penicillinase-resistant penicillin can lead to marked improvement in a patient's serum bactericidal activity against his own staphylococcal pathogen, and should be considered for any patient who does not respond to more conventional therapy.