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M L Halperin

Publications and source records attributed to M L Halperin.

At least 91 records · Page 5Linked to original sources
PubMed1994

Disorders of potassium homeostasis: an approach based on pathophysiology.

Disorders of potassium (K+) homeostasis are frequently encountered in clinical medicine and may have serious sequelae, particularly cardiac arrhythmias. Since long-term K+ balance depends on regulation of renal excretion of K+, the focus of this paper is to provide a novel way to analyze the K+ excretory process at the bedside in a noninvasive fashion. A fundamental aim was to incorporate recent new advances in K+ physiology to the clinical analysis of K+ disorders. In so doing, we have tried to replace eponyms and largely descriptive terms with more specific, but hypothetical pathophysiologic diagnoses. The approach we used focuses on an assessment of the components of K+ excretion in vivo. If the rate of excretion of K+ differs from the "expected" value for the stimulus of hypokalemia or hyperkalemia, one should determine whether the fault is with the flow rate and/or the [K+] in the terminal cortical collecting duct. The former is influenced primarily by the rate of excretion of osmoles when antidiuretic hormone acts, whereas the [K+] in the cortical collecting duct is determined by factors that modulate rate of electrogenic reabsorption of Na+ in that segment and its conductance for K+. By examining the extracellular fluid (ECF) volume status, the plasma renin activity, and the renal response to the induction of ECF volume contraction, we attempted to deduce whether the change in electrogenic reabsorption of Na+ was due to an altered Na+ transport or apparent permeability to chloride in the cortical collecting duct. We believe that an approach which draws heavily on pathophysiology can be of practical use at the bedside and, in addition, indicate areas in which more research could be fruitful. To illustrate these points, two clinical cases with hypokalemia and two with hyperkalemia were analyzed. Nevertheless, it is important to emphasize that the approach provided is speculative.

Adolescent↗
PubMed1994

What is responsible for the diurnal variation in potassium excretion?

Potassium excretion exhibits a diurnal pattern, with most excretion occurring close to noon in humans. Each component of the K+ excretion rate [urinary K+ concentration ([K+]) and flow rate] was measured and back-calculated to reflect events in the cortical collecting duct (CCD). Our purpose was to determine to what extent each component contributed to this diurnal variation in each 2-h portion of the day. In humans, K+ excretion rose threefold from nadir (0600 h) to peak (1200-1400 h), 18 h after the principal intake of K+. The variation in K+ excretion was due almost exclusively to changes in [K+] in the terminal CCD ([K+]CCD) rather than via changes in flow rate. In rats, the bulk of K+ excretion occurred shortly after eating. Both components of K+ excretion rose after meals; the rise in the [K+]CCD (3.3-fold) predominated at earlier times, and the rise in flow rate occurred later and was primarily a result of a higher rate of excretion of urea. The rise in [K+]CCD did not correlate with aldosterone levels or administration. A very large rise in the [K+]CCD only occurred in the presence of bicarbonaturia; the transtubular potassium concentration gradient was now close to 15 in the morning and evening.

Acetazolamide↗
PubMed1994

Potassium excretion: a story that is easy to digest.

The aim of this article is to consider how a large quantity of potassium (K+) can be excreted without the development of hyperkalemia. The hypothesis will focus on interactions between K+ and HCO3- primarily within the kidneys. It is speculated that the absorption of K+ from the gastrointestinal tract is accompanied by an initial addition of HCO3- to the body; this in turn could, via intrarenal events, promote the delivery of HCO3- to the cortical collecting duct (CCD), where interactions may permit the development of a very high rate of excretion of K+. To test one portion of this hypothesis, studies were performed in sheep because they normally consume approximately 10-fold more K+ per kilogram body weight than do humans. In the absence of a significant degree of anabolism, there is only a limited potential to shift K+ acutely into cells. Hence, an extremely large capacity to excrete K+ is required to avoid a severe degree of hyperkalemia. The excretion of K+ depends primarily on the ability to have a sustained rise in the (K) in each liter of luminal fluid exiting the CCD to very high levels and to have a large number of liters of fluid exit the terminal CCD while antidiuretic hormone is acting. A reasonable approximation of this CCD flow rate can be obtained by examining the osmole excretion rate when ADH acts. Because these sheep excreted 1,650 mosmol (2 L x 827 mosm/kg H2O) per day, a minimum estimate for volume delivery out of the CCD is 5 to 6 L/day.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Hyperkalemia with mild ECF volume contraction: studies to provide a possible physiologic interpretation.

A 30-y-old female presented with a history of hypertension and a modest degree of hyperkalemia. There was a mild degree of contraction of her ECF volume on clinical examination, with elevated levels of renin and aldosterone in plasma. No causes for secondary hypertension were found. Laboratory investigations revealed a slightly reduced glomerular filtration rate (GFR) and a subnormal kaliuretic response to exogenous mineralocorticoids. When a further degree of ECF volume contraction was induced, she was unable to conserve Na+ and Cl- appropriately. Moreover, expansion of the ECF volume led to a significant suppression of the levels of both renin and aldosterone in plasma. We speculate that these findings could be explained by a diminished net rate of reabsorption of Na+ in the cortical collecting duct. Such a reduction could lead to a diminished generation of an electrical gradient to favour the net secretion of K+ and lead to hyperkalemia with renal salt wasting. The resultant contraction of the extracellular fluid volume with the release of renin and aldosterone (and probably other vasoactive hormones) might have predisposed her to hypertension. This hypothesis was supported by the finding that NaCl supplements led to a significant drop in her blood pressure. This case could represent a new syndrome of hyperkalemia and "salt sensitive" hypertension.

Adult↗
PubMed1994

Does saline "correct" the abnormal mass balance in metabolic alkalosis associated with chloride depletion in the rat?

An elevated plasma pH and bicarbonate are the clinical hallmarks of metabolic alkalosis. Nevertheless, to fully define its pathophysiology, one needs a quantitative interpretation of events in 3 areas - the ECF, ICF, and urine. Accordingly, our purpose was to study mass balance in Cl--depletion metabolic alkalosis with normal initial balance for Na+ and K+. In the 20 h following the "exchange" of Cl- (loss, 2455 mumol) and HCO(3-) (gain, 2455 mumol), only 334 mumol HCO(3-) remained in the ECF and 337 mumol were excreted. The remaining 1784 mumol disappeared primarily via titration because 3051 mueq of endogenous anions were produced and excreted largely with K+. Accordingly, metabolic alkalosis was associated with a deficit rather than a surplus of HCO(3-). To reflect the shift of H+ into cells driven by the exit of K+, the cumulative deficit of Cl- was replaced as KCl or NaCl. The fall in plasma [HCO(3-)] was larger in the KCl group (13.2 vs. 9.4 mmol/L); it was largely due to H+ exit from cells; in contrast, disappearance of HCO(3-) from the ECF was due to new endogenous acid production in the NaCl group. Thus, there was an overall deficit of HCO(3-) in metabolic alkalosis associated with KCl depletion (extracellular alkalosis and intracellular acidosis); processes in the ICF were not corrected by NaCl.

Alkalosis↗
PubMed1994

Metabolic alkalosis mimicking the acute sequestration of HCl in rats: bucking the alkaline tide.

Loss or sequestration of HCl induces an acute metabolic alkalosis. The purpose of these experiments was to examine the renal handling of bicarbonate (HCO3-) in awake, euvolemic rats to determine if a significant degree of bicarbonaturia would develop because, if present, it could lead to large negative balances for sodium (Na+) and/or potassium (K+). Metabolic alkalosis was induced acutely by creating the equivalent of an acute and large loss of HCl; the net effect was to lose Cl- and gain equimolar HCO3- in rats that were in Na+ and K+ balance. A loop diuretic induced the loss of 1,860 mumol Na+, 842 mumol K+ and 2,444 mumol Cl- over a 4-h period; the loss of Cl- was replaced as its Na+ or K+ salt by infusing equivalent amounts of NaHCO3 and KHCO3 (ultimately, a "simple exchange" of 2,444 mumol of HCO3- for Cl-). Metabolic alkalosis was sustained for 4 h (mean plasma [HCO3-] = 43 mmol/L); there was a parallel fall in the plasma [Cl-]. From a renal perspective, the fractional excretion of HCO3- was only 0.4%. This adaptation could be viewed as potentially life-saving, because excretion of NaHCO3 would result quickly in a severe reduction in ECF volume and metabolic acidosis and, in addition, in a severe degree of K(+)-depletion.

Alkalosis↗
PubMed1993

Can insulin administration cause an acute metabolic acidosis in vivo? An experimental study in dogs.

Insulin is the cornerstone of therapy for diabetic ketoacidosis because it causes the rate of ketoacid production to fall; this action takes several hours to occur. Insulin also causes H+ to be transported from the intracellular fluid to the extracellular fluid in vitro. The purpose of this study was to determine if insulin led to the acute export of H+ from the intracellular fluid in vivo. If so, we wished to determine if this also occurred during chronic metabolic acidosis, to quantitate the magnitude of the H+ shift, and to evaluate the mechanisms involved. The administration of low- or high-dose insulin to normal dogs and high-dose insulin to dogs with chronic metabolic acidosis caused the concentration of bicarbonate in plasma to decline by close to 3 mmol/l. The PCO2 fell by close to 15% in all three groups of dogs, so one component of the fall was due to hyperventilation. As the pH of blood did not change, a primary metabolic acidosis also occurred. The fall in bicarbonataemia was not due to net accumulation of organic acids or to a loss of bicarbonate or organic anions in the urine. Taken together, insulin, when given at doses used to treat diabetic ketoacidosis, might induce a significantly greater degree of acidaemia in the extracellular fluid acutely after it is given.

Acidosis↗
PubMed1993

Kaliuretic response to aldosterone: influence of the content of potassium in the diet.

The excretion of potassium (K+) decreased by 50% (30 v 63 mEq/d, P < .01) when subjects consumed a diet that was low in K+ for 3 days. Although part of this conservation of K+ was achieved in part by suppressing the release of aldosterone, nevertheless providing exogenous mineralocorticoids did not lead to a large kaliuresis when there was a modest degree of K+ depletion. Accordingly, the purpose of this study was to evaluate possible mechanisms for this antikaliuretic response to mineralocorticoids. The renal handling of K+ was examined by independent analysis of the two factors that influence its excretion, the driving force to secrete K+ and the urine volume. This driving force is reflected in a noninvasive fashion by the transtubular [K+] gradient (TTKG). Stimuli to increase the rate of excretion of K+ in subjects on a normal and a low-K+ diet included the administration of 200 micrograms fludrocortisone (9 alpha F), the induction of a high urine flow rate (9 alpha F+furosemide), the induction of bicarbonaturia (9 alpha F+acetazolamide), and the excretion of Cl(-)-poor urine (< 15 mEq/L). On the low-K+ diet, the peak value for the TTKG 3 to 4 hours after 9 alpha F was less than half that while on the normal diet (6.4 v 14, P < 0.01). In contrast, the TTKG was not significantly different on either diet when there was bicarbonaturia or the excretion of a Cl(-)-poor urine (18 v 17 and 17 v 16, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetazolamide↗
PubMed1993

Relative rates of appearance of nitrogen and sulphur: implications for postprandial synthesis of proteins.

The purpose of this study was to gain insights on the temporal fate of proteins based on the rate of appearance of waste products of nitrogen (urea) and sulphur (sulphate) metabolism. Urine was collected every 2 h from 25 normal subjects to measure the rates of excretion of urea, creatinine, and sulphate throughout the 24-h cycle. Samples of blood and urine were also obtained over a 4-h period from 10 subjects who consumed a mixed meal containing 0.4 g protein/kg body weight to obtain information on the relative rates of degradation of amino acids with and without sulphur in a noninvasive fashion. The daily excretion (mean +/- SEM) of urea, creatinine, and sulphate was 396 +/- 28, 14 +/- 0.4, and 15 +/- 0.6 mmol, respectively; the molar sulphate/nitrogen (S/N) ratio was 2.0 +/- 0.1%. There were relatively minor (< 20%) excursions in the rate of excretion of urea and creatinine in any 2-h period as compared with the corresponding 24-h rate; the concentrations of urea and creatinine in plasma also varied < 20% throughout the day. Only 23% of the nitrogen in protein in the standard meal appeared as urea in the 210 min after this meal was consumed. The small changes in the rate of appearance of urea and creatinine imply that the oxidation of amino acids was spread out over the day.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Renal potassium wasting in the absence of aldosterone. Insights into the mechanism for the secretion of potassium.

This report focuses on the possible pathophysiology of a renal lesion that led to hypokalemia and the excessive excretion of potassium (K+) in a 2.5-year-old child. The rate of excretion of K+ was high, largely the result of forces leading to a very high concentration of K+ in the lumen of the terminal cortical collecting duct as revealed by very high values for the transtubular K+ concentration gradient (TTKG was 25 +/- 3). The TTKG was high despite undetectable levels of aldosterone in plasma and the absence of bicarbonaturia. The level of renin in plasma was not low and there was a tendency to contraction of the ECF volume when dietary intake was curtailed. These findings provided the basis to speculate that the underlying lesion might be a lower than normal 'permeability' of the cortical collecting duct for chloride.

Aldosterone↗
PubMed1993

A method to evaluate renal ammoniagenesis in vivo.

A reduced rate of excretion of ammonium (NH4+) can be due to either a low rate of production and/or a low transfer of NH4+ to the urine. At present, there is no way to obtain a measure of the rate of production of NH4+ in vivo without invasive techniques. Hence, our purpose was to develop a non-invasive test to reflect this rate in vivo. Conditions were selected so that there would be a wide range in the rate of production of NH4+ in the kidney. Initial experiments were performed in dogs because both the rate of production and excretion of NH4+ could be measured directly. The rate of excretion of NH4+ in normal dogs on their usual diet varied over a wide range and was not directly related to its rate of production. Nevertheless, 59% of the NH4+ produced was excreted when the pH of urine was < 6 or when the rate of flow of urine was high (after administering a loop diuretic). To produce a urine with a low pH and high flow rate in humans, a loop diuretic (20 mg of furosemide) and a mineralocorticoid (200 micrograms of fludrocortisone) were given. The pH of urine fell to 5.1 and the rate of urine flow rose to 8 ml/min; the rate of excretion of NH4+ rose from 21 to 33 mumol/min when the urine flow rate rose.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Should the urine PCO2 or the rate of excretion of ammonium be the gold standard to diagnose distal renal tubular acidosis?

A high rate of excretion of ammonium (NH4+) during chronic metabolic acidosis should rule out the diagnosis of distal renal tubular acidosis (RTA). Bearing this in mind, the purpose of this report is to demonstrate that a low urine minus blood PCO2 difference in alkaline urine (U-B PCO2) is a less reliable indicator of the diagnosis of distal RTA. The patient who is the subject of this report sniffs glue on a chronic, but intermittent basis. He presented with metabolic acidosis (pH 7.20; bicarbonate, 10 mmol/L) and an anion gap in plasma of 20 mEq/L. The urine anion gap (-14 mEq/L) and osmolal gap (185 mmol/L [mOsm/kg] H2O) suggested that there was a high, rather than a low, rate of excretion of NH4+. This was confirmed by direct measurement of NH4+ in the urine (101 mumol/min). The high rate of excretion of NH4+ suggested that the metabolic acidosis was due, in large part, to an abnormally high rate of production of acid (hippuric acid, because the rate of excretion of hippurate was 76 mumol/min). The U-B PCO2 was low (10 mm Hg) on the second hospital day, after the acidosis was corrected. Potential reasons for the discrepancy between the high rate of excretion of NH4+ and the low U-B PCO2 are discussed.

Acidosis, Renal Tubular↗
PubMed1992

Might distal renal tubular acidosis be a proximal tubular cell disorder?

Incomplete renal tubular acidosis (RTA) and overt distal RTA may be different stages of the same underlying pathophysiology in certain individuals. The rationale that draws these conditions together is the relatively alkaline pH of the urine, hypocitraturia, and a possible familial association. The rate of excretion of ammonium (NH4+), on the other hand, suggests that these conditions stem from fundamentally different lesions. To explain this difference, we suggest that two possible disorders may result in the evolution from incomplete RTA to overt distal RTA. One subgroup could have gradient-limited distal RTA, while the other subgroup may have a lower pH of the intracellular fluid of the proximal convoluted tubular epithelium. Indices of proximal intracellular pH (rates of excretion of NH4+, NH3, and citrate) were culled from the literature spanning the years 1959 to 1991 on patients with incomplete RTA and overt distal RTA. Three points emerge: (1) the rate of excretion of NH4+ was lower in patients with overt distal RTA than in normals following an acute acid load (23 +/- 1 v 49 +/- 3 mumol/min); (2) the concentration of NH3 in the urine was almost 25-fold higher in incomplete RTA than in normals (69 +/- 14 v 3 +/- 0.4 nmol/min); and (3) in incomplete RTA, the pH of the urine fell to very low values (4.9 +/- 0.1) when high urine flows were induced with furosemide. The low pH of the urine would therefore suggest that many of these patients do not gradient-limited distal RTA, but more likely have proximal renal epithelial cell acidosis. We hypothesize that this high rate of excretion of NH4+ and low rate of excretion of citrate in the absence of acidosis or hypokalemia is consistent with proximal cell acidosis. To explain a transition from incomplete RTA to overt distal RTA, we speculate that toxicity of high concentrations of NH3 in the medullary interstitium as well as nephrolithiasis and nephrocalcinosis due to low urinary citrate and possibly an alkaline medullary interstitium may lead to damage of structures in this region.

Acid-Base Equilibrium↗
PubMed1992

Energy turnover and the production of ammonium by the kidney: effect of hypernatremia.

The purpose of this study was to explore further the relation between the rates of oxygen consumption and ammonium (NH4+) production in the kidney during chronic metabolic acidosis. The experimental model was the dog with chronic metabolic acidosis because of the extensive background literature in this species. Chronic metabolic acidosis was produced by the ingestion of 10 mmol NH4Cl/kg body weight for 5 days. There was a significant increase in the rate of oxygen extraction when hypernatremia was present. Despite this rise in the rate of oxygen consumption, there was no increase in the rate of NH4+ production nor in the rate of glutamine extraction. These data suggest that hypernatremia might prevent a further augmentation in glutamine extraction when the rate of oxygen consumption rises. In addition, a larger proportion of the NH4+ produced was excreted in the urine during hypernatremia. This increase was associated with a rise in the urine flow rate, but not with a fall in urine pH.

Acidosis↗