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M L Halperin

Publications and source records attributed to M L Halperin.

At least 55 records · Page 3Linked to original sources
PubMed1999

15N enrichment of ammonium, glutamine-amide and urea, measured via mass isotopomer analysis of hexamethylenetetramine.

Ammonium is an important intermediate of protein metabolism and is a key component of acid-base balance. Investigations of the metabolism of NH(4)(+) in vivo using isotopic techniques are difficult because of the low concentration of NH(4)(+) in biological fluids and because of frequent artifactual isotopic dilution of the enrichment of NH(4)(+) during the assay. A new gas chromatographic mass spectrometric method was designed to monitor the (15)N enrichment and concentration of NH(4)(+) in vivo. These are both calculated from the mass isotopomer distribution of hexamethylenetetramine (HMT) formed by reacting NH(4)(+) with formaldehyde. The enrichment of NH(4)(+) is amplified four times since the HMT molecule contains four atoms of nitrogen derived from NH(4)(+). This allows the measurement of low (15)N enrichment of NH(4)(+), down to 0.1%. (15)N enrichment of urea and of the amide N of L-glutamine are measured by enzymatic release of NH(4)(+) and conversion of the latter to HMT. These new techniques facilitate in vivo investigations of the metabolism of NH(4)(+) and related compounds.

Amides↗
PubMed1999

Distal renal tubular acidosis and high urine carbon dioxide tension in a patient with southeast Asian ovalocytosis.

Southeast Asian ovalocytosis (SAO) is the best-documented disease in which mutation in the anion exchanger-1 (AE1) causes decreased anion (chloride [Cl-]/bicarbonate [HCO3-]) transport. Because AE1 is also found in the basolateral membrane of type A intercalated cells of the kidney, distal renal tubular acidosis (dRTA) might develop if the function of AE1 is critical for the net excretion of acid. Studies were performed in a 33-year-old woman with SAO who presented with proximal muscle weakness, hypokalemia (potassium, 2.7 mmol/L), a normal anion gap type of metabolic acidosis (venous plasma pH, 7. 32; bicarbonate, 17 mmol/L; anion gap, 11 mEq/L), and a low rate of ammonium (NH4+) excretion in the face of metabolic acidosis (26 micromol/min). However, the capacity to produce NH4+ did not appear to be low because during a furosemide-induced diuresis, NH4+ excretion increased almost threefold to a near-normal value (75 micromol/L/min). Nevertheless, her minimum urine pH (6.3) did not decrease appreciably with this diuresis. The basis of the renal acidification defect was most likely a low distal H+ secretion rate, the result of an alkalinized type A intercalated cell in the distal nephron. Unexpectedly, when her urine pH increased to 7.7 after sodium bicarbonate administration, her urine minus blood carbon dioxide tension difference (U-B Pco2) was 27 mm Hg. We speculate that the increase in U-B Pco2 might arise from a misdirection of AE1 to the apical membrane of type A intercalated cells.

Acidosis, Renal Tubular↗
PubMed1998

Potassium.

In a logical, stepwise approach to patients presenting with hypokalaemia or hyperkalaemia the clinician must first recognise circumstances in which the dyskalaemia represents a clinical emergency because therapy then takes precedence over diagnosis. If a dyskalaemia has been present for a long time, there is an abnormal renal handling of K+. The next step to analyse is the rate of excretion of K+ and, if necessary, its two components (urine flow rate and K+ concentration in the cortical collecting duct [CCD]) analysed independently. If the K+ concentration in the CCD is not in the expected range, its basis should be defined at the ion-channel level in the CCD from clinical information that can be used to deduce the relative rates of reabsorption of Na+ and Cl- in the CCD. This analysis provides the basis for diagnosis and may indicate where non-emergency therapy should then be directed.

Diagnosis, Differential↗
PubMed1998

Hyperglycemia during normothermic cardiopulmonary bypass: the role of the kidney.

BACKGROUND: Hyperglycemia commonly occurs during cardiopulmonary bypass. We studied the quantitative impact of glucose input and its renal excretion on hyperglycemia during cardiopulmonary bypass. METHODS: The quantity of glucose infused and metabolite and hormone concentrations in plasma, as well as oxygen consumption, carbon dioxide production, and renal glucose excretion, were determined before, during, and after cardiopulmonary bypass in 8 patients. RESULTS: Hyperglycemia (14 to 29 mmol/L) was accompanied by an increase in plasma insulin levels. The degree of hyperglycemia was directly related to the amount of glucose infused. The rate of oxygen consumption did not decrease and the rate of urea appearance (gluconeogenesis) did not rise. Despite a very high filtered load of glucose, there was very little glucosuria, indicating a markedly enhanced renal absorption of glucose. CONCLUSIONS: Hormonal and metabolic factors permit the development of hyperglycemia during cardiopulmonary bypass but its severity depends on the quantity of glucose infused and, what appears to be a new finding, a markedly enhanced renal reabsorption of filtered glucose. Thus the kidney plays an important role in the development of severe hyperglycemia during cardiopulmonary bypass.

Absorption↗
PubMed1998

Minimum urine flow rate during water deprivation: importance of the permeability of urea in the inner medulla.

We evaluated whether altering the rate of excretion of sodium (Na) and chloride (Cl) when antidiuretic hormone (ADH) acts would cause urea to behave as an 'effective' or 'ineffective' urinary solute. Urine composition was compared to that in the excised papillary tip in rats treated with DDAVP while on a normal or a low electrolyte diet; half the rats were given a urea load. Studies were also carried out in humans who were water restricted for 12 to 16 hours and given DDAVP. One group had a high rate of NaCl excretion induced by a thiazide diuretic, while the other group consumed a low salt diet to decrease the rate of excretion of electrolytes. Urea (3 mmol/kg) was ingested after the control urine samples were collected. On the high salt protocols, the urine flow rate was directly proportional to the rate of excretion of electrolytes ('non-urea' osmoles) and there was no change in the 'non-urea' osmolality despite large changes in Na and Cl excretion rates. After urea was administered, there was no change in urine flow rate, 'non-urea' osmolality, or 'non-urea' osmole excretion rate, whereas the urinary urea concentration, urine osmolality and the rate of excretion of urea were higher. The papilla of the salt-loaded rats had a similar urea concentration to that in the urine. In contrast, in the low electrolyte excretion protocols, the sum of the concentrations of 'non-urea' osmoles in the urine was much lower than that in the excised papilla, and the converse applied to urea. Similar changes were observed in the composition of the urine in human subjects with high and low rates of excretion of electrolytes. We conclude that urea appears to be an 'ineffective' urine osmole when there is a high rate of salt excretion, whereas urea is an 'effective' osmole when there is a low rate of excretion of electrolytes.

Adolescent↗
PubMed1998

Physiological disposal of the potential alkali load in diet of the rat: steps to achieve acid-base balance.

The purpose of this study was to provide a better understanding of the physiological role of endogenous net organic acid production in rats consuming their usual diet. Balance studies were performed over 24 h, and urine was collected in the day and night portions of the diurnal cycle. A supplemented low-electrolyte diet(LED) was fed to determine whether urinary organic anions were identical to those in the diet. A titration procedure was developed to determine the pK of titratable groups in the urine of rats studied with and without an acid load. Although normal rats excreted net acid (NAE), the latter was inversely related to the amount of food consumed. The rates of excretion of bicarbonate (HCO3), citrate, unmeasured organic anions, and NH+4 were higher in the night portion of the diurnal cycle. NAE rose dramatically when alkali intake was decreased by consuming the LED. Dietary and urinary organic anions were not identical because rats fed the LED supplemented with potassium citrate excreted <10% of this alkali load as citrate and <25% as HCO3. In the 24 h after 3,000 ¿mol NH4Cl was given intraperitoneally, H+ did not appear to be retained, yet NAE rose by only close to 2,000 ¿eq. The rate of excretion of titratable groups with a pK in the 3 to 5 pH range fell by close to 1,000 ¿eq; most of these changes occurred in the first 7 h after NH4Cl was given. We conclude that rat chow provides a large net alkali load. There appear to be two types of endogenous acid production, a form associated with a rise in NAE (e.g., sulfuric acid) and dietary alkali-driven endogenous net acid production, which titrates this alkali. Renal excretion of organic anions makes these acids end products of metabolism.

Acid-Base Equilibrium↗
PubMed1998

Studies on the pathogenesis of hypokalemia in Gitelman's syndrome: role of bicarbonaturia and hypomagnesemia.

OBJECTIVE: Hypokalemia and renal potassium (K) wasting are hallmarks of the group of disorders called Bartter's syndrome. The presence of hypomagnesemia and a low rate of excretion of calcium are currently used to characterize a subgroup of these patients as having Gitelman's syndrome (GS) in which the molecular lesion is a defect in the thiazide-sensitive NaCl cotransporter in the distal convoluted tubule. This study was undertaken to examine whether bicarbonaturia or hypomagnesemia exacerbates the kaliuresis in patients with GS. METHODS: Six patients with most of the diagnostic features of GS were examined. To examine the role of bicarbonaturia, the transtubular K concentration gradient (TTKG) was assessed before and after an oral load of NH4Cl which caused the urine pH to be < 6. To evaluate the role of hypomagnesemia, the TTKG was examined after an infusion of enough magnesium (Mg) to achieve normal levels of Mg in plasma for close to 24 h. RESULTS: The TTKG remained very high even when the pH of the urine was < 6.0. An infusion of Mg caused the TTKG to approach expected values for hypokalemia in 4 of 6 patients. The infusion of Mg was extended in 1 patient who had a sustained high TTKG for 24 h; the TTKG remained elevated for 96 h despite normal plasma Mg levels. CONCLUSIONS: Bicarbonaturia does not play a critical role in maintaining the very high TTKG in these patients. The K wasting in 4 of 6 of these patients could largely be attributed to hypomagnesemia and/or Mg depletion. The plasma aldosterone level tended to be higher in patients who did not respond to the infusion of Mg. Therefore, these patients may not represent a homogeneous group with regard to the pathophysiology of their renal K wasting.

Adult↗
PubMed1998

Variations in plasma sodium concentration in post-operative patients depend on an electrolyte-free water balance, part of a tonicity balance.

BACKGROUND: There is an inverse relationship between changes in the concentration of sodium in plasma (PNa) and intracellular fluid (ICF) volume. Intakes and losses of sodium (Na), potassium (K) and water can be divided into two volumes: isotonic and electrolyte-free water (EFW). Calculations of these volumes assess a tonicity balance, a tonicity imbalance results in a change of PNa: when EFW is added to body fluids, PNa decreases. Moreover, the concept of EFW permits a good understanding of the renal contribution to the defence of body tonicity. PURPOSE: To illustrate that the measurement of a tonicity balance provides the best estimate of changes in PNa in an ICU setting. METHODS: Twenty-two patients were admitted to the Post-Operative Intensive Care Unit. We investigated how well changes in EFW balance correlated with PNa variations and what is the best formula to calculate EFW in this setting. RESULTS: PNa changes depend on EFW balance; there is no significant relationship with other classical factors such as urinary osmolality or Na-free water. CONCLUSION: The utility of a tonicity balance is demonstrated. A formula is derived facilitating at the bedside the prediction of changes in PNa following fluid therapy: PNa2 = [(PNa1.TBW) + balance (Na + K)]/[TBW + balance H2O]. PNa changes can be understood and/or modified exclusively by a careful measurement of intakes and losses of Na, K and water.

Female↗
PubMed1998

Prevention of acute hyponatremia by mannitol: an unanticipated mechanism.

PURPOSE: To evaluate the effectiveness and mode of action of the osmotic diuretic mannitol to prevent the development of acute hyponatremia in a setting designed to mimic the acute hyponatremia observed on the day of surgery. RESULTS: Hyponatremia (129+/-1 mM, fall of 10+/-1 mM, p <0.01) was induced by the intraperitoneal administration of half-isotonic saline plus DDAVP to rats (n = 8); hyponatremia was due to a positive balance of electrolyte-free water (EFW). Rats given mannitol (10 mmol/kg body wt) in addition to the hypotonic saline plus DDAVP had only a minor degree of hyponatremia (plasma [Na+] 136+/-1 mM, fall 3+/-2 mM, p >0.05). All the mannitol given was excreted over the 16 h of observation, but the urine volume was not higher in these rats. The higher rate of excretion of EFW was due to a marked reduction in the rate excretion of Na+ with mannitol. This antinatriuresis was also present when mannitol was given intravenously. CONCLUSIONS: Although mannitol increased the excretion of EFW, the mechanism required an enhanced renal reabsorption of Na+ rather than an increase in the urine flow rate.

Animals↗
PubMed1998

Acute hyponatremia in the perioperative period: insights into its pathophysiology and recommendations for management.

Our purpose is to review the topic of acute postoperative hyponatremia by focusing on pertinent aspects of the physiology of water and solute excretion. Four areas will be highlighted: an examination of the source of addition of electrolyte-free water, an exploration of the basis for the very large natriuresis that occurs during cerebral salt wasting following neurosurgery, possible reasons to explain why acute postoperative hyponatremia may pose a greater risk for young women [Ayus and Arieff 1996, Ayus et al. 1992, Arieff 1986, Wijdick et al. 1991], and issues related to treatment of acute hyponatremia.

Acute Disease↗
PubMed1998

[Hyponatremia, toward a logical approach: the balance of tonicity].

Derangements in plasma sodium concentration are best analyzed by carefully determining entries and output for water, sodium and potassium, that is, by calculating a tonicity balance. Five clinical hyponatremic examples are discussed: the beer drinker has a severe deficit in total body sodium: the elderly female patient treated with a thiazide needs to be firstly repleted in potassium; the hypertensive transplanted patient with a multidrug treatment requires an increase of the urinary electrolyte-free water which has been obtained by the oral administration of urea; the post-operative hyponatremic cases (cases 4 and 5) are complex and involve a desalination phenomenon. Close observation, repeated determinations of electrolytes in plasma, urine and entries, together with measurements of water input and output, will allow the tonicity balance of the patient to be understood and thus occasional tragedies such as observed in cases 4 and 5 to be prevented.

Adult↗
PubMed1997

Postoperative hyponatremia despite near-isotonic saline infusion: a phenomenon of desalination.

BACKGROUND: It is widely presumed that the development of postoperative hyponatremia (which may be severe) results from administration of hypotonic fluids while antidiuretic hormone is acting. OBJECTIVE: To show that hyponatremia would occur in patients 24 hours after surgery if only near-isotonic solutions are given and to evaluate the mechanisms responsible for hyponatremia in this setting. DESIGN: Prospective cohort study. SETTING: University medical center. PATIENTS: 22 women who were having uncomplicated gynecologic surgery with infusion of near-isotonic solutions only (sodium chloride, 154 mmol/L, or Ringer lactate [sodium, 130 mmol/L, and potassium, 4 mmol/L]). MEASUREMENTS: Plasma electrolyte levels were measured at the time of induction of anesthesia and 24 hours later. Data on the balance of water and electrolytes were obtained for the same 24-hours period. RESULTS: At the time of induction of anesthesia, the plasma sodium concentration was 140 +/- 1 mmol/L; 24 hours later, it decreased in 21 of 22 patients (mean decrease, 4.2 +/- 0.4 mmol/L [P < 0.001]; lowest level, 131 mmol/L in 2 patients). The urine remained hypertonic (peak sodium plus potassium concentration in urine, 294 +/- 9 mmol/L) in all patients for the first 16 hours after induction of anesthesia. CONCLUSIONS: Postoperative hyponatremia occurred within 24 hours of induction of anesthesia when only near-isotonic fluids were infused. Hyponatremia was generally caused by generation of electrolyte-free water during excretion of hypertonic urine-a desalination process. This electrolyte-free water was retained in the body because of the actions of antidiuretic hormone. If the pathophysiology of this hyponatremic state is understood, recommendations for its prevention and treatment can be deduced.

Adult↗
PubMed1997

Renal tubular acidosis and osteopetrosis with carbonic anhydrase II deficiency: pathogenesis of impaired acidification.

Renal tubular acidosis with osteopetrosis is an autosomal recessive disorder due to deficiency of carbonic anhydrase II (CAII). A 3.5-year-old Egyptian boy with osteopetrosis and cerebral calcification has a persistent normal anion gap type of metabolic acidosis (plasma pH 7.26) and a mild degree of hypokalemia. A baseline urine pH was 7.0; ammonium (NH4+) excretion was low at 11 mumol/min per 1.73 m2; fractional excretion of bicarbonate HCO3 (FEHCO3) was high at 9% when plasma HCO3 was 20 mmol/l; citrate excretion rate was high for the degree of acidosis at 0.35 mmol/mmol creatinine. Intravenous administration of sodium bicarbonate led to a urine pH of 7.6, a FEHCO3 of 14%, a urine-blood PCO2 difference of 7 mmHg, NH4+ excretion fell to close to nil, and citrate excretion remained at 0.38 mmol/mmol creatinine. Intravenous administration of arginine hydrochloride caused the urine pH to fall to 5.8, the FEHCO3 to fall to 0, the NH4+ excretion rate to rise to 43 mumol/min per 1.73 m2, and citrate excretion to fall to < 0.01 mmol/mmol creatinine. These results show that our patient had a low rate of NH4+ excretion, a low urine minus blood PCO2 difference in alkaline urine, and a low urinary citrate excretion, but only when he was severely acidotic. He failed to achieve a maximally low urine pH. These findings indicate that his renal acidification mechanisms were impaired in both the proximal and distal tubule, the result of his CAII deficiency.

Acidosis, Renal Tubular↗
PubMed1997

A new classification for renal defects in net acid excretion.

The traditional classification of the group of disorders called renal tubular acidosis (RTA) into proximal and distal subclasses is based on which nephron segment is thought to have an abnormal function. Nevertheless, such a distinction may not be correct and also does not characterize the pathophysiology of the renal acidosis in each patient. In this article, we propose an alternative classification, one that is based on the component of net acid excretion that is abnormal. We also suggest expanding the definition of net acid excretion to include a term that describes the renal handling of metabolizable organic anions because their loss in the urine represents the loss of "potential bicarbonate." Because a low rate of excretion of ammonium (NH4+) is present in patients with both distal and isolated proximal RTA, our initial clinical step in patients with hyperchloremic metabolic acidosis (HCMA) is to evaluate the rate of excretion of NH4+. The basis for a low rate of excretion of NH4+ is shown by examining the urine pH. If the urine pH is low, further studies are performed to determine why the availability of NH3 is low; if the urine pH is high, further investigations are initiated to examine if the defect in H+ secretion involves the proximal or the distal nephron. Conversely, if the rate of excretion of NH4+ is high in a patient with HCMA, a component of the degree of acidosis could be attributable to a high rate of excretion of metabolizable organic anions. Case examples are provided to illustrate the approach and its implications for future molecular studies.

Acidosis, Renal Tubular↗
PubMed1997

Factors contributing to the degree of polyuria in a patient with poorly controlled diabetes mellitus.

Polyuria due to a glucose-induced osmotic diuresis is common in patients with hyperglycemia. This diuresis usually abates when the plasma glucose level approaches its renal threshold; the usual time course is less than 8 hours after commencing therapy. A 69-year-old man with non-insulin-dependent diabetes mellitus maintained hyperglycemia (540 mg/dL) and polyuria (4.7 L/24 hr) for 40 hours. Because there was no external supply of glucose, a balance study was conducted between the third and 40th hour after commencing treatment. In this interval, the overall concentration of glucose in the urine was less than 100 mmol/L and the urine osmolality was 378 mOsm/kg H2O. To evaluate the expected composition of the urine during a glucose-induced osmotic diuresis, urine was analyzed in normal rats infused with glucose plus urea and in untreated BB diabetic rats (plasma glucose and urea similar to that in our patient) as well as in 29 patients with hyperglycemia and polyuria. Glucose accounted for 60% of the urinary osmoles in rats and humans. Two subgroups of patients had a much lower urine glucose: one had an impaired concentrating ability (n = 6) and the other had an increased rate of renal glucose reabsorption (n = 5). In conclusion, in polyuria caused by hyperglycemia, the urine glucose should be 300 to 400 mmol/L with normal renal function. In the case we report, both the concentration of glucose and its excretion rate were much lower than expected with steady-state hyperglycemia (540 mg/dL) due to the high rate of excretion of NaCl, a concentrating defect, and excessive renal reabsorption of glucose.

Absorption↗
PubMed1997

Profound natriuresis, extracellular fluid volume contraction, and hypernatremia with hypertonic losses following trauma.

A young male sustained very serious head and soft tissue injuries in a motor vehicle accident (MVA). Three interesting problems developed in the sodium (Na) and water area in the second week in hospital. First, on day 11 after the MVA, his urine output increased to 3 liters per day; the urine osmolality was 1000 mOsm/kg H2O and Na and Cl were the principal urine osmoles. There appeared to be a salt wasting syndrome because he had a very large natriuresis (close to 900 mmol/24 hr) at a time when his central venous pressure was low. To help identify the nephron site responsible for a natriuresis with a high urine osmolality, additional studies were carried out in normal volunteers who took a loop or a thiazide diuretic on different occasions while ADH was acting. The pattern of natriuresis in the patient was similar to that after the thiazide but not the loop diuretic. The second problem concerned his hypernatremia (153 mM) because his urine was hypertonic and his intravenous therapy was isotonic saline. To explain hypernatremia while receiving more electrolyte-free water, we speculated that there was a water shift into cells resulting from particles generated and retained in his intracellular fluid. Given the large shift of water required, a lesion in muscle was suspected, a form of rhabdomyolysis. The third problem concerned the rate of catabolism of lean body mass. The metabolic consequences of generating these intracellular particles and the large amount of urea that was excreted could reflect a large degree of protein catabolism.

Adult↗
PubMed1997

Control of excretion of potassium: lessons from studies during prolonged total fasting in human subjects.

A deficit of K+ of close to 300 mmol develops in the first 2 wk of fasting, but little further excretion of K+ occurs, despite high levels of aldosterone and the delivery of ketoacid anions that are not reabsorbed in the distal nephron. Our purpose was to evaluate how aldosterone could have primarily NaCl-retaining, rather than kaliuretic, properties in this setting. To evaluate the role of distal delivery of Na+, four fasted subjects received an acute infusion of NaCl to induce a natriuresis. To assess the role of distal delivery of HCO3-, five fasted subjects were given an infusion containing NaHCO3. The natriuresis induced by an infusion of NaCl caused only a small rise in the rate of excretion of K+ (0.8 +/- 0.1 to 1.9 +/- 0.3 mmol/h); in contrast, when HCO3- replaced Cl- in the infusate, K+ excretion rose to 8.3 +/- 2.2 mmol/h, despite little excretion of HCO3- (urine, pH 5.8) and similar rates of excretion of Na+. The transtubular K+ concentration gradient was 19 +/- 3 with HCO3- and 6 +/- 2 with NaCl. We conclude that the infusion of NaHCO3 led to an increase in K+ excretion, likely reflecting an increased rate of distal K+ secretion. With a low distal delivery of HCO3-, aldosterone acts as a NaCl-retaining, rather than a kaliuretic, hormone.

Adult↗