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Biomedical subjects

Ira Kurtz

Publications and source records attributed to Ira Kurtz.

At least 19 recordsLinked to original sources
PubMed2006

Specificity of aminoacylase III-mediated deacetylation of mercapturic acids.

Trichloroethylene (TCE) and other halogenated alkenes are known environmental contaminants with cytotoxic and nephrotoxic effects, and are potential carcinogens. Their metabolism via the mercapturate metabolic pathway was shown to lead to their detoxification. The final products of this pathway, mercapturic acids or N-acetyl-l-cysteine S-conjugates, are secreted into the lumen in the renal proximal tubule. The proximal tubule may also deacetylate mercapturic acids, and the resulting cysteine S-conjugates are transformed by cysteine S-conjugate beta-lyases to nephrotoxic reactive thiols. The specificity and rate of mercapturic acid deacetylation may determine the toxicity of certain mercapturic acids; however, the exact enzymologic processes involved are not known in detail. In the present study we characterized the kinetics of the recently cloned mouse aminoacylase III (AAIII) toward a wide spectrum of halogenated mercapturic acids and N-acetylated amino acids. In general, the V(max) value of AAIII was significantly larger with chlorinated and brominated mercapturic acids, whereas fluorination significantly decreased it. The enzyme deacetylated mercapturic acids derived from the TCE metabolism including N-acetyl-S-(1,2-dichlorovinyl)-l-cysteine (NA-1,2-DCVC) and N-acetyl-S-(2,2-dichlorovinyl)-l-cysteine (NA-2,2-DCVC). Both mercapturic acids induced cytotoxicity in mouse proximal tubule mPCT cells expressing AAIII, which was decreased by an inhibitor of beta-lyase, aminooxyacetate. The toxic effect of NA-2,2-DCVC was smaller than that of NA-1,2-DCVC, indicating that factors other than the intracellular activity of AAIII mediate the cytotoxicity of these mercapturic acids. Our results indicate that in proximal tubule cells, AAIII plays an important role in deacetylating several halogenated mercapturic acids, and this process may be involved in their cyto- and nephrotoxicity.

Acetylation↗
PubMed2006

Is the osmotically inactive sodium storage pool fixed or variable?

Recently, there is renewed interest in the role of osmotically inactive Na(+) storage during Na(+) retention. Although it is well accepted that a portion of the total exchangeable Na(+) reservoir is osmotically inactive, there is current controversy as to whether the osmotically inactive Na(+) storage pool is fixed or variable during Na(+) retention. In this article, we analyze the current scientific evidence to assess whether the osmotically inactive Na(+) storage pool can be dynamically regulated. Our analysis supports the assertion that the osmotically inactive Na(+) storage pool is fixed rather than variable.

Animals↗
PubMed2006

Murine auditory brainstem evoked response: putative two-channel differentiation of peripheral and central neural pathways.

Standard noninvasive recordings of the auditory brainstem evoked response (ABR) from a single pair of obliquely oriented electrodes (typically midline vertex referenced to mastoid) confound inherently distinct signals propagating over peripheral and central neural pathways differing in location and spatial orientation. We describe here a technique for recording short-latency auditory evoked potentials that putatively differentiates peripheral and central neural activity in the mouse and rat. The technique involves recording from two orthogonally oriented electrode pairs using fast sample rates (100 k/s) to accurately measure differences in neural timing and waveform morphology. Electrodes oriented in a transverse plane (mastoid-to-mastoid) register an initial positive-going ABR peak (P1T) earlier than a series of peaks recorded from electrodes oriented along the midline (anterior and posterior to the inter-aural line). The absolute P1T latency is consistent with an origin in the primary auditory nerve, while the delayed midline latencies implicate activity farther along central neural pathways. Differences between these latencies (midline minus transverse) provide new and precise measures of central conduction time (CCT), which in one case is as brief as 0.10 ms. Results in wild type (WT) and knockout (KO) mice, as well as rats, show significant differences in absolute latencies as well as CCT.

Acoustic Stimulation↗
PubMed2006

Whole-body electrolyte-free water clearance: derivation and clinical utility in analyzing the pathogenesis of the dysnatremias.

The total exchangeable sodium (Na(e)), total exchangeable potassium (K(e)), and total body water (TBW) are the major determinants of the plasma water sodium concentration ([Na(+)](pw)). The relationship between [Na(+)](pw) and Na(e), K(e), and TBW was empirically determined by Edelman et al., where: [Na(+)](pw) = 1.11(Na(e) + K(e))/TBW - 25.6 (Eq. 1). According to Eq. 1, changes in the mass balance of Na(+), K(+), and H(2)O will therefore result in changes in the [Na(+)](pw). Historically, in evaluating the pathogenesis of the dysnatremias, free water clearance (FWC) and electrolyte-free water clearance (EFWC) have been used to evaluate the pathophysiology of the dysnatremias. However, such analyses are only valid when there is no concomitant input and non-renal output of Na(+), K(+), and H(2)O. Since the classic FWC and EFWC formulas fail to account for the input and non-renal output of Na(+), K(+), and H(2)O, these formulas cannot be used to evaluate the pathogenesis of the dysnatremias or to predict the directional change in the [Na(+)](pw). In this article, we have addressed this limitation by deriving a new formula, termed whole-body electrolyte-free water clearance (WB-EFWC), which calculates whole-body electrolyte-free water clearance for a given mass balance of Na(+), K(+), and H(2)O, rather than simply the urinary component (FWC, EFWC formulas). Unlike previous formulas, which consider only the renal component of electrolyte-free water clearance, WB-EFWC accounts for all sources of input and output of Na(+), K(+), and H(2)O, and will therefore be helpful in conceptually understanding the basis for changes in the [Na(+)](pw) in patients with the dysnatremias.

Body Water↗
PubMed2006

Use of base in the treatment of acute severe organic acidosis by nephrologists and critical care physicians: results of an online survey.

BACKGROUND: Acute severe metabolic acidosis associated with lactic acidosis or ketoacidosis can have severe detrimental effects on organ function, and might contribute to mortality. A general consensus exists that elimination of the cause of the acidosis is essential for treatment, but there is controversy concerning the use of base for the treatment of these disorders. Some physicians advocate administration of base when the acidosis is severe to prevent a decrease in cardiac output, whereas others oppose administration of base even when the acidosis is severe given the potential compromise of cardiac function. Nephrologists and critical care specialists are often the physicians developing recommendations for the treatment of severe acid-base disorders. METHODS: A short online survey of 20 questions was developed to assess the approach to the treatment of acute metabolic acidosis of program directors of fellowship programs and experts from the specialties of critical care and nephrology. RESULTS: Although there was variability among individual physicians from both specialties, a larger percentage of nephrologists than critical care physicians queried recommended administration of base for the treatment of lactic acidosis (86% vs 67%) and ketoacidosis (60% vs 28%). Also, critical care physicians in general used a lower level of blood pH when deciding when to initiate treatment. Of the physicians who gave base, most utilized sodium bicarbonate as the form of base given. CONCLUSIONS: The results of this survey indicate that the decisions whether to use base for the treatment of acute severe metabolic acidosis, and under which circumstances, vary among physicians, and indicate the need for further studies to develop evidence-based guidelines for therapy.

Acidosis↗
PubMed2006

True hyponatremia secondary to intravenous immunoglobulin.

Hyponatremia is characterized as either "true hyponatremia," which represents a decrease in the Na(+) concentration in the water phase of plasma, or "pseudohyponatremia," which is due to an increased percentage of protein or lipid in plasma, with a normal plasma water Na(+) concentration ([Na(+)]). Pseudohyponatremia is a known complication of intravenous immunoglobulin (IVIG). Because IVIG has been reported to result in post-infusional hyperproteinemia, IVIG-induced hyponatremia has been attributed to pseudohyponatremia. In this case report, we demonstrate that IVIG therapy can result in true hyponatremia, resulting from sucrose-induced translocation of water from the intracellular compartment (ICF) to the extracellular compartment (ECF), as well as the infusion of a large volume of dilute fluid, in patients with an underlying defect in urinary free water excretion.

Adult↗
PubMed2006

Fatal hyponatremia in a young woman after ecstasy ingestion.

BACKGROUND: A 20-year old, otherwise healthy, female college student presented in an unresponsive state with respiratory distress after ingesting ecstasy (3,4-methylenedioxymethamphetamine). She had initial plasma sodium concentration of 117 mmol/l. INVESTIGATIONS: Physical examination, blood chemistry panel, urinary osmolality and electrolytes, arterial blood gas, chest X-ray, and CT scan of the brain. DIAGNOSIS: Hyponatremia associated with noncardiogenic pulmonary edema and cerebral edema. MANAGEMENT: Administration of a total of 6.8 l of isotonic saline and 0.245 l of 3% hypertonic saline with sporadic administration of intravenous furosemide. The patient died approximately 12 h after admission.

Adult↗
PubMed2006

SLC4 base (HCO3 -, CO3 2-) transporters: classification, function, structure, genetic diseases, and knockout models.

In prokaryotic and eukaryotic organisms, biochemical and physiological processes are sensitive to changes in H(+) activity. For these processes to function optimally, a variety of proteins have evolved that transport H(+)/base equivalents across cell and organelle membranes, thereby maintaining the pH of various intracellular and extracellular compartments within specific limits. The SLC4 family of base (HCO(3)(-), CO(3)(2(-))) transport proteins plays an essential role in mediating Na(+)- and/or Cl(-)-dependent base transport in various tissues and cell types in mammals. In addition to pH regulation, specific members of this family also contribute to vectorial transepithelial base transport in several organ systems including the kidney, pancreas, and eye. The importance of these transporters in mammalian cell biology is highlighted by the phenotypic abnormalities resulting from spontaneous SLC4 mutations in humans and targeted deletions in murine knockout models. This review focuses on recent advances in our understanding of the molecular organization and functional properties of SLC4 transporters and their role in disease.

Amino Acid Sequence↗
PubMed2005

Quantitative interrelationship between Gibbs-Donnan equilibrium, osmolality of body fluid compartments, and plasma water sodium concentration.

The presence of negatively charged, impermeant proteins in the plasma space alters the distribution of diffusible ions in the plasma and interstitial fluid (ISF) compartments to preserve electroneutrality. We have derived a new mathematical model to define the quantitative interrelationship between the Gibbs-Donnan equilibrium, the osmolality of body fluid compartments, and the plasma water Na+ concentration ([Na+]pw) and validated the model using empirical data from the literature. The new model can account for the alterations in all ionic concentrations (Na+ and non-Na+ ions) between the plasma and ISF due to Gibbs-Donnan equilibrium. In addition to the effect of Gibbs-Donnan equilibrium on Na+ distribution between plasma and ISF, our model predicts that the altered distribution of osmotically active non-Na+ ions will also have a modulating effect on the [Na+]pw by affecting the distribution of H2O between the plasma and ISF. The new physiological insights provided by this model can for the first time provide a basis for understanding quantitatively how changes in the plasma protein concentration modulate the [Na+]pw. Moreover, this model defines all known physiological factors that may modulate the [Na+]pw and is especially helpful in conceptually understanding the pathophysiological basis of the dysnatremias.

Blood Proteins↗
PubMed2005

Time course of auditory impairment in mice lacking the electroneutral sodium bicarbonate cotransporter NBC3 (slc4a7).

Mice with a targeted disruption of the gene encoding the stilbene-insensitive electroneutral sodium bicarbonate cotransporter (NBC3; slc4a7) exhibit cochlear and retinal degeneration. To establish the progressive nature of sensory cells loss in slc4a7-/- deficient mice, we studied the morphology of cochleas of slc4a7-/- and slc4a7+/+ mice from postnatal day two (P2) to ninety (P90). Cell death was evaluated in slc4a7-/- cochleas using the TUNEL technique and caspase-3 immunoreactivity. The time course of NBC3 expression in the cochlea was assessed by immunohistochemistry using an antibody against NBC3. Between P2 and P8, slc4a7-/- mice cochlea exhibit normal morphology. There was a normal complement of inner and outer hair cells from the hook to the apical region. At P15, slc4a7-/- mice cochlea inner and outer hair cells were still present at the hook region, and vacuoles were seen underneath Hensen's cells. At P21, inner and outer hair cells were degenerated in this region. Between P30 and P90, there was a pronounced loss of hair cells and spiral ganglia neurons. Morphological analysis of the spiral ligament showed a progressive loss of type II and IV fibrocytes beginning at day 21. Transmission electron microscopy observations at P30 and P90 revealed that type II and IV fibrocytes showed shrinkage and vacuolization. In addition, hair cells were deteriorated with evidence of shrinkage and picnotic nuclei. TUNEL staining showed apoptotic cells at P8 in the organ of Corti at the basal region of the cochlea. At P15, caspase-3 immunoreactivity was present in supporting cells of the organ of Corti. NBC3 mild immunoreactivity was detected in the organ of Corti at P11. There was an increase in the expression of NBC3 in the spiral ligament between P17 and P19. From P21 to P90, NBC3 expression was confined to the spiral ligament and inner and outer sulcus cells. The vestibular sensory epithelia from slc4a7-/- mice were normal from P2 to P90. Damage of the sensory epithelia at the high frequency zone of the cochlea suggests that NBC3 may play an important physiological role in this region.

Animals↗
PubMed2005

Intercalated cell H+/OH- transporter expression is reduced in Slc26a4 null mice.

Slc26a4 (Pds) encodes pendrin, a Cl(-)/HCO(3)(-) exchanger expressed in the apical region of type B and non-A, non-B cells, which mediates secretion of OH(-) equivalents. Thus genetic disruption of Slc26a4 leads to systemic alkalosis in some treatment models. However, humans and mice with genetic disruption of Slc26a4 have normal acid-base balance under basal conditions. Thus we asked: 1) Is net acid excretion altered in Slc26a4 (-/-) mice under basal conditions? 2) In the absence of pendrin-mediated OH(-) secretion, are increases in intracellular and systemic pH minimized through changes in intercalated cell subtype abundance or intercalated cell H(+)/OH(-) transporter expression? To answer these questions, net acid excretion and H(+)/OH(-) transporter expression were examined in Slc26a4 (-/-) and Slc26a4 (+/+) mice using balance studies, immunolocalization, and immunoblotting. Excretion of ammonium, titratable acid, and citrate were the same in Slc26a4 null and wild-type mice. However, urinary pH and Pco(2) were much lower in Slc26a4 null relative to wild-type mice due to reduced urinary buffering of secreted H(+) by HCO(3)(-). Abundance of non-A, but not type A intercalated cells, was reduced within the cortical collecting ducts of Slc26a4 null mice. Moreover, kidneys from Slc26a4 null mice had reduced H(+)-ATPase, NBC3 and RhBG total protein expression, particularly within type B and non-A, non-B intercalated cells, although RhCG protein expression was unchanged. Reduced intercalated cell H(+)/OH(-) transporter expression is observed in Slc26a4 null mice, which likely attenuates the rise in intracellular and systemic pH expected with genetic disruption of Slc26a4.

Animals↗
PubMed2005

Critical amino acid residues involved in the electrogenic sodium-bicarbonate cotransporter kNBC1-mediated transport.

We have previously reported a topological model of the electrogenic Na(+)-HCO(3)(-) cotransporter (NBC1) in which the cotransporter spans the plasma membrane 10 times with N- and C-termini localized intracellularly. An analysis of conserved amino acid residues among members of the SLC4 superfamily in both the transmembrane segments (TMs) and intracellular/extracellular loops (ILs/ELs) provided the basis for the mutagenesis approach taken in the present study to determine amino acids involved in NBC1-mediated ion transport. Using large-scale mutagenesis, acidic and basic amino acids putatively involved in ion transport mediated by the predominant variant of NBC1 expressed in the kidney (kNBC1) were mutated to neutral and/or oppositely charged amino acids. All mutant kNBC1 cotransporters were expressed in HEK-293T cells and the Na(+)-dependent base flux of the mutants was determined using intracellular pH measurements with 2',7'-bis-(carboxyethyl)-5(6)-carboxyfluorescein (BCECF). Critical glutamate, aspartate, lysine, arginine and histidine residues in ILs/ELs and TMs were detected that were essential for kNBC1-mediated Na(+)-dependent base transport. In addition, critical phenylalanine, serine, tyrosine, threonine and alanine residues in TMs and ILs/ELs were detected. Furthermore, several amino acid residues in ILs/ELs and TMs were shown to be essential for membrane targeting. The data demonstrate asymmetry of distribution of kNBC1 charged amino acids involved in ion recognition in putative outward-facing and inward-facing conformations. A model summarizing key amino acid residues involved in kNBC1-mediated ion transport is presented.

Amino Acid Sequence↗
PubMed2005

Metabolic acidosis of CKD: diagnosis, clinical characteristics, and treatment.

Metabolic acidosis is noted in the majority of patients with chronic kidney disease (CKD) when glomerular filtration rate (GFR) decreases to less than 20% to 25% of normal, although as many as 20% of individuals can have acid-base parameters close to or within the normal range. Acidosis generally is mild to moderate in degree, with plasma bicarbonate concentrations ranging from 12 to 22 mEq/L (mmol/L), and it is rare to see values less than 12 mEq/L (mmol/L) in the absence of an increased acid load. Degree of acidosis approximately correlates with severity of renal failure and usually is more severe at a lower GFR. The metabolic acidosis can be of the high-anion-gap variety, although anion gap can be normal or only moderately increased even with stage 4 to 5 CKD. Several adverse consequences have been associated with metabolic acidosis, including muscle wasting, bone disease, impaired growth, abnormalities in growth hormone and thyroid hormone secretion, impaired insulin sensitivity, progression of renal failure, and exacerbation of beta 2 -microglobulin accumulation. Administration of base aimed at normalization of plasma bicarbonate concentration might be associated with certain complications, such as volume overload, exacerbation of hypertension, and facilitation of vascular calcifications. Whether normalization of plasma bicarbonate concentrations in all patients is desirable therefore requires additional study. In the present review, we describe clinical and laboratory characteristics of metabolic acidosis, discuss potential adverse effects, and address benefits and complications of therapy.

Acidosis↗
PubMed2005

Evolving concepts in the quantitative analysis of the determinants of the plasma water sodium concentration and the pathophysiology and treatment of the dysnatremias.

The physiologic and clinical implications of the empirical formula originally discovered by Edelman et al [J Clin Invest 37:1236-1256, 1958] relating the plasma water sodium concentration ([Na(+)](pw)) to the total exchangeable sodium (Na(e)), total exchangeable potassium (K(e)), and total body water (TBW) have recently been elucidated. It is quite remarkable that the full significance of the Edelman equation discovered almost 50 years ago had remained unrecognized by clinicians and physiologists until recently. Although Edelman and colleagues had shown that the [Na(+)](pw) is proportional to the magnitude of (Na(e)+ K(e))/TBW, the linear equation relating [Na(+)](pw) to (Na(e)+ K(e))/TBW had a slope greater than unity of 1.11, and a non-zero y intercept of -25.6 whose significance was unrecognized and more often than not ignored. It has recently been demonstrated that the slope and y intercept in this equation are quantitatively determined by several additional physiologic parameters, which in addition to (Na(e)+ K(e))/TBW, play a role both in modulating the [Na(+)](pw) and in the generation of the dysnatremias. Even more remarkably, based only on the theoretical principles of Gibbs-Donnan and osmotic equilibrium, all the physiologic parameters that determine the magnitude of the [Na(+)](pw) can be incorporated into a simple conceptual and mathematical framework that sheds light on a broad of range of seemingly unrelated topics that have heretofore been treated separately clinically, including (1) effect of changes in the mass balance of Na(+), K(+), and H(2)O on the [Na(+)](pw); (2) modulation of [Na(+)](pw) in hyperglycemic states; (3) definition of an isonatric solution; (4) current formulas used to quantitate electrolyte-free water excretion; (5) complex role of K(+) in modulating the [Na(+)](pw); and (6) quantitative analysis of the generation and treatment of the dysnatremias. Moreover, this analysis has also proven to be an indispensable tool for deriving new formulas to aid the clinician in both interpreting the pathogenesis and treating the dysnatremias.

Humans↗
PubMed2004

A new formula for predicting alterations in plasma sodium concentration in peritoneal dialysis.

Alterations in the plasma water sodium concentration ([Na+]pw) result from changes in the total exchangeable sodium (Na e), total exchangeable potassium (K e), and total body water (TBW). The empirical relationship between the [Na+]pw and Na e, K e, and TBW was originally demonstrated (Edelman IS, Leibman J, O'Meara MP, and Birkenfeld LW. J Clin Invest 37: 1236-1256, 1958), where [Na+]pw = 1.11(Na e + K e)/TBW - 25.6 (Eq. 1). Based on Eq. 1, alterations in the [Na+]pw can be predicted by considering changes in the mass balance of Na+, K+, and H2O. In accounting for the mass balance of Na+, K+, and H2O in patients on peritoneal dialysis, considerations must also be taken to determine the modulating effect of dialysate clearance of Na+ and K+ and fluid changes resulting from this therapeutic modality on the [Na+]pw. In this article, we derive a new formula for predicting alterations in the plasma Na+ concentration ([Na+]p) in patients on peritoneal dialysis, taking into consideration the empirical relationship between the [Na+]pw and Na e, K e, and TBW (Eq. 1) as well as changes in mass balance of Na+ + K+ and H2O.

Humans↗
PubMed2004

Derivation of a new formula for calculating urinary electrolyte-free water clearance based on the Edelman equation.

In evaluating the renal mechanisms responsible for the generation of the dysnatremias, an analysis of free water clearance (FWC) and electrolyte-free water clearance (EFWC) is often utilized to characterize the rate of urinary free water excretion in these disorders. Previous analyses of FWC and EFWC have failed to consider the relationship among plasma water Na(+) concentration ([Na(+)](pw)), total exchangeable Na(+) (Na(e)), total exchangeable K(+) (K(e)), and total body water (TBW); (Edelman IS, Leibman J, O'Meara MP, and Birkenfeld LW. J Clin Invest 37: 1236-1256, 1958). In their derivations, the classic FWC and EFWC formulas fail to consider the quantitative and physiological significance of the slope and y-intercept in this equation. Consequently, previous EFWC formulas incorrectly assume that urine is isonatric when [Na(+) + K(+)](urine) = [Na(+)](p) or [Na(+) + K(+)](urine) = [Na(+)](p) + [K(+)](p) (where [Na(+)](p) and [K(+)](p) represent plasma Na(+) and K(+) concentrations, respectively). Moreover, previous formulas cannot be utilized in the setting of hyperglycemia. In this article, we have derived a new formula termed modified electrolyte-free water clearance (MEFWC) for determining the electrolyte-free water clearance, taking into consideration the empirical relationship between the [Na(+)](pw) and Na(e), K(e), and TBW: MEFWC = V [1 - 1.03[Na(+) + K(+)](urine)/([Na(+)](p) + 23.8)]. MEFWC, unlike previous formulas, is derived based on the requirement of the Edelman equation that urine is isonatric only when [Na(+) + K(+)](urine) = (Na(e) + K(e))/TBW = 0.97[Na(+)](p) + 23.1. Furthermore, since we have shown that the y-intercept in the Edelman equation varies directly with the plasma glucose concentration, in patients with hyperglycemia, MEFWC = V [1 - 1.03[Na(+) + K(+)](urine)/{[Na(+)](p) + 23.8 + (1.6/100)([glucose](p) - 120)}]. The MEFWC formula will be especially useful in assessing the renal contribution to the generation of the dysnatremias.

Animals↗
PubMed2004

Molecular mechanism of kNBC1-carbonic anhydrase II interaction in proximal tubule cells.

We have recently shown that carbonic anhydrase II (CAII) binds in vitro to the C-terminus of the electrogenic sodium bicarbonate cotransporter kNBC1 (kNBC1-ct). In the present study we determined the molecular mechanisms for the interaction between the two proteins and whether kNBC1 and CAII form a transport metabolon in vivo wherein bicarbonate is transferred from CAII directly to the cotransporter. Various residues in the C-terminus of kNBC1 were mutated and the effect of these mutations on both the magnitude of CAII binding and the function of kNBC1 expressed in mPCT cells was determined. Two clusters of acidic amino acids, L(958)DDV and D(986)NDD in the wild-type kNBC1-ct involved in CAII binding were identified. In both acidic clusters, the first aspartate residue played a more important role in CAII binding than others. A significant correlation between the magnitude of CAII binding and kNBC1-mediated flux was shown. The results indicated that CAII activity enhances flux through the cotransporter when the enzyme is bound to kNBC1. These data are the first direct evidence that a complex of an electrogenic sodium bicarbonate cotransporter with CAII functions as a transport metabolon.

Amino Acid Sequence↗