Papers by Thomas D DuBose
American Journal of Physiology - Renal Physiology, 2015
We previously reported that the deletion of the pH sensor GPR4 causes a non-gap metabolic acidosi... more We previously reported that the deletion of the pH sensor GPR4 causes a non-gap metabolic acidosis and defective net acid excretion (NAE) in the GPR4 knockout mouse (GPR4-/-) (Sun X, Yang LV, Tiegs BC, Arend LJ, McGraw DW, Penn RB, and Petrovic S. J Am Soc Nephrol 21: 1745-1755, 2010). Since the major regulatory site of NAE in the kidney is the collecting duct (CD), we examined acid-base transport proteins in intercalated cells (ICs) of the CD and found comparable mRNA expression of kidney anion exchanger 1 (kAE1), pendrin, and the a4 subunit of H(+)-ATPase in GPR4-/- vs. +/+. However, NH4Cl loading elicited adaptive doubling of AE1 mRNA in GPR4+/+, but a 50% less pronounced response in GPR4-/-. In GPR4+/+, NH4Cl loading evoked a cellular response characterized by an increase in AE1-labeled and a decrease in pendrin-labeled ICs similar to what was reported in rabbits and rats. This response did not occur in GPR4-/-. Microperfusion experiments demonstrated that the activity of the basolateral Cl(-)/HCO3(-) exchanger, kAE1, in CDs isolated from GPR4-/- failed to increase with NH4Cl loading, in contrast to the increase observed in GPR4+/+. Therefore, the deficiency of GPR4 blunted, but did not eliminate the adaptive response to an acid load, suggesting a compensatory response from other pH/CO2/bicarbonate sensors. Indeed, the expression of the calcium-sensing receptor (CaSR) was nearly doubled in GPR4-/- kidneys, in the absence of apparent disturbances of Ca(2+) homeostasis. In summary, the expression and activity of the key transport proteins in GPR4-/- mice are consistent with spontaneous metabolic acidosis, but the adaptive response to a superimposed exogenous acid load is blunted and might be partially compensated for by CaSR.
Kidney International, 1983
Previous studies have suggested that acetate hemodialysis causes myocardial depression. This stud... more Previous studies have suggested that acetate hemodialysis causes myocardial depression. This study examines the acute effects of hemodialysis using, alternately, bicarbonate and acetate in the dialysate, on cardiac function in ten patients. These patients were also studied during acetate dialysis using a large surface area (SA) dialyzer. Each patient was dialyzed for 4 hr with: (1) 1.0 m2 SA dialyzer and bicarbonate dialysate; (2) 1.0 m2 SA dialyzer and acetate bath, and; (3) 2.5 m2 SA dialyzer and acetate dialysate. All studies were performed during isovolemic dialysis to separate the effects of changes in cardiac filling volume with hemodialysis, from changes in myocardial contractility. Myocardial function, as assessed by pre- and postdialysis echocardiographically derived fractional shortening (Fs) and mean velocity of circumferential shortening (VCF), improved (P less than 0.05) to the same extent, after all three dialysis treatments. This occurred despite greater increases (P less than 0.002) in pH and bicarbonate after bicarbonate dialysis and decreases (P less than 0.05) in PO2, PCO2 and bicarbonate after acetate dialysis with 2.5 m2 SA dialyzer. These results indicate that diffusive dialysis with both acetate and bicarbonate dialysate improves myocardial function and do not support the view that acetate influx during dialysis can lead to myocardial depression.
Kidney International, 2004
Journal of Clinical Investigation, 1983
to vasa recta was demonstrated during acetazolamide (WvtCO2 = 20.9±3.3 mM), but was abolished dur... more to vasa recta was demonstrated during acetazolamide (WvtCO2 = 20.9±3.3 mM), but was abolished during combined mannitol and acetazolamide administration (AtCO2 = 3.5±0.9 mM). It is concluded that carbonic anhydrase inhibition results in a disparate effect on nephron bicarbonate reabsorption when juxtamedullary and superficial nephron segments are compared. Our findings suggest that a mechanism for residual bicarbonate reabsorption during acetazolamide administration may be passive reabsorption driven by favorable transepithelial concentration gradients.
Journal of Clinical Investigation, 1979
A B S T R A C T Prostaglandins have been postulated to participate in the regulation of salt excr... more A B S T R A C T Prostaglandins have been postulated to participate in the regulation of salt excretion during acute volume expansion. The present papillary and cortical micropuncture studies were designed to examine the effect ofprostaglandin synthesis inhibitors on segmental chloride transport during hydropenia (with and without meclofenamate) and 10% volume expansion (with and without both meclofenamate and indomethacin). Both inhibitors significantly decreased the urinary excretion rate of prostaglandins E2 and F2,,. Clearance studies on the intact right kidney demonstrated no effect of either agent on glomerular filtration rate, but a significant reduction in chloride excretion during hydropenia and volume expansion was observed. To assess the specific site(s) of enhanced chloride reabsorption, absolute and fractional chloride delivery was measured in the late proximal tubule, thin descending limb of Henle, and the early and late distal tubules. In addition, the fraction of filtered chloride remaining at the base and tip of the papillary collecting duct was compared to that fraction remaining at the superficial late distal tubule. During hydropenia, meclofenamate had no effect on fractional chloride delivery out of the superficial late distal tubule or the juxtamedullary thin descending limb of Henle, but significantly reduced the fraction of chloride delivered Portions ofthis study were presented at the 7th International Congress of Nephrology, Montreal, Canada, 18-23 June 1978. During the course of these studies Dr. Stokes was a recipient of a National Institutes of Health fellowship grant AM 05318. Receivedfor publication 1 August 1.978 and in revisedform 2Juliy 1979.
Journal of Clinical Investigation, 1979
A B S T R A C T Previous studies evaluating the mechanism of renal HCO-reabsorption have assumed ... more A B S T R A C T Previous studies evaluating the mechanism of renal HCO-reabsorption have assumed equilibrium between systemic arterial blood and tubular fluid Pco2. We have recently reported that the Pco2 in proximal and distal tubular fluid as well as the stellate vessel significantly exceeded arterial Pco2 by 25.9 +0.92 mm Hg. The purpose of this study was to determine directly, for the first time, pH, Pco2, and total CO2 concentration in the accessible structures of the rat renal cortex with both microelectrodes and microcalorimetry. In addition, the concentrations of chloride and total CO2 were compared in the stellate vessel. The data demonstrate that: (a) values for total [CO2] in both the proximal tubule and stellate vessel calculated from in situ determination ofpH and Pco2 closely agree with the measured values for total [CO21; (b) values for chloride concentration in the stellate vessel are significantly less than the corresponding values in systemic plasma (A[CI-I = 5.6 meq/liter); and (c) the rise in [HCO3 ] from systemic to stellate vessel plasma closely approximates the observed reciprocal fall in [CI-I in this structure. J.
Critical Care Medicine, 2001
Citrate anticoagulation is commonly used for continuous venovenous hemodialysis (CVVHD) to minimi... more Citrate anticoagulation is commonly used for continuous venovenous hemodialysis (CVVHD) to minimize the risk of bleeding complications. We have previously reported a liver failure patient undergoing citrate-based CVVHD with elevated serum total to ionized calcium ratio. Diminished liver metabolism of citrate with resultant elevated systemic citrate was thought to be the cause. To determine the incidence and clinical significance of an elevated total to ionized calcium ratio during citrate-based CVVHD, 161 patients undergoing citrate-based CVVHD were screened for the presence of an elevated total to ionized calcium ratio (the subset with increased total to ionized calcium ratio comprised the study group). Because all patients in the study group had liver failure, two control groups of patients with normal total to ionized calcium ratios were formed-those without liver failure (control I) and those with liver failure (control II). An elevated total to ionized calcium ratio was detected in 12% of all patients. Thirty-three percent of liver failure patients demonstrated an elevated total to ionized calcium ratio. The study group demonstrated significantly higher mean total calcium levels, significantly lower mean ionized calcium levels, and significantly higher mean total to ionized calcium ratios than controls. As a result, the study group also had significantly increased mean calcium chloride replacement requirements in comparison with controls. The mean calcium to citrate infusion ratio was elevated in the study group in comparison with controls. An elevated total to ionized calcium ratio was associated with increased mortality in comparison with controls. No patients suffered complications from ionized hypocalcemia or elevated serum total calcium. Systemic citrate accumulation as evidenced by an elevated total to ionized calcium ratio occurs commonly in patients requiring CVVHD using citrate-based regional anticoagulation. Observing changes in the total to ionized calcium ratio can aid in early detection of patients with hepatic failure who are unable to appropriately metabolize citrate and will require calcium chloride infusion rates significantly above normal.
Clinical Journal of the American Society of Nephrology, 2007
American Journal of Nephrology, 2007
... Andrew S. Levey * , Sharon P. Andreoli , Thomas DuBose , Robert Provenzano § and Allan J.... more ... Andrew S. Levey * , Sharon P. Andreoli , Thomas DuBose , Robert Provenzano § and Allan J. Collins ... Circulation 108 : 2154 2169, 2003; Keith D, Nicholls G, Guillion C, Brown JB, Smith DH: Longitudinal follow-up and outcomes among a population with chronic ...
The American Journal of Medicine, 2006
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American Journal of Kidney Diseases, 2007
American Journal of Kidney Diseases, 1996
We report the first series demonstrating effective clearance of methotrexate using acute intermit... more We report the first series demonstrating effective clearance of methotrexate using acute intermittent hemodialysis with a high-flux dialyzer. The study was performed on six patients, two females and four males aged 13 to 72 years. All were patients at M.D. Anderson Cancer Center. Patients were dialyzed for 4 to 6 hours daily using a Fresenius F-80 membrane (Fresenius Inc, Walnut Creek, CA). Following the initiation of dialysis, there was a reduction in arterial and venous serum concentration of methotrexate with time. Mean plasma clearance of methotrexate during dialysis in these six patients was 92.1 +/- 10.3 mL/min. One patient who was nearly functionally anephric was studied in detail. In this patient, following a high dose of methotrexate (7.2 g/m2), approximately 63% of this dose was cleared with 6 hours of hemodialysis. With subsequent dialysis performed daily for 6 hours, the drug was cleared completely in 5.6 +/- 0.3 days (n = 7 separate methotrexate treatments). A reduction in plasma methotrexate concentration from 1,733 +/- 40 micromol/L 1 hour postinfusion to less than 0.3 micromol/L in 5 to 6 days was observed for these seven separate treatments. We conclude that significant clearance of methotrexate can be achieved with high-flux dialyzers, making methotrexate therapy a viable treatment option in patients with responsive malignancies despite the presence of renal failure.
American Journal of Kidney Diseases, 1997
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Papers by Thomas D DuBose