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Biomedical subjects

George J Schwartz

Publications and source records attributed to George J Schwartz.

At least 19 recordsLinked to original sources
PubMed2007

Glomerular filtration rate measurement and estimation in chronic kidney disease.

Glomerular filtration rate (GFR) assesses kidney function. GFR is measured by renal clearance techniques; inulin clearance is the gold standard but is not easily measured. Thus, other methods to determine GFR have been utilized. Endogenous creatinine clearance (CrCl) is the most widely used, but creatinine secretion falsely elevates GFR. Cimetidine inhibits creatinine secretion, such that CrCl equals GFR, provided there are no difficulties with bladder emptying. Estimation of GFR from serum creatinine (e.g. Schwartz formula) is useful clinically; however, such formulae have not been updated for enzymatic creatinine autoanalyzers. Cystatin C, a small protein, is produced at a relatively constant rate and is reabsorbed in the proximal tubule. Cystatin C may be more sensitive than creatinine in detecting a reduction in GFR, but further studies are needed to prove this. Single injection (plasma) clearance techniques are the most precise measures of GFR. Iohexol is an exogenous marker that is comparable to inulin and (51)Cr-EDTA and can be measured by high-performance liquid chromatography (HPLC). Our pilot and the Chronic Kidney Disease in Children (CKiD) North American studies show that iohexol can accurately measure GFR using a four-point plasma disappearance curve national studies show that iohexol can accurately measure GFR using a four-point plasma disappearance curve (10, 30, 120, and 300 min) or, in most cases, a two-point disappearance time (120 and 300 min).

Education, Medical, Continuing↗
PubMed2006

Differentiation of columnar epithelia: the hensin pathway.

Epithelia, the most common variety of cells in complex organisms exist in many shapes. They are sheets of polarized cells that separate two compartments and selectively transport materials from one to the other. After acquiring these general characteristics, they differentiate to become specialized types such as squamous columnar or transitional epithelia. High density seeding converts a kidney-derived cell line from flat ;generic' epithelial cells to columnar cells. The cells acquire all the characteristics of differentiated columnar cells, including microvilli, and the capacity for apical endocytosis. The high seeding density induces the deposition of a new protein termed hensin and polymerization of hensin is the crucial event that dictates changes in epithelial phenotype. Hensin is widely expressed in most epithelia. Its deletion in mice leads to embryonic lethality at the time of generation of the first columnar epithelium, the visceral endoderm. Moreover many human cancers have deletions in the hensin gene, which indicates that it is a tumor suppressor.

Animals↗
PubMed2006

Endothelin and nitric oxide mediate adaptation of the cortical collecting duct to metabolic acidosis.

Endothelin (ET) and nitric oxide (NO) modulate ion transport in the kidney. In this study, we defined the function of ET receptor subtypes and the NO guanylate cyclase signaling pathway in mediating the adaptation of the rabbit cortical collecting duct (CCD) to metabolic acidosis. CCDs were perfused in vitro and incubated for 3 h at pH 6.8, and bicarbonate transport or cell pH was measured before and after acid incubation. Luminal chloride was reversibly removed to isolate H(+) and HCO(3)(-) secretory fluxes and to raise the pH of beta-intercalated cells. Acid incubation caused reversal of polarity of net HCO(3)(-) transport from secretion to absorption, comprised of a 40% increase in H(+) secretion and a 75% decrease in HCO(3)(-) secretion. The ET(B) receptor antagonist BQ-788, as well as the NO synthase inhibitor, N(G)-nitro-l-arginine methyl ester (l-NAME), attenuated the adaptive decrease in HCO(3)(-) secretion by 40%, but only BQ-788 inhibited the adaptive increase in H(+) secretion. There was no effect of inactive d-NAME or the ET(A) receptor antagonist BQ-123. Both BQ-788 and l-NAME inhibited the acid-induced inactivation (endocytosis) of the apical Cl(-)/HCO(3)(-) exchanger. The guanylate cyclase inhibitor LY-83583 and cGMP-dependent protein kinase inhibitor KT-5823 affected HCO(3)(-) transport similarly to l-NAME. These data indicate that signaling via the ET(B) receptor regulates the adaptation of the CCD to metabolic acidosis and that the NO guanylate cyclase component of ET(B) receptor signaling mediates downregulation of Cl(-)/HCO(3)(-) exchange and HCO(3)(-) secretion.

Acclimatization↗
PubMed2005

Galectin-3 expression is induced in renal beta-intercalated cells during metabolic acidosis.

The adaptation of the cortical collecting duct (CCD) to metabolic acidosis requires the polymerization and deposition in the extracellular matrix of the novel protein hensin. HCO3(-)-secreting beta-intercalated cells remove apical Cl-:HCO3(-) exchangers and may reverse functional polarity to secrete protons. Using intercalated cells in culture, we found that galectin-3 facilitated hensin polymerization, thereby causing their differentiation into the H+-secreting cell phenotype. We examined the expression of galectin-3 in the rabbit kidney and its relationship to hensin during metabolic acidosis. In control kidneys, galectin-3 was expressed in the cortical and medullary collecting ducts. In the outer cortex 26 +/- 3% of CCD cells expressed galectin-3 compared with 64 +/- 3% of the cells of the inner cortex. In the CCD, galectin-3 was rarely expressed in beta-intercalated cells, being primarily present in alpha-intercalated and principal cells. During metabolic acidosis, the intensity of cellular staining for galectin-3 increased and more cells began to express it; the percentage of CCD cells expressing galectin-3 increased from 26 +/- 3 to 66 +/- 3% in the outer cortex and from 64 +/- 3 to 78 +/- 4% in the inner cortex. This was particularly evident in beta-intercalated cells where expression was found in only 8 +/- 2% in control animals but in 75 +/- 2% during metabolic acidosis in the outer cortex and similarly for the inner cortex (26 +/- 6 to 90 +/- 7%). Importantly, both galectin-3 and hensin were found in the extracellular matrix of microdissected CCDs; and during metabolic acidosis, many more cells exhibited this extracellular colocalization. Thus galectin-3 may play several important roles in the CCD, including mediating the adaptation of beta-intercalated cells during metabolic acidosis.

Acidosis↗
PubMed2005

Citrate reverses cyclosporin A-induced metabolic acidosis and bone resorption in rats.

BACKGROUND: Cyclosporine A (CsA) causes distal renal tubular acidosis (RTA) and osteoporosis. We have recently reported that the reduction of nitric oxide (NO) exacerbates this condition. Distal RTA may deplete bone mineral due to the chronic buffering of acid in the blood. The interaction of CsA and NO in causing metabolic acidosis and bone demineralization has not been studied previously. Nor has the salubrious effect of citrate therapy. PURPOSE: To examine the effect of systemic pH correction by citrate on renal electrolyte (Na, K, Cl, NH3, HCO3) excretion following acute water loading in CsA-treated and NO-reduced rats. We further evaluated femoral bone density and bone demineralization activity after the same treatments. METHODS: Rats received CsA, L-arginine (L-Arg), or nitro-L-arginine-methyl ester (L-NAME), or a combination of CsA+L-NAME plus or minus citrate. Urine and blood electrolytes were examined, as well as the urine excretion of deoxypyridinoline and the bone density of both femurs. RESULTS: CsA and L-NAME reduced urine pH and the serum HCO3- concentration, and increased serum K+ and Cl- concentrations. The combination of CsA with L-NAME caused more severe deficits in the serum HCO3- concentration and elevations in serum K+ and Cl- concentrations than either drug alone. Both CsA and L-NAME reduced urinary nitrate excretion, which was reversed by co-administration of L-Arg. Co-administration of citrate or L-Arg improved the CsA- and L-NAME-induced acidosis and hyperkalemia. Bone resorption and density of the femurs were decreased by CsA and L-NAME and were additive for both drugs. Co-administration of citrate or L-Arg restored both bone resorption and density to normal levels. CONCLUSION: CsA induces a hyperchloremic metabolic acidosis with hyperkalemia and a reduction in NO. The ensuing systemic acidosis causes bone resorption and demineralization. These effects were corrected by co-treatment with citrate. Citrate, at least in part, directly reduces the protonation of bone in animals treated with CsA and is recommended as a potential adjunct drug to prevent bone demineralization in patients chronically receiving CsA.

Acidosis↗
PubMed2005

Apoptotic response to albumin overload: proximal vs. distal/collecting tubule cells.

End-stage renal disease due to proteinuric states has a great impact on the quality of life by necessitating renal replacement therapy. Understanding the pathophysiologic consequences of proteinuria is crucial in order to develop treatment strategies to halt the progression. We have previously reported that cultured porcine proximal tubule cells respond to albumin overload by undergoing apoptosis. In this study, we investigated the differential apoptotic response to albumin in HKC-8 (proximal tubule) and MDCK (collecting/distal tubule) cells under high concentrations of albumin simulating the nephrotic milieu. Our results are consistent with marked cytotoxicity and apoptosis within 24 h of albumin incubation in HKC-8 cells that was closely related to the fatty acid content of the albumin. In contrast, in MDCK cells, albumin stimulated cell turnover by stimulating proliferation and late onset apoptosis regardless of the fatty acid content. Another important result of this study is the direct demonstration of albumin uptake by MDCK cells mediated by endocytosis via clathrin-coated pits. A comparison of albumin uptake between proximal and distal/collecting tubule cells revealed faster uptake in proximal tubule cells within 15 min but almost 100% albumin uptake of both cell types in 1 h. In summary, our findings demonstrate that both proximal and distal nephron segments are affected in proteinuric states, but the degrees of susceptibility to albumin and associated lipid moieties are distinct in the different nephron segments.

Albumins↗
PubMed2005

Role of urinary supersaturation in the evaluation of children with urolithiasis.

Timed urine collections are a standard part of the evaluation for predisposition to stone formation in children with urolithiasis. Supersaturation is defined as the ratio of the concentration of dissolved salt to its solubility in urine. The purpose of the present study was to determine if adding supersaturation to the standard timed urine collection increased the ability to detect a metabolic predisposition to stone formation. Thirty-two children with urolithiasis had 24-hour urine measurements of calcium, oxalate, citrate, uric acid, and cystine (the "traditional" evaluation), as well as supersaturation for calcium oxalate, calcium phosphate, and uric acid, on the same urine sample. Nine (28%) of the 32 were hypercalciuric, 2 (6%) hyperoxaluric, and 4 (12%) hypocitraturic. In total, 14 (44%) had a metabolic predisposition that was detected by the traditional evaluation. Supersaturation was elevated in 18 (56%), including nine who did not have metabolic predisposition detected by traditional evaluation. Urine volume was low in 17 (53%) of 32 children, including eight of nine children with abnormal supersaturation but normal traditional evaluation. Only one child with normal traditional evaluation and normal urine volume had elevated supersaturation. These results show that the benefit of adding supersaturation to the traditional evaluation was largely negated by consideration of urine volume.

Adolescent↗
PubMed2005

Role of hensin in mediating the adaptation of the cortical collecting duct to metabolic acidosis.

PURPOSE OF REVIEW: The cortical collecting duct is able to secrete HCO3-, a state that can be converted to acid secretion during metabolic acidosis. Bicarbonate secretion in this segment is mediated by beta-intercalated cells whereas alpha-intercalated cells perform acid secretion. During metabolic acidosis, the number of beta-intercalated cells is reduced while that of alpha-intercalated cells increases without a change in the total number of intercalated cells, suggesting conversion of one cell type to another. Using an immortalized intercalated cell line we found that this adaptation is mediated by an extracellular protein named hensin. Hensin is secreted as a monomer which is then polymerized in the extracellular environment by a complex process requiring at least three other proteins. RECENT FINDINGS: We describe that a cyclophilin, via its cis/trans prolyl isomerase activity, is required for this polymerization. This may explain the distal renal tubular acidosis observed with cyclosporin A therapy. In addition, galectin-3 is needed to aggregate the protein. Finally, we recently found that activation of integrins is also necessary for the development of the hensin fiber. Hensin is expressed in all epithelia and deletion of its gene is embryonic lethal at an early stage when the first columnar epithelia develop. SUMMARY: These studies suggest that the response of intercalated cells to metabolic acidosis uses a pathway that is involved in terminal differentiation of columnar epithelia.

Acidosis↗
PubMed2005

Expression of membrane-associated carbonic anhydrase isoforms IV, IX, XII, and XIV in the rabbit: induction of CA IV and IX during maturation.

Several carbonic anhydrase (CA) isoforms are associated with plasma membranes. It is probable that these enzymes interact with anion transporters to facilitate the movement of HCO3- into or out of the cell. A better knowledge of CA isoform expression in a given tissue would facilitate a systematic examination of any associations with such transporters. We examined the expression of CAs IV, IX, XII, and XIV mRNAs in rabbit tissues, including kidney, heart, lung, skeletal muscle, liver, pancreas, gall bladder, stomach, small intestine, colon, and spleen, using quantitative real-time reverse transcription polymerase chain reaction (RT-PCR). CA IV mRNA was mainly in kidney, heart, lung, colon, and gall bladder. CA IX mRNA was restricted to stomach, gall bladder, duodenum, and early jejunum. CA XII mRNA was found in kidney and colon. CA XIV mRNA was localized to heart, lung, skeletal muscle, and liver. The data indicate that there are different patterns of CA expression in various tissues: CA IX was expressed in the proximal gastrointestinal tract, whereas CA XII and CA IV were more distal. CA IV and CA XII are important kidney isoforms. CA XIV was abundant in metabolically active tissues such as liver, heart, lung, and skeletal muscle. Some significant species differences were noted in the expression of some of these isoforms; for example, CA XIV is not expressed in rabbit kidney, despite being abundant in mouse kidney. Maturational studies showed that the expression of CA IX mRNA and protein increased markedly with weaning ( approximately 3-4 postnatal wk) and was well correlated with the maturational expression of the alpha-subunit of the gastric H+,K+-ATPase, suggesting that function of CA IX and the gastric H+ pump might be linked in the digestion of adult foodstuffs. The unique pattern of membrane-bound CA isoforms suggests different functional associations with transporters, depending on the physiological demands on the tissue.

Aging↗
PubMed2004

Cyclosporin A produces distal renal tubular acidosis by blocking peptidyl prolyl cis-trans isomerase activity of cyclophilin.

Cyclosporin A (CsA), a widely used immunosuppressant, causes distal renal tubular acidosis (dRTA). It exerts its immunosuppressive effect by a calcineurin-inhibitory complex with its cytosolic receptor, cyclophilin A. However, CsA also inhibits the peptidyl prolyl cis-trans isomerase (PPIase) activity of cyclophilin A. We studied HCO(3)(-) transport and changes in beta-intercalated cell pH on luminal Cl(-) removal in isolated, perfused rabbit cortical collecting tubules (CCDs) before and after exposure to media pH 6.8 for 3 h. Acid incubation causes adaptive changes in beta-intercalated cells by extracellular deposition of hensin (J Clin Invest 109: 89, 2002). Here, CsA prevented this adaptation. The unidirectional HCO(3)(-) secretory flux, estimated as the difference between net flux and that after Cl(-) removal from the lumen, was -6.7 +/- 0.2 pmol.min(-1).mm(-1) and decreased to -1.3 +/- 0.2 after acid incubation. CsA in the bath prevented the adaptive decreases in HCO(3)(-) secretion and apical Cl(-):HCO(3)(-) exchange. To determine the mechanism, we incubated CCDs with FK-506, which inhibits calcineurin activity independently of the host cell cyclophilin. FK-506 did not prevent the acid-induced adaptive decrease in unidirectional HCO(3)(-) secretion. However, [AD-Ser](8) CsA, a CsA derivative, which does not inhibit calcineurin but inhibits PPIase activity of cyclophilin A, completely blocked the effect of acid incubation on apical Cl(-):HCO(3)(-) exchange. Acid incubation resulted in prominent "clumpy" staining of extracellular hensin and diminished apical surface of beta-intercalated cells [smaller peanut agglutinin (PNA) caps]. CsA and [AD-Ser](8) CsA prevented most hensin staining and the reduction of apical surface; PNA caps were more prominent. We suggest that hensin polymerization around adapting beta-intercalated cells requires the PPIase activity of cyclophilins. Thus CsA is able to prevent this adaptation by inhibition of a peptidyl prolyl cis-trans isomerase activity. Such inhibition may cause dRTA during acid loading.

Acidosis, Renal Tubular↗
PubMed2004

Distal renal tubular acidosis.

PURPOSE OF REVIEW: Research in the past several years has led to the understanding of numerous genetic mutations that lead to inheritable forms of distal renal tubular acidosis (dRTA). Most of these mutations affect the physiology of the A-intercalated cells of the renal cortical collecting duct. These include mutations of genes encoding carbonic anhydrase II, kidney anion exchanger 1, and different subunits of the H+-ATPase proton pump. Genetic defects in any one of these components may impair renal acidification and thereby result in persistent acidosis, failure to thrive, and nephrocalcinosis. RECENT FINDINGS: The present review provides a summary of the most recently identified genetic mutations resulting in a dRTA phenotype and, when possible, describes a mechanism. Most causes of dRTA are due to loss of function or inappropriate targeting of transporters. SUMMARY: The collaboration of clinicians, geneticists, and renal physiologists has enabled us to better understand at the cellular level the different mechanisms leading to dRTA. Such information should lead to earlier diagnosis and treatment, thereby minimizing the irreversible complications affecting patients with this or similar diseases.

Acidosis, Renal Tubular↗
PubMed2004

A fork in the road of cell differentiation in the kidney tubule.

The collecting ducts of the kidney are composed of intercalated cells (responsible for acid/base transport), principal cells (mediating salt and water absorption), and inner medullary cells, which mediate all three types of transport. Forkhead box (Fox) genes are a large family of transcription factors that are important in cell-type specification during organogenesis. In this issue, Blomqvist et al. find that mice lacking Foxi1 have no intercalated cells in the kidney. The collecting ducts of the null mice contained primitive cells that expressed both intercalated cell and principal cell proteins, yet the acid/base transport function of the kidney was disrupted and the mice exhibited distal renal tubular acidosis. These findings suggest that Foxi1 plays a critical role in determining cell identity during collecting duct development.

Animals↗
PubMed2003

Direct extracellular interaction between carbonic anhydrase IV and the human NBC1 sodium/bicarbonate co-transporter.

Sodium/bicarbonate co-transporters (NBC) are crucial in the regulation of intracellular pH (pH(i)) and HCO(3)(-) metabolism. Electrogenic NBC1 catalyzes HCO(3)(-) fluxes in mammalian kidney, pancreas, and heart cells. Carbonic anhydrase IV (CAIV), which is also present in these tissues, is glycosylphosphatidyl inositol-anchored to the outer surface of the plasma membrane where it catalyzes the hydration-dehydration of CO(2)/HCO(3)(-). The physical and functional interactions of CAIV and NBC1 were investigated. NBC1 activity was measured by changes of pH(i) in NBC1-transfected HEK293 cells subjected to acid loads. Cotransfection of CAIV with NBC1 increased the rate of pH(i) recovery by 44 +/- 3%, as compared to NBC1-alone. In contrast, CAIV did not increase the functional activity of G767T-NBC1 (mutated on the fourth extracellular loop (EC4) of NBC1), and G767T-NBC1, unlike wild-type NBC1, did not interact with CAIV in glutathione-S-transferase pull-down assays. This indicates that G767 of NBC1 is directly involved in CAIV interaction. NBC1-mediated pH(i) recovery rate after acid load was inhibited by 40 +/- 7% when coexpressed with the inactive human CAII mutant, V143Y. V143Y CAII competes with endogenous CAII for interaction with NBC1 at the inner surface of the plasma membrane, which indicates that NBC1/CAII interaction is needed for full pH(i) recovery activity. We conclude that CAIV binds EC4 of NBC1, and this interaction is essential for full NBC1 activity. The tethering of CAII and CAIV close to the NBC1 HCO(3)(-) transport site maximizes the transmembrane HCO(3)(-) gradient local to NBC1 and thereby activates the transport rate.

Amino Acid Sequence↗
PubMed2003

Nitric oxide production modulates cyclosporin A-induced distal renal tubular acidosis in the rat.

Cyclosporine A (CsA) causes distal renal tubular acidosis (dRTA) in humans and rodents. Because mice deficient in nitric-oxide (NO) synthase develop acidosis, we examined how NO production modulated H+ excretion during acid loading and CsA treatment in a rat model. Rats received CsA, L-arginine (L-Arg), or N omega-nitro-L-arginine methyl ester (L-NAME), or combinations of CsA and L-NAME or L-Arg, followed by NH4Cl (acute acid load). In vehicle-treated rats, NH4Cl loading reduced serum and urine (HCO3-) and urine pH, which was associated with increases in serum [K+] and [Cl-] and urine NH3 excretion. Similar to CsA (7.5 mg/kg), L-NAME impaired H+ excretion of NH4Cl-loaded animals. The combination CsA and L-NAME reduced H+ excretion to a larger extent than either drug alone. In contrast, administration of L-Arg ameliorated the effect of CsA on H+ excretion. Urine pH after NH4Cl was 5.80 +/- 0.09, 6.11 +/- 0.13*, 6.37 +/- 0.16*, and 5.77 +/- 0.09 in the vehicle, CsA, CsA + L-NAME and CsA + L-Arg groups, respectively (*P < 0.05). The effect of CsA and alteration of NO synthesis were mediated at least in part by changes in bicarbonate absorption in perfused cortical collecting ducts. CsA or L-NAME reduced net HCO3- absorption, and, when combined, completely inhibited it. CsA + L-Arg restored HCO3- absorption to near control levels. Administration of CsA along with L-NAME reduced NO production to below levels observed with either drug alone. These results suggest that CsA causes dRTA by inhibiting H+ pumps in the distal nephron. Inhibition of NO synthesis may be one of the mechanisms underlying the CsA effect.

Acidosis, Renal Tubular↗
PubMed2003

Elevated blood pressure and decreased cognitive function among school-age children and adolescents in the United States.

OBJECTIVE: To evaluate the relationship between elevated blood pressure (BP) and cognitive test performance in a nationally representative sample of children. Study design The National Health and Nutrition Examination Survey III provides cross-sectional data for children 6 to 16 years, including BP and cognitive test scores. Elevated BP was defined as systolic or diastolic BP >or=90th percentile. Cognitive tests were compared for children with elevated and normal BP. Linear regression was used to evaluate the relation between elevated BP and decreased test scores. RESULTS: Among the 5077 children, 3.4% had systolic BP >or=90th percentile and 1.6% diastolic BP >or=90th percentile. Children with elevated systolic BP had lower average scores compared with normotensive children for digit span (7.9 vs 8.7, P=.01), block design (8.6 vs 9.5, P=.03), and mathematics (89.6 vs 93.8, P=.01). Elevated diastolic BP was associated with lower average scores on block design (9.5 vs 11, P=.01). Linear regression showed that elevated systolic BP was independently associated with lower digit span scores (P=.032). CONCLUSION: Children with elevation of systolic BP are at risk for central nervous system end-organ damage, as manifested by decreased digit span test scores.

Adolescent↗