Trimethoprim-Induced Hyperkalemia in a Patient with AIDS

Choi, Michael; Fernandez, Pedro C.; Patnaik, Asit; Coupaye-Gerard, Brigitte; D’Andrea, Denise; Szerlip, Harold M.; Kleyman, Thomas R.

doi:10.1056/nejm199303113281006

Cited by 126 publications

(67 citation statements)

References 21 publications

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“…Furthermore, mutations within these H2 regions alter amiloride binding characteristics (3,12,13). Selected organic cations other than amiloride, such as 2,4,6-triaminopyrimidine, triamterene, pentamidine, and trimethoprim, also function as epithelial Na ϩ channel inhibitors, although with K i values much greater than that of amiloride (51)(52)(53). These data suggest that it is the charged guanidine moiety of amiloride and other organic cations which is interacting with the channel pore.…”

Section: Discussionmentioning

confidence: 99%

Antiidiotypic Antibody Recognizes an Amiloride Binding Domain within the α Subunit of the Epithelial Na+ Channel

Kieber‐Emmons¹,

Lin²,

Foster³

et al. 1999

Journal of Biological Chemistry

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We previously raised an antibody (RA6.3) by an antiidiotypic approach which was designed to be directed against an amiloride binding domain on the epithelial Na ؉ channel (ENaC). This antibody mimicked amiloride in that it inhibited transepithelial Na ؉ transport across A6 cell monolayers. RA6.3 recognized a 72-kDa polypeptide in A6 epithelia treated with tunicamycin, consistent with the size of nonglycosylated Xenopus laevis ␣ENaC. RA6.3 specifically recognized an amiloride binding domain within the ␣-subunit of mouse and bovine ENaC. The deduced amino acid sequence of RA6.3 was used to generate a three-dimensional model structure of the antibody. The combining site of RA6.3 was epitope mapped using a novel computer-based strategy. Organic residues that potentially interact with the RA6.3 combining site were identified by data base screening using the program LUDI. Selected residues docked to the antibody in a manner corresponding to the ordered linear array of amino acid residues within an amiloride binding domain on the ␣-subunit of ENaC. A synthetic peptide spanning this domain inhibited the binding of RA6.3 to ␣ENaC. This analysis provided a novel approach to develop models of antibody-antigen interaction as well as a molecular perspective of RA6.3 binding to an amiloride binding domain within ␣ENaC.Epithelial Na ϩ channels (ENaCs) 1 are expressed in a variety of tissues, including the distal nephron of the kidney, airway and alveolar epithelia in the lung, surface cells in the distal colon, urinary bladder epithelia, skin, and ducts within salivary and sweat glands (1). These transporters facilitate the movement of Na ϩ across the apical (or luminal) plasma membrane and have a critical role in extracellular fluid volume homeostasis, control of blood pressure, fetal lung maturation, and maintenance of airway fluids (1). ENaCs consist of at least three homologous subunits, termed ␣-, ␤-, and ␥ENaC, and are thought to form a tetrameric complex consisting of 2␣-, 1␤-, and 1␥-subunits (2-5), although one group has suggested a subunit stoichiometry of 3␣-, 3␤-, and 3␥-subunits (6). cDNAs encoding these Na ϩ channel subunits have been isolated and characterized from a variety of species. Each ENaC subunit has two predicted membrane-spanning domains. The amino-and carboxyl-terminal regions of the ENaCs are cytoplasmic, and each subunit has a large ectodomain (7-9). Domains of largely hydrophobic residues are located immediately following the putative first membrane-spanning domains and immediately preceding the second membrane-spanning domains of ␣-, ␤-and ␥rENaC (8, 10, 11). The hydrophobic domain immediately preceding the second membrane-spanning region of ENaC (referred to as the H2 domain) may insert in the membrane and form part of the channel pore (3,7,12).The diuretic drug amiloride is a prototypic inhibitor of epithelial Na ϩ channels. Several sites have been identified within the epithelial Na ϩ channel which participate in amiloride binding. Mutagenesis studies suggest that residues preceding the second ...

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Section: Discussionmentioning

confidence: 99%

Antiidiotypic Antibody Recognizes an Amiloride Binding Domain within the α Subunit of the Epithelial Na+ Channel

Kieber‐Emmons¹,

Lin²,

Foster³

et al. 1999

Journal of Biological Chemistry

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“…TMP-SMX is also in common use, representing 30% of all antibiotics prescribed for urinary tract infections (20,21). Trimethoprim is structurally related to the potassium-sparing diuretic amiloride and has been shown to block sodium channels in the distal nephron thereby limiting the electrochemical gradient driving potassium elimination (22)(23)(24)(25)(26)(27).…”

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confidence: 99%

Beta-Blockers, Trimethoprim-Sulfamethoxazole, and the Risk of Hyperkalemia Requiring Hospitalization in the Elderly

Weir¹,

Juurlink²,

Gomes³

et al. 2010

Clinical Journal of the American Society of Nephrology

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Background and objectives:The simultaneous use of beta adrenergic receptor blockers (␤-blockers) and trimethoprimsulfamethoxazole (TMP-SMX) may confer a high risk of hyperkalemia.Design, setting, participants, & measurements: Two nested case-control studies were conducted to examine the association between hospitalization for hyperkalemia and the use of TMP-SMX in older patients receiving ␤-blockers. Linked health administrative records from Ontario, Canada, were used to assemble a cohort of 299,749 ␤-blockers users, aged 66 years or older and capture data regarding medication use and hospital admissions for hyperkalemia.Results: Over the study period from 1994 to 2008, 189 patients in this cohort were hospitalized for hyperkalemia within 14 days of receiving a study antibiotic. Compared with amoxicillin, the use of TMP-SMX was associated with a substantially greater risk of hyperkalemia requiring hospital admission (adjusted odds ratio, 5.1; 95% confidence interval [CI], 2.8 to 9.4). No such risk was identified with ciprofloxacin, norfloxacin, or nitrofurantoin. When dosing was considered, the association was greater at higher doses of TMP-SMX. When the primary analysis was repeated in a cohort of non-␤-blocker users, the risk of hyperkalemia comparing TMP-SMX to amoxicillin was not significantly different from that found among ␤-blocker users.Conclusions: Although TMP-SMX is associated with an increased risk of hyperkalemia in older adults, these findings show no added risk when used in combination with ␤-blockers.

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“…Major causes for Increased potassium levels include adrenal insufficiency, hyporeninemic hypoaldosteronism [17], administration of trimethoprim or pentamidine [18]. A total of 120 subjects were taken for this study.…”

Section: Discussionmentioning

confidence: 99%

Study of Electrolyte Changes in Tuberculosis And Human Immune Deficiency Virus (HIV) Co-Infected with Tuberculosis Patients : A Hospital Based Study

Bhagyamma¹,

Sreeenivasulu²,

Ray³

2016

IOSR

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Trimethoprim-Induced Hyperkalemia in a Patient with AIDS

Cited by 126 publications

References 21 publications

Antiidiotypic Antibody Recognizes an Amiloride Binding Domain within the α Subunit of the Epithelial Na+ Channel

Antiidiotypic Antibody Recognizes an Amiloride Binding Domain within the α Subunit of the Epithelial Na+ Channel

Beta-Blockers, Trimethoprim-Sulfamethoxazole, and the Risk of Hyperkalemia Requiring Hospitalization in the Elderly

Study of Electrolyte Changes in Tuberculosis And Human Immune Deficiency Virus (HIV) Co-Infected with Tuberculosis Patients : A Hospital Based Study

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