title: Mechanisms of triple whammy acute kidney injury.
abstract: Pre-renal acute kidney injury (AKI) results from glomerular haemodynamic alterations leading to reduced glomerular filtration rate (GFR) with no parenchymal compromise. Renin-angiotensin system inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor antagonists (ARAs), non-steroidal anti-inflammatory drugs (NSAIDs) and diuretics, are highly prescribed drugs that are frequently administered together. Double and triple associations have been correlated with increased pre-renal AKI incidence, termed "double whammy" and "triple whammy", respectively. This article presents an integrative analysis of the complex interplay among the effects of NSAIDs, ACEIs/ARAs and diuretics, acting alone and together in double and triple therapies. In addition, we explore how these drug combinations alter the equilibrium of regulatory mechanisms controlling blood pressure (renal perfusion pressure) and GFR to increase the odds of inducing AKI through the concomitant reduction of blood pressure and distortion of renal autoregulation. Using this knowledge, we propose a more general model of pre-renal AKI based on a multi whammy model, whereby several factors are necessary to effectively reduce net filtration. The triple whammy was the only model associated with pre-renal AKI accompanied by a course of other risk factors, among numerous potential combinations of clinical circumstances causing hypoperfusion in which renal autoregulation is not operative or is deregulated. These factors would uncouple the normal BP-GFR relationship, where lower GFR values are obtained at every BP value.
authors.affiliation: Instituto de Estudios de Ciencias de la Salud de Castilla y León-Instituto de Investigación Biomédica de Salamanca (IECSCYL-IBSAL), Paseo de San Vicente, 58-182 - Hospital Virgen Vega, Planta 10, 37007 Salamanca, Spain; Department of Physiology & Pharmacology, University of Salamanca, Salamanca, Spain; Instituto Reina Sofía de Investigación Nefrológica, Fundación Iñigo Álvarez de Toledo, Madrid, Spain; Group of Biomedical Research in Critical Care Medicine (BioCritic), Hospital Clínico Universitario de Valladolid, Valladolid, Spain; Group of Theranostics for Renal and Cardiovascular Diseases (TERCARD), Edificio Departamental, Campus Miguel de Unamuno, Salamanca, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Prieto-García
authors.affiliation: Instituto de Estudios de Ciencias de la Salud de Castilla y León-Instituto de Investigación Biomédica de Salamanca (IECSCYL-IBSAL), Paseo de San Vicente, 58-182 - Hospital Virgen Vega, Planta 10, 37007 Salamanca, Spain; Department of Physiology & Pharmacology, University of Salamanca, Salamanca, Spain; Instituto Reina Sofía de Investigación Nefrológica, Fundación Iñigo Álvarez de Toledo, Madrid, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Pericacho
authors.affiliation: Department of Physiology & Pharmacology, University of Salamanca, Salamanca, Spain; Instituto Reina Sofía de Investigación Nefrológica, Fundación Iñigo Álvarez de Toledo, Madrid, Spain; Group of Biomedical Research in Critical Care Medicine (BioCritic), Hospital Clínico Universitario de Valladolid, Valladolid, Spain; Group of Theranostics for Renal and Cardiovascular Diseases (TERCARD), Edificio Departamental, Campus Miguel de Unamuno, Salamanca, Spain.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Sancho-Martínez
authors.affiliation: Instituto de Estudios de Ciencias de la Salud de Castilla y León-Instituto de Investigación Biomédica de Salamanca (IECSCYL-IBSAL), Paseo de San Vicente, 58-182 - Hospital Virgen Vega, Planta 10, 37007 Salamanca, Spain; Hospital Universitario de Salamanca, Unidad de Hipertensión, Salamanca, Spain.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Sánchez
authors.affiliation: Instituto de Estudios de Ciencias de la Salud de Castilla y León-Instituto de Investigación Biomédica de Salamanca (IECSCYL-IBSAL), Paseo de San Vicente, 58-182 - Hospital Virgen Vega, Planta 10, 37007 Salamanca, Spain; Department of Physiology & Pharmacology, University of Salamanca, Salamanca, Spain; Instituto Reina Sofía de Investigación Nefrológica, Fundación Iñigo Álvarez de Toledo, Madrid, Spain; Group of Biomedical Research in Critical Care Medicine (BioCritic), Hospital Clínico Universitario de Valladolid, Valladolid, Spain; Group of Theranostics for Renal and Cardiovascular Diseases (TERCARD), Edificio Departamental, Campus Miguel de Unamuno, Salamanca, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Martínez-Salgado
authors.affiliation: Instituto de Estudios de Ciencias de la Salud de Castilla y León-Instituto de Investigación Biomédica de Salamanca (IECSCYL-IBSAL), Paseo de San Vicente, 58-182 - Hospital Virgen Vega, Planta 10, 37007 Salamanca, Spain; Department of Physiology & Pharmacology, University of Salamanca, Salamanca, Spain; Instituto Reina Sofía de Investigación Nefrológica, Fundación Iñigo Álvarez de Toledo, Madrid, Spain; Group of Biomedical Research in Critical Care Medicine (BioCritic), Hospital Clínico Universitario de Valladolid, Valladolid, Spain; Group of Theranostics for Renal and Cardiovascular Diseases (TERCARD), Edificio Departamental, Campus Miguel de Unamuno, Salamanca, Spain.
authors.forename: José Miguel
authors.initials: JM
authors.lastname: López-Novoa
authors.affiliation: Instituto de Estudios de Ciencias de la Salud de Castilla y León-Instituto de Investigación Biomédica de Salamanca (IECSCYL-IBSAL), Paseo de San Vicente, 58-182 - Hospital Virgen Vega, Planta 10, 37007 Salamanca, Spain; Department of Physiology & Pharmacology, University of Salamanca, Salamanca, Spain; Instituto Reina Sofía de Investigación Nefrológica, Fundación Iñigo Álvarez de Toledo, Madrid, Spain; Group of Biomedical Research in Critical Care Medicine (BioCritic), Hospital Clínico Universitario de Valladolid, Valladolid, Spain; Group of Theranostics for Renal and Cardiovascular Diseases (TERCARD), Edificio Departamental, Campus Miguel de Unamuno, Salamanca, Spain. Electronic address: flopezher@usal.es.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: López-Hernández
mesh_terms: D058186:Acute Kidney Injury / Q000453:epidemiology / Q000209:etiology* / Q000503:physiopathology; D057911:Angiotensin Receptor Antagonists / Q000008:administration & dosage / Q000009:adverse effects; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D004232:Diuretics / Q000008:administration & dosage / Q000009:adverse effects; D005919:Glomerular Filtration Rate; D006801:Humans; D015994:Incidence; D008962:Models, Theoretical; D012084:Renin-Angiotensin System / Q000187:drug effects; D012307:Risk Factors
chemical_list: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004232:Diuretics
keywords: ACEI; ARA; Diuretic; NSAID; Pre-renal acute kidney injury; Triple whammy