Acute kidney injury secondary to a combination of renin-angiotensin system inhibitors, diuretics and NSAIDS: “The Triple Whammy”

array:19 ["pii" => "X2013251415123895" "issn" => "20132514" "estado" => "S300" "fechaPublicacion" => "2015-03-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Nefrologia (English Version). 2015;35:197-206" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 6600 "formatos" => array:3 [ "EPUB" => 310 "HTML" => 5634 "PDF" => 656 ] ] "itemSiguiente" => array:15 [ "pii" => "X2013251415124102" "issn" => "20132514" "estado" => "S300" "fechaPublicacion" => "2015-03-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Nefrologia (English Version). 2015;35:207-17" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 8374 "formatos" => array:3 [ "EPUB" => 322 "HTML" => 7246 "PDF" => 806 ] ] "en" => array:12 [ "idiomaDefecto" => true "titulo" => "Use of sevelamer in chronic kidney disease: beyond phosphorus control" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "207" "paginaFinal" => "217" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Uso del sevelamer en la enfermedad renal crónica. Más allá del control del fósforo" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "498v35n02-90412410fig1.jpg" "Alto" => 1225 "Ancho" => 1841 "Tamanyo" => 146308 ] ] "descripcion" => array:1 [ "en" => "– Scheme of the effects attributed to sevelamer and their influence on survival in patwients with renal failure." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Laura Rodríguez-Osorio, Diana Pazmiño Zambrano, Carolina Gracia-Iguacel, Jorge Rojas-Rivera, Alberto Ortiz, Jesus Egido, Emilio González Parra" "autores" => array:7 [ 0 => array:2 [ "nombre" => "Laura" "apellidos" => "Rodríguez-Osorio" ] 1 => array:2 [ "nombre" => "Diana" "apellidos" => "Pazmiño Zambrano" ] 2 => array:2 [ "nombre" => "Carolina" "apellidos" => "Gracia-Iguacel" ] 3 => array:2 [ "nombre" => "Jorge" "apellidos" => "Rojas-Rivera" ] 4 => array:2 [ "nombre" => "Alberto" "apellidos" => "Ortiz" ] 5 => array:2 [ "nombre" => "Jesus" "apellidos" => "Egido" ] 6 => array:2 [ "nombre" => "Emilio" "apellidos" => "González Parra" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251415124102?idApp=UINPBA000064" "url" => "/20132514/0000003500000002/v0_201504231604/X2013251415124102/v0_201504231606/en/main.assets" ] "itemAnterior" => array:15 [ "pii" => "X2013251415123699" "issn" => "20132514" "estado" => "S300" "fechaPublicacion" => "2015-03-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Nefrologia (English Version). 2015;35:189-96" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 5301 "formatos" => array:3 [ "EPUB" => 332 "HTML" => 4338 "PDF" => 631 ] ] "en" => array:12 [ "idiomaDefecto" => true "titulo" => "Overhydration prevalence in peritoneal dialysis – A 2 year longitudinal analysis" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "189" "paginaFinal" => "196" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Prevalencia de la sobrehidratación en la diálisis peritoneal: estudio longitudinal de 2 años" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "498v35n02-90412369fig2.jpg" "Alto" => 1504 "Ancho" => 1954 "Tamanyo" => 172162 ] ] "descripcion" => array:1 [ "en" => "– Relative overhydration over 2 years on PD. Hydration status remained fairly stable over the follow-up period, regardless of residual diuresis, PD vintage, or PD modality. The difference found on the first year evaluation (T1) between anuric and patients with diuresis >250 ml/day was normalized by the second year (T2)." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Pedro Ventura Aguiar, Olívia Santos, Laetitia Teixeira, Fernanda Silva, Pedro Azevedo, Joana Vidinha, Francisco Ferrer, Maria João Carvalho, António Cabrita, Anabela Rodrigues" "autores" => array:10 [ 0 => array:2 [ "nombre" => "Pedro" "apellidos" => "Ventura Aguiar" ] 1 => array:2 [ "nombre" => "Olívia" "apellidos" => "Santos" ] 2 => array:2 [ "nombre" => "Laetitia" "apellidos" => "Teixeira" ] 3 => array:2 [ "nombre" => "Fernanda" "apellidos" => "Silva" ] 4 => array:2 [ "nombre" => "Pedro" "apellidos" => "Azevedo" ] 5 => array:2 [ "nombre" => "Joana" "apellidos" => "Vidinha" ] 6 => array:2 [ "nombre" => "Francisco" "apellidos" => "Ferrer" ] 7 => array:2 [ "nombre" => "Maria João" "apellidos" => "Carvalho" ] 8 => array:2 [ "nombre" => "António" "apellidos" => "Cabrita" ] 9 => array:2 [ "nombre" => "Anabela" "apellidos" => "Rodrigues" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251415123699?idApp=UINPBA000064" "url" => "/20132514/0000003500000002/v0_201504231604/X2013251415123699/v0_201504231606/en/main.assets" ] "en" => array:15 [ "idiomaDefecto" => true "titulo" => "Acute kidney injury secondary to a combination of renin-angiotensin system inhibitors, diuretics and NSAIDS: “The Triple Whammy”" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "197" "paginaFinal" => "206" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "Rosa Rosa Maria Garcia Camin, Montse Cols, Julio Leonel Chevarria, Rosa García Osuna, Marc Carreras, xGarcia Camin, Josep Maria Lisbona, Jordi Coderch" "autores" => array:7 [ 0 => array:3 [ "nombre" => "Rosa Rosa Maria Garcia Camin, Montse Cols, Julio Leonel Chevarria, Rosa García Osuna, Marc Carreras," "apellidos" => "xGarcia Camin" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "affa" ] ] ] 1 => array:3 [ "nombre" => "Montse" "apellidos" => "Cols" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "affb" ] ] ] 2 => array:3 [ "nombre" => "Julio" "apellidos" => "Leonel Chevarria" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "affa" ] ] ] 3 => array:3 [ "nombre" => "Rosa" "apellidos" => "García Osuna" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "affa" ] ] ] 4 => array:3 [ "nombre" => "Marc" "apellidos" => "Carreras" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "affc" ] ] ] 5 => array:3 [ "nombre" => "Josep Maria" "apellidos" => "Lisbona" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "d" "identificador" => "affd" ] ] ] 6 => array:3 [ "nombre" => "Jordi" "apellidos" => "Coderch" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "affc" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Nephrology, Hospital de Palamós [Palamós Hospital], Palamós, Girona (Spain)" "etiqueta" => "a" "identificador" => "affa" ] 1 => array:3 [ "entidad" => "Palamós, Hospital de Palamós, Palamós, Girona (Spain)" "etiqueta" => "b" "identificador" => "affb" ] 2 => array:3 [ "entidad" => "Grup de recerca en Serveis Sanitaris i Resultats en Salut (GRESSIRES) [Research Group on Health Services and Health Outcomes], Hospital de Palamós, Palamós, Girona (Spain)" "etiqueta" => "c" "identificador" => "affc" ] 3 => array:3 [ "entidad" => "Health Care Information Unit, Hospital de Palamós, Palamós, Girona (Spain)" "etiqueta" => "d" "identificador" => "affd" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Fracaso renal agudo secundario a combinación de inhibidores del sistema renina-angiotensina, diuréticos y AINES. “La Triple Whammy”" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "498v35n02-90412389fig1.jpg" "Alto" => 1208 "Ancho" => 1862 "Tamanyo" => 216666 ] ] "descripcion" => array:1 [ "en" => "– Study schedule. (a) Drugs according to ATC classification (NSAIDs not including ASA 100-300 mg, paracetamol or metamizole). (b) AKI associated with the use of ACEI/ARB-II/Diuretics/NSAIDs. (c) Randomized sample of controls paired by specialty, sex, age and comorbidity according to the Clinical Risk Groups (CRG). AKI: Acute kidney injury; ACEI: Angiotensin converting enzyme inhibitors; ARB II: Angiotensin-II receptor blockers; NSAID: Non-steroidal anti-inflammatory drugs." ] ] ] "textoCompleto" => "Introduction The combination of renin-angiotensin system inhibitor (ACEI or ARB-II) antihypertensive drugs with diuretics, which is often associated with analgesic treatments including non-steroidal anti-inflammatory drugs (NSAIDs) in senior patients, may cause acute kidney injury (AKI). These drug interactions have not been well studied in the literature.1-4 In 1996, the incidence of AKI in Spain was 209 cases/million adults/year5 according to a study by Liaño, et al., conducted in the Madrid Community. The 2002 study by L.M. Lou, et al.6, which was conducted at a Spanish district hospital with characteristics similar to ours, indicated that 79% of hospitalizations due to AKI originated outside the hospital. The cause was volume depletion in 34.2% of cases, a datum that highlighted the elevated incidence of antihypertensive treatments (primarily renin-angiotensin system inhibitors) and/ or diuretics as coadjuvant factors for AKI. However, the study of drug-related acute kidney injury has received little attention in the literature; meanwhile, its implications in terms of increased mortality, days of hospitalization and costs are unknown. In 2000, MC Thomas7 coined the term “Triple Whammy” (TW) to refer to the adverse effects resulting from the combination of ACEI or ARB-II, diuretics and NSAIDs, particularly in seniors. Chertow, et al.8, observed that small creatinine increments of 0.3 or 0.4 mg/dL were associated with increased mortality, mean hospitalization days, and higher costs. The objectives of our study were to describe the population prevalence of consumption and the incidence of outpatient AKI secondary to Triple Whammy drugs (AKITW): ACEI, ARB-II, diuretics and NSAIDs for each type of drug and their combinations, characterizing the profile of the admitted patients and analysing their mean hospital stay, hospital costs and mortality.Methods A retrospective observational study was conducted in three stages, with a mixed design, at Palamós Hospital (Baix Empordà district hospital), which is a reference hospital for 127,151 inhabitants with 130 beds (Figure 1).<img alt="Figure 1 – Study schedule. (a) Drugs according to ATC classification (NSAIDs not including ASA 100-300 mg, paracetamol or metamizole). (b) AKI associated with the use of ACEI/ARB-II/Diuretics/NSAIDs. (c) Randomized sample of controls paired by specialty, sex, age and comorbidity according to the Clinical Risk Groups (CRG). AKI: Acute kidney injury; ACEI: Angiotensin converting enzyme inhibitors; ARB II: Angiotensin-II receptor blockers; NSAID: Non-steroidal anti-inflammatory drugs." src="498v35n02-90412389fig1.jpg"></img>Figure 1 – Study schedule. (a) Drugs according to ATC classification (NSAIDs not including ASA 100-300 mg, paracetamol or metamizole). (b) AKI associated with the use of ACEI/ARB-II/Diuretics/NSAIDs. (c) Randomized sample of controls paired by specialty, sex, age and comorbidity according to the Clinical Risk Groups (CRG). AKI: Acute kidney injury; ACEI: Angiotensin converting enzyme inhibitors; ARB II: Angiotensin-II receptor blockers; NSAID: Non-steroidal anti-inflammatory drugs. The study project complied with the principles of the World Medical Association Declaration of Helsinki and was approved by the Serveis de Salut Integrats Baix Empordà (SSIBE) [Baix Empordà Comprehensive Health Service] Clinical Research Committee. Given the study methodology, which was based on a retrospective review of clinical-administrative records, informed consent was not requested. Data collection was performed by an authorized SSIBE professional and data were managed anonymously.Design and patients First stage of the study: A cross-sectional analysis was made of the 8,029 hospital admissions in the study period (January 2011 to March 2012) in order to identify drug-related AKI cases secondary to ACEI/ARB-II, diuretics and/or NSAIDs, and to describe the clinical characteristics of the admitted patients and their previous medications. Drug-related acute kidney injury secondary to the use of Triple Whammy drugs (AKITW) was defined as hospital admission with a discharge code of AKI (ICD-9-CM 584.9) in a patient who had been receiving any of those drugs prior to admission and where, following an audit of the medical record by a nephrologist, the possible cause of AKI is attributed to the use of ACEI/ARB-II, diuretics and/or NSAIDs, either alone or in combination (a prerenal situation may be involved based on the presence of fever, vomiting or diarrhea). In addition, the patient’s baseline creatinine value was 1.3 mg/dL or lower at least one month before admission, which increased to more than 1.4 mg/dL on admission. Excluded from the study were cases of hospital-acquired AKI (defined as patients who are admitted with a creatinine value below 1.3 mg/dL that increases to more than 1.4 mg/dL during hospitalization), obstructive AKI, glomerulonephritis, hepatorenal syndrome, decompensated heart failure, multiple organ failure, infection, ischemia, poisoning, end-stage cancer, exposure to radiocontrast agents or known nephrotoxic drugs, and multifactorial casesSecond stage of the study: Four basic health care areas (BHA) share an information system of computerized medical files with our hospital. As the prescription records of the 87,160 patients belonging to the BHA were available to us, we followed up a cohort of the 15,307 outpatients who had been prescribed one or more ACEI/ARB-II, diuretics or NSAIDs in February 2011. Our goal was to analyze the prevalence of use and incidence of drug-related AKI of this population for each type of drug and their combinations. The data from this cohort were cross-referenced with the data from hospital admissions due to AKITW that had been identified in the first stage. Out of the 85 cases of AKITW detected in stage 1 (15 months of follow-up), we selected the 65 cases belonging to the population of the four BHA with available computerized medical records and drug prescription data.Third stage of the study: A cohort study was used to assess the impact of AKITW on hospital stays, costs and mortality. The study population was limited to hospitalization episodes in 2011 (12 months) of residents of the four BHA for whom prescription data pharmacy costs were available. All the hospitalization episodes due to AKITW belonging to the 4 BHA were considered cases (62 patients). The control group was made up of 62 randomly selected hospital admissions of patients without AKI, paired by medical specialty, sex, age and comorbidities according to Clinical Risk Group (CRG).9,10 Variables and data sources Data for the selection and analysis of the hospitalizations were obtained from the Palamós Hospital computerized hospital admission files. The medical records were reviewed thoroughly by a nephrologist, who compiled detailed information about patient characteristics and progression. The variables collected on hospitalization episodes for AKITW were: age, sex, use of ACEI/ARB-II, diuretics and NSAIDs before admission except for ASA 100-300 mg (drug, mean daily dose and treatment duration in weeks), history of hypertension (HTN) (defined by antihypertensive medication use), chronic kidney disease (CKD) prior to admission (defined as any patient admitted under code ICD-9: 585), chronic heart failure (CHF) (defined as any patient admitted under code ICD-9: 428), prior rheumatic disease (previous diagnosis of rheumatic disease with follow-up by a rheumatologist), associated prerenal cause (depletion due to fever, vomiting or diarrhea), signs of dehydration (admitting physician recorded dehydration on the ER report, or patient was admitted with hypotension and the examination revealed dry skin or mucosae), edema, pain and cause of pain, need for dialysis, CKD as a post-dialysis sequela (considered as patients with ICD-9 code: 585 who did not have CKD before admission), creatinine (baseline, peak on admission, on discharge and at six months following admission), albuminemia on admission, K on admission, hospital stay (days), death (date). Renal function was measured with creatinine analyzed by Jaffe’s method, alkaline picrate and kinetic reading; traceability was guaranteed with the isotopic dilution mass spectrometry (IDMS). Glomerular filtration (GF) was calculated with MDRD4 IDMS. Exacerbated CKD was considered as a patient previously diagnosed with CKD who had a creatinine level of more than 0.3 mg/dL over their baseline creatinine value, which had been measured at least one month before admission. The pharmacy data of the population were obtained from the computerized prescription files of the primary health care services. Drugs of interest were classified by groups based on ATC codes ( World Health Organizat ion Anatomical, Therapeutic, Chemical classification system): ACEI, ARB-II, diuretics and NSAIDs (not including acetylsalicylic acid 100-300 mg, paracetamol or metamizole). The ACEI and ARB-II groups were considered a single drug type because of their similar mechanism of action. The use of one, two or three diuretics and NSAIDs were considered separately. Drugs prescribed during hospitalization were not considered. Data for hospitalization costs, which are calculated yearly with the full-costing system, were obtained from the Serveis de Salut Integrats (SSIBE) costs file. This system follows the methodology and recommendations from the analytical accounting workgroup of the Servei Català de la Salut [Catalan Health Service] Central Financial Office11,12 and the Red Española de Costes Hospitalarios (RECH) [Spanish Hospital Costs Network]13,14. The cost associated with each hospitalization episode was calculated individually using the clinical and activity information recorded from admission to discharge. Thus, the cost of each hospitalization episode was obtained based on the number of hospitalization days, minutes in the operating room, dialysis sessions, single medication doses, laboratory tests, imaging tests and other tests performed from admission to discharge. In the 2011 fiscal year, the mean hospital stay cost at Palamós Hospital was €279.63, one minute in the operating room was €10.39 and each dialysis session was €146.45. The cost of single medication doses was assigned directly to the episode at the weighted mean price. Finally, the costs for laboratory tests, diagnostic imaging tests and the remaining tests was input according to the mean cost of each technique performed based on each department’s catalogue of services.Statistical analysis In order to identify the hospitalizations due to AKITW in association with these drugs, we conducted a univariate statistical analysis with frequency, mean and standard deviation, according to the characteristics of each variable. Drug combinations were analyzed as exclusive categories. To measure the impact of drug use, the population incidence was measured for each category with its 95% confidence interval. To compare groups in the case-control analysis, a bivariate statistical analysis was conducted with Student’s t-test or chi-square test, depending on the variable’s characteristics. Fisher’s exact test was used when applicable. P < 0.05 was considered statistically significant. The IBM SPSS Statistics 20.0 program was used.Results 1. First stage of the study: Identification and characterization of drug-related AKI Out of the 8,029 hospital admissions during the study period, 415 cases of AKI were identified, of which 368 were drug-related AKI and 85 were attributed directly to the use of ACEI/ ARB-II, diuretics and/or NSAIDs (AKITW) (Figure 1). These 85 cases had a similar distribution between both sexes and mean age was 78.72 years (SD 11.69). When analyzed by age groups, the case distribution clearly shifted to the older age ranges (Table 1).<img alt="Table 1 – Clinical characteristics of hospitalization episodes due to acute kidney injury associated with ACEI, ARB-II, diuretics and/or NSAIDs (Hospital de Palamós, January 2011–March 2012)" src="498v35n02-90412389fig2.jpg"></img> Practically half of the cases had a history of CKD or CHF prior to admission. In two-thirds of cases, there was a prerenal cause associated with ACEI/ARB-II, diuretics and/or NSAIDs (history of fever, vomiting or diarrhea in the days before admission). In four out of five cases, the medical records did not specify a cause of pain justifying the chronic use of NSAIDs; in 59% of cases where the cause was specified, it was chronic joint pain. The mean baseline creatinine value prior to admission was 1.32 mg/dL (SD 0.50) and the mean creatinine increase from baseline to admission was 1.77 mg/dL (SD 1.51). In 34% of patients, peak creatinine doubled baseline creatinine levels. Six months after discharge, mean creatinine had an increase of 13.89% from the pre-admission baseline creatinine. The mean baseline GFR was 57.3  mL/min/1.73m2, and at six months it was 52.77 mL/min/1.73 m2, which was a decrease of 4.6%. More than half the patients had hypoalbuminemia, which was serious (< 2.5 g/dL) in 19% of cases. One-third were admitted with hyperkalemia, and three cases were serious enough to cause death after admission. One patient required dialysis and more than 10% of patients had CKD as a sequela for six months after admission. With respect to the drugs the patients were taking before admission, ACEI prescriptions were identified in half of cases; three-quarters of these patients had been taking them for more than four weeks. The most widely used ACEI was enal-april, which was consumed by three out of four ACEI users. One-third of patients were ARB-II users, most of whom had been on treatment for more than four weeks. The most widely used form was losartan, which was being taken by a third of ARB-II users. Diuretics were prescribed in almost nine out of ten cases to treat the following: HTN in 55.4% of cases, CHF in 33.8%, and edema in 6%. Almost three-quarters of patients had been on treatment for more than four weeks and almost one-quarter had been prescribed more than one type of diuretic. The most widely used diuretic was furosemide, followed by hydrochlorothiazide. NSAIDs were prescribed in just over one-fifth of cases; two-thirds of them had been on treatment for more than four weeks. The most widely used NSAID was ibuprofen (Table 2).<img alt="Table 2 – Drugs associated with drug-related acute kidney injury: types, dose and time of exposure (Palamós Hospital, January 2011–March 2012)" src="498v35n02-90412389fig3.jpg"></img> Out of patients the admitted, 88.2% were on dual or triple therapy: 54% dual therapy, 39% combined ACEI/ARB-II + diuretics, and 34% Triple Whammy.2. Second stage of the study: Use of ACEI/ARB-II, diuretics and NSAIDs in the population and associated AKI From a population of 87,160 people, a total of 15,307 were on the target drugs, which represented 175.62 users/1,000 inhabitants (Figure 1). The population prevalence of use for each type of drug (alone and in various possible combinations among them) is shown in Figure 2. The most common type of use in the study population was monotherapy, which accounted for more than half of these users. The most common monotherapy was ACEI/ARB-II, and the least used were diuretics. More than one-third of these users were on dual therapy, the most frequent being ACEI/ARB-II + diuretics. Just over 1 person per 100 inhabitants had been prescribed the Triple Whammy.<img alt="Figure 2 – Prevalence of use of ACEI/ARB-II, diuretics and NSAIDs in Baix Empordà, February 2011. ACEI: Angiotensin converting enzyme inhibitor; ARB-II: Angiotensin-II receptor blocker; NSAID: Non-steroidal anti-inflammatory drug" src="498v35n02-90412389fig5.jpg"></img>Figure 2 – Prevalence of use of ACEI/ARB-II, diuretics and NSAIDs in Baix Empordà, February 2011. ACEI: Angiotensin converting enzyme inhibitor; ARB-II: Angiotensin-II receptor blocker; NSAID: Non-steroidal anti-inflammatory drug Table 3 shows the incidence of AKI associated with ACEI/ ARB-II, diuretics and NSAIDs in the population consuming these drugs. Overall incidence was 3.40 cases/year/1,000 users, which generally increased with the number of drugs combined. In monotherapy, the diuretics group had a relevant incidence, which increased when they were combined with ACEI/ARB-II or NSAIDs in a dual therapy. In contrast, the incidence of AKI associated with ACEI/ARB-II and NSAIDs, alone or combined among them, was lower. The incidence of associated AKI in Triple Whammy users was similar to that of users of dual therapies that included diuretics.<img alt="Table 3 – Use of ACEI/ARB-II, diuretics and NSAIDs in the overall population and associated acute kidney injury (Baix Empordà, January 2011–March 2012) " src="498v35n02-90412389fig4.jpg"></img>3. Third stage of the study: Impact of AKI associated with ACEI/ ARB-II, diuretics and/or NSAIDs In the comparison of the AKITW cases with paired non-AKI controls, no statistically significant differences were found for mean hospital stay between the two groups: 7.6 days (SD 6.4) for cases and 5.8 (SD 4.5) for controls (p = 0.07). The total number of hospital stays generated in one year due to AKI secondary to the target drugs was 473 days for 87,160 inhabitants. This represents an estimated 543 days of avoidable hospital stay/100,000 inhabitants/year. Regarding costs, the mean cost was €3,016 (SD 2,468) for cases and €2,663 (SD 2,876) for controls, with no significant differences between them (p = 0.43). When we consider that the total one-year cost was €187,049 for 87,160 inhabitants, we can estimate an annual avoidable cost of €214,604/100,000 inhabitants/year. Mortality was 11.3% for cases and 6.5% for controls during hospitalization and 40.3% and 38.7%, respectively, during the 12-month follow-up. No statistically significant differences were found between the groups at those time points or during the follow-up at three, six and nine months (Figure 3).<img alt="Figure 3 – Mortality for AKI secondary to ACEI/ARB-II, diuretics and NSAIDs compared to admission of patients with no AKI (Palamós Hospital, 2011). (a) Control group: Hospitalizations of patients with no acute kidney injury paired by sex, age and comorbidity according to Clinical Risk Group (CRG) categories. All comparisons were non-significant (p > 0.05 based on Fischer’s exact test). TW: Triple Whammy" src="498v35n02-90412389fig6.jpg"></img>Figure 3 – Mortality for AKI secondary to ACEI/ARB-II, diuretics and NSAIDs compared to admission of patients with no AKI (Palamós Hospital, 2011). (a) Control group: Hospitalizations of patients with no acute kidney injury paired by sex, age and comorbidity according to Clinical Risk Group (CRG) categories. All comparisons were non-significant (p > 0.05 based on Fischer’s exact test). TW: Triple WhammyDiscussion Our results suggest that the consumers of these drugs have an elevated incidence of AKI. Greater incidence was observed for diuretics, as monotherapy or in dual or triple therapy; the highest incidence was for the dual therapy of diuretics + NSAIDs. Triple Whammy (ACEI/ARB-II + diuretics + NSAIDs) users had an AKI incidence similar to those taking dual therapies that included diuretics. The main reason for the prescription of diuretics in our patients was high blood pressure. Out of all the patients admitted due to AKITW, 87% used diuretics, 84.6% used ACEI/ARB-II and 38.5% used NSAIDs. In the population who had been prescribed one of these drugs, 7.2% were on dual or triple therapy. Similarly to Loboz et al.2, we observed that 54% of our admitted patients were on dual therapy, of which almost 40% were prescribed the ACEI/ARB-II + diuretics combination. Loboz et al.2 noticed that an increase in the dose of diuretics was related to a decrease in GFR and, for the remaining drugs, the risk was present even at low doses. Likewise, in our case, patients were consuming therapeutic or even low doses of diuretics and other drugs. This suggests that administering small doses of these drugs in combination fails to reduce the risk of AKI. Lou LM et al.6 and Huerta et al.15 also observed an increase in AKI incidence with the combination of ACEI and diuretics. The association of ACEI/ARB-II + NSAIDs presented an elevated incidence, although with a very broad confidence interval, probably due to the limited number of cases. Huerta et al.15 did not find an increased risk for the combination of NSAIDs with renin-angiotensin system inhibitors. Our data differ from the data found by Lapi et al.16, who found no risk for AKI when using dual therapy with diuretics or ACEI/ARB-II + NSAIDs. They only found a risk for AKI with the Triple Whammy, which was particularly noticeable in the first 30 days of treatment. In our study, we have seen that the hospitalized patients had been receiving treatment for more than four weeks, regardless of the drug group, and the triggering factor for AKI had been a concurrent disease causing hypovolemia. The profile of a patient at risk of suffering AKI with these drugs is an elderly patient with multiple conditions and on multiple concomitant medicantions. This risk exists even with drugs at low therapeutic doses. The presence of hypoalbuminemia < 3 g/dL is alarming in 51% of hospitalization episodes due to AKITW, of which 19% were severe cases (< 2.5 g/ dL). This fact reflects the degree of malnutrition in a large part of the elderly population despite living at home. In 67% of cases, there was a triggering factor for AKI, such as fever, vomiting or diarrhea, in previous days. What probably makes the glomerular filtration drop abruptly is a concurrent disease causing volume depletion or, simply, an increase in baseline metabolism in a patient with intraglomerular pressure decreased by vasodilated efferent arterioles secondary to treatment with ACEI or ARB-II, combined with a circulating volume reduced by diuretics. Elderly patients are known to maintain their GF thanks to a complex system of intraglomerular resistance. Due to the vessel rigidity present in these patients, the kidneys find it hard to adapt to changes in intraglomerular pressure and, therefore, are very sensitive to volume changes. This seems to suggest that the cause of the AKI was not the treatment with these drugs, but the onset of a concurrent disease. Of the admitted patients, 74% were on chronic diuretic treatment (more than four weeks) and 21.6% were on two diuretics combined. These were patients with decreased baseline GF, in many cases with a history of CKD or CHF, who were treated with diuretics, primarily for hypertension. They generally had mild or moderate AKI, with small creatinine increases that were resolved with hydration in most cases. Nevertheless, 10% of patients had CKD as a sequela and three patients died of hyperkalemia during admission. In four of five cases, the patients’ medical records did not specify a cause of pain justifying the chronic use of NSAIDs, and in 59% of cases where the cause was specified, it was chronic joint pain. These data reflect that NSAID therapies are started at times of acute pain and are not properly withdrawn afterwards. The 2012 KDIGO guidelines17 already recommended starting treatment with ACEI and ARB-II at low doses in patients with GFR < 45 mL/min and discontinue it temporarily in cases with concurrent disease. As for NSAIDs, the recommendation is to avoid their use in patients treated with renin-angiotensin system inhibitors, and prolonged therapies are not recommended if GFR is < 60 mL/min. The STOPP/START18 criteria determine that prescribing diuretics for isolated ankle edema is inappropriate in patients older than 65 years because there is no evidence of their efficacy. They are also not recommended as first-line monotherapy in hypertension. NSAIDs should be avoided in moderate to severe hypertension and CHF, and their use for more than three months to relieve mild joint pain should be avoided. In cases of CKD, they are not recommended either. Even though NSAIDs are not formally contraindicated in the elderly, they are a high-risk population for adverse effects, particularly AKI, and their use should be the result of a thorough risk-benefit assessment. Only 58% of physicians noticed evident signs of dehydration on admission. Therefore, it is advisable that, in case of a concurrent condition, treatment with at least one of the target drugs be discontinued. This should be applied primarily to diuretics, even if the physician does not notice signs of dehydration. When initiating these combinations, renal function and creatinine values are to be monitored.19 The Fournier, et al.20 group from Toulouse has recently performed a new analysis of the review they conducted on their pharmacovigilance database of adverse pharmacological effects in 2012. Their aim was to study whether NSAID half-life had an impact on the possibility of developing AKI. An association was found, not with the drugs’ half-life, but with the number of associated drugs, which coincided with the findings in previous publications and with our results. In our case, due to the small size of our sample, it was impossible to analyze incidence differences based on the drugs’ half-lives. A cost of €214,604/100,000 inhabitants/year for hospitalization episodes derived from a combined prescription of these drugs is a significant economic problem and, evidently, the three deaths that occurred during admission due to hyperkalemia could have been avoided with correct prescription. Our study is not limited to the utilization of large databases. It is focused on drug-related AKI in conjunction with the auditing of medical records by a nephrologist to ensure that the AKITW included in this study are only due to the treatment with these drugs, either alone or combined, without the contribution of any other factor except for the prerenal situations discussed above. This avoids confusion due to the high mortality associated with AKI for other causes. Most of the studies conducted so far are based on the utilization of large databases focused on overall AKI treatment. We analyzed the clinical patient characteristics to create a profile of at-risk patients, and we quantified the personal (mortality) and economic costs of AKI caused by incorrect drug combinations. The limitations of our study are the small number of cases and not having included treatment with ASA at low doses (100 and 300 mg) as an NSAID but instead as antiplatelet drug, as indicated in the pharmaceutical coding, since a large part of the patients admitted (19) were receiving prophylactic treatment at these doses. Paracetamol at doses greater than 4 g/d could also have an NSAID effect. Both Paracetamol and the remaining NSAIDs are over-the-counter drugs in our pharmacies (our data only include NSAIDs prescribed by their physicians), so the use of NSAIDs could be underestimated. We have also not analyzed the impact of impaired renal function cases that do not require admission. Therefore, the true incidence of AKITW may be higher and may also be generating elevated expenditures in the outpatient setting.Conclusion Diuretics in monotherapy, dual and triple combination therapy (Triple Whammy) have an elevated incidence of AKI. Dual therapies including diuretics show the same incidence of AKI as the Triple Whammy. The profile of the at-risk patient is an elderly patient with an underlying renal or cardiac disease. The problem does not seem to be the drug itself but the onset of a concurrent disease causing hypovolemia. Monitoring renal function and potassium levels is recommended when these therapies are initiated and in situations of concurrent disease, following the recommendations from scientific societies (KDIGO and STOPP-START criteria). In cases of concurrent disease, the temporary discontinuation of the Triple Whammy drugs, particularly diuretics, is recommended. The use of NSAIDs should be minimized and treatment with diuretics should be monitored following hospital discharge. Patient treatment should be adjusted to the situation at hand, with special attention given to people over the age of 80 who have concurrent conditions. AKI derived from a combination of Triple Whammy drugs has demonstrated high health care-related expenditures and avoidable deaths. Health care authorities should be aware of this serious issue and limit the over-the-counter availability of NSAIDs at pharmacies.Acknowledgments The authors would like to thank the Sociedad Española de Nefrología (SEN) [Spanish Society of Nephrology] for the grant to help publish this paper. Likewise, we would like to thank Lluis Palé Mena and Maritza López Pereira for their cooperation with the fieldwork required to carry out this study. We also thank the assistance provided by the Serveis de Salut Integrats Baix Empordà research fund for the publication of this paper.Conflicts of interest There are no conflicts of interest; this study was conducted for non-profit purposes.Funding No funding has been received.<hr></hr> Sent for Review: 24 Oct. 2014 Accepted on: 16 Dec. 2014<a href="http://dx.doi.org/10.3265/Nefrologia.pre2014.Dec.12800" class="elsevierStyleCrossRefs">http://dx.doi.org/10.3265/Nefrologia.pre2014.Dec.12800</a> * Corresponding author. Rosa Maria Garcia Camin, Nephrology Department, Hospital de Palamós, Hospital, 17230, Palamós, Girona, Spain. Telephone: 696521296 E-mail:<a href="mailto:30368rgc@comb.cat" class="elsevierStyleCrossRefs">30368rgc@comb.cat</a>" "pdfFichero" => "498v35n02a90412389pdf001.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec503501" "palabras" => array:5 [ 0 => "Lesión renal aguda" 1 => "Agentes antiinflamatorios" 2 => "Agentes antihipertensivos" 3 => "Diuréticos" 4 => "Interacciones farmacológicas" ] ] ] "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec503502" "palabras" => array:5 [ 0 => "Acute kidney injury" 1 => "Antihypertensive agents" 2 => "Diuretics" 3 => "Drug interactions" 4 => "Anti-inflammatory agents" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "es" => array:1 [ "resumen" => " Introducción: Inhibidores del sistema renina-angiotensina (IECAS/ARA II), diuréticos y AINES, combinación conocida como “Triple Whammy”, pueden producir descenso de filtrado glomerular y fracaso renal agudo (FRA). Objetivos: Describir la incidencia de FRA para cada tipo de fármaco y sus combinaciones. Caracterizar el perfil de paciente que ingresa por FRA extrahospitalario secundario a fármacos de la Triple Whammy (FRAETW), evaluando costes y mortalidad. Métodos: estudio observacional retrospectivo realizado durante 15 meses y desarrollado en tres etapas: - 1º Etapa transversal de identificación y descripción de los ingresos hospitalarios por FRAETW. - 2º Etapa de seguimiento de una cohorte ambulatoria consumidora de estos fármacos (15.307 consumidores) - 3º Etapa de cohortes para evaluar costes y mortalidad, contrastando 62 pacientes ingresados con FRAETW, con 62 pacientes sin FRA, apareados por especialidad médica, sexo, edad y comorbilidad según Clinical Risk Groups. Resultados: 85 ingresos por FRAETW, 78% mayores de 70 años. Incidencia poblacional de FRAETW: 3,40 casos/1.000 consumidores/año (IC95% 2,59-4,45). Por categorías: AINES + diuréticos 8,99(IC95% 3,16-25,3), la “Triple Whammy” 8,82(IC 95% 4,4-17,3), IECA/ARA II + diuréticos 6,87(IC95% 4,81-9,82) y la monoterapia con diuréticos 3,31(IC95% 1,39-7,85). Estancia media 7,6 días (DE 6,4), estimándose coste medio evitable de 214.604 €/100.000 habitantes/ año. Mortalidad del 11,3% durante el ingreso y del 38,7% a los 12 meses, sin diferencias significativas con los controles. Conclusiones: El tratamiento con IECA, ARA II, diuréticos y/o AINES presenta elevada incidencia de ingreso por FRA, siendo los diuréticos en monoterapia, doble y triple terapia combinada los que ocasionan la mayor incidencia. El FRAETW supone elevados costes sanitarios y muertes evitables." ] "en" => array:1 [ "resumen" => " Background: Renin-angiotensin system inhibitors (ACEI/ARB-II), diuretics and NSAIDs, a combination known as “Triple Whammy”, can result in decreased glomerular filtration rate (GFR) and acute kidney injury (AKI). Objectives: To describe the incidence of AKI for each drug type and their combinations. To define the profile of patients admitted for drug-related AKI secondary to Triple Whammy drugs (AKITW), with an assessment of costs and mortality. Methods: A retrospective observational 15-month study developed in three stages: - First: a cross-sectional stage to identify and describe hospitalizations due to AKITW. - Second: a follow-up stage of an outpatient cohort consuming these drugs (15,307 subjects). - Third: a cohort stage to assess costs and mortality, which compared 62 hospitalized patients with AKITW and 62 without AKI, paired by medical specialty, sex, age and comorbidity according to their Clinical Risk Groups. Results: There were 85 hospitalization episodes due to AKITW, and 78% of patients were over the age of 70. The incidence of AKITW in the population was 3.40 cases/1000 users/year (95% CI: 2.59–4.45). By categories, these were: NSAIDs + diuretics 8.99 (95% CI: 3.16–25.3); Triple Whammy 8.82 (95% CI: 4.4–17.3); ACEI/ARB-II + diuretics 6.87 (95% CI: 4.81–9.82); and monotherapy with diuretics 3.31 (95% CI: 1.39–7.85). Mean hospital stay was 7.6 days (SD 6.4), and mean avoidable costs were estimated at €214,604/100,000 inhabitants/year. Mortality during hospitalization and at 12 months was 11.3% and 38.7% respectively, and there were no significant differences when compared with the control group. Conclusions: Treatment with ACEI, ARB-II, diuretics and/or NSAIDs shows a high incidence of hospitalization episodes due to AKI; diuretics as monotherapy or dual and triple combination therapy cause the highest incidence. AKITW involves high health care costs and avoidable mortality." ] ] "multimedia" => array:6 [ 0 => array:8 [ "identificador" => "fig1" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "498v35n02-90412389fig1.jpg" "Alto" => 1208 "Ancho" => 1862 "Tamanyo" => 216666 ] ] "descripcion" => array:1 [ "en" => "– Study schedule. (a) Drugs according to ATC classification (NSAIDs not including ASA 100-300 mg, paracetamol or metamizole). (b) AKI associated with the use of ACEI/ARB-II/Diuretics/NSAIDs. (c) Randomized sample of controls paired by specialty, sex, age and comorbidity according to the Clinical Risk Groups (CRG). AKI: Acute kidney injury; ACEI: Angiotensin converting enzyme inhibitors; ARB II: Angiotensin-II receptor blockers; NSAID: Non-steroidal anti-inflammatory drugs." ] ] 1 => array:8 [ "identificador" => "tbl1" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tablaImagen" => array:1 [ 0 => array:4 [ "imagenFichero" => "498v35n02-90412389fig2.jpg" "imagenAlto" => 1350 "imagenAncho" => 1045 "imagenTamanyo" => 195713 ] ] ] ] ] "descripcion" => array:1 [ "en" => "– Clinical characteristics of hospitalization episodes due to acute kidney injury associated with ACEI, ARB-II, diuretics and/or NSAIDs (Hospital de Palamós, January 2011–March 2012)" ] ] 2 => array:8 [ "identificador" => "tbl2" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tablaImagen" => array:1 [ 0 => array:4 [ "imagenFichero" => "498v35n02-90412389fig3.jpg" "imagenAlto" => 2820 "imagenAncho" => 2120 "imagenTamanyo" => 373580 ] ] ] ] ] "descripcion" => array:1 [ "en" => "– Drugs associated with drug-related acute kidney injury: types, dose and time of exposure (Palamós Hospital, January 2011–March 2012)" ] ] 3 => array:8 [ "identificador" => "tbl3" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tablaImagen" => array:1 [ 0 => array:4 [ "imagenFichero" => "498v35n02-90412389fig4.jpg" "imagenAlto" => 675 "imagenAncho" => 2108 "imagenTamanyo" => 187986 ] ] ] ] ] "descripcion" => array:1 [ "en" => "– Use of ACEI/ARB-II, diuretics and NSAIDs in the overall population and associated acute kidney injury (Baix Empordà, January 2011–March 2012)" ] ] 4 => array:8 [ "identificador" => "fig2" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "498v35n02-90412389fig5.jpg" "Alto" => 766 "Ancho" => 1041 "Tamanyo" => 81077 ] ] "descripcion" => array:1 [ "en" => "– Prevalence of use of ACEI/ARB-II, diuretics and NSAIDs in Baix Empordà, February 2011. ACEI: Angiotensin converting enzyme inhibitor; ARB-II: Angiotensin-II receptor blocker; NSAID: Non-steroidal anti-inflammatory drug" ] ] 5 => array:8 [ "identificador" => "fig3" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "498v35n02-90412389fig6.jpg" "Alto" => 712 "Ancho" => 1054 "Tamanyo" => 58961 ] ] "descripcion" => array:1 [ "en" => "– Mortality for AKI secondary to ACEI/ARB-II, diuretics and NSAIDs compared to admission of patients with no AKI (Palamós Hospital, 2011). (a) Control group: Hospitalizations of patients with no acute kidney injury paired by sex, age and comorbidity according to Clinical Risk Group (CRG) categories. All comparisons were non-significant (p > 0.05 based on Fischer’s exact test). TW: Triple Whammy" ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:20 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Drug interactions between antihypertensive drugs and non-steroidal anti-inflammatory agents: a descriptive study using the French Pharmacovigilance database. Fundam Clin Pharmacol. 2014;28:230-5. <a href="http://www.ncbi.nlm.nih.gov/pubmed/23190210" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Drug interactions between antihypertensive drugs and non-steroidal anti-inflammatory agents: a descriptive study using the French Pharmacovigilance database." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "Fournier JP" 1 => "Sommet A" 2 => "Durrieu G" 3 => "Poutrain JC" 4 => "Lapeyre-Mestre M" 5 => "Montastruc JL; French Network of Regional Pharmacovigilance Centres." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/fcp.12014" "Revista" => array:6 [ "tituloSerie" => "Fundam Clin Pharmacol. " "fecha" => "2014" "volumen" => "28" "paginaInicial" => "230" "paginaFinal" => "5" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23190210" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib2" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Drug combinations and impaired renal function – the “Triple Whammy.” Br J Clin Pharmacol. 2005;59:239-43. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15676048" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Drug combinations and impaired renal function – the “Triple Whammy." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Loboz KK" 1 => "Shenfield GM." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.0306-5251.2004.2188.x" "Revista" => array:6 [ "tituloSerie" => "” Br J Clin Pharmacol. " "fecha" => "2005" "volumen" => "59" "paginaInicial" => "239" "paginaFinal" => "43" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15676048" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib3" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "triple drug combinations are associated with increased hospital admission for acute kidney injury, but questions remain. BMJ. 2013;346:e8713. <a href="http://www.ncbi.nlm.nih.gov/pubmed/23516146" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "triple drug combinations are associated with increased hospital admission for acute kidney injury, but questions remain." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Nitsch D" 1 => "Tomlinson LA: Safety of coprescribing NSAIDs with multiple antihypertensive agents." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "BMJ. " "fecha" => "2013" "volumen" => "346" "paginaInicial" => "e8713" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23299846" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib4" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Nephrotoxicity in the elderly due to co-prescription of angiotensin converting enzyme inhibitors and nonsteroidal anti-inflammatory drugs. J R Soc Med. 2001;94:512-4. <a href="http://www.ncbi.nlm.nih.gov/pubmed/11581344" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Nephrotoxicity in the elderly due to co-prescription of angiotensin converting enzyme inhibitors and nonsteroidal anti-inflammatory drugs." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Adhiyaman V" 1 => "Asghar M" 2 => "Oke A" 3 => "White AD" 4 => "Shah IU." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J R Soc Med. " "fecha" => "2001" "volumen" => "94" "paginaInicial" => "512" "paginaFinal" => "4" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11581344" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib5" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Epidemiology of acute renal failure: a prospective, multicenter, community-based study. Madrid Acute Renal Failure Study Group. Kidney Int. 1996;50:811-8. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Epidemiology of acute renal failure: a prospective, multicenter, community-based study. Madrid Acute Renal Failure Study Group." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Liaño F" 1 => "Pascual J." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Kidney Int. " "fecha" => "1996" "volumen" => "50" "paginaInicial" => "811" "paginaFinal" => "8" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8872955" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib6" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Epidemiología, aspectos clínicos y manejo del fracaso renal agudo en una población envejecida dependiente de un hospital comarcal. Nefrologia. 2002;22:547-54. <a href="http://www.ncbi.nlm.nih.gov/pubmed/12516288" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Epidemiología, aspectos clínicos y manejo del fracaso renal agudo en una población envejecida dependiente de un hospital comarcal." "idioma" => "es" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Lou LM" 1 => "Boned B" 2 => "Gimeno JA" 3 => "Beguer P" 4 => "Cruz A" 5 => "Telmo S" 6 => "et al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Nefrologia. " "fecha" => "2002" "volumen" => "22" "paginaInicial" => "547" "paginaFinal" => "54" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12516288" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib7" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Diuretics, ACE inhibitors ans NSAIDs–the triple whammy. Med J Austr. 2000;172:184-5. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Diuretics, ACE inhibitors ans NSAIDs–the triple whammy." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Thomas MC." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Med J Austr. " "fecha" => "2000" "volumen" => "172" "paginaInicial" => "184" "paginaFinal" => "5" ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib8" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol. 2005;16:3365-70. <a href="http://www.ncbi.nlm.nih.gov/pubmed/16177006" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Acute kidney injury, mortality, length of stay, and costs in hospitalized patients." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Chertow GM" 1 => "Burdick E" 2 => "Honour M" 3 => "Bonventre JV" 4 => "Bates DW." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1681/ASN.2004090740" "Revista" => array:6 [ "tituloSerie" => "J Am Soc Nephrol. " "fecha" => "2005" "volumen" => "16" "paginaInicial" => "3365" "paginaFinal" => "70" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16177006" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib9" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Clinical Risk Groups (CRGs): a classification system for risk-adjusted capitation-based payment and health care management. Med Care. 2004;42:81-90. <a href="http://www.ncbi.nlm.nih.gov/pubmed/14713742" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Clinical Risk Groups (CRGs): a classification system for risk-adjusted capitation-based payment and health care management." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Hughes JS" 1 => "Averill RF" 2 => "Eisenhandler J" 3 => "Goldfield NI" 4 => "Muldoon J" 5 => "Neff JM" 6 => "et al." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/01.mlr.0000102367.93252.70" "Revista" => array:6 [ "tituloSerie" => "Med Care. " "fecha" => "2004" "volumen" => "42" "paginaInicial" => "81" "paginaFinal" => "90" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14713742" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib10" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "La medida de la morbilidad atendida en una organización sanitaria integrada. Gac Sanit. 2009;23:29-37. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19879022" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "La medida de la morbilidad atendida en una organización sanitaria integrada." "idioma" => "es" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Inoriza JM" 1 => "Coderch J" 2 => "Carreras M" 3 => "Vall-Llosera L" 4 => "García-Goñi M" 5 => "Lisbona JM" 6 => "et al." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.gaceta.2009.07.005" "Revista" => array:6 [ "tituloSerie" => "Gac Sanit. " "fecha" => "2009" "volumen" => "23" "paginaInicial" => "29" "paginaFinal" => "37" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19879022" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib11" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Análisis de costes por paciente en una organización sanitaria integrada. Fulls econòmics del sistema sanitari 2010;39:28-37 [Internet; consultado 15 May 2014]. Disponible en: http://www20.gencat. cat/docs/salut/Minisite/catsalut/Coneix_CatSalut/informacio_ economica/fulls_economics/efulls_39.pdf. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Análisis de costes por paciente en una organización sanitaria integrada." "idioma" => "es" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "Carreras M" 1 => "Ibern P" 2 => "Coderch J" 3 => "Inoriza JM." ] ] ] ] ] "host" => array:1 [ 0 => null ] ] ] ] 11 => array:3 [ "identificador" => "bib12" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Estimates of patient cost related with population morbidity: can indirect cost affect the results? Eur J Health Econ. 2011;12:289-95. <a href="http://www.ncbi.nlm.nih.gov/pubmed/20306112" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Estimates of patient cost related with population morbidity: can indirect cost affect the results? Eur J Health Econ." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "Carreras M" 1 => "Garcia-Goñi M" 2 => "Ibern P" 3 => "Coderch J" 4 => "Vall-Llosera L" 5 => "Inoriza JM." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "fecha" => "2011" "volumen" => "12" "paginaInicial" => "289" "paginaFinal" => "95" ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib13" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Red Española de Costes Hospitalarios (RECH): bases para una gestión clínica basada en la evidencia. Gest y Eval Cost Sanit 2012;13:369-83 [Internet; consultado 15 May 2014]. Disponible en: http://www.fundacionsigno.com/archivos/ publicaciones/003_SIGNO_13_3.pdf. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Red Española de Costes Hospitalarios (RECH): bases para una gestión clínica basada en la evidencia." "idioma" => "es" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Cots F" 1 => "Chiarello P" 2 => "Carreras M" 3 => "Gonzalez JG" 4 => "Heras D" 5 => "de Imaña M" 6 => "et al." ] ] ] ] ] "host" => array:1 [ 0 => null ] ] ] ] 13 => array:3 [ "identificador" => "bib14" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Grupo RECH 2010 [Internet; consultado 15 May 2014]. Disponible en: https:// www.rechosp.org/rech/cms/en/vision/1/1. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Grupo RECH 2010 [Internet." "idioma" => "de" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Red Española de Costes Hospitalarios." ] ] ] ] ] "host" => array:1 [ 0 => null ] ] ] ] 14 => array:3 [ "identificador" => "bib15" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Non steroideal anti-inflammatory drugs and risk of AFR in the general population. Am J Kidney Dis. 2005;45:531-9. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15754275" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Non steroideal anti-inflammatory drugs and risk of AFR in the general population." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "Huerta C" 1 => "Castellsagué J" 2 => "Varas-Lorenzo C" 3 => "García Rodríguez LA." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/j.ajkd.2004.12.005" "Revista" => array:6 [ "tituloSerie" => "Am J Kidney Dis. " "fecha" => "2005" "volumen" => "45" "paginaInicial" => "531" "paginaFinal" => "9" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15754275" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib16" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study. BMJ. 2013;346:e8525 [Internet; consultado 15 May 2014). Disponible en: http://dx.doi.org/10.1136/bmj.e8525. <a href="http://www.ncbi.nlm.nih.gov/pubmed/23516146" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Lapi F" 1 => "Azoulay L" 2 => "Yin H" 3 => "Nessim SJ" 4 => "Suissa S." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "tituloSerie" => "BMJ. " ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib17" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Kidney International supplements. 2013;3:91-111. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Kidney International supplements." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Other complications of CKD: CVD" 1 => "medication dosage" 2 => "patient safety" 3 => "infections" 4 => "hospitalizations and caveats for investigating complications of CKD." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "fecha" => "2013" "volumen" => "3" "paginaInicial" => "91" "paginaFinal" => "111" ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib18" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "STOPP (Screening Tool of Older Person’s Prescriptions) and START (Screening Tool to Alert doctors to Right Treatment). Consensus validation. Int J Clin Pharmacol Ther. 2008;46:72-83. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "STOPP (Screening Tool of Older Person’s Prescriptions) and START (Screening Tool to Alert doctors to Right Treatment). Consensus validation." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Gallagher P" 1 => "Ryan C" 2 => "Byrne S" 3 => "Kennedy J" 4 => "O’Mahony D." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Int J Clin Pharmacol Ther. " "fecha" => "2008" "volumen" => "46" "paginaInicial" => "72" "paginaFinal" => "83" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18218287" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib19" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Laboratory monitoring of patients treated with antihypertensive drugs and newly exposed to non steroidal anti-inflammatory drugs: a cohort study. PLoS ONE. 2012;7:e34187 [consultado 15 May 2014]. Disponible en: http:// www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal. pone.0034187. <a href="http://www.ncbi.nlm.nih.gov/pubmed/23300888" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Laboratory monitoring of patients treated with antihypertensive drugs and newly exposed to non steroidal anti-inflammatory drugs: a cohort study." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "Fournier JP" 1 => "Lapeyre-Mestre M" 2 => "Sommet A" 3 => "Dupouy J" 4 => "Poutrain JC" 5 => "Montastruc JL." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1371/journal.pone.0122551" "Revista" => array:2 [ "tituloSerie" => "PLoS ONE. " "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25879682" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib20" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "More on the “Triple Whammy”: antihypertensive drugs, non-steroidal anti-inflammatory agents and acute kidney injury - a case/non-case study in the French pharmacovigilance database. Ren Fail. 2014;36:1166-8. <a href="http://www.ncbi.nlm.nih.gov/pubmed/24826803" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "More on the “Triple Whammy”: antihypertensive drugs, non-steroidal anti-inflammatory agents and acute kidney injury - a case/non-case study in the French pharmacovigilance database." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "Fournier JP" 1 => "Sommet A" 2 => "Durrieu G" 3 => "Poutrain JC" 4 => "Lapeyre-Mestre M" 5 => "Montastruc JL; French Network of Regional Pharmacovigilance Centres." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3109/0886022X.2014.917943" "Revista" => array:6 [ "tituloSerie" => "Ren Fail. " "fecha" => "2014" "volumen" => "36" "paginaInicial" => "1166" "paginaFinal" => "8" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24826803" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/20132514/0000003500000002/v0_201504231604/X2013251415123895/v0_201504231606/en/main.assets" "Apartado" => array:4 [ "identificador" => "38708" "tipo" => "SECCION" "es" => array:2 [ "titulo" => "Originals" "idiomaDefecto" => true ] "idiomaDefecto" => "es" ] "PDF" => "https://static.elsevier.es/multimedia/20132514/0000003500000002/v0_201504231604/X2013251415123895/v0_201504231606/en/498v35n02a90412389pdf001.pdf?idApp=UINPBA000064&text.app=https://revistanefrologia.com/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251415123895?idApp=UINPBA000064"]

Statistics

Fracaso renal agudo secundario a combinación de inhibidores del sistema renina-angiotensina, diuréticos y AINES. “La Triple Whammy”

Rosa Rosa Maria Garcia Camin, Montse Cols, Julio Leonel Chevarria, Rosa García Osuna, Marc Carreras, xGarcia Camina, Montse Colsb, Julio Leonel Chevarriaa, Rosa García Osunaa, Marc Carrerasc, Josep Maria Lisbonad, Jordi Coderchc

a Nephrology, Hospital de Palamós [Palamós Hospital], Palamós, Girona (Spain)

b Palamós, Hospital de Palamós, Palamós, Girona (Spain)

c Grup de recerca en Serveis Sanitaris i Resultats en Salut (GRESSIRES) [Research Group on Health Services and Health Outcomes], Hospital de Palamós, Palamós, Girona (Spain)

d Health Care Information Unit, Hospital de Palamós, Palamós, Girona (Spain)

Read

10805

Times
was read the article

2190

Total PDF

8615

Total HTML

Share statistics

 array:19 [
  "pii" => "X2013251415123895"
  "issn" => "20132514"
  "estado" => "S300"
  "fechaPublicacion" => "2015-03-01"
  "documento" => "article"
  "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/"
  "subdocumento" => "fla"
  "cita" => "Nefrologia &#40;English Version&#41;. 2015;35:197-206"
  "abierto" => array:3 [
    "ES" => true
    "ES2" => true
    "LATM" => true
  ]
  "gratuito" => true
  "lecturas" => array:2 [
    "total" => 6600
    "formatos" => array:3 [
      "EPUB" => 310
      "HTML" => 5634
      "PDF" => 656
    ]
  ]
  "itemSiguiente" => array:15 [
    "pii" => "X2013251415124102"
    "issn" => "20132514"
    "estado" => "S300"
    "fechaPublicacion" => "2015-03-01"
    "documento" => "article"
    "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/"
    "subdocumento" => "fla"
    "cita" => "Nefrologia &#40;English Version&#41;. 2015;35:207-17"
    "abierto" => array:3 [
      "ES" => true
      "ES2" => true
      "LATM" => true
    ]
    "gratuito" => true
    "lecturas" => array:2 [
      "total" => 8374
      "formatos" => array:3 [
        "EPUB" => 322
        "HTML" => 7246
        "PDF" => 806
      ]
    ]
    "en" => array:12 [
      "idiomaDefecto" => true
      "titulo" => "Use of sevelamer in chronic kidney disease&#58; beyond&#160;phosphorus control"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => array:2 [
        0 => "es"
        1 => "en"
      ]
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "207"
          "paginaFinal" => "217"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "es" => array:1 [
          "titulo" => "Uso del sevelamer en la enfermedad renal cr&#243;nica&#46; M&#225;s all&#225; del control del f&#243;sforo"
        ]
      ]
      "contieneResumen" => array:2 [
        "es" => true
        "en" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "resumenGrafico" => array:2 [
        "original" => 0
        "multimedia" => array:8 [
          "identificador" => "fig1"
          "etiqueta" => "Figure 1"
          "tipo" => "MULTIMEDIAFIGURA"
          "mostrarFloat" => true
          "mostrarDisplay" => false
          "copyright" => "Elsevier Espa&#241;a"
          "figura" => array:1 [
            0 => array:4 [
              "imagen" => "498v35n02-90412410fig1.jpg"
              "Alto" => 1225
              "Ancho" => 1841
              "Tamanyo" => 146308
            ]
          ]
          "descripcion" => array:1 [
            "en" => "– Scheme of the effects attributed to sevelamer and their influence on survival in patwients with renal failure&#46;"
          ]
        ]
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Laura Rodr&#237;guez-Osorio, Diana Pazmi&#241;o Zambrano, Carolina Gracia-Iguacel, Jorge Rojas-Rivera, Alberto Ortiz, Jesus Egido, Emilio Gonz&#225;lez Parra"
          "autores" => array:7 [
            0 => array:2 [
              "nombre" => "Laura"
              "apellidos" => "Rodr&#237;guez-Osorio"
            ]
            1 => array:2 [
              "nombre" => "Diana"
              "apellidos" => "Pazmi&#241;o Zambrano"
            ]
            2 => array:2 [
              "nombre" => "Carolina"
              "apellidos" => "Gracia-Iguacel"
            ]
            3 => array:2 [
              "nombre" => "Jorge"
              "apellidos" => "Rojas-Rivera"
            ]
            4 => array:2 [
              "nombre" => "Alberto"
              "apellidos" => "Ortiz"
            ]
            5 => array:2 [
              "nombre" => "Jesus"
              "apellidos" => "Egido"
            ]
            6 => array:2 [
              "nombre" => "Emilio"
              "apellidos" => "Gonz&#225;lez Parra"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251415124102?idApp=UINPBA000064"
    "url" => "/20132514/0000003500000002/v0_201504231604/X2013251415124102/v0_201504231606/en/main.assets"
  ]
  "itemAnterior" => array:15 [
    "pii" => "X2013251415123699"
    "issn" => "20132514"
    "estado" => "S300"
    "fechaPublicacion" => "2015-03-01"
    "documento" => "article"
    "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/"
    "subdocumento" => "fla"
    "cita" => "Nefrologia &#40;English Version&#41;. 2015;35:189-96"
    "abierto" => array:3 [
      "ES" => true
      "ES2" => true
      "LATM" => true
    ]
    "gratuito" => true
    "lecturas" => array:2 [
      "total" => 5301
      "formatos" => array:3 [
        "EPUB" => 332
        "HTML" => 4338
        "PDF" => 631
      ]
    ]
    "en" => array:12 [
      "idiomaDefecto" => true
      "titulo" => "Overhydration prevalence in peritoneal dialysis &#8211; A 2 year longitudinal analysis"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => array:2 [
        0 => "es"
        1 => "en"
      ]
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "189"
          "paginaFinal" => "196"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "es" => array:1 [
          "titulo" => "Prevalencia de la sobrehidrataci&#243;n en la di&#225;lisis peritoneal&#58; estudio longitudinal de 2 a&#241;os"
        ]
      ]
      "contieneResumen" => array:2 [
        "es" => true
        "en" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "resumenGrafico" => array:2 [
        "original" => 0
        "multimedia" => array:8 [
          "identificador" => "fig1"
          "etiqueta" => "Figure 1"
          "tipo" => "MULTIMEDIAFIGURA"
          "mostrarFloat" => true
          "mostrarDisplay" => false
          "copyright" => "Elsevier Espa&#241;a"
          "figura" => array:1 [
            0 => array:4 [
              "imagen" => "498v35n02-90412369fig2.jpg"
              "Alto" => 1504
              "Ancho" => 1954
              "Tamanyo" => 172162
            ]
          ]
          "descripcion" => array:1 [
            "en" => "– Relative overhydration over 2 years on PD&#46; Hydration status remained fairly stable over the follow-up period&#44; regardless of residual diuresis&#44; PD vintage&#44; or PD modality&#46; The difference found on the first year evaluation &#40;T1&#41; between anuric and patients with diuresis &#62;250 ml&#47;day was normalized by the second year &#40;T2&#41;&#46;"
          ]
        ]
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Pedro Ventura Aguiar, Ol&#237;via Santos, Laetitia Teixeira, Fernanda Silva, Pedro Azevedo, Joana Vidinha, Francisco Ferrer, Maria Jo&#227;o Carvalho, Ant&#243;nio Cabrita, Anabela Rodrigues"
          "autores" => array:10 [
            0 => array:2 [
              "nombre" => "Pedro"
              "apellidos" => "Ventura Aguiar"
            ]
            1 => array:2 [
              "nombre" => "Ol&#237;via"
              "apellidos" => "Santos"
            ]
            2 => array:2 [
              "nombre" => "Laetitia"
              "apellidos" => "Teixeira"
            ]
            3 => array:2 [
              "nombre" => "Fernanda"
              "apellidos" => "Silva"
            ]
            4 => array:2 [
              "nombre" => "Pedro"
              "apellidos" => "Azevedo"
            ]
            5 => array:2 [
              "nombre" => "Joana"
              "apellidos" => "Vidinha"
            ]
            6 => array:2 [
              "nombre" => "Francisco"
              "apellidos" => "Ferrer"
            ]
            7 => array:2 [
              "nombre" => "Maria Jo&#227;o"
              "apellidos" => "Carvalho"
            ]
            8 => array:2 [
              "nombre" => "Ant&#243;nio"
              "apellidos" => "Cabrita"
            ]
            9 => array:2 [
              "nombre" => "Anabela"
              "apellidos" => "Rodrigues"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251415123699?idApp=UINPBA000064"
    "url" => "/20132514/0000003500000002/v0_201504231604/X2013251415123699/v0_201504231606/en/main.assets"
  ]
  "en" => array:15 [
    "idiomaDefecto" => true
    "titulo" => "Acute kidney injury secondary to a combination of renin-angiotensin system inhibitors&#44; diuretics and&#160;NSAIDS&#58; &#8220;The Triple Whammy&#8221;"
    "tieneTextoCompleto" => true
    "paginas" => array:1 [
      0 => array:2 [
        "paginaInicial" => "197"
        "paginaFinal" => "206"
      ]
    ]
    "autores" => array:1 [
      0 => array:3 [
        "autoresLista" => "Rosa Rosa Maria Garcia Camin&#44; Montse Cols&#44; Julio Leonel Chevarria&#44; Rosa Garc&#237;a Osuna&#44; Marc Carreras&#44; xGarcia Camin, Josep Maria Lisbona, Jordi Coderch"
        "autores" => array:7 [
          0 => array:3 [
            "nombre" => "Rosa Rosa Maria Garcia Camin&#44; Montse Cols&#44; Julio Leonel Chevarria&#44; Rosa Garc&#237;a Osuna&#44; Marc Carreras&#44;"
            "apellidos" => "xGarcia Camin"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "affa"
              ]
            ]
          ]
          1 => array:3 [
            "nombre" => "Montse"
            "apellidos" => "Cols"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">b</span>"
                "identificador" => "affb"
              ]
            ]
          ]
          2 => array:3 [
            "nombre" => "Julio"
            "apellidos" => "Leonel Chevarria"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "affa"
              ]
            ]
          ]
          3 => array:3 [
            "nombre" => "Rosa"
            "apellidos" => "Garc&#237;a Osuna"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "affa"
              ]
            ]
          ]
          4 => array:3 [
            "nombre" => "Marc"
            "apellidos" => "Carreras"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">c</span>"
                "identificador" => "affc"
              ]
            ]
          ]
          5 => array:3 [
            "nombre" => "Josep Maria"
            "apellidos" => "Lisbona"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">d</span>"
                "identificador" => "affd"
              ]
            ]
          ]
          6 => array:3 [
            "nombre" => "Jordi"
            "apellidos" => "Coderch"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">c</span>"
                "identificador" => "affc"
              ]
            ]
          ]
        ]
        "afiliaciones" => array:4 [
          0 => array:3 [
            "entidad" => "Nephrology, Hospital de Palamós [Palamós Hospital], Palamós, Girona (Spain)"
            "etiqueta" => "<span class="elsevierStyleSup">a</span>"
            "identificador" => "affa"
          ]
          1 => array:3 [
            "entidad" => "Palamós, Hospital de Palamós, Palamós, Girona (Spain)"
            "etiqueta" => "<span class="elsevierStyleSup">b</span>"
            "identificador" => "affb"
          ]
          2 => array:3 [
            "entidad" => "Grup de recerca en Serveis Sanitaris i Resultats en Salut (GRESSIRES) [Research Group on Health Services and Health Outcomes], Hospital de Palamós, Palamós, Girona (Spain)"
            "etiqueta" => "<span class="elsevierStyleSup">c</span>"
            "identificador" => "affc"
          ]
          3 => array:3 [
            "entidad" => "Health Care Information Unit, Hospital de Palamós, Palamós, Girona (Spain)"
            "etiqueta" => "<span class="elsevierStyleSup">d</span>"
            "identificador" => "affd"
          ]
        ]
      ]
    ]
    "titulosAlternativos" => array:1 [
      "es" => array:1 [
        "titulo" => "Fracaso renal agudo secundario a combinaci&#243;n de inhibidores del sistema renina-angiotensina&#44; diur&#233;ticos y AINES&#46; &#8220;La Triple Whammy&#8221;"
      ]
    ]
    "resumenGrafico" => array:2 [
      "original" => 0
      "multimedia" => array:8 [
        "identificador" => "fig1"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "498v35n02-90412389fig1.jpg"
            "Alto" => 1208
            "Ancho" => 1862
            "Tamanyo" => 216666
          ]
        ]
        "descripcion" => array:1 [
          "en" => "– Study schedule&#46; &#40;a&#41; Drugs according to ATC classification &#40;NSAIDs not including ASA 100-300 mg&#44; paracetamol or metamizole&#41;&#46; &#40;b&#41; AKI associated with the use of ACEI&#47;ARB-II&#47;Diuretics&#47;NSAIDs&#46; &#40;c&#41; Randomized sample of controls paired by specialty&#44; sex&#44; age and comorbidity according to the Clinical Risk Groups &#40;CRG&#41;&#46; AKI&#58; Acute kidney injury&#59; ACEI&#58; Angiotensin converting enzyme inhibitors&#59; ARB II&#58; Angiotensin-II receptor blockers&#59; NSAID&#58; Non-steroidal anti-inflammatory drugs&#46;"
        ]
      ]
    ]
    "textoCompleto" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">Introduction </span></p><p class="elsevierStylePara"> The combination of renin-angiotensin system inhibitor &#40;ACEI or ARB-II&#41; antihypertensive drugs with diuretics&#44; which is often associated with analgesic treatments including non-steroidal anti-inflammatory drugs &#40;NSAIDs&#41; in senior patients&#44; may cause acute kidney injury &#40;AKI&#41;&#46; These drug interactions have not been well studied in the literature&#46;<span class="elsevierStyleSup">1-4</span></p><p class="elsevierStylePara"> In 1996&#44; the incidence of AKI in Spain was 209 cases&#47;million adults&#47;year<span class="elsevierStyleSup">5</span> according to a study by Lia&#241;o&#44; et al&#46;&#44; conducted in the Madrid Community&#46; The 2002 study by L&#46;M&#46; Lou&#44; et al&#46;<span class="elsevierStyleSup">6</span>&#44; which was conducted at a Spanish district hospital with characteristics similar to ours&#44; indicated that 79&#37; of hospitalizations due to AKI originated outside the hospital&#46; The cause was volume depletion in 34&#46;2&#37; of cases&#44; a datum that highlighted the elevated incidence of antihypertensive treatments &#40;primarily renin-angiotensin system inhibitors&#41; and&#47; or diuretics as coadjuvant factors for AKI&#46;</p><p class="elsevierStylePara"> However&#44; the study of drug-related acute kidney injury has received little attention in the literature&#59; meanwhile&#44; its implications in terms of increased mortality&#44; days of hospitalization and costs are unknown&#46; In 2000&#44; MC Thomas<span class="elsevierStyleSup">7</span> coined the term &#8220;Triple Whammy&#8221; &#40;TW&#41; to refer to the adverse effects resulting from the combination of ACEI or ARB-II&#44; diuretics and NSAIDs&#44; particularly in seniors&#46; Chertow&#44; et al&#46;<span class="elsevierStyleSup">8</span>&#44; observed that small creatinine increments of 0&#46;3 or 0&#46;4 mg&#47;dL were associated with increased mortality&#44; mean hospitalization days&#44; and higher costs&#46;</p><p class="elsevierStylePara"> The objectives of our study were to describe the population prevalence of consumption and the incidence of outpatient AKI secondary to Triple Whammy drugs &#40;AKITW&#41;&#58; ACEI&#44; ARB-II&#44; diuretics and NSAIDs for each type of drug and their combinations&#44; characterizing the profile of the admitted patients and analysing their mean hospital stay&#44; hospital costs and mortality&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Methods </span></p><p class="elsevierStylePara"> A retrospective observational study was conducted in three stages&#44; with a mixed design&#44; at Palam&#243;s Hospital &#40;Baix Empord&#224; district hospital&#41;&#44; which is a reference hospital for 127&#44;151 inhabitants with 130 beds &#40;Figure 1&#41;&#46;</p><p class="elsevierStylePara"><img alt="Figure 1 – Study schedule&#46; &#40;a&#41; Drugs according to ATC classification &#40;NSAIDs not including ASA 100-300 mg&#44; paracetamol or metamizole&#41;&#46; &#40;b&#41; AKI associated with the use of ACEI&#47;ARB-II&#47;Diuretics&#47;NSAIDs&#46; &#40;c&#41; Randomized sample of controls paired by specialty&#44; sex&#44; age and comorbidity according to the Clinical Risk Groups &#40;CRG&#41;&#46; AKI&#58; Acute kidney injury&#59; ACEI&#58; Angiotensin converting enzyme inhibitors&#59; ARB II&#58; Angiotensin-II receptor blockers&#59; NSAID&#58; Non-steroidal anti-inflammatory drugs&#46;" src="498v35n02-90412389fig1.jpg"></img></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Figure 1 &#8211; Study schedule&#46; &#40;a&#41; Drugs according to ATC classification &#40;NSAIDs not including ASA 100-300 mg&#44; paracetamol or metamizole&#41;&#46; &#40;b&#41; AKI associated with the use of ACEI&#47;ARB-II&#47;Diuretics&#47;NSAIDs&#46; &#40;c&#41; Randomized sample of controls paired by specialty&#44; sex&#44; age and comorbidity according to the Clinical Risk Groups &#40;CRG&#41;&#46; AKI&#58; Acute kidney injury&#59; ACEI&#58; Angiotensin converting enzyme inhibitors&#59; ARB II&#58; Angiotensin-II receptor blockers&#59; NSAID&#58; Non-steroidal anti-inflammatory drugs&#46;</span></p><p class="elsevierStylePara"> The study project complied with the principles of the World Medical Association Declaration of Helsinki and was approved by the <span class="elsevierStyleItalic">Serveis de Salut Integrats Baix Empord&#224;</span> &#40;SSIBE&#41; &#91;Baix Empord&#224; Comprehensive Health Service&#93; Clinical Research Committee&#46; Given the study methodology&#44; which was based on a retrospective review of clinical-administrative records&#44; informed consent was not requested&#46; Data collection was performed by an authorized SSIBE professional and data were managed anonymously&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Design and patients </span></span></p><p class="elsevierStylePara"><span class="elsevierStyleItalic">First stage of the study&#58;</span> A cross-sectional analysis was made of the 8&#44;029 hospital admissions in the study period &#40;January 2011 to March 2012&#41; in order to identify drug-related AKI cases secondary to ACEI&#47;ARB-II&#44; diuretics and&#47;or NSAIDs&#44; and to describe the clinical characteristics of the admitted patients and their previous medications&#46; Drug-related acute kidney injury secondary to the use of Triple Whammy drugs &#40;AKITW&#41; was defined as hospital admission with a discharge code of AKI &#40;ICD-9-CM 584&#46;9&#41; in a patient who had been receiving any of those drugs prior to admission and where&#44; following an audit of the medical record by a nephrologist&#44; the possible cause of AKI is attributed to the use of ACEI&#47;ARB-II&#44; diuretics and&#47;or NSAIDs&#44; either alone or in combination &#40;a prerenal situation may be involved based on the presence of fever&#44; vomiting or diarrhea&#41;&#46; In addition&#44; the patient&#8217;s baseline creatinine value was 1&#46;3 mg&#47;dL or lower at least one month before admission&#44; which increased to more than 1&#46;4 mg&#47;dL on admission&#46;</p><p class="elsevierStylePara"> Excluded from the study were cases of hospital-acquired AKI &#40;defined as patients who are admitted with a creatinine value below 1&#46;3 mg&#47;dL that increases to more than 1&#46;4 mg&#47;dL during hospitalization&#41;&#44; obstructive AKI&#44; glomerulonephritis&#44; hepatorenal syndrome&#44; decompensated heart failure&#44; multiple organ failure&#44; infection&#44; ischemia&#44; poisoning&#44; end-stage cancer&#44; exposure to radiocontrast agents or known nephrotoxic drugs&#44; and multifactorial cases</p><p class="elsevierStylePara"><span class="elsevierStyleItalic">Second stage of the study&#58;</span> Four basic health care areas &#40;BHA&#41; share an information system of computerized medical files with our hospital&#46; As the prescription records of the 87&#44;160 patients belonging to the BHA were available to us&#44; we followed up a cohort of the 15&#44;307 outpatients who had been prescribed one or more ACEI&#47;ARB-II&#44; diuretics or NSAIDs in February 2011&#46; Our goal was to analyze the prevalence of use and incidence of drug-related AKI of this population for each type of drug and their combinations&#46; The data from this cohort were cross-referenced with the data from hospital admissions due to AKITW that had been identified in the first stage&#46; Out of the 85 cases of AKITW detected in stage 1 &#40;15 months of follow-up&#41;&#44; we selected the 65 cases belonging to the population of the four BHA with available computerized medical records and drug prescription data&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleItalic">Third stage of the study&#58;</span> A cohort study was used to assess the impact of AKITW on hospital stays&#44; costs and mortality&#46; The study population was limited to hospitalization episodes in 2011 &#40;12 months&#41; of residents of the four BHA for whom prescription data pharmacy costs were available&#46; All the hospitalization episodes due to AKITW belonging to the 4 BHA were considered cases &#40;62 patients&#41;&#46; The control group was made up of 62 randomly selected hospital admissions of patients without AKI&#44; paired by medical specialty&#44; sex&#44; age and comorbidities according to Clinical Risk Group &#40;CRG&#41;&#46;<span class="elsevierStyleSup">9&#44;10 </span></p><p class="elsevierStylePara"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Variables and data sources </span></span></p><p class="elsevierStylePara"> Data for the selection and analysis of the hospitalizations were obtained from the Palam&#243;s Hospital computerized hospital admission files&#46; The medical records were reviewed thoroughly by a nephrologist&#44; who compiled detailed information about patient characteristics and progression&#46; The variables collected on hospitalization episodes for AKITW were&#58; age&#44; sex&#44; use of ACEI&#47;ARB-II&#44; diuretics and NSAIDs before admission except for ASA 100-300 mg &#40;drug&#44; mean daily dose and treatment duration in weeks&#41;&#44; history of hypertension &#40;HTN&#41; &#40;defined by antihypertensive medication use&#41;&#44; chronic kidney disease &#40;CKD&#41; prior to admission &#40;defined as any patient admitted under code ICD-9&#58; 585&#41;&#44; chronic heart failure &#40;CHF&#41; &#40;defined as any patient admitted under code ICD-9&#58; 428&#41;&#44; prior rheumatic disease &#40;previous diagnosis of rheumatic disease with follow-up by a rheumatologist&#41;&#44; associated prerenal cause &#40;depletion due to fever&#44; vomiting or diarrhea&#41;&#44; signs of dehydration &#40;admitting physician recorded dehydration on the ER report&#44; or patient was admitted with hypotension and the examination revealed dry skin or mucosae&#41;&#44; edema&#44; pain and cause of pain&#44; need for dialysis&#44; CKD as a post-dialysis sequela &#40;considered as patients with ICD-9 code&#58; 585 who did not have CKD before admission&#41;&#44; creatinine &#40;baseline&#44; peak on admission&#44; on discharge and at six months following admission&#41;&#44; albuminemia on admission&#44; K on admission&#44; hospital stay &#40;days&#41;&#44; death &#40;date&#41;&#46; Renal function was measured with creatinine analyzed by Jaffe&#8217;s method&#44; alkaline picrate and kinetic reading&#59; traceability was guaranteed with the isotopic dilution mass spectrometry &#40;IDMS&#41;&#46; Glomerular filtration &#40;GF&#41; was calculated with MDRD4 IDMS&#46;</p><p class="elsevierStylePara"> Exacerbated CKD was considered as a patient previously diagnosed with CKD who had a creatinine level of more than 0&#46;3 mg&#47;dL over their baseline creatinine value&#44; which had been measured at least one month before admission&#46;</p><p class="elsevierStylePara"> The pharmacy data of the population were obtained from the computerized prescription files of the primary health care services&#46; Drugs of interest were classified by groups based on ATC codes &#40; World Health Organizat ion Anatomical&#44; Therapeutic&#44; Chemical classification system&#41;&#58; ACEI&#44; ARB-II&#44; diuretics and NSAIDs &#40;not including acetylsalicylic acid 100-300 mg&#44; paracetamol or metamizole&#41;&#46; The ACEI and ARB-II groups were considered a single drug type because of their similar mechanism of action&#46; The use of one&#44; two or three diuretics and NSAIDs were considered separately&#46; Drugs prescribed during hospitalization were not considered&#46;</p><p class="elsevierStylePara"> Data for hospitalization costs&#44; which are calculated yearly with the full-costing system&#44; were obtained from the <span class="elsevierStyleItalic">Serveis de Salut Integrats</span> &#40;SSIBE&#41; costs file&#46; This system follows the methodology and recommendations from the analytical accounting workgroup of the <span class="elsevierStyleItalic">Servei Catal&#224; de la Salut</span> &#91;Catalan Health Service&#93; Central Financial Office<span class="elsevierStyleSup">11&#44;12</span> and the <span class="elsevierStyleItalic">Red Espa&#241;ola de Costes Hospitalarios</span> &#40;RECH&#41; &#91;Spanish Hospital Costs Network&#93;<span class="elsevierStyleSup">13&#44;14</span>&#46; The cost associated with each hospitalization episode was calculated individually using the clinical and activity information recorded from admission to discharge&#46; Thus&#44; the cost of each hospitalization episode was obtained based on the number of hospitalization days&#44; minutes in the operating room&#44; dialysis sessions&#44; single medication doses&#44; laboratory tests&#44; imaging tests and other tests performed from admission to discharge&#46; In the 2011 fiscal year&#44; the mean hospital stay cost at Palam&#243;s Hospital was &#8364;279&#46;63&#44; one minute in the operating room was &#8364;10&#46;39 and each dialysis session was &#8364;146&#46;45&#46; The cost of single medication doses was assigned directly to the episode at the weighted mean price&#46; Finally&#44; the costs for laboratory tests&#44; diagnostic imaging tests and the remaining tests was input according to the mean cost of each technique performed based on each department&#8217;s catalogue of services&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Statistical analysis </span></span></p><p class="elsevierStylePara"> In order to identify the hospitalizations due to AKITW in association with these drugs&#44; we conducted a univariate statistical analysis with frequency&#44; mean and standard deviation&#44; according to the characteristics of each variable&#46;</p><p class="elsevierStylePara"> Drug combinations were analyzed as exclusive categories&#46; To measure the impact of drug use&#44; the population incidence was measured for each category with its 95&#37; confidence interval&#46;</p><p class="elsevierStylePara"> To compare groups in the case-control analysis&#44; a bivariate statistical analysis was conducted with Student&#8217;s <span class="elsevierStyleItalic">t</span>-test or chi-square test&#44; depending on the variable&#8217;s characteristics&#46; Fisher&#8217;s exact test was used when applicable&#46; <span class="elsevierStyleItalic">P</span> &#60; 0&#46;05 was considered statistically significant&#46; The IBM SPSS Statistics 20&#46;0 program was used&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Results </span></p><p class="elsevierStylePara"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">1&#46; First stage of the study&#58; Identification and characterization of&#160;drug-related AKI </span></span></p><p class="elsevierStylePara"> Out of the 8&#44;029 hospital admissions during the study period&#44; 415 cases of AKI were identified&#44; of which 368 were drug-related AKI and 85 were attributed directly to the use of ACEI&#47; ARB-II&#44; diuretics and&#47;or NSAIDs &#40;AKITW&#41; &#40;Figure 1&#41;&#46;</p><p class="elsevierStylePara"> These 85 cases had a similar distribution between both sexes and mean age was 78&#46;72 years &#40;SD 11&#46;69&#41;&#46; When analyzed by age groups&#44; the case distribution clearly shifted to the older age ranges &#40;Table 1&#41;&#46;</p><p class="elsevierStylePara"><img alt="Table 1 – Clinical characteristics of hospitalization episodes due to acute kidney injury associated with ACEI&#44; ARB-II&#44; diuretics and&#47;or NSAIDs &#40;Hospital de Palam&#243;s&#44; January 2011–March 2012&#41;" src="498v35n02-90412389fig2.jpg"></img></p><p class="elsevierStylePara"> Practically half of the cases had a history of CKD or CHF prior to admission&#46; In two-thirds of cases&#44; there was a prerenal cause associated with ACEI&#47;ARB-II&#44; diuretics and&#47;or NSAIDs &#40;history of fever&#44; vomiting or diarrhea in the days before admission&#41;&#46; In four out of five cases&#44; the medical records did not specify a cause of pain justifying the chronic use of NSAIDs&#59; in 59&#37; of cases where the cause was specified&#44; it was chronic joint pain&#46;</p><p class="elsevierStylePara"> The mean baseline creatinine value prior to admission was 1&#46;32 mg&#47;dL &#40;SD 0&#46;50&#41; and the mean creatinine increase from baseline to admission was 1&#46;77 mg&#47;dL &#40;SD 1&#46;51&#41;&#46; In 34&#37; of patients&#44; peak creatinine doubled baseline creatinine levels&#46; Six months after discharge&#44; mean creatinine had an increase of 13&#46;89&#37; from the pre-admission baseline creatinine&#46; The mean baseline GFR was 57&#46;3&#160; mL&#47;min&#47;1&#46;73m<span class="elsevierStyleSup">2</span>&#44; and at six months it was 52&#46;77 mL&#47;min&#47;1&#46;73 m<span class="elsevierStyleSup">2</span>&#44; which was a decrease of 4&#46;6&#37;&#46;</p><p class="elsevierStylePara"> More than half the patients had hypoalbuminemia&#44; which was serious &#40;&#60; 2&#46;5 g&#47;dL&#41; in 19&#37; of cases&#46; One-third were admitted with hyperkalemia&#44; and three cases were serious enough to cause death after admission&#46; One patient required dialysis and more than 10&#37; of patients had CKD as a sequela for six months after admission&#46;</p><p class="elsevierStylePara"> With respect to the drugs the patients were taking before admission&#44; ACEI prescriptions were identified in half of cases&#59; three-quarters of these patients had been taking them for more than four weeks&#46; The most widely used ACEI was enal-april&#44; which was consumed by three out of four ACEI users&#46; One-third of patients were ARB-II users&#44; most of whom had been on treatment for more than four weeks&#46; The most widely used form was losartan&#44; which was being taken by a third of ARB-II users&#46; Diuretics were prescribed in almost nine out of ten cases to treat the following&#58; HTN in 55&#46;4&#37; of cases&#44; CHF in 33&#46;8&#37;&#44; and edema in 6&#37;&#46; Almost three-quarters of patients had been on treatment for more than four weeks and almost one-quarter had been prescribed more than one type of diuretic&#46; The most widely used diuretic was furosemide&#44; followed by hydrochlorothiazide&#46; NSAIDs were prescribed in just over one-fifth of cases&#59; two-thirds of them had been on treatment for more than four weeks&#46; The most widely used NSAID was ibuprofen &#40;Table 2&#41;&#46;</p><p class="elsevierStylePara"><img alt="Table 2 – Drugs associated with drug-related acute kidney injury&#58; types&#44; dose and time of exposure &#40;Palam&#243;s&#160;Hospital&#44;&#160;January 2011–March 2012&#41;" src="498v35n02-90412389fig3.jpg"></img></p><p class="elsevierStylePara"> Out of patients the admitted&#44; 88&#46;2&#37; were on dual or triple therapy&#58; 54&#37; dual therapy&#44; 39&#37; combined ACEI&#47;ARB-II &#43; diuretics&#44; and 34&#37; Triple Whammy&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">2&#46; Second stage of the study&#58; Use of ACEI&#47;ARB-II&#44; diuretics and NSAIDs in the population and associated AKI </span></span></p><p class="elsevierStylePara"> From a population of 87&#44;160 people&#44; a total of 15&#44;307 were on the target drugs&#44; which represented 175&#46;62 users&#47;1&#44;000 inhabitants &#40;Figure 1&#41;&#46;</p><p class="elsevierStylePara"> The population prevalence of use for each type of drug &#40;alone and in various possible combinations among them&#41; is shown in Figure 2&#46; The most common type of use in the study population was monotherapy&#44; which accounted for more than half of these users&#46; The most common monotherapy was ACEI&#47;ARB-II&#44; and the least used were diuretics&#46; More than one-third of these users were on dual therapy&#44; the most frequent being ACEI&#47;ARB-II &#43; diuretics&#46; Just over 1 person per 100 inhabitants had been prescribed the Triple Whammy&#46;</p><p class="elsevierStylePara"><img alt="Figure 2 – Prevalence of use of ACEI&#47;ARB-II&#44; diuretics and&#160;NSAIDs in Baix Empord&#224;&#44; February 2011&#46; ACEI&#58; Angiotensin converting enzyme inhibitor&#59; ARB-II&#58; Angiotensin-II receptor blocker&#59; NSAID&#58; Non-steroidal anti-inflammatory drug" src="498v35n02-90412389fig5.jpg"></img></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Figure 2 &#8211; Prevalence of use of ACEI&#47;ARB-II&#44; diuretics and&#160;NSAIDs in Baix Empord&#224;&#44; February 2011&#46; ACEI&#58; Angiotensin converting enzyme inhibitor&#59; ARB-II&#58; Angiotensin-II receptor blocker&#59; NSAID&#58; Non-steroidal anti-inflammatory drug</span></p><p class="elsevierStylePara"> Table 3 shows the incidence of AKI associated with ACEI&#47; ARB-II&#44; diuretics and NSAIDs in the population consuming these drugs&#46; Overall incidence was 3&#46;40 cases&#47;year&#47;1&#44;000 users&#44; which generally increased with the number of drugs combined&#46; In monotherapy&#44; the diuretics group had a relevant incidence&#44; which increased when they were combined with ACEI&#47;ARB-II or NSAIDs in a dual therapy&#46; In contrast&#44; the incidence of AKI associated with ACEI&#47;ARB-II and NSAIDs&#44; alone or combined among them&#44; was lower&#46; The incidence of associated AKI in Triple Whammy users was similar to that of users of dual therapies that included diuretics&#46;</p><p class="elsevierStylePara"><img alt="Table 3 – Use of ACEI&#47;ARB-II&#44; diuretics and NSAIDs in the overall population and associated acute kidney injury &#40;Baix&#160;Empord&#224;&#44; January 2011–March 2012&#41; " src="498v35n02-90412389fig4.jpg"></img></p><p class="elsevierStylePara"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">3&#46; Third stage of the study&#58; Impact of AKI associated with ACEI&#47; ARB-II&#44; diuretics and&#47;or NSAIDs </span></span></p><p class="elsevierStylePara"> In the comparison of the AKITW cases with paired non-AKI controls&#44; no statistically significant differences were found for mean hospital stay between the two groups&#58; 7&#46;6 days &#40;SD 6&#46;4&#41; for cases and 5&#46;8 &#40;SD 4&#46;5&#41; for controls &#40;<span class="elsevierStyleItalic">p</span> &#61; 0&#46;07&#41;&#46; The total number of hospital stays generated in one year due to AKI secondary to the target drugs was 473 days for 87&#44;160 inhabitants&#46; This represents an estimated 543 days of avoidable hospital stay&#47;100&#44;000 inhabitants&#47;year&#46;</p><p class="elsevierStylePara"> Regarding costs&#44; the mean cost was &#8364;3&#44;016 &#40;SD 2&#44;468&#41; for cases and &#8364;2&#44;663 &#40;SD 2&#44;876&#41; for controls&#44; with no significant differences between them &#40;<span class="elsevierStyleItalic">p</span> &#61; 0&#46;43&#41;&#46; When we consider that the total one-year cost was &#8364;187&#44;049 for 87&#44;160 inhabitants&#44; we can estimate an annual avoidable cost of &#8364;214&#44;604&#47;100&#44;000 inhabitants&#47;year&#46;</p><p class="elsevierStylePara"> Mortality was 11&#46;3&#37; for cases and 6&#46;5&#37; for controls during hospitalization and 40&#46;3&#37; and 38&#46;7&#37;&#44; respectively&#44; during the 12-month follow-up&#46; No statistically significant differences were found between the groups at those time points or during the follow-up at three&#44; six and nine months &#40;Figure 3&#41;&#46;</p><p class="elsevierStylePara"><img alt="Figure 3 – Mortality for AKI secondary to ACEI&#47;ARB-II&#44; diuretics and NSAIDs compared to admission of patients with no AKI &#40;Palam&#243;s Hospital&#44; 2011&#41;&#46; &#40;a&#41; Control group&#58; Hospitalizations of patients with no acute kidney injury paired by sex&#44; age and comorbidity according to Clinical Risk Group &#40;CRG&#41; categories&#46; All comparisons were non-significant &#40;p &#62; 0&#46;05 based on Fischer’s exact test&#41;&#46; TW&#58; Triple Whammy" src="498v35n02-90412389fig6.jpg"></img></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Figure 3 &#8211; Mortality for AKI secondary to ACEI&#47;ARB-II&#44; diuretics and NSAIDs compared to admission of patients with no AKI &#40;Palam&#243;s Hospital&#44; 2011&#41;&#46; &#40;a&#41; Control group&#58; Hospitalizations of patients with no acute kidney injury paired by sex&#44; age and comorbidity according to Clinical Risk Group &#40;CRG&#41; categories&#46; All comparisons were non-significant &#40;p &#62; 0&#46;05 based on Fischer&#8217;s exact test&#41;&#46; TW&#58; Triple Whammy</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Discussion </span></p><p class="elsevierStylePara"> Our results suggest that the consumers of these drugs have an elevated incidence of AKI&#46; Greater incidence was observed for diuretics&#44; as monotherapy or in dual or triple therapy&#59; the highest incidence was for the dual therapy of diuretics &#43; NSAIDs&#46; Triple Whammy &#40;ACEI&#47;ARB-II &#43; diuretics &#43; NSAIDs&#41; users had an AKI incidence similar to those taking dual therapies that included diuretics&#46; The main reason for the prescription of diuretics in our patients was high blood pressure&#46; Out of all the patients admitted due to AKITW&#44; 87&#37; used diuretics&#44; 84&#46;6&#37; used ACEI&#47;ARB-II and 38&#46;5&#37; used NSAIDs&#46; In the population who had been prescribed one of these drugs&#44; 7&#46;2&#37; were on dual or triple therapy&#46;</p><p class="elsevierStylePara"> Similarly to Loboz et al&#46;<span class="elsevierStyleSup">2</span>&#44; we observed that 54&#37; of our admitted patients were on dual therapy&#44; of which almost 40&#37; were prescribed the ACEI&#47;ARB-II &#43; diuretics combination&#46; Loboz et al&#46;<span class="elsevierStyleSup">2 </span>noticed that an increase in the dose of diuretics was related to a decrease in GFR and&#44; for the remaining drugs&#44; the risk was present even at low doses&#46; Likewise&#44; in our case&#44; patients were consuming therapeutic or even low doses of diuretics and other drugs&#46; This suggests that administering small doses of these drugs in combination fails to reduce the risk of AKI&#46; Lou LM et al&#46;<span class="elsevierStyleSup">6</span> and Huerta et al&#46;15 also observed an increase in AKI incidence with the combination of ACEI and diuretics&#46;</p><p class="elsevierStylePara"> The association of ACEI&#47;ARB-II &#43; NSAIDs presented an elevated incidence&#44; although with a very broad confidence interval&#44; probably due to the limited number of cases&#46;</p><p class="elsevierStylePara"> Huerta et al&#46;<span class="elsevierStyleSup">15</span> did not find an increased risk for the combination of NSAIDs with renin-angiotensin system inhibitors&#46;</p><p class="elsevierStylePara"> Our data differ from the data found by Lapi et al&#46;<span class="elsevierStyleSup">16</span>&#44; who found no risk for AKI when using dual therapy with diuretics or ACEI&#47;ARB-II &#43; NSAIDs&#46; They only found a risk for AKI with the Triple Whammy&#44; which was particularly noticeable in the first 30 days of treatment&#46; In our study&#44; we have seen that the hospitalized patients had been receiving treatment for more than four weeks&#44; regardless of the drug group&#44; and the triggering factor for AKI had been a concurrent disease causing hypovolemia&#46;</p><p class="elsevierStylePara"> The profile of a patient at risk of suffering AKI with these drugs is an elderly patient with multiple conditions and on multiple concomitant medicantions&#46; This risk exists even with drugs at low therapeutic doses&#46; The presence of hypoalbuminemia &#60; 3 g&#47;dL is alarming in 51&#37; of hospitalization episodes due to AKITW&#44; of which 19&#37; were severe cases &#40;&#60; 2&#46;5 g&#47; dL&#41;&#46; This fact reflects the degree of malnutrition in a large part of the elderly population despite living at home&#46; In 67&#37; of cases&#44; there was a triggering factor for AKI&#44; such as fever&#44; vomiting or diarrhea&#44; in previous days&#46; What probably makes the glomerular filtration drop abruptly is a concurrent disease causing volume depletion or&#44; simply&#44; an increase in baseline metabolism in a patient with intraglomerular pressure decreased by vasodilated efferent arterioles secondary to treatment with ACEI or ARB-II&#44; combined with a circulating volume reduced by diuretics&#46; Elderly patients are known to maintain their GF thanks to a complex system of intraglomerular resistance&#46; Due to the vessel rigidity present in these patients&#44; the kidneys find it hard to adapt to changes in intraglomerular pressure and&#44; therefore&#44; are very sensitive to volume changes&#46; This seems to suggest that the cause of the AKI was not the treatment with these drugs&#44; but the onset of a concurrent disease&#46; Of the admitted patients&#44; 74&#37; were on chronic diuretic treatment &#40;more than four weeks&#41; and 21&#46;6&#37; were on two diuretics combined&#46;</p><p class="elsevierStylePara"> These were patients with decreased baseline GF&#44; in many cases with a history of CKD or CHF&#44; who were treated with diuretics&#44; primarily for hypertension&#46; They generally had mild or moderate AKI&#44; with small creatinine increases that were resolved with hydration in most cases&#46; Nevertheless&#44; 10&#37; of patients had CKD as a sequela and three patients died of hyperkalemia during admission&#46; In four of five cases&#44; the patients&#8217; medical records did not specify a cause of pain justifying the chronic use of NSAIDs&#44; and in 59&#37; of cases where the cause was specified&#44; it was chronic joint pain&#46; These data reflect that NSAID therapies are started at times of acute pain and are not properly withdrawn afterwards&#46;</p><p class="elsevierStylePara"> The 2012 KDIGO guidelines<span class="elsevierStyleSup">17</span> already recommended starting treatment with ACEI and ARB-II at low doses in patients with GFR &#60; 45 mL&#47;min and discontinue it temporarily in cases with concurrent disease&#46; As for NSAIDs&#44; the recommendation is to avoid their use in patients treated with renin-angiotensin system inhibitors&#44; and prolonged therapies are not recommended if GFR is &#60; 60 mL&#47;min&#46;</p><p class="elsevierStylePara"> The STOPP&#47;START<span class="elsevierStyleSup">18</span> criteria determine that prescribing diuretics for isolated ankle edema is inappropriate in patients older than 65 years because there is no evidence of their efficacy&#46; They are also not recommended as first-line monotherapy in hypertension&#46; NSAIDs should be avoided in moderate to severe hypertension and CHF&#44; and their use for more than three months to relieve mild joint pain should be avoided&#46; In cases of CKD&#44; they are not recommended either&#46;</p><p class="elsevierStylePara"> Even though NSAIDs are not formally contraindicated in the elderly&#44; they are a high-risk population for adverse effects&#44; particularly AKI&#44; and their use should be the result of a thorough risk-benefit assessment&#46;</p><p class="elsevierStylePara"> Only 58&#37; of physicians noticed evident signs of dehydration on admission&#46; Therefore&#44; it is advisable that&#44; in case of a concurrent condition&#44; treatment with at least one of the target drugs be discontinued&#46; This should be applied primarily to diuretics&#44; even if the physician does not notice signs of dehydration&#46; When initiating these combinations&#44; renal function and creatinine values are to be monitored&#46;<span class="elsevierStyleSup">19</span></p><p class="elsevierStylePara"> The Fournier&#44; et al&#46;<span class="elsevierStyleSup">20</span> group from Toulouse has recently performed a new analysis of the review they conducted on their pharmacovigilance database of adverse pharmacological effects in 2012&#46; Their aim was to study whether NSAID half-life had an impact on the possibility of developing AKI&#46; An association was found&#44; not with the drugs&#8217; half-life&#44; but with the number of associated drugs&#44; which coincided with the findings in previous publications and with our results&#46; In our case&#44; due to the small size of our sample&#44; it was impossible to analyze incidence differences based on the drugs&#8217; half-lives&#46;</p><p class="elsevierStylePara"> A cost of &#8364;214&#44;604&#47;100&#44;000 inhabitants&#47;year for hospitalization episodes derived from a combined prescription of these drugs is a significant economic problem and&#44; evidently&#44; the three deaths that occurred during admission due to hyperkalemia could have been avoided with correct prescription&#46;</p><p class="elsevierStylePara"> Our study is not limited to the utilization of large databases&#46; It is focused on drug-related AKI in conjunction with the auditing of medical records by a nephrologist to ensure that the AKITW included in this study are only due to the treatment with these drugs&#44; either alone or combined&#44; without the contribution of any other factor except for the prerenal situations discussed above&#46; This avoids confusion due to the high mortality associated with AKI for other causes&#46; Most of the studies conducted so far are based on the utilization of large databases focused on overall AKI treatment&#46; We analyzed the clinical patient characteristics to create a profile of at-risk patients&#44; and we quantified the personal &#40;mortality&#41; and economic costs of AKI caused by incorrect drug combinations&#46;</p><p class="elsevierStylePara"> The limitations of our study are the small number of cases and not having included treatment with ASA at low doses &#40;100 and 300 mg&#41; as an NSAID but instead as antiplatelet drug&#44; as indicated in the pharmaceutical coding&#44; since a large part of the patients admitted &#40;19&#41; were receiving prophylactic treatment at these doses&#46; Paracetamol at doses greater than 4 g&#47;d could also have an NSAID effect&#46; Both Paracetamol and the remaining NSAIDs are over-the-counter drugs in our pharmacies &#40;our data only include NSAIDs prescribed by their physicians&#41;&#44; so the use of NSAIDs could be underestimated&#46; We have also not analyzed the impact of impaired renal function cases that do not require admission&#46; Therefore&#44; the true incidence of AKITW may be higher and may also be generating elevated expenditures in the outpatient setting&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Conclusion </span></p><p class="elsevierStylePara"> Diuretics in monotherapy&#44; dual and triple combination therapy &#40;Triple Whammy&#41; have an elevated incidence of AKI&#46; Dual therapies including diuretics show the same incidence of AKI as the Triple Whammy&#46; The profile of the at-risk patient is an elderly patient with an underlying renal or cardiac disease&#46; The problem does not seem to be the drug itself but the onset of a concurrent disease causing hypovolemia&#46; Monitoring renal function and potassium levels is recommended when these therapies are initiated and in situations of concurrent disease&#44; following the recommendations from scientific societies &#40;KDIGO and STOPP-START criteria&#41;&#46;</p><p class="elsevierStylePara"> In cases of concurrent disease&#44; the temporary discontinuation of the Triple Whammy drugs&#44; particularly diuretics&#44; is recommended&#46; The use of NSAIDs should be minimized and treatment with diuretics should be monitored following hospital discharge&#46; Patient treatment should be adjusted to the situation at hand&#44; with special attention given to people over the age of 80 who have concurrent conditions&#46; AKI derived from a combination of Triple Whammy drugs has demonstrated high health care-related expenditures and avoidable deaths&#46; Health care authorities should be aware of this serious issue and limit the over-the-counter availability of NSAIDs at pharmacies&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Acknowledgments </span></p><p class="elsevierStylePara"> The authors would like to thank the <span class="elsevierStyleItalic">Sociedad Espa&#241;ola de Nefrolog&#237;a</span> &#40;SEN&#41; &#91;Spanish Society of Nephrology&#93; for the grant to help publish this paper&#46;</p><p class="elsevierStylePara"> Likewise&#44; we would like to thank Lluis Pal&#233; Mena and Maritza L&#243;pez Pereira for their cooperation with the fieldwork required to carry out this study&#46;</p><p class="elsevierStylePara"> We also thank the assistance provided by the <span class="elsevierStyleItalic">Serveis de Salut Integrats Baix Empord&#224;</span> research fund for the publication of this paper&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Conflicts of interest </span></p><p class="elsevierStylePara"> There are no conflicts of interest&#59; this study was conducted for non-profit purposes&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Funding </span></p><p class="elsevierStylePara"> No funding has been received&#46;</p><hr></hr><p class="elsevierStylePara"> Sent for Review&#58; 24 Oct&#46; 2014 <br></br> Accepted on&#58; 16 Dec&#46; 2014</p><p class="elsevierStylePara"><a href="http&#58;&#47;&#47;dx&#46;doi&#46;org&#47;10&#46;3265&#47;Nefrologia&#46;pre2014&#46;Dec&#46;12800" class="elsevierStyleCrossRefs">http&#58;&#47;&#47;dx&#46;doi&#46;org&#47;10&#46;3265&#47;Nefrologia&#46;pre2014&#46;Dec&#46;12800</a></p><p class="elsevierStylePara"> &#42; <span class="elsevierStyleItalic">Corresponding author</span>&#46;<br></br> Rosa Maria Garcia Camin&#44; <br></br> Nephrology Department&#44; Hospital de Palam&#243;s&#44; Hospital&#44; <br></br> 17230&#44; Palam&#243;s&#44; Girona&#44; Spain&#46; <br></br> Telephone&#58;&#160;696521296<br></br><span class="elsevierStyleItalic">E-mail&#58;</span><a href="mailto&#58;30368rgc&#64;comb&#46;cat" class="elsevierStyleCrossRefs">30368rgc&#64;comb&#46;cat</a></p>"
    "pdfFichero" => "498v35n02a90412389pdf001.pdf"
    "tienePdf" => true
    "PalabrasClave" => array:2 [
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec503501"
          "palabras" => array:5 [
            0 => "Lesi&#243;n renal aguda"
            1 => "Agentes antiinflamatorios"
            2 => "Agentes antihipertensivos"
            3 => "Diur&#233;ticos"
            4 => "Interacciones farmacol&#243;gicas"
          ]
        ]
      ]
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec503502"
          "palabras" => array:5 [
            0 => "Acute kidney injury"
            1 => "Antihypertensive agents"
            2 => "Diuretics"
            3 => "Drug interactions"
            4 => "Anti-inflammatory agents"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "es" => array:1 [
        "resumen" => "<p class="elsevierStylePara"> <span class="elsevierStyleItalic">Introducci&#243;n&#58;</span> Inhibidores del sistema renina-angiotensina &#40;IECAS&#47;ARA II&#41;&#44; diur&#233;ticos y AINES&#44; combinaci&#243;n conocida como &#8220;Triple Whammy&#8221;&#44; pueden producir descenso de filtrado glomerular y fracaso renal agudo &#40;FRA&#41;&#46;</p> <p class="elsevierStylePara"> <span class="elsevierStyleItalic">Objetivos&#58;</span> Describir la incidencia de FRA para cada tipo de f&#225;rmaco y sus combinaciones&#46; Caracterizar el perfil de paciente que ingresa por FRA extrahospitalario secundario a f&#225;rmacos de la Triple Whammy &#40;FRAETW&#41;&#44; evaluando costes y mortalidad&#46;</p> <p class="elsevierStylePara"> <span class="elsevierStyleItalic">M&#233;todos&#58;</span> estudio observacional retrospectivo realizado durante 15 meses y desarrollado en tres etapas&#58; <br /> - 1&#186; Etapa transversal de identificaci&#243;n y descripci&#243;n de los ingresos hospitalarios por FRAETW&#46; <br /> - 2&#186; Etapa de seguimiento de una cohorte ambulatoria consumidora de estos f&#225;rmacos <br /> &#40;15&#46;307 consumidores&#41; <br /> - 3&#186; Etapa de cohortes para evaluar costes y mortalidad&#44; contrastando 62 pacientes ingresados con FRAETW&#44; con 62 pacientes sin FRA&#44; apareados por especialidad m&#233;dica&#44; sexo&#44; edad y comorbilidad seg&#250;n Clinical Risk Groups&#46;</p> <p class="elsevierStylePara"> <span class="elsevierStyleItalic">Resultados&#58;</span> 85 ingresos por FRAETW&#44; 78&#37; mayores de 70 a&#241;os&#46; Incidencia poblacional de FRAETW&#58; 3&#44;40 casos&#47;1&#46;000 consumidores&#47;a&#241;o &#40;IC95&#37; 2&#44;59-4&#44;45&#41;&#46; Por categor&#237;as&#58; AINES &#43; diur&#233;ticos 8&#44;99&#40;IC95&#37; 3&#44;16-25&#44;3&#41;&#44; la &#8220;Triple Whammy&#8221; 8&#44;82&#40;IC 95&#37; 4&#44;4-17&#44;3&#41;&#44; IECA&#47;ARA II &#43; diur&#233;ticos 6&#44;87&#40;IC95&#37; 4&#44;81-9&#44;82&#41; y la monoterapia con diur&#233;ticos 3&#44;31&#40;IC95&#37; 1&#44;39-7&#44;85&#41;&#46; Estancia media 7&#44;6 d&#237;as &#40;DE 6&#44;4&#41;&#44; estim&#225;ndose coste medio evitable de 214&#46;604 &#8364;&#47;100&#46;000 habitantes&#47; a&#241;o&#46; Mortalidad del 11&#44;3&#37; durante el ingreso y del 38&#44;7&#37; a los 12 meses&#44; sin diferencias significativas con los controles&#46;</p> <p class="elsevierStylePara"> <span class="elsevierStyleItalic">Conclusiones&#58;</span> El tratamiento con IECA&#44; ARA II&#44; diur&#233;ticos y&#47;o AINES presenta elevada incidencia de ingreso por FRA&#44; siendo los diur&#233;ticos en monoterapia&#44; doble y triple terapia combinada los que ocasionan la mayor incidencia&#46; El FRAETW supone elevados costes sanitarios y muertes evitables&#46;</p>"
      ]
      "en" => array:1 [
        "resumen" => "<p class="elsevierStylePara"> <span class="elsevierStyleItalic">Background&#58;</span> Renin-angiotensin system inhibitors &#40;ACEI&#47;ARB-II&#41;&#44; diuretics and NSAIDs&#44; a combination known as &#8220;Triple Whammy&#8221;&#44; can result in decreased glomerular filtration rate &#40;GFR&#41; and acute kidney injury &#40;AKI&#41;&#46;</p> <p class="elsevierStylePara"> <span class="elsevierStyleItalic">Objectives&#58;</span> To describe the incidence of AKI for each drug type and their combinations&#46; To define the profile of patients admitted for drug-related AKI secondary to Triple Whammy drugs &#40;AKITW&#41;&#44; with an assessment of costs and mortality&#46;</p> <p class="elsevierStylePara"> <span class="elsevierStyleItalic">Methods&#58;</span> A retrospective observational 15-month study developed in three stages&#58; <br /> - First&#58; a cross-sectional stage to identify and describe hospitalizations due to AKITW&#46; <br /> - Second&#58; a follow-up stage of an outpatient cohort consuming these drugs &#40;15&#44;307 subjects&#41;&#46; <br /> - Third&#58; a cohort stage to assess costs and mortality&#44; which compared 62 hospitalized patients with AKITW and 62 without AKI&#44; paired by medical specialty&#44; sex&#44; age and comorbidity according to their Clinical Risk Groups&#46;</p> <p class="elsevierStylePara"> <span class="elsevierStyleItalic">Results&#58;</span> There were 85 hospitalization episodes due to AKITW&#44; and 78&#37; of patients were over the age of 70&#46; The incidence of AKITW in the population was 3&#46;40 cases&#47;1000 users&#47;year &#40;95&#37; CI&#58; 2&#46;59&#8211;4&#46;45&#41;&#46; By categories&#44; these were&#58; NSAIDs &#43; diuretics 8&#46;99 &#40;95&#37; CI&#58; 3&#46;16&#8211;25&#46;3&#41;&#59; Triple Whammy 8&#46;82 &#40;95&#37; CI&#58; 4&#46;4&#8211;17&#46;3&#41;&#59; ACEI&#47;ARB-II &#43; diuretics 6&#46;87 &#40;95&#37; CI&#58; 4&#46;81&#8211;9&#46;82&#41;&#59; and monotherapy with diuretics 3&#46;31 &#40;95&#37; CI&#58; 1&#46;39&#8211;7&#46;85&#41;&#46; Mean hospital stay was 7&#46;6 days &#40;SD 6&#46;4&#41;&#44; and mean avoidable costs were estimated at &#8364;214&#44;604&#47;100&#44;000 inhabitants&#47;year&#46; Mortality during hospitalization and at 12 months was 11&#46;3&#37; and 38&#46;7&#37; respectively&#44; and there were no significant differences when compared with the control group&#46;</p> <p class="elsevierStylePara"> <span class="elsevierStyleItalic">Conclusions&#58;</span> Treatment with ACEI&#44; ARB-II&#44; diuretics and&#47;or NSAIDs shows a high incidence of hospitalization episodes due to AKI&#59; diuretics as monotherapy or dual and triple combination therapy cause the highest incidence&#46; AKITW involves high health care costs and avoidable mortality&#46;</p>"
      ]
    ]
    "multimedia" => array:6 [
      0 => array:8 [
        "identificador" => "fig1"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "498v35n02-90412389fig1.jpg"
            "Alto" => 1208
            "Ancho" => 1862
            "Tamanyo" => 216666
          ]
        ]
        "descripcion" => array:1 [
          "en" => "– Study schedule&#46; &#40;a&#41; Drugs according to ATC classification &#40;NSAIDs not including ASA 100-300 mg&#44; paracetamol or metamizole&#41;&#46; &#40;b&#41; AKI associated with the use of ACEI&#47;ARB-II&#47;Diuretics&#47;NSAIDs&#46; &#40;c&#41; Randomized sample of controls paired by specialty&#44; sex&#44; age and comorbidity according to the Clinical Risk Groups &#40;CRG&#41;&#46; AKI&#58; Acute kidney injury&#59; ACEI&#58; Angiotensin converting enzyme inhibitors&#59; ARB II&#58; Angiotensin-II receptor blockers&#59; NSAID&#58; Non-steroidal anti-inflammatory drugs&#46;"
        ]
      ]
      1 => array:8 [
        "identificador" => "tbl1"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tablaImagen" => array:1 [
                0 => array:4 [
                  "imagenFichero" => "498v35n02-90412389fig2.jpg"
                  "imagenAlto" => 1350
                  "imagenAncho" => 1045
                  "imagenTamanyo" => 195713
                ]
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "– Clinical characteristics of hospitalization episodes due to acute kidney injury associated with ACEI&#44; ARB-II&#44; diuretics and&#47;or NSAIDs &#40;Hospital de Palam&#243;s&#44; January 2011–March 2012&#41;"
        ]
      ]
      2 => array:8 [
        "identificador" => "tbl2"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tablaImagen" => array:1 [
                0 => array:4 [
                  "imagenFichero" => "498v35n02-90412389fig3.jpg"
                  "imagenAlto" => 2820
                  "imagenAncho" => 2120
                  "imagenTamanyo" => 373580
                ]
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "– Drugs associated with drug-related acute kidney injury&#58; types&#44; dose and time of exposure &#40;Palam&#243;s&#160;Hospital&#44;&#160;January 2011–March 2012&#41;"
        ]
      ]
      3 => array:8 [
        "identificador" => "tbl3"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tablaImagen" => array:1 [
                0 => array:4 [
                  "imagenFichero" => "498v35n02-90412389fig4.jpg"
                  "imagenAlto" => 675
                  "imagenAncho" => 2108
                  "imagenTamanyo" => 187986
                ]
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "– Use of ACEI&#47;ARB-II&#44; diuretics and NSAIDs in the overall population and associated acute kidney injury &#40;Baix&#160;Empord&#224;&#44; January 2011–March 2012&#41;"
        ]
      ]
      4 => array:8 [
        "identificador" => "fig2"
        "etiqueta" => "Figure 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "498v35n02-90412389fig5.jpg"
            "Alto" => 766
            "Ancho" => 1041
            "Tamanyo" => 81077
          ]
        ]
        "descripcion" => array:1 [
          "en" => "– Prevalence of use of ACEI&#47;ARB-II&#44; diuretics and&#160;NSAIDs in Baix Empord&#224;&#44; February 2011&#46; ACEI&#58; Angiotensin converting enzyme inhibitor&#59; ARB-II&#58; Angiotensin-II receptor blocker&#59; NSAID&#58; Non-steroidal anti-inflammatory drug"
        ]
      ]
      5 => array:8 [
        "identificador" => "fig3"
        "etiqueta" => "Figure 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "498v35n02-90412389fig6.jpg"
            "Alto" => 712
            "Ancho" => 1054
            "Tamanyo" => 58961
          ]
        ]
        "descripcion" => array:1 [
          "en" => "– Mortality for AKI secondary to ACEI&#47;ARB-II&#44; diuretics and NSAIDs compared to admission of patients with no AKI &#40;Palam&#243;s Hospital&#44; 2011&#41;&#46; &#40;a&#41; Control group&#58; Hospitalizations of patients with no acute kidney injury paired by sex&#44; age and comorbidity according to Clinical Risk Group &#40;CRG&#41; categories&#46; All comparisons were non-significant &#40;p &#62; 0&#46;05 based on Fischer’s exact test&#41;&#46; TW&#58; Triple Whammy"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "Bibliography"
      "seccion" => array:1 [
        0 => array:1 [
          "bibliografiaReferencia" => array:20 [
            0 => array:3 [
              "identificador" => "bib1"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Drug interactions between antihypertensive drugs and non-steroidal anti-inflammatory agents: a descriptive study using the French Pharmacovigilance database. Fundam Clin Pharmacol. 2014;28:230-5.  <a href="http://www.ncbi.nlm.nih.gov/pubmed/23190210" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Drug interactions between antihypertensive drugs and non-steroidal anti-inflammatory agents&#58; a descriptive study using the French Pharmacovigilance database&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "Fournier JP"
                            1 => "Sommet A"
                            2 => "Durrieu G"
                            3 => "Poutrain JC"
                            4 => "Lapeyre-Mestre M"
                            5 => "Montastruc JL&#59; French Network of Regional Pharmacovigilance Centres&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/fcp.12014"
                      "Revista" => array:6 [
                        "tituloSerie" => "Fundam Clin Pharmacol. "
                        "fecha" => "2014"
                        "volumen" => "28"
                        "paginaInicial" => "230"
                        "paginaFinal" => "5"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23190210"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib2"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Drug combinations and impaired renal function – the “Triple Whammy.” Br J Clin Pharmacol. 2005;59:239-43.  <a href="http://www.ncbi.nlm.nih.gov/pubmed/15676048" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Drug combinations and impaired renal function – the “Triple Whammy&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Loboz KK"
                            1 => "Shenfield GM&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.0306-5251.2004.2188.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "” Br J Clin Pharmacol. "
                        "fecha" => "2005"
                        "volumen" => "59"
                        "paginaInicial" => "239"
                        "paginaFinal" => "43"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15676048"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib3"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "triple drug combinations are associated with increased hospital admission for acute kidney injury, but questions remain. BMJ. 2013;346:e8713.  <a href="http://www.ncbi.nlm.nih.gov/pubmed/23516146" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "triple drug combinations are associated with increased hospital admission for acute kidney injury&#44; but questions remain&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Nitsch D"
                            1 => "Tomlinson LA&#58; Safety of coprescribing NSAIDs with multiple antihypertensive agents&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "BMJ. "
                        "fecha" => "2013"
                        "volumen" => "346"
                        "paginaInicial" => "e8713"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23299846"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib4"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Nephrotoxicity in the elderly due to co-prescription of angiotensin converting enzyme inhibitors and nonsteroidal anti-inflammatory drugs. J R Soc Med. 2001;94:512-4.  <a href="http://www.ncbi.nlm.nih.gov/pubmed/11581344" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Nephrotoxicity in the elderly due to co-prescription of angiotensin converting enzyme inhibitors and nonsteroidal anti-inflammatory drugs&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "Adhiyaman V"
                            1 => "Asghar M"
                            2 => "Oke A"
                            3 => "White AD"
                            4 => "Shah IU&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J R Soc Med. "
                        "fecha" => "2001"
                        "volumen" => "94"
                        "paginaInicial" => "512"
                        "paginaFinal" => "4"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11581344"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib5"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Epidemiology of acute renal failure: a prospective, multicenter, community-based study. Madrid Acute Renal Failure Study Group. Kidney Int. 1996;50:811-8. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Epidemiology of acute renal failure&#58; a prospective&#44; multicenter&#44; community-based study&#46; Madrid Acute Renal Failure Study Group&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Lia&#241;o F"
                            1 => "Pascual J&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Kidney Int. "
                        "fecha" => "1996"
                        "volumen" => "50"
                        "paginaInicial" => "811"
                        "paginaFinal" => "8"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8872955"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib6"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Epidemiología, aspectos clínicos y manejo del fracaso renal agudo en una población envejecida dependiente de un hospital comarcal. Nefrologia. 2002;22:547-54.  <a href="http://www.ncbi.nlm.nih.gov/pubmed/12516288" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Epidemiolog&#237;a&#44; aspectos cl&#237;nicos y manejo del fracaso renal agudo en una poblaci&#243;n envejecida dependiente de un hospital comarcal&#46;"
                      "idioma" => "es"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Lou LM"
                            1 => "Boned B"
                            2 => "Gimeno JA"
                            3 => "Beguer P"
                            4 => "Cruz A"
                            5 => "Telmo S"
                            6 => "et al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Nefrologia. "
                        "fecha" => "2002"
                        "volumen" => "22"
                        "paginaInicial" => "547"
                        "paginaFinal" => "54"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12516288"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib7"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Diuretics, ACE inhibitors ans NSAIDs–the triple whammy. Med J Austr. 2000;172:184-5. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Diuretics&#44; ACE inhibitors ans NSAIDs–the triple whammy&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "Thomas MC&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Med J Austr. "
                        "fecha" => "2000"
                        "volumen" => "172"
                        "paginaInicial" => "184"
                        "paginaFinal" => "5"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib8"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol. 2005;16:3365-70.  <a href="http://www.ncbi.nlm.nih.gov/pubmed/16177006" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Acute kidney injury&#44; mortality&#44; length of stay&#44; and costs in hospitalized patients&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "Chertow GM"
                            1 => "Burdick E"
                            2 => "Honour M"
                            3 => "Bonventre JV"
                            4 => "Bates DW&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1681/ASN.2004090740"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Am Soc Nephrol. "
                        "fecha" => "2005"
                        "volumen" => "16"
                        "paginaInicial" => "3365"
                        "paginaFinal" => "70"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16177006"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib9"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Clinical Risk Groups (CRGs): a classification system for risk-adjusted capitation-based payment and health care management. Med Care. 2004;42:81-90.  <a href="http://www.ncbi.nlm.nih.gov/pubmed/14713742" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Clinical Risk Groups &#40;CRGs&#41;&#58; a classification system for risk-adjusted capitation-based payment and health care management&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Hughes JS"
                            1 => "Averill RF"
                            2 => "Eisenhandler J"
                            3 => "Goldfield NI"
                            4 => "Muldoon J"
                            5 => "Neff JM"
                            6 => "et al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/01.mlr.0000102367.93252.70"
                      "Revista" => array:6 [
                        "tituloSerie" => "Med Care. "
                        "fecha" => "2004"
                        "volumen" => "42"
                        "paginaInicial" => "81"
                        "paginaFinal" => "90"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14713742"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib10"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "La medida de la morbilidad atendida en una organización sanitaria integrada. Gac Sanit. 2009;23:29-37.  <a href="http://www.ncbi.nlm.nih.gov/pubmed/19879022" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "La medida de la morbilidad atendida en una organizaci&#243;n sanitaria integrada&#46;"
                      "idioma" => "es"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Inoriza JM"
                            1 => "Coderch J"
                            2 => "Carreras M"
                            3 => "Vall-Llosera L"
                            4 => "Garc&#237;a-Go&#241;i M"
                            5 => "Lisbona JM"
                            6 => "et al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.gaceta.2009.07.005"
                      "Revista" => array:6 [
                        "tituloSerie" => "Gac Sanit. "
                        "fecha" => "2009"
                        "volumen" => "23"
                        "paginaInicial" => "29"
                        "paginaFinal" => "37"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19879022"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib11"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Análisis de costes por paciente en una organización sanitaria integrada. Fulls econòmics del sistema sanitari 2010;39:28-37 [Internet; consultado 15 May 2014]. Disponible en: http://www20.gencat. cat/docs/salut/Minisite/catsalut/Coneix_CatSalut/informacio_ economica/fulls_economics/efulls_39.pdf. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "An&#225;lisis de costes por paciente en una organizaci&#243;n sanitaria integrada&#46;"
                      "idioma" => "es"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "Carreras M"
                            1 => "Ibern P"
                            2 => "Coderch J"
                            3 => "Inoriza JM&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib12"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Estimates of patient cost related with population morbidity: can indirect cost affect the results? Eur J Health Econ. 2011;12:289-95.  <a href="http://www.ncbi.nlm.nih.gov/pubmed/20306112" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Estimates of patient cost related with population morbidity&#58; can indirect cost affect the results&#63; Eur J Health Econ&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "Carreras M"
                            1 => "Garcia-Go&#241;i M"
                            2 => "Ibern P"
                            3 => "Coderch J"
                            4 => "Vall-Llosera L"
                            5 => "Inoriza JM&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "fecha" => "2011"
                        "volumen" => "12"
                        "paginaInicial" => "289"
                        "paginaFinal" => "95"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib13"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Red Española de Costes Hospitalarios (RECH): bases para una gestión clínica basada en la evidencia. Gest y Eval Cost Sanit 2012;13:369-83 [Internet; consultado 15 May 2014]. Disponible en: http://www.fundacionsigno.com/archivos/ publicaciones/003_SIGNO_13_3.pdf. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Red Espa&#241;ola de Costes Hospitalarios &#40;RECH&#41;&#58; bases para una gesti&#243;n cl&#237;nica basada en la evidencia&#46;"
                      "idioma" => "es"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Cots F"
                            1 => "Chiarello P"
                            2 => "Carreras M"
                            3 => "Gonzalez JG"
                            4 => "Heras D"
                            5 => "de Ima&#241;a M"
                            6 => "et al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib14"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Grupo RECH 2010 [Internet; consultado 15 May 2014]. Disponible en: https:// www.rechosp.org/rech/cms/en/vision/1/1. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Grupo RECH 2010 &#91;Internet&#46;"
                      "idioma" => "de"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "Red Espa&#241;ola de Costes Hospitalarios&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib15"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Non steroideal anti-inflammatory drugs and risk of AFR in the general population. Am J Kidney Dis. 2005;45:531-9.  <a href="http://www.ncbi.nlm.nih.gov/pubmed/15754275" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Non steroideal anti-inflammatory drugs and risk of AFR in the general population&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "Huerta C"
                            1 => "Castellsagu&#233; J"
                            2 => "Varas-Lorenzo C"
                            3 => "Garc&#237;a Rodr&#237;guez LA&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/j.ajkd.2004.12.005"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Kidney Dis. "
                        "fecha" => "2005"
                        "volumen" => "45"
                        "paginaInicial" => "531"
                        "paginaFinal" => "9"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15754275"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib16"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study. BMJ. 2013;346:e8525 [Internet; consultado 15 May 2014). Disponible en: http://dx.doi.org/10.1136/bmj.e8525.  <a href="http://www.ncbi.nlm.nih.gov/pubmed/23516146" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Concurrent use of diuretics&#44; angiotensin converting enzyme inhibitors&#44; and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury&#58; nested case-control study&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "Lapi F"
                            1 => "Azoulay L"
                            2 => "Yin H"
                            3 => "Nessim SJ"
                            4 => "Suissa S&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:1 [
                        "tituloSerie" => "BMJ. "
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib17"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Kidney International supplements. 2013;3:91-111. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Kidney International supplements&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "Other complications of CKD&#58; CVD"
                            1 => "medication dosage"
                            2 => "patient safety"
                            3 => "infections"
                            4 => "hospitalizations and caveats for investigating complications of CKD&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "fecha" => "2013"
                        "volumen" => "3"
                        "paginaInicial" => "91"
                        "paginaFinal" => "111"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib18"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "STOPP (Screening Tool of Older Person’s Prescriptions) and START (Screening Tool to Alert doctors to Right Treatment). Consensus validation. Int J Clin Pharmacol Ther. 2008;46:72-83. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "STOPP &#40;Screening Tool of Older Person’s Prescriptions&#41; and START &#40;Screening Tool to Alert doctors to Right Treatment&#41;&#46; Consensus validation&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "Gallagher P"
                            1 => "Ryan C"
                            2 => "Byrne S"
                            3 => "Kennedy J"
                            4 => "O’Mahony D&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Clin Pharmacol Ther. "
                        "fecha" => "2008"
                        "volumen" => "46"
                        "paginaInicial" => "72"
                        "paginaFinal" => "83"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18218287"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib19"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Laboratory monitoring of patients treated with antihypertensive drugs and newly exposed to non steroidal anti-inflammatory drugs: a cohort study. PLoS ONE. 2012;7:e34187 [consultado 15 May 2014]. Disponible en: http:// www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal. pone.0034187.  <a href="http://www.ncbi.nlm.nih.gov/pubmed/23300888" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Laboratory monitoring of patients treated with antihypertensive drugs and newly exposed to non steroidal anti-inflammatory drugs&#58; a cohort study&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "Fournier JP"
                            1 => "Lapeyre-Mestre M"
                            2 => "Sommet A"
                            3 => "Dupouy J"
                            4 => "Poutrain JC"
                            5 => "Montastruc JL&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1371/journal.pone.0122551"
                      "Revista" => array:2 [
                        "tituloSerie" => "PLoS ONE. "
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25879682"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib20"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "More on the “Triple Whammy”: antihypertensive drugs, non-steroidal anti-inflammatory agents and acute kidney injury - a case/non-case study in the French pharmacovigilance database. Ren Fail. 2014;36:1166-8.  <a href="http://www.ncbi.nlm.nih.gov/pubmed/24826803" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "More on the “Triple Whammy”&#58; antihypertensive drugs&#44; non-steroidal anti-inflammatory agents and acute kidney injury - a case&#47;non-case study in the French pharmacovigilance database&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "Fournier JP"
                            1 => "Sommet A"
                            2 => "Durrieu G"
                            3 => "Poutrain JC"
                            4 => "Lapeyre-Mestre M"
                            5 => "Montastruc JL&#59; French Network of Regional Pharmacovigilance Centres&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3109/0886022X.2014.917943"
                      "Revista" => array:6 [
                        "tituloSerie" => "Ren Fail. "
                        "fecha" => "2014"
                        "volumen" => "36"
                        "paginaInicial" => "1166"
                        "paginaFinal" => "8"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24826803"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
          ]
        ]
      ]
    ]
  ]
  "idiomaDefecto" => "en"
  "url" => "/20132514/0000003500000002/v0_201504231604/X2013251415123895/v0_201504231606/en/main.assets"
  "Apartado" => array:4 [
    "identificador" => "38708"
    "tipo" => "SECCION"
    "es" => array:2 [
      "titulo" => "Originals"
      "idiomaDefecto" => true
    ]
    "idiomaDefecto" => "es"
  ]
  "PDF" => "https://static.elsevier.es/multimedia/20132514/0000003500000002/v0_201504231604/X2013251415123895/v0_201504231606/en/498v35n02a90412389pdf001.pdf?idApp=UINPBA000064&text.app=https://revistanefrologia.com/"
  "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251415123895?idApp=UINPBA000064"
]

Article information

ISSN: 20132514
Original language: English

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	7	6	13
2024 October	44	32	76
2024 September	48	23	71
2024 August	65	49	114
2024 July	43	24	67
2024 June	89	41	130
2024 May	58	32	90
2024 April	55	26	81
2024 March	51	24	75
2024 February	58	36	94
2024 January	37	20	57
2023 December	29	21	50
2023 November	36	29	65
2023 October	93	21	114
2023 September	73	18	91
2023 August	37	23	60
2023 July	38	26	64
2023 June	40	20	60
2023 May	50	48	98
2023 April	28	12	40
2023 March	38	18	56
2023 February	40	16	56
2023 January	43	24	67
2022 December	85	25	110
2022 November	60	46	106
2022 October	90	40	130
2022 September	40	35	75
2022 August	43	53	96
2022 July	34	42	76
2022 June	44	29	73
2022 May	32	23	55
2022 April	38	44	82
2022 March	40	37	77
2022 February	39	37	76
2022 January	42	27	69
2021 December	31	39	70
2021 November	41	34	75
2021 October	46	37	83
2021 September	45	38	83
2021 August	55	33	88
2021 July	41	36	77
2021 June	29	16	45
2021 May	53	27	80
2021 April	100	65	165
2021 March	83	30	113
2021 February	71	12	83
2021 January	72	14	86
2020 December	61	11	72
2020 November	31	16	47
2020 October	57	14	71
2020 September	43	4	47
2020 August	58	12	70
2020 July	63	14	77
2020 June	46	8	54
2020 May	80	7	87
2020 April	87	20	107
2020 March	70	13	83
2020 February	76	20	96
2020 January	87	17	104
2019 December	98	29	127
2019 November	95	18	113
2019 October	60	23	83
2019 September	82	17	99
2019 August	82	18	100
2019 July	55	20	75
2019 June	62	23	85
2019 May	29	21	50
2019 April	84	24	108
2019 March	51	21	72
2019 February	32	14	46
2019 January	30	16	46
2018 December	62	39	101
2018 November	125	18	143
2018 October	92	8	100
2018 September	66	14	80
2018 August	45	13	58
2018 July	42	17	59
2018 June	43	17	60
2018 May	51	8	59
2018 April	61	12	73
2018 March	38	7	45
2018 February	27	2	29
2018 January	26	9	35
2017 December	27	9	36
2017 November	38	12	50
2017 October	33	4	37
2017 September	29	8	37
2017 August	34	8	42
2017 July	26	10	36
2017 June	54	12	66
2017 May	38	11	49
2017 April	29	4	33
2017 March	25	10	35
2017 February	30	6	36
2017 January	18	8	26
2016 December	76	13	89
2016 November	87	11	98
2016 October	104	7	111
2016 September	157	10	167
2016 August	236	0	236
2016 July	223	0	223
2016 June	200	0	200
2016 May	186	0	186
2016 April	151	0	151
2016 March	143	0	143
2016 February	174	0	174
2016 January	147	0	147
2015 December	131	1	132
2015 November	134	1	135
2015 October	157	5	162
2015 September	177	6	183
2015 August	192	19	211
2015 July	361	0	361
2015 June	244	0	244
2015 May	361	43	404
2015 April	42	0	42

Show all

Indexed in:

Follow us:

Statistics

Indexed in:

Follow us:

Statistics

Subscribe to our newsletter