Early detection of chronic kidney disease: multidisciplinary document

El aumento de la prevalencia de pacientes con Enfermedad Renal Crónica (ERC), la ha convertido en un problema de Salud Pública mundial, no sólo por el requerimiento de tratamiento sustitutivo renal, sino porque el desarrollo de enfermedad cardiovascular constituye la primera causa de muerte en estos pacientes. La creatinina plasmática (Crp) no siempre resulta un marcador precoz, pues su valor en sangre se eleva por encima del límite superior del intervalo de referencia cuando el Índice de Filtrado Glomerular (IFG) disminuye a la mitad. La medición del IFG con marcadores exógenos es el mejor indicador para evaluar la función renal (FR), aunque su uso en la práctica clínica se reserva para situaciones especiales. El Índice de depuración de creatinina (IDC) puede presentar errores por causa de una mala recolección de orina. Además, sobreestima el IFG debido a que la creatinina, además de ser excretada, se secreta a nivel tubular. La utilización de fórmulas asociadas a Crp está recomendada por la mayoría de las sociedades científicas. La ecuación MDRD-4 se adoptó por consenso "IFGe (mL/min/1,73 m2)= 186 x (Crp) -1.154 x (edad) -0.203 x (0,742 mujer) x (1,212 raza negra)". El factor inicial es 175 cuando el resultado de Crp es trazable a Espectrometría de Masa con Dilución Isotópica (EM-DI). Esta fórmula no es aplicable en casos de embarazadas, hospitalizados, menores de 18 o mayores de 70 años, amputados, etc. Dado que la medición de Crp es la mayor fuente de error para el cálculo de IFGe, el laboratorio debe validar su procedimiento analítico para determinar creatinina. El Error Total no debe superar el 8% para que no produzca un aumento mayor del 10% en la estimación del IFG. Para la detección de ERC se recomienda: 1) Estimar la VFG utilizando la ecuación MDRD-4 asociada a Crp (fuerza de recomendación C). 2) Informar valores de más de 60 mL/min/1,73 m2 sólo como "mayor de 60" y los valores menores de 60, como el número exacto obtenido; 3) Excluir en sistemas con cálculos automáticos las situaciones que limitan el uso de la ecuación.The increase in prevalence of patients with Chronic Kidney Disease (CKD) has turned it a worldwide public health problem not only due to its requirement of a kidney replaceable treatment, but also because cardiovascular disease is now the main cause of death among these patients. Plasma Creatinine (Crp) is not always an early marker, due to the fact that its blood levels exceed the highest limit of the reference range when the Glomerular Filtration Rate (GFR) decreases to a half. GFR measurement with exogenous markers is the best indicator to test renal function (RF), although its use in the clinical practice is only restricted to special situations. Creatinine Clearance (CC) may have errors caused by an inadequate urine collection. Moreover, it overestimates the GFR considering that creatinine is not only excreted but also secreted at the tubular level. The utilization of formulas associated to Crp is recommended by most of the Scientific Societies. The MDRD-4 equation has been adopted by consensus "eGFR (mL/min/1.73 m2)= 186 x (Crp) -1.154 x (age) -0.203 x (0.742 woman) x (1.212 black people)". When the creatinine results are traceable to isotope Dilution/Mass Spectrometry reference method, the initial factor is 175. This formula does not apply to pregnant women, hospitalized patients, people under 18 or older than 70 years old, amputees, etc. Given that the measurement of Crp is the biggest cause of error for the calculation of eGFR, the lab should validate the analytical procedure to determine creatinine. The Total Error should not exceed 8% in order not to yield an increase over 10% of GFR estimation. For CKD detection, it is recommended as follows: 1) Estimate the GFR using MDRD-4´s equation associated to Crp. (Strength of Recommendation C); 2) Report values over 60 mL/min/1.73 m2 only as "over 60" and values under 60 as the exact number obtained; 3) Exclude from automatic calculation systems, situations that limit the use of the equation.Fil: Alles, Alberto. Sociedad Argentina de Nefrología; ArgentinaFil: Fraga, Adriana Raquel. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Sociedad Argentina de Nefrología; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Investigaciones Medicas; ArgentinaFil: García, Roberto Daniel. Fundación Bioquímica Argentina; ArgentinaFil: Gómez, Alejandra. Asociación Bioquímica Argentina; ArgentinaFil: Greloni, Gustavo. Sociedad Argentina de Nefrología; ArgentinaFil: Inserra, Pablo Ignacio Felipe. Sociedad Argentina de Nefrología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Mazziotta, Daniel. Fundación Bioquímica Argentina; ArgentinaFil: Torres, María Lía. Fundación Bioquímica Argentina; ArgentinaFil: Villagra, Alberto. Asociación Bioquímica Argentina; Argentin

Rebiopsias en glomerulonefritis asociadas a ANCA: ¿Cuál es su utilidad en la toma de decisiones?

El objetivo de este estudio fue evaluar la utilidad de la rebiopsia renal en pacientes con glomerulonefritis ANCA en la toma de decisiones. Se incluyeron en forma retrospectiva todos los pacientes con glomerulonefritis ANCA diagnosticados por biopsia renal entre enero de 2002 y mayo de 2017. Se revisó la histología de las rebiopsias y fue correlacionada con los hallazgos clínicos (hematuria, proteinuria y caída del filtrado) y resultados histológicos de la primera y segunda biopsia. Sesenta pacientes (77% mujeres) fueron incluidos

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Cystatin C as Marker of Cardiorenal Syndrome and Poor Prognosis in Patients Hospitalized with Acute Heart Failure and Normal Renal Function

Background: The development of renal dysfunction in patients hospitalized for acute heart failure is known as cardiorenal syndrome type 1 (CRS). Worsening renal function (WRF) during hospitalization is associated with poor prognosis. Cystatin C has emerged as an alternative renal function marker to creatinine.Objective: The aim of this study was to demonstrate the usefulness of cystatin C as predictor of WRF and prognostic factor in patients with acute heart failure and normal renal function assessed by creatinine level on admission.Methods: A prospective, observational study was performed on consecutive patients with acute heart failure and normal renal function defined as serum creatinine <1.3 mg/dL on admission. Cystatin C was measured on admission. The primary endpoint was WRF, and secondary endpoints were in-hospital mortality, total mortality and rehospitalization for heart failure.Results: A total of 166 patients were included in the study. Median age was 85 years (IQR 77.7- 89 years). The incidence of WRF was 29.7%, with in-hospital mortality of 3.1% and total mortality of 24.4%. Median follow-up was 193 days. Serum cystatin C was significantly higher in patients who developed WRF (1.72±0.58 mg/dL vs. 1.51±0.41 mg/dL, p=0.03) and in patients who died during follow up (1.76±0.49 vs. 1.51±0.46, p=0.004). Multivariate analysis showed that cystatin C was an independent predictor of mortality (OR 3.03, 95% CI 1.22-7.47) and WRF (OR 2.38, 95% CI 1.02-5.5). The optimal cystatin C cutoff point was 1.6 mg/dL, with 61.22% sensitivity and 60.34% specificity for the development of WRF, and 61.54% sensitivity and 61.98% specificity for total mortality.Conclusions: Cystatin C on admission is a predictor of in-hospital WRF and increased mortality in this population hospitalized with acute heart failure and preserved renal function.Introducción El desarrollo de disfunción renal en el contexto de una falla cardíaca aguda  se conoce como síndrome cardio-renal (SCR) tipo 1. El empeoramiento de la función renal (EFR)  durante la internación es un predictor de mal pronóstico. La cistatina C ha surgido  como un marcador alternativo a la a creatinina de función renal. Objetivo Demostrar la utilidad clínica de la cistatina C como predictor de EFR  y factor pronostico en pacientes con insuficiencia cardíaca aguda y sin disfunción renal, evaluada por creatinina al ingreso. Materiales y métodos Se llevó a cabo un estudio observacional, prospectivo de pacientes consecutivos con diagnóstico de insuficiencia cardíaca aguda y sin disfunción renal, definida como un valor de creatinina <1,3mg/dl al ingreso. Se realizó un dosaje de cistatina C al ingreso. El punto final primario fue EFR, y los secundarios mortalidad hospitalaria,  mortalidad total y  reinternación por insuficiencia cardiaca Resultados Se incluyeron un total de 166 pacientes con una mediana de edad de 85 años (IIC 77,7-89).  La incidencia de EFR fue de 29,7%, con una mortalidad hospitalaria de 3,1% y una mortalidad total de 24,4%. La mediana de seguimiento fue  193 días. El valor de cistatina C fue significativamente mayor en los pacientes que desarrollaron EFR  (1,72±0,58 vs 1,51±; 0,41, p=0.03)  y en los pacientes que murieron en el seguimiento (1,76±0,49 vs 1,51±0,46, p=0.004). La cistatina C resulto predictor independiente de mortalidad  (OR 3,03, IC 1,22-7,47) y EFR (OR 2,38, IC 1,02-5,5)  en el análisis multivariado. Se halló un punto de corte óptimo de 1,6 mg/dl de cistatina  con una sensibilidad y especificidad de61,22% y 60,34%   para el desarrollo de EFR y 61,54% y 61,98%   para mortalidad total. Conclusión El valor de cistatina C al ingreso es predictor de desarrollo EFR  durante la internación y de mayor mortalidad en esta población con insuficiencia cardiaca aguda y función renal conservada al ingreso

Guia de prática clínica para o diagnóstico e tipificação da amiloidose: Parte 1/3. Ano 2020

Métodos: Se generó un listado de preguntas con el formato PICO centradas en la especificidad y sensibilidad de las pruebas diagnósticas en amiloidosis. Se realizó la búsqueda en PubMed durante julio-agosto del 2019, en inglés y español. Los niveles de evidencia y los grados de recomendación se basan en el sistema GRADE (http://www.gradeworkinggroup.org/index.htm). Las recomendaciones se graduaron según su dirección (a favor o en contra) y según fuerza (fuertes y débiles). Las recomendaciones finales fueron evaluadas con la herramienta GLIA para barreras y facilitadores en la implementación de éstas. Interpretación de recomendaciones: Las recomendaciones fuertes indican alta confianza, ya sea a favor o en contra, de una intervención. En esta guía se utiliza el lenguaje “se recomienda” cuando se define una recomendación fuerte. Las recomendaciones débiles indican que los resultados para una intervención, favorable o desfavorable, son dudosos. En este caso, se utiliza el lenguaje “se sugiere”, cuando se define una recomendación débil. Como utilizar estas pautas: Las recomendaciones deben ser interpretadas en el contexto de la atención especializada, con estudios diagnósticos validados y realizados por médicos entrenados. Se asume que el médico tratante tiene alto nivel de sospecha de amiloidosis. Asume que los estudios diagnósticos son realizados por médicos entrenados con métodos validados y estandarizados. Esta guía es relevante para los profesionales de la salud y los involucrados en las políticas sanitarias, para ayudar a asegurar que existan los acuerdos necesarios para brindar la atención adecuada. Recomendaciones En pacientes con sospecha de amiloidosis se recomienda: ● La confirmación en el tejido mediante biopsia y tinción con rojo Congo con la característica birrefringencia verde bajo luz polarizada. ● La confirmación mediante microscopía electrónica en el tejido de biopsia. ● La tipificación de la proteína mediante espectrometría de masa. ● La tipificación de la proteína mediante inmunomicroscopía óptica y/o electrónica, en la medida que haya anticuerpos confiables. ● La medición de las cadenas livianas libres séricas para evaluación de un trastorno proliferativo de células plasmáticas monoclonales. ● La Inmunofijación sérica y urinaria para la evaluación de un trastorno proliferativo de células plasmáticas monoclonales. ● La medición de las cadenas livianas libres sérica, más la Inmunofijación sérica y urinaria para la evaluación de un trastorno proliferativo de células plasmáticas monoclonales. En pacientes con sospecha de amiloidosis se sugiere: ● Demostración de un trastorno proliferativo de células plasmáticas monoclonales mediante la demostración de plasmocitos clonales por la técnica más sensible disponible en la médula ósea para el diagnóstico de amiloidosis de tipo AL. ● La confirmación de amiloidosis ATTRv mediante secuenciación de ADN del gen TTR amiloidogénico de los 4 exones en pacientes con sospecha de amiloidosis por ATTRvMethod: Use the PICO format to generate a series of questions, focusing on the specificity and sensitivity of the amyloidosis diagnostic test. PubMed searches were conducted in English and Spanish from July to August 2019. The level of evidence and recommendation are based on the GRADE system (http://www.gradeworkinggroup.org/index.htm). The recommendations are graded according to their direction (for or against) and strength (strong and weak). Finally, it is recommended to use GLIA tools to evaluate the obstacles and facilitators in implementation. Suggested explanation: A strong suggestion indicates a high degree of trust in support or opposition to the intervention. When defining a strong recommendation, this guide uses the "recommended" language. The weaker recommendations indicate that the outcome of the intervention (favorable or unfavorable) is doubtful. In this case, if a weak recommendation is defined, the "recommendation" language is used. How to use these guidelines: Recommendations must be explained within the scope of special care in validated diagnostic studies conducted by specially trained doctors. Presumably, the attending physician has a high degree of suspicion of amyloidosis. It assumes that diagnostic research is conducted by well-trained doctors using a validated standardized method. This guide is intended for health care professionals and those involved in health care policies to help ensure that the necessary agreements have been reached to provide appropriate care. Recommendations For patients with suspected amyloidosis, it is recommended: ● Confirmation in the tissue by biopsy and Congo red staining with the characteristic green birefringence under polarized light is recommended. ● Confirmation by electron microscopy of the biopsy tissue is recommended. ● Protein typing by mass spectrometry is recommended. ● Protein typing by optical and / or electronic immunomicroscopy is recommended, as long as there are reliable antibodies. ● Measurement of serum free light chains is recommended for evaluation of a monoclonal plasma cell proliferative disorder. ● Serum and urinary immunofixation is recommended for evaluation of a monoclonal plasma cell proliferative disorder. ● Measurement of serum free light chains, plus serum and urinary immunofixation is recommended for the evaluation of a monoclonal plasma cell proliferative disorder. For patients suspected of having amyloidosis, it is suggested: ● Demonstration of a monoclonal plasma cell proliferative disorder by demonstration of clonal plasma cells by the most sensitive technique available in the bone marrow for the diagnosis of AL-type amyloidosis. ● Confirmation of ATTRv amyloidosis by DNA sequencing of the 4-exon amyloidogenic TTR gene in patients with suspected ATTRv amyloidosis.Method: Use o formato PICO para gerar uma série de perguntas, com foco no especificidade e sensibilidade do teste diagnóstico de amiloidose. Pesquisas PubMed foram conduzido em inglês e espanhol de julho a agosto de 2019. O nível de evidência e as recomendações são baseadas no sistema GRADE (http://www.gradeworkinggroup.org/index.htm). As recomendações são avaliadas de acordo com sua direção (a favor ou contra) e força (forte e fraca). Enfim, é recomendado o uso de ferramentas GLIA para avaliar os obstáculos e facilitadores em implementação. Explicação sugerida: uma sugestão forte indica um alto nível de confiança no apoio ou oposição à intervenção. Ao definir recomendações fortes, este guia usa uma linguagem "recomendada". As recomendações mais fracas indicam que o resultado da intervenção (favorável ou desfavorável) é duvidoso. Nesse caso, se uma recomendação fraca for definida, a linguagem de "recomendação" será usada. Como usar essas diretrizes: As recomendações devem ser explicadas no contexto de cuidados especializados e estudos de diagnóstico validados realizados por médicos treinados. Suponha que o médico assistente suspeite de um alto nível de amiloidose. Ele presumiu que a pesquisa diagnóstica foi conduzida por médicos bem treinados usando métodos padronizados validados. Este guia se aplica a profissionais de saúde e todos os envolvidos na política de saúde para ajudar a garantir que os arranjos necessários sejam feitos para fornecer cuidados adequados. Em pacientes com suspeita de amiloidose, é recomendado: ● Confirmação do tecido por biópsia e coloração com vermelho do Congo com a birrefringência verde característica sob luz polarizada é recomendada. ● Confirmação por microscopia eletrônica do tecido da biópsia é recomendada. ● Tipagem de proteínas por espectrometria de massa é recomendada. ● Tipagem de proteínas por imunomicroscopia ótica e / ou eletrônica é recomendada, desde que haja anticorpos confiáveis. ● Medição das cadeias leves livres séricas é recomendada para avaliação de um distúrbio proliferativo de células plasmáticas monoclonais. ● Imunofixação sérica e urinária é recomendada para avaliação de um distúrbio proliferativo de células plasmáticas monoclonais. ● Medição das cadeias leves livres séricas, além da imunofixação sérica e urinária, é recomendada para a avaliação de um distúrbio proliferativo de células plasmáticas monoclonais. Em pacientes com suspeita de amiloidose, sugere-se: ● A demonstração de um distúrbio proliferativo de células plasmáticas monoclonais demonstração de plasmócitos clonais pela técnica mais sensível disponível na medula óssea para o diagnóstico de amiloidose do tipo AL. ● A confirmação da amiloidose ATTRv por sequenciamento de DNA do gene TTR amiloidogênico de 4 exon em pacientes com suspeita de amiloidose ATTRv.Fil: Posadas Martinez, Maria Lourdes. Hospital Italiano. Departamento de Medicina. Servicio de Clínica Médica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Aguirre, Maria Adela. Hospital Italiano. Departamento de Medicina. Servicio de Clínica Médica; ArgentinaFil: Belziti, César. Hospital Italiano; ArgentinaFil: Brouet, Eva. Clinica Giuliani Charata; ArgentinaFil: Auteri, Miguel Angel. Centro Médico de Avanzada; ArgentinaFil: Forte, Ana Luz. Centro Privado; ArgentinaFil: Greloni, Gustavo. Hospital Italiano. Departamento de Medicina. Servicio de Clínica Médica; ArgentinaFil: Marciano, Sebastian. Hospital Italiano. Departamento de Medicina. Servicio de Clínica Médica; ArgentinaFil: Matoso, María Dolores. Hospital Italiano; ArgentinaFil: Perez de Arenaza, Diego. Hospital Italiano; ArgentinaFil: Pitzus, Ariel Edgardo. Hospital Italiano; ArgentinaFil: Rugiero, Marcelo. Hospital Italiano; ArgentinaFil: Saez, María Soledad. Hospital Italiano; ArgentinaFil: Sorroche, Patricia Beatriz. Hospital Italiano; ArgentinaFil: Tomei, Mauricio. Clinica Giuliani Charata; ArgentinaFil: Zinser, Bettina. Clinica Giuliani Charata; ArgentinaFil: Peuchot, Veronica Andrea. Hospital Italiano. Departamento de Medicina. Servicio de Clínica Médica; ArgentinaFil: Nucifora, Elsa Mercedes. Hospital Italiano. Departamento de Medicina. Servicio de Clínica Médica; Argentin

Effect of SGLT2 Inhibitors on Stroke and Atrial Fibrillation in Diabetic Kidney Disease: Results From the CREDENCE Trial and Meta-Analysis

BACKGROUND AND PURPOSE: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus.METHODS: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-analysis.RESULTS: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: total stroke (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (&lt;45 mL/min/1.73 m2]) subgroup (HRpooled, 0.50 [95% CI, 0.31-0.79]).CONCLUSIONS: Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02065791