Association of prior outpatient diabetes screening with cardiovascular events and mortality among people with incident diabetes: a population-based cohort study.

BACKGROUND: Outcomes of diabetes screening in contemporary, multi-ethnic populations are unknown. We examined the association of prior outpatient diabetes screening with the risks of cardiovascular events and mortality in Ontario, Canada. METHODS: We conducted a population-based cohort study using administrative databases among adults aged ≥ 20 years with incident diabetes diagnosed during 2014-2016. The exposure was outpatient diabetes screening performed within 3 years prior to diabetes diagnosis. The co-primary outcomes were (1) a composite of all-cause mortality and hospitalization for myocardial infarction, stroke, coronary revascularization, and (2) all-cause mortality (followed up until 2018). We calculated standardized rates of each outcome and conducted cause-specific hazard modelling to determine the adjusted hazard ratio (HR) of the outcomes, adjusting for prespecified confounders and accounting for the competing risk of death. RESULTS: We included 178,753 Ontarians with incident diabetes (70.2% previously screened). Individuals receiving prior screening were older (58.3 versus 53.4 years) and more likely to be women (49.6% versus 40.0%) than previously unscreened individuals. Individuals receiving prior screening had relatively lower standardized event rates than those without prior screening across all outcomes (composite: 12.8 versus 18.1, mortality: 8.2 versus 11.1 per 1000 patient-years). After multivariable adjustment, prior screening was associated with 34% and 32% lower risks of the composite (HR 0.66, 0.63-0.69) and mortality (0.68, 0.64-0.72) outcomes. Among those receiving prior screening, a result in the prediabetes range was associated with lower risks of the composite (0.82, 0.77-0.88) and mortality (0.71, 0.66-0.78) outcomes than a result in the normoglycemic range. CONCLUSIONS: Previously screened individuals with diabetes had lower risks of cardiovascular events and mortality versus previously unscreened individuals. Better risk assessment tools are needed to support wider and more appropriate uptake of diabetes screening, especially among young adults.

Risk of Chronic Kidney Disease in Hospitalized Patients with Hidradenitis Suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is associated with several comorbidities such as diabetes mellitus and cardiovascular diseases. These comorbidities are also risk factors for chronic kidney disease (CKD), yet little is known about the risk of CKD in HS patients. OBJECTIVES: The objective was to study the prevalence of CKD in HS patients. METHODS: Cross-sectional population-based study using the United States National Inpatient Sample database between January 1, 2002 and December 31, 2012 was performed. RESULTS: We identified 23,767 hospital admissions for HS patients and 95,068 admissions for age- and gender-matched controls. The prevalence of CKD in HS patients was 6.3% (1,497/23,767) compared to non-HS controls which was 4.3% (4,052/95,068). The association of CKD was strongest in HS patients, who were ≥60 years old, 16.9% (475/2,811), male 7.3% (695/9,556), obese 7.8% (407/5,209), diabetic 12.5% (890/7,105), hyperlipidemic 13.3% (416/3,126), and had cardiovascular diseases 12.5% (631/5,045). The crude odds ratio of CKD in HS patients was 1.5 (95% CI: 1.420-1.605) compared to non-HS patients. The association remained significant after adjusting for important covariates with adjusted odds ratio of CKD in HS patients of 1.1 (95% CI: 1.014-1.176) compared to non-HS patients. CONCLUSIONS: Our findings show that there is a possible association of HS with CKD. Any signs of CKD should be assessed by a nephrologist as early diagnosis can hopefully prevent further progression.

Management of Blood Pressure in Patients With Chronic Kidney Disease Not Receiving Dialysis: Synopsis of the 2021 KDIGO Clinical Practice Guideline.

DESCRIPTION: The Kidney Disease: Improving Global Outcomes (KDIGO) 2021 clinical practice guideline for the management of blood pressure (BP) in patients with chronic kidney disease (CKD) not receiving dialysis is an update of the KDIGO 2012 guideline on the same topic and reflects new evidence on the risks and benefits of BP-lowering therapy among patients with CKD. It is intended to support shared decision making by health care professionals working with patients with CKD worldwide. This article is a synopsis of the full guideline. METHODS: The KDIGO leadership commissioned 2 co-chairs to convene an international Work Group of researchers and clinicians. After a Controversies Conference in September 2017, the Work Group defined the scope of the evidence review, which was undertaken by an evidence review team between October 2017 and April 2020. Evidence reviews were done according to the Cochrane Handbook. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach was used to guide the development of the recommendations and rate the strength and quality of the evidence. Practice points were included to provide guidance when evidence was insufficient to make a graded recommendation. The guideline was revised after public consultation between January and March 2020. RECOMMENDATIONS: The updated guideline comprises 11 recommendations and 20 practice points. This synopsis summarizes key recommendations pertinent to the diagnosis and management of high BP in adults with CKD, excluding those receiving kidney replacement therapy. In particular, the synopsis focuses on recommendations for standardized BP measurement and a target systolic BP of less than 120 mm Hg, because these recommendations differ from some other guidelines.

Ups and downs of hypertension control in Canada: critical factors and lessons learned.

As the leading risk for death, population control of increased blood pressure represents a major challenge for all countries of the Americas. In the early 1990's, Canada had a hypertension control rate of 13%. The control rate increased to 68% in 2010, accompanied by a sharp decline in cardiovascular disease. The unprecedented improvement in hypertension control started around the year 2000 when a comprehensive program to implement annually updated hypertension treatment recommendations started. The program included a comprehensive monitoring system for hypertension control. After 2011, there was a marked decrease in emphasis on implementation and evaluation and the hypertension control rate declined, driven by a reduction in control in women from 69% to 49%. A coalition of health and scientific organizations formed in 2011 with a priority to develop advocacy positions for dietary policies to prevent and control hypertension. By 2015, the positions were adopted by most federal political parties, but implementation has been slow. This manuscript reviews key success factors and learnings. Some key success factors included having broad representation on the program steering committee, multidisciplinary engagement with substantive primary care involvement, unbiased up to date credible recommendations, development and active adaptation of education resources based on field experience, extensive implementation of primary care resources, annual review of the program and hypertension indicators and developing and emphasizing the few interventions important for hypertension control. Learnings included the need for having strong national and provincial government engagement and support, and retaining primary care organizations and clinicians in the implementation and evaluation.

La hipertensión arterial representa el principal riesgo de muerte; controlarla a nivel de la población constituye un desafío importante para todos los países de la Región de las Américas. A principios de la década de 1990, Canadá presentaba una tasa de control de la hipertensión del 13%. La tasa de control aumentó al 68% en el 2010, lo que vino acompañado por una disminución importante de las enfermedades cardiovasculares. Esta mejora sin precedentes en el control de la hipertensión empezó alrededor del año 2000 cuando se inició un programa integral para aplicar las recomendaciones sobre el tratamiento de la hipertensión, actualizadas anualmente. El programa incluyó un sistema de monitoreo integral para el control de la hipertensión. Después del 2011, hubo una marcada disminución del énfasis en la implementación y la evaluación, y la tasa de control de la hipertensión disminuyó, impulsada por una reducción en el control en las mujeres, que pasó del 69% al 49%. En el 2011, se formó una coalición de organizaciones científicas y de salud con la prioridad de elaborar una campaña de defensa y promoción de las políticas alimentarias para prevenir y controlar la hipertensión. Para el año 2015, esta postura fue adoptada por la mayoría de los partidos políticos federales, aunque la implementación ha sido lenta.En este artículo se revisan los factores clave de éxito y las lecciones aprendidas. Algunos factores clave de éxito fueron tener una amplia representación en el comité directivo del programa; el compromiso multidisciplinario con la participación sustantiva del sector de la atención primaria; unas recomendaciones creíbles, imparciales y actualizadas; el desarrollo y la adaptación activa de recursos educativos basados en la experiencia en el terreno; la amplia implementación de los recursos de la atención primaria; la revisión anual del programa y de los indicadores de hipertensión; y el desarrollo y el énfasis en unas pocas intervenciones importantes para el control de la hipertensión. Entre las lecciones aprendidas se encontró la necesidad de contar con un fuerte compromiso y apoyo del gobierno nacional y provincial, y de mantener a las organizaciones de atención primaria y al personal médico en la implementación y la evaluación.

O controle populacional da hipertensão arterial ­ o maior fator de risco de morte ­ representa um grande desafio para todos os países das Américas. No início da década de 1990, o Canadá tinha uma taxa de controle de hipertensão de 13%. Esse índice aumentou para 68% em 2010, acompanhado por um declínio acentuado das doenças cardiovasculares. A melhoria sem precedentes no controle da hipertensão começou por volta do ano 2000, quando teve início um programa abrangente para implementar recomendações de tratamento de hipertensão atualizadas anualmente. O programa incluía um sistema integral de monitoramento do controle da hipertensão. Após 2011, houve uma acentuada redução da ênfase na implementação e avaliação, e a taxa de controle de hipertensão caiu, principalmente às custas de uma redução deste controle em mulheres (de 69% para 49%). Uma coalizão de organizações científicas e de saúde formou-se em 2011 com a prioridade de desenvolver posições de defesa de políticas alimentares para prevenir e controlar a hipertensão. Até 2015, essas posições haviam sido adotadas pela maioria dos partidos políticos federais, mas a implementação tem sido lenta.Este manuscrito examina fatores-chave de sucesso e aprendizados. Alguns fatores-chave de sucesso incluíram uma ampla representatividade no comitê diretor do programa, engajamento multidisciplinar (com envolvimento significativo da atenção primária), recomendações imparciais e confiáveis, elaboração e adaptação ativa de recursos didáticos com base na experiência de campo, ampla implementação dos recursos da atenção primária, revisão anual do programa e dos indicadores de hipertensão e desenvolvimento e ênfase das poucas intervenções realmente importantes para o controle da hipertensão. As lições aprendidas incluíram a necessidade de ter forte envolvimento e apoio dos governos nacional e subnacionais e manter organizações e médicos da atenção primária engajados na implementação e avaliação.

Executive summary of the KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease.

The Kidney Disease: Improving Global Outcomes (KDIGO) 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease for patients not receiving dialysis represents an update to the KDIGO 2012 guideline on this topic. Development of this guideline update followed a rigorous process of evidence review and appraisal. Guideline recommendations are based on systematic reviews of relevant studies and appraisal of the quality of the evidence. The strength of recommendations is based on the "Grading of Recommendations Assessment, Development and Evaluation" (GRADE) approach. The scope includes topics covered in the original guideline, such as optimal blood pressure targets, lifestyle interventions, antihypertensive medications, and specific management in kidney transplant recipients and children. Some aspects of general and cardiovascular health, such as lipid and smoking management, are excluded. This guideline also introduces a chapter dedicated to proper blood pressure measurement since all large randomized trials targeting blood pressure with pivotal outcomes used standardized preparation and measurement protocols adhered to by patients and clinicians. Based on previous and new evidence, in particular the Systolic Blood Pressure Intervention Trial (SPRINT) results, we propose a systolic blood pressure target of less than 120 mm Hg using standardized office reading for most people with chronic kidney disease (CKD) not receiving dialysis, the exception being children and kidney transplant recipients. The goal of this guideline is to provide clinicians and patients a useful resource with actionable recommendations supplemented with practice points. The burden of the recommendations on patients and resources, public policy implications, and limitations of the evidence are taken into consideration. Lastly, knowledge gaps and recommendations for future research are provided.

A retrospective observational population-based study to assess the prevalence and burden of illness of type 2 diabetes with an estimated glomerular filtration rate < 90 mL/min/1.73 m2 in Ontario, Canada.

AIM: To better understand the healthcare burden of people with type 2 diabetes (T2D) and estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m2 in Ontario, Canada. MATERIALS AND METHODS: We used administrative data to evaluate the prevalence of T2D, eGFR < 90 mL/min/1.73 m2 and adverse cardiovascular co-morbidities in individuals aged ≥ 30 years living in Ontario, Canada. We also examined incremental healthcare costs and healthcare resource utilization (HCRU) for these patients with specific incident cardiovascular and renal outcomes, in comparison with controls without these outcomes. RESULTS: While the prevalence of T2D in the general population aged ≥ 30 years in Ontario increased by 1.8% over a 5-year period (2011-2012 to 2015-2016), the prevalence of eGFR < 90 mL/min/1.73 m2 among people with T2D increased by 35%. In comparison with corresponding controls without these outcomes, the per patient average total costs (Canadian dollars) over a 2-year analysis period were higher for patients with cardiovascular disease/chronic kidney disease related death ($69 827; n = 32 407), doubling of serum creatinine ($52 260; n = 22 825), those who started dialysis ($150 627; n = 3499) or received a kidney transplant ($50 664; n = 651). Similarly, HCRU was significantly greater for patients with these incident outcomes. CONCLUSIONS: This real-world retrospective study highlights an increasing prevalence of T2D, eGFR < 90 mL/min/1.73 m2 , and the substantially higher healthcare costs and HCRU when these patients have adverse cardiovascular and renal outcomes. The existence of such a large economic burden underpins the importance of preventing these diabetes-related complications.

Inter-individual variability in atrasentan exposure partly explains variability in kidney protection and fluid retention responses: A post hoc analysis of the SONAR trial.

AIM: To evaluate whether atrasentan plasma exposure explains between-patient variability in urinary albumin-to-creatinine ratio (UACR) response, a surrogate for kidney protection, and B-type natriuretic peptide (BNP) response, a surrogate for fluid expansion. METHODS: Type 2 diabetic patients with chronic kidney disease (n = 4775) received 0.75 mg atrasentan for 6 weeks in the active run-in period. Individual area under the concentration-time-curve (AUC) was estimated using a population pharmacokinetic model. The association between atrasentan AUC, other clinical characteristics, and UACR and BNP response, was estimated using linear regression. RESULTS: The median atrasentan AUC was 43.8 ng.h/mL with a large variation among patients (2.5th-97.5th percentiles [P]: 12.6 to 197.5 ng.h/mL). Median UACR change at the end of enrichment was -36.0% and median BNP change was 8.7%, which also varied among patients (UACR, 2.5th-97.5th P: -76.2% to 44.5%; BNP, 2.5th-97.5th P: -71.5% to 300.0%). In the multivariable analysis, higher atrasentan AUC was associated with greater UACR reduction (4.88% per doubling in ng.h/mL [95% confidence interval {CI}: 6.21% to 3.52%], P < .01) and greater BNP increase (3.08% per doubling in ng.h/mL [95% CI: 1.12% to 4.11%], P < .01) independent of estimated glomerular filtration rate, haemoglobin or BNP. Caucasian patients compared with black patients had greater UACR reduction (7.06% [95% CI: 1.38% to 13.07%]) and also greater BNP increase (8.75% [95% CI: 1.65% to 15.35%]). UACR response was not associated with BNP response (r = 0.06). CONCLUSION: Atrasentan plasma exposure varied among individual patients and partially explained between-patient variability in efficacy and safety response.

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 m2 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 m2 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.

Blood pressure in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

In September 2017, KDIGO (Kidney Disease: Improving Global Outcomes) convened a Controversies Conference titled Blood Pressure in Chronic Kidney Disease (CKD). The purpose of the meeting was to consider which recommendations from the 2012 KDIGO Clinical Practice Guideline for the Management of Blood Pressure in CKD should be reevaluated based on new evidence from clinical trials. Participants included a multidisciplinary panel of clinical and scientific experts. Discussions focused on the optimal means for measuring blood pressure (BP) as well as managing BP in CKD patients. Consistent with the 2012 Guideline, the conference did not address BP management in patients on maintenance dialysis.

Wise Practices for Cultural Safety in Electronic Health Research and Clinical Trials With Indigenous People: Secondary Analysis of a Randomized Clinical Trial.

BACKGROUND: There is a paucity of controlled clinical trial data based on research with Indigenous peoples. A lack of data specific to Indigenous peoples means that new therapeutic methods, such as those involving electronic health (eHealth), will be extrapolated to these groups based on research with other populations. Rigorous, ethical research can be undertaken in collaboration with Indigenous communities but requires careful attention to culturally safe research practices. Literature on how to involve Indigenous peoples in the development and evaluation of eHealth or mobile health apps that responds to the needs of Indigenous patients, providers, and communities is still scarce; however, the need for community-based participatory research to develop culturally safe technologies is emerging as an essential focus in Indigenous eHealth research. To be effective, researchers must first gain an in-depth understanding of Indigenous determinants of health, including the harmful consequences of colonialism. Second, researchers need to learn how colonialism affects the research process. The challenge then for eHealth researchers is to braid Indigenous ethical values with the requirements of good research methodologies into a culturally safe research protocol. OBJECTIVE: A recent systematic review showed that Indigenous peoples are underrepresented in randomized controlled trials (RCTs), primarily due to a lack of attention to providing space for Indigenous perspectives within the study frameworks of RCTs. Given the lack of guidelines for conducting RCTs with Indigenous communities, we conducted an analysis of our large evaluation data set collected in the Diagnosing Hypertension-Engaging Action and Management in Getting Lower Blood Pressure in Indigenous Peoples and Low- and Middle- Income Countries (DREAM-GLOBAL) trial over a period of five years. Our goal is to identify wise practices for culturally safe, collaborative eHealth and RCT research with Indigenous communities. METHODS: We thematically analyzed survey responses and qualitative interview/focus group data that we collected over five years in six culturally diverse Indigenous communities in Canada during the evaluation of the clinical trial DREAM-GLOBAL. We established themes that reflect culturally safe approaches to research and then developed wise practices for culturally safe research in pragmatic eHealth research. RESULTS: Based on our analysis, successful eHealth research in collaboration with Indigenous communities requires a focus on cultural safety that includes: (1) building a respectful relationship; (2) maintaining a respectful relationship; (3) good communication and support for the local team during the RCT; (4) commitment to co-designing the innovation; (5) supporting task shifting with the local team; and (6) reflecting on our mistakes and lessons learned or areas for improvement that support learning and cultural safety. CONCLUSIONS: Based on evaluation data collected in the DREAM-GLOBAL RCT, we found that there are important cultural safety considerations in Indigenous eHealth research. Building on the perspectives of Indigenous staff and patients, we gleaned wise practices for RCTs in Indigenous communities. TRIAL REGISTRATION: ClinicalTrials.gov NCT02111226; https://clinicaltrials.gov/ct2/show/NCT02111226.

Rationale and protocol of the Study Of diabetic Nephropathy with AtRasentan (SONAR) trial: A clinical trial design novel to diabetic nephropathy.

AIMS: Individuals with diabetes and chronic kidney disease (CKD) are at high risk for renal events. Recent trials of novel treatments have been negative, possibly because of variability in response to treatment of the target risk factor. Atrasentan is a selective endothelin A receptor antagonist that reduces urinary albumin-to-creatinine ratio (UACR), with a large variability between patients. We are assessing its effect on renal outcomes in the Study Of diabetic Nephropathy with AtRasentan (SONAR; NCT01858532) with an enrichment design (>30% lowering of albuminuria) to select patients most likely to benefit. MATERIALS AND METHODS: SONAR is a randomized, double-blind, placebo-controlled trial with approximately 3500 participants who have stage 2-4 CKD and macroalbuminuria and are receiving a maximum tolerated dose of a renin-angiotensin system inhibitor. RESULTS: After 6 weeks of exposure to atrasentan 0.75 mg once daily (enrichment period), participants with ≥30% UACR decrease and no tolerability issues (responders) were randomly assigned to placebo or atrasentan 0.75 mg/day. The responder group will be used for primary efficacy and safety analyses. Approximately 1000 participants with <30% UACR reduction (non-responders) were also randomized to placebo or atrasentan. The primary endpoint is a composite of a sustained doubling of serum creatinine or end-stage renal disease. The original power calculation indicated that a total of 425 primary renal events in the responder group provides 90% power to detect a 27% reduction in relative risk (alpha level of .05). CONCLUSION: SONAR aims to determine whether atrasentan added to guideline-recommended therapies safely reduces the risk of CKD progression and delays the onset of end-stage renal disease in patients with type 2 diabetes and nephropathy. SONAR also aims to establish whether the enrichment of patients based on their initial "surrogate" response to atrasentan will deliver a trial design in accord with personalized treatment of diabetic kidney disease.

Baseline characteristics and enrichment results from the SONAR trial.

AIM: The SONAR trial uses an enrichment design based on the individual response to the selective endothelin receptor antagonist atrasentan on efficacy (the degree of the individual response in the urinary albumin-to-creatinine ratio [UACR]) and safety/tolerability (signs of sodium retention and acute increases in serum creatinine) to assess the effects of this agent on major renal outcomes. The patient population and enrichment results are described here. METHODS: Patients with type 2 diabetes with an estimated glomerular filtration rate (eGFR) within 25 to 75 mL/min/1.73 m2 and UACR between 300 and 5000 mg/g were enrolled. After a run-in period, eligible patients received 0.75 mg/d of atrasentan for 6 weeks. A total of 2648 responder patients in whom UACR decreased by ≥30% compared to baseline were enrolled, as were 1020 non-responders with a UACR decrease of <30%. Patients who experienced a weight gain of >3 kg and in whom brain natriuretic peptide exceeded ≥300 pg/mL, or who experienced an increase in serum creatinine >20% (0.5 mg/dL), were not randomized. RESULTS: Baseline characteristics were similar for atrasentan responders and non-responders. Upon entry to the study, median UACR was 802 mg/g in responders and 920 mg/g in non-responders. After 6 weeks of treatment with atrasentan, the UACR change in responders was -48.8% (95% CI, -49.8% to -47.9%) and in non-responders was -1.2% (95% CI, -6.4% to 3.9%). Changes in other renal risk markers were similar between responders and non-responders except for a marginally greater reduction in systolic blood pressure and eGFR in responders. CONCLUSIONS: The enrichment period has successfully identified a population with a profound UACR reduction without clinical signs of sodium retention in whom a large atrasentan effect on clinically important renal outcomes is possible. The SONAR trial aims to establish whether atrasentan confers renal protection.

Oral curcumin in elective abdominal aortic aneurysm repair: a multicentre randomized controlled trial.

BACKGROUND: Curcumin, a popular herbal supplement from the plant turmeric, has prevented ischemic reperfusion and toxin-induced injury in many animal studies and a single-centre randomized human trial. We sought to test whether perioperative oral curcumin (compared with placebo) affects the inflammatory response and risk of postrepair complications after elective abdominal aortic aneurysm repair in humans. METHODS: We conducted a parallel-group, randomized, placebo-controlled trial of patients from 10 hospitals in Canada who were scheduled to undergo elective repair of an unruptured abdominal aortic aneurysm (November 2011 to November 2014). Patients in the treatment group received perioperative oral curcumin (2000-mg doses 8 times over 4 d). Patients, health care providers and local research staff were unaware of the treatment assignment. The primary outcomes were median concentrations of 4 bio markers indicating injury and inflammation (postoperative urine interleukin-18 and perioperative rise in serum creatinine, plasma N-terminal pro-B-type natriuretic peptide and plasma high-sensitivity C-reactive protein). RESULTS: Baseline characteristics were similar in the 2 groups (606 patients overall; median age 76 yr). More than 85% of patients in each group took more than 80% of their scheduled capsules. Neither curcumin nor placebo significantly affected any of the 4 biomarkers (p > 0.05 for all comparisons). Regarding the secondary outcomes, there was a higher risk of acute kidney injury with curcumin than with placebo (17% v. 10%, p = 0.01), but no between-group difference in the median length of hospital stay (5 v. 5 days, p > 0.9) or the risk of clinical events (9% v. 9%, p = 0.9). INTERPRETATION: Curcumin had no beneficial effects when used in elective abdominal aortic aneurysm repair. These findings emphasize the importance of testing turmeric and curcumin before espousing their health benefits, as is currently done in the popular media. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT01225094.

Acute change in glomerular filtration rate with inhibition of the renin-angiotensin system does not predict subsequent renal and cardiovascular outcomes.

Initiation of blockade of the renin-angiotensin system may cause an acute decrease in glomerular filtration rate (GFR): the prognostic significance of this is unknown. We did a post hoc analysis of patients with, or at risk for, vascular disease, in two randomized controlled trials: Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and the Telmisartan Randomized AssessmeNt Study in ACE iNtolerant participants with cardiovascular Disease (TRANSCEND), whose median follow-up was 56 months. In 9340 patients new to renin-angiotensin system blockade, who were then randomized to renin-angiotensin system blockade, a fall in GFR of 15% or more at 2 weeks after starting renin-angiotensin system blockade was seen in 1480 participants (16%), with persistence at 8 weeks in 700 (7%). Both acute increases and decreases in GFR after initiation of renin-angiotensin system blockade were associated with tendencies, mostly not statistically significant, to increased risk of cardiovascular outcomes, which occurred in 1280 participants, and of microalbuminuria, which occurred in 864. Analyses of creatinine-based outcomes were suggestive of regression to the mean. In more than 3000 patients randomized in TRANSCEND to telmisartan or placebo, there was no interaction between acute change in GFR and renal or cardiovascular benefit from telmisartan. Thus, both increases and decreases in GFR on initiation of renin-angiotensin system blockade are common, and may be weakly associated with increased risk of cardiovascular and renal outcomes. Changes do not predict increased benefit from therapy.

Comparison of exposure response relationship of atrasentan between North American and Asian populations.

AIMS: The selective endothelin (ET) A receptor antagonist atrasentan has been shown to lower albuminuria in North American and Asian patients with type 2 diabetes and nephropathy. As drug responses to many drugs may differ between North American and Asian populations, we assessed the influence of geographical region on the albuminuria and fluid retention response to atrasentan. MATERIALS AND METHODS: Two 12-week double-blind randomised controlled trials were performed with atrasentan 0.75 or 1.25 mg/d vs placebo in patients with type 2 diabetes and nephropathy. The efficacy endpoint was the percentage change in albuminuria. Bodyweight change, a proxy of fluid retention, was used as a safety endpoint. Pharmacodynamics were determined in Asians (N = 77) and North Americans (N = 134). Atrasentan plasma concentration was measured in 161 atrasentan-treated patients. RESULTS: Mean albuminuria reduction in Asian, compared to North American, patients was, respectively, -34.4% vs -26.3% for 0.75 mg/d ( P = .44) and -48.0% vs -28.9% for 1.25 mg/d ( P = .035). Bodyweight gain did not differ between North American and Asian populations. Atrasentan plasma concentrations were higher in Asians compared to North Americans and correlated with albuminuria response (7.2% albuminuria reduction per doubling atrasentan concentration; P = .024). Body surface area (ß = -1.09 per m2 ; P < .001) and bilirubin, as a marker of hepatic organic anion transporter activity, (ß = 0.69 per mg/dL increment; P = .010) were independent determinants of atrasentan plasma concentration; correction by body surface area and bilirubin left no significant difference in plasma concentration between Asian and North American populations. CONCLUSION: The higher exposure and albuminuria reduction of atrasentan in Asian patients is not associated with more fluid retention, suggesting that Asian patients are less sensitive to atrasentan-induced sodium retention.

The effects of atrasentan on urinary metabolites in patients with type 2 diabetes and nephropathy.

We assessed the effect of atrasentan therapy on a pre-specified panel of 13 urinary metabolites known to reflect mitochondrial function in patients with diabetic kidney disease. This post-hoc analysis was performed using urine samples collected during the RADAR study which was a randomized, double-blind, placebo-controlled trial that tested the effects of atrasentan on albuminuria reduction in patients with type 2 diabetes and nephropathy. At baseline, 4 of the 13 metabolites, quantified by gas-chromatography mass spectrometry, were below detectable levels, and 6 were reduced in patients with eGFR < 60 mL/min/1.73 m2 . After 12 weeks of atrasentan treatment in patients with eGFR < 60 mL/min/1.73 m2 , a single-value index of the metabolites changed by -0.31 (95%CI -0.60 to -0.02; P = .035), -0.08 (-12 to 0.29; P = .43) and 0.01 (-0.21 to 0.19; P = .913) in placebo, atrasentan 0.75 and 1.25 mg/d, respectively. The metabolite index difference compared to placebo was 0.13 (-0.17 to 0.43; P = .40) and 0.35 (0.05-0.65; P = .02) for atrasentan 0.75 and 1.25 mg/d, respectively. These data corroborate previous findings of mitochondrial dysfunction in patients with type 2 diabetes, nephropathy and eGFR < 60 mL/min/1.73 m2 , suggesting that atrasentan may prevent the progression of mitochondrial dysfunction common to this specific patient population. Future studies of longer treatment duration with atrasentan are indicated.