Kidney Outcomes Research Articles

Updated evidence on cardiovascular and renal effects of GLP-1 receptor agonists and combination therapy with SGLT2 inhibitors and finerenone: a narrative review and perspectives.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have a reliable hypoglycaemic and weight-loss effect that can intervene in obesity, which is the basis of type 2 diabetes pathology. GLP-1RA therapy has shown potential benefits in reducing the risk of major adverse cardiovascular events and improving kidney outcomes in patients with diabetes at high risk for cardiovascular disease. More recent evidence is expanding their benefits to heart failure with preserved ejection fraction and clinically important renal outcomes in patients with and without diabetes. Some sub-analyses of large clinical trials suggest that GLP-1RA and sodium-glucose cotransporter 2 inhibitor combination therapy may provide more significant reductions in heart failure hospitalization and renal composite events than each alone. Moreover, the addition of finerenone to this combination therapy could potentially provide stronger cardiorenal protective benefits. Further studies are needed to assess the potential cardiovascular and renal benefits of combination therapy and to determine suitable patient population for the therapy.

Identification and outcomes of acute kidney disease in patients presenting in Bolivia, Brazil, South Africa, and Nepal.

The International Society of Nephrology proposes an acute kidney disease (AKD) management strategy that includes a risk score to aid AKD identification in low- and low-middle-income countries (LLMICs). We investigated the performance of the risk score and determined kidney and patient outcomes from AKD at multiple LLMIC sites. Adult patients presenting to healthcare facilities in Bolivia, Brazil, South Africa, and Nepal were screened using a symptom-based risk score and clinical judgment. Those at AKD risk underwent serum creatinine testing, predominantly with a point-of-care (POC) device. Clinical data were collected prospectively between September 2018 and November 2020. We analyzed risk score performance and determined AKD outcomes at discharge and over follow-up of 90 days. A total of 4,311 patients were at increased risk of AKD, and 2,922 (67.8%) had AKD confirmed. AKD prevalence was 80.2% in patients enrolled based on the risk score and 32.5% when enrolled on clinical judgment alone (p < 0.0001). The area under the receiver operating characteristic curve was 0.73 for the risk score to detect AKD. Death during admission occurred in 84 (2.9%) patients with AKD and 3 (0.2%) patients without kidney disease (p < 0.0001). Death after discharge occurred in 206 (9.7%) AKD patients, and 1865 AKD patients underwent reassessment of kidney function after discharge; 902 (48.4%) patients had persistent kidney disease including 740 (39.7%) patients reclassified with de novo or previously undiagnosed chronic kidney disease (CKD). The study was pragmatically designed to assess outcomes as part of routine healthcare, and there was heterogeneity in clinical practice and outcomes between sites, in addition to selection bias during cohort identification. The use of a risk score can aid AKD identification in LLMICs. High rates of persistent kidney disease and mortality after discharge highlight the importance of AKD follow-up in low-resource settings.

Abstract 4137991: Association of the 2022 AHA/ACC/HFSA Heart Failure Staging and Cardiovascular and Kidney Outcomes in Patients with Diabetes and Kidney Disease: A Secondary Analysis of the SCORED Trial

Introduction: The 2022 AHA/ACC/HFSA heart failure (HF) classification newly incorporates cardiac biomarkers to identify patients at risk of HF. Research Question: Given shared risk factors between HF and other cardiorenal events, the HF stages may also guide prognosis and management of cardiovascular (CV) and kidney-related events beyond HF. Aims: Examine the association of HF stage with CV and kidney events. Methods: SCORED was a randomized trial in diabetes with kidney disease comparing sotagliflozin (sota) v. placebo on CV death, hospitalizations for HF, and urgent HF visits. SCORED participants were grouped by HF stage post hoc . Stage A: No HF, normal cardiac biomarkers (NT-proBNP; &lt;125 pg/mL, hs-cTnT; &lt;14 ng/L) and normal cardiac structure/function by echocardiography. Stage B (pre-HF): No HF but elevated NTproBNP, hsTNT or abnormal echocardiography. Stage C/D: symptomatic HF. Endpoints of interest included the primary composite endpoint (CV death and HF-related events), major adverse CV events (MACE), and kidney-related composites (See Figure caption). Using Cox regression, we examined the association between HF stage and these endpoints, and whether the effect of sota v. placebo varied by HF stage. Results: There were 741 patients in stage A, 6560 in stage B (pre-HF) and 3283 in stage C/D (established HF). The mean NTproBNP and hs-cTnT increased with HF stage. Stepwise increases in HF stage were associated with a 2-4 fold higher incidence of the primary, MACE and kidney endpoints in the placebo group, although the incidence of the kidney-specific composite was similar in stage B and C/D (Figure). The relative risk reduction with sota v. placebo for all endpoints was similar irrespective of HF stage (p-interaction&gt;0.05), with higher absolute benefit in each HF stage (Figure). The absolute benefit for the kidney-specific endpoint was comparable for stage B and C/D. Conclusions: Increasing HF stage is associated with higher risk of HF, MACE, and kidney events, but the risk of kidney events is similar in stage B (pre-HF) and stage C/D (established HF). Sota has similar relative benefits for all endpoints, irrespective of HF stage, with a corresponding increase in absolute benefits at higher stages.

Abstract 4116975: Safety signals with SGLT2 inhibitor use in diabetic males with erythrocytosis, but not in females: Findings from the CANVAS Program and CREDENCE trial

Backgrounds: Mediation analyses have shown that an increase in hematocrit (Hct) levels significantly contributes to the cardiorenal benefits of SGLT2 inhibitors (SGLT2i). However, given the link between erythrocytosis and poor prognosis, concerns remain about whether SGLT2i-induced erythropoiesis in patients with erythrocytosis may increase thromboembolic events (TE) including myocardial infarction (MI). Methods: We conducted a pooled analysis utilizing individual participant data from the CANVAS Program and the CREDENCE trial, both aimed to evaluate the efficacy and safety of canagliflozin versus placebo in diabetic patients. The primary outcome was a composite of MI, stroke, or any other TE. Sex-specific Cox analyses were performed to assess effect modifications by baseline Hct levels, treated as categorical (anemia, normal, and erythrocytosis) or continuous variable. Results: Of the participants for whom baseline Hct values were available (98.5% [14,321/14,543]), 35% were female. Canagliflozin significantly increased the percentage of erythrocytosis from baseline to 1 year in males (5.6% to 16.9%) and females (1.9% to 5.2%), unlike placebo. Overall, canagliflozin did not alter the risk of the primary outcome for either male (HR 0.97; 95% CI, 0.86–1.10) or female (HR 0.95; 95% CI, 0.78–1.15). In males, baseline Hct levels modified treatment effect on the primary outcome, whether treated as categorical or continuous variables (Pinteraction &lt;0.05), with benefits in anemic patients and harm in those with erythrocytosis (Figure). Meanwhile, no effect modifications were noted in females. In analyses for each component of the primary outcome, canagliflozin consistently reduced the risk of MI, stroke, and any TE in anemic male patients (HR 0.53, 0.49, and 0.71, respectively). However, mixed results were observed in those with erythrocytosis (HR 1.77, 0.62, and 1.11, respectively), suggesting detrimental effects on the primary outcome in these patients were primarily driven by MI. No heterogeneity by Hct was found for heart failure hospitalization or kidney outcome in both sexes. Conclusion: Canagliflozin may pose a safety concern regarding the risk of TE in diabetic male patients with erythrocytosis.

Open-label, controlled, phase 2 clinical trial assessing the safety, efficacy, and pharmacokinetics of INM004 in pediatric patients with Shiga toxin-producing Escherichia coli-associated hemolytic uremic syndrome.

Shiga toxin-producing Escherichia coli-associated hemolytic uremic syndrome (STEC-HUS) is a severe condition mainly affecting children. It is one of the leading causes of acute kidney injury in the pediatric population. There is no established therapy for this disease. INM004 is an anti-Shiga toxin composed of equine polyclonal antibodies. This study is aimed at assessing the safety, pharmacokinetics, and efficacy of INM004 in pediatric patients with STEC-HUS. Phase 2, open-label clinical trial with an historical control arm. Patients in the treatment arm received two doses of INM004. The primary endpoints were the safety profile, pharmacokinetics, and efficacy (dialysis days) of INM004. Secondary endpoints included other kidney and extrarenal outcomes. Propensity score matching was used for efficacy comparisons between arms. Fifty-seven and 125 patients were enrolled in the treatment and control arm, respectively. After propensity score matching, 52 patients remained in each arm. INM004 was well-tolerated. Eight adverse events were considered possibly related, none of which were serious or severe. In the primary efficacy endpoint, patients of the treatment arm presented a non-statistically significant difference of two dialysis days. On secondary endpoints, non-statistically significant trends toward fewer patients needing dialysis and dialysis for more than 10days, and shorter time to glomerular filtration rate normalization, were observed favoring the treatment arm. INM004 showed an adequate safety profile. Efficacy non-statistically significant trends suggesting a beneficial effect in the amelioration of kidney injury were observed. These results encourage the conduction of a phase 3 study of INM004 in pediatric patients with STEC-HUS.

Baseline Diastolic BP and BP-Lowering Effects on Cardiovascular Outcomes and All-Cause Mortality: A Meta Analysis.

Lowering blood pressure (BP) in persons with low diastolic BP could be harmful. Hence, we examined whether baseline diastolic BP modifies the effects of BP lowering on clinical outcomes in a meta-analysis of five large BP lowering trials. In a study-level meta-analysis based on individual participant data of the Systolic Blood Pressure Intervention Trial (N = 9361), the Action to Control Cardiovascular Risk in Diabetes Blood Pressure (N = 2362), the Secondary Prevention of Small Subcortical Strokes (N = 3020), the African American Study of Kidney Disease and Hypertension (N = 1094) and the Modification of Diet in Renal Disease (N = 840) studies, we used DerSimonian-Laird random-effects models to examine the dependence of the effect of the BP lowering intervention on baseline diastolic BP for cardiovascular, all-cause mortality and kidney outcomes. Mean baseline age was 65 ± 10 years old. Mean baseline systolic and diastolic BP were 141 ± 17 and 79 ± 12 mm Hg, respectively. More intensive BP control resulted in lower risk of composite cardiovascular outcome (HR 0.79, 95% CI 0.72, 0.87) and all-cause mortality (HR 0.86, 95% CI 0.75, 0.99) without evidence that the BP intervention effects differed by level of baseline diastolic BP (interaction p = 0.76 for cardiovascular composite and 0.85 for all-cause mortality). The mean baseline diastolic BP in the lowest and the upper three quartiles of baseline diastolic BP were 65 ± 6 mm Hg and 84 ± 9 mm Hg, respectively but the effects of the BP interventions on the outcomes were similar in both groups. Furthermore, there was no evidence of interaction of the BP intervention and baseline diastolic BP for kidney outcomes. Within the included diastolic BP range, there was no evidence that baseline diastolic BP modified the beneficial effects of intensive BP lowering.

Benefits and Harms of Coronary Revascularization in Non-Dialysis-Dependent Chronic Kidney Disease and Ischemic Heart Disease: A Systematic Review and Meta-Analysis.

Key Points In people with non–dialysis-dependent CKD, revascularization may lower all-cause mortality and risk of cardiovascular events.Adverse kidney events, which are often cited as a reason to avoid revascularization, were uncommon.Additional research on the effect of revascularization on patient-reported outcomes in people with non–dialysis-dependent CKD is needed. Background Cardiovascular disease is the leading cause of death in people with CKD. Coronary revascularization can improve cardiac function and prognosis in people with ischemic heart disease; however, in people with CKD, there is concern that potential harms could outweigh benefits of revascularization. Evidence on the balance of these risks and benefits, specifically in people with non–dialysis-dependent CKD, is lacking. Methods We conducted a systematic review of randomized controlled trials to assess the risks and benefits of revascularization, compared with medical management, among adults or children with ischemic heart disease and CKD not requiring KRT (dialysis or transplantation). We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials through December 12, 2023. Two people independently screened titles and abstracts followed by full-text review, serially extracted data using standardized forms, independently assessed risk of bias, and graded the certainty of evidence (COE). Results Evaluating data from nine randomized controlled trials, we found that people with CKD and ischemic heart disease treated with revascularization may experience lower all-cause mortality compared with people receiving medical management (risk ratio [RR], 0.80; 95% confidence interval [CI], 0.64 to 0.98; COE, low). Revascularization may reduce incidence of myocardial infarction (RR, 0.81; 95% CI, 0.64 to 1.04; COE, low) and heart failure (RR, 0.80; 95% CI, 0.52 to 1.23; COE, low). The effect on cardiovascular mortality is uncertain (hazard ratio, 0.67; 95% CI, 0.37 to 1.20; COE, very low). Evidence was insufficient for patient-reported outcomes and adverse kidney events. Data were limited by heterogeneity of patient populations and the limited number of trials. Conclusions In people with non–dialysis-dependent CKD, revascularization may be associated with lower all-cause mortality compared with medical management and may also lower the risk of cardiovascular events. Additional data surrounding kidney and patient-reported outcomes are needed to comprehensively engage in shared decision making and determine optimal treatment strategies for people with CKD and ischemic heart disease. Clinical Trial registry name and registration number: CRD42022349820 (PROSPERO).

Prognostic value of serum complement cleavage factor Bb in idiopathic membranous nephropathy and establishment of nomogram model

Complement activation is involved in idiopathic membranous nephropathy (IMN). We aimed to investigate the relationship of serum complement cleavage factor Bb with IMN progression, and to establish a model for early prediction of kidney outcomes. We measured serum factor Bb in a retrospective cohort of 449 IMN patients at the time of kidney biopsy. Cox regression analysis showed that higher levels of serum factor Bb were independently associated with IMN progression event defined as end-stage renal disease or ≥ 40% decline in estimated glomerular filtration rate. Patients in the middle and highest tertiles of serum factor Bb had respectively 2.1-, and 2.6-fold higher risk for disease progression compared with those in the lowest tertile. We developed an optimized prognostic nomogram model incorporating age, log serum anti-PLA2R antibody, log serum Bb, proteinuria and tubular atrophy/interstitial fibrosis. The model demonstrated good predictive ability with a concordance index of 0.77 (bootstrap-corrected of 0.76) for predicting 3-, and 5-year kidney survival. Calibration curves and decision curve analysis confirmed the model’s good calibration and clinical utility. Our findings suggest that serum factor Bb may serve as an essential prognostic indicator of IMN. The novel nomogram model may offer important guidance on the management of this patient population.

Association of variabilities in body mass index and metabolic parameters with post-kidney transplantation renal outcomes

Metabolic syndrome is a significant risk factor for poor graft outcomes in kidney transplant (KT) patients. However, the effects of variability in metabolic parameters on graft outcomes in KT patients have not been completely elucidated. A total of 852 KT patients were included from the Korean Organ Transplantation Registry. The study exposure was variability in body mass index (BMI) or other metabolic parameters measured at 6 months, 1 year, and 2 years after KT. Patients were classified into tertiles according to the degree of variability. The primary outcome was a composite of adverse kidney outcomes, such as death-censored graft loss or ≥ 30% decline in estimated glomerular filtration rate. The adverse kidney outcomes occurred in 73 (8.6%) participants. The high-BMI variability group had a higher risk for adverse kidney outcomes compared to the low-variability group. High variabilities in triglyceride, fasting blood glucose, and systolic blood pressure were also associated with adverse kidney outcomes. Furthermore, high variability in metabolic syndrome-related composite indices, such as the triglyceride and glucose index and metabolic variability scores, showed a higher risk for adverse kidney outcomes. In conclusion, high variability in metabolic parameters could be associated with an increased risk of adverse kidney outcome in KT patients.

Association between different proportions of crescents and the progression of IgA nephropathy (IgAN): a systematic review and meta-analysis.

Immunoglobulin A nephropathy (IgAN) is a complex renal disease with a highly variable clinical course. Identifying reliable prognostic markers is crucial for risk stratification and treatment decisions. This study aimed to understand the influence of different proportions of crescents (Cs) on the progression of IgAN. Four databases (PubMed, Web of Science, Embase, and Cochrane Library) were searched until September 25, 2023. The study encompassed IgAN patients, focusing on kidney outcomes and end-stage kidney disease (ESKD). Statistical analysis included calculating hazard ratios (HR) for binary outcomes and examining publication bias. The meta-analysis involved thirteen studies comprising 11,849 patients. For kidney outcomes, crescent formation may be linked to an elevated risk (HR = 2.01, 95%CI 1.40-2.87, P < 0.001). Furthermore, significantly increased risks of kidney outcomes were observed with a crescent proportion > 10 (HR = 1.8, 95%CI 1.32-2.45, P < 0.001) and > 25%(HR = 2.11, 95% CI 1.47-3.02, P < 0.001). Regarding ESKD, a proportion > 25% also displayed an elevated risk (HR = 1.70, 95% CI 1.18-2.44, P = 0.004). However, a proportion > 10% (including > 25%) did not show a significant association with ESKD (HR = 1.12, 95% CI 0.36-3.47, P = 0.842) versus less. This systematic review and meta-analysis established a strong association between crescent proportions and the progression of IgAN. Higher proportions, notably exceeding 25%, were reliable prognostic markers, indicating a greater risk of adverse kidney outcomes and ESKD. These findings have significant clinical implications, offering the potential for more precise risk stratification in IgAN patients.

In T2D, SGLT-2 inhibitor effects on CV and kidney outcomes were consistent regardless of GLP-1 receptor agonist use.

Apperloo EM, Neuen BL, Fletcher RA, et al. Efficacy and safety of SGLT2 inhibitors with and without glucagon-like peptide 1 receptor agonists: a SMART-C collaborative meta-analysis of randomised controlled trials. Lancet Diabetes Endocrinol. 2024;12:545-557. 38991584.

Kidney disease and reproductive health.

Understanding the relationship between reproductive health and kidney function is important to provide holistic care for people living with kidney disease. Chronic kidney disease (CKD) has negative impacts on both male and female fertility owing to factors including inflammation, hormonal dysregulation, reduced ovarian reserve, reduced sperm quality and sexual dysfunction. However, pregnancy is achievable for most cisgender women with kidney disease, including kidney transplant recipients and patients on dialysis. CKD in pregnancy is associated with health risks to the mother and child, including increased risk of progression of kidney disease, hypertensive complications of pregnancy, and neonatal complications including fetal growth restriction, preterm birth and stillbirth. However, with appropriate pre-pregnancy counselling, fertility assessment and support, health optimization, and evidence-based antenatal care, the majority of patients will achieve a good outcome. Medication safety should be reviewed before and during pregnancy and lactation, weighing the risk of disease flare against potential adverse effects on the offspring. Important areas for further research include the optimal timing of delivery and the short- and long-term cardiovascular and renal impacts of pregnancy in patients with CKD, as well as long-term kidney and cardiovascular outcomes in their offspring.

Evaluating a multicomponent intervention for managing kidney outcomes among patients with moderate or advanced chronic kidney disease (CKD): protocol for the Strategies for Kidney Outcomes Prevention and Evaluation (SKOPE) randomized controlled trial

BackgroundChronic kidney disease (CKD) poses a global health challenge with high morbidity and mortality rates. Early detection and prompt intervention are critical in preventing progression to end-stage kidney disease (ESKD) and cardiovascular complications. Effective CKD management requires comprehensive care packages that integrate both pharmacological and non-pharmacological interventions within collaborative, team-based models, aiming to enhance patient outcomes and overall quality of life. The goal of the Strategies for Kidney Outcomes Prevention and Evaluation (SKOPE) study is to establish effective multicomponent intervention (MCI) strategies for evaluating and preventing kidney outcomes in patients with moderate to advanced CKD within primary care settings in Singapore.MethodsThis study is a 3-year randomized controlled trial among 896 participants aged between 40 and 80 years with moderate or advanced CKD in five government-subsidized polyclinics in Singapore. The components of the MCI are (1) nurses/service coordinators trained as health coaches for motivational conversation and CKD-specific lifestyle counseling on diet and exercise, using a hybrid follow-up approach of in-person, telephone, and secure video meetings; (2) training physicians in algorithm-based standardized management of CKD; (3) subsidy on SGLT2i medications for CKD; and (4) regular CKD case review meetings. The primary outcome is the estimated glomerular filtration rate (eGFR) total slope from randomization to final follow-up at 36 months.DiscussionIf shown to be effective, cost-effective, and acceptable, SKOPE should be considered for scaling country-wide and in similar regional healthcare systems.Trial registrationClinicalTrials.gov NCT05295368. Registered on March 25, 2022.

Changing Epidemiology and Outcomes of Hemolytic Uremic Syndrome in Children: A Prospective National Cohort Study from the Polish Pediatric HUS Registry and the Polish Registry of Renal Replacement Therapy in Children.

Background/Objectives: Hemolytic uremic syndrome (HUS) is a known cause of acute kidney injury in children, but there are few recent reports on its epidemiology and outcome. We aimed to investigate trends in the incidence and the long-term outcomes of both Shiga toxin-producing Escherichia coli -HUS (STEC-HUS) and atypical HUS (aHUS) in Poland over the last 12 years (2012-2023), based on the Polish Pediatric HUS and Pediatric Renal Replacement Therapy (RRT) Registries. Methods: A total of 436 patients (301 with STEC-HUS and 135 with aHUS) were included. Results: The incidence of STEC-HUS increased during the observation period, with a mean of 3.9 cases per million age-related population (marp). The incidence of aHUS was relatively constant with a mean of 1.8/marp. The majority of patients fully recovered, although kidney sequelae were observed at 5-year follow-ups in 31% of children with STEC-HUS, 57% of aHUS subjects in the pre-eculizumab era, and 37% of aHUS subjects who had received eculizumab. The overall mortality rate was 2% for STEC-HUS and 3.7% for aHUS, with no deaths reported in children on eculizumab and mortality mainly attributed to neurological damage. A decreasing incidence of chronic kidney disease stage 5 (CKD5) due to HUS was observed. Conclusions: Despite an unchanging incidence of aHUS and an increasing incidence of STEC-HUS, the kidney outcomes of both diseases have improved significantly over the last 12 years. Mortality from HUS has dropped due to improved symptomatic treatment and the introduction of anti-C5 therapy. The development of CKD5 in childhood as a consequence of HUS has become exceptional.

C3 glomerulopathy is highly prevalent in French Polynesia

ObjectiveTo compare the natural history of C3 glomerulopathy (C3G) to acute post-infectious glomerulonephritis (APIGN) in a cohort of patients with a relative homogeneity of environment conditions and genetic background. MethodsWe retrospectively reviewed the characteristics of all patients with biopsy proven C3G or APIGN referred in 2013–2019 to the only renal unit in French Polynesia. ResultsPoint prevalence of C3G is ∼23 cases per 100,000 inhabitants. A recurrent variation of CFI (p.Arg406His) was identified at the heterozygous state in 4/8 (50 %) patients with C3G but its pathogenicity remain elusive. Characteristics at presentation and kidney outcomes were roughly similar between C3G (n = 16) and APIGN (n = 20), excepted for the presence of humps on kidney biopsy. ConclusionsC3G is highly prevalent in French Polynesia suggesting specific genetic or environmental susceptibility factors. Systematic diagnosis workflow should be proposed to all patients with C3 predominant glomerulonephritis.

Long-Term Kidney Outcomes after Pediatric Acute Kidney Injury: Future Studies Need to Explore Further

Long-Term Kidney Outcomes after Pediatric Acute Kidney Injury: Future Studies Need to Explore Further

Bidirectional relationship between kidney disease progression and cardiovascular events in type 2 diabetes: new Insights from the CANVAS Program and CREDENCE trial

Abstract Background The extent to which chronic kidney disease (CKD) progression increases cardiovascular risk, and whether different types of cardiovascular events affect risk of CKD progression, is incompletely understood. Purpose We sought to explore risk of cardiovascular events before and after CKD progression, and CKD progression before and after different cardiovascular events in patients with type 2 diabetes. Methods We conducted a pooled individual participant data analysis of the CANVAS Program and CREDENCE trial. Using Poisson regression, we assessed the incidence of major adverse cardiovascular events ([MACE] stroke, myocardial infarction, or cardiovascular death) and hospitalised heart failure (HHF) or cardiovascular death before and after CKD progression (defined as 40% decline in estimated glomerular filtration rate [eGFR] or kidney failure), and CKD progression before and after nonfatal cardiovascular events, with no adjustment for confounding related to subgroups defined by post-randomization variables. We estimated the cumulative incidence of all-cause mortality after different nonfatal cardiovascular and kidney outcomes, including different thresholds of CKD progression (kidney failure, 40% or 50% decline in eGFR or doubling of serum creatine) using Cox regression models. Results Among 14,464 participants (mean age 63.7 years, 35.3% female, mean eGFR 55mL/min/1.73m2 and median urinary albumin:creatinine ratio 34mg/g) over a median follow-up of 2.5 years, 1,482, 1,076 and 1,020 experienced MACE, HHF or cardiovascular death, and CKD progression, respectively. After (vs. before) CKD progression, there was an approximate 3-fold increase in incidence of MACE (30.2 vs. 93.8 per 1000-patient-years) and 4-fold increase in HHF or cardiovascular death (21.0 vs. 79.3 per 1000-patient-years). Conversely, the incidence of CKD progression was approximately 1.5-fold higher after (vs. before) nonfatal myocardial infarction or stroke (21.7 vs. 34.1 per 1000-patient-years) and 5-fold higher after HHF (21.2 vs. 108.2 per 1000-patient-years). These patterns were consistent in both treatment arms, with unadjusted incidence rates for clinical events appearing numerically lower in canagliflozin compared to placebo-treated participants (Figure 1). Of all non-fatal cardio-kidney outcomes, HHF and doubling of serum creatine or kidney failure conferred the highest risk of death (Figure 2). Conclusion Atherosclerotic and heart failure risk increases substantially after CKD progression. CKD progression was accelerated after cardiovascular events, particularly HHF. Treatment with canagliflozin was associated with lower event rates before and after a serious cardio-kidney outcome, suggesting continued use of canagliflozin may be beneficial even after cardiovascular events and CKD progression.Figure 1.Figure 2.

Impact of appendicular skeletal muscle mass on effect of intensive blood pressure control

Abstract Background Appendicular skeletal muscle mass (ASM) is associated with cardiovascular diseases (CVDs) and chronic kidney diseases (CKDs). However, whether low ASM affects the efficacy of intensive systolic blood pressure control is currently uncertain. Purpose To examine the impact of low ASM on the effects of intensive SBP control on cardiovascular and kidney outcomes. Methods Data from the Systolic Blood Pressure Intervention Trial (SPRINT) and the Action to Control Cardiovascular Risk in Diabetes Blood Pressure (ACCORD-BP) trials was used. The primary outcome was a composite of myocardial infarction, acute coronary syndrome without myocardial infarction, stroke, heart failure, and cardiovascular death. The prespecified incident CKD was defined as a &amp;gt;30% decrease in estimated glomerular filtration rate to a value &amp;lt;60 mL/min/1.73 m2. Results A total of 14,017 patients were included in this study, 2203 (15.7%) of whom had low ASM. Over a median follow-up of 3.26 years, 1,032 primary outcomes and 460 incident CKD were observed. Patients with low ASM had a significantly higher risk of primary outcome and CKD. Intensive SBP control effects on cardiovascular outcomes were not significantly different on a relative scale or absolute scale. But low ASM significantly amplified the increased risk of CKD associated with intensive SBP control, on an absolute scale (P for interaction = 0.04). Conclusions Low ASM is one of the markers of increased risk of CVD and CKD, and it did not affect the cardiovascular benefits of intensive treatment, but significantly amplified the increased risk of CKD associated with intensive SBP control.

Dapagliflozin versus empagliflozin and major adverse cardiovascular events in type 2 diabetes: a nationwide cohort study

Abstract Background Large randomized clinical trials have shown that sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of adverse kidney and cardiovascular outcomes in patients with heart failure, chronic kidney disease, or type 2 diabetes mellitus (T2DM) at high risk of atherosclerotic cardiovascular disease. Whether these effects might differ between individual SGLT2-inhbitors remain unclear given the lack of head-to-head comparisons. Purpose To examine the association between treatment with dapagliflozin versus empagliflozin and the long-term rate of major adverse cardiovascular events (MACE) in patients with T2DM. Methods Using nationwide registries, all Danish residents with T2DM, who initiated treatment with dapagliflozin or empagliflozin from 2015 to 2020, were identified. Only treatment with dapagliflozin or empagliflozin was considered in the present analysis, since approximately 3% initiated treatment with other SGLT2-inhibitors (i.e., canagliflozin and ertugliflozin). Patients were followed from date of the first claimed prescription of dapagliflozin or empagliflozin until the outcome of interest, emigration, death, or end of study (December 31, 2021). The primary outcome was a composite endpoint of major adverse cardiovascular events (i.e., time to first heart failure hospitalisation, acute myocardial infarction (AMI), stroke, or all-cause mortality). The primary outcome was compared between the dapagliflozin and empagliflozin group, overall and in prespecified subgroups of interest, with multivariable Cox proportional hazards regression models. Results In total, 61,031 patients with T2DM initiated treatment with dapagliflozin (N=21,028; 34.5%) or empagliflozin (N=40,003; 65.5%). The median age of study population was 62.6 years (25th-75th percentile, 54.2-70.8 years), and 62.6% were men. There were no clinically significant differences between the dapagliflozin and empagliflozin group with respect to age, sex, and clinical characteristics. The median follow-up was 3.1 years (25th-75th percentile, 1.9-4.5 years). The adjusted long-term hazard ratios of the primary outcome, overall and in prespecified subgroups of interest, are displayed in the Figure. Compared with empagliflozin, treatment with dapagliflozin was not associated with a significantly different rate of the primary outcome (HR 1.02 [95% CI, 0.97-1.07]). The observed association was consistent across clinically relevant subgroups, including in patients with and without heart failure, chronic kidney disease, and atherosclerotic cardiovascular disease. Conclusion In a large, nationwide cohort of patients with T2DM, treatment with dapagliflozin was associated with a similar rate of major adverse cardiovascular outcomes compared with empagliflozin, and this association was consistent across clinically relevant subgroups. These findings suggest that the benefits of SGLT2-inhibitors can be characterized as a class-effect.

Heart failure and renal outcomes in patient treated with GLP1 agonists

Abstract Introduction Glucagon-like peptide-1 receptor (GLP1) agonists are emerging as a primordial treatment for diabetes and to reduce cardiovascular burden, both of them factors that play an important role in the developing of renal chronic disease and heart failure, and vice versa. The debut of renal chronic disease and the manifestation of acute renal injury/failure can lead to the discontinuation of treatment, which in patients suffering from heart failure who tend to be polymedicated could end up in lessening their survival. Methods A metanalysis of randomized clinical trials (RCT) comparing GLP1 agonists with placebo was performed. The endpoint of the study was to analyze all-cause mortality, hospitalization or urgent medical visit for heart failure, a kidney outcome composite, which is slightly heterogenic depending on the RCT, and the manifestation of acute renal injury/failure as an adverse effect or that lead to the discontinuation of treatment. The meta-analysis was performed using the inverse variance method, using the fixed effects model when there was no heterogeneity and the random effects model when heterogeneity is significant. Results A sum of 9 randomized controlled trial were included where a GLP1 agonists such as albiglutide, dulaglutide, exenatide, liraglutide, lixinatide or semaglutide compared with placebo. 77684 patients were incorporated, while 39497 were treated with a GLP1 agonists. The mean age was of 63.7 years (SD ± 1.97 years), 60080 (77.3%) suffered from diabetes, 60552 (77.9%) from cardiovascular disease and 14367 from chronic heart failure (18.4%). The mean eGFR was 77.3 mL/min (SD ± 3.3 mL/min). As showed in the forest plots, treatment with GLP1 agonists reduced all-cause mortality by 12% (RR: 0.88, 95% CI 0.83-0.92; p&amp;lt;0.001), hospitalization or urgent medical visit for heart failure by 10% (RR: 0.90, 95% CI 0.83-0.98; p&amp;lt;0.001), the kidney composite outcome by 22% (RR: 0.78, 95% CI 0.70-0.87; p&amp;lt;0.001), while it showed no statistical reduction in acute renal injury/failure (RR: 0.89, 95% CI 0.79-1.01; p=0.069). Conclusion Treatment with a GLP1 agonists reduced the incidence of all-cause mortality by 12%. In addition, hospitalization or urgent medical visit for heart failure was decreased by 10%. In terms of renal asessment, the composite of kidney function was reduced by 22%, while the manifestation of acute renal injury/failure, though no statistical signification was accomplished, showed some evidence of beneficial effect but more RCTs are needed to prove it. Hence, GLP1 analogues appear as a possible new pillar of treatment for heart failure and renal disease in determined patients.