Finerenone cardiovascular and kidney outcomes by age and sex: FIDELITY post hoc analysis of two phase 3, multicentre, double-blind trials.

OBJECTIVES: This study aimed to evaluate the efficacy and safety of finerenone, a selective, non-steroidal mineralocorticoid receptor antagonist, on cardiovascular and kidney outcomes by age and/or sex. DESIGN: FIDELITY post hoc analysis; median follow-up of 3 years. SETTING: FIDELITY: a prespecified analysis of the FIDELIO-DKD and FIGARO-DKD trials. PARTICIPANTS: Adults with type 2 diabetes and chronic kidney disease receiving optimised renin-angiotensin system inhibitors (N=13 026). INTERVENTIONS: Randomised 1:1; finerenone or placebo. PRIMARY AND SECONDARY OUTCOME MEASURES: Cardiovascular (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalisation for heart failure (HHF)) and kidney (kidney failure, sustained ≥57% estimated glomerular filtration rate (eGFR) decline or renal death) composite outcomes. RESULTS: Mean age was 64.8 years; 45.2%, 40.1% and 14.7% were aged <65, 65-74 and ≥75 years, respectively; 69.8% were male. Cardiovascular benefits of finerenone versus placebo were consistent across age (HR 0.94 (95% CI 0.81 to 1.10) (<65 years), HR 0.84 (95% CI 0.73 to 0.98) (65-74 years), HR 0.80 (95% CI 0.65 to 0.99) (≥75 years); Pinteraction=0.42) and sex categories (HR 0.86 (95% CI 0.77 to 0.96) (male), HR 0.89 (95% CI 0.35 to 2.27) (premenopausal female), HR 0.87 (95% CI 0.73 to 1.05) (postmenopausal female); Pinteraction=0.99). Effects on HHF reduction were not modified by age (Pinteraction=0.70) but appeared more pronounced in males (Pinteraction=0.02). Kidney events were reduced with finerenone versus placebo in age groups <65 and 65-74 but not ≥75; no heterogeneity in treatment effect was observed (Pinteraction=0.51). In sex subgroups, finerenone consistently reduced kidney events (Pinteraction=0.85). Finerenone reduced albuminuria and eGFR decline regardless of age and sex. Hyperkalaemia increased with finerenone, but discontinuation rates were <3% across subgroups. Gynaecomastia in males was uncommon across age subgroups and identical between treatment groups. CONCLUSIONS: Finerenone improved cardiovascular and kidney composite outcomes with no significant heterogeneity between age and sex subgroups; however, the effect on HHF appeared more pronounced in males. Finerenone demonstrated a similar safety profile across age and sex subgroups. TRIAL REGISTRATION NUMBERS: NCT02540993, NCT02545049.

Sevelamer and CKD-associated cardiovascular disease: going further, but far from there.

Cardiovascular disease is a major complication of chronic kidney disease (CKD), and current data support its link to mineral metabolism disturbances. However, there is an intense debate over whether CKD-mineral and bone disorder therapy could change the cardiovascular burden in CKD. The study by Maizel and colleagues shows the benefits of a phosphate binder, sevelamer, for the progression of aortic stiffness and endothelial dysfunction as well as left ventricular dysfunction and hypertrophy in mice with CKD.

Fluid overload is associated with use of a higher number of antihypertensive drugs in hemodialysis patients.

INTRODUCTION: Hypertension is multifactorial, highly prevalent in the hemodialysis (HD) population and its adequate control requires, in addition to adequate volume management, often the use of multiple antihypertensive drugs. We aimed to describe the use of antihypertensive agents in a group of HD patients and to evaluate the factors associated with the use of multiple classes (≥3) of antihypertensives. METHODS: We analyzed the baseline data from the HDFit study. Clinically stable patients with HD vintage between 3 and 24 months without any severe mobility limitation were recruited from sites throughout southern Brazil. Fluid status was measured pre-dialysis with the Body Composition Monitor (BCM; Fresenius, Germany). Fluid overload (FO) was considered when the overhydration index (OH) was greater than 7% of extracellular water (OH/ECW > 7%) and overweight was defined as a body mass index (BMI) greater than 25 kg/m2 . Prescriptions of antihypertensive drugs were obtained from participants' reports and medical records. Logistic regression was employed to determine factors associated with excessive use of antihypertensive medication (≥3 classes). FINDINGS: Of 195 studied patients, 171 with complete data were included (70% male, 53 ± 15 years old, 57% of them with FO). Pre-dialysis systolic blood pressure (SBP) was 150 ± 24 mmHg and patients used a median of 2 (1-3) antihypertensive drugs. Vasodilators (20%) were of lowest prevalence, use of other classes varied from 40% to 53%. Sixty-two (36%) subjects used ≥3 classes and presented a higher prevalence of diabetes and FO, lower prevalence of overweight, and higher SBP. In a logistic regression model age, BMI <25 kg/m2 , and OH/ECW > 7% were associated with excessive drug use. DISCUSSION: More than one-third of participants used ≥3 classes of antihypertensive drugs, and it was associated with older age, BMI <25 kg/m2 and FO. Strategies that better manage FO may aid better blood pressure control and avoid the use of multiple antihypertensive medications.

Impact of dialyzer membrane on apoptosis and function of polymorphonuclear cells and cytokine synthesis by peripheral blood mononuclear cells in hemodialysis patients.

In an in vivo crossover trial, we compared a cellulosic with a synthetic dialyzer with respect to polymorphonuclear cells (PMN) function and apoptosis, cytokine serum levels and synthesis by peripheral blood mononuclear cells (PBMC), and complement activation. Twenty hemodialysis (HD) patients were assigned in alternate order to HD with cellulose acetate (CA) or polysulfone (PS) dialyzer. After 2 weeks, patients were crossed over to the second dialyzer and treated for another 2 weeks. Apoptosis was assessed by flow cytometry in freshly isolated PMN. Phagocytosis and production of peroxide by PMN were studied by flow cytometry in whole blood. PBMC were isolated from blood samples and incubated for 24 h with or without lipopolysaccharide (LPS). There was no impact of dialyzer biocompatibility on PMN apoptosis and function, cytokine synthesis by PBMC or on their serum levels, serum levels of C3a, and terminal complement complex (TCC). Nevertheless, after HD, serum levels of complement correlated negatively with PMN phagocytosis and peroxide production, and positively with PMN apoptosis and cytokine production by PBMC. Although the results did not show a dialyzer advantage on the immunologic parameters, complement activation may have modulated cell function and apoptosis after HD.

Serum and cellular interleukin-6 in haemodialysis patients: relationship with energy expenditure.

BACKGROUND: Inflammation is a highly prevalent condition among end-stage renal disease (ESRD) patients and it has been implicated with several metabolic derangements. Considering the harmful effect of hypermetabolism on nutritional status and clinical outcomes of ESRD patients, we aimed to investigate the relationship between proinflammatory cytokine interleukin-6 (IL-6) and energy expenditure in this population. METHODS: This cross-sectional study enrolled 80 adult haemodialysis patients for the evaluation of serum IL-6 and energy expenditure. The production of IL-6 by peripheral blood mononuclear cells (PBMCs) (spontaneous and endotoxin-stimulated production) was examined in a subgroup of 30 haemodialysis patients and in 11 healthy control subjects. IL-6 was measured by immunoenzymatic assay. The resting energy expenditure was evaluated by means of indirect calorimetry. Body composition was assessed by bioelectrical impedance analysis and skinfold thicknesses. RESULTS: Serum IL-6 [6.3 (2.2-163.5) pg/ml] correlated positively with age (R = 0.26; P = 0.02) and C-reactive protein (R = 0.31; P < 0.01). Resting energy expenditure correlated positively with lean body mass (R = 0.68; P < 0.001) and BMI (R = 0.44; P < 0.001), and negatively with Kt/V (R = -0.37; P < 0.01). In the multivariate analysis, controlling for age and lean body mass, serum IL-6 was positively associated with resting energy expenditure (n = 80; beta = 2.4; P = 0.01). The production of IL-6 by PBMCs did not reach statistically significant differences between patients and controls [spontaneous production 6541 (96-7739) pg/ml vs 3410 (50-7806) pg/ml, respectively; and stimulated production 6530 (579-7671) pg/ml vs 5304 (1527-7670) pg/ml, respectively]. IL-6 secreted by monocytes showed no association with either serum IL-6 or resting energy expenditure. CONCLUSION: Serum IL-6 was associated with an increase of energy expenditure in haemodialysis patients.