Finerenone Attenuates Endothelial Dysfunction and Albuminuria in a Chronic Kidney Disease Model by a Reduction in Oxidative Stress

Albuminuria is an early marker of renovascular damage associated to an increase in oxidative stress. The Munich Wistar Frömter (MWF) rat is a model of chronic kidney disease (CKD), which exhibits endothelial dysfunction associated to low nitric oxide availability. We hypothesize that the new highly selective, non-steroidal mineralocorticoid receptor (MR) antagonist, finerenone, reverses both endothelial dysfunction and microalbuminuria. Twelve-week-old MWF (MWF-C; MWF-FIN) and aged-matched normoalbuminuric Wistar (W-C; W-FIN) rats were treated with finerenone (FIN, 10 mg/kg/day p.o.) or vehicle (C) for 4-week. Systolic blood pressure (SBP) and albuminuria were determined the last day of treatment. Finerenone lowered albuminuria by >40% and significantly reduced SBP in MWF. Aortic rings of MWF-C showed higher contractions to either noradrenaline (NA) or angiotensin II (Ang II), and lower relaxation to acetylcholine (Ach) than W-C rings. These alterations were reversed by finerenone to W-C control levels due to an upregulation in phosphorylated Akt and eNOS, and an increase in NO availability. Apocynin and 3-amino-1,2,4-triazole significantly reduced contractions to NA or Ang II in MWF-C, but not in MWF-FIN rings. Accordingly, a significant increase of Mn-superoxide dismutase (SOD) and Cu/Zn-SOD protein levels were observed in rings of MWF-FIN, without differences in p22phox, p47phox or catalase levels. Total SOD activity was increased in kidneys from MWF-FIN rats. In conclusion, finerenone improves endothelial dysfunction through an enhancement in NO bioavailability and a decrease in superoxide anion levels due to an upregulation in SOD activity. This is associated with an increase in renal SOD activity and a reduction of albuminuria

Influence of high cardiovascular risk in asymptomatic people on the duration and cost of sick leave: results of the ICARIA study

Aims We investigated the potential influence of a moderate-to-high cardiovascular (CV) risk (CVR) (defined as a Systematic COronary Risk Evaluation model, or SCORE ≥ 4%), in the absence of an established CV disease, on the duration and cost of CV and non-CV sick leave (SL) resulting from common and occupational accidents or diseases. Methods and results We conducted a prospective cohort study on 690 135 workers with a 1-year follow-up and examined CV- and non-CV-related SL episodes. To obtain baseline values, CVR factors were initially assessed at the beginning of the year during routine medical examination. The CVR was calculated with the SCORE charts for all subjects. Moderate-to-high CVR was defined as SCORE ≥ 4%. A baseline SCORE ≥ 4% was associated with a higher risk for long-term CV and non-CV SL, as revealed by follow-up assessment. This translated into an increased cost, estimated at €5 801 464.18 per year. Furthermore, pharmacological treatment for hypertension or hyperlipidaemia was significantly associated with longer SL duration. Conclusion Moderate-to-high CVR in asymptomatic subjects was significantly associated with the duration and cost of CV and non-CV SL. These results constitute the first body of evidence that the SCORE charts can be used to identify people with a non-established CV disease, which might ultimately translate into more lost workdays and therefore increased cost for societ

Endothelial Factors in The Pathogenesis and Treatment of Chronic Kidney Disease Part II: Role in Disease Conditions. A Joint Consensus Statement from the ESH Working Group on Endothelin and Endothelial Factors And The Japanese Society of Hypertension

: After examining in Part I the general mechanisms of endothelial cell injury in the kidney, the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension and the Japanese Society of Hypertension will herein review current knowledge on the role of endothelial dysfunction in multiple disease conditions that affect the kidney, including diabetes mellitus, preeclampsia, solid organ transplantation, hyperhomocysteinemia and antiangiogenic therapy in cancer. The few available randomized controlled clinical trials specifically designed to evaluate strategies for correcting endothelial dysfunction in patients with hypertension and/or chronic kidney disease are also discussed alongside their cardiovascular and renal outcomes

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

SPRINT. Counteracting the risk of prehypertension?

The SPRINT trial1 has raised the possibility that systolic blood pressure (BP) values <120 mm Hg constitute the future goal for high-risk hypertensive patients. At baseline, around 50% of the patients were within the frame of prehypertension, whereas the remaining were hypertensive after an unusual but reliable (for daily clinical practice standard) measurement of office BP. Prehypertension is characterized by an increased cardiovascular risk, particularly in Stage 2 (systolic BP: 130–139 mm Hg) that can attain 40% at 10 years if established cardiovascular disease, diabetes, or both are presented.Sin financiación3.263 JCR (2016) Q2, 24/63 Peripheral Vascular DiseaseUE

Angiotensin blockade in type 2 diabetic renal disease

Angiotensin blockade in type 2 diabetic renal disease. The available evidence on renal protection in type 2 diabetes mellitus favors the administration of an angiotensin receptor blocker (ARB) more than that of an angiotensin converting enzyme inhibitor (ACEi). This evidence is based on recent studies showing that losartan and irbesartan can prevent the development of overt diabetic nephropathy in microalbuminuric type 2 diabetic patients as well as slow the velocity of progression to end-stage renal disease in patients with overt type 2 diabetic nephropathy. These studies do not deny the possibility that ACEi are equally effective, but studies of an adequate magnitude are lacking. These findings on ARB administration do not preclude the importance of strict control of blood pressure and proteinuria and/or albuminuria to avoid or retard renal damage in type 2 diabetic patients

Renin–angiotensin system blockade: Finerenone

Finerenone is a novel selective nonsteroidal mineralocorticoid receptor antagonist. Results in preclinical studies showed that lower doses of finerenone were needed to achieve similar cardiorenal protective effects compared to both spironolactone and eplerenone and phase II studies in finerenone in patients with heart failure, type-2 diabetes mellitus and/or chronic kidney disease are encouraging as the drug is effective and safe in patients on renin–angiotensin system inhibitors (significant reduction in albuminuria and a low rate of hyperkalemia), but the primary end points were “soft” end points (serum potassium, estimated glomerular filtration rate, albuminuria, N-terminal prohormone B-type natriuretic peptide levels). Thus, further, large-scale, long-term phase III trials are needed to confirm whether the greater affinity and selectivity is translated into improved clinical outcomes.Sin financiación0.479 JCR (2017) Q4, 72/76 Urology and NephrologyUE

Aldosterone a relevant factor in the beginning and evolution of arterial hypertension

Sin financiación3.046 JCR (2017) Q2, 23/65 Peripheral Vascular DiseaseUE