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Chronic kidney disease (CKD) is projected to become a leading global cause of death by 2040, and its early detection is critical for effective and timely management. The current definition of CKD identifies only advanced stages, when kidney injury has already destroyed >50% of functioning kidney mass as reflected by an estimated glomerular filtration rate six-fold higher than physiological levels (i.e. > 30 mg/g). An elevated urinary albumin-excretion rate is a known early predictor of future cardiovascular events. There is thus a ‘blind spot’ in the detection of CKD, when kidney injury is present but is undetectable by current diagnostic criteria, and no intervention is made before renal and cardiovascular damage occurs. The present review discusses the CKD ‘blind spot’ concept and how it may facilitate a holistic approach to CKD and cardiovascular disease prevention and implement the call for albuminuria screening implicit in current guidelines. Cardiorenal risk associated with albuminuria in the high-normal range, novel genetic and biochemical markers of elevated cardiorenal risk, and the role of heart and kidney protective drugs evaluated in recent clinical trials are also discussed. As albuminuria is a major risk factor for cardiovascular and renal disease, starting from levels not yet considered in the definition of CKD, the implementation of opportunistic or systematic albuminuria screening and therapy, possibly complemented with novel early biomarkers, has the potential to improve cardiorenal outcomes and mitigate the dismal 2040 projections for CKD and related cardiovascular burden.

Instituto de Salud Carlos III FIS/Fondos FEDER (PI17/01093, PI17/01193, CP15/00129, CPII20/00022, PI18/01366, PI19/00588, PI19/00815, PI20/00763, DTS18/00032) ERA-PerMedJTC2018 (KIDNEY ATTACK AC18/00064 and PERSTIGAN AC18/00071, ISCIII-RETIC REDinREN RD016/0009) Sociedad Española de Nefrología, FRIAT, Comunidad de Madrid en Biomedicina (B2017/BMD-3686 CIFRA2- CM) 35.855 JCR (2021) Q1, 3/143 Cardiac & Cardiovascular Systems 4.118 SJR (2021) Q1, 9/356 Cardiology and Cardiovascular Medicine No data IDR 2021 UEM

Aims The complementary studies FIDELIO-DKD and FIGARO-DKD in patients with type 2 diabetes and chronic kidney disease (CKD) examined cardiovascular and kidney outcomes in different, overlapping stages of CKD. The purpose of the FIDELITY analysis was to perform an individual patient-level prespecified pooled efficacy and safety analysis across a broad spectrum of CKD to provide more robust estimates of safety and efficacy of finerenone compared with placebo. Methods and results For this prespecified analysis, two phase III, multicentre, double-blind trials involving patients with CKD and type 2 diabetes, randomized 1:1 to finerenone or placebo, were combined. Main time-to-event efficacy outcomes were a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure, and a composite of kidney failure, a sustained ≥57% decrease in estimated glomerular filtration rate from baseline over ≥4 weeks, or renal death. Among 13 026 patients with a median follow-up of 3.0 years (interquartile range 2.3–3.8 years), the composite cardiovascular outcome occurred in 825 (12.7%) patients receiving finerenone and 939 (14.4%) receiving placebo [hazard ratio (HR), 0.86; 95% confidence interval (CI), 0.78–0.95; P = 0.0018]. The composite kidney outcome occurred in 360 (5.5%) patients receiving finerenone and 465 (7.1%) receiving placebo (HR, 0.77; 95% CI, 0.67–0.88; P = 0.0002). Overall safety outcomes were generally similar between treatment arms. Hyperkalaemia leading to permanent treatment discontinuation occurred more frequently in patients receiving finerenone (1.7%) than placebo (0.6%). Conclusion Finerenone reduced the risk of clinically important cardiovascular and kidney outcomes vs. placebo across the spectrum of CKD in patients with type 2 diabetes. Key Question Does finerenone, a novel selective, nonsteroidal mineralocorticoid receptor antagonist, added to maximum tolerated renin–angiotensin system inhibition reduce cardiovascular disease and kidney disease progression over a broad range of chronic kidney disease in patients with type 2 diabetes? Key Finding In a prespecified, pooled individual-level analysis from two randomized trials, we found reductions both in cardiovascular events and kidney failure outcomes with finerenone. Because 40% of the patients had an estimated glomerular filtration rate of >60 mL/min/1.73m2 they were identified solely on the basis of albuminuria. Take Home Message Finerenone reduces the risk of clinical cardiovascular outcomes and kidney disease progression in a broad range of patients with chronic kidney disease and type 2 diabetes. Screening for albuminuria to identify at-risk patients among patients with type 2 diabetes facilitates reduction of both cardiovascular and kidney disease burden.

Cardiovascular disease and cancer continue to be the major causes of death worldwide and the two conditions have more in common than previously acknowledged. In fact, both diseases share many predisposing factors and mechanisms, with a common background of low-grade inflammation. Thus, both cardiologists and oncologists should score both cardiovascular and cancer risk factors and develop risk reduction strategies for their patients. Sin financiación 29.983 JCR (2020) Q1, 2/142 Cardiac & Cardiovascular Systems 4.336 SJR (2020) Q1, 9/349 Cardiology and Cardiovascular Medicine No data IDR 2020 UEM

The interest in RDN for hypertension has fluctuated recently, with a flurry of initial enthusiasm followed by sudden loss of interest by researchers and device manufacturers, with an almost as sudden resurgence in clinical trials activity and device innovation more recently. There is widespread consensus that this therapeutic strategy can be effective, at least for some of the technologies available. Major uncertainties remain as to the clinical role of RDN, and whether any of the emerging technologies such as AV-anastomosis formation, carotid body ablation, carotid bulb expansion, or baroreflex stimulation will have a future as effective treatment options in patients with hypertension. In our first consensus report in 2015, the European Expert Group pointed to the major unmet need of standardization of measurements, trial design and procedural performance.6 With the large number of different technologies currently in the pipeline, this need has even increased. Only through high-quality, collaborative research and openness to new methods for recruitment, patient selection, and assessment of outcomes will it be possible to establish incontrovertibly whether device therapies for hypertension are effective and what are preferred patient populations. Once the proof of concept is established, further studies with a design relevant to clinical reality will be needed to establish the place of new devices in the treatment armoury. The clinical and research community has a large responsibility to prove or disprove the value of new therapies, in order to ensure that antihypertensive devices provide future patients with the greatest benefit and the smallest risk. copy; The Author 2017. Published by Oxford University Press on behalf of the European Society of Cardiology.

Although cardiovascular disease is a major health burden for patients with chronic kidney disease, most cardiovascular outcome trials have excluded patients with advanced chronic kidney disease. Moreover, the major cardiovascular outcome trials that have been conducted in patients with end-stage renal disease have not demonstrated a treatment benefit. Thus, clinicians have limited evidence to guide the management of cardiovascular disease in patients with chronic kidney disease, particularly those on dialysis. Several factors contribute to both the paucity of trials and the apparent lack of observed treatment effect in completed studies. Challenges associated with conducting trials in this population include patient heterogeneity, complexity of renal pathophysiology and its interaction with cardiovascular disease, and competing risks for death. The Investigator Network Initiative Cardiovascular and Renal Clinical Trialists (INI-CRCT), an international organization of academic cardiovascular and renal clinical trialists, held a meeting of regulators and experts in nephrology, cardiology, and clinical trial methodology. The group identified several research priorities, summarized in this paper, that should be pursued to advance the field towards achieving improved cardiovascular outcomes for these patients. Cardiovascular and renal clinical trialists must partner to address the uncertainties in the field through collaborative research and design clinical trials that reflect the specific needs of the chronic and end-stage kidney disease populations, with the shared goal of generating robust evidence to guide the management of cardiovascular disease in patients with kidney disease. Sin financiación 22.673 JCR (2019) Q1, 2/138 Cardiac & Cardiovascular Systems 5.883 SJR (2019) Q1, 4/362 Cardiology and Cardiovascular Medicine No data IDR 2019 UEM

Sin financiación 22.673 JCR (2019) Q1, 2/138 Cardiac & Cardiovascular Systems 5.883 SJR (2019) Q1, 4/362 Cardiology and Cardiovascular Medicine No data IDR 2019 UEM

Heart failure guidelines suggest evaluating renal function as a routine work-up in every patient with heart failure. Specifically, it is advised to calculate glomerular filtration rate and determine blood urea nitrogen. The reason for this is that renal impairment and worsening renal function (WRF) are common in heart failure, and strongly associate with poor outcome. Renal function, however, consists of more than glomerular filtration alone, and includes tubulointerstitial damage and albuminuria. For each of these renal entities, different biomarkers exist that have been investigated in heart failure. Hypothetically, and in parallel to data in nephrology, these markers may aid in the diagnosis of renal dysfunction, or for risk stratification, or could help in therapeutic decision-making. However, as reviewed in the present manuscript, while these markers may carry prognostic information (although not always additive to established markers of renal function), their role in predicting WRF is limited at best. More importantly, none of these markers have been evaluated as a therapeutic target nor have their serial values been used to guide therapy. The evidence is most compelling for the oldest-serum creatinine (in combination with glomerular filtration rate)-but even for this biomarker, evidence to guide therapy to improve outcome is circumstantial at best. Although many new renal biomarkers have emerged at the horizon, they have only limited usefulness in clinical practice until thoroughly and prospectively studied. For now, routine measurement of (novel) renal biomarkers can help to determine cardiovascular risk, but there is no role for these biomarkers to change therapy to improve clinical outcome in heart failure.

Approximately 8–18% of all patients with high blood pressure (BP) are apparently resistant to drug treatment.1,2 In this situation, new strategies to help reduce BP are urgently needed but the complex pathophysiology of resistant hypertension makes this search difficult. Not surprisingly in this context, the latest non-drug treatment which triggered controversy is catheter-based renal denervation (RDN).3,4 The method uses radiofrequency energy, or alternatively ultrasound or chemical denervation, to disrupt renal nerves within the renal artery wall, thereby reducing sympathetic efferent and sensory afferent signalling to and from the kidneys.5,6 Various experimental models of hypertension strongly support this concept7,8 and available evidence also suggests that sympathetic nervous system activation contributes to the development and progression of hypertension and subsequently to target organ damage.7–11 Historical observations have shown that surgical sympathectomy can reduce BP as well as morbidity and mortality in patients with uncontrolled hypertension.12,13 However, the clinical evidence in support of RDN as an effective interventional technique in patients with resistant hypertension is conflicting. A number of observational studies and three randomized, controlled trials (Symplicity HTN-2, Prague-15, and DENERHTN) support both safety and efficacy of this new therapy14–22 but some smaller studies and the large, single-blind, randomized, sham-controlled symplicity HTN-3 trial failed to show superiority of RDN when compared with medical therapy alone.23–25 Whatever the shortcomings of individual trials may be, the possibility remains that the observed BP responses were due to placebo response, the Hawthorne effect, regression to the mean, unknown co-interventions or other bias.26 The design, conduct, and interpretation …

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 euro5 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 society.

This editorial refers to ‘Aliskiren alone or with other antihypertensives in the elderly with borderline and stage 1 hypertension: the APOLLO trial’[†][1], by K.K.Teo et al. , on page 1743 and ‘Renin–angiotensin system antagonists and clinical outcomes in stable coronary artery disease without heart failure’[‡][2], by E. Sorbets et al. , on page 1760. A series of randomized clinical trials demonstrated that when compared with placebo, angiotensin-converting enzyme (ACE) inhibitiors or angiotensin receptor blockers (ARBs) were drugs able to improve the prognosis of patients with heart failure accompanied by low ejection fraction, patients with a myocardial infarction (MI), and patients with chronic kidney disease (CKD; most notably demonstrated by ARBs in diabetic nephropathy), allowing the recognition by Guidelines that blockade of the renin–angiotensin system (RAS) must be used in all these situations. The use of ACE inhibitors and also of ARBs was later expanded to patients with an increased global cardiovascular (CV) risk, patients with stable coronary artery disease (CAD), diabetic patients independently of the presence of established CV or renal disease, and hypertensive patients if clustering of CV risk factors or target organ damage was present. Table 1 lists the different clinical situations where RAS blockade is indicated according to Guidelines that led to the wide use of ACE inhibitors and ARBs in clinical practice; as an example, either alone or in combination, these drugs are prescribed in > 30–40% of the hypertensive population.1 View this table: Table 1 Clinical situations where the use of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker has demonstrated positive effects Recently, the first orally active renin inhibitor was launched as an antihypertensive drug able theoretically to improve the degree … [1]: #fn-2 [2]: #fn-3

Aim There are limited data on the quality of treated blood pressure (BP) control during normal daily life, and in particular, the prevalence of ‘masked uncontrolled hypertension’ (MUCH) in people with treated and seemingly well-controlled BP is unknown. This is important because masked hypertension in ‘treatment naive’ patients is associated with a high risk of cardiovascular events. We therefore conducted the first study to define the prevalence and characteristics of MUCH among a large sample of hypertensive patients in routine clinical practice in whom BP was treated and controlled to recommended clinic BP goals. Methods and results We analysed data from the Spanish Society of Hypertension ambulatory blood pressure monitoring (ABPM) Registry and identified patients with treated and controlled BP according to current international guidelines (clinic BP

Chronic kidney disease (CKD) is frequently observed in patients with arterial hypertension. The same factors that promote the appearance and progression of atherosclerosis can also promote the development of CKD. Two parameters are usually measured to estimate alterations in renal function, the presence of albuminuria, and the estimation of glomerular filtration rate (GFR). Microalbuminuria and a decreased estimated GFR (

This editorial refers to ‘Adherence to antihypertensive therapy prior to the first presentation of stroke in hypertensive adults: population-based study’[†][1], by K. Herrtua et al. , on page 2933 Cardiovascular (CV) disease is the leading cause of death worldwide, accounting for 30% of all deaths, and arterial hypertension is the most important modifiable risk factor to diminish this burden.1 According to the latest Guidelines, daily compliance and long-term adherence to therapy are the most important aims for the adequate control of arterial hypertension.2 As can be seen in Figure 1 , the most relevant reasons for a poor or low compliance depend in the first place on a poor relationship between doctor and patient preventing the latter from attaining … [1]: #fn-2

Background: Cardiac structural adaptation develops early in hypertension and diabetes and is aggravated if both conditions coexist. Blockade of the angiotensin receptors may attenuate these cardiac processes and we tested the ability of olmesartan to prevent or delay left ventricular (LV) remodeling and hypertrophy in various subgroups of type-2 diabetes. Methods: In the ROADMAP study, a double blind, placebo controlled, multicenter, phase IIIb study on prevention of microalbuminuria in diabetic patients, comparing olmesartan 40mg vs. placebo (additional anti-hypertensive medication allowed, except ACEI & ARBs), also 12-lead ECGs have been conducted at baseline and in yearly intervals over the mean study duration of 3.2 years. All ECGs were centrally and independently evaluated by two investigators in a blinded fashion. Results: In 1.513 patients interpretable ECGs were available at baseline and at last examination (N=736 in the placebo and N=777 in the olmesartan group). 90% of the patients were hypertensive at baseline. Dividing the study population into 4 quartiles defined by the Cornell voltage QRS duration product at baseline, the prevalence of patients in the highest quartile (ie. ≥ 200 mV*msec) increased from 25% to 26.5% in the placebo but decreased from 25% to 22.3% in the olmesartan group (odds ratio 0.598 [95% CI: 0.440-0.813], p=0.001) demonstrating a reduced prevalence by 40% with olmesartan. When adjusted for potential confounders (incl. blood pressure), the odds ratio did not change. Subgroup analysis revealed that the prevalence of the Cornell voltage QRS duration product was significantly reduced in diabetic patients with BP 7,0% (RR 46.1%, p=0.0023) and with a duration of diabetes > 5 years (RR 37.7%, p=0.0039). There was a numerical trend with HbA1c < 7.0% (RR 31.0%, p=0.1378), or duration < 5 years (RR 60.8%, p=0.1022). A significant reduction was also seen in patients with or without cardiovascular (CV) complications (RR 82.4% and 34.5%, p=0.010 and 0.0044, respectively) or with or without coronary heart disease (CHD) (RR 34.5% and 35.1%, p=0.0177 and 0.01, respectively) at baseline. Conclusion: Olmesartan significantly decreased the process of ECG left ventricular remodeling. This was even more pronounced in type 2 diabetic patients with a longer duration of or less controlled diabetes and irrespective of blood pressure or concomitant CV disease.