GLP-1 receptor agonists and cardiorenal outcomes in type 2 diabetes: an updated meta-analysis of eight CVOTs.

BACKGROUND: A meta-analysis is presented of cardiovascular outcome trials (CVOTs) comparing glucagon-like peptide-1 receptor agonists (GLP-1RA) versus placebo on cardiorenal outcomes in patients with type 2 diabetes mellitus (T2DM). METHODS: We did an electronic search up to June 30, 2021, for eligible trials. We did a meta-analysis of available trial data using a random-effects model to calculate overall hazard ratios (HRs) and 95% CI (confidence intervals). We included data from 8 CVOTs and 60,080 patients (72.4% with established cardiovascular disease). RESULTS: GLP-1RA reduced major cardiovascular events (MACE) by 14% (HR = 0.86, 95% CI 0.79-0.94, P = 0.006) with a non-significant heterogeneity between subgroups of patients with and without cardiovascular disease (P = 0.127). GLP-1RA also reduced the risk of cardiovascular death by 13% (P = 0.016), nonfatal stroke by 16% (P = 0.007), hospitalization for heart failure by 10% (P = 0.023), all-cause mortality by 12% (P = 0.012), and the broad composite kidney outcome by 17% (P = 0.012), which was driven by a reduction in macroalbuminuria only (HR = 0.74, 0.67-0.82, P < 0.001). CONCLUSIONS: GLP-1RA have moderate benefits on MACE, and also reduce hospitalization for heart failure and all-cause mortality; they also have robust benefits on reducing the incidence of macroalbuminuria.

MicroRNA-21 regulates peroxisome proliferator-activated receptor alpha, a molecular mechanism of cardiac pathology in Cardiorenal Syndrome Type 4.

Cardiovascular events are the leading cause of death in patients with chronic kidney disease (CKD), although the pathological mechanisms are poorly understood. Here we longitudinally characterized left ventricle pathology in a 5/6 nephrectomy rat model of CKD and identify novel molecular mediators. Next-generation sequencing of left ventricle mRNA and microRNA (miRNA) was performed at physiologically distinct points in disease progression, identifying alterations in genes in numerous immune, lipid metabolism, and inflammatory pathways, as well as several miRNAs. MiRNA miR-21-5p was increased in our dataset and has been reported to regulate many identified pathways. Suppression of miR-21-5p protected rats with 5/6 nephrectomy from developing left ventricle hypertrophy and improved left ventricle function. Next-generation mRNA sequencing revealed that miR-21-5p suppression altered gene expression in peroxisome proliferator-activated receptor alpha (PPARα) regulated pathways in the left ventricle. PPARα, a miR-21-5p target, is the primary PPAR isoform in the heart, importantly involved in regulating fatty acid metabolism. Therapeutic delivery of low-dose PPARα agonist (clofibrate) to rats with 5/6 nephrectomy improved cardiac function and prevented left ventricle dilation. Thus, comprehensive characterization of left ventricle molecular changes highlights the involvement of numerous signaling pathways not previously explored in CKD models and identified PPARα as a potential therapeutic target for CKD-related cardiac dysfunction.

Do Renin-Angiotensin Blockers Affect Renal Function and Cardiac Outcomes in Patients Undergoing Partial Nephrectomy?

PURPOSE: Currently no data exist to guide renal surgeons on the perioperative use of renin-angiotensin blockers despite potential cardiorenal benefits. We aimed to assess the impact of resuming renin-angiotensin blockers on postoperative renal function and adverse cardiac events following partial nephrectomy. MATERIALS AND METHODS: This is an observational analysis of patients who underwent robot-assisted laparoscopic partial nephrectomy from 2006 to 2014 at a single institution. The Wilcoxon rank sum and chi-square tests, and logistic regression were used to assess the risk of adverse renal and cardiac events stratified by history and pattern of renin-angiotensin blockade perioperatively. RESULTS: We identified 900 patients with a median followup of 16.3 months (IQR 1.4-39.1). There were no significant differences in severe renal dysfunction at last followup on univariate analysis or adverse cardiac events at 30 days on multivariate analysis in patients stratified by a history of renin-angiotensin blockade. Of the 338 patients 137 (41.9%) resumed renin-angiotensin blockade immediately after surgery, which did not result in any significant difference in the postoperative glomerular filtration rate (p >0.05). Resuming renin-angiotensin blockade at discharge home was associated with a decreased risk of heart failure within 30 days of surgery (0.3% vs 11.8% of cases) and stage IV/V chronic kidney disease at last followup (2.6% vs 25.5%, each p <0.001). CONCLUSIONS: Renin-angiotensin blockers appear safe to continue immediately after renal surgery. Discharge home with angiotensin converting enzyme inhibitors/angiotensin receptor blockers was associated with a decreased risk of heart failure and severe renal dysfunction. However, this risk may be overstated as a result of the small number of patients discharged without resuming the home medication.

Relationship between history of coronary heart disease at dialysis initiation and onset of events associated with heart disease: a propensity-matched analysis of a prospective cohort study.

BACKGROUND: Chronic kidney disease (CKD) is an independent risk factor for cardiovascular disease (CVD) events, and a number of reports have shown a relationship between CKD and CVD in pre-dialysis or maintenance dialysis patients. However, few studies have reported serial observations during dialysis initiation and maintenance. Therefore, we examined whether the incidence of heart disease events differed between CKD patients with and without a history of coronary heart disease (CHD) at dialysis initiation. METHODS: The subjects were patients in the 17 centers participating in the Aichi Cohort Study of Prognosis in Patients Newly Initiated into Dialysis (AICOPP) from October 2011 to September 2013. We excluded nine patients whose outcomes were unknown, as determined by a survey conducted at the end of March 2015. Thus, we enrolled 1,515 subjects into the study. We classified patients into 2 groups according to the history of CHD (i.e., a CHD group and a non-CHD group). Propensity scores (PS) represented the probability of being assigned to a group with or without a history of CHD. Onset of heart disease events and associated mortality and all-cause mortality were compared in PS-matched patients by using the log-rank test for Kaplan-Meier curves. Factors contributing to heart disease events were examined using stepwise multivariate Cox proportional hazards analysis. RESULTS: There were 254 patients in each group after PS-matching. During observation, heart disease events occurred in 85 patients (33.5%) in the CHD group and 48 (18.9%) patients in the non-CHD group. The incidence was significantly higher in the CHD group (p < 0.0001). The CHD group was associated with higher incidence of heart disease events (vs. the non-CHD group, hazard ratio = 1.750, 95% confidence interval = 1.160-2.639). In addition, comorbidities such as diabetes mellitus, low body mass index, and low serum high-density lipoprotein cholesterol were associated with higher incidence of events. CONCLUSION: History of CHD at dialysis initiation was associated with a higher incidence of heart disease events and mortality and all-cause mortality. TRIAL REGISTRATION: UMIN 000007096 . Registered 18 January 2012.

Renal denervation has blood pressure-independent protective effects on kidney and heart in a rat model of chronic kidney disease.

We elucidate the underlying mechanisms of bidirectional cardiorenal interaction, focusing on the sympathetic nerve driving disruption of the local renin-angiotensin system (RAS). A rat model of N(ω)-nitro-L-arginine methyl ester (L-NAME; a nitric oxide synthase inhibitor) administration was used to induce damage in the heart and kidney, similar to cardiorenal syndrome. L-NAME induced sympathetic nerve-RAS overactivity and cardiorenal injury accompanied by local RAS elevations. These were suppressed by bilateral renal denervation, but not by hydralazine treatment, despite the blood pressure being kept the same between the two groups. Although L-NAME induced angiotensinogen (AGT) protein augmentation in both organs, AGT mRNA decreased in the kidney and increased in the heart in a contradictory manner. Immunostaining for AGT suggested that renal denervation suppressed AGT onsite generation from activated resident macrophages of the heart and circulating AGT excretion from glomeruli of the kidney. We also examined rats treated with L-NAME plus unilateral denervation to confirm direct sympathetic regulation of intrarenal RAS. The levels of urinary AGT and renal angiotensin II content and the degrees of renal injury from denervated kidneys were less than those from contralateral innervated kidneys within the same rats. Thus, renal denervation has blood pressure-independent beneficial effects associated with local RAS inhibition.

Vitamin D analogues to target residual proteinuria: potential impact on cardiorenal outcomes.

Residual proteinuria, the amount of proteinuria that remains during optimally dosed renin-angiotensin-aldosterone system (RAAS) blockade, is an independent risk factor for progressive renal function loss and cardiovascular complications in chronic kidney disease (CKD) patients. Dual RAAS blockade may reduce residual proteinuria but without translating into improved cardiorenal outcomes at least in diabetic nephropathy; rather, dual RAAS blockade may increase the risk of adverse events. These findings have challenged the concept of residual proteinuria as an absolute treatment target. Therefore, new strategies must be explored to address whether by further reduction of residual proteinuria using interventions not primarily targeting the RAAS benefit in terms of cardiorenal risk reduction would accrue. Both clinical and experimental intervention studies have demonstrated that vitamin D can reduce residual proteinuria through both RAAS-dependent and RAAS-independent pathways. Future research should prospectively explore vitamin D treatment as an adjunct to RAAS blockade in an interventional trial exploring clinically relevant cardiorenal end points.

Cardiorenal syndrome: the emerging role of protein-bound uremic toxins.

Cardiorenal syndrome is a condition in which a complex interrelationship between cardiac dysfunction and renal dysfunction exists. Despite advances in treatment of both cardiovascular and kidney disease, cardiorenal syndrome remains a major global health problem. Characteristic of the pathophysiology of cardiorenal syndrome is bidirectional cross-talk; mediators/substances activated by the disease state of 1 organ can play a role in worsening dysfunction of the other by exerting their biologically harmful effects, leading to the progression of the syndrome. Accumulation of uremic toxins is a hallmark of renal excretory dysfunction. Removal of some toxins by conventional dialysis is particularly problematic because of their high protein binding. In this review, we demonstrate that protein-bound uremic toxins may play an important role in progression of cardiovascular disease in the setting of chronic kidney disease. The highly protein-bound uremic toxin indoxyl sulfate has emerged as a potent toxin adversely affecting both the kidney and heart. Direct cardiac effects of this toxin have been recently demonstrated both in vitro and in vivo. Specifically, potent fibrogenic and prohypertrophic effects, as well as oxidative stress-inducing effects, appear to play a central role in both renal and cardiac pathology. Many of these adverse effects can be suppressed by use of a gut adsorbent, AST-120. Potential mechanisms underlying indoxyl sulfate-induced cardiorenal fibrosis are discussed. Future research and clinical implications conclude this review.

[Cardiorenal syndrome type 2--literature review]. / Kardiorenalni sindrom tip 2--pregled literature.

We performed literature search in the Pubmed database in July 2013. The key word used for search was cardiorenal syndrome type 2, limited to English language and humans. Over the last decade, a significant advance in the understanding of the cardiorenal syndrome has been achieved. However, precise pathogenesis remains to be clarified. Current treatment in postponing progression of cardiorenal syndrome type 2 is not efficient, although novel drugs like levosimendan and tezosentan seem promising. Future research is necessary to determine their role in the treatment of cardiorenal syndrome type 2.

[The chronic kidney disease "epidemy"]. / Krónikus vesebetegségek "epidémiája"

Chronic kidney disease is a general term for heterogenous disorders with >3 months duration affecting kidney structure and function. Nowadays, involving 10-16% of the adult population worldwide, chronic kidney disease is recognised as a major global public health problem. The number of cases is continuously increasing. In this review, epidemiology, definition, new classification and a conceptual model for development, progression and complications of chronic kidney disease as well as strategies to improve outcome are summarized.

Oxidative stress in the cardiorenal metabolic syndrome.

Excess visceral adiposity contributes to inappropriate activation of the renin-angiotensin-aldosterone system despite a state of volume expansion and of salt retention that contributes to subclinical elevations of pro-oxidant mechanisms. These adverse effects are mediated by excess generation of reactive oxygen species (ROS) and diminished antioxidant defense mechanisms. Excess tissue (i.e., skeletal muscle, liver, heart) free oxygen radicals contribute to impairments in the insulin-dependent metabolic signaling pathways that regulate glucose utilization/disposal and systemic insulin sensitivity. The generation of ROS is required for normal cell signaling and physiological responses. It is a loss of redox homeostasis that results in a proinflammatory/profibrotic milieu that promotes impairments in insulin metabolic signaling, reduced endothelial-mediated vasorelaxation, and associated cardiovascular and renal structural and functional abnormalities. These maladaptive processes are increasingly recognized as important in the progression of hypertension in the cardiorenal metabolic phenotype. There is increasing evidence to support a critical role for Ang II signaling through the AT(1)R and aldosterone actions through the MR in conjunction with an altered redox-mediating impaired endothelial, cardiac and renal function in this metabolic phenotype. There are emerging clinical data that indicate that therapies that target the renin angiotensin-aldosterone system (RAAS) also attenuate oxidative stress, and improve endothelial, cardiac and renal functions, which collectively contribute to reductions in hypertension.

[Italian Society of Cardiology-Italian Society of Nephrology Consensus document: The cardio-renal interaction in the prevention and treatment of cardiovascular diseases - Part I: From cardiovascular risk factors to the mechanisms of cardio-renal syndrome]. / Documento di consenso Società Italiana di Cardiologia- Società Italiana di Nefrologia: Ruolo dell'asse cardio-renale nella prevenzione e trattamento delle patologie cardiovascolari ­ Parte I: Dai fattori di rischio cardiovascolare ai meccanismi di danno cardio-renale.

Chronic kidney disease (CKD) and cardiovascular (CV) disease are highly prevalent conditions in the general population and are strictly connected to each other with a bidirectional interaction. In patients affected by CKD, the leading cause of morbidity and mortality is represented by CV disease, since CKD promotes the atherosclerotic process increasing inflammation, and modifying lipid and bone mineral metabolism. On the other side, a strict relationship exists between CKD and CV risk factors, which are prevalent in nephropathic patients and impose a stringent assessment of the risk of CV events in this population together with an optimized pharmacological approach, complicated by the coexistence of the two pathological conditions. The first part of this consensus document focuses on the mechanisms of cardio-renal damage and on the impact, as well as the management, of the main CV risk factors in the context of CKD.

Klotho relieves inflammation and exerts a cardioprotective effect during renal ischemia/reperfusion-induced cardiorenal syndrome.

BACKGROUND: Renal ischemia and reperfusion injury (IRI) is the main cause of acute kidney injury (AKI). AKI induces the development of cardiac hypertrophy (CH) during cardiorenal syndrome (CRS), and cardiomyocyte calcium mishandling though systemic inflammation after 8 days of renal IRI. Klotho has recently been described as an anti-inflammatory component. Given this, Klotho treatment could prevent or attenuate the inflammation, thereby also preventing electrical cardiac outcomes incurred by CRS. The aim of this study was to investigate the therapeutic role of Klotho in CRS after unilateral renal IRI through its anti-inflammatory action. METHODS: We examined renal tissue structure and function, intracellular Ca2+ dynamics in adult ventricular cardiomyocytes and serum cytokine levels from C57BL/6 mice that suffered unilateral renal IRI by occluding the left pedicle for 60 min and reperfusion for 8 days. The animals were treated with recombinant Klotho protein starting from the day of the surgery, then daily for 8 days. RESULTS: After Klotho treatment for 8 days, the left renal tissue remained damaged, however the renal function was restored due to the right kidney tissue preservation. In parallel, Klotho also prevented an increase in serum interleukin (IL-) 6, IL-1ß, and tumor necrosis factor alpha (TNF-α) levels. CH and low cell contraction were also prevented, as well as a decrease in systolic Ca2+ transients and sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) activity measured as Ca2+ transient decay, an increase in spontaneous Ca2+ release and the incidence of pro-arrhythmic events. CONCLUSIONS: The Klotho treatment showed promise, playing an important role in the pathophysiology of CRS. We were unable to observe a total renoprotective role of the compound in the model; in turn, a cardioprotective role of Klotho was demonstrated through the prevention of hypertrophy and normalization of the Ca2+ cycle dysfunction of cardiomyocytes. We propose that Klotho acts in the cardiorenal syndrome by systematically preventing inflammation and increased FGF23, alleviating cardiac outcomes.

The Healthy, Aging, and Diseased Kidney: Relationship with Cardiovascular Disease.

The cardiovascular and renal systems share an intimate physiological relationship, wherein a perturbance in one system may have an adverse effect on the other. Since the burden of renal disease increases with age, there is a considerable interest in the pathophysiology of kidney disease in the geriatric patient population. This review will explore the physiological dynamics behind the increased susceptibility to kidney disease in this population. A better understanding of these pathophysiological changes may lead to improved prevention and management strategies.

Association of Optimal Blood Pressure With Critical Cardiorenal Events and Mortality in High-Risk and Low-Risk Patients Treated With Antihypertension Medications.

Importance: There are few studies comparing the optimal level of treated blood pressure (BP) between high- and low-risk patients. Objective: To examine whether optimally treated BP is different according to risk status. Design, Setting, and Participants: Population-based cohort study using data from the National Health Information Database in Korea from 2002 to 2015 and 2006 to 2017. A total of 1 402 975 adults aged 40 to 79 years who had no known cardiorenal disease were included. Exposures: Systolic BP treated with antihypertensive medication. Main Outcomes and Measures: The yearly rates of critical cardiorenal events and all-cause death were estimated according to the levels of treated systolic BP and the presence of 5 risk factors (hypertension, diabetes, hyperlipidemia, proteinuria, and smoking). Results: During the study periods, 225 103 of 487 412 participants (54.0% male; median [interquartile range] age, 50 [44-59] years) in the primary cohort and 360 503 of 915 563 participants (50.1% male; median [interquartile range] age, 52 [46-60] years) in the secondary cohort received antihypertensive treatment. In total, 28 411 of 51 292 cardiorenal incidents and 33 102 of 72 500 deaths were noted in ever-treated participants. The absolute increase in cardiorenal and mortality risk associated with inadequately treated BP was greater in participants with multiple risk factors than in those with 1 or 0 risk factors. The hazard ratios for critical cardiorenal events increased as the treated systolic BP increased to more than 130 to 140 mm Hg. The hazard ratio for all-cause mortality for patients with 3 or more risk factors and treated systolic BP within the range of 110 to 119 mm Hg was 1.21 (95% CI, 1.07-1.37); 130 to 139 mm Hg, 1.04 (95% CI, 0.98-1.11); 140 to 149 mm Hg, 1.12 (95% CI, 1.05-1.20); 150 to 159 mm Hg, 1.21 (95% CI, 1.11-1.32); and 160 mm Hg or greater, 1.46 (95% CI, 1.32-1.62) compared with high-risk patients with BP of 120 to 129 mm Hg. For participants with 1 or 0 risk factors and treated systolic BP within the range of 110 to 119 mm Hg, the hazard ratio was 1.14 (95% CI, 1.07-1.22); 130 to 139 mm Hg, 0.97 (95% CI, 0.93-1.02); 140 to 149 mm Hg, 1.00 (95% CI, 0.91-1.09); 150 to 159 mm Hg, 1.06 (95% CI, 0.99-1.14); and 160 mm Hg or greater, 1.26 (95% CI, 1.15-1.37). However, when categorized using cardiovascular risk calculators, there was no consistent trend in mortality thresholds of BP across the risk score categories. Conclusions and Relevance: These results suggest that intensive BP control is appropriate for reducing all-cause mortality in addition to cardiorenal risk in higher- rather than lower-risk patients. However, caution may be required when determining BP targets using current risk calculators.

Canagliflozin, a sodium-glucose cotransporter 2 inhibitor, normalizes renal susceptibility to type 1 cardiorenal syndrome through reduction of renal oxidative stress in diabetic rats.

AIMS/INTRODUCTION: Type 2 diabetes mellitus is a risk factor of acute kidney injury after myocardial infarction (MI), a form of cardiorenal syndrome. Recent clinical trials have shown that a sodium-glucose cotransporter 2 (SGLT2) inhibitor improved both cardiac and renal outcomes in patients with type 2 diabetes mellitus, but effects of an SGLT2 inhibitor on cardiorenal syndrome remain unclear. MATERIALS AND METHODS: Type 2 diabetes mellitus (Otsuka Long-Evans Tokushima Fatty rats [OLETF]) and control (Long-Evans Tokushima Otsuka rats [LETO]) were treated with canagliflozin, an SGLT2 inhibitor, for 2 weeks. Renal tissues were analyzed at 12 h after MI with or without preoperative fasting. RESULTS: Canagliflozin reduced blood glucose levels in OLETF, and blood ß-hydroxybutyrate levels were increased by canagliflozin only with fasting. MI increased neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 protein levels in the kidney by 3.2- and 1.6-fold, respectively, in OLETF, but not in LETO. The renal messenger ribonucleic acid level of Toll-like receptor 4 was higher in OLETF than in LETO after MI, whereas messenger ribonucleic acid levels of cytokines/chemokines were not significantly different. Levels of lipid peroxides, nicotinamide adenine dinucleotide phosphate oxidase (NOX)2 and NOX4 proteins after MI were significantly higher in OLETF than in LETO. Canagliflozin with pre-MI fasting suppressed MI-induced renal expression of neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 in OLETF, together with reductions in lipid peroxides and NOX proteins in the kidney. Blood ß-hydroxybutyrate levels before MI were inversely correlated with neutrophil gelatinase-associated lipocalin protein levels in OLETF. Pre-incubation with ß-hydroxybutyrate attenuated angiotensin II-induced upregulation of NOX4 in NRK-52E cells. CONCLUSIONS: The findings suggest that SGLT2 inhibitor treatment with a fasting period protects kidneys from MI-induced cardiorenal syndrome, possibly by ß-hydroxybutyrate-mediated reduction of NOXs and oxidative stress, in type 2 diabetic rats.

Cardioprotective Effects of Paricalcitol Alone and in Combination With FGF23 Receptor Inhibition in Chronic Renal Failure: Experimental and Clinical Studies.

BACKGROUND: In uremic animals, vitamin D receptor (VDR) agonists like paricalcitol (Pc) attenuate cardiac hypertrophy, but this effect has not been replicated consistently in humans with chronic kidney disease. Elevated fibroblast growth factor 23 (FGF23) levels cause cardiac hypertrophy with activation of the myocardial calcineurin/nuclear factor of activated T cell (NFAT) axis and may antagonize the cardioprotective effects of VDR agonist therapy. We hypothesized that the effectiveness of Pc may depend on the prevailing circulating levels of FGF23 and could be potentiated by the combined administration of a pan-FGF23 receptor (FGFR) blocker agent (PD173074). METHODS: In rats with 5/6 nephrectomy treated with Pc or PD173074 or both agents concurrently, myocardial mRNA expression of renin-angiotensin system, VDR, FGFR4, and calcineurin/NFAT target genes was determined. In adolescents on hemodialysis, we analyzed sequential echocardiograms, blood pressures and serial FGF23 measurements, and their relations to the cumulative administered dose of parenteral Pc. RESULTS: The ratio of Pc dose/plasma levels of FGF23 correlated inversely (P < 0.005) with the cardiac mass in uremic rats and in hemodialysis patients, independently of hypertension. Despite persistently elevated FGF23 levels and myocardial FGFR4 activation, Pc suppressed upregulated myocardial calcineurin/NFAT target genes, and the effects were amplified by coadministration of PD173074. CONCLUSIONS: The beneficial effects of Pc on uremic cardiac hypertrophy are counterbalanced by the increased FGF23 levels. Blockade of FGF23-mediated signaling increased the Pc-induced suppression of the myocardial calcineurin/NFAT system. Higher doses of Pc should be considered in the treatment of patients with uremic cardiomyopathy.