Search

Cardiorenal syndrome I (CRS-1) denotes a state in which acute kidney injury occurs in the setting of acute heart failure (AHF). Isoproterenol (Iso) administration is widly used as an AHF model by transiently inducing extreme tachycardia, hypotension, and myocyte apoptosis and/or necrosis. To gain potential insights into renal manifestations of CRS-1, mice were subjected to the Iso-AHF model (50 mg Iso/kg), followed by renal functional and renal cortical assessments over 4 hours Iso induced acute azotemia (doubling of BUN, plasma creatinine) and significantly reduced renal plasma flow (prolonged plasma para-amino-hippurate clearance). Although no morphologic tubular injury was identified, marked increases in renal cortical 'stress markers' (NGAL, HO-1, IL-6, MCP-1 mRNAs) and oxidant stress (decreased glutathione, increased malondialdehyde) were observed. These changes were catalytic Fe dependent, given that the iron chelator desferrioxamine (DFO) significantly blunted, or completely reversed, these renal cortical abnormalities. Despite these acute changes, no lasting renal injury was observed (assessed over 3 days). To determine whether Iso directly impacts tubular cell integrity, cultured proximal tubule (HK-2) cells were exposed to Iso. Substantial Fe dependent cell injury (decreased MTT uptake), and Fe independent increases in HO-1/IL-6 mRNA expression were observed. We conclude that Iso-induced AHF is a useful reversible model of CRS-1. Despite its largely hemodynamic ('pre-renal') nature, Fe-mediated oxidative stress and pro-inflammatory reactions are induced. These arise, at least in part, from direct Iso- induced tubular cell toxicity, rather than simply being secondary to Iso-mediated hemodynamic events. Finally, Iso-triggered renal cytokine production can potentially contribute to 'organ cross talk' and a systemic pro-inflammatory state.

Background Malnutrition is frequent in patients with heart failure (HF) and contributes to increased systemic congestion, but also hinders its correct assessment, especially during decompensations. Estimating the degree of malnutrition and its relationship with systemic congestion is important to optimize treatment during decompensations. Material and methods Retrospective cohort study in patients with acute HF. The population was stratified according to CONUT (Controlling Nutritional Status) and PNI (Prognostic Nutritional Index) nutrition indices in order to analyse their relationship with objective parameters of congestion and the prognostic value of malnutrition. Results 309 patients were included. More than half presented some degree of malnutrition upon admission. The degree of congestion was significantly higher in malnourished patients, with a higher proportion of «comet tail artifacts» and a higher relative plasma volume. NT-proBNP concentrations, both on admission and at discharge, were also significantly higher in malnourished patients, regardless of the scale used. The univariate analysis identified the CONUT and PNI index as factors associated with one-year mortality from any cause (HR 1.62 [1.22–2.14]; p = 0.001) and PNI (HR 65 [0.53–0.80]; p ≤ 0.001), respectively. Conclusions A higher degree of malnutrition (determined by means of the CONUT and PNI indices) in patients with acute HF was associated with a higher presence of objective parameters of congestion and a higher one-year all-cause mortality.

Sacubitril/valsartan (Sac/Val), a combined angiotensin-II receptor blocker (Val) and neprilysin inhibitor (Sac) in a 1:1 molar ratio, was shown to decrease the risk of cardiovascular death or heart failure (HF) hospitalization in patients with HF and reduced left ventricular (LV) ejection fraction. This study examined the effects of Sac/Val on LV structure, function, and bioenergetics, and on biomarkers of kidney injury and kidney function in dogs with experimental cardiorenal syndrome.Fourteen dogs with cardiorenal syndrome (coronary microembolization-induced HF and renal dysfunction) were randomized to 3 months Sac/Val therapy (100 mg once daily, n = 7) or no therapy (control, n = 7). LV ejection fraction and troponin-I, as well as biomarkers of kidney injury/function including serum creatinine and urinary kidney injury molecule-1 were measured before and at end of therapy and the change (treatment effect change) calculated. Mitochondrial function measures, including the maximum rate of adenosine triphosphate synthesis, were measured in isolated cardiomyocytes at end of therapy. In Sac/Val dogs, the change in ejection fraction increased compared with controls, 6.9 ± 1.4 vs 0.7 ± 0.6%, P.002, whereas change in troponin I decreased, -0.16 ± 0.03 vs -0.03 ± 0.02 ng/mL, P.001. Urinary change in kidney injury molecule 1 decreased in Sac/Val-treated dogs compared with controls, -17.2 ± 7.9 vs 7.7 ± 3.0 mg/mL, P.007, whereas the change in serum creatinine was not significantly different. Treatment with Sac/Val increased adenosine triphosphate synthesis compared with controls, 3240 ± 121 vs 986 ± 84 RLU/µg protein, P.05.In dogs with cardiorenal syndrome, Sac/Val improves LV systolic function, improves mitochondrial function and decreases biomarkers of heart and kidney injury. The results offer mechanistic insights into the benefits of Sac/Val in HF with compromised renal function.

International audience; Sodium-glucose cotransporter 2 inhibitors offer cardiovascular and renal benefits in patients with chronic kidney disease through not yet clearly defined mechanisms. Juni et al. showed that sodium-glucose cotransporter 2 inhibitor empagliflozin exposure in vitro can restore cardiomyocyte function by counteracting harmful effects of uremic serum on the endothelium-cardiomyocyte crosstalk between endothelial cells and cardiomyocytes. The author's findings improved our understanding of cardiovascular impairment in chronic kidney disease and provided new perspectives for the beneficial effects of sodium-glucose cotransporter 2 inhibitor therapy.

Background Previously we found that cardiac chambers' volumes correlate with estimated glomerular filtration rate (eGFR) of hospitalized patients. Currently we aimed to demonstrate this relation among apparently healthy individuals. Methods Ambulatory participants who underwent electrocardiography-gated cardiac computed tomography angiography (CCTA) were included. Subjects with an eGFR Results The cohort consisted of 89 apparently healthy individuals, mostly of male gender (70%), with a mean age of 51 years and a mean eGFR of 79.5 ml/min/1.73m2. A low calcium score (≤10HU) was found in 67.4%(n = 60) of the cohort. After adjustment for baseline characteristics, renal function was associated exclusively with the volume of the left atrium (LA; b-coefficient-0.15, 95%CI -0.3- -0.01, p = .041). A 15.9% (95%CI 0.3–33.9%, p = .045) increase in LA volume index (LAVI) was found among participants with eGFR of 80–90 when compared to those with eGFR>90 ml/min/1.73m2. Participants with a low calcium score showed an increase in LAVI only when eGFR was reduced from normal (>90 ml/min/1.73m2) to 70-80 ml/min/1.73m2 (and not to 80-90 ml/min/1.73m2), revealing a percentage increase of 24.7% (95%CI 5.5–47.4%, p = .011). Conclusions Renal function is closely related to LA volume even in the absence of overt renal failure, demonstrating that minor changes in eGFR instigate an increase in volumes. Risk factors for this interaction should be identified and treated prior to the development of cardio-renal syndrome.

Background Cardiorenal syndrome (CRS) is a major health burden worldwide in need of novel therapies, as current treatments remain suboptimal. The present study assessed the therapeutic potential of apoptosis signal-regulating kinase 1 (ASK1) inhibition in a rat model of CRS. Methods Adult male Sprague-Dawley rats underwent surgery for myocardial infarction (MI) (week 0) followed by 5/6 subtotal nephrectomy (STNx) at week 4 to induce to induce a combined model of heart and kidney dysfunction. At week 6, MI + STNx animals were randomized to receive either 0.5% carboxymethyl cellulose (Vehicle, n = 15, Sham = 10) or G226 (15 mg/kg daily, n = 11). Cardiac and renal function was assessed by echocardiography and glomerular filtration rate (GFR) respectively, prior to treatment at week 6 and endpoint (week 14). Haemodynamic measurements were determined at endpoint prior to tissue analysis. Results G226 treatment attenuated the absolute change in left ventricular (LV) fractional shortening and posterior wall thickness compared to Vehicle. G226 also attenuated the reduction in preload recruitable stroke work. Increased myocyte cross sectional area, cardiac interstitial fibrosis, immunoreactivity of cardiac collagen-I and III and cardiac TIMP-2 activation, were significantly reduced following G226 treatment. Although we did not observe improvement in GFR, G226 significantly reduced renal interstitial fibrosis, diminished renal collagen-I and -IV, kidney injury molecule-1 immunoreactivity as well as macrophage infiltration and SMAD2 phosphorylation. Conclusion Inhibition of ASK1 ameliorated LV dysfunction and diminished cardiac hypertrophy and cardiorenal fibrosis in a rat model of CRS. This suggests that ASK1 is a critical pathway with therapeutic potential in the CRS setting.

The clinical epidemiology of organ outcomes in pediatric traumatic brain injury (TBI) has not been examined. We describe associated markers of cerebral, cardiac and renal injury after pediatric TBI.Prospective observational study.Children 0-18 years who were hospitalized with TBI.Measures of myocardial (at least one elevated plasma troponin [cTnI] ≥ 0.4 ng/ml) and multiorgan (hemodynamic variables, cerebral perfusion, and renal) function were examined within the first ten days of hospital admission and within 24 h of each other.Data from 28 children who were 11[IQR 10.3] years, male (64.3%), with isolated TBI (67.9%), injury severity score (ISS) 25[10], and admission Glasgow coma score (GCS) 11[9] were examined. Overall, 50% (14 children) had elevated cTnI, including those with isolated TBI (57.9%; 11/19), polytrauma (33.3%; 3/9), mild TBI (57.1% 8/14), and severe TBI (42.9%; 6/11). Elevated cTnI occurred within the first six days of admission and across all age groups, in both sexes, and regardless of TBI lesion type, GCS, and ISS. Age-adjusted admission tachycardia was associated with cTnI elevation (AUC 0.82; p 0.001). Reduced urine output occurred more commonly in patients with isolated TBI (27.3% elevated cTnI vs. 0% normal cTnI).Myocardial injury commonly occurs during the first six days after pediatric TBI irrespective of injury severity, age, sex, TBI lesion type, or polytrauma. Age-adjusted tachycardia may be a clinical indicator of myocardial injury, and elevated troponin may be associated with cardio-cerebro-renal dysfunction.

The significance of effective renal perfusion is relatively underemphasized in the current literature. From a renal standpoint, besides optimizing cardiac output, renal perfusion should be maximized as well. Among the several additional variables of the critically ill, such as intra-abdominal pressure, the presence of venous congestion and elevated central venous pressures, airway pressures generated by mechanical ventilation do affect net renal perfusion. These forces represent both a potential danger and an ongoing opportunity to improve renal outcomes in the critically ill and an opportunity to move beyond the simplified viewpoint of optimizing volume status. Therefore, to optimize nephron-protective therapies, nephrologists and intensive care physicians should be familiar with the concept of net renal perfusion pressure. This review appraises the background literature on renal perfusion pressure, including the initial animal data and historical human studies up to the most current developments in the field, exploring potential avenues to assess and improve renal blood supply.

Plasma aldosterone concentration increases in proportion to the severity of heart failure, even during treatment with renin-angiotensin system inhibitors. This study investigated alternative regulatory mechanisms of aldosterone production that are significant in heart failure. Dahl salt-sensitive rats on a high-salt diet, a rat model of heart failure with cardio-renal syndrome, had high plasma aldosterone levels and elevated β3-adrenergic receptor expression in hypoxic zona glomerulosa cells. In H295R cells (a human adrenocortical cell line), hypoxia-induced β3-adrenergic receptor expression. Hypoxia-mediated β3-adrenergic receptor expression augmented aldosterone production by facilitating hydrolysis of lipid droplets though ERK-mediated phosphorylation of hormone-sensitive lipase, also known as cholesteryl ester hydrolase. Hypoxia also accelerated the synthesis of cholesterol esters by acyl-CoA:cholesterol acyltransferase, thereby increasing the cholesterol ester content in lipid droplets. Thus, hypoxia enhanced aldosterone production by zona glomerulosa cells via promotion of the accumulation and hydrolysis of cholesterol ester in lipid droplets. In conclusion, hypoxic zona glomerulosa cells with heart failure show enhanced aldosterone production via increased catecholamine responsiveness and activation of cholesterol trafficking, irrespective of the renin-angiotensin system.

Cardiovascular complications are the leading causes of death in patients with chronic kidney disease (CKD), accounting for approximately 50% of deaths. Despite significant advances in the understanding of cardiac disease due to CKD, the underlying mechanisms involved in many pathological changes have not been fully elucidated. In our previous study, we observed severe fibrosis in the contralateral kidney of a 6-month-old rat UUO model. In the present experiment, we also observed severe fibrosis in the hearts of rats subjected to UUO and the macrophage-to-myofibroblast transition (MMT). These effects were inhibited by the mineralocorticoid receptor (MR) blocker eplerenone. Notably, in vitro, aldosterone-activated MR induced the MMT and subsequently promoted the secretion of CTGF, the target of MR, from macrophages; these changes were inhibited by eplerenone. The CTGF also induced the MMT and both the aldosterone and CTGF-induced MMT could be alleviated by the CTGF blocker. In conclusion, our results suggest that targeting the MR/CTGF pathway to inhibit the MMT may be an effective therapeutic strategy for the treatment of cardiac fibrosis.

Cardiorenal syndrome type-3 (CRS-3) is an abrupt worsening of cardiac function secondary to acute kidney injury. Mitochondrial dysfunction is a key pathological mechanism of CRS-3, and empagliflozin can improve mitochondrial biology by promoting mitophagy. Here, we assessed the effects of empagliflozin on mitochondrial quality surveillance in a mouse model of CRS-3.Cardiomyocyte-specific FUNDC1-knockout (FUNDC1CRS-3 model mice exhibited lower heart function, increased inflammatory responses and exacerbated myocardial oxidative stress than sham-operated controls; however, empagliflozin attenuated these alterations. Empagliflozin stabilized the mitochondrial membrane potential, suppressed mitochondrial reactive oxygen species production, increased mitochondrial respiratory complex activity and restored the oxygen consumption rate in cardiomyocytes from CRS-3 model mice. Empagliflozin also normalized the mitochondrial morphology, mitochondrial dynamics and mitochondrial permeability transition pore opening rate in cardiomyocytes. Cardiomyocyte-specific ablation of FUN14 domain-containing protein 1 (FUNDC1) in mice abolished the protective effects of empagliflozin on mitochondrial homeostasis and myocardial performance. Empagliflozin activated β-catenin and promoted its nuclear retention, thus increasing FUNDC1-induced mitophagy in heart tissues; however, a β-catenin inhibitor reversed these effects.In summary, empagliflozin activated Wnt/β-catenin to stimulate FUNDC1-dependent mitochondrial quality surveillance, ultimately improving mitochondrial function and cardiac performance during CRS-3. Thus, empagliflozin could be considered for the clinical management of heart function following acute kidney injury.

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.We examined renal tissue structure and function, intracellular CaAfter 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-1β, and tumor necrosis factor alpha (TNF-α) levels. CH and low cell contraction were also prevented, as well as a decrease in systolic CaThe 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 Ca

A cardio-renal syndrome (CRS) is a medical condition in which kidney problems are accompanied by heart problems and diagnosed when acute kidney injury contributes to the development of acute cardiac injury. Regenerative medicine is becoming increasingly interested in adipose stem cells. We evaluated the effect of both adipose-derived stem cell extracellular vesicles (ADSCs-EVs) and adipose stem cells (ADSCs) on an experimental model of CRSIII. In this study, isolation, and further identification of ADSCs and ADSCs-EVs by transmission electron microscopy and flow cytometric analysis. Cardio-renal syndrome in rats was induced by renal artery ligation RAL followed by a single dose injection of both ADSCs and ADSCs-EVs in separate groups. The effects of ADSCs-EVs and ADSCs against induced CRSIII were evaluated by both renal and cardiac oxidant/antioxidant biomarkers, renal function, and mRNA gene expression quantitation for atrial natriuretic peptide (ANP), p300, and myocyte enhancer factor 2 (MEF2C and MEF2A), as well as myocardin (MYOCD), as molecules associated with cardiac hypertrophy. Additionally, histological and immunohistochemical studies of cardiac and renal tissues were done. ADSCs-EVs were effectively isolated and characterized. ADSCs-EVs and ADSCs reversed induced CRSIII, evidenced by considerably decreased serum urea and creatinine levels. Returned oxidant/antioxidant stability, and decreased caspase 3-mediated apoptotic programmed cell death in cardiac and renal tissues. Additionally, they led to successful down-regulation of hypertrophic cardiac genes levels and reversed histopathological cardiac and renal injures. ADSCs-derived extracellular vesicles and ADSCs injection restored damaged cardiac and renal tissue and improved its function greatly following induced CRSIII. They could therefore be useful as a means of protecting the heart from the deleterious effects of acute renal injury and reprogramed injured cardiac cells by activating regenerative processes. SIMPLE SUMMARY: Cardiorenal syndrome (CRS) type III is a subcategory of CRS whereby acute kidney injury (AKI) could contribute to the development of acute cardiac dysfunction. This study provided innovatory data regarding the role of adipose-derived stem cell extracellular vesicles ADSCs-EVs and adipose stem cells (ADSCs) in acute renal and cardiac dysfunction and renal biopsy specimens in the form of interstitial inflammation/tubular degeneration. The main cause of renal and cardiac dysfunction is identified to be the activation and accumulation of inflammatory cells and oxidants in the interstitium, surrounded by increased amounts of extracellular matrix, and ADSCs-EVs have been proposed as a contributor factor. The study has evidenced that both ADSCs-EVs and adipose stem cells display beneficial effects on renal and cardiac tissues survival in terms of the frequent occurrence of cardio-renal syndrome, ADSC-EVs treatment repaired damaged renal and cardiac tissues and recovered their function. ADSC-EVs reversed the effects of cardio-renal syndrome and reprogramed injured cells by activating regenerative processes. The clinical significance of the results presented in future studies needs to be investigated further.

Matsushita et al. describe a model of acute kidney injury to chronic kidney disease progression in mice surviving cardiac arrest: mice develop severe acute kidney injury that initially recovers but is followed by the onset of impaired renal function on longer-term follow-up. These findings suggest that distinct cardiorenal toxicities and/or injury dynamics are operative in this cardiac arrest model that do not occur in traditional models of acute kidney injury, providing new opportunities for therapeutic and biomarker discovery for an important clinical problem.

Aims The mechanisms underlying cardiorenal syndromes are complex and not fully understood; Fibrosis seems to be a primary driver of the diseases' pathophysiology. Spironolactone can reduce cardiac or renal fibrosis by inhibiting endothelial-mesenchymal transition (EndMT). Spironolactone protection may rely on activation of adenosine receptors, but the role of the adenosine A2A receptor (A2AR) is unclear. We hypothesize that spironolactone may modulate A2AR to suppress EndMT and reduce cardiorenal remodeling. Main methods A model of renal injury followed by heart failure was established by subcutaneous administration of isoprenaline (Iso) to rats. Assessment of cardiac and renal function, fibrosis, EndMT markers, adenosine and A2AR expression was performed. TGF-β was used to induce EndMT in primary human umbilical vein endothelial cells (HUVECs). Rats or cells were divided into four groups: those that treated with spironolactone alone or in combination with A2AR antagonist ZM241385 or neither, and compared to normal controls. Key findings Isoprenaline-treated rats exhibited cardiac and renal fibrosis, impaired cardiac and renal function, enhanced EndMT, and lower A2AR expression. Spironolactone significantly up-regulated A2AR expression and inhibited EndMT in vivo and in vitro. Moreover, spironolactone improved cardiorenal remodeling and reduced dysfunction. These changes were exacerbated by administration of ZM241385. Together, these findings show that spironolactone up-regulated A2AR to reduce EndMT and ameliorate cardiorenal fibrosis. Significance The anti-fibrotic effects of spironolactone may partly depend on the up-regulation of A2AR, and that A2AR might be a potential therapeutic target for the treatment of cardiorenal syndrome.

This review discusses the diagnostic value of urinary parameters in the setting of advanced chronic kidney disease and we present the key concepts that summarize the suggestions of the manuscript. Urinary volume: The amount of fluid intake may be a non-established risk factor for CKD. For these patients, a urinary output ≥2–3 l/day is a reasonable proposal. This recommendation is not applicable to patients with cardiorenal syndrome or fluid overload risk. Naur: This determination is very useful to monitor salt intake. Reducing urinary Na

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are commonly used to control pain, inflammation, and limit the cardinal signs of injury in humans. However, prolonged use of NSAIDs increases the risk of heart attack (myocardial infarction; MI) and the subsequent risk of heart and renal failure. The molecular and cellular mechanism of action for this adverse effect, particularly along the cardiorenal network, is incomplete. To define the mechanism, carprofen (CAP), an NSAID was administered at the dose of 5 mg/kg to C57BL/6 male mice for two weeks. After last dose of CAP treatment mice were subjected to permanent occlusion of coronary artery that induces irreversible cardiac remodeling while maintaining naive and MI-controls. After MI, cardiac pathology and dysfunction were confirmed, along with additional measurements of kidney function, histology, and injury markers, such as plasma creatinine. CAP treatment increased plasma creatinine levels and subsequently, myocardial structural disorganization increased. Kidney neutrophil gelatinase associated lipocalin (NGAL) and protein expression were increased post-MI. After two weeks CAP treatment, the expression of pyrogenic pro-inflammatory cytokines TNF-α and IL-1β were increased compared to non-CAP treated mice, indicative of amplified inflammatory response. There was also evidence that renal injury of both the post-CAP treatment controls and post-CAP MI were much greater than the non-CAP treated naïve controls, as serum creatinine and NGAL levels were elevated along with obvious structural impairment of the glomerulus. Therefore, CAP treatment tampers with the acute inflammatory response that promotes cardiorenal syndrome and non-resolving inflammation post-MI in acute heart failure.

Cardiorenal syndrome (CRS) remains the leading cause of death in hospitalized patients for all disease entities. Sacubitril/Valsartan (Sac/Val) therapy has been proved to improve prognostic outcome in patients with heart failure or chronic kidney disease. This study tested the hypothesis that combined levosimendan and Sac/Val was superior to just one therapy on protecting the heart and kidney against simultaneous heart and kidney ischemia (I) (for 50-min)-reperfusion (R) (for 7-days) (i.e., double IR) injury (defined as CRS).Adult-male Spraque-Dawley rats (n = 40) were equally categorized into group 1 (sham-operated control), group 2 (double IR), group 3 [double IR+levosimendan (10 mg/kg by intra-peritoneum administration at 30 min/followed by days 1-5 once daily after IR procedure)], group 4 [double IR+Sac/Val (10 mg/kg, orally at 30 min/followed by days 1-5 twice daily after IR procedure)], and group 5 (double IR+Sac/Val+levosimendan). By day 7 after double-IR, the left-ventricular-ejection fraction (LVEF)/left-ventricular-fraction-shortening (LVFS) were highest in group 1, lowest in group 2 and significantly higher in group 5 than in groups 3/4, but they showed no difference between groups 3/4, whereas the circulatory heart-failure (brain-natriuretic peptide)/proinflammatory (suppression of tumorigenicity-2) biomarkers, blood-urea-nitrogen/creatinine and ratio of urine protein to creatinine (all p 0.0001) exhibited an opposite pattern of LVEF among the groups. The protein expressions of inflammatory (tumor necrosis factor-α/interleukin-1ß/matrix metalloproteinase-9)/oxidative-stress (NOX-1/NOX-2/NOX-4)/apoptotic (mitochondrial-Bax/caspase-3/poly-(ADP-ribose)-polymerase)/fibrotic (Smad3/transforming growth factor-ß)/mitochondrial-damaged (cytosolic-cytochrome-C)/myocardial-hypertrophic (ß-MHC) biomarkers in LV myocardium exhibited an opposite pattern of LVEF among the groups (all p 0.0001). The cellular expressions of inflammatory (CD68)/DNA-damaged (γ-H2AX) biomarkers and infarct/fibrotic areas in LV myocardium and kidney displayed an opposite pattern of LVEF among the groups (all p 0.0001).Combined levosimendan and Sac/Val was superior to merely one therapy on protecting the heart and kidney as well as preserving their functions against double IR injury.

It has been suggested that mitochondrial dysfunction underlies the myocardial injury seen following cardiorenal syndrome type 3 (CRS-3). Both mitophagy and the mitochondrial unfolded protein response (UPR

Chronic diseases of the heart and of the kidneys commonly coexist in individuals. Certainly combined and persistent heart and kidney failure can arise from a common pathologic insult, for example, as a consequence of poorly controlled hypertension or of severe diffuse arterial disease. However, strong evidence is emerging to suggest that cross talk exists between the heart and the kidney. Independent processes are set in motion when kidney function is chronically diminished, and these processes can have distinct adverse effects on the heart. The complex chronic heart condition that results from chronic kidney disease (CKD) has been termed cardiorenal syndrome type 4. This review will include an updated description of the cardiac morphology in patients who have CKD, an overview of the most likely CKD-sourced culprits for these cardiac changes, and the potential therapeutic strategies to limit cardiac complications in patients who have CKD.

It is well established that a large number of patients with acute decompensated heart failure present with various degrees of heart and kidney dysfunction usually primary disease of heart or kidney often involve dysfunction or injury to the other. The term cardiorenal syndrome increasingly had been used without a consistent or well-accepted definition. To include the vast array of interrelated derangements and to stress the bidirectional nature of heart-kidney interactions, a new classification of the cardiorenal syndrome with 5 subtypes that reflect the pathophysiology, the time frame, and the nature of concomitant cardiac and renal dysfunction was proposed. Cardiorenal syndrome can generally be defined as a pathophysiological disorder of the heart and kidneys, in which acute or chronic dysfunction of one organ may induce acute or chronic dysfunction to the other. Although cardiorenal syndrome was usually referred to as acute kidney dysfunction following acute cardiac disease, it is now clearly established that impaired kidney function can have an adverse impact on cardiac function.

Managing the cardiovascular complications of renal failure is a major therapeutic challenge in clinical practice. Mineralocorticoid Receptor (MR) blockade is a highly effective strategy for the management of heart failure, but the use of MR antagonists (MRA) is limited by their side effects rendering them contraindicated in patients with renal failure. Finerenone is a new non-steroidal MRA that shows fewer hyperkaliaemic events than the traditional steroidal MRAs and could therefore represent an alternative to these molecules in patients with damaged kidney function. The aim of this study is to characterize the effects of Finerenone on the cardiac complications of renal failure in a mouse model of chronic kidney disease (CKD). CKD was induced by subtotal nephrectomy (Nx), and finerenone was administered at a low dose (2.5 mg/kg/d) from week 4 to week 10 post-Nx. Cardiac function was assessed by echocardiography and invasive hemodynamics while cardiac fibrosis was measured by Sirius Red staining. Renal failure induced cardiac systolic and diastolic dysfunctions in the untreated CKD mice, as well as minor changes on cardiac structure. We also observed alterations in the phosphorylation of proteins playing key roles in the calcium handling (Phospholamban, Calmodulin kinase II) in these mice. Finerenone prevented most of these lesions with no effects on neither the renal dysfunction nor kaliemia. The benefits of finerenone suggest that activation of MR is involved in the cardiac complication of renal failure and strengthen previous studies showing beneficial effects of MRA in patients with CKD.

Background Cardiorenal syndrome includes numerous conditions affecting the heart and kidney, and is a strong predictor of cardiovascular mortality. Methods An analysis was performed on 157 consecutive patients admitted to the Coronary Care Unit of the Camilo Cienfuegos Hospital due to an ST-segment elevation myocardial infarction and heart failure, from January 2013 to December 2016. An analysis was made of the presence of cardiorenal syndrome and its relationship with epidemiological, clinical, and analytical variables, as well as complementary explorations. The relationship between cardiorenal syndrome and in-hospital mortality was assessed using binary logistical regression. Results A total of 52 (33.1%) patients had a cardiorenal syndrome. The haemoglobin level was lower in the group of patients with cardiorenal syndrome (117.2 ± 15.3 vs. 123.3 ± 15.1, p = 0.019), and in left ventricular ejection fraction (34.8 ± 8 vs. 43.2 ± 10.8). A positive correlation was found between the Killip class and the increase in serum creatinine after 48 h. The serum creatinine was associated with left ventricular ejection fraction (r = 0.166; p = 0.038). The multivariate analysis showed that cardiorenal syndrome was an independent predictor of in-hospital mortality when adjusted for a history of ischaemic heart disease, diabetes mellitus status, atrial fibrillation, ventricular arrhythmias, left ventricular ejection fraction, age and systolic blood pressure. Conclusion The presence of cardiorenal syndrome has an influence on the prognosis of patients who suffer a cardiorenal syndrome. Its detection could be useful in the risk stratification.

Interactions of the heart and kidney provide basis for the cardiorenal syndrome, a condition in which failure of one organ (either the heart or the kidney) leads to, or exacerbates, failure of the other organ. This heterogeneous and complex clinical entity is linked to higher morbidity and mortality, thus, warranting identification of novel molecular biomarkers that can be implemented to early diagnosis of cardiorenal syndrome (CRS) patients and to predict their disease stage and clinical outcome. Here, we used a microarray dataset for the identification of key differentially expressed genes (DEGs). Initial analysis based on the cut off criteria [i.e., p -value 0.5] revealed 11 upregulated and 10 down-regulated DEGs. All these 21 DEGs were subjected to network analysis separately that showed 5 genes (ADRB2, DAB2, CX3CR1, DHRS9 and CCZ1B) in upregulated and 6 genes (FOS, FOSB, EGR1, ABCA1, DUSP1, and CXCL8) in downregulated network modules. Ten functionally enriched DEGs out of 11 were further subjected to determine the cardiorenal syndrome-specific miRNA-mRNA regulatory network. Finally, resulting 12 node network revealed 4 hub genes (DAB2: upregulated and FOS, EGR1, and CXCL8: downregulated) associated with 8 miRNAs (hsa-let-7b-5p, hsa-miR-17-5p, hsa-miR-147a, hsa-miR-16-5p, hsa-miR-129-2-3p, hsa-miR-124,3p, hsa-miR-20a-5p, and hsa-miR-429). In Feed-Forward Loop (FFL) analysis among these four hub genes, three namely DAB2, FOS and EGR1 showed their roles in regulation and inhibition. With the assumption of this disease candidate gene prioritization, we report that DAB2, FOS, EGR1 and CXCL8 may serve as robust biomarkers in CRS.

AIMS Fabry disease (FD) is a rare X-linked lysosomal storage disease with a deficiency of α-galactosidase A leading to progressive sphingolipid accumulation in different organs, among them heart and kidney. We evaluated the impact of cardio-renal syndrome (CRS) on the incidence of major cardiovascular complications and death in a prospective FD cohort. METHODS AND RESULTS A total of 104 genetically proven FD patients were annually followed at the University Hospitals Zurich and Bern. The main outcome was a composite of incident renal replacement therapy (RRT), hospitalisation due to decompensated Heart Failure, new onset atrial fibrillation, pacemaker/ICD implantation, stroke/TIA and death. Estimated glomerular filtration rate (eGFR) and left ventricular myocardial mass index (LVMMI) where explored as the primary exposure variables. During the median follow-up of 103 [59-155] months, events occurred in 27 patients. In a Cox regression analysis, both higher LVMMI and lower eGFR were independently associated with a greater risk of developing adverse events after adjustment for multiple confounders (HR 1.67 [1.04-2.73] P=0.03 per SD increase in LVMMI, HR 0.45 [0.25-0.83], P=0.01 per SD decrease in eGFR). In patients with CRS, the risk to develop events was significantly increased if adjusted for demographics and RRT (HR 4.46 [1.07-18.62], P=0.04), approaching significance if additionally adjusted for hypertension (HR 4.05 [0.95-17.29], P=0.06). In Kaplan-Meier-Analysis, the poorest event-free survival was observed among patients with CRS. CONCLUSIONS CRS was associated with a high risk to develop cardiovascular complications and death, emphasizing the importance of its prevention and early recognition. A focus on cardio-reno-protective therapies is crucial.

Introduction and objectives The optimal treatment of patients with acute heart failure (AHF) and cardiorenal syndrome type 1 (CRS-1) is far from being well-defined. Arterial hypoperfusion in concert with venous congestion plays a crucial role in the pathophysiology of CRS-I. Plasma carbohydrate antigen 125 (CA125) has emerged as a surrogate of fluid overload in AHF. The aim of this study was to evaluate the clinical usefulness of CA125 for tailoring the intensity of diuretic therapy in patients with CRS-1. Methods Multicenter, open-label, parallel clinical trial, in which patients with AHF and serum creatinine ≥ 1.4 mg/dL on admission will be randomized to: a) standard diuretic strategy: titration-based on conventional clinical and biochemical evaluation, or b) diuretic strategy based on CA125: high dose if CA125 > 35 U/mL, and low doses otherwise. The main endpoint will be renal function changes at 24 and 72 hours after therapy initiation. Secondary endpoints will include: a) clinical and biochemical changes at 24 and 72 hours, and b) renal function changes and major clinical events at 30 days. Results The results of this study will add important knowledge on the usefulness of CA125 for guiding diuretic treatment in CRS-1. In addition, it will pave the way toward a better knowledge of the pathophysiology of this challenging situation. Conclusions We hypothesize that higher levels of CA125 will identify a patient population with CRS-1 who could benefit from the use of a more intense diuretic strategy. Conversely, low levels of this glycoprotein could select those patients who would be harmed by high diuretic doses.

Introduction We have recently reported the crucial role of Galectin-3 (Gal3) in the progression of type 3 cardio-renal syndrome (CRS-3). Indeed, Gal3 overexpression after renal ischemia reperfusion (IRr) was associated with cardiac fibrosis and dysfunction, which were prevented by Gal3 pharmacological or genetic inhibition. Objective Our present aim was to better define the initial role of kidney Gal3 for triggering CRS-3. Method A murine irradiated and graft model having IRr was used to differentiate the Gal3 expressed by tissue (WT irradiated mice grafted with Gal3-/- bone marrow (BM) cells, WTGal3-/-BM) from Gal3 expressed by immune cells (Gal3-/- irradiated mice grafted with WT BM cells: Gal3-/-WTBM) and were killed after 2 or 28 days. Cardiac and renal phenotypes were evaluated using echocardiography and real-time PCR. Results After IRr, WTGal3-/-BM exhibit normal cardiac phenotype whereas Gal3-/-WTBM developed cardiac dysfunction and high Fibronectin (Fn) mRNA expression ( Fig. 1 A). In contrast, WTGal3-/-BM showed short- and long-term kidney damages with increased renal NGAL mRNA level by day 2 and increased Fn mRNA by 28d ( Fig. 1 B). In kidney after IRr, the increased levels of endothelial marker transcripts (ICAM-1, VCAM-1) mainly in WTGal3-/-BM mice suggested that tissue Gal3 expression is involved in the endothelial activation. Conclusion After IRr the organ dysfunction varies according to the Gal3 cell type origin; kidney Gal3 plays a major role in renal damage, whereas Gal3 from infiltrated BM cells in the heart is deleterious for cardiac function. It remains now to define how tissue Gal3 acts and interacts with endothelial cells, to assess Gal3 as a key-point for CRS-3 understanding.

The pathologic crosstalk between the heart and kidney is known as cardiorenal syndrome (CRS). While the specific mechanisms underlying this crosstalk remain poorly understood, CRS is associated with exacerbated dysfunction of either or both organs and reduced survival. Maladaptive fibrotic remodeling is a key component of both heart and kidney failure pathogenesis and progression. G-protein coupled receptor (GPCR) signaling is a crucial regulator of cardiovascular and renal function. Chronic/pathologic GPCR signaling elicits the interaction of the G-protein Gβγ subunit with GPCR kinase 2 (GRK2), targeting the receptor for internalization, scaffolding to pathologic signals, and receptor degradation. Targeting this pathologic Gβγ-GRK2 interaction has been suggested as a possible strategy for the treatment of HF. In the current review, we discuss recent updates in understanding the role of GPCR-Gβγ-GRK2 signaling as a crucial mediator of maladaptive organ remodeling detected in HF and kidney dysfunction, with specific attention to small molecule-mediated inhibition of pathologic Gβγ-GRK2 interactions. Further, we explore the potential of GPCR-Gβγ-GRK2 signaling as a possible therapeutic target for cardiorenal pathologies.

Acute decompensated heart failure is a common cause of hospitalization with worsening kidney function or acute kidney injury often complicating the admission, which can result in further dysfunction of both systems in the form of a cardiorenal syndrome. Therapy in this arena has been largely empiric as rigorous clinical trial data to inform therapeutic choices are lacking. Here we review and discuss the available clinical evidence for common approaches to the management of this condition. A multidisciplinary approach to the care of patients with cardiorenal syndrome that relies on the experience of nephrologists and cardiologists to individualize treatment is critical given the paucity of rigorous clinical trial data.

High-sensitivity troponin T assays (Hs-TnT) have been carried out in selected populations in clinical trials and in registries of the general population with low cardiovascular risk (CVR). The aim of this study was to determine the proportion of individuals with detectable Hs-TnT and the proportion of individuals with elevated Hs-TnT in a Spanish population of asymptomatic individuals with very high CVR, as well as the parameters associated with Hs-TnT elevation.The study included 690 patients. Hs-TnT detection and Hs-TnT elevation (≥99th percentile value), as well the association of elevated Hs-TnT and clinical, analytical, and treatment data were analyzed.Hs-TnT was analyzed in 646 patients and was detected in 645. Elevated TnT was detected in 212 patients (32.9%). On multivariate analysis, elevated TnT was independently associated with male sex (OR, 2.81; 95%CI, 1.67-4.73; P .001), older age (OR, 1.06; 95%CI, 1.04-1.09; P .001), a higher body mass index (OR, 1.07; 95%CI, 1.02-1.12; P .002), insulin therapy (OR, 1.99; 95%CI, 1.15-3.46; P = .01), history of heart failure (OR, 3.92; 95%CI, 1.24-12.39; P = .02), and estimated glomerular filtration rate calculated by CKD-EPI (OR, 0.96; 95%CI, 0.95-0.97; P .001).In a Spanish population of asymptomatic individuals at very high CVR, Hs-TnT was associated with older age, male sex, higher body mass index, insulin therapy, history of heart failure, and lower glomerular filtration rate.

Despite the accelerated discovery of genes associated with syndromic traits, the majority of families affected by such conditions remain undiagnosed. Here, we employed whole-exome sequencing in two unrelated consanguineous kindreds with central nervous system (CNS), cardiac, renal, and digit abnormalities. We identified homozygous truncating mutations in TMEM260, a locus predicted to encode numerous splice isoforms. Systematic expression analyses across tissues and developmental stages validated two such isoforms, which differ in the utilization of an internal exon. The mutations in both families map uniquely to the long isoform, raising the possibility of an isoform-specific disorder. Consistent with this notion, RT-PCR of lymphocyte cell lines from one of the kindreds showed reduced levels of only the long isoform, which could be ameliorated by emetine, suggesting that the mutation induces nonsense-mediated decay. Subsequent in vivo testing supported this hypothesis. First, either transient suppression or CRISPR/Cas9 genome editing of zebrafish tmem260 recapitulated key neurological phenotypes. Second, co-injection of morphants with the long human TMEM260 mRNA rescued CNS pathology, whereas the short isoform was significantly less efficient. Finally, immunocytochemical and biochemical studies showed preferential enrichment of the long TMEM260 isoform to the plasma membrane. Together, our data suggest that there is overall reduced, but not ablated, functionality of TMEM260 and that attenuation of the membrane-associated functions of this protein is a principal driver of pathology. These observations contribute to an appreciation of the roles of splice isoforms in genetic disorders and suggest that dissection of the functions of these transcripts will most likely inform pathomechanism.

OBJECTIVE To investigate the effect of Shenfuqiangxin capsule and the underlying mechanism on cardio-renal syndrome (CRS) in rats induced by infrarenal aortic-clamping after renal ischaemia. METHODS Male Wistar rats underwent infrarenal aortic-clamping after renal ischaemia or sham operation. The surviving CRS rats were divided randomly into three groups: CRS group (CRS + 10 mL · kg −1 · d −1 pure water by gavage), SFQX group (CRS +13.2 g crude drug · kg −1 · d −1 Shenfuqiangxin by gavage), and handle region peptide (HRP) group (CRS + 10mg/kg HRP by vein). Sham operation rats were given 10 mL · kg −1 · d −1 pure water. Treatments were given 8 weeks after surgery, which lasted for 4 weeks. The rats were detected for heart structure and function by transthoracic echocardiography. PPR mRNA was detected by Reverse Transcription Polymerase Chain Reaction (RT-PCR). To determine whether the mitogen-activated protein kinase (MAPK) signal pathway is included in the heart and kidney protective function of Shenfuqiangxin capsule, MAPK related proteins such as posophorylated C-Jun amino terminal kinase (p-JNK), posophorylated extracellular signal-regulated kinase ½ (p-ERK1/2), posophorylated p38 (p-p38) were examined by Western Blot. Apoptosis in heart and kidney tissues were detected by dUTP Nick End Labeling staining. RESULTS Shenfuqiangxin capsule alleviated myocardial apoptosis and inhibited PRR mRNA expression and p-JNK, p-ERK1/2, p-p38 proteins expression in CRS rats. CONCLUSION All the results suggest that Shenfuqiangxin capsule improves the injured heart and kidney function maybe through inhibition of MAPK response pathway.

Introduction The heart and the kidneys are tightly interlinked with each other. So, primary disorder of one of these organs often results in the secondary dysfunction of other. Such interactions play a vital role in the pathogenesis of a clinical entity called cardio-renal syndrome (CRS). CRS type 4 refers to the development of cardiac failure in the patients with CKD. Objectives To study the prevalence of various cardiac diseases in the patients with CKD and risk factors for it. Methods Eighty patients with CKD who were being treated at KIMS, Hubli, from 1st January 2015 to 30th June 2015 were selected. Clinical evaluation and relevant investigations including echocardiography were done. Results Mean age of study population was 43.50 ± 14.53 years. Heart failure with reduced ejection fraction (HFrEF) and Heart Failure with preserved ejection fraction (HFpEF) were present in 21 (26.25%) and 59 (73.75%) respectively. Left ventricular (LV) hypertrophy was present in 55(68.75%). Thus, the prevalence of CRS type 4 was 61 (76.25%). Pericardial effusion was present in 12 (15%). Complete heart block was present in 2 (2.5%). Pulmonary hypertension (PH) was present in 35 (43.75%). Mean central venous pressure (CVP) and interdialysis fluid retention were significantly greater among those with LV failure, compared to those without LV failure (p = 0.0002, p = 0.025 respectively). Mean hemoglobin was significantly lower among patients with LV failure, compared to those without LV failure (p = 0.032). Conclusion The prevalence of cardiorenal syndrome type 4 is substantially high in patients with CKD and carries adverse outcome in relation to patient management.

Heart failure and chronic renal diseases are usually progressive and only partially amenable to therapy. These disorders can be the sequelae of hypertension or worsened by hypertension. They are associated with the tissue up-regulation of multiple peptides, many of which are capable of acting within the cell interior. This article proposes that these peptides, intracrines, can form self-sustaining regulatory loops that can spread through heart or kidney, producing progressive disease. Moreover, mineralocorticoid activation seems capable of amplifying some of these peptide networks. This view suggests an expanded explanation of the pathogenesis of progressive cardiorenal disease and suggests new approaches to treatment.

Background Cardiorenal syndrome (CRS) is the association of heart failure (HF) and renal failure (RF). This association is poor in terms of prognosis. Purpose To determine the correlation between glomerular filtration rate (GFR) and left ventricular ejection fraction (LVEF), and their impact on death. Methods This cross-sectional study, by document analysis, was conducted from January 2016 to December 2017 in the departments of cardiology and nephrology at University Hospital of Brazzaville. We had included the patients with association HF and RF. Results One hundred and eighty-six patients, 105 men (56.5%) were included. The mean age was 58 ± 15.5 years (range: 17 to 90 years). The risk factors were: hypertension (n = 128, 68.8%), diabetes (n = 56, 30%) and alcoholism (n = 23, 12.4%). At admission, the mean serum creatinine level was 47.2 ± 55.5 mg/L (range 16 to 136) and the mean GFR was 24.5 ± 22.8 ml/min (range: 2.1 and 100). In echocardiography, mean LVEF was 47.8 ± 18.2% (range: 22 to 87). LVEF 100 mg/L (n = 9, 50%, OR 11.8, CI95% 4–35, P 100 mg/L was independent determinant of death (OR 10.7, 95% CI 2.3–44, P = 0.001). Conclusion The prognosis of CRS is poor because the direct relation of blood creatinine level and death. Indeed, due to the limited access to dialysis in our country, the overall care of patients remains difficult. The extension and implantation of dialysis centers in our country remain the major challenges.

The Acute Dialysis Quality Initiative consensus conference proposed a classification of cardiorenal syndrome (CRS), aiming for a better delineation of each subtype. Although the exact pathophysiology of type 4 CRS is not completely understood, the mechanisms involved are probably multifactorial. There is growing evidence that oxidative stress is a major connector in the development and progression of type 4 CRS. Giving its complexity, poor prognosis and increasing incidence, type 4 CRS is becoming a significant public health problem. Patients with chronic kidney disease are particularly predisposed to cardiac dysfunction, due to the high prevalence of traditional cardiovascular risk factors in this population, but the contribution of risk factors specific to chronic kidney disease should also be taken into account.Much remains to be elucidated about type 4 CRS: despite progress over the last decade, there are still significant questions regarding its pathophysiology and there is as yet no specific therapy. A better understanding of the mechanisms involved may provide potential targets for intervention.The present review will provide a brief description of the definition, epidemiology, diagnosis, prognosis, biomarkers and management strategies of type 4 CRS, and the pathophysiological mechanisms and risk factors presumably involved in its development will be particularly highlighted. Resumo: A definição e classificação de síndrome cardiorrenal foram avançadas pela conferência Acute Dialysis Quality Initiave, visando uma melhor compreensão acerca de cada subtipo desta patologia. Embora a fisiopatologia exata não esteja completamente definida, os mecanismos envolvidos na síndrome cardiorrenal tipo 4 são potencialmente multifatoriais. Há crescente evidência de que o stress oxidativo é um conector principal no desenvolvimento e progressão desta síndrome. Dada a sua complexidade, pior prognóstico e incidência crescente, a síndrome cardiorrenal tipo 4 tem vindo a tornar-se num importante problema de saúde pública. Os pacientes com doença renal crónica estão particularmente predispostos a desenvolver disfunção cardíaca, devido à elevada prevalência de fatores de risco cardiovasculares nesta população, mas a contribuição de fatores de risco específicos da doença renal crónica devem ser tidos em conta.Muito permanece por esclarecer acerca da síndrome cardiorrenal tipo 4: apesar do progresso ao longo da última década, persistem questões importantes relativamente à sua fisiopatologia e ainda não existe tratamento específico. É sublinhada a necessidade de elaborar recomendações científicas para a prevenção e estratégias terapêuticas eficazes para a síndrome cardiorrenal tipo 4, sendo que um conhecimento mais aprofundado acerca dos mecanismos envolvidos na síndrome cardiorrenal tipo 4 poderão conferir potenciais alvos de intervenção.A presente revisão irá focar-se na síndrome cardiorrenal tipo 4: a sua definição, epidemiologia, diagnóstico, prognóstico, biomarcadores e estratégias terapêuticas serão brevemente descritos, mas uma particular atenção será dada aos mecanismos fisiopatológicos e fatores de risco presumivelmente envolvidos nesta patologia. Keywords: Type 4 cardiorenal syndrome, Chronic kidney disease, Heart failure, Cardiovascular risk factors, End-stage renal disease, Neurohormonal activation, Oxidative stress, Palavras-chave: Síndrome cardiorrenal tipo 4, Doença renal crónica, Insuficiência cardíaca, Fatores de risco cardiovascular, Doença renal crónica terminal, Ativação neuro-hormonal, Stresse oxidativo

Heart failure and cardiovascular death are common in patients with chronic kidney disease (CKD) and extremely prevalent in patients undergoing dialysis. It has been shown that the excess of cardiovascular mortality in this patient population is not fully accounted for by the traditional cardiovascular risk factors. Substantial evidence exists for the presence of sympathetic over-activity in patients with dialytic and non-dialytic CKD. Several studies have also been reported on reversible segmental left ventricular wall motion abnormality consistent with myocardial stunning in association with dialysis especially hemodialysis. In the literature, the most acceptable underpinning hypothesis for the myocardial stunning in CKD is "demand myocardial ischemia". However, the occurrence of cardiac sympathetic over-activation-disruption and repeated reversible myocardial stunning in patients with CKD can be compared to that occurring in acute Takotsubo syndrome where local cardiac sympathetic disruption may cause acute regional circumferential pattern of myocardial stunning. In this manuscript, converging evidences suggestive for the fact that acute, repetitive, and chronic TS may be one of the important causes of cardiac morbidity including myocardial stunning and heart failure and mortality in patients with CKD are provided.

Patients with Duchenne muscular dystrophy (DMD) develop dilated cardiomyopathy and are at risk for kidney injury. Creatinine based estimated glomerular filtration rate (eGFR) is limited by low muscle mass with low serum creatinine levels in DMD. We assessed the relationship between cardiac function, modified Schwartz eGFR and cystatin C eGFR in patients with DMD. Ninety-three patients with DMD were screened for renal dysfunction in an outpatient neuromuscular clinic. Patients with new nephrotoxic medications, recent hospitalization or decompensated heart failure were excluded from the analysis. Eleven (12%) patients had evidence of renal dysfunction identified by cystatin C eGFR, while no patients had renal dysfunction by Schwartz eGFR. There was no significant correlation between cystatin C eGFR and age (r = -0.2, p = 0.11), prednisone dose (r = 0.06, p = 0.89) or deflazacort dose (r = -0.01, p = 0.63). There was a significant correlation between left ventricular ejection fraction and cystatin C GFR among patients with chronic left ventricular dysfunction (r = 0.46, p 0.01), but not normal function (r = -0.07, p = 0.77). There was no significant correlation between left ventricular ejection fraction and Schwartz eGFR among patients with (r = 0.07, p = 0.59) or without (r = -0.27, p = 0.07) chronic left ventricular dysfunction. Cystatin C eGFR correlates with cardiac dysfunction in patients with DMD, thus providing novel evidence of cardio-renal syndrome in this population. Routine monitoring of renal function is recommended in patients with DMD.

Renal dysfunction and heart failure commonly co-exist; it is termed the cardiorenal syndrome (CRS). This combination of renal and cardiac impairment presents a substantial clinical challenge and is associated with adverse prognosis. The pathogenesis of the CRS is complex, including chronic activation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system, together with reduced renal perfusion. Chronic activation of the RAAS can impair mitochondrial function, and increase mitochondrial derived oxidative stress which in turn can lead to renal injury and sodium and water retention. For example, it has been shown that exogenous Ang II augments renal mitochondrial oxidative stress, reduces GFR and induces albuminuria in rats with heart failure. Administration of Ang II also augmented renal mitochondrial dysfunction in aged mice. Current treatments for CRS, including angiotensin-converting enzyme inhibitors, exert limited renal protection if any at all. Therefore, novel treatments particularly those that can target renal mechanisms downstream to chronic activation of the renal renin-angiotensin system are likely to exert renoprotection in the setting of CRS.

Background Renal dysfunction (RD) is a potent risk factor for death in patients with cardiovascular disease. This relationship may be causal; experimentally induced RD produces findings such as myocardial necrosis and apoptosis in animals. Cardiac transplantation provides an opportunity to investigate this hypothesis in humans. Methods and Results Cardiac transplantations from the United Network for Organ Sharing registry were studied (n = 23,056). RD was defined as an estimated glomerular filtration rate 2 . RD was present in 17.9% of donors and 39.4% of recipients. Unlike multiple donor characteristics, such as older age, hypertension, or diabetes, donor RD was not associated with recipient death or retransplantation (age-adjusted hazard ratio [HR] = 1.00, 95% confidence interval [CI] 0.94–1.07, P = .92). Moreover, in recipients with RD the highest risk for death or retransplantation occurred immediately posttransplant (0–30 day HR = 1.8, 95% CI 1.54–2.02, P P = .33). Conclusions The risk for adverse recipient outcomes associated with RD does not appear to be transferrable from donor to recipient via the cardiac allograft, and the risk associated with recipient RD is greatest immediately following transplant. These observations suggest that the risk for adverse outcomes associated with RD is likely primarily driven by nonmyocardial factors.

Renal impairment and fluctuations in renal function are common in patients recently hospitalized for acute heart failure and in those with atrial fibrillation. The aim of the present study was to evaluate the hypothetical need for dosage adjustment (based on fluctuations in kidney function) of dabigatran, rivaroxaban and apixaban during the first 6 months after hospital discharge in patients with concomitant atrial fibrillation and heart failure.An observational study was conducted in 162 patients with nonvalvular atrial fibrillation after hospitalization for acute decompensated heart failure who underwent creatinine determinations during follow-up. The hypothetical recommended dosage of dabigatran, rivaroxaban and apixaban according to renal function was determined at discharge. Variations in serum creatinine and creatinine clearance and consequent changes in the recommended dosage of these drugs were identified during 6 months of follow-up.Among the overall study population, 44% of patients would have needed dabigatran dosage adjustment during follow-up, 35% would have needed rivaroxaban adjustment, and 29% would have needed apixaban dosage adjustment. A higher proportion of patients with creatinine clearance60 mL/min or with advanced age (≥ 75 years) would have needed dosage adjustment during follow-up.The need for dosage adjustment of nonvitamin K oral anticoagulants during follow-up is frequent in patients with atrial fibrillation after acute decompensated heart failure, especially among older patients and those with renal impairment. Further studies are needed to clarify the clinical importance of these needs for drug dosing adjustment and the ideal renal function monitoring regime in heart failure and other subgroups of patients with atrial fibrillation.

Red cell distribution width (RCDW) has not been fully investigated for its prognostic impact in patients with acute heart failure (AHF) with or without the cardiorenal anemia syndrome (CRAS). A total of 978 patients (age 75 ± 14 years, 70% men, 43% with CRAS) hospitalized for AHF were enrolled. During a median follow-up duration of 31 months, 472 subjects (48%) died. The postdischarge mortality was positively associated with the increasing RCDW. After accounting for age, gender, co-morbidities, hemoglobin, renal function, sodium level, and N-terminal probrain natriuretic peptide, RCDW remained an independent predictor of mortality (hazard ratio [HR] and 95% CI for a 1% increase of RCDW: 1.09, 1.00 to 1.17, p = 0.04). In the subgroups of patients with or without CRAS, RCDW was an independent predictor of total mortality for both subgroups (HR 1.05, 95% CI 1.00 to 1.10 and HR 1.11, 95% CI 1.07 to 1.15, respectively). In conclusion, elevated RCDW was independently associated with mortality in patients hospitalized for AHF, with or without CRAS.