Arterial-renal Syndrome in Patients with ESRD, a New Disease Paradigm.

BACKGROUND: Patients with end-stage renal disease (ESRD) often present with an increased risk of cardiovascular disease. Conditions of compromised cardiovascular health such as atrial fibrillation (AFIB) and peripheral arterial disease (PAD) may alter biomarker levels in a way that reflects worsening ESRD. This study profiled biomarkers and laboratory parameters of endothelium dysfunction in patients with ESRD, categorized by additional AFIB and PAD conditions. METHODS: Citrated blood samples were collected from 95 patients with ESRD. Biomarker levels were measured from plasma samples using sandwich ELISAs, including tissue plasminogen activator (tPA), D-dimer, and nitrotyrosine. Lab parameters, including BUN, calcium, creatinine, parathyroid hormone, phosphate, alkaline phosphatase, ferritin, transferrin, and total iron capacity, and patient comorbidities were obtained from patient medical records. The comorbidities were determined through provider notes, and evidence of applicable testing. RESULTS: 14.89% of patients were found to have atrial fibrillation (n = 14), 30.85% of patients were found to have peripheral arterial disease (n = 29), and 6.38% of patients were found to have both peripheral arterial disease and atrial fibrillation (n = 6). When compared to patients with only ESRD, patients with ESRD and PAD showed elevated levels of D-Dimer (p = .0314) and nitrotyrosine (p = .0330). When compared to patients with only ESRD, patients with atrial fibrillation showed elevated levels of D-Dimer (p = .0372), nitrotyrosine (p = .0322), and tPA (p = .0198). CONCLUSION: When compared to patients with just ESRD, patients with concomitant PAD had elevated levels of Nitrotyrosine and D-dimer; while patients with concomitant Afib had elevated levels of nitrotyrosine, D-dimer, as well as tPA.

Altered Amino Acid Metabolism in Patients with Cardiorenal Syndrome Type 2: Is It a Problem for Protein and Exercise Prescriptions?

The goal of this retrospective study was to document any alterations in plasma amino acids (AAs) in subjects with cardiorenal syndrome type 2 (CRS 2). We analyzed data from sixteen patients with CRS 2 and eight healthy subjects (control group, C), whose plasma arterial (A) and venous (V) AA concentrations had been measured. Compared to C, the group of CRS 2 patients showed significant reductions by more than 90% in A (p < 0.01) and V (p < 0.01) individual AAs, whereas negative A-V differences that indicated a net muscle AA release (muscle hypercatabolism) were found in 59% of CRS 2 patients (p < 0.03). No significant differences in plasma A and V AA concentrations nor in A-V differences were found between patients with mild kidney damage (N = 5; estimated glomerular filtration rate, eGFR ≥ 60 mL/min/1.73 m2) and patients with moderate-severe kidney damage (N = 11; eGFR < 60 mL/min/1.73 m2). Several plasma arterial AAs correlated with hemodynamic variables, but not with GFR. The study showed that patients with CRS 2 had very low concentrations of circulating AAs, independent of the degree of GFR damage.

Evaluation of the diagnostic value of the renal resistive index as a marker of the subclinical development of cardiorenal syndrome in MMVD dogs.

INTRODUCTION: Myxomatous mitral valve disease (MMVD) in dogs inevitably causes renal dysfunction. These interactions are known as the cardiorenal syndrome (CRS). The main aims of the study were to evaluate whether renal resistive index (RRI) may be useful as a non-invasive marker in subclinical stage of kidney injury in dogs with MMVD and to compare RRI with SDMA and Cyst C. METHODS: Forty-four dogs were divided into two groups: control-15 healthy dogs and the heart group-29 dogs with MMVD (ACVIM class Cc). Study protocol included: anamnesis, clinical examination, electrocardiography, echocardiography, chest radiography, abdominal ultrasonography with measurements of the renal resistive index (RRI), urine, and blood analysis. RESULTS: The RRI in the heart group was significantly higher 0.725 ± 0.035 versus control group 0.665 ± 0.028 (p < 0.00085). The RRI cut-off point in dogs with stable chronic heart failure (CHF) under 8 years is 0.775, in older 0.64. RRI was similar in MMVD dogs treated with ACE-I + furosemide and dogs treated ACE-I + torasemide + pimobendan + spironolactone. There was no correlation between RRI and SDMA or Cyst C. CONCLUSION: RRI is more sensitive than creatinine, SDMA and Cyst C to reveal kidney injury in MMVD dogs class Cc younger than 8 years.

Sacubitril-Valsartan Improves Anemia of Cardiorenal Syndrome (CRS).

BACKGROUND AND AIMS: Anemia is a common complication of heart failure and Chronic Kidney Disease (CKD). Sacubitril-valsartan is a novel therapy for the treatment of chronic Heart Failure with a reduced Ejection Fraction (HFrEF). We have evaluated the short-term effects of sacubitril- valsartan on the anemia of CRS. METHODS: The study group comprised 39 patients with HFrEF, who were followed-up for three months. The study is a retrospective analysis of clinical data. Data of 3 months' and baseline visits were recorded including plasmatic creatinine, glomerular filtration rate, cystatin C, kaliemia, haemoglobin, pro-BNP, and albuminuria. RESULTS: In all, 34 patients ended the follow-up. Mean sacubitril-valsartan dosage at baseline was 101 ± 62 mg/day and 126 ± 59 mg/day at end. Mean hemoglobin increased from 12.2 ± 1.1 g/dl at baseline to 12.9 ± 1.0 g/dl (p = 0.001,). Prevalence of anemia was 64.7% (95%CI, 47.9-78.5%) at baseline and 38.4 (95%CI, 23.9-55.0%) after the follow-up (p = 0.016). Serum cystatin C levels decreased from 2.71 ± 1.0 to 2.48 ± 1.0 mg/l (p = 0.028). Serum K levels remained unchanged (baseline 4.94 ± 0.60, three months visit 4.94 ± 0.61 mmol/l, p = 0.998). CONCLUSION: Sacubitril-valsartan improves anemia in CRS patients. An improvement in serum cystatin levels was observed. Few untoward effects were detected. These findings should be confirmed in wider clinical trials.

Cardiorenal syndrome in thalassemia patients.

BACKGROUND: Cardiorenal syndrome (CRS), a serious condition with high morbidity and mortality, is characterized by the coexistence of cardiac abnormality and renal dysfunction. There is limited information about CRS in association thalassemia. This study aimed to investigate the prevalence of CRS in thalassemia patients and also associated risk factors. METHODS: Thalassemia patients who attended the out-patient clinic of a tertiary care university hospital from October 2016 to September 2017 were enrolled onto this cross-sectional study. Clinical and laboratory findings from 2 consecutive visits, 3 months apart, were assessed. The criteria for diagnosis of CRS was based on a system proposed by Ronco and McCullough. Cardiac abnormalities are assessed by clinical presentation, establishment of acute or chronic heart failure using definitions from 2016 ESC guidelines or from structural abnormalities shown in an echocardiogram. Renal dysfunction was defined as chronic kidney disease according to the 2012 KDIGO guidelines. RESULTS: Out of 90 thalassemia patients, 25 (27.8%) had CRS. The multivariable analysis showed a significant association between CRS and extramedullary hematopoiesis (EMH) (odds ratio (OR) 20.55, p = 0.016); thalassemia type [ß0/ßE vs ß0/ß0 thalassemia (OR 0.005, p = 0.002)]; pulmonary hypertension (OR 178.1, p = 0.001); elevated serum NT-proBNP (OR 1.028, p = 0.022), and elevated 24-h urine magnesium (OR 1.913, p = 0.016). There was no association found between CRS and frequency of blood transfusion, serum ferritin, liver iron concentration, cardiac T2*, type of iron chelating agents, or urine neutrophil gelatinase-associated lipocalin level. CONCLUSIONS: CRS is relatively common in thalassemia patients. Its occurrence is associated with laboratory parameters which are easily measured in clinical practice.

The dynamic relationship between serum chloride and cardiorenal syndrome.

Low serum sodium concentration has long been recognized as an established marker of short- and long-term morbidity and mortality in patients with heart failure (HF), and is commonly included in various risk prediction models. Mechanisms leading to hyponatremia (e.g. maladaptive neurohormonal activation) could also lead to concurrent decline in serum chloride levels. Besides, chloride has distinct biological roles (e.g. modulation of renal tubular sodium transporters) that are relevant to the pathophysiology and therapy of HF, making it a potent cardiorenal connector. Several clinical studies have recently reported on a potentially overlooked link between low serum chloride levels and adverse outcomes in patients with a wide variety of HF syndromes, which could indeed be stronger than that of sodium. While evidence on predictive value of chloride is accumulating in various patient populations and settings, the limited available interventional studies have so far yielded conflicting results. It remains to be elucidated whether hypochloremia represents a marker of disease severity and prognosis, or it is an actual pathogenetic mechanism, hence being a potential novel target of therapy. Current ongoing studies are designed to better understand the mechanistic aspects of the role of hypochloremia in HF and shed light on its clinical applicability.

Clinical Potential of Targeting Fibroblast Growth Factor-23 and αKlotho in the Treatment of Uremic Cardiomyopathy.

Chronic kidney disease is highly prevalent, affecting 10% to 15% of the adult population worldwide and is associated with increased cardiovascular morbidity and mortality. As chronic kidney disease worsens, a unique cardiovascular phenotype develops characterized by heart muscle disease, increased arterial stiffness, atherosclerosis, and hypertension. Cardiovascular risk is multifaceted, but most cardiovascular deaths in patients with advanced chronic kidney disease are caused by heart failure and sudden cardiac death. While the exact drivers of these deaths are unknown, they are believed to be caused by uremic cardiomyopathy: a specific pattern of myocardial hypertrophy, fibrosis, with both diastolic and systolic dysfunction. Although the pathogenesis of uremic cardiomyopathy is likely to be multifactorial, accumulating evidence suggests increased production of fibroblast growth factor-23 and αKlotho deficiency as potential major drivers of cardiac remodeling in patients with uremic cardiomyopathy. In this article we review the increasing understanding of the physiology and clinical aspects of uremic cardiomyopathy and the rapidly increasing knowledge of the biology of both fibroblast growth factor-23 and αKlotho. Finally, we discuss how dissection of these pathological processes is aiding the development of therapeutic options, including small molecules and antibodies, directly aimed at improving the cardiovascular outcomes of patients with chronic kidney disease and end-stage renal disease.

Circulating miRNA-21 as a diagnostic biomarker in elderly patients with type 2 cardiorenal syndrome.

Circulating miRNAs have attracted attention as serum biomarkers for several diseases. In this study, we aimed to evaluate the diagnostic value of circulating miRNA-21 (miR-21) as a novel biomarker for elderly patients with type 2 cardiorenal syndrome (CRS-2). A total of 157 elderly patients with chronic heart failure (CHF) were recruited for the study. According to an estimated glomerular filtration rate (eGFR) cut-off of 60 ml/min/1.73 m2, 84 patients (53.5%) and 73 patients (46.5%) were assigned to the CRS group and the CHF group, respectively. Expression levels of serum miR-21 and biomarkers for CRS, such as kidney injury factor-1 (KIM-1), neutrophil gelatinase-related apolipoprotein (NGAL), cystatin C (Cys C), amino-terminal pro-B-type natriuretic peptide (NT-proBNP), N-acetyl-κ-D-glucosaminidase (NAG), and heart-type fatty acid-binding protein (H-FABP), were detected. Serum miR-21, KIM-1, NGAL, Cys C, NT-proBNP and H-FABP levels were significantly higher in the CRS group than in the CHF group (P < 0.01), whereas NAG expression was not significantly different between the two groups (P > 0.05). Cys C, H-FABP and eGFR correlated significantly with miR-21 expression, but correlations with miR-21 were not significant for NT-proBNP, NGAL, NAG and KIM-1. Moreover, multivariate logistic regression found that serum miR-21, increased serum Cys C, serum KIM-1, hyperlipidaemia and ejection fraction (EF) were independent influencing factors for CRS (P < 0.05). The AUC of miR-21 based on the receiver operating characteristic (ROC) curve was 0.749, with a sensitivity of 55.95% and a specificity of 84.93%. Furthermore, combining miR-21 with Cys C enhanced the AUC to 0.902, with a sensitivity of 88.1% and a specificity of 83.6% (P < 0.001). Our findings suggest that circulating miR-21 has medium diagnostic value in CRS-2. The combined assessment of miR-21 and Cys C has good clinical value in elderly patients with CRS-2.

The impact of kidney dysfunction categorized by urinary to serum creatinine ratio on clinical outcomes in patients with heart failure.

Kidney dysfunction (KD) is closely associated with poor clinical outcome in patients with heart failure (HF). KD is classified as intrinsic and pre-renal KD. However, the impact of each KD on the clinical outcome in patients with HF has not yet been fully elucidated. We measured the urinary to serum creatinine (UC/SC) ratio, a marker for intrinsic and pre-renal KD, in 1009 consecutive patients with HF at admission. There were 314 cardio-renal events including HF and advanced end-stage renal dysfunction during the median follow-up period of 1154 days. There were 63 (6%) patients with intrinsic KD (UC/SC ratio < 20), 118 (12%) patients with intermediate KD (UC/SC ratio 20-40), 607 (60%) patients with pre-renal KD (UC/SC ratio > 40), and 221 (22%) patients with no KD. Multivariate Cox's proportional hazard regression analysis demonstrated that intrinsic and intermediate KDs were significantly associated with poor clinical outcome. The prediction model for cardio-renal events was significantly improved by the addition of UC/SC ratio to the confounding risk factors. Subgroup analysis in patients with HF with severely reduced glomerular filtration rates showed that the prevalence rates of intrinsic, intermediate, and pre-renal KDs were 23%, 30%, and 47%, respectively. The cardio-renal event rate was the highest in the intrinsic KD group compared with that in the other groups. Intrinsic KD was closely associated with extremely poor clinical outcome in patients with HF. The UC/SC ratio could provide important clinical information for the treatment and management of KD in patients with HF.

Emergence of Chloride as an Overlooked Cardiorenal Connector in Heart Failure.

Several studies have recently challenged the sodium-centric view that has been dominating the field of heart failure (HF) and cardiorenal syndrome. The previously observed benefits of severe dietary restriction of salt do not seem to be consistently reproduced by contemporary studies. Moreover, there is evidence that too low intake may paradoxically lead to adverse outcomes in more advanced stages of HF. Facing the escalating controversy, investigators have shifted their focus from sodium to its often overlooked counter ion in salt, the chloride. Emerging data suggest that serum chloride levels could portend robust independent prognostic value in a wide range of HF syndromes possibly stronger than that of sodium. The untoward impact of hypochloremia on the outcomes could be mechanistically linked to renal tubular regulatory pathways, neurohormonal activation, and diuretic resistance. As such, it can be a potential target of therapy in this setting. In this article, the authors provide a brief overview of the role of serum chloride as a cardiorenal connector and explore the context in which the contemporary data should be interpreted. Implementation of predictive and therapeutic strategies incorporating the emerging evidence would be refined through discussion of nuances of such findings as well as their biological and clinical relevance.

Uremic Toxin-Targeting as a Therapeutic Strategy for Preventing Cardiorenal Syndrome.

Chronic kidney disease (CKD) is a global health problem. CKD patients are at high risk of developing cardiovascular disease (CVD), including coronary artery disease, heart failure and stroke. Several factors invoke a vicious cycle of CKD and CVD, which is referred as to "cardiorenal syndrome". Among these factors, the compounds retained through loss of renal excretion play a pathological role in causing atherosclerosis and CVD. These compounds have been broadly classified as uremic toxins because of their accumulation with declining renal function and cytotoxicity. The major uremic toxins contributing to CVD are asymmetric dimethylarginine (ADMA), advanced glycation endproducts (AGE), and trimethyl amine N-oxide (TMAO). ADMA is linked to CVD through regulation of nitric oxide, reactive oxygen species, and renal anemia. AGE not only directly accumulates in the heart and kidney, but interacts with the receptor for AGE (RAGE), leading to cell damage in CVD. TMAO correlates with a high prevalence of CVD and promotes organ fibrosis by itself. The levels of these and other uremic toxins rise with worsening CKD, inducing multiplicative damage in the heart and kidney. Therefore, a better understanding of uremic toxins has great clinical importance for preventing cardiorenal syndrome. This review highlights the molecular mechanism by which these uremic toxins are implicated in CVD and suggests the possible mutual relationship between them.

Optimally managing hyperkalemia in patients with cardiorenal syndrome.

Renin-angiotensin-aldosterone system inhibitors (RAASi) are now a standard treatment in most patients with cardiovascular disease, especially in those with heart failure (HF). The European Society of Cardiology and the American College of Cardiology/American Heart Association gave a Class IA recommendation for the use of RAASi in the treatment of Classes II-IV symptomatic HF with reduced ejection fraction (HFREF), based on their strong clinical benefits of lowering all-cause mortality and HF hospitalizations in these subjects. However, RAASi therapy or adding mineralocorticoid receptor antagonists in subjects receiving background angiotensin-converting enzyme inhibitors or angiotensin receptor blockers may be associated with an increased risk of hyperkalemia (HK), especially in those with reduced kidney function. As a result, a significant proportion of these subjects either have RAASi dose reduced or more often discontinued when they develop HK. Discontinuation of RAASi in patients hospitalized with HFREF was associated with higher postdischarge mortality and rehospitalization rates, while optimal dosing of RAASi significantly reduced median hospital stays, outpatient visits and related costs. Thus, effective treatment is required to lower potassium level and maintain normokalemia in subjects with HF and reduced kidney disease who develop or are at risk of HK, thus enabling them to continue their RAASi therapy and maximize benefits from RAASi. In this review, we provide an up-to-date review of the prevalence and significance of HK in patients with cardiorenal syndrome, as well as their optimal management of HK with recent novel therapies.

Change in the NT-proBNP/Mature BNP Molar Ratio Precedes Worsening Renal Function in Patients With Acute Heart Failure: A Novel Predictor Candidate for Cardiorenal Syndrome.

Background Early detection for worsening renal function (WRF) is indispensable in patients with acute decompensated heart failure (HF). We tested the hypothesis that the difference in the circulating levels of each B-type or brain natriuretic peptide (BNP) molecular form is associated with the occurrence of WRF. Methods and Results Circulating levels of proBNP, the NT-proBNP (N-terminal proBNP), and total BNP (proBNP+mature BNP) were prospectively measured in patients with acute decompensated HF using specific and sensitive enzyme immunochemiluminescent assays. An estimated mature BNP (emBNP) concentration was calculated by subtracting proBNP levels from total BNP levels. WRF was defined as a >20% decrease in the estimated glomerular filtration rate during the hospitalization. One-way repeated-measures ANOVA was used to compare the changes of variables between the patients with and without WRF. In patients with acute decompensated HF (New York Heart Association class III-IV; 96%) hospitalized for HF, NT-proBNP levels did not differ during the hospitalization between patients with and without WRF (n=42 and 140, respectively). By contrast, emBNP levels were lower in patients with WRF than in those without WRF on day 3 after admission. NT-proBNP/emBNP molar ratios were elevated on day 3 after admission in the patients with WRF, before estimated glomerular filtration rate declined, but were unchanged in patients without WRF. On day 3 after hospital admission, NT-proBNP/emBNP ratios were strongly associated with percentage decreases in estimated glomerular filtration rate. Conclusions These findings suggest that elevation of NT-proBNP/emBNP ratio precedes WRF in patients with acute HF and can be a potentially useful biomarker for risk stratification of cardiorenal syndrome.

Tidal peritoneal dialysis versus ultrafiltration in type 1 cardiorenal syndrome: A prospective randomized study.

BACKGROUND: Ultrafiltration is an alternative strategy to diuretic therapy for the treatment of patients with acute decompensated heart failure. Little is known about the efficacy and safety of peritoneal dialysis in patients with acute decompensated heart failure complicated by acute cardiorenal syndrome. METHODS: We randomly assigned a total of 88 patients with type 1 acute cardiorenal syndrome to a strategy of ultrafiltration therapy (44 patients) or tidal peritoneal dialysis (44 patients). The primary endpoint was the change from baseline in the serum creatinine level and left ventricular function represented as ejection fraction, as assessed 72 and 120 h after random assignment. Patients were followed for 90 days after discharge from the hospital. RESULTS: Ultrafiltration therapy was inferior to tidal peritoneal dialysis therapy with respect to the primary endpoint of the change in the serum creatinine levels at 72 and 120 h (p = 0.041) and ejection fraction at 72 and 120 h after enrollment (p = 0.044 and p = 0.032), owing to both an increase in the creatinine level in the ultrafiltration therapy group and a decrease in its level in the tidal peritoneal dialysis group. At 120 h, the mean change in the creatinine level was 1.4 ± 0.5 mg/dL in the ultrafiltration therapy group, as compared with 2.4 ± 1.3 mg/dL in the tidal peritoneal dialysis group (p = 0.023). At 72 and 120 h, there was a significant difference in weight loss between patients in the ultrafiltration therapy group and those in the tidal peritoneal dialysis group (p = 0.025). Net fluid loss was also greater in tidal peritoneal dialysis patients (p = 0.018). Adverse events were more observed in the ultrafiltration therapy group (p = 0.007). At 90 days post-discharge, tidal peritoneal dialysis patients had fewer rehospitalization for heart failure (14.3% vs 32.5%, p = 0.022). CONCLUSION: Tidal peritoneal dialysis is a safe and effective means for removing toxins and large quantities of excess fluid from patients with intractable heart failure. In patients with cardiorenal syndrome type 1, the use of tidal peritoneal dialysis was superior to ultrafiltration therapy for the preservation of renal function, improvement of cardiac function, and net fluid loss. Ultrafiltration therapy was associated with a higher rate of adverse events.

Cardiorenal Syndrome: Pathophysiology.

Cardiorenal syndrome commonly refers to the collective dysfunction of heart and kidney resulting in a cascade of feedback mechanism causing damage to both the organs and is associated with adverse clinical outcomes. The pathophysiology of cardiorenal syndrome is complex, multifactorial, and dynamic. Improving the understanding of disease mechanisms will aid in developing targeted pharmacologic and nonpharmacologic therapies for the management of this syndrome. This article discusses the various mechanisms involved in the pathophysiology of the cardiorenal syndrome.

Plasma Lipopolysaccharide Concentrations in Cardiorenal Syndrome Type 1.

BACKGROUND: Cardiorenal syndrome (CRS) type 1 is characterized by a rapid worsening of cardiac function that leads to acute kidney injury (AKI). This study evaluated the role of lipopolysaccharide (LPS) in the development of AKI in patients with acute heart failure (AHF) and its relationship with renal parameters, to enable a better comprehension of the pathophysiology of CRS type 1. METHODS: We enrolled 32 AHF patients, 15 of whom were classified as having CRS type 1. Eight of these 15 exhibited AKI at the time of admission (caused by AHF) and the other 7 developed AKI during their stay in hospital (in the first 48 h). We evaluated the plasmatic LPS concentrations as well as conventional (serum creatinine [sCr] and urea) and unconventional (neutrophil gelatinase-associated lipocalin [NGAL] and cystatin C) renal markers. RESULTS: LPS levels were significantly higher in the CRS type 1 patients. No significant difference in LPS level was found in patients who were admitted with AKI and those developed AKI in hospital, but there was a tendency towards a higher level of LPS in CRS type 1 patients admitted with AKI. The LPS concentrations at admission were similar in CRS type 1 survivors (n = 12) and nonsurvivors (n = 3) (p = 0.22). We observed a positive correlation between LPS level and NGAL, Scr at admission and peak Scr during hospitalization and urea at admission. CONCLUSION: CRS type 1 patients present with an increased level of LPS and there is a direct correlation between LPS and renal parameters. This pilot research is the first study to explore the premise of LPS as novel pathophysiological factor in CRS type 1.

Association between high Gal-3 serum levels and worsening of renal function in chronic heart failure outpatients.

Aim: The aim of the study was to evaluate the association between Gal-3 serum levels and the progression of renal dysfunction in chronic heart failure outpatients. Methods & results: This prospective study of 260 chronic heart failure patients showed that Gal-3 was associated with 1-year worsening of renal function both in univariate (odds ratio: 1.12; 95% CI: 1.06-1.18; p < 0.001) and in forward stepwise multivariate (odds ratio: 1.09; 95% CI: 1.03-1.15; p = 0.004) logistic regression analyses. Moreover, high Gal-3 levels at baseline were associated with a progressive decline in the estimated glomerular filtration rate. Conclusion: Gal-3 is a biomarker associated with the progression of renal function decline thus further supporting its possible usefulness in predicting cardiorenal syndrome progression.

The therapeutic impact of entresto on protecting against cardiorenal syndrome-associated renal damage in rats on high protein diet.

BACKGROUND: This study tested the hypothesis that Entresto could safely and effectively preserve heart and kidney function in rats with cardiorenal syndrome (CRS) induced by 5/6 nephrectomy and intra-peritoneal doxorubicin administration (accumulated dosage up to 7.5 mg/kg) together with daily high-protein-diet (HPD). METHODS AND RESULTS: Adult male Sprague-Dawley rats (n = 24) were equally categorized into Group 1 (sham-operated control + HPD), Group 2 (CRS + HPD) and Group 3 [CRS + HPD + Entresto (100 mg/kg/day orally) since Day 14 after CRS induction] and euthanized by Day 63 after CRS induction. By Day 63, circulatory BUN and creatinine levels and ratios of urine protein to creatinine were significantly higher in Group 2 than those in Groups 1 and 3, and significantly higher in Group 3 than in Group 1, whereas left-ventricular ejection fraction and kidney weight showed an opposite pattern among all groups (all p < 0.001). Microscopically, fibrosis area and intensity of oxidative stress (i.e., DCFDA stain) in kidney/heart tissues exhibited a pattern identical to that of creatinine level among all groups (all p < 0.0001). Kidney injury score and protein expressions of autophagy (i.e., beclin-1/Atg-5/protein ratio of LC3-BII/LC3-BI), fibrosis (Smad3/TGF-ß), apoptosis (mitochondrial-Bax/capase2/3/9), oxidative-stress (NOX-4/oxidized protein/xanthine-oxidase/catalase), membranous p47phox phosphorylation and mitochondrial-damage biomarker (cytosolic-cytochrome-C) were higher in Group 2 than those in Groups 1 and 3, and significantly higher in Group 3 than in Group 1, while protein expressions of anti-apoptosis (Bcl-2/Bcl-XL) and mitochondrial integrity (mitochondrial-cytochrome-C) markers displayed an opposite pattern among all groups in kidney tissues (all p < 0.0001). CONCLUSION: Oral administration of entresto was safe and could offer protection against CRS-induced heart and kidney damage.

Lipopolysaccharide in systemic circulation induces activation of inflammatory response and oxidative stress in cardiorenal syndrome type 1.

BACKGROUND: Cardiorenal syndrome type 1 (CRS type 1) is characterized by a rapid worsening of cardiac function leading to acute kidney injury. In this study, we evaluate the role of lipopolysaccharide (LPS) and various inflammatory markers in the developing acute kidney injury (AKI) in acute heart failure (AHF) patients. METHODS: We enrolled 31 AHF patients and 20 CRS type 1 (the cause of AKI was presumed to be related to cardiac dysfunction) and 17 healthy volunteers without AHF, AKI or CKD, as control group (CTR). We assessed levels of LPS, proinflammatory cytokines (TNF-α, IL-6, IL-18), and oxidative stress marker (myeloperoxidase, MPO). RESULTS: We observed a significant increase in LPS, TNF-α, IL-6, IL-18 and MPO levels in CRS type 1 and AHF group compared to CTR. LPS levels resulted significantly higher in CRS type 1 patients compared with AHF (118.2 pg/mL, IQR 77.8-217.6 versus 13.5 pg/mL, IQR 12.0-17.0, p = 0.008). We found a cytokines and oxidative stress dysregulation in CRS type 1 patients compared with AHF. Furthermore, we observed a strong positive significant correlation between LPS levels and IL-6 (Spearman's rho = 0.79, p < 0.001), and IL-18 (Spearman's rho = 0.77, p < 0.001) and MPO (Spearman's rho = 0.80, p < 0.001), all confirm by simple linear regression analysis. CONCLUSION: CRS type 1 patients presented an increased level of LPS, pro-inflammatory cytokines, and MPO. Furthermore, there is a direct correlation between LPS and pro-inflammatory cytokines and stress oxidative marker. LPS may play a role in the pathophysiology of CRS type 1 inducing inflammation, oxidative stress and finally kidney damage.