Determinants of Monocyte Apoptosis 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 (AKI). Its pathophysiology is complex and not completely understood. In this study, we examined the role of apoptosis and the caspase pathways involved. Material and Methods: We enrolled 40 acute heart failure (AHF) patients, 11 of whom developed AKI characterizing CRS type 1. We exposed the human cell line U937 to plasma from the CRS type 1 and AHF groups and then we evaluated apoptotic activity by annexin-V evaluation, determination of caspase-3, -8 and -9 levels, and BAX, BAD, and FAS gene expression. Results: We observed significant upregulation of apoptosis in monocytes exposed to CRS type 1 plasma compared to AHF, with increased levels of caspase-3 (p < 0.01), caspase-9 (p < 0.01), and caspase-8 (p < 0.03) showing activation of both intrinsic and extrinsic pathways. Furthermore, monocytes exposed to CRS type 1 plasma had increased gene expression of BAX and BAD (intrinsic pathways) (p = 0.010 for both). Furthermore, strong significant correlations between the caspase-9 levels and BAD and BAX gene expression were observed (Spearman ρ = – 0.76, p = 0.011, and ρ = – 0.72, p = 0.011). Conclusion: CRS type 1 induces dual apoptotic pathway activation in monocytes; the two pathways converged on caspase-3. Many factors may induce activation of both intrinsic and extrinsic apoptotic pathways in CRS type 1 patients, such as upregulation of proinflammatory cytokines and hypoxia/ischemia. Further investigations are necessary to corroborate the present findings, and to better understand the pathophysiological mechanism and consequent therapeutic and prognostic implications for CRS type 1.

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Cardiorenal Syndrome Type 1: Activation of Dual Apoptotic Pathways

Cardiorenal Medicine ◽

10.1159/000438831 ◽

2015 ◽

Vol 5 (4) ◽

pp. 306-315 ◽

Cited By ~ 8

Author(s):

Silvia Pastori ◽

Grazia Maria Virzì ◽

Alessandra Brocca ◽

Massimo de Cal ◽

Vincenzo Cantaluppi ◽

...

Keyword(s):

Caspase 3 ◽

Kidney Injury ◽

Cardiorenal Syndrome ◽

Tubular Epithelial Cell ◽

P Value ◽

Caspase 8 ◽

Syndrome Type ◽

Monocyte Apoptosis ◽

Induced Apoptosis

Cardiorenal syndrome type 1 (CRS1) pathophysiology is complex, and immune-mediated damage, including alterations in the immune response with monocyte apoptosis and cytokine release, has been reported as a potential mechanism. In this study, we examined the putative role of renal tubular epithelial cell (RTC) apoptosis as a pathogenic mechanism in CRS1. In particular, we investigated the caspase pathways involved in induced apoptosis. We enrolled 29 patients with acute heart failure (AHF), 11 patients with CRS1, and 15 controls (CTR) without AHF or acute kidney injury (AKI). Patients who had AKI prior to the episode of AHF or who had any other potential causes of AKI were excluded. Plasma from different groups was incubated with RTCs for 24 h. Subsequently, cell apoptosis, DNA fragmentation, and caspase-3, -8, and -9 activities were investigated in RTCs incubated with AHF, CRS1, and CTR plasma. A p value <0.5 was considered statistically significant. A quantitative analysis of apoptosis showed significantly higher apoptosis rates in CRS1 patients compared to AHF patients and CTR (p < 0.01). This increase in apoptosis was strongly confirmed by caspase-3 levels (ρ = 0.73). Caspase-8 and -9 were significantly higher in CRS1 patients compared to AHF patients and CTR (p < 0.01). Furthermore, caspase-3 levels showed a significantly positive correlation with caspase-8 (ρ = 0.57) and -9 (ρ = 0.47; p < 0.001). This study demonstrated the significantly heightened presence of dual apoptotic disequilibrium in CRS1. Our findings indicated that apoptosis may have a central role in the mechanism of CRS1, and it could be a potential therapeutic target in this syndrome.

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The Role of Cell-Free Plasma DNA in Patients with Cardiorenal Syndrome Type 1

Cardiorenal Medicine ◽

10.1159/000518553 ◽

2021 ◽

pp. 1-8

Author(s):

Grazia Maria Virzì ◽

Anna Clementi ◽

Sabrina Milan Manani ◽

Chiara Castellani ◽

Giovanni Giorgio Battaglia ◽

...

Keyword(s):

Caspase 3 ◽

Kidney Injury ◽

Cardiorenal Syndrome ◽

Syndrome Type ◽

Plasma Dna ◽

Apoptosis And Inflammation ◽

Factor Α ◽

Clinical Conditions

Background: Recent research highlighted the potential role of circulating cell-free DNA (cfDNA), resulted by apoptosis or cell necrosis, as a prognostic marker in the setting of different clinical conditions. Cardiorenal syndrome type 1 (CRS type 1) is characterized by a rapid worsening of cardiac function leading to acute kidney injury (AKI). Apoptosis of renal epithelial cells is proposed as a mechanism involved in CRS type 1. In this study, we investigated cfDNA levels in patients with acute heart failure (AHF) and CRS type 1 and the possible correlation between cfDNA levels and inflammatory and apoptotic parameters. Methods: We enrolled 17 AHF patients and 15 CRS type 1 who exhibited AKI at the time of admission (caused by AHF) or developed AKI during the first 48 h from admission. cfDNA was extracted from plasma and quantified by real-time polymerase chain reaction. Plasma levels of NGAL, tumor necrosis factor-α, interleukin (IL)-6, IL-18, and caspase-3 were measured. Results: We observed significantly higher levels of cfDNA in patients with CRS type 1 than patients with AHF. Caspase-3, IL-6, IL-18, and NGAL levels resulted significantly increased in patients with CRS type 1. Moreover, a positive correlation between cfDNA levels and caspase-3 levels was found, as well as between cfDNA levels and IL-6 and renal parameters. Conclusion: Our study explores the premise of cfDNA as a marker for apoptosis and inflammation in CRS type 1 patients. cfDNA could potentially serve as an index for noninvasive monitoring of tissue damage and apoptosis in patients with AKI induced by AHF.

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Acute kidney injury in cardiorenal syndrome type 1: a meta-analysis

Critical Care ◽

10.1186/cc13554 ◽

2014 ◽

Vol 18 (Suppl 1) ◽

pp. P364

Author(s):

W Vandenberghe ◽

S Gevaert ◽

H Peperstraete ◽

I Herck ◽

J Decruyenaere ◽

...

Keyword(s):

Acute Kidney Injury ◽

Meta Analysis ◽

Kidney Injury ◽

Cardiorenal Syndrome ◽

Syndrome Type

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Oxidative Stress: Dual Pathway Induction in Cardiorenal Syndrome Type 1 Pathogenesis

Oxidative Medicine and Cellular Longevity ◽

10.1155/2015/391790 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 29

Author(s):

Grazia Maria Virzì ◽

Anna Clementi ◽

Massimo de Cal ◽

Alessandra Brocca ◽

Sonya Day ◽

...

Keyword(s):

Oxidative Stress ◽

Kidney Injury ◽

Cardiorenal Syndrome ◽

Syndrome Type ◽

Copper Zinc Superoxide Dismutase ◽

Stress Markers ◽

Oxidative Stress Pathway ◽

Significant Augmentation ◽

Copper Zinc

Cardiorenal Syndrome Type 1 (Type 1) is a specific condition which is characterized by a rapid worsening of cardiac function leading to acute kidney injury (AKI). Even though its pathophysiology is complex and not still completely understood, oxidative stress seems to play a pivotal role. In this study, we examined the putative role of oxidative stress in the pathogenesis of CRS Type 1. Twenty-three patients with acute heart failure (AHF) were included in the study. Subsequently, 11 patients who developed AKI due to AHF were classified as CRS Type 1. Quantitative determinations for IL-6, myeloperoxidase (MPO), nitric oxide (NO), copper/zinc superoxide dismutase (Cu/ZnSOD), and endogenous peroxidase activity (EPA) were performed. CRS Type 1 patients displayed significant augmentation in circulating ROS and RNS, as well as expression of IL-6. Quantitative analysis of all oxidative stress markers showed significantly lower oxidative stress levels in controls and AHF compared to CRS Type 1 patients (P<0.05). This pilot study demonstrates the significantly heightened presence of dual oxidative stress pathway induction in CRS Type 1 compared to AHF patients. Our findings indicate that oxidative stress is a potential therapeutic target, as it promotes inflammation by ROS/RNS-linked pathogenesis.

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CARDIORENAL SYNDROME IN PATIENTS WITH CHRONIC HEART FAILURE AS A STAGE OF THE CARDIORENAL CONTINUUM (PART I): DEFINITION, CLASSIFICATION, PATHOGENESIS, DIAGNOSIS, EPIDEMIOLOGY

The Russian Archives of Internal Medicine ◽

10.20514/2226-6704-2019-9-1-5-22 ◽

2019 ◽

Vol 9 (1) ◽

pp. 5-22 ◽

Cited By ~ 5

Author(s):

E. V. Reznik ◽

I. G. Nikitin

Keyword(s):

Heart Failure ◽

Acute Kidney Injury ◽

Chronic Heart Failure ◽

Impaired Renal Function ◽

Prognostic Value ◽

Kidney Injury ◽

Cardiorenal Syndrome ◽

Syndrome Type ◽

Patients With Heart Failure

The combination of heart failure and renal failure is called cardiorenal syndrome. It is a stage of the cardiorenal continuum and, possibly, a small link of the cardiorenal-cerebral-metabolic axis. Despite the fact that the phrase “cardiorenal syndrome” and its five types have become a part of the medical lexicon, many aspects of this problem are still not clear. Cardiorenal syndrome can be diagnosed in 32-90.3% of patients with heart failure. Cardiorenal syndrome type 1 or 2 develops in most cases of heart failure: cardiorenal syndrome presents with the development ofchronic kidney disease in patients with chronic heart failure and acute kidney injury in patients with acute heart failure. Impaired renal function has an unfavorable prognostic value. It leads to an increase in the mortality of patients with heart failure. It is necessary to timely diagnose the presence of cardiorenal syndrome and take into account its presence when managing patients with heart failure. Further researches are needed on ways toprevent the development and prevent the progression of kidney damage in patients with heart failure, to which the efforts of the multidisciplinary team should be directed. The first part of this review examines the currently definition, classification, pathogenesis, epidemiology and prognosis of cardiorenal syndrome in patients with heart failure.

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Plasma Lipopolysaccharide Concentrations in Cardiorenal Syndrome Type 1

Cardiorenal Medicine ◽

10.1159/000500480 ◽

2019 ◽

Vol 9 (5) ◽

pp. 308-315

Author(s):

Grazia Maria Virzì ◽

Andrea Breglia ◽

Ghada Ankawi ◽

Chiara Bolin ◽

Massimo de Cal ◽

...

Keyword(s):

Kidney Injury ◽

Cardiorenal Syndrome ◽

Syndrome Type ◽

Neutrophil Gelatinase Associated Lipocalin ◽

Significant Difference ◽

Renal Markers ◽

Neutrophil Gelatinase ◽

Time Of Admission

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.

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Cardiorenal Syndrome Type 1: A Defective Regulation of Monocyte Apoptosis Induced by Proinflammatory and Proapoptotic Factors

Cardiorenal Medicine ◽

10.1159/000371898 ◽

2015 ◽

Vol 5 (2) ◽

pp. 105-115 ◽

Cited By ~ 10

Author(s):

Silvia Pastori ◽

Grazia Maria Virzì ◽

Alessandra Brocca ◽

Massimo de Cal ◽

Anna Clementi ◽

...

Keyword(s):

Caspase 3 ◽

Cardiorenal Syndrome ◽

Syndrome Type ◽

Caspase Activity ◽

Similar Concentration ◽

Immune Mediated ◽

Tnf Α ◽

Monocyte Apoptosis ◽

Cytokine Quantification

In this study, we examined the possible immune-mediated mechanisms in cardiorenal syndrome (CRS) type 1 pathogenesis. We enrolled 40 patients with acute heart failure (AHF), 11 patients with CRS type 1 and 15 controls. Plasma from the different groups was incubated with monocytes; subsequently, cell apoptosis was evaluated by DNA fragmentation, caspase activity and cytofluorometric assay. Cytokine quantification in plasma and supernatant was performed by ELISA. Monocytes treated with CRS type 1 plasma showed significantly higher apoptosis compared with those treated with AHF and the controls (p < 0.05). Caspase-3 (CRS type 1: 2.20 ng/ml, IQR 2.06-2.33; AHF: 1.48 ng/ml, IQR 1.31-1.56; controls: 0.71 ng/ml, IQR 0.67-0.81) and caspase-8 levels (CRS type 1: 1.49 ng/ml, IQR 1.42-1.57; AHF: 0.94 ng/ml, IQR 0.84-0.98; controls: 0.56 ng/ml, IQR 0.51-0.58) in cells incubated with plasma from these patients demonstrated a significantly higher concentration. We observed a strong upregulation of plasma IL-6 and IL-18 in CRS type 1 compared with AHF and the controls (p < 0.05). Interestingly, we observed a similar concentration of TNF-α in CRS type 1 and AHF. In CRS type 1 patients, IL-6 (52.13 ng/ml, IQR 47.29-66.83) and IL-18 levels (197.75 ng/ml, IQR 120.80-265.49) in supernatant were significantly higher than in AHF patients (IL-6: 28.79 ng/ml, IQR 19.90-36.10; IL-18: 21.98 ng/ml, IQR 15.98-29.85) and controls (IL-6: 5.02 ng/ml, IQR 4.56-6.44; IL-18: 7.91 ng/ml, IQR 5.57-10.62). These findings suggest the presence of a defective regulation of monocyte apoptosis in CRS type 1 patients and the involvement of an immune-mediated mechanism in the pathophysiology of this syndrome.

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Determination of renal function and injury using near-infrared fluorimetry in experimental cardiorenal syndrome

AJP Renal Physiology ◽

10.1152/ajprenal.00573.2016 ◽

2017 ◽

Vol 312 (4) ◽

pp. F629-F639 ◽

Cited By ~ 11

Author(s):

Mizuko Ikeda ◽

Rumie Wakasaki ◽

Katie J. Schenning ◽

Thomas Swide ◽

Jeong Heon Lee ◽

...

Keyword(s):

Acute Kidney Injury ◽

Renal Function ◽

Cardiac Arrest ◽

Cardiopulmonary Resuscitation ◽

Filtration Rate ◽

Near Infrared ◽

Kidney Injury ◽

Cardiorenal Syndrome ◽

Syndrome Type

Cardiorenal syndrome type 1 causes acute kidney injury but is poorly understood; animal models and diagnostic aids are lacking. Robust noninvasive measurements of glomerular filtration rate are required for injury models and clinical use. Several have been described but are untested in translational models and suffer from biologic interference. We developed a mouse model of cardiorenal syndrome and tested the novel near-infrared fluorophore ZW800-1 to assess renal and cardiac function. We performed murine cardiac arrest and cardiopulmonary resuscitation followed by transthoracic echocardiography, 2 and 24 h later. Transcutaneous fluorescence of ZW800-1 bolus dispersion and clearance was assessed with whole animal imaging and compared with glomerular filtration rate (GFR; inulin clearance), tubular cell death (using unbiased stereology), and serum creatinine. Correlation, Bland-Altman, and polar analyses were used to compare GFR with ZW800-1 clearance. Cardiac arrest and cardiopulmonary resuscitation caused reversible cardiac failure, halving fractional shortening of the left ventricle ( n = 12, P = 0.03). Acute kidney injury resulted with near-zero GFR and sixfold increase in serum creatinine 24 h later ( n = 16, P < 0.01). ZW800-1 biodistribution and clearance were exclusively renal. ZW800-1 t1/2 and clearance correlated with GFR ( r = 0.92, n = 31, P < 0.0001). ZW800-1 fluorescence was reduced in cardiac arrest, and cardiopulmonary resuscitation-treated mice compared with sham animals 810 s after injection ( P < 0.01) and bolus time-dispersion curves demonstrated that ZW800-1 fluorescence dispersion correlated with left ventricular function ( r = 0.74, P < 0.01). Cardiac arrest and cardiopulmonary resuscitation lead to experimental cardiorenal syndrome type 1. ZW800-1, a small near-infrared fluorophore being developed for clinical intraoperative imaging, is favorable for evaluating cardiac and renal function noninvasively.

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Acute Cardiorenal Syndrome: Models and Heart-Kidney Connectors

Nephron ◽

10.1159/000509353 ◽

2020 ◽

Vol 144 (12) ◽

pp. 629-633 ◽

Cited By ~ 1

Author(s):

Yoshio Funahashi ◽

Sheuli Chowdhury ◽

Mahaba B. Eiwaz ◽

Michael P. Hutchens

Keyword(s):

Heart Failure ◽

Cell Culture ◽

Acute Kidney Injury ◽

Renal Function ◽

Kidney Injury ◽

Cardiorenal Syndrome ◽

Syndrome Type ◽

Culture Models ◽

Cell Culture Models

Cardiorenal syndrome type 1 (CRS-1) is an acute kidney injury (AKI) due to acute worsening of cardiac function. More than 20% of patients with acute heart failure develop AKI, and AKI predicts poor outcome. Although a number of potential pathways have been suggested as heart-kidney connectors which might drive the syndrome, there are significant barriers to investigation, such as a paucity of animal models, a lack of specific biomarkers, and an inconsistent temporal and causal relationship between changes in cardiac flow and development of renal dysfunction. Thus, mechanisms of heart-kidney interaction are still unclear, and there is no specific or effective therapy for CRS-1. This review, therefore, focuses on mitigating these challenges in the investigation of CRS-1. We review the available models and focus on mechanistic insights gained from those models. In particular, we focus on non-flow and endocrine mediators of CRS-1 such as heart-derived messengers which alter renal function and which may represent targetable pathways in this syndrome. As precise connectors of heart-kidney interaction remain unclear, the establishment of animal and relevant cell-culture models and further investigation are required.

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