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Journal of the American Society of... Mar 2022Understanding nephron loss is a primary strategy for preventing CKD progression. Death of renal tubular cells may occur by apoptosis during developmental and... (Review)
Review
Understanding nephron loss is a primary strategy for preventing CKD progression. Death of renal tubular cells may occur by apoptosis during developmental and regenerative processes. However, during AKI, the transition of AKI to CKD, sepsis-associated AKI, and kidney transplantation ferroptosis and necroptosis, two pathways associated with the loss of plasma membrane integrity, kill renal cells. This necrotic type of cell death is associated with an inflammatory response, which is referred to as necroinflammation. Importantly, the necroinflammatory response to cells that die by necroptosis may be fundamentally different from the tissue response to ferroptosis. Although mechanisms of ferroptosis and necroptosis have recently been investigated in detail, the cell death propagation during tubular necrosis, although described morphologically, remains incompletely understood. Here, we argue that a molecular switch downstream of tubular necrosis determines nephron regeneration versus nephron loss. Unraveling the details of this "switch" must include the inflammatory response to tubular necrosis and regenerative signals potentially controlled by inflammatory cells, including the stimulation of myofibroblasts as the origin of fibrosis. Understanding in detail the molecular switch and the inflammatory responses to tubular necrosis can inform the discussion of therapeutic options.
Topics: Acute Kidney Injury; Apoptosis; Female; Humans; Kidney; Kidney Cortex Necrosis; Male; Necrosis; Nephrons; Renal Insufficiency, Chronic
PubMed: 35022311
DOI: 10.1681/ASN.2021101293 -
Nature Reviews. Nephrology May 2023Disorders of cell number that result from an imbalance between the death of parenchymal cells and the proliferation or recruitment of maladaptive cells contributes to... (Review)
Review
Disorders of cell number that result from an imbalance between the death of parenchymal cells and the proliferation or recruitment of maladaptive cells contributes to the pathogenesis of kidney disease. Acute kidney injury can result from an acute loss of kidney epithelial cells. In chronic kidney disease, loss of kidney epithelial cells leads to glomerulosclerosis and tubular atrophy, whereas interstitial inflammation and fibrosis result from an excess of leukocytes and myofibroblasts. Other conditions, such as acquired cystic disease and kidney cancer, are characterized by excess numbers of cyst wall and malignant cells, respectively. Cell death modalities act to clear unwanted cells, but disproportionate responses can contribute to the detrimental loss of kidney cells. Indeed, pathways of regulated cell death - including apoptosis and necrosis - have emerged as central events in the pathogenesis of various kidney diseases that may be amenable to therapeutic intervention. Modes of regulated necrosis, such as ferroptosis, necroptosis and pyroptosis may cause kidney injury directly or through the recruitment of immune cells and stimulation of inflammatory responses. Importantly, multiple layers of interconnections exist between different modalities of regulated cell death, including shared triggers, molecular components and protective mechanisms.
Topics: Humans; Apoptosis; Kidney; Necrosis; Acute Kidney Injury; Ferroptosis
PubMed: 36959481
DOI: 10.1038/s41581-023-00694-0 -
Journal of the American Heart... Apr 2019
Review
Topics: Cardiac Catheterization; Continuous Renal Replacement Therapy; Coronary Angiography; Diagnosis, Differential; Electrocardiography; Extracorporeal Membrane Oxygenation; Fluid Therapy; Heart Failure; Heart-Assist Devices; Hemodynamics; Humans; Intra-Aortic Balloon Pumping; Monitoring, Physiologic; Myocardial Infarction; Noninvasive Ventilation; Oxygen Inhalation Therapy; Percutaneous Coronary Intervention; Respiration, Artificial; Shock, Cardiogenic; Vasoconstrictor Agents
PubMed: 30947630
DOI: 10.1161/JAHA.119.011991 -
Vascular Health and Risk Management 2021The causes and mechanisms of increased cardiac troponin T and I (cTnT and cTnI) concentrations are numerous and are not limited to acute myocardial infarction (AMI)... (Review)
Review
The Main Causes and Mechanisms of Increase in Cardiac Troponin Concentrations Other Than Acute Myocardial Infarction (Part 1): Physical Exertion, Inflammatory Heart Disease, Pulmonary Embolism, Renal Failure, Sepsis.
The causes and mechanisms of increased cardiac troponin T and I (cTnT and cTnI) concentrations are numerous and are not limited to acute myocardial infarction (AMI) (ischemic necrosis of cardiac myocytes). Any type of reversible or irreversible cardiomyocyte injury can result in elevated serum cTnT and cTnI levels. Researchers and practitioners involved in the diagnosis and treatment of cardiovascular disease, including AMI, should know the key causes and mechanisms of elevated serum cTnT and cTnI levels. This will allow to reduce or completely avoid diagnostic errors and help to choose the most correct tactics for further patient management. The purpose of this article is to discuss the main causes and mechanisms of increase in cardiac troponins concentrations in frequently occurring physiological (physical exertion, psycho-emotional stress) and pathological conditions (inflammatory heart disease, pulmonary embolism, chronic renal failure and sepsis (systemic inflammatory response)) not related to myocardial infarction.
Topics: Acute Disease; Biomarkers; Humans; Myocardial Infarction; Physical Exertion; Pulmonary Embolism; Pulmonary Heart Disease; Renal Insufficiency; Sepsis; Troponin; Troponin I; Troponin T
PubMed: 34584417
DOI: 10.2147/VHRM.S327661 -
The New England Journal of Medicine Oct 2012In current international guidelines, intraaortic balloon counterpulsation is considered to be a class I treatment for cardiogenic shock complicating acute myocardial... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In current international guidelines, intraaortic balloon counterpulsation is considered to be a class I treatment for cardiogenic shock complicating acute myocardial infarction. However, evidence is based mainly on registry data, and there is a paucity of randomized clinical trials.
METHODS
In this randomized, prospective, open-label, multicenter trial, we randomly assigned 600 patients with cardiogenic shock complicating acute myocardial infarction to intraaortic balloon counterpulsation (IABP group, 301 patients) or no intraaortic balloon counterpulsation (control group, 299 patients). All patients were expected to undergo early revascularization (by means of percutaneous coronary intervention or bypass surgery) and to receive the best available medical therapy. The primary efficacy end point was 30-day all-cause mortality. Safety assessments included major bleeding, peripheral ischemic complications, sepsis, and stroke.
RESULTS
A total of 300 patients in the IABP group and 298 in the control group were included in the analysis of the primary end point. At 30 days, 119 patients in the IABP group (39.7%) and 123 patients in the control group (41.3%) had died (relative risk with IABP, 0.96; 95% confidence interval, 0.79 to 1.17; P=0.69). There were no significant differences in secondary end points or in process-of-care measures, including the time to hemodynamic stabilization, the length of stay in the intensive care unit, serum lactate levels, the dose and duration of catecholamine therapy, and renal function. The IABP group and the control group did not differ significantly with respect to the rates of major bleeding (3.3% and 4.4%, respectively; P=0.51), peripheral ischemic complications (4.3% and 3.4%, P=0.53), sepsis (15.7% and 20.5%, P=0.15), and stroke (0.7% and 1.7%, P=0.28).
CONCLUSIONS
The use of intraaortic balloon counterpulsation did not significantly reduce 30-day mortality in patients with cardiogenic shock complicating acute myocardial infarction for whom an early revascularization strategy was planned. (Funded by the German Research Foundation and others; IABP-SHOCK II ClinicalTrials.gov number, NCT00491036.).
Topics: Aged; Angioplasty, Balloon, Coronary; Coronary Artery Bypass; Female; Humans; Intention to Treat Analysis; Intra-Aortic Balloon Pumping; Male; Middle Aged; Myocardial Infarction; Practice Guidelines as Topic; Prospective Studies; Shock, Cardiogenic; Stents; Survival Rate; Treatment Failure
PubMed: 22920912
DOI: 10.1056/NEJMoa1208410 -
BMC Cardiovascular Disorders Feb 2017Most studies of outcomes after myocardial infarction (MI) focus on the acute phase after the index event. We assessed mortality and morbidity trends after the first year... (Review)
Review
BACKGROUND
Most studies of outcomes after myocardial infarction (MI) focus on the acute phase after the index event. We assessed mortality and morbidity trends after the first year in survivors of acute MI, by conducting a systematic literature review.
METHODS
Literature searches were conducted in Embase, MEDLINE, and the Cochrane Database of Systematic Reviews to identify epidemiological studies of long-term (>10 years) mortality and morbidity trends in individuals who had experienced an acute MI more than 1 year previously.
RESULTS
Thirteen articles met the inclusion criteria. Secular trends showed a consistent decrease in mortality and morbidity after acute MI from early to more recent study periods. The relative risk for all-cause death and cardiovascular outcomes (recurrent MI, cardiovascular death) was at least 30% higher than that in a general reference population at both 1-3 years and 3-5 years after MI. Risk factors leading to worse outcomes after MI included comorbid diabetes, hypertension and peripheral artery disease, older age, reduced renal function, and history of stroke.
CONCLUSIONS
There have been consistent improvements in secular trends for long-term survival and cardiovascular outcomes after MI. However, MI survivors remain at higher risk than the general population, particularly when additional risk factors such as diabetes, hypertension, or older age are present.
Topics: Age Factors; Aged; Aged, 80 and over; Cause of Death; Comorbidity; Female; Humans; Male; Middle Aged; Myocardial Infarction; Prognosis; Risk Assessment; Risk Factors; Survivors; Time Factors
PubMed: 28173750
DOI: 10.1186/s12872-017-0482-9 -
American Heart Journal Jan 2023The main objective of the Danish German Cardiogenic Shock trial (DanGer Shock ClinicalTrials.gov Identifier: NCT01633502) is to assess the efficacy of the trans valvular...
BACKGROUND
The main objective of the Danish German Cardiogenic Shock trial (DanGer Shock ClinicalTrials.gov Identifier: NCT01633502) is to assess the efficacy of the trans valvular axial flow device Impella CP in treating patients with AMICS shock due to STEMI undergoing emergency percutaneous coronary intervention.
METHODS
This statistical analysis plan represents an overview of the statistical methods which will be used for analyzing the DanGer Shock trial.
RESULTS
The primary study endpoint is death from all causes through 180 days in the intention to treat population (all randomized consented patients). The secondary endpoints comprise; composite event of the need for additional mechanical support, need for cardiac transplantation, and death of all causes whichever comes first; and days alive and out of hospital. As exploratory analyses an as treated analysis of primary endpoint will be performed. Composite safety endpoint will comprise of major bleeding, vascular complications, device malfunction, damage to the aortic valve, and significant hemolysis. The primary endpoint death rate at 180 days will be analyzed using Cox proportional hazards analysis. The result will be reported as hazard ratio and corresponding 95% confidence interval (95% CI). No imputation of missing values will be performed. Additional statistical analyses for predefined hemodynamic, metabolic, renal, hematological, and health economics substudies will be specified in separate protocols.
CONCLUSION
Main analyses of the primary and secondary outcomes of the DanGer Shock trial will be conducted according to this publication.
Topics: Humans; Shock, Cardiogenic; Heart-Assist Devices; Percutaneous Coronary Intervention; ST Elevation Myocardial Infarction; Hemodynamics; Treatment Outcome
PubMed: 36272450
DOI: 10.1016/j.ahj.2022.10.078 -
The New England Journal of Medicine Dec 2017In patients who have acute myocardial infarction with cardiogenic shock, early revascularization of the culprit artery by means of percutaneous coronary intervention... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
In patients who have acute myocardial infarction with cardiogenic shock, early revascularization of the culprit artery by means of percutaneous coronary intervention (PCI) improves outcomes. However, the majority of patients with cardiogenic shock have multivessel disease, and whether PCI should be performed immediately for stenoses in nonculprit arteries is controversial.
METHODS
In this multicenter trial, we randomly assigned 706 patients who had multivessel disease, acute myocardial infarction, and cardiogenic shock to one of two initial revascularization strategies: either PCI of the culprit lesion only, with the option of staged revascularization of nonculprit lesions, or immediate multivessel PCI. The primary end point was a composite of death or severe renal failure leading to renal-replacement therapy within 30 days after randomization. Safety end points included bleeding and stroke.
RESULTS
At 30 days, the composite primary end point of death or renal-replacement therapy had occurred in 158 of the 344 patients (45.9%) in the culprit-lesion-only PCI group and in 189 of the 341 patients (55.4%) in the multivessel PCI group (relative risk, 0.83; 95% confidence interval [CI], 0.71 to 0.96; P=0.01). The relative risk of death in the culprit-lesion-only PCI group as compared with the multivessel PCI group was 0.84 (95% CI, 0.72 to 0.98; P=0.03), and the relative risk of renal-replacement therapy was 0.71 (95% CI, 0.49 to 1.03; P=0.07). The time to hemodynamic stabilization, the risk of catecholamine therapy and the duration of such therapy, the levels of troponin T and creatine kinase, and the rates of bleeding and stroke did not differ significantly between the two groups.
CONCLUSIONS
Among patients who had multivessel coronary artery disease and acute myocardial infarction with cardiogenic shock, the 30-day risk of a composite of death or severe renal failure leading to renal-replacement therapy was lower among those who initially underwent PCI of the culprit lesion only than among those who underwent immediate multivessel PCI. (Funded by the European Union 7th Framework Program and others; CULPRIT-SHOCK ClinicalTrials.gov number, NCT01927549 .).
Topics: Aged; Coronary Artery Disease; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Renal Insufficiency; Renal Replacement Therapy; Risk; Shock, Cardiogenic; Time-to-Treatment
PubMed: 29083953
DOI: 10.1056/NEJMoa1710261 -
Cell Apr 2017The activation of mixed lineage kinase-like (MLKL) by receptor-interacting protein kinase-3 (RIPK3) results in plasma membrane (PM) disruption and a form of regulated...
The activation of mixed lineage kinase-like (MLKL) by receptor-interacting protein kinase-3 (RIPK3) results in plasma membrane (PM) disruption and a form of regulated necrosis, called necroptosis. Here, we show that, during necroptosis, MLKL-dependent calcium (Ca) influx and phosphatidylserine (PS) exposure on the outer leaflet of the plasma membrane preceded loss of PM integrity. Activation of MLKL results in the generation of broken, PM "bubbles" with exposed PS that are released from the surface of the otherwise intact cell. The ESCRT-III machinery is required for formation of these bubbles and acts to sustain survival of the cell when MLKL activation is limited or reversed. Under conditions of necroptotic cell death, ESCRT-III controls the duration of plasma membrane integrity. As a consequence of the action of ESCRT-III, cells undergoing necroptosis can express chemokines and other regulatory molecules and promote antigenic cross-priming of CD8 T cells.
Topics: Animals; Calcium; Cell Membrane; Cell Survival; Endosomal Sorting Complexes Required for Transport; HT29 Cells; Humans; Jurkat Cells; Mice; NIH 3T3 Cells; Necrosis; Phosphatidylserines; Protein Kinases; Signal Transduction
PubMed: 28388412
DOI: 10.1016/j.cell.2017.03.020 -
International Journal of Molecular... Jul 2019Apoptotic cell death is usually a response to the cell's microenvironment. In the kidney, apoptosis contributes to parenchymal cell loss in the course of acute and... (Review)
Review
Apoptotic cell death is usually a response to the cell's microenvironment. In the kidney, apoptosis contributes to parenchymal cell loss in the course of acute and chronic renal injury, but does not trigger an inflammatory response. What distinguishes necrosis from apoptosis is the rupture of the plasma membrane, so necrotic cell death is accompanied by the release of unprocessed intracellular content, including cellular organelles, which are highly immunogenic proteins. The relative contribution of apoptosis and necrosis to injury varies, depending on the severity of the insult. Regulated cell death may result from immunologically silent apoptosis or from immunogenic necrosis. Recent advances have enhanced the most revolutionary concept of regulated necrosis. Several modalities of regulated necrosis have been described, such as necroptosis, ferroptosis, pyroptosis, and mitochondrial permeability transition-dependent regulated necrosis. We review the different modalities of apoptosis, necrosis, and regulated necrosis in kidney injury, focusing particularly on evidence implicating cell death in ectopic renal calcification. We also review the evidence for the role of cell death in kidney injury, which may pave the way for new therapeutic opportunities.
Topics: Acute Kidney Injury; Animals; Apoptosis; Apoptosis Regulatory Proteins; Calcinosis; Epithelial Cells; Ferroptosis; Gene Expression Regulation; Humans; Immunogenic Cell Death; Kidney; Mitochondrial Transmembrane Permeability-Driven Necrosis; Necroptosis; Necrosis; Protective Agents; Pyroptosis; Reperfusion Injury
PubMed: 31340541
DOI: 10.3390/ijms20143598