Targeting ferroptosis protects against experimental (multi)organ dysfunction and death.

The most common cause of death in the intensive care unit (ICU) is the development of multiorgan dysfunction syndrome (MODS). Besides life-supporting treatments, no cure exists, and its mechanisms are still poorly understood. Catalytic iron is associated with ICU mortality and is known to cause free radical-mediated cellular toxicity. It is thought to induce excessive lipid peroxidation, the main characteristic of an iron-dependent type of cell death conceptualized as ferroptosis. Here we show that the severity of multiorgan dysfunction and the probability of death are indeed associated with plasma catalytic iron and lipid peroxidation. Transgenic approaches underscore the role of ferroptosis in iron-induced multiorgan dysfunction. Blocking lipid peroxidation with our highly soluble ferrostatin-analogue protects mice from injury and death in experimental non-septic multiorgan dysfunction, but not in sepsis-induced multiorgan dysfunction. The limitations of the experimental mice models to mimic the complexity of clinical MODS warrant further preclinical testing. In conclusion, our data suggest ferroptosis targeting as possible treatment option for a stratifiable subset of MODS patients.

Increased serum catalytic iron may mediate tissue injury and death in patients with COVID-19.

The pathophysiology and the factors determining disease severity in COVID-19 are not yet clear, with current data indicating a possible role of altered iron metabolism. Previous studies of iron parameters in COVID-19 are cross-sectional and have not studied catalytic iron, the biologically most active form of iron. The study was done to determine the role of catalytic iron in the adverse outcomes in COVID-19. We enrolled adult patients hospitalized with a clinical diagnosis of COVID-19 and measured serum iron, transferrin saturation, ferritin, hepcidin and serum catalytic iron daily. Primary outcome was a composite of in-hospital mortality, need for mechanical ventilation, and kidney replacement therapy. Associations between longitudinal iron parameter measurements and time-to-event outcomes were examined using a joint model. We enrolled 120 patients (70 males) with median age 50 years. The primary composite outcome was observed in 25 (20.8%) patients-mechanical ventilation was needed in 21 (17.5%) patients and in-hospital mortality occurred in 21 (17.5%) patients. Baseline levels of ferritin and hepcidin were significantly associated with the primary composite outcome. The joint model analysis showed that ferritin levels were significantly associated with primary composite outcome [HR (95% CI) = 2.63 (1.62, 4.24) after adjusting for age and gender]. Both ferritin and serum catalytic iron levels were positively associated with in-hospital mortality [HR (95% CI) = 3.22 (2.05, 5.07) and 1.73 (1.21, 2.47), respectively], after adjusting for age and gender. The study shows an association of ferritin and catalytic iron with adverse outcomes in COVID-19. This suggests new pathophysiologic pathways in this disease, also raising the possibility of considering iron chelation therapy.

Serum catalytic iron and progression of chronic kidney disease: findings from the ICKD study.

BACKGROUND: The non-transferrin bound catalytic iron moiety catalyses production of toxic reactive oxygen species and is associated with adverse outcomes. We hypothesized that serum catalytic iron (SCI) is associated with progression of chronic kidney disease (CKD). METHODS: Baseline samples of the Indian Chronic Kidney Disease participants with at least one follow up visit were tested for total iron, iron binding capacity, transferrin saturation, SCI, ferritin and hepcidin. SCI was measured using the bleomycin-detectable iron assay that detects biologically active iron. Association with the incidence of major kidney endpoints, (MAKE, a composite of kidney death, kidney failure or > 40% loss of eGFR) was examined using Cox proportional hazards model adjusted for sex and age. RESULTS: 2002 subjects (49.9 ± 11.6 years, 68.1% males, baseline eGFR 41.01 ml/min/1.73m2) were enrolled. After a median follow up of 12.6 (12.2, 16.7) months, the composite MAKE occurred in 280 (14%). After adjusting for age and sex, increase from 25th to 75th percentile in SCI, transferrin saturation, ferritin and hepcidin were associated with 78% (43-122%), 34% (10-62%), 57% (24-100%) and 74% (35-124%) increase in hazard of MAKE, respectively. SCI was associated with MAKE and kidney failure after adjustment for occupational exposure, hypertension, diabetes, tobacco, alcohol use, history of AKI, baseline eGFR, uACR, and allowing baseline hazard to vary by centre. CONCLUSIONS: SCI is strongly and independently associated with composite MAKE in patients with mild to moderate CKD. Confirmation in other studies will allow consideration of SCI as a risk marker and treatment target.

Iron, Hepcidin, and Death in Human AKI.

BACKGROUND: Iron is a key mediator of AKI in animal models, but data on circulating iron parameters in human AKI are limited. METHODS: We examined results from the ARF Trial Network study to assess the association of plasma catalytic iron, total iron, transferrin, ferritin, free hemoglobin, and hepcidin with 60-day mortality. Participants included critically ill patients with AKI requiring RRT who were enrolled in the study. RESULTS: Of the 807 study participants, 409 (51%) died by day 60. In both unadjusted and multivariable adjusted models, higher plasma concentrations of catalytic iron were associated with a significantly greater risk of death, as were lower concentrations of hepcidin. After adjusting for other factors, patients with catalytic iron levels in the highest quintile versus the lowest quintile had a 4.06-fold increased risk of death, and patients with hepcidin levels in the lowest quintile versus the highest quintile of hepcidin had a 3.87-fold increased risk of death. These findings were consistent across multiple subgroups. Other iron markers were also associated with death, but the magnitude of the association was greatest for catalytic iron and hepcidin. Higher plasma concentrations of catalytic iron and lower concentrations of hepcidin are each independently associated with mortality in critically ill patients with AKI requiring RRT. CONCLUSIONS: These findings suggest that plasma concentrations of catalytic iron and hepcidin may be useful prognostic markers in patients with AKI. Studies are needed to determine whether strategies to reduce catalytic iron or increase hepcidin might be beneficial in this patient population.

Does carbon dioxide pneumoperitoneum affect the renal function in donors following laparoscopic donor nephrectomy? A prospective study.

CONTEXT: Although the technical feasibility of laparoscopic donor nephrectomy (LDN) has been established, concerns have been raised about the impaired renal function resulting from pneumoperitoneum and its short- and long-term effects. AIMS: We used urinary biomarkers of acute kidney injury including urinary neutrophil gelatinase-associated lipocalin (uNGAL) and urinary N-acetyl-beta-D-glucosaminidase (uNAG) to study the injury caused to the donor's retained kidney by pneumoperitoneum. SETTINGS AND DESIGN: This was a prospective cohort study of thirty consecutive patients who underwent LDN at our hospital. SUBJECTS AND METHODS: We measured urinary creatinine, uNAG and uNGAL at the time of induction of anaesthesia, at 1 h after starting surgery, at 5 min after clamping the ureter, at the time of skin closure and then at 4, 8 and 24 h after the surgery. RESULTS: The uNAG level showed a gradual increase from the start of the surgery and reached the peak at the time of the closure. Thereafter, there was a gradual fall in the level and reached to pre-operative level at 24 h post-surgery. Similarly, the uNGAL also showed a similar trend although it did not reach pre-operative value by 24 h. CONCLUSIONS: We objectively confirm that although there is acute injury to the retained kidney in the donor after LDN due to the CO2pneumoperitoneum, the renal function improves and reaches close to the pre-operative level within 24 h after surgery.

Catalytic iron in acute myocardial infarction complicated by cardiogenic shock - A biomarker substudy of the IABP-SHOCK II-trial.

BACKGROUND: Catalytic iron (CI) is unbound ferric iron with the potential to generate reactive oxygen species with further deleterious vascular effects. In acute coronary syndromes, high levels of CI are linked to all-cause mortality. The prognostic impact of CI and iron metabolism in cardiogenic shock (CS) is currently undetermined. Aims of this study were to investigate the prognostic impact of CI and to identify predictors of high CI levels in patients with CS complicating acute myocardial infarction. METHODS: The Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial randomized 600 patients with CS to either therapy with intraaortic balloon pump or control. In 185 of these patients, blood samples were systematically collected at baseline and day 3. CI levels were measured using a modified bleomycin detectable iron assay. Furthermore, levels of free hemoglobin, total serum iron, transferrin, total iron binding capacity, ferritin, hepcidin, and transferrin saturation were assessed. RESULTS: Patients with baseline CI levels in the highest quartile had a worse outcome in comparison to patients with lower CI (day 1: HR 1.91 [1.11-3.31], p=0.005; day 3: HR 2.15 [1.06-4.34], p=0.01). In multivariable Cox-regression analysis baseline CI remained an independent predictor of 30-day mortality (HR per 10LOG 2.08 [1.25-3.47], p=0.005). Predictors of CI levels on day 3 were baseline CI, bleeding events, and baseline troponin T. CONCLUSIONS: CI levels were associated with increased short-term mortality in CS complicating acute myocardial infarction. High levels of CI at day 3 were associated with bleeding and high troponin levels.

Origin of nonlinearity and plausible turbulence by hydromagnetic transient growth in accretion disks: Faster growth rate than magnetorotational instability.

We investigate the evolution of hydromagnetic perturbations in a small section of accretion disks. It is known that molecular viscosity is negligible in accretion disks. Hence, it has been argued that a mechanism, known as magnetorotational instability (MRI), is responsible for transporting matter in the presence of a weak magnetic field. However, there are some shortcomings, which question the effectiveness of MRI. Now the question arises, whether other hydromagnetic effects, e.g., transient growth (TG), can play an important role in bringing nonlinearity into the system, even at weak magnetic fields. In addition, it should be determined whether MRI or TG is primarily responsible for revealing nonlinearity in order to make the flow turbulent. Our results prove explicitly that the flows with a high Reynolds number (Re), which is the case for realistic astrophysical accretion disks, exhibit nonlinearity via TG of perturbation modes faster than that by modes producing MRI. For a fixed wave vector, MRI dominates over transient effects only at low Re, lower than the value expected to be in astrophysical accretion disks, and low magnetic fields. This calls into serious question the (overall) persuasiveness of MRI in astrophysical accretion disks.

Increased plasma catalytic iron in patients may mediate acute kidney injury and death following cardiac surgery.

Catalytic iron, the chemical form of iron capable of participating in redox cycling, is a key mediator of acute kidney injury (AKI) in multiple animal models, but its role in human AKI has not been studied. Here we tested in a prospective cohort of 250 patients undergoing cardiac surgery whether plasma catalytic iron levels are elevated and associated with the composite outcome of AKI requiring renal replacement therapy or in-hospital mortality. Plasma catalytic iron, free hemoglobin, and other iron parameters were measured preoperatively, at the end of cardiopulmonary bypass, and on postoperative days 1 and 3. Plasma catalytic iron levels, but not other iron parameters, rose significantly at the end of cardiopulmonary bypass and were directly associated with bypass time and number of packed red blood cell transfusions. In multivariate analyses adjusting for age and preoperative eGFR, patients in the highest compared with the lowest quartile of catalytic iron on postoperative day 1 had a 6.71 greater odds of experiencing the primary outcome, and also had greater odds of AKI, hospital mortality, and postoperative myocardial injury. Thus, our data are consistent with and expand on findings from animal models demonstrating a pathologic role of catalytic iron in mediating adverse postoperative outcomes. Interventions aimed at reducing plasma catalytic iron levels as a strategy for preventing AKI in humans are warranted.

Plasma catalytic iron, AKI, and death among critically ill patients.

BACKGROUND AND OBJECTIVES: Catalytic iron has been hypothesized to be a key mediator of AKI. However, the association between plasma catalytic iron levels and AKI has not been well studied in humans. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS: A single-center, prospective, nonconsecutive cohort study of 121 critically ill patients admitted to intensive care units (ICUs) between 2008 and 2012 was performed. Plasma catalytic iron, free hemoglobin, and other iron markers were measured on ICU days 1 and 4. The primary end point was in-hospital mortality or AKI requiring RRT. Secondary end points included mortality (assessed during hospitalization, at 30 days, and 1 year) and incident AKI, defined by modified Kidney Disease Improving Global Outcomes criteria. RESULTS: ICU day 1 plasma catalytic iron levels were higher among patients who reached the primary end point (median, 0.74 µmol/l [interquartile range, 0.31-3.65] versus 0.29 µmol/l [0.22-0.46]; P<0.01). ICU day 1 plasma catalytic iron levels were associated with number of packed red blood cell transfusions before ICU arrival (rs=0.29; P<0.001) and plasma free hemoglobin levels on ICU day 1 (rs=0.32; P<0.001). Plasma catalytic iron levels on ICU day 1 were significantly associated with in-hospital mortality or AKI requiring RRT, even after adjusting for age, enrollment eGFR, and number of packed red blood cell transfusions before ICU arrival (13 events; adjusted odds ratio per 1-SD higher ln[catalytic iron], 3.33; 95% confidence interval, 1.79 to 6.20). ICU day 1 plasma catalytic iron levels were also significantly associated with incident AKI, RRT, hospital mortality, and 30-day mortality. CONCLUSIONS: Among critically ill patients, elevated plasma catalytic iron levels on arrival to the ICU are associated with a greater risk of incident AKI, RRT, and hospital mortality.

Magnetohydrodynamic stability of stochastically driven accretion flows.

We investigate the evolution of magnetohydrodynamic (or hydromagnetic as coined by Chandrasekhar) perturbations in the presence of stochastic noise in rotating shear flows. The particular emphasis is the flows whose angular velocity decreases but specific angular momentum increases with increasing radial coordinate. Such flows, however, are Rayleigh stable but must be turbulent in order to explain astrophysical observed data and, hence, reveal a mismatch between the linear theory and observations and experiments. The mismatch seems to have been resolved, at least in certain regimes, in the presence of a weak magnetic field, revealing magnetorotational instability. The present work explores the effects of stochastic noise on such magnetohydrodynamic flows, in order to resolve the above mismatch generically for the hot flows. We essentially concentrate on a small section of such a flow which is nothing but a plane shear flow supplemented by the Coriolis effect, mimicking a small section of an astrophysical accretion disk around a compact object. It is found that such stochastically driven flows exhibit large temporal and spatial autocorrelations and cross-correlations of perturbation and, hence, large energy dissipations of perturbation, which generate instability. Interestingly, autocorrelations and cross-correlations appear independent of background angular velocity profiles, which are Rayleigh stable, indicating their universality. This work initiates our attempt to understand the evolution of three-dimensional hydromagnetic perturbations in rotating shear flows in the presence of stochastic noise.

Establishing a relation between the mass and the spin of stellar-mass black holes.

Stellar mass black holes (SMBHs), forming by the core collapse of very massive, rapidly rotating stars, are expected to exhibit a high density accretion disk around them developed from the spinning mantle of the collapsing star. A wide class of such disks, due to their high density and temperature, are effective emitters of neutrinos and hence called neutrino cooled disks. Tracking the physics relating the observed (neutrino) luminosity to the mass, spin of black holes (BHs) and the accretion rate (M) of such disks, here we establish a correlation between the spin and mass of SMBHs at their formation stage. Our work shows that spinning BHs are more massive than nonspinning BHs for a given M. However, slowly spinning BHs can turn out to be more massive than spinning BHs if M at their formation stage was higher compared to faster spinning BHs.

Impact of catalytic iron on mortality in patients with acute coronary syndrome exposed to iodinated radiocontrast-The Iscom Study.

BACKGROUND: Catalytic iron (CI) mediates vascular injury by generating reactive oxygen species. We evaluated role of CI in predicting mortality in patients with acute coronary syndrome (ACS) and studied association of contrast nephropathy with CI levels. METHODS: We investigated 806 patients with ACS undergoing contrast exposure for a cardiac procedure who were followed up for 30 days. RESULTS: Overall mortality was 1.6% at 30 days. Catalytic iron at baseline predicted mortality with CI levels significantly higher in those who died, 0.45 µmol/L (0.37, 0.68) compared with survivors 0.31 µmol/L (0.21, 0.40); P = .004. Catalytic iron was associated with increased risk of death in the highest quartile compared with lower 3 quartiles (hazard ratio 7.88, P = .001) after adjustment for age, diabetes, ST deviation, Killip class, ejection fraction, baseline creatinine, hemoglobin level, and troponin. Fifty-five patients (6.8%) developed contrast nephropathy. Patients with contrast nephropathy had a 27% increase in median CI levels from baseline up to 48 hours compared with a marginal 2.9% increase in those without contrast nephropathy (0.37, 0.14 µmol/L to 0.47, 0.20 µmol/L versus 0.35, 0.12 µmol/L to 0.36, 0.14 µmol/L, P < .0001). Patients with contrast nephropathy had significantly higher mortality compared with those without contrast nephropathy (9.1% vs 1.1%, P = .001). CONCLUSION: High baseline CI levels predicted mortality in patients with ACS. Occurrence of contrast nephropathy was associated with rise in CI levels and higher mortality. Therapeutic options to buffer or chelate CI may have beneficial effects on mortality in this setting.

Prognostic evaluation of catalytic iron in patients with acute coronary syndromes.

BACKGROUND: The potential of iron to generate reactive oxygen species has motivated a long-standing interest in whether excess iron is causally linked to atherosclerotic heart disease. Circulating catalytic iron ("free" iron) is that which is not bound to transferrin or ferritin and is available to generate reactive oxygen species that may have deleterious vascular effects. HYPOTHESIS: We hypothesized that increased levels of catalytic iron would be associated with increased cardiovascular events. METHODS: We investigated the association of catalytic iron with clinical outcomes in 1701 patients with unstable angina, non-ST-segment elevation myocardial infarction (MI), or ST-segment elevation MI who were followed for a median of 10 months. All endpoints were adjudicated by a blinded Clinical End Points Committee. RESULTS: The median catalytic iron level was significantly higher in those who died, 0.45 µmol/L (0.37, 0.57), compared with survivors, 0.37µmol/L (0.31, 0.46; P = 0.016). Catalytic iron was associated with a stepwise increased risk of death, with the highest quartile at an almost 4-fold risk compared with baseline (hazard ratio: 3.94, P = 0.035), which persisted after adjustment for age, diabetes, prior MI, prior congestive heart failure, ST-segment deviation, creatinine clearance, B-type natriuretic peptide, smoking, and Killip class (adjusted hazard ratio: 3.97, P = 0.036). There was no association between catalytic iron and risk of MI, recurrent ischemia, heart failure, or bleeding. CONCLUSIONS: Increasing catalytic iron levels were associated with increased all-cause mortality. Although our findings suggest that catalytic iron is not likely to add to available tools as a routine biomarker for risk stratification of recurrent ischemic events, its association with mortality is intriguing and leaves open the question of whether cardiovascular therapeutics aimed at catalytic iron may be useful. The TIMI Study Group has received research grant support from the Muljibhai Patel Society for Research in Nephro-Urology.

New mass limit for white dwarfs: super-Chandrasekhar type ia supernova as a new standard candle.

Type Ia supernovae, sparked off by exploding white dwarfs of mass close to the Chandrasekhar limit, play the key role in understanding the expansion rate of the Universe. However, recent observations of several peculiar type Ia supernovae argue for its progenitor mass to be significantly super-Chandrasekhar. We show that strongly magnetized white dwarfs not only can violate the Chandrasekhar mass limit significantly, but exhibit a different mass limit. We establish from a foundational level that the generic mass limit of white dwarfs is 2.58 solar mass. This explains the origin of overluminous peculiar type Ia supernovae. Our finding further argues for a possible second standard candle, which has many far reaching implications, including a possible reconsideration of the expansion history of the Universe.

Association of catalytic iron with cardiovascular disease.

The ability of iron to cycle reversibly between its ferrous and ferric oxidation states is essential for the biological functions of iron but may contribute to vascular injury through the generation of powerful oxidant species. We examined the association between chemical forms of iron that can participate in redox cycling, often referred to as "catalytic" or "labile" iron, and cardiovascular disease (CVD). In our cross-sectional study of 496 participants, 85 had CVD. Serum catalytic iron was measured using the bleomycin-detectable iron assay that detects biologically active iron. The odds of existing CVD for subjects in the upper third of catalytic iron were 10 times that of subjects with lower catalytic iron in unadjusted analyses. The association was decreased by 1/2 by age adjustment, but little additional attenuation occurred after adjusting for age, Framingham Risk Score, estimated glomerular filtration rate, hypertension status, high-density lipoprotein cholesterol, and systolic blood pressure, with the association remaining strong and significant (odds ratio 3.8, 95% confidence interval 1.4 to 10.1). In conclusion, we provide preliminary evidence for a strong detrimental association between high serum catalytic iron and CVD even after adjusting for several co-morbid conditions; however, broader prospective studies are needed to confirm these findings, which would support therapeutic trials to assess the beneficial effects of iron chelators on CVD.

On a population pathogen model incorporating species dispersal with temporal variation in dispersal rate.

In the present paper, we consider a mathematical model of ecosystem population interaction where the population suffers from a susceptible-infectious-susceptible disease. Dispersal of both the susceptible and the infective is incorporated using reaction-diffusion equations. We first study the stability criteria of the basic (non-spatial) model around the disease-free and the infected steady states. We find that the loss rate of the infective species controls disease prevalence. Also without predation pressure, the disease will continue to exist among the population. Then we analyze the spatial model with species dispersal in constant as well as in time-varying form. It is observed that though constant dispersal is unable to generate diffusion-driven instability, dispersal with sinusoidal variation in dispersion rate can generate diffusive instability when the wave number of the perturbation lies within a given range. Numerical simulations are performed to illustrate analytical studies.

Urinary catalytic iron in obesity.

INTRODUCTION: Obesity precedes the development of many cardiovascular disease risk factors, including type 2 diabetes mellitus (DM), hypertension, and chronic kidney disease. Catalytic iron, which has been associated with these chronic diseases, may be one of the links between obesity and these multifactorial diverse disorders. OBJECTIVE: We investigated whether urinary catalytic iron is increased in obese individuals without DM and overt kidney disease. STUDY DESIGN: We measured urinary catalytic iron using established methods in 200 randomly selected individuals without DM [100 who were obese (body mass index ≥30 kg/m(2)) and 100 who were nonobese (body mass index ≤27)]. Participants were selected from an outpatient clinic and community setting and were part of an ongoing cross-sectional study of obesity in individuals between the ages of 18 and 70 years. RESULTS: There was a significant difference in mean (95% CI) urinary catalytic iron excretion between the obese participants and the nonobese participants, 463 (343-582) nmol/mg [52.3 (38.8-65.8) nmol/µmol] vs 197 (141-253) nmol/mg [22.3 (15.9-28.6) nmol/µmol]; P < 0.001. The significant predictors of increased urinary catalytic iron were obesity (P = 0.001) and waist-to-hip ratio (P = 0.03). CONCLUSIONS: Our study results demonstrate that obesity and waist-to-hip ratio are associated with increased urinary catalytic iron, which may be a useful marker of oxidative stress. Additional studies are needed to determine the role of catalytic iron in increased cardiovascular disease and chronic kidney disease associated with obesity.

Enzymuria pattern in early post renal transplant period: Diagnostic usefulness in graft dysfunction.

Serum creatinine does not distinguish between various causes of graft dysfunction. Serial assay of proximal tubular enzymes N-Acetyl-D-glucosaminidase (NAG), Alanine aminopeptidase (AAP) and Gamma glutamyl transferase (GGT) in urine was done to assess their usefulness in distinguishing various causes of graft dysfunction. Daily serum creatinine and enzymuria were measured in 32 consecutive renal allograft recipients for first 15 postoperative days. Graft dysfunction was defined as >20% increase in serum creatinine and >100% increase in enzymuria over the baseline. The diagnosis of graft dysfunction was based upon clinical criteria, ultrasonography, cyclosporin trough level, allograft biopsy, response to anti-rejection therapy and alteration of cyclosporin dosage. Fifteen episodes of graft dysfunction were identified in 15 patients. The sensitivity and specificity of the enzymes (NAG, AAP and GGT) for predicting graft dysfunction were 87.5%, 86.9%, 88.5% and 98.2%, 98.2%, 97.9% respectively. There was a significant increase in enzymuria during acute tubular necrosis (ATN) and acute rejection episode compared to cyclosporin nephrotoxicity (p<0.01). Enzymuria assay provides a simple, reliable and noninvasive method to distinguish cyclosporin nephrotoxicity from acute tubular necrosis and acute rejection in renal allograft recipients.