Banibrata Mukhopadhyay

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.

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.

Prognostic Evaluation of Catalytic Iron in Patients With Acute Coronary Syndromes

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.

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.

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

BACKGROUNDnCatalytic 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.nnnMETHODSnWe investigated 806 patients with ACS undergoing contrast exposure for a cardiac procedure who were followed up for 30 days.nnnRESULTSnOverall 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).nnnCONCLUSIONnHigh 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.

Urinary Catalytic Iron in Obesity

INTRODUCTIONnObesity 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.nnnOBJECTIVEnWe investigated whether urinary catalytic iron is increased in obese individuals without DM and overt kidney disease.nnnSTUDY DESIGNnWe 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.nnnRESULTSnThere 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).nnnCONCLUSIONSnOur 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.

Plasma Catalytic Iron, AKI, and Death among Critically Ill Patients

BACKGROUND AND OBJECTIVESnCatalytic 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.nnnDESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTSnA 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.nnnRESULTSnICU 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.nnnCONCLUSIONSnAmong 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.

Serum catalytic Iron: A novel biomarker for coronary artery disease in patients on maintenance hemodialysis.

Cardiovascular disease is the leading cause of morbidity and mortality in maintenance hemodialysis (MHD) patients. We evaluated the role of serum catalytic iron (SCI) as a biomarker for coronary artery disease (CAD) in patients on MHD. SCI was measured in 59 stable MHD patients. All patients underwent coronary angiography. Significant CAD was defined as a > 70% narrowing in at least one epicardial coronary artery. Levels of SCI were compared with a group of healthy controls. Significant CAD was detected in 22 (37.3%) patients, with one vessel disease in 14 (63.63%) and multi-vessel disease in eight (36.36%) patients. The MHD patients had elevated levels of SCI (4.70 ± 1.79 μmol/L) compared with normal health survey participants (0.11 ± 0.01 μmol/L) (P < 0.0001). MHD patients who had no CAD had SCI levels of 1.36 ± 0.34 μmol/L compared with those having significant CAD (8.92 ± 4.12 μmol/L) (P < 0.0001). Patients on MHD and diabetes had stronger correlation between SCI and prevalence of CAD compared with non-diabetics. Patients having one vessel disease had SCI of 8.85 ± 4.67 μmol/L versus multi-vessel disease with SCI of 9.05 ± 8.34 μmol/L, P = 0.48. In multivariate analysis, SCI and diabetes mellitus were independently associated with significant CAD. We confirm the high prevalence of significant CAD in MHD patients. Elevated SCI levels are associated with presence of significant coronary disease in such patients. The association of SCI is higher in diabetic versus the non-diabetic subgroup. This is an important potentially modifiable biomarker of CAD in MHD patients.

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 donors 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

BACKGROUNDnCatalytic 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.nnnMETHODSnThe 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.nnnRESULTSnPatients 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.nnnCONCLUSIONSnCI 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.