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.

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.

Burden and predictors of hypertension in India: results of SEEK (Screening and Early Evaluation of Kidney Disease) study.

BACKGROUND: Hypertension (HTN) is one of the major causes of cardiovascular morbidity and mortality. The objective of the study was to investigate the burden and predictors of HTN in India. METHODS: 6120 subjects participated in the Screening and Early Evaluation of Kidney disease (SEEK), a community-based screening program in 53 camps in 13 representative geographic locations in India. Of these, 5929 had recorded blood pressure (BP) measurements. Potential predictors of HTN were collected using a structured questionnaire for SEEK study. RESULTS: HTN was observed in 43.5% of our cohort. After adjusting for center variation (p < 0.0001), predictors of a higher prevalence of HTN were older age ≥ 40 years (p < 0.0001), BMI of ≥ 23 Kg/M2 (p < 0.0004), larger waist circumference (p < 0.0001), working in sedentary occupation (p < 0.0001), having diabetes mellitus (p < 0.0001), having proteinuria (p < 0.0016), and increased serum creatinine (p < 0.0001). High school/some college education (p = 0.0016), versus less than 9th grade education, was related with lower prevalence of HTN. Of note, proteinuria and CKD were observed in 19% and 23.5% of HTN subjects. About half (54%) of the hypertensive subjects were aware of their hypertension status. CONCLUSIONS: HTN was common in this cohort from India. Older age, BMI ≥ 23 Kg/M2, waist circumference, sedentary occupation, education less, diabetes mellitus, presence of proteinuria, and raised serum creatinine were significant predictors of hypertension. Our data suggest that HTN is a major public health problem in India with low awareness, and requires aggressive community-based screening and education to improve health.

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.

Effect of deferiprone, an oral iron chelator, in diabetic and non-diabetic glomerular disease.

Compelling experimental evidence exists for the role of oxidants and iron in glomerular disease. In preliminary studies, we confirmed increased urinary catalytic iron in patients with glomerulonephritis and diabetic nephropathy. We conducted two separate single-center, prospective, single-armed, open-labeled, proof-of-concept studies to evaluate the safety and efficacy of an oral iron chelator in patients with glomerulonephritis and diabetic nephropathy. Study 1 comprised 15 patients with biopsy-proven glomerulonephritis who had persistent proteinuria despite treatment with steroids and/or cyclophosphamides. Study 2 comprised 38 adult patients with diabetic nephropathy. Patients in Study 1 were treated with deferiprone (50 mg/kg/day) in three divided doses for 6 months and Study 2 patients were treated for 9 months. In Study 1, two patients had severe gastrointestinal intolerance and withdrew from the study after one dose and are not included in the results. There was a significant reduction (47 ± 9% mean) in 24-h urinary protein (4.01 ± 1.61 to 2.21 ± 1.62 [p = 0.009]), with no significant changes in serum creatinine. In Study 2, treatment with deferiprone resulted in a marked, persistent drop in the mean albumin/creatinine ratio (187 ± 47 at baseline to 25 ± 7 mg/g, [p = 0.01]) and stable renal function over a 9-month period. No clinically significant adverse events were observed in either study. Although these are small, open-labeled, and non-randomized studies, our results suggest that future randomized, double-blind trials examining the utility of deferiprone to treat glomerular diseases appear warranted.

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.

The role of labile iron in kidney disease and treatment with chelation.

There are two major forms of kidney disease: acute renal failure [also referred to as acute kidney injury (AKI)] and chronic kidney disease (CKD). Acute renal failure is an abrupt loss of kidney function within 48 h, whereas CKD is a loss of kidney function greater than 3 months. There is a large amount of experimental evidence for an increase of labile iron in a wide variety of models of kidney disease. Additionally, iron chelators provide protection, indicating an important role of labile iron in these diseases. These observations suggest that iron chelators may provide a new modality of prevention and treatment of kidney disease.

Radiation nephropathy is not mitigated by antagonists of oxidative stress.

Abstract Persistent, chronic oxidative injury may play a mechanistic role in late radiation injury. Thus antioxidants may be useful as mitigators of radiation injury. The antioxidants deferiprone, genistein and apocynin were tested in a rat radiation nephropathy model that uses single-fraction total-body irradiation (TBI) followed by syngeneic bone marrow transplant. Deferiprone was added to the drinking water at 1.0 or 2.5 g/liter, starting 3 days after the TBI. Urinary bleomycin-detectable iron, which could enhance production of oxygen radicals, was reduced in the rats on deferiprone compared to untreated rats, but deferiprone did not mitigate radiation nephropathy. Genistein added to the chow at 750 mg/kg starting immediately after TBI did not mitigate radiation nephropathy. Apocynin added to the drinking water at 250 mg/liter immediately after TBI did not mitigate radiation nephropathy. Thus three different types of antioxidants, when used at doses consistent with an antioxidant effect, had no mitigation efficacy against radiation nephropathy.

Management of non-neoplastic renal hemorrhage by transarterial embolization.

OBJECTIVES: To assess the role of transarterial embolization (TAE) and critically appraise its feasibility and efficacy in the management of non-neoplastic renal hemorrhage. Percutaneous TAE is an effective method for the control of hemorrhage, irrespective of the cause. Injury to the renal artery or its branch, after trauma or during open or percutaneous urologic procedures, can be accurately diagnosed using angiography and treated by percutaneous embolization techniques. Because the technique and technology have evolved, it is now possible to perform highly selective embolization of the injured vessel while preserving vascularity of the rest of the renal parenchyma. METHODS: The medical records of all patients who underwent angioembolization for hemorrhagic urologic emergencies at our institute from January 1996 to December 2007 were reviewed. RESULTS: A total of 41 patients, aged 7-72 years, underwent TAE because of hemorrhage after percutaneous nephrolithotomy (n = 27), open pyelolithotomy (n = 3), renal biopsy (n = 8), and spontaneous occurrence (n = 3). All patients had a normal coagulation profile before surgery. A total of 35 patients (85.3%) underwent successful embolization and none required a postprocedural blood transfusion. Of those with postpercutaneous nephrolithotomy bleeding, angioembolization failed in 6 patients. Of these, only 2 required nephrectomy to save the patient's life. No serious procedure-related complications occurred. CONCLUSIONS: TAE is a minimally invasive, safe, simple, and highly effective modality, in expert hands, for the management of postprocedural renal bleeding. This option should be considered early in the management of these cases because it is not only a life-saving, but ultimately a kidney-sparing, procedure.