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Glenn M Chertow - One of the best experts on this subject based on the ideXlab platform.
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a pilot randomized trial of Ferric Citrate coordination complex for the treatment of advanced ckd
Journal of The American Society of Nephrology, 2019Co-Authors: Geoffrey A Block, Myles Wolf, Gerard Smits, Martha S Block, Rupal Mehta, Tamara Isakova, Glenn M ChertowAbstract:BACKGROUND Researchers have yet to determine the optimal care of patients with advanced CKD. Evidence suggests that anemia and CKD-related disordered mineral metabolism (including abnormalities in phosphate and fibroblast growth factor 23 [FGF23]) contribute to adverse outcomes in this population. METHODS To investigate whether fixed-dose Ferric Citrate coordination complex favorably affects multiple biochemical parameters in patients with advanced CKD, we randomly assigned 203 patients with eGFR≤20 ml/min per 1.73 m2 2:1 to receive a fixed dose of Ferric Citrate coordination complex (two tablets per meal, 210 mg Ferric iron per tablet) or usual care for 9 months or until 3 months after starting dialysis. No single biochemical end point was designated as primary; sample size was determined empirically. RESULTS The two groups had generally similar baseline characteristics, although diabetes and peripheral vascular disease were more common in the usual-care group. Ferric Citrate coordination complex significantly increased hemoglobin, transferrin saturation, and serum ferritin, and it significantly reduced serum phosphate and intact FGF23 (P<0.001 for all). Of the 133 patients randomized to Ferric Citrate coordination complex, 31 (23%) initiated dialysis during the study period, as did 32 of 66 (48%) patients randomized to usual care (P=0.001). Compared with usual care, Ferric Citrate coordination complex treatment resulted in significantly fewer annualized hospital admissions, fewer days in hospital, and a lower incidence of the composite end point of death, provision of dialysis, or transplantation (P=0.002). CONCLUSIONS The beneficial effects of fixed-dose Ferric Citrate coordination complex on biochemical parameters, as well as the exploratory results regarding the composite end point and hospitalization, suggest that fixed-dose Ferric Citrate coordination complex has an excellent safety profile in an unselected population with advanced CKD and merits further study.
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effect of Ferric Citrate on serum phosphate and fibroblast growth factor 23 among patients with nondialysis dependent chronic kidney disease path analyses
Nephrology Dialysis Transplantation, 2019Co-Authors: Geoffrey A Block, Steven Fishbane, Pablo E Pergola, Julian G Martins, Robin D Lewinter, Katrin Uhlig, John F Neylan, Glenn M ChertowAbstract:BACKGROUND Among patients with nondialysis-dependent chronic kidney disease (NDD-CKD) and iron-deficiency anemia (IDA), Ferric Citrate increases hemoglobin and iron parameters and reduces serum phosphate and fibroblast growth factor 23 (FGF23), a key phosphate-regulating hormone. We conducted post hoc analyses of a phase 3 trial to explore associations between iron replacement, serum phosphate changes and FGF23 regulation. METHODS We employed multivariable regression and longitudinal mixed-effects models to identify and confirm, respectively, whether baseline demographic and laboratory variables were associated with Ferric Citrate-induced changes in serum phosphate or FGF23 concentrations. We employed path analyses to determine whether changes in FGF23 concentrations were mediated via changes in serum phosphate and/or transferrin saturation (TSAT). RESULTS We analyzed a total of 117 and 115 Ferric Citrate-treated and placebo-treated patients, respectively. At 16 weeks, Ferric Citrate significantly reduced serum phosphate versus placebo (P = 0.006) only among patients with elevated baseline serum phosphate (≥4.5 mg/dL) and did not reduce serum phosphate among patients with baseline serum phosphate within the population reference range. Ferric Citrate reduced intact FGF23 and C-terminal FGF23 partially via changes in TSAT (for C-terminal FGF23) and serum phosphate (for intact FGF23) and partially via unknown/unmeasured mechanisms. CONCLUSIONS Ferric Citrate reduced serum FGF23 concentrations (partially via effects on serum phosphate and iron balance) and did not reduce serum phosphate among patients with baseline serum phosphate concentrations within the population reference range.
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safety and efficacy of Ferric Citrate in patients with nondialysis dependent chronic kidney disease
PLOS ONE, 2017Co-Authors: Glenn M Chertow, Geoffrey A Block, Pablo E Pergola, Katrin Uhlig, John F Neylan, Steven FishbaneAbstract:Two randomized, placebo-controlled trials conducted in patients with nondialysis-dependent (NDD) chronic kidney disease (CKD), iron deficiency anemia, and normal or elevated serum phosphorus demonstrated that Ferric Citrate (FC) significantly increased hemoglobin and decreased serum phosphate concentrations. Pooling these trial results could provide a more robust evaluation of the safety and efficacy of FC in this population. We pooled results of a phase 2 (n = 149) and 3 trial (n = 233) of patients randomized and treated for up to 12 and 16 weeks, respectively. The starting dose in both trials was three 1-g (elemental iron 210 mg) tablets/day with food, up to 12 tablets/day. Doses were titrated in the phase 2 and 3 trials to lower serum phosphate concentrations to a target range (0.97–1.13 mmol/L) and to achieve a ≥10-g/L hemoglobin increase, respectively. Safety was assessed in all patients who received ≥1 dose of FC (n = 190) and placebo (n = 188). Treatment-emergent adverse events (AEs) were reported in 143 of 190 (75.3%) FC-treated and 116 of 188 (61.7%) placebo-treated patients; gastrointestinal AEs were the most frequent (94 [49.5%] vs. 52 [27.7%], respectively). Specific events reported in >5% of patients (FC vs. placebo, respectively) included discolored feces (41 [21.6%] vs. 0 [0.0%]), diarrhea (39 [20.5%] vs. 23 [12.2%]), constipation (35 [18.4%] vs. 19 [10.1%]), and nausea (18 [9.5%] vs. 8 [4.3%]). Twenty FC-treated (10.5%) and 21 placebo-treated patients (11.2%) experienced a serious AE. Two patients (1.1%) died in each group. A pooled efficacy assessment demonstrated a consistent hemoglobin rise and modest serum phosphate decline, with few excursions below the normal range. When used for treatment of patients with NDD-CKD, FC contributes to gastrointestinal AEs at higher rates than placebo, while simultaneously correcting two of the principal metabolic manifestations of CKD (iron deficiency anemia and relative hyperphosphatemia).
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effects of Ferric Citrate in patients with nondialysis dependent ckd and iron deficiency anemia
Journal of The American Society of Nephrology, 2017Co-Authors: Steven Fishbane, Geoffrey A Block, Pablo E Pergola, Katrin Uhlig, John F Neylan, Lisa C Loram, Glenn M ChertowAbstract:Iron deficiency anemia is common and consequential in nondialysis-dependent CKD (NDD-CKD). Efficacy and tolerability of conventional oral iron supplements are mixed; intravenous iron administration associates with finite but important risks. We conducted a randomized double-blind clinical trial in adults with NDD-CKD and iron deficiency anemia to compare the safety and efficacy of oral Ferric Citrate (n=117) and placebo (n=115). The primary end point was the proportion of patients who achieved a ≥1.0 g/dl increase in hemoglobin at any time during a 16-week randomized period. Patients who completed the 16-week period could also participate in an 8-week open-label extension period. Significantly more patients randomized to Ferric Citrate achieved the primary end point (61 [52.1%] versus 22 [19.1%] with placebo; P<0.001). All secondary end points reached statistical significance in the Ferric Citrate group, including the mean relative change in hemoglobin (0.84 g/dl; 95% confidence interval, 0.58 to 1.10 g/dl; P<0.001) and the proportion of patients who achieved a sustained increase in hemoglobin (≥0.75 g/dl over any 4-week period during the randomized trial; 57 [48.7%] versus 17 [14.8%] with placebo; P<0.001). Rates of serious adverse events were similar in the Ferric Citrate (12.0%) and placebo groups (11.2%). Gastrointestinal disorders were the most common adverse events, with diarrhea reported in 24 (20.5%) and 19 (16.4%) and constipation in 22 (18.8%) and 15 (12.9%) patients treated with Ferric Citrate and placebo, respectively. Overall, in patients with NDD-CKD, we found oral Ferric Citrate to be a safe and efficacious treatment for iron deficiency anemia.
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net budgetary impact of Ferric Citrate as a first line phosphate binder for the treatment of hyperphosphatemia a markov microsimulation model
Drugs in R & D, 2017Co-Authors: Steven M. Brunelli, Andrew Hsieh, Scott Sibbel, David B Van Wyck, Amit Sharma, Glenn M ChertowAbstract:Ferric Citrate (FC) has demonstrated efficacy as a phosphate binder and reduces the requirements for erythropoiesis-stimulating agents (ESAs) and intravenous (IV) iron in dialysis patients. We developed a net budgetary impact model to evaluate FC vs. other phosphate binders from the vantage of a large dialysis provider. We used a Markov microsimulation model to simulate mutually referential longitudinal effects between serum phosphate and phosphate binder dose; categories of these defined health states. Health states probabilistically determined treatment attendance and utilization of ESA and IV iron. We derived model inputs from a retrospective analysis of incident phosphate binder users from a large dialysis organization (January 2011–June 2013) and incorporated treatment effects of FC from a phase III trial. The model was run over a 1-year time horizon. We considered fixed costs of providing dialysis; costs of administering ESA and IV iron; and payment rates for dialysis, ESAs, and IV iron. In the base-case model, FC had a net budgetary impact (savings) of +US$213,223/year per 100 patients treated vs. standard of care. One-way sensitivity analyses showed a net budgetary impact of up to +US$316,296/year per 100 patients treated when higher hemoglobin levels observed with FC translated into a 30% additional ESA dose reduction, and up to +US$223,281/year per 100 patients treated when effects on missed treatment rates were varied. Two-way sensitivity analyses in which acquisition costs for ESA and IV iron were varied showed a net budgetary impact of +US$104,840 to +US$213,223/year per 100 patients treated. FC as a first-line phosphate binder would likely yield substantive savings vs. standard of care under current reimbursement.
Geoffrey A Block - One of the best experts on this subject based on the ideXlab platform.
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a pilot randomized trial of Ferric Citrate coordination complex for the treatment of advanced ckd
Journal of The American Society of Nephrology, 2019Co-Authors: Geoffrey A Block, Myles Wolf, Gerard Smits, Martha S Block, Rupal Mehta, Tamara Isakova, Glenn M ChertowAbstract:BACKGROUND Researchers have yet to determine the optimal care of patients with advanced CKD. Evidence suggests that anemia and CKD-related disordered mineral metabolism (including abnormalities in phosphate and fibroblast growth factor 23 [FGF23]) contribute to adverse outcomes in this population. METHODS To investigate whether fixed-dose Ferric Citrate coordination complex favorably affects multiple biochemical parameters in patients with advanced CKD, we randomly assigned 203 patients with eGFR≤20 ml/min per 1.73 m2 2:1 to receive a fixed dose of Ferric Citrate coordination complex (two tablets per meal, 210 mg Ferric iron per tablet) or usual care for 9 months or until 3 months after starting dialysis. No single biochemical end point was designated as primary; sample size was determined empirically. RESULTS The two groups had generally similar baseline characteristics, although diabetes and peripheral vascular disease were more common in the usual-care group. Ferric Citrate coordination complex significantly increased hemoglobin, transferrin saturation, and serum ferritin, and it significantly reduced serum phosphate and intact FGF23 (P<0.001 for all). Of the 133 patients randomized to Ferric Citrate coordination complex, 31 (23%) initiated dialysis during the study period, as did 32 of 66 (48%) patients randomized to usual care (P=0.001). Compared with usual care, Ferric Citrate coordination complex treatment resulted in significantly fewer annualized hospital admissions, fewer days in hospital, and a lower incidence of the composite end point of death, provision of dialysis, or transplantation (P=0.002). CONCLUSIONS The beneficial effects of fixed-dose Ferric Citrate coordination complex on biochemical parameters, as well as the exploratory results regarding the composite end point and hospitalization, suggest that fixed-dose Ferric Citrate coordination complex has an excellent safety profile in an unselected population with advanced CKD and merits further study.
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effect of Ferric Citrate on serum phosphate and fibroblast growth factor 23 among patients with nondialysis dependent chronic kidney disease path analyses
Nephrology Dialysis Transplantation, 2019Co-Authors: Geoffrey A Block, Steven Fishbane, Pablo E Pergola, Julian G Martins, Robin D Lewinter, Katrin Uhlig, John F Neylan, Glenn M ChertowAbstract:BACKGROUND Among patients with nondialysis-dependent chronic kidney disease (NDD-CKD) and iron-deficiency anemia (IDA), Ferric Citrate increases hemoglobin and iron parameters and reduces serum phosphate and fibroblast growth factor 23 (FGF23), a key phosphate-regulating hormone. We conducted post hoc analyses of a phase 3 trial to explore associations between iron replacement, serum phosphate changes and FGF23 regulation. METHODS We employed multivariable regression and longitudinal mixed-effects models to identify and confirm, respectively, whether baseline demographic and laboratory variables were associated with Ferric Citrate-induced changes in serum phosphate or FGF23 concentrations. We employed path analyses to determine whether changes in FGF23 concentrations were mediated via changes in serum phosphate and/or transferrin saturation (TSAT). RESULTS We analyzed a total of 117 and 115 Ferric Citrate-treated and placebo-treated patients, respectively. At 16 weeks, Ferric Citrate significantly reduced serum phosphate versus placebo (P = 0.006) only among patients with elevated baseline serum phosphate (≥4.5 mg/dL) and did not reduce serum phosphate among patients with baseline serum phosphate within the population reference range. Ferric Citrate reduced intact FGF23 and C-terminal FGF23 partially via changes in TSAT (for C-terminal FGF23) and serum phosphate (for intact FGF23) and partially via unknown/unmeasured mechanisms. CONCLUSIONS Ferric Citrate reduced serum FGF23 concentrations (partially via effects on serum phosphate and iron balance) and did not reduce serum phosphate among patients with baseline serum phosphate concentrations within the population reference range.
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safety and efficacy of Ferric Citrate in patients with nondialysis dependent chronic kidney disease
PLOS ONE, 2017Co-Authors: Glenn M Chertow, Geoffrey A Block, Pablo E Pergola, Katrin Uhlig, John F Neylan, Steven FishbaneAbstract:Two randomized, placebo-controlled trials conducted in patients with nondialysis-dependent (NDD) chronic kidney disease (CKD), iron deficiency anemia, and normal or elevated serum phosphorus demonstrated that Ferric Citrate (FC) significantly increased hemoglobin and decreased serum phosphate concentrations. Pooling these trial results could provide a more robust evaluation of the safety and efficacy of FC in this population. We pooled results of a phase 2 (n = 149) and 3 trial (n = 233) of patients randomized and treated for up to 12 and 16 weeks, respectively. The starting dose in both trials was three 1-g (elemental iron 210 mg) tablets/day with food, up to 12 tablets/day. Doses were titrated in the phase 2 and 3 trials to lower serum phosphate concentrations to a target range (0.97–1.13 mmol/L) and to achieve a ≥10-g/L hemoglobin increase, respectively. Safety was assessed in all patients who received ≥1 dose of FC (n = 190) and placebo (n = 188). Treatment-emergent adverse events (AEs) were reported in 143 of 190 (75.3%) FC-treated and 116 of 188 (61.7%) placebo-treated patients; gastrointestinal AEs were the most frequent (94 [49.5%] vs. 52 [27.7%], respectively). Specific events reported in >5% of patients (FC vs. placebo, respectively) included discolored feces (41 [21.6%] vs. 0 [0.0%]), diarrhea (39 [20.5%] vs. 23 [12.2%]), constipation (35 [18.4%] vs. 19 [10.1%]), and nausea (18 [9.5%] vs. 8 [4.3%]). Twenty FC-treated (10.5%) and 21 placebo-treated patients (11.2%) experienced a serious AE. Two patients (1.1%) died in each group. A pooled efficacy assessment demonstrated a consistent hemoglobin rise and modest serum phosphate decline, with few excursions below the normal range. When used for treatment of patients with NDD-CKD, FC contributes to gastrointestinal AEs at higher rates than placebo, while simultaneously correcting two of the principal metabolic manifestations of CKD (iron deficiency anemia and relative hyperphosphatemia).
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effects of Ferric Citrate in patients with nondialysis dependent ckd and iron deficiency anemia
Journal of The American Society of Nephrology, 2017Co-Authors: Steven Fishbane, Geoffrey A Block, Pablo E Pergola, Katrin Uhlig, John F Neylan, Lisa C Loram, Glenn M ChertowAbstract:Iron deficiency anemia is common and consequential in nondialysis-dependent CKD (NDD-CKD). Efficacy and tolerability of conventional oral iron supplements are mixed; intravenous iron administration associates with finite but important risks. We conducted a randomized double-blind clinical trial in adults with NDD-CKD and iron deficiency anemia to compare the safety and efficacy of oral Ferric Citrate (n=117) and placebo (n=115). The primary end point was the proportion of patients who achieved a ≥1.0 g/dl increase in hemoglobin at any time during a 16-week randomized period. Patients who completed the 16-week period could also participate in an 8-week open-label extension period. Significantly more patients randomized to Ferric Citrate achieved the primary end point (61 [52.1%] versus 22 [19.1%] with placebo; P<0.001). All secondary end points reached statistical significance in the Ferric Citrate group, including the mean relative change in hemoglobin (0.84 g/dl; 95% confidence interval, 0.58 to 1.10 g/dl; P<0.001) and the proportion of patients who achieved a sustained increase in hemoglobin (≥0.75 g/dl over any 4-week period during the randomized trial; 57 [48.7%] versus 17 [14.8%] with placebo; P<0.001). Rates of serious adverse events were similar in the Ferric Citrate (12.0%) and placebo groups (11.2%). Gastrointestinal disorders were the most common adverse events, with diarrhea reported in 24 (20.5%) and 19 (16.4%) and constipation in 22 (18.8%) and 15 (12.9%) patients treated with Ferric Citrate and placebo, respectively. Overall, in patients with NDD-CKD, we found oral Ferric Citrate to be a safe and efficacious treatment for iron deficiency anemia.
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a 12 week double blind placebo controlled trial of Ferric Citrate for the treatment of iron deficiency anemia and reduction of serum phosphate in patients with ckd stages 3 5
American Journal of Kidney Diseases, 2015Co-Authors: Geoffrey A Block, Myles Wolf, Steven Fishbane, Mariano Rodriguez, Gerard Smits, Shay Shemesh, Pablo E Pergola, Glenn M ChertowAbstract:Background Iron deficiency anemia and serum phosphate levels > 4.0mg/dL are relatively common in chronic kidney disease stages 3 to 5 and are associated with higher risks of progressive loss of kidney function, cardiovascular events, and mortality. Study Design Double-blind, placebo-controlled, randomized trial. Setting & Participants 149 patients with estimated glomerular filtration rates 2 , iron deficiency anemia (hemoglobin, 9.0-12.0g/dL; transferrin saturation [TSAT]≤30%, serum ferritin ≤ 300ng/mL), and serum phosphate levels ≥ 4.0 to 6.0mg/dL. Use of intravenous iron or erythropoiesis-stimulating agents was prohibited. Intervention Randomization to treatment for 12 weeks with Ferric Citrate coordination complex (Ferric Citrate) or placebo. Outcomes & Measurements Coprimary end points were change in TSAT and serum phosphate level from baseline to end of study. Secondary outcomes included change from baseline to end of treatment in values for ferritin, hemoglobin, intact fibroblast growth factor 23 (FGF-23), urinary phosphate excretion, and estimated glomerular filtration rate. Results Ferric Citrate treatment increased mean TSAT from 22% ± 7% (SD) to 32% ± 14% and reduced serum phosphate levels from 4.5±0.6 to 3.9±0.6mg/dL, while placebo exerted no effect on TSAT (21% ± 8% to 20% ± 8%) and less effect on serum phosphate level (4.7±0.6 to 4.4±0.8mg/dL; between-group P P P P =0.02 vs placebo). The incidence and severity of adverse effects were similar between treatment arms. Limitations The study is limited by relatively small sample size and short duration and by having biochemical rather than clinical outcomes. Conclusions Short-term use of Ferric Citrate repletes iron stores, increases hemoglobin levels, and reduces levels of serum phosphate, urinary phosphate excretion, and FGF-23 in patients with chronic kidney disease stages 3 to 5.
Steven Fishbane - One of the best experts on this subject based on the ideXlab platform.
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effect of Ferric Citrate on serum phosphate and fibroblast growth factor 23 among patients with nondialysis dependent chronic kidney disease path analyses
Nephrology Dialysis Transplantation, 2019Co-Authors: Geoffrey A Block, Steven Fishbane, Pablo E Pergola, Julian G Martins, Robin D Lewinter, Katrin Uhlig, John F Neylan, Glenn M ChertowAbstract:BACKGROUND Among patients with nondialysis-dependent chronic kidney disease (NDD-CKD) and iron-deficiency anemia (IDA), Ferric Citrate increases hemoglobin and iron parameters and reduces serum phosphate and fibroblast growth factor 23 (FGF23), a key phosphate-regulating hormone. We conducted post hoc analyses of a phase 3 trial to explore associations between iron replacement, serum phosphate changes and FGF23 regulation. METHODS We employed multivariable regression and longitudinal mixed-effects models to identify and confirm, respectively, whether baseline demographic and laboratory variables were associated with Ferric Citrate-induced changes in serum phosphate or FGF23 concentrations. We employed path analyses to determine whether changes in FGF23 concentrations were mediated via changes in serum phosphate and/or transferrin saturation (TSAT). RESULTS We analyzed a total of 117 and 115 Ferric Citrate-treated and placebo-treated patients, respectively. At 16 weeks, Ferric Citrate significantly reduced serum phosphate versus placebo (P = 0.006) only among patients with elevated baseline serum phosphate (≥4.5 mg/dL) and did not reduce serum phosphate among patients with baseline serum phosphate within the population reference range. Ferric Citrate reduced intact FGF23 and C-terminal FGF23 partially via changes in TSAT (for C-terminal FGF23) and serum phosphate (for intact FGF23) and partially via unknown/unmeasured mechanisms. CONCLUSIONS Ferric Citrate reduced serum FGF23 concentrations (partially via effects on serum phosphate and iron balance) and did not reduce serum phosphate among patients with baseline serum phosphate concentrations within the population reference range.
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usefulness of oral Ferric Citrate in patients with iron deficiency anemia and chronic kidney disease with or without heart failure
American Journal of Cardiology, 2018Co-Authors: Peter A Mccullough, Katrin Uhlig, Pablo E Pergola, John F Neylan, Steven FishbaneAbstract:Patients with chronic inflammatory conditions including chronic kidney disease (CKD) and heart failure (HF) are undertreated with iron-deficiency anemia (IDA). Progressive inflammation and reduced iron transport associated with CKD and HF may reduce the efficacy of oral iron therapy. Oral Ferric Citrate improves anemia markers in CKD, but its effects in patients with CKD and concomitant HF have not been described. Patients with CKD not on dialysis and IDA from a phase 2 and 3 trial were treated with Ferric Citrate (n = 190) or placebo (n = 188); patients with HF were identified from medical histories. Hemoglobin response was defined as a ≥10.0-g/L increase in hemoglobin. Changes in hemoglobin, transferrin saturation, ferritin, and serum phosphate from baseline to week 12 and the incidence of adverse events potentially related to HF were evaluated. HF was reported in 22% (n = 81) of patients. The proportion of patients with hemoglobin response to Ferric Citrate treatment did not significantly differ in patients with and without HF (43% vs 49%, respectively; p = 0.47); changes from baseline in hemoglobin, iron parameters, and serum phosphate were similar. Adverse events potentially related to HF were noted more frequently in patients with HF (Ferric Citrate, 23%; placebo, 17%) versus those without HF (Ferric Citrate, 12%; placebo, 11%). In conclusion, these results indicate a potential role for Ferric Citrate in the treatment of IDA in patients with CKD not on dialysis and concomitant HF.
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safety and efficacy of Ferric Citrate in patients with nondialysis dependent chronic kidney disease
PLOS ONE, 2017Co-Authors: Glenn M Chertow, Geoffrey A Block, Pablo E Pergola, Katrin Uhlig, John F Neylan, Steven FishbaneAbstract:Two randomized, placebo-controlled trials conducted in patients with nondialysis-dependent (NDD) chronic kidney disease (CKD), iron deficiency anemia, and normal or elevated serum phosphorus demonstrated that Ferric Citrate (FC) significantly increased hemoglobin and decreased serum phosphate concentrations. Pooling these trial results could provide a more robust evaluation of the safety and efficacy of FC in this population. We pooled results of a phase 2 (n = 149) and 3 trial (n = 233) of patients randomized and treated for up to 12 and 16 weeks, respectively. The starting dose in both trials was three 1-g (elemental iron 210 mg) tablets/day with food, up to 12 tablets/day. Doses were titrated in the phase 2 and 3 trials to lower serum phosphate concentrations to a target range (0.97–1.13 mmol/L) and to achieve a ≥10-g/L hemoglobin increase, respectively. Safety was assessed in all patients who received ≥1 dose of FC (n = 190) and placebo (n = 188). Treatment-emergent adverse events (AEs) were reported in 143 of 190 (75.3%) FC-treated and 116 of 188 (61.7%) placebo-treated patients; gastrointestinal AEs were the most frequent (94 [49.5%] vs. 52 [27.7%], respectively). Specific events reported in >5% of patients (FC vs. placebo, respectively) included discolored feces (41 [21.6%] vs. 0 [0.0%]), diarrhea (39 [20.5%] vs. 23 [12.2%]), constipation (35 [18.4%] vs. 19 [10.1%]), and nausea (18 [9.5%] vs. 8 [4.3%]). Twenty FC-treated (10.5%) and 21 placebo-treated patients (11.2%) experienced a serious AE. Two patients (1.1%) died in each group. A pooled efficacy assessment demonstrated a consistent hemoglobin rise and modest serum phosphate decline, with few excursions below the normal range. When used for treatment of patients with NDD-CKD, FC contributes to gastrointestinal AEs at higher rates than placebo, while simultaneously correcting two of the principal metabolic manifestations of CKD (iron deficiency anemia and relative hyperphosphatemia).
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effects of Ferric Citrate in patients with nondialysis dependent ckd and iron deficiency anemia
Journal of The American Society of Nephrology, 2017Co-Authors: Steven Fishbane, Geoffrey A Block, Pablo E Pergola, Katrin Uhlig, John F Neylan, Lisa C Loram, Glenn M ChertowAbstract:Iron deficiency anemia is common and consequential in nondialysis-dependent CKD (NDD-CKD). Efficacy and tolerability of conventional oral iron supplements are mixed; intravenous iron administration associates with finite but important risks. We conducted a randomized double-blind clinical trial in adults with NDD-CKD and iron deficiency anemia to compare the safety and efficacy of oral Ferric Citrate (n=117) and placebo (n=115). The primary end point was the proportion of patients who achieved a ≥1.0 g/dl increase in hemoglobin at any time during a 16-week randomized period. Patients who completed the 16-week period could also participate in an 8-week open-label extension period. Significantly more patients randomized to Ferric Citrate achieved the primary end point (61 [52.1%] versus 22 [19.1%] with placebo; P<0.001). All secondary end points reached statistical significance in the Ferric Citrate group, including the mean relative change in hemoglobin (0.84 g/dl; 95% confidence interval, 0.58 to 1.10 g/dl; P<0.001) and the proportion of patients who achieved a sustained increase in hemoglobin (≥0.75 g/dl over any 4-week period during the randomized trial; 57 [48.7%] versus 17 [14.8%] with placebo; P<0.001). Rates of serious adverse events were similar in the Ferric Citrate (12.0%) and placebo groups (11.2%). Gastrointestinal disorders were the most common adverse events, with diarrhea reported in 24 (20.5%) and 19 (16.4%) and constipation in 22 (18.8%) and 15 (12.9%) patients treated with Ferric Citrate and placebo, respectively. Overall, in patients with NDD-CKD, we found oral Ferric Citrate to be a safe and efficacious treatment for iron deficiency anemia.
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ferritin elevation and improved responsiveness to erythropoiesis stimulating agents in patients on Ferric Citrate hydrate
Kidney International Reports, 2017Co-Authors: Keitaro Yokoyama, Steven Fishbane, Takashi Akiba, Masafumi Fukagawa, Masaaki Nakayama, Toshiya Otoguro, Kana Yamada, Yasuo Nagamine, Hideki HirakataAbstract:Introduction In hemodialysis patients on Ferric Citrate hydrate, the increase in ferritin level is mainly due to the administration of the compound. We investigated possible other factors associated with ferritin level and how erythropoietin resistance index and erythropoiesis in those patients were affected. We looked at ferritin-elevating factors using data from a Japanese phase III long-term clinical trial of Ferric Citrate hydrate. Methods The factors with a strong association with ferritin levels at week 28 were selected by the process of variable selection. In addition, selected factors were analyzed by Mixed Model for Repeated Measurement. Subjects were divided into 3 groups by quantiles (
Ferric Citrate hydrate treatment, resulting in a decrease of erythropoietin resistance index.
Pablo E Pergola - One of the best experts on this subject based on the ideXlab platform.
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effect of Ferric Citrate on serum phosphate and fibroblast growth factor 23 among patients with nondialysis dependent chronic kidney disease path analyses
Nephrology Dialysis Transplantation, 2019Co-Authors: Geoffrey A Block, Steven Fishbane, Pablo E Pergola, Julian G Martins, Robin D Lewinter, Katrin Uhlig, John F Neylan, Glenn M ChertowAbstract:BACKGROUND Among patients with nondialysis-dependent chronic kidney disease (NDD-CKD) and iron-deficiency anemia (IDA), Ferric Citrate increases hemoglobin and iron parameters and reduces serum phosphate and fibroblast growth factor 23 (FGF23), a key phosphate-regulating hormone. We conducted post hoc analyses of a phase 3 trial to explore associations between iron replacement, serum phosphate changes and FGF23 regulation. METHODS We employed multivariable regression and longitudinal mixed-effects models to identify and confirm, respectively, whether baseline demographic and laboratory variables were associated with Ferric Citrate-induced changes in serum phosphate or FGF23 concentrations. We employed path analyses to determine whether changes in FGF23 concentrations were mediated via changes in serum phosphate and/or transferrin saturation (TSAT). RESULTS We analyzed a total of 117 and 115 Ferric Citrate-treated and placebo-treated patients, respectively. At 16 weeks, Ferric Citrate significantly reduced serum phosphate versus placebo (P = 0.006) only among patients with elevated baseline serum phosphate (≥4.5 mg/dL) and did not reduce serum phosphate among patients with baseline serum phosphate within the population reference range. Ferric Citrate reduced intact FGF23 and C-terminal FGF23 partially via changes in TSAT (for C-terminal FGF23) and serum phosphate (for intact FGF23) and partially via unknown/unmeasured mechanisms. CONCLUSIONS Ferric Citrate reduced serum FGF23 concentrations (partially via effects on serum phosphate and iron balance) and did not reduce serum phosphate among patients with baseline serum phosphate concentrations within the population reference range.
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usefulness of oral Ferric Citrate in patients with iron deficiency anemia and chronic kidney disease with or without heart failure
American Journal of Cardiology, 2018Co-Authors: Peter A Mccullough, Katrin Uhlig, Pablo E Pergola, John F Neylan, Steven FishbaneAbstract:Patients with chronic inflammatory conditions including chronic kidney disease (CKD) and heart failure (HF) are undertreated with iron-deficiency anemia (IDA). Progressive inflammation and reduced iron transport associated with CKD and HF may reduce the efficacy of oral iron therapy. Oral Ferric Citrate improves anemia markers in CKD, but its effects in patients with CKD and concomitant HF have not been described. Patients with CKD not on dialysis and IDA from a phase 2 and 3 trial were treated with Ferric Citrate (n = 190) or placebo (n = 188); patients with HF were identified from medical histories. Hemoglobin response was defined as a ≥10.0-g/L increase in hemoglobin. Changes in hemoglobin, transferrin saturation, ferritin, and serum phosphate from baseline to week 12 and the incidence of adverse events potentially related to HF were evaluated. HF was reported in 22% (n = 81) of patients. The proportion of patients with hemoglobin response to Ferric Citrate treatment did not significantly differ in patients with and without HF (43% vs 49%, respectively; p = 0.47); changes from baseline in hemoglobin, iron parameters, and serum phosphate were similar. Adverse events potentially related to HF were noted more frequently in patients with HF (Ferric Citrate, 23%; placebo, 17%) versus those without HF (Ferric Citrate, 12%; placebo, 11%). In conclusion, these results indicate a potential role for Ferric Citrate in the treatment of IDA in patients with CKD not on dialysis and concomitant HF.
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safety and efficacy of Ferric Citrate in patients with nondialysis dependent chronic kidney disease
PLOS ONE, 2017Co-Authors: Glenn M Chertow, Geoffrey A Block, Pablo E Pergola, Katrin Uhlig, John F Neylan, Steven FishbaneAbstract:Two randomized, placebo-controlled trials conducted in patients with nondialysis-dependent (NDD) chronic kidney disease (CKD), iron deficiency anemia, and normal or elevated serum phosphorus demonstrated that Ferric Citrate (FC) significantly increased hemoglobin and decreased serum phosphate concentrations. Pooling these trial results could provide a more robust evaluation of the safety and efficacy of FC in this population. We pooled results of a phase 2 (n = 149) and 3 trial (n = 233) of patients randomized and treated for up to 12 and 16 weeks, respectively. The starting dose in both trials was three 1-g (elemental iron 210 mg) tablets/day with food, up to 12 tablets/day. Doses were titrated in the phase 2 and 3 trials to lower serum phosphate concentrations to a target range (0.97–1.13 mmol/L) and to achieve a ≥10-g/L hemoglobin increase, respectively. Safety was assessed in all patients who received ≥1 dose of FC (n = 190) and placebo (n = 188). Treatment-emergent adverse events (AEs) were reported in 143 of 190 (75.3%) FC-treated and 116 of 188 (61.7%) placebo-treated patients; gastrointestinal AEs were the most frequent (94 [49.5%] vs. 52 [27.7%], respectively). Specific events reported in >5% of patients (FC vs. placebo, respectively) included discolored feces (41 [21.6%] vs. 0 [0.0%]), diarrhea (39 [20.5%] vs. 23 [12.2%]), constipation (35 [18.4%] vs. 19 [10.1%]), and nausea (18 [9.5%] vs. 8 [4.3%]). Twenty FC-treated (10.5%) and 21 placebo-treated patients (11.2%) experienced a serious AE. Two patients (1.1%) died in each group. A pooled efficacy assessment demonstrated a consistent hemoglobin rise and modest serum phosphate decline, with few excursions below the normal range. When used for treatment of patients with NDD-CKD, FC contributes to gastrointestinal AEs at higher rates than placebo, while simultaneously correcting two of the principal metabolic manifestations of CKD (iron deficiency anemia and relative hyperphosphatemia).
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effects of Ferric Citrate in patients with nondialysis dependent ckd and iron deficiency anemia
Journal of The American Society of Nephrology, 2017Co-Authors: Steven Fishbane, Geoffrey A Block, Pablo E Pergola, Katrin Uhlig, John F Neylan, Lisa C Loram, Glenn M ChertowAbstract:Iron deficiency anemia is common and consequential in nondialysis-dependent CKD (NDD-CKD). Efficacy and tolerability of conventional oral iron supplements are mixed; intravenous iron administration associates with finite but important risks. We conducted a randomized double-blind clinical trial in adults with NDD-CKD and iron deficiency anemia to compare the safety and efficacy of oral Ferric Citrate (n=117) and placebo (n=115). The primary end point was the proportion of patients who achieved a ≥1.0 g/dl increase in hemoglobin at any time during a 16-week randomized period. Patients who completed the 16-week period could also participate in an 8-week open-label extension period. Significantly more patients randomized to Ferric Citrate achieved the primary end point (61 [52.1%] versus 22 [19.1%] with placebo; P<0.001). All secondary end points reached statistical significance in the Ferric Citrate group, including the mean relative change in hemoglobin (0.84 g/dl; 95% confidence interval, 0.58 to 1.10 g/dl; P<0.001) and the proportion of patients who achieved a sustained increase in hemoglobin (≥0.75 g/dl over any 4-week period during the randomized trial; 57 [48.7%] versus 17 [14.8%] with placebo; P<0.001). Rates of serious adverse events were similar in the Ferric Citrate (12.0%) and placebo groups (11.2%). Gastrointestinal disorders were the most common adverse events, with diarrhea reported in 24 (20.5%) and 19 (16.4%) and constipation in 22 (18.8%) and 15 (12.9%) patients treated with Ferric Citrate and placebo, respectively. Overall, in patients with NDD-CKD, we found oral Ferric Citrate to be a safe and efficacious treatment for iron deficiency anemia.
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a 12 week double blind placebo controlled trial of Ferric Citrate for the treatment of iron deficiency anemia and reduction of serum phosphate in patients with ckd stages 3 5
American Journal of Kidney Diseases, 2015Co-Authors: Geoffrey A Block, Myles Wolf, Steven Fishbane, Mariano Rodriguez, Gerard Smits, Shay Shemesh, Pablo E Pergola, Glenn M ChertowAbstract:Background Iron deficiency anemia and serum phosphate levels > 4.0mg/dL are relatively common in chronic kidney disease stages 3 to 5 and are associated with higher risks of progressive loss of kidney function, cardiovascular events, and mortality. Study Design Double-blind, placebo-controlled, randomized trial. Setting & Participants 149 patients with estimated glomerular filtration rates 2 , iron deficiency anemia (hemoglobin, 9.0-12.0g/dL; transferrin saturation [TSAT]≤30%, serum ferritin ≤ 300ng/mL), and serum phosphate levels ≥ 4.0 to 6.0mg/dL. Use of intravenous iron or erythropoiesis-stimulating agents was prohibited. Intervention Randomization to treatment for 12 weeks with Ferric Citrate coordination complex (Ferric Citrate) or placebo. Outcomes & Measurements Coprimary end points were change in TSAT and serum phosphate level from baseline to end of study. Secondary outcomes included change from baseline to end of treatment in values for ferritin, hemoglobin, intact fibroblast growth factor 23 (FGF-23), urinary phosphate excretion, and estimated glomerular filtration rate. Results Ferric Citrate treatment increased mean TSAT from 22% ± 7% (SD) to 32% ± 14% and reduced serum phosphate levels from 4.5±0.6 to 3.9±0.6mg/dL, while placebo exerted no effect on TSAT (21% ± 8% to 20% ± 8%) and less effect on serum phosphate level (4.7±0.6 to 4.4±0.8mg/dL; between-group P P P P =0.02 vs placebo). The incidence and severity of adverse effects were similar between treatment arms. Limitations The study is limited by relatively small sample size and short duration and by having biochemical rather than clinical outcomes. Conclusions Short-term use of Ferric Citrate repletes iron stores, increases hemoglobin levels, and reduces levels of serum phosphate, urinary phosphate excretion, and FGF-23 in patients with chronic kidney disease stages 3 to 5.
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occurrence and regulation of the Ferric Citrate transport system in escherichia coli b klebsiella pneumoniae enterobacter aerogenes and photorhabdus luminescens
Archives of Microbiology, 2005Co-Authors: Susanne Mahren, Heidrun Schnell, Volkmar BraunAbstract:In Escherichia coli K-12, transcription of the Ferric Citrate transport genes fecABCDE is initiated by binding of diFerric diCitrate to the outer membrane protein FecA which elicits a signaling cascade from the cell surface to the cytoplasm. The FecI sigma factor is only active in the presence of FecR, which transfers the signal across the cytoplasmic membrane. In other bacteria, fecIRA homologues control iron transport gene transcription by siderophores other than Citrate. However, in most cases, the FecI homologues are active in the absence of the FecR homologues, which might function as anti-sigma factors. Since not all E. coli strains contain a fec system, we determined the occurrence of fec genes in selected Enterobacteriaceae and the dependence of FecI activity on FecR. Incomplete FecIRA systems were chromosomally encoded in Enterobacter aerogenes strains and plasmid-encoded in K. pneumoniae. E. coli B, Photorhabdus luminescens and one of three Klebsiella pneumoniae strains had a functional FecIRA regulatory system as in E. coli K-12. The cytoplasmic N-terminal FecR fragments caused constitutive FecI activity in the absence of Ferric Citrate. The PCR-generated mutant FecI(D40G) was inactive and FecI(S15P) was partially active. FecR of E. coli K-12 activated FecI of all tested strains except FecI encoded on the virulence plasmid pLVPK of K. pneumoniae, which differed from E. coli K-12 FecI by having mutations in region 4, which is important for interaction with FecR. The C-terminally truncated FecR homologue of pLVPK was inactive. pLVPK-encoded FecA contains a 38-residue sequence in front of the signal sequence that did not prevent processing and proper integration of FecA into the outer membrane of E. coli and lacks the signaling sequence required for transcription initiation of the fec transport genes, making it induction-incompetent but transport-competent. The evidence indicates that fecIRABCDE genes are acquired by horizontal DNA transfer and can undergo debilitating mutations.
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interactions between the outer membrane Ferric Citrate transporter feca and tonb studies of the feca tonb box
Journal of Bacteriology, 2003Co-Authors: Monica Ogierman, Volkmar BraunAbstract:Both induction of transcription of the Ferric Citrate transport genes and transport of Ferric Citrate by the Escherichia coli outer membrane receptor FecA require energy derived from the proton motive force (PMF) of the inner membrane. The energy is transduced to FecA by the inner membrane complex, TonB, ExbB, and ExbD. Region 160 of TonB and the conserved TonB box of other TonB-dependent receptors are implicated as sites of interaction. In the present study, the postulated TonB box (D80A81L82T83V84) of FecA was deleted in frame, with a subsequent loss of both FecA functions. DALTV of FecA could be functionally replaced with the core TonB boxes of FhuA (DTITV) and FepA (DTIVV). Each residue of the TonB box of FecA was sequentially replaced with cysteine residues, and only the D80C replacement showed a loss (reduction) of both FecA functions. A physical interaction between TonB and FecA was demonstrated using both in vivo site-specific disulfide bond cross-linking and nonspecific formaldehyde (FA) cross-linking. Pairwise combinations of FecA (DALTV)/Cys substitutions were cross-linked via disulfide bond formation with TonBQ160C, TonBQ162C, and TonBY163C. Unexpectedly, this cross-linking was not enhanced by substrate (Ferric Citrate). In contrast, the TonB-FecA interaction was enhanced by Ferric Citrate in the FA-cross-linking assay. Energy derived from the PMF was not required for the TonB-FecA interaction in either the disulfide- or FA-cross-linking assay. TonB/CysExbB/ExbD(D25N) was still able to cross-link with the FecA (DALTV)/Cys derivatives in a tonB tolQ background, even though ExbD25N renders the TonB/ExbBD complex nonfunctional (V. Braun, S. Gaisser, C. Herrmann, K. Kampfenkel, H. Killmann, and I. Traub, J. Bacteriol. 178:2836-2845, 1996). TonB cross-linked to FecA via FA was not inhibited by either carbonylcyanide-m-chlorophenylhydrazone or 1 mM 2,4-dinitrophenol, which dissipate the electrochemical potential of the cytoplasmic membrane and disrupt both FecA functions. The studies shown here demonstrate the significance of the TonB box for FecA functions and are consistent with the view that it is the structure and not the sequence of the TonB box that is important for activity. Demonstrated here for the first time is the physical interaction of TonB and FecA, which is enhanced by Ferric Citrate.
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functional interaction of region 4 of the extracytoplasmic function sigma factor feci with the cytoplasmic portion of the fecr transmembrane protein of the escherichia coli Ferric Citrate transport system
Journal of Bacteriology, 2002Co-Authors: Susanne Mahren, Sabine Enz, Volkmar BraunAbstract:Transcriptional regulation of the Ferric Citrate transport genes of Escherichia coli is initiated by the binding of Ferric Citrate to the outer membrane protein FecA. This binding elicits a signal that is transmitted by FecR across the cytoplasmic membrane into the cytoplasm, where the sigma factor FecI directs the RNA polymerase to the promoter upstream of the fecABCDE genes. An in vivo deletion analysis using a bacterial two-hybrid system assigned the interaction of the FecR and FecI proteins to the cytoplasmic portion of the FecR transmembrane protein and region 4 of FecI. Missense mutations randomly generated by PCR were localized to region 4 of FecI, and the mutants were impaired with regard to the interaction of FecR with FecI and fecB-lacZ transcription. The cloned region 4 of FecI interfered with fecB-lacZ transcription. Interaction of N-proximal regions of predicted FecR homologs with region 4 of predicted FecI homologs of Pseudomonas aeruginosa was demonstrated. The interaction was specific in that only cognate protein pairs interacted with each other; no interactions occurred between heterologous combinations of the P. aeruginosa proteins and between a P. aeruginosa FecI homolog and E. coli FecR. The results demonstrate that region 4 of FecI specifically binds FecR and that this binding is necessary for FecI to function as a sigma factor.
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control of the Ferric Citrate transport system of escherichia coli mutations in region 2 1 of the feci extracytoplasmic function sigma factor suppress mutations in the fecr transmembrane regulatory protein
Journal of Bacteriology, 2001Co-Authors: Alfred Stiefel, Susanne Mahren, Sabine Enz, Martina Ochs, Petra T Schindler, Volkmar BraunAbstract:Transcription of the Ferric Citrate transport genes is initiated by binding of Ferric Citrate to the FecA protein in the outer membrane of Escherichia coli K-12. Bound Ferric Citrate does not have to be transported but initiates a signal that is transmitted by FecA across the outer membrane and by FecR across the cytoplasmic membrane into the cytoplasm, where the FecI extracytoplasmic-function (ECF) sigma factor becomes active. In this study, we isolated transcription initiation-negative missense mutants in the cytoplasmic region of FecR that were located at four sites, L13Q, W19R, W39R, and W50R, which are highly conserved in FecR-like open reading frames of the Pseudomonas aeruginosa, Pseudomonas putida, Bordetella pertussis, Bordetella bronchiseptica, and Caulobacter crescentus genomes. The cytoplasmic portion of the FecR mutant proteins, FecR1–85, did not interact with wild-type FecI, in contrast to wild-type FecR1–85, which induced FecI-mediated fecB transport gene transcription. Two missense mutations in region 2.1 of FecI, S15A and H20E, partially restored induction of Ferric Citrate transport gene induction of the fecR mutants by Ferric Citrate. Region 2.1 of ς70 is thought to bind RNA polymerase core enzyme; the residual activity of mutated FecI in the absence of FecR, however, was not higher than that of wild-type FecI. In addition, missense mutations in the fecI promoter region resulted in a twofold increased transcription in fecR wild-type cells and a partial restoration of fec transport gene transcription in the fecR mutants. The mutations reduced binding of the Fe2+ Fur repressor and as a consequence enhanced fecI transcription. The data reveal properties of the FecI ECF factor distinct from those of ς70 and further support the novel transcription initiation model in which the cytoplasmic portion of FecR is important for FecI activity.
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surface signaling in Ferric Citrate transport gene induction interaction of the feca fecr and feci regulatory proteins
Journal of Bacteriology, 2000Co-Authors: Sabine Enz, Susanne Mahren, Uwe H Stroeher, Volkmar BraunAbstract:In Escherichia coli, transcription of the Ferric Citrate transport genes fecABCDE is controlled by a novel signal transduction mechanism that starts at the cell surface. Binding of Ferric Citrate to the outer membrane protein FecA initiates a signal that is transmitted by FecR across the cytoplasmic membrane into the cytoplasm where FecI, the sigma factor, is activated. Interaction between the signaling proteins was demonstrated by utilizing two methods. In in vitro binding assays, FecR that was His tagged at the N terminus [(His)10-FecR] and bound to a Ni-nitrilotriacetic acid agarose column was able to retain FecA, and FecR that was His tagged at the C terminus [FecR-(His)6] retained FecI on the column. An N-terminally truncated, induction-negative but transport-active FecA protein did not bind to (His)10-FecR. The in vivo assay involved the determination of the FecA, FecR, and FecI interacting domains with the bacterial two-hybrid Lex-based system. FecA1–79 interacts with FecR101–317 and FecR1–85 interacts with FecI1–173. These data clearly support a model that proposes interaction of the periplasmic N terminus of FecA with the periplasmic C-terminal portion of FecR and interaction of the cytoplasmic N terminus of FecR with FecI, which results in FecI activation.