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Renoprotective effects of ferric citrate in a mouse model of chronic kidney disease.

ABSTRACT: In chronic kidney disease, ferric citrate has been shown to be an effective phosphate binder and source of enteral iron; however, the effects of ferric citrate on the kidney have been less well-studied. Here, in Col4α3 knockout mice-a murine model of progressive chronic kidney disease, we evaluated the effects of five weeks of 1% ferric citrate dietary supplementation. As expected, ferric citrate lowered serum phosphate concentrations and increased serum iron levels in the Col4α3 knockout mice. Consistent with decreased enteral phosphate absorption and possibly improved iron status, ferric citrate greatly reduced circulating fibroblast growth factor 23 levels. Interestingly, ferric citrate also lessened systemic inflammation, improved kidney function, reduced albuminuria, and decreased kidney inflammation and fibrosis, suggesting renoprotective effects of ferric citrate in the setting of chronic kidney disease. The factors mediating possible ferric citrate renoprotection, the mechanisms by which they may act, and whether ferric citrate affects chronic kidney disease progression in humans deserves further study.

SUBMITTER: Hanudel MR

PROVIDER: S-EPMC9035171 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Renoprotective effects of ferric citrate in a mouse model of chronic kidney disease.

Hanudel Mark R MR Czaya Brian B Wong Shirley S Jung Grace G Chua Kristine K Qiao Bo B Gabayan Victoria V Ganz Tomas T

Scientific reports 20220423 1

In chronic kidney disease, ferric citrate has been shown to be an effective phosphate binder and source of enteral iron; however, the effects of ferric citrate on the kidney have been less well-studied. Here, in Col4α3 knockout mice-a murine model of progressive chronic kidney disease, we evaluated the effects of five weeks of 1% ferric citrate dietary supplementation. As expected, ferric citrate lowered serum phosphate concentrations and increased serum iron levels in the Col4α3 knockout mice. ...[more]

PMID: 35461329

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Project description: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).

Project description:Background and objectiveAnemia caused by iron depletion is common in patients with hemodialysis-dependent stage 5 chronic kidney disease (CKD-5HD) patients. To maintain the iron levels, external administration of iron is essential. Ferric pyrophosphate citrate (FPC) is a novel, water-soluble complex iron salt. The present study was conducted to evaluate the pharmacokinetic (PK) parameters and safety of FPC in adult healthy Chinese subjects and patients with CKD-5HD.MethodsTwo open-label, single-center studies were conducted in healthy subjects and patients with CKD-5HD. Healthy subjects received a single intravenous dose of 6.5 mg FPC solution, while CKD-5HD patients were randomized to two different sequences of FPC administration at two sequential hemodialysis (HD) treatments (dose 1 and dose 2). Patients received 27.2 mg of FPC at a dialysate concentration of 95 μg/L for 4 h or a single 6.5 mg dose of FPC administered intravenously via the pre-dialyzer blood circuit. The primary objective was to determine the PK parameters of total serum iron (Fetot), while the secondary objective was the safety of the FPC solution. PK parameters were calculated using Phoenix WinNonlin 8.1 and other parameters were analyzed using SAS 9.4 software. Comparison between HD dose 2 and HD dose 1 was performed using the Wilcoxon rank-sum test and analysis of variance (ANOVA).ResultsA total of 14 healthy subjects with a mean age of 30.8 ± 5.92 years and 12 HD patients with a mean age of 54.3 ± 16.47 years were included. In healthy subjects, the peak serum concentration was reached at the end of infusion of FPC, with an adjusted mean maximum concentration (Cmax,) of 33.46 ± 4.83 μmol/L at a mean time to reach Cmax (Tmax) of 4.09 ± 0.19 h. In patients with CKD-5HD, the adjusted mean Cmax of HD dose 2 was 25.37 ± 4.30 μmol/L at a Tmax, of 3.09 ± 0.32 h, whereas the Cmax, of HD dose 1 was 24.59 ± 4.77 μmol/L at a Tmax, of 3.96 ± 0.26 h. The Fetot concentration-time curves were observed to be similar for both administration methods (HD doses 1 and 2), while the PK parameters differed significantly for Tmax (p = 0.001; baseline correction) and area under the concentration-time curve from time zero to time t (AUCt) [p = 0.031 for cycle variance; without baseline correction] between HD doses 1 and 2. The geometric mean ratios (HD dose 1/HD dose 2) for Cmax and AUCt were within the 85-125% range (Cmax 96.56%; AUCt 96.07%). A total of three and two incidences of adverse events were reported in healthy subjects and patients with CKD-5HD, respectively.ConclusionFPC showed a good PK and safety profile and hence can be used as maintenance therapy for patients with CKD-5HD by choosing a better method of administration based on clinical feasibility and requirement.Clinical trial registrationCTR20181113 and CTR20181119.

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Renoprotective effects of ferric citrate in a mouse model of chronic kidney disease.

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Renoprotective effects of ferric citrate in a mouse model of chronic kidney disease.

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