The differential effect of intravenous iron in patients with non-dialysis chronic kidney disease in terms of fibroblast growth factor 23, phosphate, bone metabolism, functional status and quality of life and cardiovascular variables “Iron and Phosphaturia in CKD”

Background: Modern intravenous iron preparations (e.g. ferric derisomaltose (FDI), ferric carboxymaltose (FCM)) are commonly used in non-dialysis-dependent chronic kidney disease (CKD) patients. Despite similar efficacy and safety in terms of previously described side-effect profile, a differential effect in hypophosphatemia has been noted with FCM. This appears to be related to fibroblast growth factor 23 (FGF23). Fibroblast growth factor 23 is an important phosphatonin with intertwined effects to phosphate metabolism, relevant to vitamin D and parathyroid hormone, leading to enhanced phosphaturia. In addition such alterations may lead to changes in bone turnover, and may be responsible for subtle differences in clinical and patient reported outcome measures. No previous randomised study evaluated this phenomenon in patients with non-dialysis dependent CKD. Moreover, no prior study adopting such a methodology evaluated any differential effect in terms of clinical and patient reported outcome measures, alongside potential cardiovascular implications. The primary hypothesis under study was whether any differential effect could arise secondary to the use of various modern intravenous iron compounds. This study primarily examined the comparative effects of FDI and FCM on FGF23, phosphate and other bone metabolism markers. In addition, it secondarily evaluated the impact of intravenous iron on functional status and cardiovascular variables, and assessed for any difference between the two compounds.
Methods: This single-center double-blind randomised controlled trial primarily assessed the effects of FCM and FDI on intact FGF23 and phosphate, whilst also studying the impact on vitamin D, parathyroid hormone and phosphaturia. Bone turnover markers (alkaline phosphatase, bone-specific alkaline phosphatase, cross-linked C-telopeptide of type I collagen, N-terminal propeptides of Type I collagen), functional status (fatigue severity scale, 36-Item Short Form Health Survey, Duke Activity Status Index and 1-minute-sit-to-stand test) and cardiovascular variables (NT-pro-BNP, troponin T and pulse wave velocity) were monitored. Non-dialysis-dependent CKD patients with iron deficiency with/without anemia (serum ferritin <200µg/L or transferrin saturation ≤20% and serum ferritin 200-299µg/L) were randomised to receive FDI or FCM (1:1). At baseline 1000mg of intravenous iron was administered followed by 500-1000mg at one month. Measurements were performed at baseline, 1-2 days following iron administration, 14 days, 1 month, 1-2 days following second administration, 2 months and 3 months following initial infusion. Safety was assessed throughout the study.
Results: Twenty-six patients were randomized to FDI (n=14) and FCM (n=12). Intact FGF23 increased following iron administration, which was significantly higher with FCM compared to FDI (Baseline to 1-2 days following 1st administration: FDI: 3.0 (IQR: - 15.1 - 13.8) % vs. FCM: 146.1 (IQR: 108.1-203.1) %; p < 0.001 and Baseline to 1-2 days following 2nd administration: FDI: 3.2 (IQR: - 3.5 - 25.4) % vs. FCM: 235.1 (138.5-434.6) %; p = 0.001). Phosphate levels decreased in the FCM group, causing a significant difference versus FDI at 14 days (FDI: 1.26 (IQR: 1.05–1.66) mmol/L vs. FCM: 1.09 (IQR: 0.94–1.23) mmol/L; p = 0.049). No clinically significant hypophosphataemia was detected ad either group. A significantly greater decrease in 1,25 (OH)2 Vitamin D was noted with FCM. A trend for increased phosphaturia was noted with FDI, albeit not statistically significant. Several bone turnover markers significantly changed following FCM administration but not FDI, both in terms of resorption and formation. Functional status improved in the total cohort and more specifically FDI in certain domains. This was particularly evident in those pertinent to fatigue and physical function as indicated both by the 36-Item Short Form Health Survey questionnaire and the Fatigue Severity Scale. No cardiovascular detriment was identified. Clinical efficacy and safety were similar between the two groups.
Conclusions: The study suggests a differential effect in FGF23 following FCM administration in non-dialysis-dependent CKD patients. This may lead to changes consistent with hypovitaminosis D and alterations in bone turnover with potential clinical consequences. A common complication of non-dialysis-dependent CKD is mineral bone disease, characterised by impact on quality of life, strength and succeptibility to fractures. This is fueled by changes in the metabolism of both vitamin D and parathyroid hormone. It is hence possible that any further detriment to the already fragile kidney-bone axis secondary to such differential effect can have a significant clinical impact on patients with reduced kidney function. This becomes increasingly important, as the cumulative effect of repeated intravenous iron infusions is yet to be established. The positive effect of iron on patient reported outcome measures and functional status, alongside the similar efficacy and safety displayed, complement evidence relevant to intravenous iron, and can increase the confidence of clinicians in the use of such compounds. Nonetheless, as this study was small in nature with certain inherent limitations, further definitive studies are required to understand these differences and provide further insights, both clinical and mechanistic, into any arising differences.