Modern intravenous iron compounds (e.g., ferric carboxymaltose [FCM] and ferric derisomaltose [FDI]) are utilized in the treatment of iron deficiency anemia in non-dialysis-dependent chronic kidney disease (ND-CKD). Product-specific alterations in the metabolism of fibroblast growth factor 23 (FGF-23) leading to hypophosphatemia have been described for certain intravenous iron compounds, such as FCM, with potential effects on bone and cardiovascular health and quality of life. No prior head-to-head comparison between FCM and FDI exists in ND-CKD. This single-center exploratory double-blind randomized controlled trial primarily aimed to investigate the differential impact of FCM and FDI on FGF-23 and phosphate in patients with iron deficiency +/− anemia and ND-CKD (stages 3a–5 – serum ferritin <200 μg/L or serum ferritin 200–299 μg/L and transferrin saturation <20%). Patients were randomized (1:1) to receive either FCM or FDI over two infusions (1 month apart). Follow-up was 3 months. Measurements of serum intact FGF-23, phosphate, vitamin D metabolites, parathyroid hormone, other bone metabolism, cardiovascular, and quality of life markers were monitored. 168 patients were prescreened. Thirty-five patients were screened; 26 patients were randomized. The mean (standard deviation) age was 67.9 (12.4) years and 17 participants were male. Most participants had stage 4 CKD (median [interquartile range] estimated glomerular filtration rate [eGFR]: 18.0 [11.3] mL/min/1.73 m2). A higher than normal median (interquartile range) level of intact FGF-23 (212.1 [116.4] pg/mL) was noted. Serum phosphate was within normal range, while parathyroid hormone was higher and 1,25 (OH)2 vitamin D lower than the normal range. The “Iron and Phosphaturia – ExplorIRON-CKD” trial will provide important information regarding the differential effect of intravenous iron products in terms of FGF-23, phosphate, and other markers of bone and cardiovascular metabolism, alongside patient-reported outcome measures in patients with ND-CKD.

© 2023 The Author(s). Published by S. Karger AG, Basel

Introduction

Anemia is a common complication of chronic kidney disease with a number of implications ranging from impacts on mortality and morbidity to quality of life and healthcare economics [1]. It has a multifaceted pathophysiology that involves multiple factors such as nutritional deficiency, impaired iron metabolism, reduced erythropoietin production, and decreased red cell survival. Iron absorption and utilization are key in its development [1]. Therefore, addressing iron deficiency (absolute and functional) remains fundamental [2].

Intravenous iron is utilized in the treatment of iron deficiency anemia associated with non-dialysis-dependent chronic kidney disease (ND-CKD) [3]. Historical concerns regarding the safety of intravenous iron are slowly but persistently addressed [3], with large randomized controlled trials in both hemodialysis-dependent and ND-CKD patients suggesting improved outcomes with proactive correction of iron deficiency anemia [4, 5]. The development of third generation/modern intravenous iron compounds (e.g., ferumoxytol, ferric derisomaltose [FDI], ferric carboxymaltose [FCM]) appears to improve stability, iron release and reduce immunogenicity and has led to a decrease in severe hypersensitivity and allergic reactions [3, 6]. Systematic reviews and meta-analyses in both ND-CKD and hemodialysis-dependent CKD (combined trials: 46; n > 140,000) have commented and provided reassurance on the improved safety profile of intravenous iron throughout the CKD spectrum [7, 8]. However, hypophosphatemia has emerged as a distinct side effect secondary to intravenous iron therapy [9].

Initial theories proposed a link between hypophosphatemia incidence and intravenous iron use based on increased hematopoiesis; however, it has now transpired that this phenomenon is associated noticeably more with certain compounds [9]. Four systematic reviews and meta-analyses have concluded that hypophosphatemia is significantly more likely to be associated with FCM when compared to other intravenous iron compounds while also more severe and longer lasting [10–13]. Indeed, case series have isolated hypophosphatemia secondary to FCM and other intravenous iron preparations with similar carbohydrate moieties to be related to a number of bone complications including severe osteomalacia and fractures [9, 14]; such cases have not been witnessed with other modern intravenous iron compounds (e.g., ferumoxytol, FDI).

Research led by Wolf and colleagues revealed that hypophosphatemia stems from alterations in the metabolism of fibroblast growth factor 23 (FGF-23) [15]. Fibroblast growth factor 23 is a phosphatonin that stimulates phosphate loss through increased phosphaturia [16]. This is due to its klotho-associated action at the proximal convoluted tubule. Additionally, FGF-23 exerts phosphate-lowering effects via action on vitamin D and parathyroid hormone (PTH) [16]. The 6H syndrome is a term summarizing the sequelae of iatrogenic increase in FGF-23 due to intravenous iron (shown in Fig. 1) [17].

Fig. 1.

Concept of the iatrogenic 6H syndrome secondary to the infusion of certain intravenous iron products, which lead to impaired FGF-23 cleavage and increase in iFGF-23, in a two-hit hypothesis. The increase in iFGF-23 leads to decreased active vitamin D and increased phosphaturia, potentially having a key role in the development of secondary hyperparathyroidism.

Fibroblast growth factor 23 can be detected using two different assays: one focusing on intact (biologically active) FGF-23 (iFGF-23) and the other identifying the c-terminal part of FGF-23 (cFGF-23), hence sensing both iFGF-23 and c-terminal fragments of cleaved FGF-23 [18]. A number of genetic disorders can affect FGF-23 metabolism, while other acquired conditions such as CKD and iron deficiency also disturb the synthesis/cleavage mechanism [18]. Chronic kidney disease represents a state of increased FGF-23 concentration, which potentially is key in the development of CKD mineral bone disorder [19]. The exact nature of alterations in metabolism of FGF-23 in CKD is poorly understood, and therefore it is difficult to explain the discrepancies that exist between FGF-23 concentrations (iFGF-23 and cFGF-23) following intravenous iron administration in hemodialysis-dependent patients [20–24]. Nonetheless, a key study (n = 65) prospectively examined the effects of 1,000 mg of FCM on FGF-23 in patients with normal renal function, pregnant individuals, and patients with ND-CKD [25]. Focusing on the ND-CKD group , a 3.7-fold increase in iFGF-23 was noted within 2 days (130 [IQR: 96–162] pg/mL to 453 [IQR: 350–811] pg/mL; p < 0.0001) which was associated with a decrease in phosphate and 1,25 (OH)2 vitamin D. A decrease in cFGF-23 was noted [25]. These findings propose that in ND-CKD, the metabolism of FGF-23 is affected in a similar fashion following administration of FCM as that in patients with normal renal function and as demonstrated in comparative randomized controlled studies in patients without CKD [26, 27]. In essence, FCM can cause alterations in the cleavage of FGF-23 that may mimic the pathophysiology of autosomal dominant hypophosphatemic rickets [18]. This leads to an increased iFGF-23 in comparison to cFGF-23 and amplified availability of bioactive FGF-23, causing the phenomena associated with the 6H syndrome [18].

Beyond the effects of FGF-23 on hypophosphatemia, rickets, hyperparathyroidism, and the development of CKD mineral bone disorder, FGF-23 expresses other potential pathological signals both klotho dependent and klotho independent [28]. A systematic review and meta-analysis (studies: 34, n > 22,000) noted an increased risk ratio of myocardial infarction (1.33 [95% confidence interval (CI): 1.12–1.58]), heart failure (1.48 [95% CI: 1.29–1.69]), stroke (1.26 [95% CI: 1.13–1.41]), cardiovascular mortality (1.42 [95% CI: 1.27–1.60]), and all-cause mortality (non-cardiovascular) (1.52 [95% CI: 1.28–1.79]) in patients with raised FGF-23 concentrations [29]. Cohort studies focusing on patients with ND-CKD have identified an association between increased FGF-23 and cardiovascular mortality, worsening kidney function, and progression to hemodialysis even after classical risk factor adjustment [30, 31]. Increased FGF-23 concentrations have also been linked with left ventricular hypertrophy and fibrosis, pro-arrhythmogenic and hypertensive effects, and vascular pathology in vitro, in murine models, and in observational studies [32–36]. These may explain the worsening prognosis reported at higher FGF-23 concentrations. Intriguingly, raised FGF-23 levels have been associated with frailty and reduced functional status as determined by the 6-min walk test and peak VO2[37, 38]. Additionally, phase 1/2 studies investigating the effect of burosumab, an anti-FGF-23 human monoclonal antibody, on patients with X-linked hypophosphatemia and tumor-induced hypophosphatemia identified trends of improved quality of life [39, 40].

As modern intravenous iron products are increasingly used in ND-CKD, certain questions arise regarding the plausibility of a differential effect on FGF-23 and phosphate. As phosphate is a key mineral in the mitochondrial machinery and energy production and elevated FGF-23 has a number of potentially harmful effects, it is important to assess intravenous iron treatment effects in this patient group relevant to the 6H syndrome, bone metabolism, patient-related outcome measures, and cardiovascular status. In order to address these, the ExplorIRON-CKD exploratory trial was set up to aid in signal detection, trend identification, and hypothesis generation.

Methods/DesignTrial Design

This was a single-center, double-blind, randomized controlled trial aiming to recruit 30 patients with CKD stages 3a–5 (non-dialysis) and iron deficiency with/without anemia at a large tertiary renal center in the UK. Participants were randomized (1:1 ratio) to receive either FCM (Ferinject®; Vifor Pharma UK, Staines-upon-Thames, UK) or FDI (Monofer®; Pharmacosmos UK, Reading, UK) on two different occasions, 1 month apart. Total follow-up time was 3 months. Dosing was based on the summary of product characteristics of the two compounds (Table 1).

Table 1.HemoglobinWeight: 50–70 kgWeight: >70 kg≥100 g/LN/A1,500 mg<100 g/L1,500 mg2,000 mg

This trial was designed to primarily investigate the effect of intravenous iron compounds on iFGF-23 and phosphate concentrations. Other markers of the 6H syndrome and bone metabolism were also monitored. Additional secondary parameters included quality of life and functional status, markers of cardiovascular function and injury, hematopoietic response, kidney function, and safety. The outcomes are displayed in Table 2.

Table 2.OutcomeDomainPrimary outcome Percentage (%) change in iFGF-23 from baseline to 1–2 days post-infusion between FDI and FCMFGF-23, phosphate, and bone metabolismCo-primary outcome Composite of change in iFGF-23 and delta change in phosphate at 2 days and 2 weeks.FGF-23, phosphate, and bone metabolismPrespecified secondary outcomes % change in iFGF-23 from baseline to 2 weeks post-infusion between FDI and FCMFGF-23, phosphate, and bone metabolism Difference between the two treatments in 1,25 (OH)2 vitamin D at each time pointFGF-23, phosphate, and bone metabolism Difference between the two treatments in calcium at each time pointFGF-23, phosphate, and bone metabolism Difference between the two treatments in PTH at each time pointFGF-23, phosphate, and bone metabolism Difference between the two treatments in ALP at each time pointFGF-23, phosphate, and bone metabolism Difference between the two treatments in BALP at each time point and othersFGF-23, phosphate, and bone metabolism Difference between the two treatments in serum phosphate levels at each time pointFGF-23, phosphate, and bone metabolism Incidence of hypophosphatemia (<0.65 mmol/L) and severe hypophosphatemia (<0.3 mmol/L) at each time pointFGF-23, phosphate, and bone metabolism % failed repeat infusion due to hypophosphatemiaFGF-23, phosphate, and bone metabolism Effect /difference on quality of life (The Fatigue Severity Scale and The Short Form [36] Health Survey [SF-36])Functional status and patient-related outcome measures Effect on functional status (Duke Activity Status Index Score [DASI] and 1-min sit-to-stand test) over specific times cumulatively and between two groupsFunctional status and patient-related outcome measures Difference in the co-analysis of clinical endpoints including hemoglobin, ferritin response, and othersClinical measures Difference between the two treatments in NT-proBNPCardiovascular effect Difference between the two treatments in troponin TCardiovascular effect Effect of intravenous iron on pulse wave velocity measurementCardiovascular effect Difference in ECG parameters throughout the study period (PR interval prolongation; QRS prolongation, arrhythmia presence)Cardiovascular effect

No statistical calculation was employed to perform a power calculation, as this was a pilot exploratory trial looking for trends and to be used as hypothesis generation. The composite effect for change in FGF-23 and phosphate was designed based on prior studies in patients with ND-CKD receiving FCM as delineated below [25, 41].

Approvals and Ethics

The trial was conducted in accordance with the Good Clinical Practice Guidelines and the Declaration of Helsinki and received the favorable opinion of the Health Research Authority and the Research Ethics Committee Leeds West (20/YH/0005) and clinical trial authorization by the Medicines and Healthcare Products Regulatory Agency of the UK. The trial was registered with the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT number: 2019-004370-26) and was covered by NHS Indemnity Insurance.

Selection of Participants

Patients with stable ND-CKD (defined as a <20% variation in eGFR in the preceding 3 months) that were referred to the specialist renal anemia team were identified as potential participants. These patients were prescreened against the eligibility criteria (Table 3). Patients that fulfilled the hematological parameters set for iron deficiency +/− anemia were contacted and a comprehensive description of the trial was provided to gauge interest. Individuals that declined were asked where possible to provide the reason for declining. The patients expressing interest were sent the patient information summary. A second conversation ensued with an explanation of the rationale, design, and personal implications of the trial. At least 24 h were provided to patients before a final contact to ensure interest in the trial and subsequent screening. Questions were answered at all stages of the recruitment process. An informed consent was signed during screening, and patients were recruited once all eligibility criteria were met.

Table 3.

Inclusion/exclusion criteria

InclusionExclusion• Men and women aged ≥18 years• Pregnancy or lactation• Patients with CKD stages 3a–5 (not on dialysis)• Patients being investigated for potential blood loss• Resting blood pressure ≤160/95 mm Hg;• Dialysis patients (either peritoneal or hemodialysis)• Able to give written and signed informed patient consent• Weight ≤70kg; if hemoglobin is ≥100 g/L• Able to complete study assessments• Bleeding (>500 mL) or surgery in the 30 days prior to recruitment• Ferritin level ≤200 μg/L or transferrin saturation ≤20% and serum ferritin between 200 and 299 μg/L• Known allergy to iron therapy• Symptomatic ischemic heart disease• Hemoglobin <150 g/L• Hemochromatosis or history of acquired iron overload• Serum phosphate >0.8 mmol/L
• A negative pregnancy test for females of childbearing potential
• Suitable contraception for females of childbearing potential for duration of study• Parenteral iron therapy or red blood cell transfusion within the previous 6 weeks
• Inability to co-operate with study protocol
• Active infection or a CRP >50 mg/L where clinical suspicion arises
• Patients with potential confounding factors – cancer (with exception of basal cell or squamous cell carcinoma of the skin and cervical intraepithelial neoplasia)
• Patients who are unable or do not wish to give consent• Patients with known hemoglobinopathy, myelodysplasia, myeloma• Involvement in another clinical trial of an investigational medicinal product within the past 4 weeksRandomization Process

Participants were randomized in a 1:1 fashion using an online software (sealedenvelope.com). Participants and investigator were blind to allocation. The administering nurse and pharmacy were aware of preparation provided and held details of iron therapy, with no access to the investigator. A specific drug prescription card was designed. No stratification took place.

The Intervention

Participants received either FDI or FCM on visit 2 (baseline) and visit 5 as per randomization. The iron product was dissolved in 100 mL of 0.9% sodium chloride and was administered as an intravenous infusion over 15–30 min. The initial dose offered to all participants in the first administration was 1,000 mg. The participants would receive either a total of 1,500 or 2,000 mg based on baseline hemoglobin concentration and weight. Patients who developed moderate hypophosphatemia (serum phosphate <0.65 mmol/L) after the first dose were excluded from receiving a second dose.

Follow-Up

The trial duration from initial administration of intravenous iron product (visit 2) was 3 months and included 8 visits. Table 4 outlines the schedule of events accompanying Figure 2 that represents the study proceedings. The investigator sought information on safety and well-being, recording adverse and serious adverse events, and monitoring any new symptomatology at all visits.

Table 4.Visit 1:
−30 – 0 days after screeningVisit 2: baseline
1st IV ironVisit 3:
1–2 days post visit 2Visit 4:
11–17 days post visit 2Visit 5:
25–35 days post visit 2; 2nd IV iron (if phosphate >0.65 mmol/LVisit 6: 26–37 days post visit 2Visit 7: 53–60 days post visit 2Visit 8:
75–105 days post visit 2Eligibility screening and consentXDemographicsXComorbidities including CKD etiology and lifestyleXPhysical examinationXConcomitant medication including erythropoiesis stimulating agent doseXXXXXXXXSafety assessment (adverse events)XXXXXXXIntervention Intravenous ironXXClinically relevant markers (blood and urine) HemoglobinXXXXX Hematinics (transferrin saturation, ferritin)XXXXXX Renal function (eGFR, creatinine)XXXX Inflammation (C-reactive protein)+/−XXXX Renal injury (urinary protein:creatinine ratio)XXXXBone markers (blood and urine) Urinary excretion of phosphate (24 h and fractional excretion of phosphate)XXXXXX CalciumXXXXXX PhosphateXXXXXX PTHXXXXXX Vitamin D and metabolitesXXXXXX ALPXXXXXX BALPXXXXXX CTxXXXXXX P1NPXXXXXX 24-h urinary phosphate collectionXXXXXX Intact fibroblast growth factor 23XXXXXXCardiac assessment NT-proBNPXXXX Troponin TXXXXXXX ElectrocardiographyXXXXX Pulse wave velocityXXXXQuality of Life Questionnaires Fatigue Severity ScaleXXXX Short-form 36 Questionnaire – Version 1.0XXXXFunctional status Duke Activity Status Index scoreXXXX 1-min sit-to-stand testXXXXFig. 2.

Study schematic – patients were randomized in a 1:1 ratio to receive either FCM or FDI, with weight and hemoglobin based dosing. Follow-up is according to Table 4.

Baseline Measurements

Eligible participants were invited to attend a baseline visit, where demographics (sex, age, height, weight, smoking status), concise background medical history (CKD stage, underlying pathology, cardiovascular comorbidity, malignancy), and medications were recorded. A physical examination took place.

Blood Investigations

Blood samples were collected to measure the concentration of bone metabolism markers (iFGF-23, phosphate, calcium, vitamin D and metabolites, PTH, alkaline phosphatase [ALP], bone-specific ALP, C-terminal cross-linked telopeptide, procollagen-type 1 N-terminal propeptide), the clinical and hematinic response (hemoglobin, transferrin saturation, ferritin, creatinine, eGFR, CRP), and cardiovascular status (troponin T and NT-proBNP). Blood investigations relevant to bone metabolism were taken at every visit except visit 8 (3 months following initial iron administration). Certain samples were analyzed at the Hull University Teaching Hospitals NHS Trust at the time of collection and did not require further handling. Samples including iFGF-23, vitamin D and metabolites, bone-specific ALP, and C-terminal cross-linked telopeptide were analyzed at the University of East Anglia, therefore requiring centrifugation (3,000 rpm) and storage in secure freezers at −80°C. These samples were transferred over dry ice and slowly thawed and analyzed at the University of East Anglia. All blood handling, storage, transfer, and analysis took place according to the Human Tissue Act. The assays used in bone and cardiovascular metabolism are listed in Table 5. Vitamin D metabolites except 1,25 (OH)2 vitamin D were analyzed using the methods previously described by Tang and colleagues [42].

Table 5.

Assays used for bone/cardiovascular markers

MeasureAssay/method usedIntact FGF-23Chemiluminescence Assay (Liaison XL, DiaSorin S.p.A., Saluggia, Italy)1,25(OH)2 vitamin DChemiluminescence Assay (Liaison XL, DiaSorin S.p.A., Saluggia, Italy)25(OH)2 vitamin D and 24(R),25(OH)2 vitamin DMethod used: liquid chromatography tandem mass spectrometry as described by Tang et al., 2017PTHTwo-site immunoenzymatic (“sandwich”) assay – Access Intact PTH Assay (Beckman Coulter, California, USA)BALPEnzyme-linked immunosorbent assays (Quidel, San Diego, California, USA)CTxElectrochemiluminescence sandwich immunoassay (Roche Diagnostics, Risch-Rotkreuz, Switzerland)P1NPElectrochemiluminescence assay – Elecsys total P1NP assay (Roche Diagnostics, Risch-Rotkreuz, Switzerland)NT-proBNPElectrochemiluminescence assay – Elecsys proBNP II immunoassay (Roche Diagnostics, Risch-Rotkreuz, Switzerland)Troponin TElectrochemiluminescence assay – Elecsys Troponin T assay (Roche Diagnostics, Risch-Rotkreuz, Switzerland)Urine Investigations

Spot urine and 24-h urine collections took place during the trial. Spot urine was used only in the calculation of protein:creatinine ratio as evidence of proteinuria. 24-h urine collection was used to measure the 24-h secretion of phosphate and calculate fractional excretion of phosphate as measures of phosphaturia. Fractional excretion of phosphate was quantified using the Walton and Bijvoet equation [43].

Fractional excretion of phosphate = (24-h urine phosphate × serum creatinine) × 100/(serum phosphate × 24-h urine creatinine)

Urine investigations associated with phosphaturia were obtained at every visit except visit 8.

Quality of Life and Functional Status

Quality of life was assessed using the SF-36 questionnaire v1.0 [44] and the Fatigue Severity Scale (FSS) [45], which have previously shown good validity, and test-retest reliability. In particular, the SF-36 v1.0 has demonstrated such elements in patients with CKD and anemia [46]. Quality of life was evaluated at baseline, 1 month (visit 5), 2 months (visit 7), and 3 months following first iron administration (visit 8).

The Duke Activity Status Index (DASI) and the 1-min sit-to-stand test were used to assess functional status. The DASI uses 12 questions to noninvasively evaluate the VO2 peak, a surrogate measure of aerobic fitness, and is considered reliable in patients with CKD [47, 48]. The reported scores of DASI were used to calculate the metabolic cost of task (MET) as a measure of functional status. During the 1-min sit-to-stand test, the full sit-stand cycles from a standard height chair (46 cm) without armrests were counted. The same chair was used throughout the study. The 1-min sit-to-stand test is considered reproducible and relevant in CKD [48–50].

Cardiovascular Status

Electrocardiography (12-lead) took place at baseline, visit 3, visit 5, visit 7, and visit 8 to identify any potential pro-arrhythmogenic effect or changes to electrical conductance intervals including PR, QRS, and QTc. Pulse wave velocity, which is advocated for noninvasive arterial stiffness determination by the American Heart Association, was measured at baseline, visits 5, 7, and 8 using the Enverdis® Vascular Explorer (Enverdis GmbH Medical Solutions, Jena, Germany). A single investigator performed all measurements as per manufacturer’s instructions.

Statistical Analysis

Statistical analysis will be reported as per our statistical analysis plan. Baseline results are presented below. The findings will be reported in accordance with the Consort Statement for Pilot and Feasibility trials. Categorical data are represented as number (%). Continuous data are reported as mean (standard deviation) where normal distribution exists and median (IQR) in non-normal distribution. Descriptive statistics will be employed to identify any trends given the exploratory nature of the trial. Percentage change will be calculated in terms of the two outcomes of interest that form the primary and co-primary outcomes (iFGF-23 and phosphate). The two groups will be compared at each time point statistically using independent T-test or Mann-Whitney U test.

The combined effect of intravenous iron on FGF-23 and phosphate as composite change will be assessed based on previous work by Huang and colleagues (maximum %change iFGF-23 on day 2: 248% [p < 0.0001], maximum % change in phosphate on day 7: −23% [p < 0.0001]) and Stöhr and colleagues (maximum %change iFGF-23 on day 1: 80% [nonsignificant], maximum % change in phosphate day 14: −20% [nonsignificant]) in patients with ND-CKD receiving FCM [25, 41].

Baseline Results

A total of 168 patients were referred to the renal anemia service between March 2020 and July 2021 and were prescreened; 99 fulfilled the eligibility criteria and were contacted. Sixty-four individuals declined participation. The commonest reason for declining, where provided, was the COVID-19 pandemic (n = 13; 43.3%). The flow of patients from screening to randomization, alongside reasons for not attending, is summarized in Figure 3.

Fig. 3.

Patient flow in study from prescreening to randomization.

Thirty-five individuals accepted to be screened; 9 were ineligible at screening. High ferritin concentration was the commonest reason for ineligibility (n = 4; 44.4%). One individual who was initially excluded from the study due to active infection was later re-referred to the renal anemia services and was eligible. Twenty-seven individuals were recruited. One individual withdrew from the trial prior to randomization. The baseline characteristics of our cohort are displayed in Table 6 in terms of continuous data and Table 7 relevant to categorical variables.

Table 6.

Baseline data for whole cohort – continuous variables

VariablePopulation**Value (median [IQR]/mean [SD])Reference range – normal values (where applicable)Age,* years2667.9 (12.4)N/ABMI, kg/m22627.8 (8.4)N/AiFGF-23, pg/mL26212.1 (116.4)28.0–121.0Phosphate, mmol/L261.28 (0.31)0.80–1.50Hemoglobin,* g/L26100.3 (13.5)>120.0Serum ferritin, μg/L2676.5 (118.8)>100.0Transferrin saturation, %2615.0 (6.8)>20%Creatinine,* μmol/L26269.5 (88.2)N/AeGFR, mL/min/1.73 m22618.0 (11.3)N/ACRP, mg/L267.4 (14.0)<8.0urinary PCR, mg/mmoL2487.5 (311.3)<50.024-h urinary phosphate, mmol/24 h2617.5 (11.3)16.0–48.0Fractional excretion of phosphate, %2643.2 (22.7)<20%Calcium,* mmol/L262.35 (0.08)2.20–2.60PTH, pmol/L2617.4 (11.3)1.30–9.301,25 (OH)2 vitamin D,* pmol/L2645.6 (22.2)48.0–150.025 (OH)2 vitamin D, nmol/L