Effect of Active Vitamin D and Etelcalcetide on Human Osteoclasts in Patients With Chronic Kidney Disease
Condition: Bone Disorder; Chronic Kidney Diseases
MeSH terms: Bone Diseases; Kidney Diseases; Renal Insufficiency, Chronic
Study type: Observational

Summary: 
      The optimal management of mineral and bone disorders associated to chronic kidney disease
      (CKD-MBD) is a daily challenge for nephrologists. Its consequences may be immediate
      (biological abnormalities such as hypocalcemia, hyperphosphatemia, hyperparathyroidism, etc.)
      or delayed (fractures, renal osteodystrophy, vascular calcifications, increased
      morbi-mortality and growth retardation in the youngest patients). CKD-MBD is defined by the
      association of one or more of the following abnormalities: 1/ disturbances in calcium,
      phosphate, PTH or vitamin D metabolism, 2/ bone and growth abnormalities, and 3/
      calcifications of vessels or soft tissues .

      Three main bone characteristics can be modified by CKD, namely turnover, mineralization and
      volume. They should therefore be carefully assessed to distinguish between the different
      sub-types of renal osteodystrophy, as defined in the 2006 K-DIGO guidelines on the TMV
      classification . The primary bone lesion in pediatric CKD, at least in pediatric patients
      reaching end-stage renal disease without any previous management, is the
      high-turnover/hyperparathyroidism, because of high circulating PTH levels with low 1-25
      vitamin D levels. Conversely, low turnover (or adynamic bone) may be observed in dialysis
      children receiving too much calcium and/or vitamin D analogs. All these lesions are
      deleterious on the long-term, increasing both the risk of growth retardation, fractures and
      vascular calcifications .

      In order to better understand the complex pathophysiology of renal osteodystrophy, biomarkers
      of bone and phosphate/calcium metabolism may be used, but their interpretation may be
      challenging in the context of CKD. The gold standard remains bone biopsy at the iliac crest
      with histomorphometry, but it is rarely performed in Europe .

      The research team of this study has developed and validated a unique non-invasive technique
      to differentiate circulating human monocytes into mature and functional osteoclasts, using
      only 15 mL of total blood (instead of conventional techniques they used to use, with 200 to
      250 mL of total blood). They propose to use this innovative tool in the specific setting of
      CKD.

      The current management of CKD-MBD consists mainly of correcting native vitamin D deficiency,
      decreasing phosphate levels (using nutritional management and phosphate-binders), and
      decreasing PTH levels (using active vitamin D, calcimimetics such as cinacalcet and
      etelcalcetide, and/or surgical parathyroidectomy) . Active vitamin D analogs and
      calcimimetics are cornerstone of this management.

      The first working hypothesis is the following: when CKD progresses and glomerular filtration
      rate (GFR) decreases, 1-25-D is able to inhibit osteoclastic differentiation, however to a
      lesser extent to what is observed in healthy controls with normal renal function.

      The second working hypothesis is therefore the following: etecalcetide could be an inhibitor
      of osteoclastic resorption and a stimulator of osteoblastogenesis. When CKD worsens and GFR
      decreases, etelcalcetide inhibits osteoclastic differentiation, however to a lesser extent to
      what is observed in subjects with normal renal function.

      Aims In Vitro

        1. Effects of 1-25-D and etecalcetide on human osteoclastogenesis and osteoclastic
           resorption (in cells obtained from CKD patients at different stages of CKD)

        2. Effects of 1-25-D and etecalcetide on murine osteoblastogenesis and mineralization
    


Intervention name(s): Measure of etecalcetide on osteoclastic biology
Intervention type(s): Other
Intervention description(s): In vitro evaluation of osteoclastic biology after blood sampling of patients.
Observational model: Other
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        35 children with chronic kidney disease (CKD). 5 children per CKD group: CKD stage 1, stage
        2, stage 3, stage 4, stage 5, dialysis, transplantation.
      
Biospecimen description: 
      Samples specific to the study (urea, creatininemia, CA²+, Phosphorus, PTH, Alkaline
      phosphatase, vitamin D) will be collected and analyzed as part of the usual care. An
      additional 20 mL blood is collected for analysis of osteoclastogenesis