Validation of New Markers of Glomerular Filtration Rate: Dota Gadolinium and Calcium EDTA (MultiGFR)

Study Overview
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Brief Summary
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The purpose of this study is to validate in comparison to a reference method (inuline) two novel non-radioactive biomarkers for glomerular filtration rate (GFR) measurement in chronic-kidney disease (CKD) patients and in healthy volunteers: Calcium-EDTA and Gd-DOTA.

Detailed Description
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Research on estimation and measurement of renal function has been greatly stimulated by the international concept of chronic kidney disease (CKD) and its classification into stages of severity based on the level of glomerular filtration rate (GFR) (National Kidney Foundation KDOQI and ANAES in 2002, KDIGO conference in 2005), and by the development of recommendations for clinical practice according to this stages. Many efforts have focused on the validation of new formula to estimate GFR from endogenous markers. Nevertheless, the performance of these formula is limited by a large inter individual variability, that requires in many cases the use of GFR measurement using exogenous tracers (extreme anthropometric characteristics, abnormal production of endogenous tracers, potential kidney donors, dose adjustment, nephrotoxicity monitoring…). The use of GFR measurement is burdened by a lack of availability due to methodological, biological and regulatory (for radioactive tracers) constraints. That's why a need exists for new validated tracers that will be more accessible and easier to use. Moreover, there are differences between the measurement techniques: single injection of the tracer or concentration equilibrium obtained by continuous infusion; plasma or urinary clearance. Two new tracers for GFR measurement are here offered for validation: Gd-DOTA and Calcium-EDTA. Gd-DOTA is a macrocyclic paramagnetic contrast product, which can be measured using an ELISA type immunoassay. Although being widely used in radiology with higher doses than those that will be used for GFR measurement in the multi-GFR study, Gd-DOTA has never been involved in systemic nephrogenic fibrosis cases (ProFinest study). Calcium-EDTA has been used for many years for the chelation of heavy metals. Recently, a colorimetric assay for Calcium-EDTA measurement has been developed. Gd-DOTA and Calcium-EDTA clearance for GFR measurement will be compared to inuline clearance in healthy volunteers (25 for each new tracer) and CKD patients (150 for each new tracer).

Official Title
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MultiGFR: Equivalency Study of Different Methods of Measuring Glomerular Filtration Rate

Conditions
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Renal Insufficiency, Chronic, Kidney Diseases

Intervention / Treatment
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* Drug: Calcium EDTA
* Drug: Gd-DOTA


Participation Criteria
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Eligibility Criteria
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Patients : Inclusion Criteria: males or females without pregnancy age : 18-75 stable chronic kidney disease stages 1 to 4 (MDRD KDIGO 2005), estimated GFR > 15 mL/min/1.73m² clinical GFR measurement indication Exclusion Criteria: kidney transplantation allergic acute disease leading to acute change in GFR heavy metals poisoning (treated or not) gadolinium contrast agent in the previous month Healthy volunteers : Inclusion criteria males, 18-35 years old weight : 60-100 kg , BMI 18-27 kg/m² estimated GFR > 90 mL/min/1.73 m² (MDRD) acute diseases in the previous 7 days Exclusion criteria : uro-nephrological disease (past or present) nephrotoxic drug chronic use in the previous 2 months allergic systemic disease (acute or chronic)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inuline - Calcium EDTA<br>Calcium EDTA clearance for GFR measurement is compared to inuline clearance in healthy volunteers and CKD patients (stage 1 to 4). | Drug: Calcium EDTA<br>* Calcium EDTA for equilibrium GFR measurement : bolus injection 30 mg/kg, then 10 mg/min perfusion for estimated renal clearance 100 mL /min for 4 hours. Calcium EDTA for single injection GFR measurement : bolus injection depending on the estimated GFR<br>* Other names: Edetate Disodium Calcium;|
| Experimental: Inuline - Gd-DOTA<br>Gd-DOTA clearance for GFR measurement is compared to inuline clearance in healthy volunteers and CKD patients (stage 1 to 4). | Drug: Gd-DOTA<br>* Gd-DOTA for equilibrium GFR measurement : bolus injection 56 ng/kg, then 28 ng/min perfusion for estimated renal clearance 100 mL /min for 4 hours. Gd-DOTA for single injection GFR measurement : bolus injection depending on the estimated GFR<br>* Other names: Dota gadolinium;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Calcium EDTA and Gd-DOTA clearance for glomerular filtration rate measurement | Calcium EDTA or Gd-DOTA clearance for GFR measurement is compared to inuline clearance in healthy volunteers (n= 25) and in CKD patients (n= 150, stages 1 to 4, 30 patients for each stage) at equilibrium by measuring urinary clearances of inuline and Calcium EDTA or Gd-DOTA continuously co-infused after a loading dose. | 1 day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Calcium EDTA and Gd-DOTA clearance for glomerular filtration rate measurement in each CKD stage | Calcium EDTA or Gd-DOTA clearance for GFR measurement is compared to inuline clearance in healthy volunteers (n= 25) and in CKD patients (n= 150, stages 1 to 4, 30 patients for each stage) at equilibrium by measuring urinary clearances of inuline and Calcium EDTA or Gd-DOTA continuously co-infused after a loading dose. | 1 day | 
| Calcium EDTA and Gd-DOTA clearance reproducibility for GFR measurement | Calcium EDTA or Gd-DOTA clearance is measured twice at day 1 and day 15 in healthy volunteers (n= 25) and in CKD patients (n= 25, stages 1 to 4, 5 patients for each stage) at equilibrium by measuring urinary clearances of inuline and Calcium EDTA or Gd-DOTA continuously co-infused after a loading dose. | 15 days | 
| Calcium EDTA and Gd-DOTA clearance with single injection for GFR measurement | Calcium EDTA or Gd-DOTA clearance is measured twice at day 1 and day 15 in healthy volunteers (n= 25) and in CKD patients (n= 25, stages 1 to 4, 5 patients for each stage) at equilibrium at day 1 by measuring urinary clearances of inuline and Calcium EDTA or Gd-DOTA continuously co-infused after a loading dose and at day 15 with a single loading dose of Calcium EDTA or Gd-DOTA | 15 days | 
| Volumes of distribution of Calcium EDTA and Gd-DOTA | Calcium EDTA or Gd-DOTA apparent volumes of distribution are compared to inuline apparent volume of distribution in healthy volunteers (n= 25) and in CKD patients (n= 150, stages 1 to 4, 30 patients for each stage). | 1 day | 
| Number of participants with adverse events as a measure of safety. | Each event following Calcium EDTA or Gd-DOTA infusion will be listed in healthy volunteers (n = 50) and in patients (n = 300). | 45 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Inulin, Ca-EDTA, Gd-DOTA, Chronic kidney disease, glomerular filtration rate measurement