Evaluation of Interaction Between Immunosuppressive Drugs and Protein-bound Uremic Toxins in Renal Transplant Patients (DRUGTOX)

The majority of studies conducted on uremic toxins involve patients before end stage renal failure or dialysis patients. Only a few studies have focused on transplant patients. In addition, the relationship between serum concentrations of uremic toxins and immunosuppressive drug concentrations has never been studied to date.

The investigator research hypothesis is that, due to the strong plasma protein binding of calcineurin inhibitors, an interaction with protein-bound uremic toxins could alter drug concentrations that explain difficulties in reaching therapeutic targets.

Study Overview

• Status: Withdrawn
• Conditions: Immunosuppression; Kidney Transplant; Uremic; Toxemia
• Intervention / Treatment: Other: calcineurin inhibitor dosage

Detailed Description

In France, the national prevalence of end-stage kidney disease (including dialysis and renal transplantation) is 1,232 per million inhabitants. As in all transplants, renal transplantation needs immunosuppressive therapy. This treatment may be difficult to adjust in some patients. However, achieving the therapeutic target is essential to have an efficiency synonymous with graft survival and better tolerance to the drug. The immunosuppressive class drug of interest in the present project is the class of calcineurin inhibitors (tacrolimus and ciclosporin) that are widely used in both initial and maintenance immunosuppression. These drugs have the pharmacological specificities to be highly bound to plasma proteins and requiring pharmacological therapeutic monitoring.

With the progression of chronic kidney disease, many molecules accumulate as a result of decreased kidney excretion capacity, such as compounds called uremic toxins. The investigators research is part of the European network for the study of these toxins (Eutox group) and has largely contributed to the better knowledge of these toxins. In particular, they are defined by their dose-dependent deleterious effects. These molecules are classified, according to their molecular weight, into small molecules, medium molecules and molecules strongly bound to plasma proteins (p-cresyl sulphate [pCS], indoxyl sulphate [IS] and indol acetic acid [IAA]). This last group of protein will be evaluated in this project.

The majority of studies conducted on uremic toxins involve patients before end stage renal failure or dialysis patients. Only a few studies have focused on transplant patients. In addition, the relationship between serum concentrations of uremic toxins and immunosuppressive drug concentrations has never been studied to date.

the investigator research hypothesis is that, due to the strong plasma protein binding of calcineurin inhibitors, an interaction with protein-bound uremic toxins could alter drug concentrations that explain difficulties in reaching therapeutic targets.

• Study Type: Observational

Contacts and Locations

Study Locations

• France
  • Amiens, France, 80480
    • CHU Amiens

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Kidney transplant population followed at CHU Amiens (group 1 ⇾ DFG> 40 ml / min, group 2 ⇾ DFG < 40 ml / min).

Description

Inclusion Criteria:

• renal transplant patient followed at the University Hospital of Amiens and transplanted for over a year
• patient treated with a calcineurin inhibitor
• patient having a blood test for evaluation of calcineurin inhibitor concentrations by the toxicology pharmacology laboratory of the Amiens-Picardie University Hospital,
• patient affiliated with social security.

Exclusion Criteria:

• patient in phase of acute rejection of the graft,
• patient having opposed his participation,
• patient under guardianship or curatorship or deprived of public right

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
DFG> 40 ml / min; Kidney transplant population followed at CHU Amiens (group 1 ⇾ DFG> 40 ml / min).	Other: calcineurin inhibitor dosage; The dosage of calcineurin inhibitors will be done as usual by the toxicology pharmacology laboratory of the CHU Amiens-Picardie. If the patient does not object, the determination of protein-bound uremic toxins from the rest of the collected blood tube will be performed using high performance liquid chromatography.
DFG < 40 ml / min; Kidney transplant population followed at CHU Amiens (group 2 ⇾ DFG < 40 ml / min).	Other: calcineurin inhibitor dosage; The dosage of calcineurin inhibitors will be done as usual by the toxicology pharmacology laboratory of the CHU Amiens-Picardie. If the patient does not object, the determination of protein-bound uremic toxins from the rest of the collected blood tube will be performed using high performance liquid chromatography.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
plasma tacrolimus concentration without plasma uremic toxin adjustment	at day 0
plasma tacrolimus concentration with plasma uremic toxin adjustment	at day 0

Secondary Outcome Measures

Outcome Measure	Time Frame
plasma ciclosporin concentration without plasma uremic toxin adjustment	at day 0
plasma ciclosporin concentration with plasma uremic toxin adjustment	at day 0

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire, Amiens
• Investigators: Principal Investigator: Sandra Bodeau, MD, CHU Amiens; Principal Investigator: Youssef Bennis, MD, CHU Amiens

Study record dates

Study Major Dates

• Study Start (Actual): July 6, 2021
• Primary Completion (Actual): September 12, 2023
• Study Completion (Actual): September 12, 2023

Study Registration Dates

• First Submitted: July 6, 2021
• First Submitted That Met QC Criteria: July 6, 2021
• First Posted (Actual): July 15, 2021

Study Record Updates

• Last Update Posted (Actual): September 14, 2023
• Last Update Submitted That Met QC Criteria: September 12, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Immunosuppression; Kidney Transplant; Uremic; Toxemia
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Calcineurin Inhibitors
• Other Study ID Numbers: PI2019_843_0060

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No