Contribution of Renal Function to Endothelial Dysfunction in Living Kidney Donors and Transplant Recipients (CONFUCIUS)

Estimating the Contribution of Renal Function to Endothelial Dysfunction by a Two-cohort Study: Living Kidney Donors and Their Transplant Recipients

Endothelial dysfunction one-year after transplantation mainly depends on transplant-associated factors and only marginally on reduced renal function.

OBJETIVES Primary objective Estimate the contribution of renal dysfunction to endothelial dysfunction in two cohorts of patients, living kidney donors and their transplant recipients.

Secondary objectives

To evaluate in both cohorts of patients before and after nephrectomy/transplantation the evolution of the following parameters:

1. Renal function (iohexolGFR, proteinuria/microalbuminuria).
2. Blood pressure (24 h ambulatory blood pressure measurement)
3. Surrogate variables of subclinical atherosclerosis (carotid ultrasound, ankle-brachial index, pulse wave velocity).

DESIGN Non-interventional, prospective, multicenter, longitudinal study of two cohorts: living kidney donors and their transplant recipients.

Study Overview

• Status: Unknown
• Conditions: Chronic Kidney Disease; Endothelial Dysfunction; Disorder Related to Renal Transplantation
• Intervention / Treatment: Other: Endothelial dysfunction

Detailed Description

HYPOTHESIS

BACKGROUND: Chronic kidney disease (CKD) is associated with endothelial dysfunction, but the link between cardiovascular risk and CKD is difficult to establish because other conditions such as diabetes, hypertension and transplant-related factors are present in these patients. Living donors are healthy individuals that represent a near-ideal experimental model of CKD since they undergo a time-defined reduction of GFR after nephrectomy in the absence of other confounding factors present in patients with mild to moderate CKD.

HYPOTHESIS: Reduction of GFR after donation is associated with increased while renal transplantation is associated with reduced endothelial dysfunction markers.

AIM: To prospectively evaluate biomarkers of endothelial dysfunction and surrogate variables of subclinical atherosclerosis in a cohort of living kidney donors before and one year after donation and in their recipients before and one year after transplantation.

PATIENTS AND METHODS: In two cohorts of 60 living kidney donors (1 month before and 1 year after donation) and in their 60 renal transplant recipients (1 month before and 1 year after transplantation) the following variables will be recorded: iohexol glomerular filtration rate (GFR), proteinuria, microalbuminuria, insulinemia, oral glucose tolerance test, total and LDL/HDL cholesterol, number of carotid plaques and intima-media thickness, carotid-femoral pulse wave velocity, ankle-brachial index, 24-hours ambulatory monitoring of blood pressure. The following biomarkers of endothelial dysfunction and subclinical inflammation will be determined: SVCAM-1, PTX3, ICAM-1, von Willebrand factor, E-selectin, platelet/endothelial cell adhesion molecule (PECAM1), interleukin 6 (IL-6), soluble receptor of tumor necrosis factor (sTNFR1 and sTNFR2), high sensitive C reactive protein (hs-CRP) and soluble TNF-like weak inducer of apoptosis (sTWEAK).

EXPECTED RESULTS. In healthy subjects decrease of renal function after living donation will be associated with increased endothelial dysfunction markers. On the contrary, after transplantation a decrease of endothelial dysfunction markers will be observed. Despite at one year both cohorts of patients will have a similar GFR, the investigators expect that amelioration of endothelial dysfunction in transplants will be higher than worsening of endothelial dysfunction in their donors. Thus, the study of these two cohorts will allow estimating the contribution of renal dysfunction per se and transplant-associated comorbidities to endothelial dysfunction in chronic kidney disease.

• Study Type: Observational
• Enrollment (Anticipated): 120

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08003
    • Recruiting
    • Hospital del Mar
    • Contact: Julio Pascual, MD, PhD; Phone Number: +34 932 48 31 62; Email: 99176@parcdesalutmar.cat
    • Sub-Investigator: Marta Crespo, MD,PhD
  • Barcelona, Spain, 08035
    • Recruiting
    • Vall d'Hebron Research Institute
    • Contact: Francesc Moreso, MD, PhD; Phone Number: +34 93 274 60 79; Email: fjmoreso@vhebron.net
    • Principal Investigator: Francesc Moreso, MD, PhD
    • Principal Investigator: Daniel Seron, MD, PhD
    • Sub-Investigator: Manel Perello, MD
    • Sub-Investigator: Carme Cantarell, MD
    • Sub-Investigator: Joana Sellarés, MD
    • Sub-Investigator: Natalia Ramos, MD, PhD
  • Malaga, Spain, 29010
    • Recruiting
    • Hospital Regional Universitario Carlos Haya
    • Contact: Domingo Hernandez, MD, PhD; Phone Number: +34 951 29 11 74; Email: domingohernandez@gmail.com
    • Sub-Investigator: Mercedes Cabello
  • Islas Canarias
    • Santa Cruz de Tenerife, Islas Canarias, Spain, 38320
      • Not yet recruiting
      • Hospital Universitario Canarias
      • Contact: Armando Torres, MD, PhD; Phone Number: +34 922 31 93 38; Email: atorres@gmail.com
      • Sub-Investigator: Ana Gonzalez-Rinne, MD
      • Sub-Investigator: Esteban Porrini, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Cohort 1

Healthy subjects who will undergo a nephrectomy as part of the living donor program at each participating center.

Cohort 2

Renal transplant recipients from cohort 1

Description

Inclusion Criteria cohort 1:

• No history of familiar nephropathies and/other diseases that may increase the risk for renal disease in the future.
• Donor age ≥ 18 years
• Isotopic GFR > 80 ml/min/1.73m2
• Microalbuminuria< 30 mg/g
• Normal urinary sediment
• Normal blood pressure defined as <120/90 mmHg and without other risk factors for cardiovascular disease, and with good/normal kidney function or well-controlled hypertension with one anti-hypertensive drug,
• No previous history of diabetes including gestational diabetes and fasting glucose < 126 mg/dl and 2h serum glucose after 75 g oral glucose tolerance test < 200 mg/dl
• Signed informed consent

Inclusion criteria cohort 2:

• Chronic kidney disease stage 5
• Negative complement dependent lymphocytotoxicity donor-recipient cross-match.
• Informed signed consent

Exclusion Criteria cohort 1:

• History of cancer except non-melanoma cutaneous neoplasia
• History of vasculitis (e.g. lupus), sarcoidosis, gastrointestinal inflammatory diseases, autoimmune-disease
• History of major cardiovascular events
• History of deep vein thrombosis or pulmonary embolism.
• Active infection including hepatitis B, C and HIV infections.
• Anatomic vascular variants precluding laparoscopic nephrectomy
• Renal stones except a solitary lithiasis< 1.5 cm once metabolic disorders are ruled out
• Major psychiatric disorders
• Active alcohol, tobacco or drug abuse
• Obesity defined as body mass index > 35 kg/m2.
• Pregnancy

Exclusion criteria cohort 2:

• Glomerulonephritis with high recurrence rate after transplantation (focal segmental glomerulosclerosis and type II membranoproliferative glomerulonephritis)
• Severe aortoiliac atherosclerosis precluding transplantation
• Major psychiatric disorders
• Alcohol and drug abuse
• Active infection
• Patients requiring desensitization treatment before transplantation.
• Pregnancy

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Endothelial dysfunction in Cohort 1; Assessment of endothelial dysfunction in healthy subjects who will undergo a nephrectomy as part of the living donor program at each participating center.	Other: Endothelial dysfunction; One month before surgery and one year after, the following procedures will be performed in donors and recipients: Blood samples will be obtained for the measurement of endothelial dysfunction and low grade inflammation markers.; Atherosclerotic burden: carotid ultrasound to determine the number of plaques and intima-media thickness, carotid-femoral pulse wave velocity (m/s) will be performed by pulse tonometry.; Ambulatory blood pressure monitoring with overnight-automated ABPM monitor; Estimation of glomerular filtration rate by Iohexol method
Endothelial dysfunction in Cohort 2; Assessment of endothelial dysfunction in renal transplant recipients from cohort 1	Other: Endothelial dysfunction; One month before surgery and one year after, the following procedures will be performed in donors and recipients: Blood samples will be obtained for the measurement of endothelial dysfunction and low grade inflammation markers.; Atherosclerotic burden: carotid ultrasound to determine the number of plaques and intima-media thickness, carotid-femoral pulse wave velocity (m/s) will be performed by pulse tonometry.; Ambulatory blood pressure monitoring with overnight-automated ABPM monitor; Estimation of glomerular filtration rate by Iohexol method

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentual change of sVCAM	Biomarker of endothelial dysfunction: Soluble VCAM (vascular cell adhesion molecule). Determination of serum levels by Luminex. Percentual change between baseline and 1 year levels.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glomerular filtration rate	Renal function will be estimated before donation by iohexol clearance and expressed as mL/min/1.73 m2 in donors and at 1 year in donors and recipients.	1 year
Microalbuminuria	Microalbuminuria (mg/g creatinine) will be determined before donation and at 1 year in donors and at 1 year in transplant recipients.	1 year
Blood pressure (24 h ambulatory blood pressure measurement)	Ambulatory blood pressure monitoring (mm Hg) with overnight-automated ABPM monitor (Spacelab 90207; Spacelabs Healthcare,USA) with appropriate cuff sizes for each patient.	1 year
Number of carotid plaques and carotid intima-media thickness	Atherosclerotic burden: carotid ultrasound to determine the number of plaques and intima-media thickness will be held in both carotid arteries with a high-frequency (8-12 MHz) linear transducer (ESAOTE, 7300, Florence, Italy),	1 year
Pulse wave velocity.	Carotid-femoral pulse wave velocity (m/s) will be measured by pulse tonometry (Sphingmocor Atcor, EM3, Australia).	1 year
Percentual change of sICAM	Biomarker of endothelial dysfunction: Soluble ICAM (intercellular adhesion molecule). Determination of serum levels by Luminex. Percentual change between baseline baseline and 1 year levels.	1 year
Percentual change of PECAM	Biomarker of endothelial dysfunction: PECAM (platelet/endothelial cell adhesion molecule). Determination of serum levels by Luminex. Percentual change between baseline baseline and 1 year levels.	1 year
Percentual change of vWF	Biomarker of endothelial dysfunction: vWF (von Willebrand factor). Determination of serum levels by Luminex. Percentual change between baseline baseline and 1 year levels.	1 year
Percentual change of E-selectin	Biomarker of endothelial dysfunction: Soluble E-selectin. Determination of serum levels by Luminex.Percentual change between baseline baseline and 1 year levels.	1 year
Percentual change of PTX3	Biomarker of endothelial dysfunction: PTX3 (pentraxin). Determination of serum levels by ELISA. Percentual change between baseline baseline and 1 year levels.	1 year
Percentual change of hs-CRP	Biomarker of subclinical inflammation: hs-CRP (high sensitive C reactive protein). Determination of serum levels by nephelometry. Percentual change between baseline baseline and 1 year levels.	1 year
Percentual change of IL-6	Biomarker of subclinical inflammation: IL-6 IL-6 (interleukin 6). Determination of serum levels by Luminex. Percentual change between baseline baseline and 1 year levels.	1 year
Percentual change of sTNFR1 and sTNFR2	Biomarker of subclinical inflammation: sTNFR1 and sTNFR2 (soluble tumor necrosis factor receptor). Determination of serum levels by Luminex. Percentual change between baseline baseline and 1 year levels.	1 year
Percentual change of sTWEAK	Biomarker of subclinical inflammation: sTWEAK (soluble TNF-like weak inducer of apoptosis). Determination of serum levels by ELISA. Percentual change between baseline baseline and 1 year levels.	1 year

Collaborators and Investigators

• Sponsor: Hospital Universitari Vall d'Hebron Research Institute
• Collaborators: Teva Pharmaceutical Industries, Ltd.
• Investigators: Principal Investigator: Francesc Moreso, MD, PhD, Hospital Vall d'Hebron

Study record dates

Study Major Dates

• Study Start: July 1, 2015
• Primary Completion (Anticipated): December 1, 2017
• Study Completion (Anticipated): December 1, 2017

Study Registration Dates

• First Submitted: July 10, 2015
• First Submitted That Met QC Criteria: August 4, 2015
• First Posted (Estimate): August 5, 2015

Study Record Updates

• Last Update Posted (Actual): March 28, 2017
• Last Update Submitted That Met QC Criteria: March 27, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urologic Diseases; Renal Insufficiency; Kidney Diseases; Renal Insufficiency, Chronic
• Other Study ID Numbers: PR(AG)219/2014