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

Chronic Kidney Disease Clinical Trial

— CONFUCIUS  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02515643
• Other study ID #: PR(AG)219/2014
• Status: Recruiting
• Phase: N/A
• First received: July 10, 2015
• Last updated: March 27, 2017
• Start date: July 2015
• Est. completion date: December 2017

Study information

• Verified date: March 2017
• Source: Hospital Universitari Vall d'Hebron Research Institute
• Contact: Francesc Moreso, MD, PhD
• Phone: +34932746079
• Email: fjmoreso[@]vhebron.net
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 120
• Est. completion date: December 2017
• Est. primary completion date: December 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Chronic Kidney Disease
• Disorder Related to Renal Transplantation
• Endothelial Dysfunction
• Kidney Diseases
• Renal Insufficiency, Chronic

Intervention

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

Locations

Country	Name	City	State
Spain	Hospital del Mar	Barcelona
Spain	Vall d'Hebron Research Institute	Barcelona
Spain	Hospital Regional Universitario Carlos Haya	Malaga
Spain	Hospital Universitario Canarias	Santa Cruz de Tenerife	Islas Canarias

Sponsors (2)

Lead Sponsor	Collaborator
Hospital Universitari Vall d'Hebron Research Institute	Teva Pharmaceutical Industries, Ltd.

Country where clinical trial is conducted

Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Pulse wave velocity.	Carotid-femoral pulse wave velocity (m/s) will be measured by pulse tonometry (Sphingmocor Atcor, EM3, Australia).	1 year
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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