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

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.

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.

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