Capillary rarefaction in chronic kidney disease (CKD) (Cap-CKD): A survey on microvasculature and renal function in patients undergoing a nephrectomy

Rationale:
Chronic kidney disease (CKD) affects 10-15% of the general population and is an
independent risk factor for cardiovascular disease. Symptoms of CKD become
noticeable at a late stage, and better insight into the underlying
pathophysiology is needed to enable early disease detection. From the field of
renal transplantation we know that histological damage in kidney tissue
precedes renal function decline, and recently we and others have found an
important role for loss of microvascular stability (i.e. capillary rarefaction)
as an underlying pathophysiological mechanism. We would like to translate these
findings to the general population in relation to the development of CKD. As
renal tissue cannot be routinely obtained, we aim to study nephrectomy
specimens for pathological alterations and capillary rarefaction. In order to
relate these findings to CKD and vascular parameters we will study patients who
are well phenotyped for these specific parameters before and after nephrectomy
for a renal cell carcinoma.

Objectives:
The main objective is to study renal tissue in relation to renal function
before and after nephrectomy with a specific focus on microvascular structure
and function. A second objective is to study renal microvascular alterations in
relation to systemic microvascular and macrovascular dysfunction.

Study design:
This is a prospective observational study, with a follow-up duration of 24
months. In this study, renal function and vascular parameters will be assessed
in relation to renal tissue examination in 281 patients who undergo a
nephrectomy for a suspected renal cell carcinoma.

Intervention:
This is a non-interventional study.

Main study parameters/endpoints:
This will comprise a selection of minimally invasive measurements and
laboratory parameters, as well as medical history and physical examination. We
will include:
Medical history: detailed, i.e. including smoking history, birth weight, use of
medication
Physical examination: 24 hour blood pressure measurement, body mass index, and
waist circumference will be taken before nephrectomy and two years after
nephrectomy.
Renal function: eGFR will be calculated using the CKD-epi and the Cockcroft
Gault formula using gender, race, age, weight and serum creatinine (see below).
This will be done before the nephrectomy, 4-8 weeks after the nephrectomy, and
2 years after the nephrectomy.
Serum and plasma collection and analysis: Sodium, potassium, calcium,
phosphate, urea, creatinin, albumin, cholesterol, glucose, hemoglobn, tCO2, PTH
and uric acid. Furthermore, serum and plasma will be stored for future
analyses.
Urine collection and analysis: Three 24 hour urine collections (volume, total
protein, microalbuminuria, creatinin, phosphate, urea, sodium) and one morning
urine sample (urinary sediment) before, 4-8 weeks and 2 years after
nephrectomy. Furthermore, urine samples will be stored for future analyses.
Vascular function measurements: Systemic capillary function will be measured in
the skin using intravital microscopy with and without arterial and venous
occlusion. Furthermore, skin microvascular function will be studied using
laser-doppler flowmetry. Finally, pulse wave velocity will be determined.
Renal tissue analysis: Renal tissue adjacent to the tumour will be sampled for
histological and molecular analysis with e.g. immunohistochemistry,
morphometry, electron microscopy (EM), angiogenic profiling, mass spectrometry
imaging (MSI) and flow cytometry (FACS).

Nature and extent of the burden and risks associated with participation,
benefit and group relatedness:
In this study, only minimally invasive techniques will be performed using
mobile equipment, which pose a minimal burden to the patient. Blood sampling
will coincide as much as possible with regular blood takings for clinical
purposes before nephrectomy. Before the nephrectomy an additional visit to the
out-patient clinic is necessary. The follow up renal function measurements,
several weeks and two years after the nephrectomy, will coincide with the
routine follow-up visit of the patient with the urologist to diminish burden
for the patient. Renal tissue adjacent to the tumour will be sampled during
routine pathological analysis of the nephrectomy specimen. The study will not
have direct benefit for the participants. The study can only be performed
within this specific patient group.