Dysfunction of bone marrow progenitor cells in chronic kidney disease

CKD is a growing health problem, affecting up to 10% of the population, mainly
due to the increase in diabetes, hypertension en obesity. CKD may lead to end
stage renal disease (ESRD), is associated with an increase in cardiovascular
risk and has great health and economic impact. Slowing CKD is therefore a major
health priority.

CKD is characterized by reduced renal and vascular regenerative capacity. In
1997 Asahara et al. discovered the putative EPC, which is derived from the BM
and present in the adult circulation. EPC have been shown to home to sites of
neovascularization and differentiate into endothelial cells in situ. We
previously reported that BM-EPC can also contribute to regeneration of the
highly specialized glomerular microvasculature. These observations have raised
much interest in BM cell therapy for the treatment of cardiovascular as well as
renal diseases.

BM-cell therapy for cardiovascular and renal disease
In recent years many studies have been performed to test the therapeutic
potential of BM-derived cells in cardiac and limb ischemia. Two recent
meta-analyses of clinical trials in ischemic heart disease confirmed safety of
BM-cell therapy and reported modest yet significant and clinically relevant
benefits on cardiac function and remodelling. Small human clinical trials in
patients with limb ischemia suggested improved clinical outcome of BM-cell
administration.
BM-progenitor cell therapy has also been shown to induce renal recovery in
animal models of acute renal failure. We recently showed that that injection of
healthy BM-cells can reduce progression of CKD in a rat model of established,
progressive CKD.

BM cell dysfunction in cardiovascular and renal disease
Several studies have demonstrated that circulating BM-derived EPC are reduced
and dysfunctional in the presence of risk factors for cardiovascular disease.
We and others demonstrated that this dysfunction of circulating EPCs is also
present in patients with predialysis CKD, cardiorenal syndrome and patients
with end stage renal disease on hemodialysis or peritoneal dialysis. In
patients with chronic ischemic heart disease such functional impairment has
been shown to extend to BM stem and progenitor cells. A small clinical study,
comparing the angiogenic potency of the BM cells of patients undergoing
thoracic surgery, suggests that in patients with renal failure, the angiogenic
potency of the BM cells is significantly compromised. In line, our recent data
show that whereas administration of healthy rat BM cells in a rat model of
established CKD significantly reduced CKD progression, administration of BM
cells obtained from a rat CKD BM donor had a markedly attenuated effect.

It is important to note that when considering BM cell therapy, this will
involve autologous BM cells. A functional impairment of BM stem and progenitor
cells may limit the therapeutic potential of autologous BM cell therapy in CKD
patients. Our objective is to study the functional characteristics of the BM
progenitor cells obtained from patients with CKD (preemptive and on dialysis)
as compared to healthy controls, relate BM cells* dysfunction to clinical
parameters and to explore methods to improve BM progenitor cell function in
vitro and in vivo.


Hypothesis

In CKD, despite standard medication, dysfunction of BM stem and progenitor
cells is present, which may hamper the clinical applicability of current
progenitor cell based strategies to reduce CKD progression.

1. To quantify and characterize BM progenitor cells in patients with CKD as
compared to healthy controls.

2. To explore strategies to improve BM stem and progenitor cell function ex
vivo.

A cross-sectional case-control study.

After obtaining informed consent, BM-aspirates will be drawn from 20 patients
with CKD (recipients from our donor kidney program) and 20 controls.
The controls will consist of donors from our living-donor program and healthy
patients undergoing surgery who agree to donate BM to UMCU BioBank. For the
latest a separate proposal will be prepared and submitted to the Biobank
Scientific Advisory Board (BSAB; WARB in Dutch) for approval.
Human BM-samples will be compared for cell composition, migration-capacity in
response to angiogenic factors and differentiation capacity to EPC and human
mesenchymal stem cells (MSC). EPC will be studied with respect to
proliferative-, adhering-, and angiogenic capacity. MSC will be cultured
according to clinical protocol in our Gene & Cell Facility. BM-cells, EPC, and
MSC from CKD patients and controls will be studied for differences in gene
expression and secretion of growth factors.

BM punction (taking 20ml BM aspirate and a BM biopsy) and peripheral blood
collections (20 ml) will be performed in the operating room, under general
anaesthesia, before start of the operative procedure. Large studies have shown
that complications during this procedure, rarely occur (<0.1%). The patient
will not have direct potential benefits by participating in this research.
However the patient will contribute to innovating stem cell technologies which
will be a significant improvement to current existing techniques to treat
cardiovascular and kidney diseases.