Research Suggests a Novel Cell-Based Therapy for Chronic Kidney Disease and CKD-Associated Heart Failure
This Nephrology Now Research Showcase is submitted by Darren A. Yuen MD and Richard E. Gilbert MD PhD. Nephrology Now Research Showcases summarize important bodies of work in clinical or experimental Nephrology.
New therapies are needed for CKD and its cardiovascular complications
Chronic kidney disease (CKD) is a major cause of hospitalization, premature mortality, diminished quality of life and heath care expenditure . Despite its importance and increasing prevalence, little progress in its treatment has been made over the past 20 years, with blood pressure reduction and blockade of the renin-angiotensin system still the mainstays of therapy.
Patients with CKD are not only at high risk of developing heart failure, but frequently have heart failure with preserved left ventricular ejection fraction . These patients with CKD and diastolic dysfunction are a highly prevalent population that is faced with a particularly poor prognosis . Importantly, in contrast to patients with reduced left ventricular ejection fraction, there is no evidence-based treatment for those with preserved ejection fraction in which RCTs failed to show a beneficial effect for either ACE inhibitors  or angiotensin receptor blockers [4,5]. Additional therapies are therefore needed.
The importance of fibrovascular injury in mediating progression of renal and cardiac injury in CKD
Renal and cardiac biopsy studies of animals and patients with progressive CKD demonstrate progressive capillary loss and fibrosis in both organs [6,7]. These two inter-related pathological features are thought to contribute to progressive injury and dysfunction in the kidney and heart in CKD .
Bone marrow-derived early outgrowth cells (EOCs)The bone marrow harbours novel cell populations with potent tissue protective and regenerative properties . Named for their early appearance in culture (7 – 10 days) when peripheral blood mononuclear cells  or whole bone marrow cells [11,12] are grown in endothelial culture medium, early outgrowth cells (EOCs) have been shown to exert potent pro-angiogenic [13,14,15] and anti-fibrotic [12,16] effects in various disease models.
EOCs exert powerful renal and cardiac protective effects in experimental CKD
Intra-venous EOC infusion attenuates renal and cardiac damage and dysfunction
As shown in our Study Design depicted in Figure 1, using the 5/6 subtotal nephrectomy (SNX) rat as a model of progressive experimental CKD that develops diastolic dysfunction, we demonstrated that a single intra-venous infusion of 106 EOCs significantly attenuated the progressive capillary loss and fibrosis that occurs in the kidney and heart of animals with established experimental CKD (Figures 2 – 4) .
Figure 4. Cardiac fibrosis is attenuated by EOC therapy in the SNX rat.Importantly, these changes were associated with preservation of organ function, as manifested by a reduction in plasma creatinine, urinary protein excretion, and left ventricular (LV) end-diastolic pressure-volume relationship, a measure of LV stiffness (Figures 5 – 6) .
EOCs mediate their benefits from remote locations in the body
To test whether the beneficial effects of EOC infusion are dependent upon EOC delivery to the kidney and heart, we compared the effects of intra-arterial versus intra-venous EOC infusion. Interestingly, both the renal and cardiac tissue protective effects of EOC infusion were observed regardless of route of intravascular administration (Figure 7) .
To determine where the EOCs localize post-infusion, we fluorescently labeled the EOCs, and infused them into SNX rats. Despite the dramatic structural and functional benefits seen upon EOC infusion in the kidney and heart, very few labeled cells were found in either organ, contrasting with their relative abundance in the liver and spleen [Figure 8] .
The results of our studies are the first to demonstrate that EOC infusion may significantly attenuate the renal and cardiac injury that accumulates as CKD progresses. Given the marked morbidity and mortality associated with CKD, we believe that our data may form the preclinical foundation for clinical trials of EOC therapy for CKD and CKD-associated heart failure.
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