Researchers at the Center for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh reported in the May 19, 2021, issue of Science Translational Medicine that the Bcl2/w/xL targeting senolytic compound, ABT-263 (navitoclax) could reverse the age-related fibrosis characteristic of and improve kidney function.

Principal investigator David Ferenbach, senior research fellow at the University of Edinburgh's Center for Inflammatory Research, told BioWorld Science, "Our kidneys scar more easily with aging, but the data we present in this paper demonstrates that this increased risk of scarring is not necessarily irreversible. We have shown that in animal experiments that we seem to be able to turn back the clock back. Our results in experimental models of kidney disease show that in both aged and scarred kidneys, their susceptibility to further scarring can be reversed by removing senescent cells. I hope that future experiments will move some of these observations from the laboratory to the clinic."

Chronic kidney disease (CKD) is a common condition affecting about 1 out of 7 adults that is characterized by accumulated fibrosis with associated decreases in function. Chronic kidney disease is generally considered to be irreversible and is associated with major increases in the risk of cardiovascular disease. It may also progress, leading ultimately to stage end-stage disease that is completely dependent on dialysis.

First author Katie Mylonas and her co-investigators observed that by targeting senescent tubular epithelial cells with ABT-263, they could reduce fibrosis and improve kidney function after subsequent injury. Experiments involved aged mice with demonstrable increases in senescent cells, and irradiation-induced cellular senescence in young mice. Both models showed increased senescent cells compared younger healthy controls. The study supports the concept that senescent cells represent a potential target for treating patients with CKD.

The researchers observed greater numbers of senescent cells in tissue derived from patient biopsies than from an age-matched healthy kidney. Ferenbach said that there has long been a suspicion that there are more senescent cells in settings when a patient becomes more vulnerable to scarring, but whether this was causing problems with kidney function had been unknown.

The investigators started by looking at published databases and observed that markers of senescence increased with tissue staining. This was the first study using the senolytic ABT-263 to selectively kill senescent cells. ABT-263 works by inhibiting the Bcl-2 family of antiapoptotic proteins.

Ferenbach noted that he is not making the claim that treatment with ABT-263 completely abolished injury or reversed aging. Nonetheless, the approach could restore the capacity of kidneys to regenerate back to a healthier prior status. In clinical treatments, this would be expected to exert a very measurable Improvement in kidney function.

One reservation that has limited ABT-263 in clinical trials for cancer treatment has been the finding of lower platelet counts. This is due to an on-target effect, due to platelet survival being dependent in part on these Bcl-2 family proteins. This aspect has concerned the ABT-263 medical community involved in clinical trials.

However, there are two potential approaches to the adverse event of platelet loss. A patient could take ABT-263 for a few days leading to a longer-term effect, on the order of months. It may also be possible to treat a kidney that has just been obtained for transplantation with ABT-263 prior to its reimplantation in a donor, meaning the patient is never subjected to ABT-263, but may be receiving an improved kidney.

Ferenbach, Mylonas and their colleagues plan to pursue research that is focused along these lines. They will be receiving kidneys that have been offered for transplantation but rejected because they are not functioning well. They plan to use a normothermic perfusion which will allow them to trial drugs and measure their effects without ever giving an experimental drug to a patient.