AN END TO
KIDNEY FAILURE

ESRD is a global crisis. A report in The Lancet stated that the condition is responsible for one out of every 57 fatal outcomes across the world, while, in the UK, approximately 64,000 people are currently being treated for the condition. These figures are set to rise in line with an ageing population and increases in chronic conditions such as type 2 diabetes and hypertension (abnormally high blood pressure), prime causes of ESRD. Research published in the American Journal of Kidney Diseases and led by RTI International predicted that by 2030, 17% of US adults aged 30 or older will have ESRD.

Currently, patients are subjected to ongoing dialysis or have to undergo a kidney transplant to stay alive. Dialysis is a procedure that artificially removes waste products and excess fluid from the circulation. The blood is diverted to a dialysis machine, or dialyzer, so that it can be cleaned. Kidney transplantation is recognised as the best available treatment for ESRD in terms of cost, quality of life and prognosis. However, a shortage of donors limits transplantation as a treatment option. Unless you are in the fortunate position of having a family member or friend with a similar tissue type who is willing to make a living donation, those on the waiting list for a kidney transplant can expect, on average, to have a two- to three-year wait to receive a kidney in the UK. This means that finding innovative solutions is more important than ever.

Another option is to cure the conditions that cause ESRD in the first place; mainly type 2 diabetes and hypertension. Chronic conditions tend to be complex and driven by multiple factors and type 2 diabetes is no exception. The disease is driven by a mix of behavioural, environmental and genetic factors.

Our understanding of type 2 diabetes has improved over time through painstaking research, but serendipitous discoveries can also act as an important trigger for progress. This was demonstrated when scientists working at Renova Therapeutics discovered that a gene therapy being tested in mice, which the team expected to increase cardiac output and decrease blood pressure, also reduced blood glucose levels. Renova Therapeutics’ work into type 2 diabetes is encouraging as it delivers a therapeutic gene that codes for urocortin 2 (a protein involved in regulating aspects of appetite and stress response in mammals) – using a one-off intravenous injection, a common procedure that can be administered in any doctor’s office.

As historic challenges associated with gene therapy such as safety have been gradually resolved and new technologies are being developed, gene therapy might be close to becoming a widely-used therapeutic approach across rare and chronic diseases. In this case, removing the threat of type 2 diabetes could have a dramatic effect on rates of ESRD.

False colour transmission electron micrograph (TEM) showing kidney cells.

Growth factor

Another solution to the growth of ESRD would be to regenerate the kidneys. This might sound fanciful, and indeed we may still be far away from being able to regenerate a fully functional kidney, but the progress made over the past few years is encouraging.

In 2014, scientists from the Stanford Institute for Stem Cell Biology and Regenerative Medicine in the US and the Sackler School of Medicine in Israel discovered that kidneys regenerate and repair themselves throughout our lifetimes. Not only does this overturn decades of accepted wisdom that dictated that kidneys did not regenerate, researchers also discovered a cellular pathway that facilitates regeneration. In the future, it might be possible to target a certain protein in the pathway and thereby to promote the regenerative capacity of the kidneys.

Thanks to advancements in stem cell research, scientists can transform any cell, for example a skin cell, into a naive cell (stem cell) that can later be triggered and developed into any cell required, in this case a kidney cell. This approach uses what are termed ‘induced pluripotent stem’ (iPS) cells. In research published in the Journal of the American Society of Nephrology, scientists from Kumamoto University in Japan used this technique to engineer kidney tissue in vitro using human-iPS cells, which they then transplanted into a mouse kidney. The researchers found that the mice’s blood vessels readily connected to the human tissue.

Other studies have suggested that a particular type of human kidney cell has the potential to promote kidney injury repair after being injected into the bloodstream intravenously. In work published in the journal Stem Cells Translational Medicine, researchers from the University of Liverpool and the University of Heidelberg in Germany demonstrated that any regeneration involved using this method is likely to be mediated by cell-to-cell communication rather than the injected cells directly interacting with the recipient’s kidney to form new tissue.

Cell-to-cell communication involves one cell producing a signal that induces changes in the behaviour of another cell. It is an approach that could yet develop into a viable treatment for ESRD. For example, a Japanese company, SanBio, is performing advanced clinical trials into a treatment for traumatic brain injury that is based on the same principle.

ESRD is both a complicated and debilitating condition, with an equally complex set of solutions. While the innovations discussed here offer a glimpse of an improved future for patients, too many people are still having to endure the misery of waiting for a donor organ that may never arrive.

This is why it is vital to continue pushing the parameters of scientific knowledge in the hope of identifying novel and transformational solutions. The challenge for investors is to identify which technology will benefit patients the most in the long term and invest their time and capital in supporting those companies to execute on that promise. Although early stage, the innovations taking place illustrate that preventative and curative solutions, as opposed to managing ESRD through dialysis, are becoming increasingly realistic treatment options. They also demonstrate the benefits of scientists’ perseverance and wider disciplinary collaboration.

Background Image: Light micrograph of normal human kidney.