Thursday, June 20, 2013

A New Approach to Treating Chronic Kidney Disease: Replenishing Your Nephrons

As some of you may know, I have chronic kidney disease (CKD). Thanks to my wife and the scare put into me by my nephrologist, that I would soon have to begin dialysis, I have managed to get my CKD  in remission, or at least under control. My GFR number (that indicates when you must start dialysis) has held steady, or actually gotten better since my wife put me on a strict diet and I have lost about 15 pounds – and my nephrologist took me off of lisinopril (for blood pressure control), which seemed to raise my GFR by about three points. So, it appears I won’t have to go on dialysis any time soon.

All that being said, and with my strong interest in the use of stem cells and gene therapy in treating retinal diseases in ophthalmology, I have been searching the web for research on the use of stem cells to treat kidney disease or to produce new nephrons, the kidney cells that filter the blood as it passes through the kidney – and that go bad or die causing CKD. I think I have found very early research of that possibility.

Earlier this week, I saw a news  release from the University of Queensland in Australia that said that Dr. Melissa Little and her research group at the Institute of Molecular Bioscience (IMB) have found a set of six genes that can prompt some types of adult kidney cells to regress to an earlier stage of development (stem cells) and act like the precursors to the cells of the nephron. Since it is death or damage of nephrons that causes chronic kidney disease, by forcing adult cells to act like early nephrons, they may have potentially found a way to trigger the growth of new filters in the kidney.

All of your nephron cells are formed before birth and people with fewer nephrons are at higher risk of kidney disease.

Note: Dr. Little is one of sources that I had found in my web search as she had published a paper on “Stem Cell Options for Kidney Disease” in 2008, and we had corresponded at the beginning of this year when I began my search for a stem cell answer.

"This discovery is the first of its kind and offers hope to patients with chronic kidney disease. If we can find a way to provide new nephrons to an adult or increase nephron numbers in babies at birth, we could potentially reduce the risk of disease progression," said Professor Little.

This landmark paper, “Direct Transcriptional Reprogramming of Adult Cells to Embryonic Nephron Progenitors”, by Caroline E. Hendry, Jessica M. Vanslambrouck, Jessica Ineson, Norseha Suhaimi, Minoru Takasato, under the supervision of Professors Fiona Rae and Melissa H. Little, was published June 14th in the Journal of the American Society of Nephrology, the world's leading nephrology journal.

Professor Little said, “There was still more work to be done to encourage these reprogrammed early nephron cells to function and integrate. While this is a beginning, we hope it will inspire industry leaders and researchers around the world to invest further in cellular and bioengineering approaches to kidney repair and regeneration."

Stem Cells Australia Program Leader and Chair of Stem Cell Science at The University of Melbourne, Professor Martin Pera welcomed the research findings. "This innovative study provides evidence that adult cells can be reprogrammed to resemble the cells in the embryo that give rise to the kidney. The results pave the way for future studies that will enable researchers to produce human kidney cells in the laboratory, for use in studies of renal disorders, and for testing new drugs. Eventually this technology might help to make cells for transplantation to treat kidney disease," said Professor Pera.

The Technology

I have attempted to read Dr. Little’s paper on reprogramming kidney cells, and with her assistance, this is what I understand she and her colleagues have done, which is a very early step in the long road to someday being able to replenish nephron cells in an adult kidney.

In an earlier paper written by Caroline Hendry and Dr. Little, “Reprogramming the kidney: a novel approach for regeneration”, they discussed the various approaches that might be taken to re-create viable cells within a diseased kidney, including using  induced pluripotent stem cells (iPSCs) derived from skin cells or other sites, or even the use of embryonic stem cells (ESCs) that would be introduced into the kidney to form new nephrons (?), if they could – as shown in the accompanying figure (but how would you control the formation of the new cells?). But they concluded that the best approach would be reprogramming existing kidney cells to the progenitor stage, with the hope that these would develop into the needed new cells, or in this case, nephrons, the approach they ultimately used in this new research.

Figure1 | The application of reprogramming to the kidney, indicating the feasible starting cells and target phenotypes.
(i) Reprogramming may involve the directed differentiation of human embryonic stem cells (hESCs)/induced pluripotent stem cells (iPSCs) to a renal lineage. The iPSCs may be recipient-derived and may be derived from adult kidney cells or any other available adult cell type using the same factors. Directed differentiation is likely to recapitulate development; hence, it is likely to require differentiation through a nephron progenitor intermediate (induced nephron progenitor cell; iNP) but may continue on to more specific mature renal cell types.
(ii) A specific renal lineage may also be achieved via lineage-instructive reprogramming directly to that state from an adult cell type. Again, this may be the renal epithelium, renal stroma, or any other available differentiated adult cell type; however, this is likely to be more successful if the attractor states of the starting and target cell type are as close as possible. Reprogramming may be to the iNP state or directly to a more mature renal cell fate.
(iii) Finally, reprogramming may use the classical Yamanaka factors until the cells pass the point of no return, after which a renal lineage may be reached via the application of the appropriate environmental cues. Such cues may once again target the iNP state or aim to directly induce a more mature renal cell type.

As previously stated, the nephron progenitor population of the embryonic kidney gives rise to all of the nephron cells that will be present in the adult kidney, prior to birth. So, currently, what you’ve got at birth is what you live with.

Using a screening technique, the researchers were able to identify a group of six genes, that activate a network of genes that can reprogram adult proximal tubule cells back to the nephron progenitor stage – which in turn can form adult nephron cells. Although the researchers believe that other factors are required, they concluded that these results suggest that re-initiation of kidney development (nephron cells) from a population of adult cells (proximal tubule cells) by generating embryonic progenitors may be feasible, opening the way for additional cellular and bioengineering approaches to renal repair and regeneration.

In their literature search, they could not find any previous reports of kidney cells being reprogrammed back to a progenitor cell type. Their hope is that this discovery will lead others to follow their lead and begin further work in the possible reprogramming of adult kidney cells for the repair and rejuvenation of diseased kidneys.


News Releases:
Research reprograms future of kidney health, Institute for Molecular Bioscience and Stem Cells Australia, June 14, 2013


Reprogramming the kidney: a novel approach for regeneration, Hendry and Little, Kidney International, March 21, 2012

Stem Cell Options for Kidney Disease, Hopkins et al, Jnl of Pathology, October 20, 2008

Resource: recently launched a free, interactive "Human Body Maps" tool. One of the “maps” is of the kidney, showing and explaining how the kidney works to cleanse the body of waste material carried by the blood. To see a "map" of the kidney, and read how it functions, please follow this link.


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