- New research conducted in a laboratory setting may potentially have significant effects on the management of polycystic kidney disease (PKD), a condition impacting more than
500,000 individualsin the United States.
- Organoids are similar in appearance to tiny kidneys, as they are comprised of filtering cells linked to tubes, and are capable of reacting to infections and treatments in a manner that mimics the response of human kidneys.
- Now, a new study suggests that sugar may contribute to the development of fluid-filled cysts that are characteristic of PKD. These cysts grow large enough in humans to obstruct kidney function and ultimately result in organ failure, necessitating dialysis or even a transplant.
The research team cultivated organoids that are similar in appearance to tiny kidneys to generate cysts associated with PKD.
However, the precise mechanisms behind the development of these cysts still remain unclear.
The focus of this study was on the influence of fluid movement within the kidney on PKD.
The researchers developed a novel method of studying these effects by integrating a kidney organoid with a microfluidic chip.
This enabled the flow of a solution containing water, sugar, amino acids, and other essential nutrients over genetically-engineered organoids that simulated PKD.
The scientists anticipated that the PKD cysts in the organoids would deteriorate further when subjected to the fluid flow, as the condition is linked to flow rates.
However, they discovered that the cyst-swelling process involved the absorption of fluid, with the intake occurring inwardly through the cells from outside the cyst. This was contrary to the belief that cysts form as fluid is pushed outward through the cells.
The researchers said this novel approach offered a fresh perspective on cyst formation.
The team observed that in the microfluidic chips, the cells that line the walls of the PKD cysts were positioned externally, stretching and expanding so that the tops of the cells were situated on the outside of the cysts.
This reversed configuration, where the cells would be oriented internally in actual kidneys, implies that cysts increase in size by drawing in fluid that contains high levels of sugar, rather than by secreting the fluid.
They said the discovery provided new insights into the formation of cysts in organoids, although further research will be required to confirm their findings.
Benjamin S. Freedman, PhD, an assistant professor in the division of nephrology, department of medicine at the University of Washington and lead author of the study, explained the key findings to Medical News Today.
We discovered that PKD cysts in mini-kidney structures, when subjected to large volumes of fluid flow, rapidly swell and expand. This turned out to be due to uptake of sugars (glucose) in the fluid by cysts, which was accompanied by water. Blocking sugar uptake also blocked cyst growth. Altogether this suggests an important role for sugar uptake in polycystic kidney disease, which was not previously appreciated.
Benjamin S. Freedman
Dr. Anjay Rastogi, the director of the University of California Los Angeles’ PKD program CORE Kidney Program at the David Geffen School of Medicine at UCLA, was not involved in this research.
He told MNT that “this is a very interesting paper with significant implications.”
Freedman highlighted that “one of the major implications of our research for patients and the public is that sugar uptake could be a target for PKD therapy. This is quite timely because several drugs have recently been developed that affect sugar uptake, for other conditions.”
“Now we can consider trying these for PKD as well. Combining human mini-organ structures with chip devices that simulate blood flow is a new way to gain insight into diseases such as PKD,” Freedman explained.
Rastogi noted how the research contributes to a better understanding of cystogenesis in ADPKD.
“We have been focusing on secretion but this paper brings our attention to absorption and more specifically absorption of glucose by the tubular epithelia,” Rastogi said.
“The latter point is interesting and important as
SGLT-2 inhibitorsthat inhibit glucose absorption in the proximal tubule are now a part of what I call the foundation therapy of Chronic Kidney Disease slowing down not just kidney disease but also cardiovascular disease – the number one cause of death in patients with kidney disease. However, this class of drugs are not indicated at this point to be used for patients with ADPKD. This will need to be looked into further as based on this paper, SGLT-2 inhibitors might have beneficial effects in cysts that are more proximal but potentially harmful for the cysts that are more distal because of increased glucose delivery.
Dr. Anjay Rastogi
Dr. Pierre Antoine Brown, MSc, FRCP(C), an associate professor and medical director of the hemodialysis program and polycystic kidney disease clinic at The Ottawa Hospital, was also not involved in the study.
He commented that “this is an exciting publication.”
First, the use of the organoid-on-chip model may accelerate research on polycystic kidney diseases as it provides researches with a model that seems to more closely approximate what happens in a human kidney affected by PKD, and cysts can be directly observed and measured, something that is not possible in other methods such as an animal model. Second, the discovery that blocking glucose transport inside the kidney tubular cells blocks cyst growth could have a major impact in the future as it may become a new area for treatment of PKD.
Dr. Pierre Antoine Brown
Freedman noted there are limitations to the research.
For example, “we still don’t understand is how exactly PKD affects sugar uptake. Does it increase overall transport of sugar? Or do transport levels remain the same, but the cells respond to this stimulus in a different way?”
“It will be important to connect our findings back to the genes that are deficient in PKD. We know which genes are involved but we do not yet understand what they do to prevent cysts from forming,” Freedman said.
Brown agreed, saying “this is a big first step, but some of the concepts here will need to be tested in humans before we know with certainty if this could translate into treatments that slow down the progression of PKD.”
However, the SGLT2 inhibitor that was used in this experiment to block glucose transport (and blocked cyst growth) has already been shown to greatly reduce the risk of developing kidney failure in other kidney diseases such as diabetic kidney disease. If proven effective in trials of patients with PKD, it would be somewhat of a paradigm shift in the treatment of PKD as clinicians would have access to a new treatment that it is safe, very well studied already, well tolerated and readily available throughout the world.
Dr. Pierre Antoine Brown
Brown concluded by saying that “as a clinician, I am very excited about this possibility and can only hope that human trials confirm what has been seen in this experiment.”