From Science Daily, Singapore Nanyang Technological University
Mini kidneys grown from stem cells give new insights into kidney disease and therapies
An international team of researchers led by Nanyang Technological University, Singapore (NTU Singapore) has grown 'miniature kidneys' in the laboratory that could be used to better understand how kidney diseases develop in individual patients.
The mini kidneys, known as kidney organoids, were grown outside the body from skin cells derived from a single patient who has polycystic kidney disease, one of the most common inherited causes of kidney failure in adults.
The researchers reprogrammed these cells to obtain patient-specific pluripotent stem cells, which, under the right conditions, can develop into kidney organoids similar to human fetal kidneys in the first three to six months of development.
The kidney organoids were then used to validate the therapeutic effects of two drug molecules with potential for treating genetic polycystic kidney disease, demonstrating that the research could be of significant value in developing personalised treatments for people with this disease.
Existing approaches to testing potential treatments through such 'drug screening' do not take account of the fact that the genetic errors that cause kidney diseases vary from patient to patient.
By generating induced pluripotent stem cells from an adult patient with a genetic kidney disease, and then growing kidney organoids from them, the research team has paved the way for tailoring treatment plans specific to each patient, which could be extended to a range of kidney diseases.
The research, led by NTU Singapore Assistant Professor Xia Yun and her team, which includes NTU Assistant Professor Foo Jia Nee and Professor Juan Carlos Izpisua Belmonte from the Salk Institute for Biological Studies, in San Diego, California, was published in Cell Stem Cell in July 2019.
Assistant Professor Xia from the NTU Lee Kong Chian School of Medicine (LKCMedicine), said, "A patient's genetic makeup is closely intertwined with how their kidney disease will develop, as the type of mutation within the disease-causing gene can differ from patient to patient.
"Our kidney organoids, grown from the cells of a patient with inherited polycystic kidney disease, have allowed us to find out which drugs will be most effective for this specific patient. We believe that this approach can be extended to study many other types of kidney disease, such as diabetic nephropathy."
Professor Juan Carlos Izpisua Belmonte, an international collaborator of this study, said, "Although we are still quite far away from using these kidney organoids for replacement therapy, this study has made a small step closer to this ultimate goal."
New insights into human kidney development
The kidney organoids developed by Asst Prof Xia and her team may also offer new insights into human kidney development, which currently cannot be studied in depth due to concerns surrounding human stem cell research.
While the origin of kidney blood vessel networks is not fully known, it is widely accepted that a type of stem cell known as 'vascular progenitors' is involved in their formation by developing into blood vessel cells.
By examining the genetic information within single cells of the organoid, the NTU-led team also discovered a new source of stem cells that contribute to making these blood vessel networks: nephron progenitor cells. Prior to this discovery, these cells were known only as precursors to nephrons, the kidney's filtering units.
NTU LKCMedicine Assistant Professor Foo Jia Nee, said, "We observed very robust and consistent development of blood vessel networks within our kidney organoids, which opens new doors to investigate the developmental origin of renal blood vessel networks, which is still not fully understood. Using this novel organoid platform, we unexpectedly discovered a new source of renal blood vessels that may improve our understanding of kidney development."
The mini kidneys may also be used to better understand the development of nephrons in the kidney. The number of nephrons at birth is inversely correlated with incidence of hypertension and kidney failure later in life. Being born with a high nephron number appears to provide some degree of protection against these conditions.
Asst Prof Xia said, "A thorough understanding of human embryonic kidney development, especially how environmental factors influence the process, may help us develop ways to promote a high birth nephron number for foetuses as they develop during pregnancy."
Stem cell scientist Dr Jonathan Loh Yuin-Han, senior principal investigator at the Institute of Molecular and Cell Biology at the Agency for Science, Technology and Research, who was not involved in the study, said, "The new vascularised kidney organoids created by Xia Yun and her team represent a transforming advance in the field. The organoids model anatomical and functional hallmarks of the real organ, so they provide deep insights into the kidney developmental processes. This could inspire future works on individualised bioengineered mini organs for application in personalised medicine and treatment of complex diseases."
Understanding the inner workings of a diseased kidney
To study the effects of genetic polycystic kidney disease, Asst Prof Xia and her team first took regular adult cells from an adult patient with the disease and genetically reprogrammed them into stem cells.
The creation of these induced pluripotent stem cells is necessary because the adult human body does not have any kidney stem cells. Two essential chemicals are then added to direct these induced pluripotent stem cells to grow into kidney organoids.
Four to five weeks later, these organoids developed fluid-filled cysts that are characteristic of the disease. This signaled that they were ready to be used to test the efficacy of potential drug candidates for drug development.
The same approach can be employed to generate kidney organoids from stem cells derived from healthy individuals. When these kidney organoids were implanted into mice, the blood vessel network of these mini kidneys successfully connected with the host mice circulation system and developed a more mature architecture capable of preliminary filtration and reabsorption.
From MDLinx
Among asymptomatic autosomal dominant polycystic kidney disease (ADPKD) patients not on dialysis (n = 110), researchers assessed global longitudinal strain (GLS) distribution as evaluated by two-dimensional speckle-tracking in this prospective study. They also investigated clinical variables related to higher (less negative) strain measurements in these patients, given that transmitral early filling velocity to early diastolic strain rate (E/SRe) represents a new measure of left ventricular filling pressure, which is frequently affected early in cardiac disease. Among ADPKD patients, higher GLS and E/SRe were commonly detected, even in those with preserved estimated glomerular filtration rate and normal left ventricular ejection fraction. Following multivariate logistic regression with backward model selection, male gender and β-blocker use continued to be significant as factors related to higher GLS, and β-blocker use remained significant as a factor related to higher E/SRe. Since GLS and E/SRe are early markers of cardiac dysfunction, these may be helpful in cardiovascular risk stratification in patients with ADPKD.
Artificial Kidney
From healio.com
Researchers and developers at the Center for Dialysis Innovation at the University of Washington in Seattle, one of the winners in the KidneyX competition, are developing the Ambulatory Kidney to Improve Vitality, an external, wearable, miniaturized dialysis system that the developers hope will be “low-cost, water-efficient, requires minimal anticoagulation, offers complication-free blood access and [be] patient-friendly.”
In an interview with Healio/Nephrology, Jonathan Himmelfarb, MD, a chief investigator on the project, said the group is in the second year of developing the device.
“We have put together a world-class team to work on this wearable kidney and set a goal of having the [Ambulatory Kidney to Improve Vitality] AKTIV ready in 5 years for trials,” Himmelfarb said. “We are at the stage where we still need time to do more research and development.”
The researchers said they hope the device will allow for “almost unlimited mobility, dramatically reduce pharmaceutical burden and reduce dietary restrictions.” Once available, however, Himmelfarb acknowledges that the AKTIV will not be for everyone. “Renal replacement therapies should not be about one size fits all. What we are doing is trying to create more options.”
Devices like the AKTIV would create mobility for many patients.
“Most patients don’t want to be doing dialysis tied to a chair. They want to be able to live their life while getting their treatment. And that is where the wearable, portable, implantable devices can be transformative because you would not be tied to being at home,” Himmelfarb said.
Other researchers on the project include Buddy Ratner, PhD; Larry Kessler, ScD; Kassandra Thomson, PhD; Glenda V. Roberts and Anna Galperin, PhD. – by Mark E. Neumann
Reference:
www.kidneyx.org/WhatWeDo/PrizeCompetitions/redesigndialysisphasei
Kidney Transplants Covered by Medicaid Increased in States After Medicaid Expansion
Medicaid expansion has helped more young, low-income adults with advanced kidney disease to avoid the costs and poor quality-of-life associated with dialysis, reports a study in the Journal of General Internal Medicine from researchers at Drexel University College of Medicine and the Dornsife School of Public Health at Drexel.
The study included 15,775 United States adults age 21-64 who received a pre-emptive kidney transplant (i.e., a transplant before needing dialysis treatment) from 2010-2017.
The team examined the numbers of living and deceased donor kidney transplants, respectively, that occurred during the four years leading up to Medicaid expansion and the four years following the date of expansion in states that opted to expand Medicaid as part of the Affordable Care Act, compared to trends in preemptive transplants in states that chose not to expand Medicaid.
Researchers found that the overall number of pre-emptive kidney transplants covered by Medicaid have increased by 37 percent in states that did not expand Medicaid and by 66 percent in states that did expand Medicaid. Medicaid-covered preemptive, living-donor kidney transplants increased by 0.7 percentage points in non-expansion states, and by 2.2 percentage points in expansion states.
The Affordable Care Act became law in March 2010, expanding the nation’s Medicaid program, particularly to almost all non-elderly adults whose income is at or below 138 percent of the federal poverty level. This 100 percent federal funding coverage — for states that elected to receive it — began Jan. 1, 2014, (90 percent coverage starting in 2020).
“More Americans die from chronic kidney disease than from breast cancer, prostate cancer, and many other well-known diseases,” said lead author Meera N. Harhay, MD, an associate professor of Medicine at Drexel College of Medicine. “From improving early detection of kidney disease to increasing outreach and educational efforts, there are many steps that we can take to advance care for those with kidney disease. To promote early access to transplants, expanding Medicaid was clearly one of those steps.”
Approximately 37 million Americans suffer from chronic kidney disease, a condition in which the kidneys cannot properly pass waste and filter blood. In the advanced form of chronic kidney disease, a living donor transplant is often the best option to avoid dialysis, but health insurance is needed to cover the costs of the procedure. Although transplant before the need for dialysis treatment is the ideal scenario for individuals with advanced kidney disease, Medicare coverage is only available to non-elderly individuals after they begin dialysis. The shortage of kidneys available for transplant requires that people without a living donor often wait for five to 10 years on dialysis before receiving a transplant, and many die on dialysis before they get that opportunity.
The research findings come amidst President Donald Trump signing an executive order in July aimed at improving kidney care. Its goals include increasing rates of preemptive kidney transplant, identifying and treating at-risk populations in earlier stages of kidney disease, removing financial barriers to living organ donation, among others. The study also comes at a time when the fate of the ACA, and Medicaid expansion, are also in question.
Last year, there were 36,500 transplants of any organ in the United States. A total of 21,167 of these, 59 percent, were kidney transplants, according to the United Network for Organ Sharing.
A total of 33 states and Washington D.C. have expanded Medicaid under the Affordable Care Act (ACA), covering millions of previously uninsured Americans – including those with kidney disease who are not dialysis-dependent. The latest research follows a study Harhay published in Journal of General Internal Medicine in October 2018 with Ryan M. McKenna, PhD, an assistant professor in Drexel’s Dornsife School of Public Health, which found that 30 percent of the lowest -income individuals in the U.S. with kidney disease were uninsured in 2015 and 2016, despite coverage gains made by Medicaid.
The authors of the study were funded to conduct this research by grants from the National Institutes of Health’s National Institutes of Diabetes and Digestive and Kidney Diseases and National Heart, Lung, and Blood Institute, as well as support from the Health Resources and Services Administration.
In addition to Harhay and McKenna, an additional author on the research includes Michael O. Harhay, PhD, from the University of Pennsylvania.
In an interview with Healio/Nephrology, Jonathan Himmelfarb, MD, a chief investigator on the project, said the group is in the second year of developing the device.
“We have put together a world-class team to work on this wearable kidney and set a goal of having the [Ambulatory Kidney to Improve Vitality] AKTIV ready in 5 years for trials,” Himmelfarb said. “We are at the stage where we still need time to do more research and development.”
The researchers said they hope the device will allow for “almost unlimited mobility, dramatically reduce pharmaceutical burden and reduce dietary restrictions.” Once available, however, Himmelfarb acknowledges that the AKTIV will not be for everyone. “Renal replacement therapies should not be about one size fits all. What we are doing is trying to create more options.”
Devices like the AKTIV would create mobility for many patients.
“Most patients don’t want to be doing dialysis tied to a chair. They want to be able to live their life while getting their treatment. And that is where the wearable, portable, implantable devices can be transformative because you would not be tied to being at home,” Himmelfarb said.
Other researchers on the project include Buddy Ratner, PhD; Larry Kessler, ScD; Kassandra Thomson, PhD; Glenda V. Roberts and Anna Galperin, PhD. – by Mark E. Neumann
Reference:
www.kidneyx.org/WhatWeDo/PrizeCompetitions/redesigndialysisphasei
Kidney Transplant
From Drexel Now, Drexel University
The study included 15,775 United States adults age 21-64 who received a pre-emptive kidney transplant (i.e., a transplant before needing dialysis treatment) from 2010-2017.
The team examined the numbers of living and deceased donor kidney transplants, respectively, that occurred during the four years leading up to Medicaid expansion and the four years following the date of expansion in states that opted to expand Medicaid as part of the Affordable Care Act, compared to trends in preemptive transplants in states that chose not to expand Medicaid.
Researchers found that the overall number of pre-emptive kidney transplants covered by Medicaid have increased by 37 percent in states that did not expand Medicaid and by 66 percent in states that did expand Medicaid. Medicaid-covered preemptive, living-donor kidney transplants increased by 0.7 percentage points in non-expansion states, and by 2.2 percentage points in expansion states.
The Affordable Care Act became law in March 2010, expanding the nation’s Medicaid program, particularly to almost all non-elderly adults whose income is at or below 138 percent of the federal poverty level. This 100 percent federal funding coverage — for states that elected to receive it — began Jan. 1, 2014, (90 percent coverage starting in 2020).
“More Americans die from chronic kidney disease than from breast cancer, prostate cancer, and many other well-known diseases,” said lead author Meera N. Harhay, MD, an associate professor of Medicine at Drexel College of Medicine. “From improving early detection of kidney disease to increasing outreach and educational efforts, there are many steps that we can take to advance care for those with kidney disease. To promote early access to transplants, expanding Medicaid was clearly one of those steps.”
Approximately 37 million Americans suffer from chronic kidney disease, a condition in which the kidneys cannot properly pass waste and filter blood. In the advanced form of chronic kidney disease, a living donor transplant is often the best option to avoid dialysis, but health insurance is needed to cover the costs of the procedure. Although transplant before the need for dialysis treatment is the ideal scenario for individuals with advanced kidney disease, Medicare coverage is only available to non-elderly individuals after they begin dialysis. The shortage of kidneys available for transplant requires that people without a living donor often wait for five to 10 years on dialysis before receiving a transplant, and many die on dialysis before they get that opportunity.
The research findings come amidst President Donald Trump signing an executive order in July aimed at improving kidney care. Its goals include increasing rates of preemptive kidney transplant, identifying and treating at-risk populations in earlier stages of kidney disease, removing financial barriers to living organ donation, among others. The study also comes at a time when the fate of the ACA, and Medicaid expansion, are also in question.
Last year, there were 36,500 transplants of any organ in the United States. A total of 21,167 of these, 59 percent, were kidney transplants, according to the United Network for Organ Sharing.
A total of 33 states and Washington D.C. have expanded Medicaid under the Affordable Care Act (ACA), covering millions of previously uninsured Americans – including those with kidney disease who are not dialysis-dependent. The latest research follows a study Harhay published in Journal of General Internal Medicine in October 2018 with Ryan M. McKenna, PhD, an assistant professor in Drexel’s Dornsife School of Public Health, which found that 30 percent of the lowest -income individuals in the U.S. with kidney disease were uninsured in 2015 and 2016, despite coverage gains made by Medicaid.
The authors of the study were funded to conduct this research by grants from the National Institutes of Health’s National Institutes of Diabetes and Digestive and Kidney Diseases and National Heart, Lung, and Blood Institute, as well as support from the Health Resources and Services Administration.
In addition to Harhay and McKenna, an additional author on the research includes Michael O. Harhay, PhD, from the University of Pennsylvania.
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