Young pregnant women, who appear to have fully recovered from an acute injury that reduced their kidney function, have higher rates of significant problems like preeclampsia and low birthweight babies, problems which indicate their kidneys have not actually fully recovered.
Now scientists have developed a rodent model that is enabling studies to better understand, identify and ideally avoid this recently identified association, they report in the Journal of the American Society of Nephrology.
“We are talking about a population of young women that we usually think about as protected and healthy, and they are not if they have had a kidney insult,” says Dr. Jennifer C. Sullivan, pharmacologist and physiologist in the Department of Physiology at the Medical College of Georgia and interim dean of The Graduate School at Augusta University. “We think there is injury, potentially even years later, in some of these young women that we are not seeing, and we need to be able to quantify how much injury is still there.”
Acute kidney injuries, or AKIs, result from the rapid, temporary loss of adequate oxygen-rich blood to the organ that constantly filters our blood of toxins and resorbs essentials like water, glucose and potassium. An AKI can result from a literal blow to the kidney, like a car accident, from pharmaceuticals like the chemotherapy drug cisplatin, or from a major surgery or sickness that puts you in intensive care, like COVID-19, which is known to have a direct effect on the kidney.
The incidence of AKI has been on the increase, and the COVID pandemic very likely will accelerate that, says Dr. Ellen E. Gillis, senior postdoctoral fellow in Sullivan’s lab and the study’s corresponding author. A COVID-related AKI is associated with high mortality and considered an independent risk factor for death in patients with COVID. In fact, the clear emerging relationship was the focus of the virtual 25th Consensus Conference of the Acute Disease Quality Initiative.
“Any loss of blood flow to the kidneys can result in reduced function and an AKI,” says Gillis. Pregnancy is one of the biggest stressors the kidneys face, she says. “Basically every system in your body changes during pregnancy.”
Their new model is helping identify how calamity can occur when the two conditions collide, even if they are separated by years.
During pregnancy, maternal circulation must support fetal circulation so cardiac output increases, total body volume increases as well as plasma volume so the kidneys have an increased load to filter, Gillis says. “There is an increase in plasma volume to ensure the high metabolic demands of both baby and mother are met,” Sullivan adds. In this scenario, the baby actually gets preferential protection.
Two recent clinical studies and their new model suggest that even years later, some young women have lingering damage that can prevent these usual responses and protections. It can happen despite the fact that the mother’s kidney function appeared normal before pregnancy, including normal creatinine levels, a waste product that healthy kidneys filter from your blood that is measured in the blood and/or urine as a standard assessment of kidney function.
Two clinical studies, one published in 2017 and the second a year later, looked at women an average age of 30, often years out from their AKI with multiple assessments that indicated their kidneys had recovered. The research led by Massachusetts General Hospital found significant increases in problems with both mother and baby, including preeclampsia, low birthweight and loss of the baby.
The MCG scientists now report the same findings in their animal model: they experience an AKI, they recover based on usual measures of kidney function, but problems with the mother and/or baby still occur.
Their model closely mimics what happens in humans: a period of compromised blood flow to the kidney followed by restoration of blood flow, called ischemia reperfusion injury, a known, common cause of AKI in humans, followed by a recovery period in which, again like the young women, creatinine levels returned to normal.
They monitored the rats throughout pregnancy, and watched uterine artery resistance go up, uterine blood flow go down and babies born smaller because they were not getting adequate nutrition. The uterine artery provides most of the blood to the uterus, where the baby develops, and should enlarge significantly during pregnancy.
“Typically during pregnancy your vasculature relaxes and blood pressure decreases to accommodate this increase in plasma volume,” Gillis says. “You should see relaxation and vasodilation of the uterine artery,” Sullivan adds. Normally there is some new blood vessel growth for the placenta to accommodate the demand, but not in the mother’s kidneys. “The kidneys just have to work harder, which normally isn’t a problem,” Sullivan adds. But the previously injured kidney, which has functioned fine for the woman alone, may not be up for this additional significant task.
“You should see changes in the vasculature to promote increased perfusion, increased delivery to the pups. There are a lot of things that should be happening that the gross measurements we make today suggest aren’t happening,” Sullivan says.
Rather in their model, and in the young women, pregnancy appears to induce renal insufficiency, driving up levels of creatinine in the blood as well as urea, a byproduct of protein metabolism from your body and the food you eat, whose increased blood levels indicate kidney problems and/or high meat consumption. Creatinine levels should decrease in pregnant women because of that increased plasma volume, but the limited clinical trials have shown they go up in women who have had AKIs.
Plasma volume, which should double, increases some, but not sufficiently, Gillis says. They don’t yet know the exact mechanism for why plasma volume increase is insufficient, but suspect it’s because the kidneys just can’t handle the volume. Sullivan notes there is crosstalk between the kidneys, uterus and placenta that the previous insult to the kidney appears to change. Sodium retention is one way to increase plasma volume, so problems with sodium transport by the kidneys following an AKI could be an issue.
The rat mothers also have more waste product in their blood, another indicator the kidneys are not working at a premium. In fact, the high creatinine levels they are seeing would indicate that pregnancy itself has caused another AKI, Gillis says. The scientists note that it’s widely acknowledged that creatinine levels are not an ideal indicator of kidney function, and one of the goals of their work is to find a better biomarker and better treatment.
Gillis is now exploring whether regulatory T cells, which help protect the fetus from the mother’s immune system during pregnancy and also should increase in number in pregnancy, are part of the problem. Regulatory T cells can, for example, produce the powerful blood vessel dilator nitric oxide, and they don’t see the increase in these calming T cells in their new model. Perhaps the AKI generated an altered inflammatory response that decreases the ability to prompt this important increase in regulatory T cells, Gillis says. If that is the problem, more regulatory T cells, an approach which already has been studied in humans, for example, to better protect their transplanted organ, could be given to help, Sullivan says.
They note that preeclampsia and low birthweight have long been concerns, just not concerns associated with the kidneys. “We thought of them being placental disease,” Sullivan says.
Still there have been known overlaps. AKIs increase the risk for chronic kidney disease, women are more likely to get chronic kidney disease and issues occurring during pregnancy may be one of the reasons, they say. Women with poor kidney function are known to have difficulties with pregnancy, but these young women are considered to be recovered from their kidney injury, the scientists emphasize.
And they are concerned the newly discovered association will only increase with rates of both AKI and maternal death on the rise. The Centers for Disease Control and Prevention reports that death rates of pregnant women are on the rise in the United States, which has the highest maternal mortality among developed countries.
COVID could worsen the problem. A study of more than 5,000 veterans hospitalized with COVID, for example, indicated that about 32% developed an AKI and that nearly half of them did not have fully recovered kidney function at discharge from the hospital. Veterans with an AKI were at increased risk of death and Black veterans were at most risk.
The first looks at pregnancy outcomes following what appeared to be full recovery from an AKI was a retrospective study of women who had babies between 1998 and 2016. It found that women who had an AKI had an increased rate of preeclampsia — the worse the AKI, the greater the preeclampsia risk — and that their infants were born at an earlier gestational age and were more likely to be small for their gestational age. The emerging association of AKI and preeclampsia and adverse fetal outcomes held even when matched with women of a similar age, race, body mass index and blood pressure — including rates of preexisting hypertension — at their first prenatal visit. Creatinine levels the six months before conception also were similar in the nearly 40% of the women on whom that data was available.
Gillis last year received a K99 Pathway to Independence Award from the National Heart, Lung and Blood Institute to develop a model to further explore why pregnant women who seemed to recover from their acute kidney injury, had these associated problems.
Outcomes for an individual with an AKI include hypertension and chronic kidney disease, potentially including the need for kidney dialysis. Preeclampsia is the most common complication of pregnancy and typically occurs in women with a previously healthy blood pressure. Traditional risk factors have actually included not having children as well as obesity and hypertension.
Read the full study.
USC Stem Cell study identifies molecular ‘switch’ that turns precursors into kidney cells
Kidney development is a balancing act between the self-renewal of stem and progenitor cells to maintain and expand their numbers, and the differentiation of these cells into more specialized cell types. In a new study in the journal eLife from Andy McMahon’s laboratory in the Department of Stem Cell Biology and Regenerative Medicine at the Keck School of Medicine of USC, former graduate student Alex Quiyu Guo and a team of scientists demonstrate the importance of a molecule called β-catenin in striking this balance.
β-catenin is a key driver at the end of a complex signaling cascade known as the Wnt pathway. Wnt signaling plays critical roles in the embryonic development of multiple organs including the kidneys. By partnering with other Wnt pathway molecules, β-catenin controls the activity of hundreds to thousands of genes within the cell.
The new study builds on the McMahon Lab’s previous discovery that Wnt/β-catenin can initiate progenitor cells to execute a lengthy and highly orchestrated program of forming structures in the kidney called nephrons. A healthy human kidney contains a million nephrons that balance body fluids and remove soluble waste products. Too few nephrons results in kidney disease.
Previous studies from the UT Southwestern Medical Center laboratory of Thomas Carroll, a former postdoctoral trainee in the McMahon Lab, suggested that Wnt/β-catenin signaling plays opposing roles in ensuring the proper number of nephrons: promoting progenitor maintenance and self-renewal, and stimulating progenitor cell differentiation.
“It sounded like Wnt/β-catenin is doing two things–both maintenance and differentiation–that seem to be opposite operations,” said Guo. “Therefore, the hypothesis was that different levels of Wnt/β-catenin can dictate different fates of the nephron progenitors: when it’s low, it works on maintenance; when it’s high, it directs differentiation.”
In 2015, it became more possible to test this hypothesis when Leif Oxburgh, a scientist at the Rogosin Institute in New York and a co-author of the eLife study, developed a system for growing large numbers of nephron progenitor cells, or NPCs, in a Petri dish.
Relying on this game-changing new system, Guo and his collaborators grew NPCs, added different levels of a chemical that activates β-catenin, and saw their hypothesis play out in the Petri dishes.
They observed that high levels of β-catenin triggered a “switch” in part of the Wnt pathway that relies on another family of transcription factors known as TCF/LEF. There are two types of TCF/LEF transcription factors: one type inhibits genes related to differentiation, and the other activates these genes. In response to high levels of β-catenin, the “activating” members of TCF/LEF switched places with the “inhibiting” members, effectively taking charge. This “switch” triggered NPCs to differentiate into more specialized types of kidney cells.
When they looked at low levels of β-catenin, they saw NPCs self-renewing and maintaining their populations, as expected. However, they were surprised to learn that β-catenin was not engaged with any of the known genes related to self-renewal and maintenance.
“β-catenin does something,” said Guo. “That is for sure. But how it does it is kind of mysterious right now.”
After publishing these results in eLife, Guo earned his PhD from USC, and began his postdoctoral training at UCLA. Helena Bugacov, a current PhD student in the McMahon Lab and a co-author of the eLife study, is now taking the lead in continuing the project–which has implications far beyond the kidney field, due to the broad role of Wnt throughout the body.
“Understanding how Wnt regulates these two very distinct cell outcomes of self-renewal and differentiation, which is very important for kidney development, is also important for understanding the development of other organs and adult stem cells, as Wnt signaling plays important roles in almost all developmental systems,” said Bugacov. “There is also a lot of attention from cancer researchers, as this process can go awry in cancer. Many therapeutics are trying to target this process.”
She added, “The more we know about things, the better we can inform work on developing human kidney organoid cultures, which can be more readily used to understand problems in human health, regeneration and development.”
Additional co-authors of the eLife study include: Albert Kim, Andrew Ransick, Xi Chen, and Nils Lindstrom from USC; Aaron Brown from the Maine Medical Center Research Institute; and Bin Li and Bing Ren from the University of California, San Diego. The research was supported by federal funding from the National Institute of Diabetes and Digestive and Kidney Diseases (grant number R01 DK054364).
Evidence of Antarctic glacier’s tipping point confirmed for first time
Researchers have confirmed for the first time that Pine Island Glacier in West Antarctica could cross tipping points, leading to a rapid and irreversible retreat which would have significant consequences for global sea level
Researchers have confirmed for the first time that Pine Island Glacier in West Antarctica could cross tipping points, leading to a rapid and irreversible retreat which would have significant consequences for global sea level.
Pine Island Glacier is a region of fast-flowing ice draining an area of West Antarctica approximately two thirds the size of the UK. The glacier is a particular cause for concern as it is losing more ice than any other glacier in Antarctica.
Currently, Pine Island Glacier together with its neighbouring Thwaites glacier are responsible for about 10% of the ongoing increase in global sea level.
Scientists have argued for some time that this region of Antarctica could reach a tipping point and undergo an irreversible retreat from which it could not recover. Such a retreat, once started, could lead to the collapse of the entire West Antarctic Ice Sheet, which contains enough ice to raise global sea level by over three metres.
While the general possibility of such a tipping point within ice sheets has been raised before, showing that Pine Island Glacier has the potential to enter unstable retreat is a very different question.
Now, researchers from Northumbria University have shown, for the first time, that this is indeed the case.
Their findings are published in leading journal, The Cryosphere.
Using a state-of-the-art ice flow model developed by Northumbria’s glaciology research group, the team have developed methods that allow tipping points within ice sheets to be identified.
For Pine Island Glacier, their study shows that the glacier has at least three distinct tipping points. The third and final event, triggered by ocean temperatures increasing by 1.2C, leads to an irreversible retreat of the entire glacier.
The researchers say that long-term warming and shoaling trends in Circumpolar Deep Water, in combination with changing wind patterns in the Amundsen Sea, could expose Pine Island Glacier’s ice shelf to warmer waters for longer periods of time, making temperature changes of this magnitude increasingly likely.
The lead author of the study, Dr Sebastian Rosier, is a Vice-Chancellor’s Research Fellow in Northumbria’s Department of Geography and Environmental Sciences. He specialises in the modelling processes controlling ice flow in Antarctica with the goal of understanding how the continent will contribute to future sea level rise.
Dr Rosier is a member of the University’s glaciology research group, led by Professor Hilmar Gudmundsson, which is currently working on a major £4million study to investigate if climate change will drive the Antarctic Ice Sheet towards a tipping point.
Dr Rosier explained: “The potential for this region to cross a tipping point has been raised in the past, but our study is the first to confirm that Pine Island Glacier does indeed cross these critical thresholds.
“Many different computer simulations around the world are attempting to quantify how a changing climate could affect the West Antarctic Ice Sheet but identifying whether a period of retreat in these models is a tipping point is challenging.
“However, it is a crucial question and the methodology we use in this new study makes it much easier to identify potential future tipping points.”
Hilmar Gudmundsson, Professor of Glaciology and Extreme Environments worked with Dr Rosier on the study. He added: “The possibility of Pine Island Glacier entering an unstable retreat has been raised before but this is the first time that this possibility is rigorously established and quantified.
“This is a major forward step in our understanding of the dynamics of this area and I’m thrilled that we have now been able to finally provide firm answers to this important question.
“But the findings of this study also concern me. Should the glacier enter unstable irreversible retreat, the impact on sea level could be measured in metres, and as this study shows, once the retreat starts it might be impossible to halt it.”
The paper, The tipping points and early warning indicators for Pine island Glacier, West Antarctica, is now available to view in The Cryosphere.
Northumbria is fast becoming the UK’s leading university for research into Antarctic and extreme environments.
As well as the £4m tipping points study, known as TiPPACCs, Northumbria is also the only UK university to play a part in two projects in the £20m International Thwaites Glacier Collaboration – the largest joint project undertaken by the UK and USA in Antarctica for more than 70 years – where Northumbria is leading the PROPHET and GHC projects. This particular study was funded through both TiPPACCs and PROPHET.
Diversity can prevent failures in large power grids
Integrated power grids offer benefits, but also pose challenges best addressed by leveraging differences
The recent power outages in Texas brought attention to its power grid being separated from the rest of the country. While it is not immediately clear whether integration with other parts of the national grid would have completely eliminated the need for rolling outages, the state’s inability to import significant amounts of electricity was decisive in the blackout.
A larger power grid has perks, but also has perils that researchers at Northwestern University are hoping to address to expedite integration and improvements to the system.
An obvious challenge in larger grids is that failures can propagate further — in the case of Texas, across state lines. Another is that all power generators need to be kept synchronized to a common frequency in order to transmit energy. The U.S. is served by three “separate” grids: The Eastern interconnection, the Western interconnection and the Texas interconnection, interlinked only by direct-current power lines. Any persistent deviation in frequencies within a region can lead to an outage.
As a result, researchers are searching for ways to stabilize the grid by looking for methods to mitigate deviations in the power generators’ frequencies.
The new Northwestern research shows that counter to assumptions held by some, there are stability benefits to heterogeneity in the power grid. Examining several power grids across the U.S. and Europe, a team led by Northwestern physicist Adilson Motter recently reported that generators operating on different frequencies return to their normal state more quickly when they are damped by “breakers” at different rates than generators around them.
The paper was published March 5 in the journal Nature Communications.
Motter is the Charles E. and Emma H. Morrison Professor in the department of physics and astronomy in the Weinberg College of Arts and Sciences. His research focuses on nonlinear phenomena in complex systems and networks.
Motter compares power grids to a choir: “It’s a little bit like a choir without a conductor. The generators have to listen to others and speak in sync. They react and respond to each other’s frequencies.”
Listen to an out-of-whack frequency, and the result can be a failure. Given the interconnected makeup of the system, a failure can propagate across the network. Historically, these malfunctions have been prevented by using active controllers. However, failures are often caused precisely by control and equipment errors. This points to a need to build additional stability within the design of the system. To achieve that, the team looked into leveraging the natural heterogeneities of the grid.
When the frequencies of the power generators are moved away from the synchronous state, they can swing around for a long time and even become more erratic. To mitigate these fluctuations, they came up with something akin to a door mechanism used to close a door the fastest, but without slamming.
“Mathematically, the problem of damping frequency deviations in a power generator is analogous to the problem of optimally damping a door to get it to close the fastest, which has a known solution in the case of a single door,” Motter said. “But it’s not a single door in this analogy. It’s a network of many doors that are coupled with each other, if you can imagine the doors as power generators.”
When creating an “optimal damping” effect, they discovered that rather than making each damper identical, damping the power generators in a way that is suitably different from each other can further optimize their ability to synchronize to the same frequency as quickly as possible. That is, suitably heterogenous damping across the network can lead to improved stability in the power grids studied by the team.
This discovery could have implications for future grid design as developers work to optimize technology and in considerations to further integrate now separated networks.
The paper is titled “Asymmetry underlies stability in power grids.” Additional co-authors include former postdoctoral researcher Ferenc Molnar and research professor Takashi Nishikawa.
The study was supported by Northwestern University’s Finite Earth Initiative (supported by Leslie and Mac McQuown) and ARPA-E Award No. DE-AR0000702 and also benefited from logistical support from the Northwestern Institute for Sustainability and Energy.
How Fortnite and Zelda can up your surgical game (no joke!)
Scalpel? Check. Gaming console? Check. Study finds video games can be a new tool on surgical tray for medical students
Video games offer students obvious respite from the stresses of studies and, now, a study from a University of Ottawa medical student has found they could benefit surgical skills training.
Arnav Gupta carries a heavy course load as a third-year student in the Faculty of Medicine, so winding down with a game of Legend of Zelda always provides relief from the rigorous of study. But Zelda may be helping improve his surgical education, too, as Gupta and a team of researchers from the University of Toronto found in a paper they recently published in the medical journal Surgery.
“Given the limited availability of simulators and the high accessibility of video games, medical students interested in surgical specialties should know that video games may be a valuable adjunct training for enhancing their medical education, especially in surgical specialties where it can be critical,” says Gupta, whose findings were deciphered from a systematic review of 16 studies involving 575 participants.
“Particularly, in robotic surgery, being a video gamer was associated with improvements in time to completion, economy of motion, and overall performance. In laparoscopic surgery, video games-based training was associated with improvement in duration on certain tasks, economy of motion, accuracy, and overall performance,” explains Gupta, who has been a gamer since age 8.
This study builds on past reviews and is the first to focus on a specific medical student population where this style of training could be feasibly implemented. Their timely study found some of the most beneficial games for students of robotic surgery and laparoscopy were: Super Monkey Ball, Half Life, Rocket League and Underground. Underground is purposely designed to assist medical students with their robotic surgery training via a video game console.
“While video games can never replace the value of first-hand experience, they do have merit as an adjunctive tool, especially when attempting to replicate important movements to surgery. For example, first-person shooting games require you to translate three dimensional motions onto a two-dimensional screen, which is like the concept of laparoscopic surgery,” says Gupta, whose studies are focused on surgery in ophthalmology, which makes games like Resident Evil 4 or Trauma Center: New Blood fitted for his own ambitions.
“I’m not joking when I say that games such as Fortnite have the potential to enhance those necessary movements, providing stronger motivational components and in a low stakes environment.”
Reports suggest 55 percent of university students are gamers and enjoy proficiency with video consoles. Yet, many medical students don’t admit to owning and using a gaming console.
“I think there definitely is some ambivalence towards video games in medicine,” says Gupta, who is also a fan of Witcher 3. “Given how accessible games have become and how video game technology is advancing, video games definitely are an easy go-to for the students who do love them in some capacity. The hope is that maybe this study can inspire someone to take advantage of video games’ unique capabilities, reduce the general ambivalence towards it, and develop some fun ways to let students engage with surgical education.”
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