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Researchers create embryo-like structures from monkey embryonic stem cells

Source: Cell Press
Date: 4/6/2023
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Human embryo development and early organ formation remain largely unexplored due to ethical issues surrounding the use of embryos for research as well as limited availability of materials to study. In a paper published April 6 in the journal Cell Stem Cell, a team of investigators from China report for the first time the creation of embryo-like structures from monkey embryonic stem cells. The investigators also transferred these embryo-like structures into the uteruses of female monkeys and determined that the structures were able to implant and elicit a hormonal response similar to pregnancy.

“The molecular mechanisms of human embryogenesis and organogenesis are largely unclear,” says co-corresponding author Zhen Liu of the Chinese Academy of Sciences (CAS) in Shanghai. “Because monkeys are closely related to humans evolutionarily, we hope the study of these models will deepen our understanding of human embryonic development, including shedding light on some of the causes of early miscarriages.”

“This research has created an embryo-like system that can be induced and cultured indefinitely,” says co-corresponding author Qiang Sun, also of CAS. “It provides new tools and perspectives for the subsequent exploration of primate embryos and reproductive medical health.”

The investigators started with macaque embryonic stem cells, which they exposed to a number of growth factors in cell culture. These factors induced the stem cells to form embryo-like structures for the first time using non-human primate cells.

When studied under a microscope, the embryo-like structures, also called blastoids, were found to have similar morphology to natural blastocysts. As they further developed in vitro, they formed arrangements that looked like the amnion and yolk sac. The blastoids also started to form the types of cells that eventually make up the three germ layers of the body. Single-cell RNA sequencing revealed that the different types of cells found within the structures had similar gene expression patterns to cells found in natural blastocysts or post-implantation embryos.

The blastoids were then transferred into the uteruses of 8 female monkeys; in 3 of the 8, the structures implanted. This implantation resulted in the release of progesterone and chorionic gonadotropin, hormones normally associated with pregnancy. The blastoids also formed early gestation sacs, fluid-filled structures that develop early in pregnancy to enclose an embryo and amniotic fluid. However, they did not form fetuses and the structures disappeared after about a week.

In future work, the investigators plan to focus on further developing the system of culturing embryo-like structures from monkey cells. “This will provide us with a useful model for future study,” says co-corresponding author Fan Zhou of Tsinghua University. “Further application of monkey blastoids can help to dissect the molecular mechanisms of primate embryonic development.”

The researchers acknowledge the ethical concerns surrounding this type of research but emphasize that there are still many differences between these embryo-like structures and natural blastocysts. Importantly, the embryo-like structures do not have full developmental potential. They note that for this field to advance it’s important to have discussions between the scientific community and the public.

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Cultural Barriers to Genetic Testing

Source: Cell Press
Date: 6/7/2022
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As prices for genetic testing go down and awareness of what these tests can do goes up, more and more people are choosing to have their DNA analyzed. The underrepresentation of non-European ancestry groups in genomic databases, however, complicates the interpretation of their genetic test results.

In a commentary published on June 2 in the American Journal of Human Genetics(link is external and opens in a new window), researchers examine how “variants of uncertain significance” (VUS)—a genetic change whose impact on the individual’s disease risk is not yet known—are more likely to be identified in populations underrepresented in genetic databases, as well as ways to reduce their incidence.  

“A great deal of effort goes into broad-based projects that aim to recruit diverse segments of the population,” says first author Paul Appelbaum, MD, director of the Center for Research on Ethical, Legal & Social Implications of Psychiatric, Neurologic & Behavioral Genetics at Columbia University. “What’s different about our contribution here is the recognition that broad-based recruitment will need to be complemented by more focused efforts that take group concerns into account.”

There are practical and ethical reasons that VUS are important to address. Tests that yield a VUS fail to generate information that is useful clinically. Additionally, although current guidelines discourage clinicians from making treatment decisions based on a VUS, many clinicians and patients may feel compelled to act on them anyway. Discovery of a VUS can lead to anxiety, distress—especially variants in genes known to increase the risk of diseases like cancer—and, in some cases. even drastic interventions like prophylactic surgery.

Cultural Concerns

In this paper, the investigators focused on cultural issues among two ancestry groups, as well as culturally informed ways to address and overcome those issues.

For the first group—the Sephardi Jewish community in New York—they focus on the Dor Yeshorim project, an effort created to reduce the incidence of genetic diseases in the Jewish community, with an initial focus on Tay Sachs. The second group was the Silent Genomes Project, an effort housed at the University of British Columbia that aims to reduce healthcare disparities and improve diagnostic success for children with genetic diseases from Indigenous populations in Canada.

The two communities have very different concerns about contributing to genomic research and datasets. Sephardi concerns focus on the possible negative effects of genetic findings on the marriage prospects of family members. Canadian Indigenous populations seek control over the research uses to which their genetic data would be put.

“Both groups have specific cultural reasons for being hesitant to provide genetic data,” says Dr. Appelbaum, who is the Elizabeth K. Dollard Professor of Psychiatry, Medicine and Law at Columbia. “By working with them to find ways to address their concerns, we can overcome these hesitations.” 

Dr. Appelbaum acknowledges challenges in scaling up these kinds of efforts to reach other underrepresented populations and the lack of a one-size-fits-all approach. “For each of these groups, we need to recognize the reasons for their underrepresentation and work with them to find ways to address those concerns,” he says. He adds that it’s vital to obtain more funding for targeted recruitment efforts and to develop a governance structure that involves the relevant communities in an ongoing fashion.

“It’s crucial to know the frequency of variants in the population,” Dr. Appelbaum says. “And given differences in variant frequency across population groups and the prevalence of population-specific variants, comparisons with reference data from a specific ancestral group may be crucial. That’s true in both clinical settings and in research.”

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Many IVF embryos not implanted due to mosaic abnormalities may be viable

Source: Cell Press
Date: 11/18/2021
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One factor that limits the success of in vitro fertilization (IVF) procedures is the number of viable embryos available for implantation in the uterus. A study published November 18 in the American Journal of Human Genetics suggests that many of the embryos that are discarded or downgraded due to chromosomal abnormalities have the potential to lead to successful pregnancies. These findings could have important implications for people undergoing IVF treatments.

“We believe the clinical data generated from this trial will resolve some of the major concerns that arise during pre-implantation genetic testing and will be of fundamental importance for helping many infertile patients make more informed reproductive decisions,” says first author Antonio Capalbo (@antonio_capalbo), a specialist in reproductive genetics at Igenomix Italy, a company that provides genetic testing services. “This trial has the potential to drive a radical change in the clinical management of IVF and to support the development of updated guidelines and recommendation from scientific societies.”

The researchers focused on the prevalence and distribution of aneuploid cells (cells with chromosome imbalances) within lab-created blastocysts, the precursor to embryos. In particular, they looked at a condition called mosaicism, in which embryos have a mix of normal and aneuploid cells. Currently, fewer than 3% of these mosaic embryos are used in IVF treatments, and several clinics in the US do not allow them to be transferred. But in many blastocysts with this type of mosaicism, the area of abnormal cells is localized to a small area that may not affect development.

In the current study, investigators conducted a double-blinded trial in which patients undergoing IVF at five hospitals in Italy had their embryos tested with pre-implantation genetic testing that looked specifically for mosaic aneuploidy. In addition to euploid embryos (those with no aneuploidy), embryos with low-grade mosaicism (20%–30% aneuploid cells) and medium-grade mosaicism (30%–50% aneuploid cells) were blindly reported as euploid and implanted. The primary outcome of the trial was defined as live birth rate, and the secondary outcome was miscarriage rate.

“It was already known that putative mosaic embryos can develop to term and make healthy babies, but many of the previous studies that looked at this issue were affected by selection bias toward a population of patients that had a poor prognosis because they had previously failed implantations with euploid embryos,” he says. “Alternatively, mosaic embryos have been transferred into patients producing only aneuploid embryos, again introducing a strong selection bias toward a poor-prognosis population.”

The researchers say the current study avoided that bias by being a non-selection trial, in which any embryos that fit the defined criteria were eligible for transfer. Overall, they found that across 484 euploid, 282 low-grade mosaic, and 131 medium-grade mosaic embryos, the rates of live births and miscarriages were similar. The obstetrical and neonatal outcomes were also similar.

“We did this study because we were concerned about the unmotivated dismissal of putative mosaic embryos from clinical use without robust data to support this practice,” Capalbo says. “Our findings suggest that reporting mosaicism as it is currently performed doesn’t provide any element of clinical utility for IVF patients. Accordingly, it seems reasonable these genetic findings not be reported after pre-implantation genetic testing, similar to what is done for variants of unknown significance in clinical genetic testing. If these findings are reported, patients should be aware that the embryos are otherwise healthy and normal.”

The investigators expect that this study will immediately impact clinical practice, driving an update of guidelines and recommendations from relevant scientific societies and allowing IVF patients to improve their decision-making process when evaluating the transfer of mosaic embryos. “In the future, we encourage the preliminary use of data from non-selection trials before incorporating new pre-implantation genetic testing algorithms and aneuploidy classification criteria in routine practice,” Capalbo says.

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Scientists generate human-monkey chimeric embryos

Source: Cell Press
Date: 4/15/2021
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Investigators in China and the United States have injected human stem cells into primate embryos and were able to grow chimeric embryos for a significant period of time — up to 20 days. The research, despite its ethical concerns, has the potential to provide new insights into developmental biology and evolution. It also has implications for developing new models of human biology and disease. The work appears April 15 in the journal Cell.

“As we are unable to conduct certain types of experiments in humans, it is essential that we have better models to more accurately study and understand human biology and disease,” says senior author Juan Carlos Izpisua Belmonte, a professor in the Gene Expression Laboratory at the Salk Institute for Biological Sciences. “An important goal of experimental biology is the development of model systems that allow for the study of human diseases under in vivo conditions.”

Interspecies chimeras in mammals have been made since the 1970s, when they were generated in rodents and used to study early developmental processes. The advance that made the current study possible came last year when this study’s collaborating team — led by Weizhi Ji of Kunming University of Science and Technology in Yunnan, China — generated technology that allowed monkey embryos to stay alive and grow outside the body for an extended period of time.

In the current study, six days after the monkey embryos had been created, each one was injected with 25 human cells. The cells were from an induced pluripotent cell line known as extended pluripotent stem cells, which have the potential to contribute to both embryonic and extra-embryonic tissues. After one day, human cells were detected in 132 embryos. After 10 days, 103 of the chimeric embryos were still developing. Survival soon began declining, and by day 19, only three chimeras were still alive. Importantly, though, the percentage of human cells in the embryos remained high throughout the time they continued to grow.

“Historically, the generation of human-animal chimeras has suffered from low efficiency and integration of human cells into the host species,” Izpisua Belmonte says. “Generation of a chimera between human and non-human primate, a species more closely related to humans along the evolutionary timeline than all previously used species, will allow us to gain better insight into whether there are evolutionarily imposed barriers to chimera generation and if there are any means by which we can overcome them.”

The investigators performed transcriptome analysis on both the human and monkey cells from the embryos. “From these analyses, several communication pathways that were either novel or strengthened in the chimeric cells were identified,” Izpisua Belmonte explains. “Understanding which pathways are involved in chimeric cell communication will allow us to possibly enhance this communication and increase the efficiency of chimerism in a host species that’s more evolutionarily distant to humans.”

An important next step for this research is to evaluate in more detail all the molecular pathways that are involved in this interspecies communication, with the immediate goal of finding which pathways are vital to the developmental process. Longer term, the researchers hope to use the chimeras not only to study early human development and to model disease, but to develop new approaches for drug screening, as well as potentially generating transplantable cells, tissues, or organs.

An accompanying Preview in Cell outlines potential ethical considerations surrounding the generation of human/non-human primate chimeras. Izpisua Belmonte also notes that “it is our responsibility as scientists to conduct our research thoughtfully, following all the ethical, legal, and social guidelines in place.” He adds that before beginning this work, “ethical consultations and reviews were performed both at the institutional level and via outreach to non-affiliated bioethicists. This thorough and detailed process helped guide our experiments.”

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Researchers simulate privacy leaks in functional genomics studies

Source: Cell Press
Date: 11/12/2020
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The functional genomics field, which looks at the activities of the genome and levels of gene expression rather than particular gene mutations, generally relies on aggregating information from many samples for its statistical power. This means that broadly sharing raw data is vital; however, sharing these data currently is challenging because of the privacy concerns of individuals within those datasets, leading to these data being largely inaccessible behind firewalls.

In a study publishing November 12 in the journal Cell, a team of investigators demonstrates that it’s possible to de-identify those data to ensure patient privacy. They also demonstrate how these raw data could be linked back to specific individuals through their gene variants by something as simple as an abandoned coffee cup if these sanitation measures are not put in place.

“The purpose of this study is to come up with practical ways to broadly share the raw data without creating undue privacy concerns,” says senior author Mark Gerstein, a professor of bioinformatics at Yale University.

Functional genomics research is frequently tied to a specific disease. For example, an investigation into a particular psychiatric condition might look at the expression of certain genes in a type of neuron. And, by nature of having their genetic material included in such a study, an individual’s medical status with regard to that condition could inadvertently be revealed.

This can happen through what’s known as a quasi-identifier. The way a quasi-identifier works is that if someone has enough individual data points about you, even if those data on their own are not sensitive or unique, they can be combined to create an identifier that is unique to you. In a non-genetic setting, this means if someone has your zip code, birthday, the model of car you drive, and other similar data that might not be considered private or sensitive on their own, they might eventually be able to combine them and create a unique profile that would link you to other data that you wouldn’t want public — data like financial records that were collected when you applied for a car loan. The same thing could happen if someone were able to obtain some of your genetic variants and link those variants to the presence of your genetic material in a study on a particular disease. This could in turn reveal a diagnosis, such as HIV status or an inherited cancer predisposition, that you would prefer to keep private.

In their study, the researchers constructed a “linkage attack” scenario to demonstrate how someone could make these kinds of connections from functional genomics studies’ data by using DNA obtained from a discarded coffee cup. After adding samples from two consenting participants to a functional genomics database, the researchers gathered used coffee cups from the same individuals. They sequenced genetic material left on the cups and were able to successfully match that material to the samples in the database and infer sensitive health information about the participants. The researchers were also able to use DNA information “stolen” from a genotyping database to match the identities of 421 people with phenotypic information found in a test functional-genomics dataset that the researchers constructed for 436 people.

However, the researchers also identified steps that can be taken to thwart these kinds of linkage attacks and safeguard participants’ health information when functional genomics datasets are shared. “Functional genomics is special because variants are usually not needed for data processing,” says first author Gamze Gürsoy, a postdoctoral researcher at the Gerstein lab. “Because of this, we can sanitize the variants to prevent data being linked back to the private information connected to the phenotypes included in these studies, while still retaining the utility of the data.”

To achieve this balance between privacy and data usefulness, the researchers propose a file-format manipulation that will allow raw functional genomics data to be shared while largely reducing sensitive information leakage by generalizing information about phenotypic variants. The file format is based on a widely used standard file-format system, is compatible with a range of software and pipelines, and when tested, showed little loss of utility. The researchers have also developed a framework with which other researchers can tune the level of privacy and utility balance they want to achieve with the file format based on the policies and consents of the donors.

“As more data are released for these kinds of functional genomics studies, concerns about security and privacy shouldn’t be lost,” Gerstein says. “At the dawn of the Internet, people didn’t realize how important their online activities would become. Now that type of digital privacy has become so important to us. If we move into an era where getting your genome sequenced becomes routine, we don’t want these worries about health privacy to become dominating.”

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Why the ‘wimpy’ Y chromosome hasn’t evolved out of existence

Source: Cell Press
Date: 8/17/2020
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An Opinion paper co-authored by a UNSW scientist – published online this month in the journal Trends in Genetics – outlines a new theory, called the “persistent Y hypothesis”, to explain why the Y chromosome may be more resilient than it first appears. 

Much smaller than its counterpart, the X chromosome, the Y chromosome has shrunken drastically over 200 million years of evolution. Even those who study it have used the word “wimpy” to describe it, and yet it continues to stick around even though sex chromosomes in non-mammalian vertebrates are known to experience quite a bit of evolutionary turnover.

“The Y chromosome is generally thought to be protected from extinction by having important functions in sex determination and sperm production, which, if moved to somewhere else in the genome, would signal its demise,” says co-author Paul Waters, an Associate Professor at the UNSW Sydney. “However, we propose that the future of the Y chromosome is secure because it carries executioner genes that are critical for successful progression of male meiosis–and unlike other genes on the Y, these executioners self-regulate.”

During meiosis, sexually reproducing organisms form haploid gametes (eggs and sperm), each of which contains only one copy of each chromosome. They do this through one round of genome replication followed by two consecutive rounds of cell division. This meiotic process is tightly regulated to avoid infertility and chromosome abnormalities. 

One step of meiosis requires the silencing of both the X and Y chromosomes during a specific window. “Importantly, the Y chromosome bears genes that regulate this process, a feature that has been known for years now,” says co-author Aurora Ruiz-Herrera, a professor at Universitat Autònoma de Barcelona in Spain. “We believe that bearing these genes is what protects the Y chromosome from extinction. The genes that regulate the silencing process, the Zfy genes, are called ‘executioner’ genes. When these genes are turned on at the wrong time and at the wrong place during meiosis, they are toxic and execute the developing sperm cell. They essentially act as their own judge, jury, and executioner, and in doing so, protect the Y from being lost.”

The Y chromosome is present in all but a handful of mammalian species. Important contributions to understanding the Y chromosome have come from looking at the rare mammals that don’t follow the rules–for example, a handful of species of rodents. “I’ve always been a firm believer that the comparison of unusual systems is informative to other systems,” A/Prof. Waters says. “Determining the common prerequisites for rare Y chromosome loss enabled us to build a hypothesis for how Y chromosomes persist in most species.”

The collaboration between Waters and Ruiz-Herrera–based half a world apart–began to bear fruit during the COVID-19 pandemic. “Earlier this year, we put together a grant application to examine aspects of X chromosome silencing during meiosis,” says Waters. “After the shutdown of our labs, we decided to massage our discussions into a review article. We had no idea we would essentially stumble onto such an intuitive mechanism to explain why the mammal Y chromosome has persisted in most species.” Going forward, the researchers plan to take a closer look at how the executioner genes evolved, and how they are regulated from evolutionary and functional perspectives.

“The mammalian Y has been taken as a symbol of masculinity, not only in popular culture but also in the scientific community,” Ruiz-Herrera says. “Despite that, many have projected that, given enough time, it will be eventually lost. However, we propose the Y chromosome can escape this fatal fate. So our male colleagues can breathe easy: the Y will persist!”

Paul Waters is supported by the Australian Research Council. Aurora Ruiz-Herrera is supported by the Spanish Ministry of Science and Innovation.

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Studying the Neanderthal DNA found in modern humans using stem cells and organoids

Source: Cell Press
Date: 6/18/2020
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Protocols that allow the transformation of human induced pluripotent stem cell (iPSC) lines into organoids have changed the way scientists can study developmental processes and enable them to decipher the interplay between genes and tissue formation, particularly for organs where primary tissue is not available. Now, investigators are taking this technology and applying it to study the developmental effects of Neanderthal DNA. The findings are reported June 18 in the journal Stem Cell Reports.

“Using iPSC lines to study the functions of archaic human DNA is an untapped but very interesting approach,” says senior author J. Gray Camp of the Max Planck Institute for Evolutionary Anthropology in Germany and the University of Basel in Switzerland. “No one has ever been able to look at the role Neanderthal DNA plays during development.”

Studies have found that about 2% of the genomes of modern humans from outside Africa are composed of Neanderthal DNA. This archaic DNA is a result of mating between the two groups tens of thousands of years ago.

In the new study, the team used resources from the Human Induced Pluripotent Stem Cells Initiative (HipSci), an international consortium that provides data and cell lines for research. Nearly all of the data and cell lines in HipSci are from people of UK and Northern European descent. The researchers analyzed this cell line resource for its Neanderthal DNA content and annotated functional Neanderthal variants for each of the cell lines.

“Some Neanderthal alleles have relatively high frequency in this population,” Camp explains. “Because of that, this iPSC resource contains certain genes that are homozygous for Neanderthal alleles, including genes associated with skin and hair color that are highly prevalent in Europeans.”

Camp’s team used five cell lines to generate brain organoids and generated single-cell RNA sequencing data to analyze their cell composition. They showed that this transcriptomic data could be used to track Neanderthal-derived RNA across developmental processes. “This is a proof-of-principal study showing that you can use these resources to study the activity of Neanderthal DNA in a developmental process,” Camp says. “The real challenge will be scaling up the number of lines in one experiment, but this is already starting to be possible.”

Camp notes that this research could be expanded to study other ancient human populations, including Denisovans, which have genes that are present primarily in Oceanian populations. His team also plans to continue studying Neanderthal alleles using HipSci and other resources. “Organoids can be used to study a number of different developmental processes and phenotypes controlled by Neanderthal DNA, including the intestinal tract and digestion, cognition and neural function, and the immune response to pathogens,” he concludes.

The researchers have generated a web browser with this information to make the data easily accessible for future research.

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A CASE STUDY: TAVR IN PATIENT WITH CONGENITAL HEART DEFECT

Source: Brigham and Women's Hospital
Date: 11/24/2020
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Over the past decade, transcatheter aortic valve replacement (TAVR) has evolved from a high-risk procedure to one that has become a standard of care. Each year, thousands of patients undergo this minimally invasive procedure.

Recently, however, a multidisciplinary team of specialists at Brigham and Women’s Hospital planned and performed a TAVR procedure that was anything but standard: The 78-year-old patient had a congenitally corrected transposition of the great arteries (cc-TGA), a rare condition.

In 2008, the patient’s cardiologist in Maine referred them to the Brigham for replacement of the tricuspid valve. The valve, which was on the left side of the heart rather than the right due to their cc-TGA, was no longer able to withstand the pressure of essentially functioning as a mitral valve. When the patient was referred to the Brigham again in 2020, the ventricle that supplied blood for systemic circulation was found to be weak. Further studies revealed the aortic valve had developed severe calcification and become severely stenotic, resulting in pressure overload in the ventricle.

“The patient was not felt to be a good surgical candidate by the doctors in Maine because of the prior operation, the complexities of the congenital condition and the patient’s age,” said cardiovascular medicine specialist Pinak Bipin Shah, MD, director of the Interventional Cardiovascular Disease Training Program and director of the Cardiac Catheterization Laboratory at the Brigham. “The patient was sent to us to determine if we could safely perform TAVR.”

Congenital Heart Defect Heightens Risk of Complications

Upon arrival at the Brigham, the patient underwent an extensive evaluation in conjunction with several medical teams: cardiac imaging, interventional cardiology, cardiac surgery, adult congenital heart disease and advanced heart disease. “We put our heads together to figure out what diagnostic testing was needed and to come up with a plan for the patient’s survival,” Dr. Shah said.

The patient’s congenital defect meant that undergoing TAVR was especially high-risk. “The anatomy of the heart was rather atypical,” said Tsuyoshi Kaneko, MD, a surgical director of the Structural Heart Disease Program and a cardiac surgeon who specializes in endovascular approaches. “The aortic valve was more toward the left side of the heart. But with the expertise of our Structural Heart Disease Program as well as the anesthesiology team, we were able to do the procedure safely.”

The patient’s heart failure likely was due to the combination of the cc-TGA and the stenotic aortic valve. In people with cc-TGA, the right ventricle must maintain systemic pressure for the whole body, not just the pressure needed to pump blood to the lungs.

“Over time, that right ventricle wears out. It doesn’t have the motor to sustain the blood supply to the whole body,” Dr. Kaneko said. “The patient’s heart did well with this condition for 78 years, but once the ventricle began to fail, they deteriorated significantly over a relatively short period of time.”

Collaboration Leads to Successful TAVR Procedure

During the TAVR procedure, which was done in the Brigham’s catheterization laboratory, the patient was sedated but did not receive general anesthesia. The complex anatomy that switched the ventricle and the great arteries made the procedure complicated. However, thanks to extensive imaging and preprocedural planning, a balloon-expandable TAVR prosthesis was deployed safely. The team also placed an embolic protection device in from the patient’s right arm, as they were worried about stroke risk due to the high levels of calcium in the blood vessels.

A very limited number of cases of people with cc-TGA undergoing TAVR have been reported, and the Brigham team believes this patient is the oldest. “We had a total of five teams involved,” Dr. Kaneko said. “Although the procedure carried high risk, we were confident that by leveraging the expertise of all the teams involved, the benefits for this patient would greatly outweigh the risks.”

A postoperative echocardiogram revealed the gradient across the valve was much better than what the patient had had before. The patient required dobutamine for the first few days due to their poor ventricular function but was discharged four days after the procedure. At the time of discharge to Maine, the patient reported tremendous symptomatic relief, was eating and sleeping well and no longer felt short of breath with exertion. Fatigue also improved dramatically.

“The fact that we treated a patient who would have had no treatment option a decade ago shows the vast treatment possibilities offered by our team,” Dr. Kaneko concluded.

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EXAMINING IMPACT OF RACE IN STAGING CHRONIC KIDNEY DISEASE

Source: Brigham and Women's Hospital
Date: 11/12/2020
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An equation used for over a decade to estimate kidney function and stage chronic kidney disease (CKD) can underestimate kidney function and lead to gaps in care delivery in African-American patients, according to research led by investigators at Brigham and Women’s Hospital.

The researchers say the “race multiplier factor,” which is used as part of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) equations to estimate kidney function, can contribute to health disparities in African Americans with CKD. This is particularly important because African-American patients with CKD are known to have worse clinical outcomes with respect to hypertension control, timely nephrology referral, dialysis fistula or graft placement, adequate dialysis treatment and transplantation access.

“The race multiplier is something that all of us were taught to use during medical school and residency training,” said Mallika L. Mendu, MD, MBA, a Brigham nephrologist and senior author of the study, published in October in the Journal of General Internal Medicine (JGIM). “I was surprised to learn how many patients are impacted by the use of the race multiplier and its potential implications on care delivery, particularly referral to kidney transplantation.”

Changing the Math Results in Reclassification of CKD

The calculation in question uses serum creatinine levels to obtain the estimated glomerular filtration rate (eGFR). To account for differences among individuals, the equation includes factors for age, sex, weight and race to improve statistical precision.

Earlier research suggested African Americans had higher measured glomerular filtration rate with the same creatinine levels, leading to the adjustment. But there was no clear biological explanation for why it would be different, Dr. Mendu said.

The new JGIM study led by Dr. Mendu analyzed data and electronic health records from 56,845 patients who were in the Partners HealthCare system’s CKD registry as of June 2019; 2,225 of them self-identified as African American. The researchers recalculated eGFR for these patients, removing the race multiplier of 1.159, and classified the severity of the patients’ disease based on the revised eGFR numbers.

They found the race multiplier essentially designated African-American patients as being healthier than people of other races who had the same clinical findings. Overall, one in three African-American patients was reclassified to a more severe stage of disease when the multiplier was removed. One-quarter of them were moved from Stage 3 to Stage 4.

Differences in staging of patients with more advanced disease ultimately could affect whether they were considered for transplant surgery, the researchers said. Notably, 64 African-American patients were reclassified to an eGFR less than or equal to 20 (a common threshold for kidney transplant referral), but none had a referral. This indicated to Dr. Mendu and the co-authors that there were real, potential adverse consequences to using the race multiplier that could exacerbate disparities.

A Focus on Reducing Health Disparities

Leaders at the Brigham stopped using the race multiplier in June based on preliminary findings from the JGIM study. The team’s research has caught the attention of policymakers, and other hospital systems have said they will refrain from using the race multiplier as well.

Dr. Mendu said the findings from this study may help advance the use of cystatin C as a marker for CKD instead of creatinine. She considers cystatin C to be another acceptable measure of eGFR, as this test does not use a race adjustment factor. The Brigham has always been a leading institution when it comes to CKD treatment, she noted, adding that changing the way patients with CKD are staged and ensuring health equity are other key areas in which the institution can play a pivotal role.

“There are so many complicated issues related to race in medicine and health disparities, something that the COVID-19 pandemic has made very clear,” Dr. Mendu concluded. “But this is one problem we think is quite solvable.”

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FOCUS ON FAMILY MEMBERS POINTS TO NEW CLUES ABOUT IPF

Source: Brigham and Women's Hospital
Date: 11/16/2020
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Idiopathic pulmonary fibrosis (IPF) is more common than once thought. According to the American Lung Association, over 130,000 people are affected in the United States and about 50,000 new cases are diagnosed each year.

“IPF has a mortality rate that’s worse than that of most cancers, yet it gets far less attention,” said Gary “Matt” Hunninghake, MD, director of the Interstitial Lung Disease Program at Brigham and Women’s Hospital. “Because of that, our group has been trying to find ways to detect this disease at its early stages, which we think could eventually lead to better outcomes for those at risk.”

IPF often does not cause symptoms until it’s at an advanced stage. So, to learn more about what early disease looks like and how it behaves, researchers took advantage of a distinct feature of the disease: About 30 to 40 percent of cases have a strong hereditary component. This is different from other common lung diseases such as emphysema and chronic obstructive pulmonary disease, which are overwhelmingly caused by smoking and other environmental factors.

Looking to Relatives for Clues

In May 2020, Dr. Hunninghake had a study published in the American Journal of Respiratory and Critical Care Medicine looking at family members of people with IPF. The researchers surveyed 105 first-degree relatives of patients with IPF. The family members were screened with questionnaires, pulmonary function tests, chest CTs, blood sampling for immunophenotyping, telomere length assessment and genetic testing.

The researchers found that 31 percent (33 individuals) had evidence of chest CT abnormalities, which may be a precursor to the more serious IPF. Their findings suggested that undiagnosed interstitial lung disease may be present in greater than one in six older first-degree relatives of IPF patients.

“These findings suggest that it would be rational to screen for IPF in close relatives,” Dr. Hunninghake said. “It also provides an opportunity for us to learn more about the earlier stages of IPF, if we can identify and follow these family members.”

A Focus on Preventive Care for IPF

According to Dr. Hunninghake, the ultimate goal of this research is to create better diagnostic methods and to eventually develop interventions for treating the disease early. “The paradigm is similar to the approach that’s been used over the years with cardiovascular disease,” he said. In the past, most people who had heart attacks experienced poor outcomes. Now, a significant component of cardiovascular disease care and research is focused on preventive cardiology.

“We think that same preventive model could be applied to IPF in the future,” he noted. “We can identify those who are at highest risk of having bad outcomes so that we can intervene.”

According to Dr. Hunninghake, studies published in 2014 demonstrating that pirfenidone and nintedanib showed some efficacy in treating IPF marked a turning point for treating the disease. “These drugs don’t provide a cure, but they do slow down the progression of the IPF by targeting fibrotic pathways,” he said.

Dr. Hunninghake and his colleagues, whose previous research was funded by the National Heart, Lung, and Blood Institute, have applied for additional funding to continue studying IPF in families. “We hope that one day we can identify interventions—not only pharmaceuticals, but lifestyle interventions—that might benefit people with this disease,” he concluded.