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Scientists find culprit responsible for calcified blood vessels in kidney disease

Stem cell finding informs research to prevent hardening of arteries By Julia Evangelou Strait September 8, 2016 A new study indicates that stem cells called Gli1 cells (shown in red) are responsible for depositing calcium in the arteries, increasing the risk of atherosclerosis. Over time, the condition can lead to cardiovascular disease and is especially common in patients with chronic kidney disease. The research may help scientists find ways to prevent hardening of arteries. (Image: Humphries Lab)Scientists have implicated a type of stem cell in the calcification of blood vessels that is common in patients with chronic kidney disease. The research will guide future studies into ways to block minerals from building up inside blood vessels and exacerbating atherosclerosis, the hardening of the arteries. The study, led by researchers at Washington University School of Medicine in St. Louis, appears Sept. 8 in the journal Cell Stem Cell. “In the past, this calcification process was viewed as passive — just mineral deposits that stick to the walls of vessels, like minerals sticking to the walls of water pipes,” said senior author Benjamin D. Humphreys, MD, PhD, director of the Division of Nephrology and an associate professor of medicine. “More recently, we’ve learned that calcification is an active process directed by cells. But there has been a lot of controversy over which cells are responsible and where they come from.” The cells implicated in clogging up blood vessels with mineral deposits live in the outer layer of arteries and are called Gli1 positive stem cells, according to the study. Because they are adult stem cells, Gli1 cells have the potential to become different types of connective tissues, including smooth muscle, fat and bone. Humphreys and his colleagues [...]

Bioengineered Blood Vessel Shows Early Promise for Dialysis Patients

Fri, 05/13/2016 - 9:12am Duke University Man-made blood vessels developed by researchers at Duke University, Yale University and the tissue engineering company Humacyte appear to be both safe and more durable than commonly used synthetic versions in patients undergoing kidney dialysis, the researchers report. The findings, published May 12 in The Lancet, resulted from a phase 2 study among 60 patients with kidney failure who required dialysis, which often requires a synthetic graft when the patient’s own blood vessel degrades from frequent needle sticks. Such grafts, however, are prone to infection, clotting, and other complications. And alternative bioengineered grafts derived from the patient, a donor, or animal tissue have been shown to perform no better than synthetics. The Duke and Yale research team -- along with surgeons in Poland and the United States and scientists at Humacyte, which is developing the bioengineered vessel -- tested a human acellular vessel, or HAV, that is manufactured to be available to patients on demand, rather than made-to-order using an individual’s own cells. “The bioengineered blood vessel represents a critical step in tissue engineering,” said Jeffrey Lawson, M.D., Ph.D., professor of surgery and pathology at Duke and chief medical officer of Humacyte. “Because these vessels contain no living cells, patients have access to off-the-shelf engineered grafts that can be used without any waiting period associated with tailor-made products.” Lawson and co-author Laura Niklason, M.D., Ph.D., professor of anesthesiology and biomedical engineering at Yale, are principals of Humacyte, Inc., which supported the clinical trial. To create the vessels, the researchers first isolated vascular cells from human donors and grew them in tissue culture. They then placed the cells on a degradable scaffold shaped like a blood vessel. As the tissue grew, [...]

Good as gold​​​

Precious metal, artificial antibodies combine for kidney injury test October 22, 2015 By Erika Ebsworth-GooldGold is one of the world’s best-known precious metals. For thousands of years, it’s been crafted into jewelry, medals and coins. When mixed with alloys, it can take on a white or rose-colored cast, but its natural hue is a deep, rich, unmistakable yellow. It’s hoped that gold nanocages, paired with artificial antibodies, can be used for a test to detect acute kidney damage. But chopped down in nano-sized bits (nanostructures), the metal becomes a chameleon, turning shades of green, blue, and even red, that can readily be seen with the human eye. The color changes are seen when the size and shape of the particles are changed or there is a change in the immediate environment surrounding the nanostructures. It’s that color-shifting quality that researchers at Washington University in St. Louis are using to develop new technologies for medical diagnostic assays, and their current objective — to create an easily-utilized test for acute kidney damage that provides rapid results. Singamaneni Srikanth Singamaneni, PhD, associate professor of materials science in the School of Engineering & Applied Science, has received a two-year, $411,246 grant from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (NIH) to design and produce new biosensors that will combine gold nanocages and specifically engineered artificial antibodies to detect biochemical signs of kidney damage. “Instead of using natural antibodies, which can take months or years to develop, we use artificial antibodies integrated with the gold nanostructures that eliminate the need for stringent storage and shelf-life constraints, and significantly lowers the cost of the biosensors,” Singamaneni said. The plan is to imprint the nanocages [...]

Yale scientists develop novel technique for kidney research

By Ziba Kashef August 24, 2015 One in four patients treated with the widely used anti-cancer drug cisplatin develop chronic kidney disease. To better understand how the treatment leads to kidney damage, and possibly prevent it, a team of researchers at Yale School of Medicine developed a new 3D-imaging technique to peer deep into these vital organs. Their study was published online Aug. 24 in the Journal of the American Society of Nephrology. New imaging technique shows internal structures of normal kidney (a) versus damage in response to anti-cancer drug (b and c). Using a mouse model, the Yale team, led by professor of nephrology Dr. Robert Safirstein, administered doses of cisplatin two weeks apart. To examine the effect of the drug on kidneys, the researchers combined a powerful imaging technique, multiphoton microscopy, with a clearing solution that produced high-resolution 3D images of the organ. The novel strategy provided an unusually deep view of the kidney’s internal structures. “Before this technique, you could only look at the very superficial surface, so you really couldn’t examine the entire kidney,” said Safirstein. To their surprise, the researchers uncovered evidence that the kidneys failed and developed damaged tubules (key structures that the kidney uses to transport fluids) before damage was detectable through more traditional methods. The findings could shift the direction of kidney research. “It changes the focus of research in kidney disease to find out how lesions form,” Safirstein noted. The imaging technique could also inform the study of diabetes and other conditions. “We think this is going to be applicable in a wide variety of diseases,” he noted. Additional authors include Dr. Richard Torres, Heino Velazquez, Dr. John J. Chang, Michael J. Levene, Dr. Gilbert Moeckel, [...]

UTSW Researchers Find Molecule Able to Accelerate Tissue Regeneration Upon Injury

July 20, 2015 Patricia Silva - A study recently published in the renowned journal Science revealed a molecule able to accelerate tissue regeneration after bone marrow transplantation and other tissue injuries in mice. The study is entitled “Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration” and was led by researchers at the University of Texas Southwestern Medical Center, Case Western Reserve University and the University of Kentucky. Tissue regeneration is an important feature in several clinical settings including diseases, injury, and certain treatments such as the recovery of the hematopoietic system after bone marrow transplantation, a common treatment for leukemia patients. Because of this, there is interest in developing agents able to accelerate the tissue regeneration process, especially if they can benefit several organ systems. Researchers have now discovered a molecule that may accelerate tissue regeneration. The prostaglandin PGE2 is a signaling factor that is involved in the expansion of several types of tissue stem cells, contributing to tissue regeneration. In the study, researchers identified a prostaglandin-degrading enzyme known as 15-hydroxyprostaglandin dehydrogenase (15-PGDH), and investigated its potential role as a negative regulator of tissue regeneration. The team used mice with depleted 15-PGDH in order to determine the role of this enzyme in controlling PGE2 levels and the tissue repair capacity in several organs. Researchers also developed a potent small-molecule inhibitor against 15-PGDH – SW033291. Researchers found that 15-PGDH–deficient mice have a twofold increase in PGE2 levels in different tissues (including bone marrow, colon and liver) in comparison to wild-type mice, an increased capability to respond to cell damage in these particular tissues, and an enhanced hematopoietic capacity. Remarkably, by inhibiting 15–PGDH with SW033291, researchers found that it was possible to rescue the damaged hematopoietic [...]

Organ transplant rejection may not be permanent

Organ transplant rejection in previously tolerant hosts does not lead to permanent immune memory, mouse study shows July 7, 2015 Rejection of transplanted organs in hosts that were previously tolerant may not be permanent, report scientists from the University of Chicago. Using a mouse model of cardiac transplantation, they found that immune tolerance can spontaneously recover after an infection-triggered rejection event, and that hosts can accept subsequent transplants as soon as a week after. This process depends on regulatory T-cells, a component of the immune system that acts as a "brake" for other immune cells. The findings, published online in Nature Communicationson July 7, support inducing immune tolerance as a viable strategy to achieve life-long transplant survival. "Transplantation tolerance appears to be a resilient and persistent state, even though it can be transiently overcome," said Anita Chong, PhD, professor of transplantation surgery at the University of Chicago and co-senior author of the study. "Our results change the paradigm that immune memory of a transplant rejection is invariably permanent." To prevent transplant rejection in patients with end-stage organ failure, a lifelong regimen of immune-suppressing drugs is almost always required. While difficult to achieve, immune tolerance -- in which a transplanted organ is accepted without long-term immunosuppression -- can be induced in some patients. However, rejection can still be triggered by events such as bacterial infection, even after long periods of tolerance. It has been assumed that the immune system remembers rejection and prevents future transplants from being tolerated. Chong and her colleagues have previously shown in mice that certain bacterial infections can disrupt tolerance and trigger rejection of an otherwise stable transplant. As they further studied this phenomenon, they made a surprising observation. Infection-triggered rejection caused [...]

Washington University develops genetic test for inherited kidney diseases

March 26, 2015 By Michael C. Purdy and Gaia Remerowski GPS A new test from Washington University’s Genomic Pathology Services will help physicians quickly zero in on genetic mutations that may be contributing to kidney disease. Many kidney disorders are difficult to diagnose. To address this problem, scientists and clinicians have developed a diagnostic test that identifies genetic changes linked to inherited kidney disorders. This testing is now available nationwide through Genomic Pathology Services (GPS) at Washington University School of Medicine in St. Louis. “For many kidney diseases, diagnosis can be an odyssey in which you sequence one gene after another over a long period of time to learn what’s going wrong and what the best options are for treatment,” said GPS chief medical officer and Washington University pathologist Jonathan Heusel, MD, PhD. “It makes more sense to screen all the possible contributing genes at once with a single test and consider options for treatment.”To make this possible, the GPS team developed the test with kidney disease specialists, including Joseph Gaut, MD, PhD, a renal pathologist. The test employs next-generation sequencing technology to decode genes associated with kidney disease. Using software developed at the university, clinical genomics specialists analyze and interpret the observed genetic alterations to identify disease-related genetic changes, or variants. They then must determine whether a given variant poses clinical risks based on available medical knowledge. “The variants have to be evaluated on a case-by-case basis, which can be time-consuming and labor-intensive,” Heusel said. GPS continues to update the kidney test as new links between kidney problems and DNA are identified. “We stay abreast of the literature, and as new genes become clinically meaningful, we will incorporate those into the test,” said Catherine [...]

Doctors getting clearer picture of how to slow or stop kidney disease in children

BY ALAN BAVLEY THE KANSAS CITY STAR 03/19/2015   Marley Martinac, 2, is a kidney patient at Children’s Mercy Hospital, but mom Katie Martinac says the girl is as spunky as ever. Marley used her Doc McStuffins mobile cart to give her dog, Kamo, a checkup at the family’s home in Bates City. KEITH MYERS THE KANSAS CITY STAR Two-year-old Marley Martinac has a serious chronic kidney disease, but she’s going to have a better shot at a healthy life than kids born just a decade earlier. Thanks largely to an ongoing national study with leadership at Children’s Mercy Hospital, doctors now have a clearer picture of the best ways to stop or slow the progression of kidney disease in children like Marley. The goal is to keep the children growing and thriving for as long as possible, preventing, or at least postponing, the need for kidney dialysis or a transplant. “Thank God, we’re not at that point at all,” said Marley’s mother, Katie Martinac of Bates City. “She’s pretty spunky. She hasn’t lost that.” About 16 percent of the U.S. population has chronic kidney disease, a gradual loss of kidney function caused by high blood pressure, diabetes and a variety of other conditions. How many children have these conditions isn’t known, but 2,500 children nationwide are on dialysis and more than 5,000 have received kidney transplants. “We’re aiming to head things off in childhood,” said Children’s Mercy kidney specialist Bradley Warady, “to prevent children from requiring dialysis or a kidney transplant, or maybe delay it to give children more chance to grow and for their minds to develop.” Warady, along with researchers at Children’s Hospital of Philadelphia, is coordinating the Chronic Kidney Disease in Children (CKiD) [...]

Kidney Cancer Detected Early With Urine Test

By Jim Dryden When kidney cancer is diagnosed early — before it spreads — 80 percent of patients survive. But early diagnosis is a challenge. Now, Washington University School of Medicine researchers Evan D. Kharasch, MD, PhD (left) and Jeremiah J. Morrissey, PhD, have developed a noninvasive method to screen for kidney cancer by measuring the presence of proteins in the urine. Image courtesy of Elizabethe Holland Durando March 19, 2015 – If kidney cancer is diagnosed early — before it spreads — 80 percent of patients survive. However, finding it early has been among the disease’s greatest challenges. Now, researchers at Washington University School of Medicine in St. Louis have developed a noninvasive method to screen for kidney cancer that involves measuring the presence of proteins in the urine. The findings are reported March 19 in the journal JAMA Oncology. The researchers found that the protein biomarkers were more than 95 percent accurate in identifying early-stage kidney cancers. In addition, there were no false positives caused by non-cancerous kidney disease. “These biomarkers are very sensitive and specific to kidney cancer,” said senior author Evan D. Kharasch, MD, PhD. Kidney cancer is the seventh most common cancer in men and the 10th most common in women, affecting about 65,000 people each year in the United States. About 14,000 patients die of the disease annually. Like most cancers, kidney tumors are easier to treat when diagnosed early. But symptoms of the disease, such as blood in the urine and abdominal pain, often don’t develop until later, making early diagnosis difficult. “The most common way that we find kidney cancer is as an incidental, fortuitous finding when someone has a CT or MRI scan,” said Kharasch, the Russell D. [...]

Researchers Generate Kidney Tubular Cells from Stem Cells

ScienceDaily, by Staff Dec. 19, 2013 — Investigators have discovered a cocktail of chemicals which, when added to stem cells in a precise order, turns on genes found in kidney cells in the same order that they turn on during embryonic kidney development. The kidney cells continued to behave like kidney cells when transplanted into adult or embryonic mouse kidneys. Researchers have successfully coaxed stem cells to become kidney tubular cells, a significant advance toward one day using regenerative medicine, rather than dialysis and transplantation, to treat kidney failure. The findings are published in the Journal of the American Society of Nephrology (JASN). Chronic kidney disease is a major global public health problem, and when patients progress to kidney failure, their treatment options are limited to dialysis and kidney transplantation. Regenerative medicine -- which involves rebuilding or repairing tissues and organs -- may offer a promising alternative. Albert Lam, MD, Benjamin Freedman, PhD, Ryuji Morizane, MD, PhD (Brigham and Women's Hospital), and their colleagues have been working for the past five years to develop strategies to coax human pluripotent stem cells -- particularly human embryonic stem (ES) cells and human induced pluripotent stem (iPS) cell -- into kidney cells for the purposes of kidney regeneration. "Our goal was to develop a simple, efficient, and reproducible method of differentiating human pluripotent stem cells into cells of the intermediate mesoderm, the earliest tissue in the developing embryo that is fated to give rise to the kidneys," said Dr. Lam. He noted that these cells would be the "starting blocks" for deriving more specific kidney cells. The researchers discovered a cocktail of chemicals which, when added to stem cells in a precise order, causes them to turn off [...]