From AJMC, by Mary Caffrey
Normally the size of a fist, a kidney covered by cysts can expand beyond the size of a football and weigh more than 35 pounds. People with this condition experience intense abdominal pain, high blood pressure, infections, and kidney stones, typically starting between age 30 and 40.
ADPKD progresses at different rates in different patients; some will not need dialysis or a kidney transplant until age 70 but others whose disease is rapidly progressing may reach end-stage renal disease (ESRD) in their 50s. Until recently, there were no treatments of PKD; in August, Otsuka Pharmaceutical won approval for tolvaptan (Jynarque), which can slow the loss of kidney function by blocking water reabsorption in the kidney ducts.
But research over the past decade suggests that it’s possible to target the mechanism that triggers the growth of cysts in the first place. Sanofi Genzyme is developing a treatment to do this, and last month announced it is enrolling patients in a pivotal trial for venglustat, an investigational oral therapy that has shown promise in mouse models of blocking the substances that drive tumor growth.1
These substances, called glucosphingolipids (GSLs), are overexpressed in patients across an array of renal diseases, from diabetic nephropathy and renal cell carcinoma, as well as PKD. GSLs are known to regulate many cellular processes, including cell proliferation. A 2010 paper that explored the mechanism of blocking GSLs in mouse models discussed the idea that if the GSL metabolism is sped up, this may boost the growth of cysts in PKD; conversely, blocking this pathway could cause the cysts to stop growing or even retreat.
Describing the possible mechanisms of action in a 2016 paper, James A. Shayman, MD, wrote that so far, the experimental use of inhibitors looks promising in reversing the disease characteristics.2 He writes, that understanding the link between GSL inhibition and “reversal of either renal hypertrophy or cyst growth is more than a scientific exercise.”
This is precisely what researchers hope to see as they recruit the first patients for treatment with venglustat in a clinical trial, said Gianluca Pirozzi, MD, PhD, head of Development for Rare Diseases and the head of Translational Gene Therapy at Sanofi, in an interview with The American Journal of Managed Care®. Pirozzi, who previously led development of dupilumab (Dupixent), which blocks key immune system pathways to treat atopic dermatitis, is optimistic; he said that FDA recognizes the therapy could address an enormous unmet need. Venglustat has received Orphan Drug Designation.
Unlike tolvaptan, which Pirozzi said will relieve symptoms of rapidly progressing PKD, venglustat aims to disrupt the disease mechanism itself. If the treatment works as Sanofi hopes, the key will be to identify the 30% of PKD patients who are “rapid progressors,” whose kidney function is declining at a comparatively young age and who face years of dialysis or early death from the disease. ESRD treatment costs are rising faster than others in healthcare, to at least $90,000 per year. Those diagnosed with ESRD before age 65 become eligible for Medicare because treatment is so expensive.
Thus, for affected patients, the prospect of halting cyst growth by taking a pill once a day, “could be life changing,” Pirozzi said.
Because venglustat would need to be taken daily for the rest of a patient’s life, targeting the right population will be a major point of discussion with payers, he said.
“We need to find ways to identify who are the right patients, the fast progressors,” Pirozzi said. His recommendation would be to start treatment, “as soon as possible.”
From MedicalXpress
Scientists hoping to develop better treatments for kidney disease have turned their attention to growing clusters of kidney cells in the lab. One day, so-called organoids—grown from human stem cells—may help repair damaged kidneys in people or be used to test drugs developed to fight kidney disease.
But new research from Washington University School of Medicine in St. Louis has identified rogue cells—namely brain and muscle cells—lurking within kidney organoids. Such cells make up only 10 to 20 percent of an organoid's cells, the scientists found, but their presence indicates that the "recipes" used to coax stem cells into becoming kidney cells inadvertently are churning out other cell types.
While at first glance the discovery might be viewed as a setback for using kidney organoids as stand-ins for human kidneys, there's still promise. The researchers found an easy way to prevent most of those wayward cells from forming, and that same approach could be adopted by other scientists who find rogue cells in other organoids, such as those of the brain, lung or heart.
The research is published Nov. 15 in Cell Stem Cell.
"There's a lot of enthusiasm for growing organoids as models for diseases that affect people," said senior author Benjamin D. Humphreys, MD, Ph.D., director of the Division of Nephrology. "But scientists haven't fully appreciated that some of the cells that make up those organoids may not mimic what we would find in people. The good news is that with a simple intervention, we could block most of the rogue cells from growing. This should really accelerate our progress in making organoids better models for human kidney disease and drug discovery, and the same technique could be applied to targeting rogue cells in other organoids."
A major reason for the excitement around kidney organoids is the challenge of caring of patients with kidney failure. In the United States alone, nearly 500,000 people receive dialysis for end-stage kidney disease.
"Developing kidney organoids is driven by the reality that we have so many patients with failing kidneys and no effective drugs to offer them," said Humphreys, who is also the Joseph Friedman Professor of Renal Diseases in Medicine.
For the current study, the researchers looked at two recipes widely used by scientists worldwide to grow kidney organoids. One starts with embryonic stem cells approved for research by the National Institutes of Health (NIH), and the other begins with induced pluripotent stem cells, which are reprogrammed from adult cells and have the ability to develop into any type of human cell.
A cocktail of drugs and growth factors are added to the stem cells, channeling their development into kidney cells. After growing the organoids in the lab for four weeks, a time frame long enough for the cells to specialize, the researchers asked: What kinds of cells did we get?
Rather than conduct a spot check to identify cells that made up the organoids, the researchers relied on a relatively new technique to take a deep dive. Using single cell RNA sequencing, they analyzed the activity of many thousands of genes in 83,130 cells from 65 kidney organoids.
"This generates massive amounts of data, and there's no way our brains can make sense of it all," Humphreys explained. "But computers can easily compare gene activity across 83,000 cells and, using artificial intelligence, group cell types together based on their gene expression. So rather than looking for cells that we think we thought we'd find in the organoid, it helped us find cells even if we'd never imagined they'd be there."
Regardless of the recipe, the researchers found that 10 to 20 percent of the cells in the organoids missed the cue to develop into kidney cells and instead became brain and muscle cells. However, by reconstructing the step-by-step process by which stem cells developed into brain cells, for example, they were able to see precisely where things went off the rails and block the formation of off-target cells. This reduced the number of brain cells by 90 percent, and the approach provides a road map to help other scientists eliminate rogue cells in other types of organoids.
"Progress to develop better treatments for kidney disease is slow because we lack good models," Humphreys said. "We rely on mice and rats, and they are not little humans. There are many examples of drugs that have done magically well at slowing or curing kidney disease in rodents but failed in clinical trials. So, the notion of channeling human stem cells to organize into a kidney-like structure is tremendously exciting because many of us feel that this potentially eliminates that 'lost in translation' aspect of going from a mouse to a human."
From Star2.com, BY REVATHI MURUGAPPAN
When Simah Empaling heard her child was gravely ill from kidney failure in 2012, she went on a hunger strike. She badly wanted to see her daughter, Ibi Uding, who was on dialysis.
Simah lives in Kampung Merakai, Serian, a village about 85km from Kuching, Sarawak, while Ibi was then in Kuching.
Alas, none of her other children were willing to take her to the hospital for fear that she might not be able to withstand the pain of seeing Ibi suffer.
So she refused to eat.
Eventually, Simah made the journey and broke down when she saw a pale Ibi in the ward, hooked up to a machine.
Ibi, 56, recalls: “She hugged me and cried, saying she could not allow her child to die before her. She kept asking what she could do to help.
“By then, I was constantly vomiting, urinating blood, giddy, couldn’t eat or drink, and had lost more than 15kg.”
Ibi had been diagnosed with polycystic kidney disease, an inherited disorder in which clusters of cysts develop primarily within the kidneys, causing them to enlarge and lose function over time.
“The symptoms started in 2007 with blood in the urine and a bloated stomach. If I carried heavy objects, I’d have back pain.
“I didn’t think much of it because I had three teenage kids and was busy running a business with my husband.
“I must admit that my diet wasn’t the best either,” says the former PKR Sarawak Wanita chief, who is saluted as the Iban torchbearer in her relentless fight for their rights.
As organ transplants involving non-relatives are not allowed in Malaysia and none of her other relatives were a compatible match, Ibi was in dire straits.
Then Simah offered to donate her kidney.
Initially, the doctors were hesitant as she was 79 then. However, Simah passed all the medical tests necessary for a kidney donor with flying colours.
“Prior to the transplant, my grandmother had never been admitted to hospital except when she delivered her six children.
“Her lifestyle is healthy as she used to plant padi and corn in the kampung.
“She also loves fishing, but we had to stop her because she cannot hear well anymore. We’re afraid she might not be able to hear the motorboats,” relates Ibi’s daughter, Seraphina Shantee, 26.
The adorable Simah chips in while Seraphina translates: “My late husband taught me how to fish, but now my children won’t let me go to the river.
“I used to be a strong rower, but I don’t have the same strength anymore.”
The only hitch was that Simah and Ibi were of different blood types.
Fortunately, consultant nephrologist Datuk Dr Tan Si Yen and his team were able to perform blood group incompatible, or ABOi, kidney transplants – the first in Malaysia to do so.
Thus, Simah became the oldest living kidney donor in South-East Asia.
Following the transplant, the doctors were amazed that Simah’s kidney functioned like it belonged to a 40-year-old.
She was out walking within three days of the operation, while it took Ibi a longer time to recover.
The first 100 days were crucial and Ibi adhered strictly to her doctor’s advice, although she contracted urinary tract infections twice.
It has been six years since the transplant was performed and the duo are doing well. They only have to go for check-ups annually.
Seraphina says: “My grandma has not fallen sick since. She needs assistance to walk and might complain from a bit of joint pain now and then, but that’s it.
“She doesn’t even have scars from the surgery. Her skin has healed so well.”
Simah, 84, lives alone in the village (her son lives next door) and continues to enjoy what life has to offer.
“From young, I eat only fish or chicken, and plenty of vegetables. I cook daily, mop and clean the house. I wake up at 8am and hand wash all my clothes,” she says.
Occasionally, Ibi, who now lives in Kuala Lumpur, will fly her mother over for a holiday.
“But she finds it boring here because we’re all at work. She will go knocking on people’s doors and make conversation with them.
“And because she can only speak Iban, the neighbours think she is a crazy woman and complain to the management!” says Ibi, laughing.
“One time we were in Kuching and I told her to stay downstairs while I went upstairs to take a shower.
“When I came down, I found the gates open, the air-conditioners and all lights switched on!
“She was sitting on the sofa and looking at me innocently. She has a curious nature and will turn on buttons to test what happens.”
Simah flashes me her warmest smile, oblivious to our discussion.
“Grandma is such a loving and caring person,” Seraphina adds.
Choking with emotion, a teary Ibi says: “I don’t know what I would have done without her. She’s proven that it’s never too late to donate a kidney. She’s been amazing… my saviour.”
But new research from Washington University School of Medicine in St. Louis has identified rogue cells—namely brain and muscle cells—lurking within kidney organoids. Such cells make up only 10 to 20 percent of an organoid's cells, the scientists found, but their presence indicates that the "recipes" used to coax stem cells into becoming kidney cells inadvertently are churning out other cell types.
While at first glance the discovery might be viewed as a setback for using kidney organoids as stand-ins for human kidneys, there's still promise. The researchers found an easy way to prevent most of those wayward cells from forming, and that same approach could be adopted by other scientists who find rogue cells in other organoids, such as those of the brain, lung or heart.
The research is published Nov. 15 in Cell Stem Cell.
"There's a lot of enthusiasm for growing organoids as models for diseases that affect people," said senior author Benjamin D. Humphreys, MD, Ph.D., director of the Division of Nephrology. "But scientists haven't fully appreciated that some of the cells that make up those organoids may not mimic what we would find in people. The good news is that with a simple intervention, we could block most of the rogue cells from growing. This should really accelerate our progress in making organoids better models for human kidney disease and drug discovery, and the same technique could be applied to targeting rogue cells in other organoids."
A major reason for the excitement around kidney organoids is the challenge of caring of patients with kidney failure. In the United States alone, nearly 500,000 people receive dialysis for end-stage kidney disease.
"Developing kidney organoids is driven by the reality that we have so many patients with failing kidneys and no effective drugs to offer them," said Humphreys, who is also the Joseph Friedman Professor of Renal Diseases in Medicine.
For the current study, the researchers looked at two recipes widely used by scientists worldwide to grow kidney organoids. One starts with embryonic stem cells approved for research by the National Institutes of Health (NIH), and the other begins with induced pluripotent stem cells, which are reprogrammed from adult cells and have the ability to develop into any type of human cell.
A cocktail of drugs and growth factors are added to the stem cells, channeling their development into kidney cells. After growing the organoids in the lab for four weeks, a time frame long enough for the cells to specialize, the researchers asked: What kinds of cells did we get?
Rather than conduct a spot check to identify cells that made up the organoids, the researchers relied on a relatively new technique to take a deep dive. Using single cell RNA sequencing, they analyzed the activity of many thousands of genes in 83,130 cells from 65 kidney organoids.
"This generates massive amounts of data, and there's no way our brains can make sense of it all," Humphreys explained. "But computers can easily compare gene activity across 83,000 cells and, using artificial intelligence, group cell types together based on their gene expression. So rather than looking for cells that we think we thought we'd find in the organoid, it helped us find cells even if we'd never imagined they'd be there."
Regardless of the recipe, the researchers found that 10 to 20 percent of the cells in the organoids missed the cue to develop into kidney cells and instead became brain and muscle cells. However, by reconstructing the step-by-step process by which stem cells developed into brain cells, for example, they were able to see precisely where things went off the rails and block the formation of off-target cells. This reduced the number of brain cells by 90 percent, and the approach provides a road map to help other scientists eliminate rogue cells in other types of organoids.
"Progress to develop better treatments for kidney disease is slow because we lack good models," Humphreys said. "We rely on mice and rats, and they are not little humans. There are many examples of drugs that have done magically well at slowing or curing kidney disease in rodents but failed in clinical trials. So, the notion of channeling human stem cells to organize into a kidney-like structure is tremendously exciting because many of us feel that this potentially eliminates that 'lost in translation' aspect of going from a mouse to a human."
Kidney Donors
When Simah Empaling heard her child was gravely ill from kidney failure in 2012, she went on a hunger strike. She badly wanted to see her daughter, Ibi Uding, who was on dialysis.
Simah lives in Kampung Merakai, Serian, a village about 85km from Kuching, Sarawak, while Ibi was then in Kuching.
Alas, none of her other children were willing to take her to the hospital for fear that she might not be able to withstand the pain of seeing Ibi suffer.
So she refused to eat.
Eventually, Simah made the journey and broke down when she saw a pale Ibi in the ward, hooked up to a machine.
Ibi, 56, recalls: “She hugged me and cried, saying she could not allow her child to die before her. She kept asking what she could do to help.
“By then, I was constantly vomiting, urinating blood, giddy, couldn’t eat or drink, and had lost more than 15kg.”
Ibi had been diagnosed with polycystic kidney disease, an inherited disorder in which clusters of cysts develop primarily within the kidneys, causing them to enlarge and lose function over time.
“The symptoms started in 2007 with blood in the urine and a bloated stomach. If I carried heavy objects, I’d have back pain.
“I didn’t think much of it because I had three teenage kids and was busy running a business with my husband.
“I must admit that my diet wasn’t the best either,” says the former PKR Sarawak Wanita chief, who is saluted as the Iban torchbearer in her relentless fight for their rights.
As organ transplants involving non-relatives are not allowed in Malaysia and none of her other relatives were a compatible match, Ibi was in dire straits.
Then Simah offered to donate her kidney.
Initially, the doctors were hesitant as she was 79 then. However, Simah passed all the medical tests necessary for a kidney donor with flying colours.
“Prior to the transplant, my grandmother had never been admitted to hospital except when she delivered her six children.
“Her lifestyle is healthy as she used to plant padi and corn in the kampung.
“She also loves fishing, but we had to stop her because she cannot hear well anymore. We’re afraid she might not be able to hear the motorboats,” relates Ibi’s daughter, Seraphina Shantee, 26.
The adorable Simah chips in while Seraphina translates: “My late husband taught me how to fish, but now my children won’t let me go to the river.
“I used to be a strong rower, but I don’t have the same strength anymore.”
The only hitch was that Simah and Ibi were of different blood types.
Fortunately, consultant nephrologist Datuk Dr Tan Si Yen and his team were able to perform blood group incompatible, or ABOi, kidney transplants – the first in Malaysia to do so.
Thus, Simah became the oldest living kidney donor in South-East Asia.
Following the transplant, the doctors were amazed that Simah’s kidney functioned like it belonged to a 40-year-old.
She was out walking within three days of the operation, while it took Ibi a longer time to recover.
The first 100 days were crucial and Ibi adhered strictly to her doctor’s advice, although she contracted urinary tract infections twice.
It has been six years since the transplant was performed and the duo are doing well. They only have to go for check-ups annually.
Seraphina says: “My grandma has not fallen sick since. She needs assistance to walk and might complain from a bit of joint pain now and then, but that’s it.
“She doesn’t even have scars from the surgery. Her skin has healed so well.”
Simah, 84, lives alone in the village (her son lives next door) and continues to enjoy what life has to offer.
“From young, I eat only fish or chicken, and plenty of vegetables. I cook daily, mop and clean the house. I wake up at 8am and hand wash all my clothes,” she says.
Occasionally, Ibi, who now lives in Kuala Lumpur, will fly her mother over for a holiday.
“But she finds it boring here because we’re all at work. She will go knocking on people’s doors and make conversation with them.
“And because she can only speak Iban, the neighbours think she is a crazy woman and complain to the management!” says Ibi, laughing.
“One time we were in Kuching and I told her to stay downstairs while I went upstairs to take a shower.
“When I came down, I found the gates open, the air-conditioners and all lights switched on!
“She was sitting on the sofa and looking at me innocently. She has a curious nature and will turn on buttons to test what happens.”
Simah flashes me her warmest smile, oblivious to our discussion.
“Grandma is such a loving and caring person,” Seraphina adds.
Choking with emotion, a teary Ibi says: “I don’t know what I would have done without her. She’s proven that it’s never too late to donate a kidney. She’s been amazing… my saviour.”
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