From New York Times, By Gina Kolata
It was not the most ominous sign of health trouble, just a nosebleed that would not stop. So in February 2017, Michael Schaffer, who is 60 and lives near Pittsburgh, went first to a local emergency room, then to a hospital where a doctor finally succeeded in cauterizing a tiny cut in his nostril.
Then the doctor told Mr. Schaffer something he never expected to hear: “You need a liver transplant.”
Mr. Schaffer had no idea his liver was failing. He had never heard of the diagnosis: Nash, for nonalcoholic steatohepatitis, a fatty liver disease not linked to alcoholism or infections.
The disease may have no obvious symptoms even as it destroys the organ. That nosebleed was a sign that Mr. Schaffer’s liver was not making proteins needed for blood to clot. He was in serious trouble.
The news was soon followed by another eye-opener: Doctors asked Mr. Schaffer to become the first patient in an experiment that would attempt something that transplant surgeons have dreamed of for more than 65 years.
If it worked, he would receive a donated liver without needing to take powerful drugs to prevent the immune system from rejecting it.
Before the discovery of anti-rejection drugs, organ transplants were simply impossible. The only way to get the body to accept a donated organ is to squelch its immune response. But the drugs are themselves hazardous, increasing the risks of infection, cancer, high cholesterol levels, accelerated heart disease, diabetes and kidney failure.
Within five years of a liver transplant, 25 percent of patients on average have died. Within 10 years, 35 to 40 percent have died.
“Even though the liver may be working, patients may die of a heart attack or stroke or kidney failure,” said Dr. Abhinav Humar, a transplant surgeon at the University of Pittsburgh Medical Center who is leading the study Mr. Schaffer joined. “It may not be entirely due to the anti-rejection meds, but the anti-rejection meds contribute.”
Kidneys in particular may be damaged. “It is not uncommon to end up doing a kidney transplant in patients who previously had a lung or liver or heart transplant,” Dr. Humar added.
Patients usually know about the drugs’ risks, but the alternative is worse: death for those needing livers, hearts or lungs; or, for kidney patients, a life on dialysis, which brings an even worse life expectancy and quality of life than does a transplanted kidney.
A glimmer of hope
In 1953, Dr. Peter Medawar and his colleagues in Britain did an experiment with a result so stunning that he shared a Nobel Prize for it. He showed that it was possible to “train” the immune systems of mice so that they would not reject tissue transplanted from other mice.
His method was not exactly practical. It involved injecting newborn or fetal mice with white blood cells from unrelated mice. When the mice were adults, researchers placed skin grafts from the unrelated mice onto the backs of those that had received the blood cells.
The mice accepted the grafts as if they were their own skin, suggesting that the immune system can be modified. The study led to a scientific quest to find a way to train the immune systems of adults who needed new organs.
That turned out to be a difficult task. The immune system is already developed in adults, while in baby mice it is still “learning” what is foreign and what is not.
“You are trying to fool the body’s immune system,” Dr. Humar said. “That is not easy to do.”
Most of the scientific research so far has focused on liver and kidney transplant patients for several reasons, said Dr. James Markmann, chief of the division of transplant surgery at Massachusetts General Hospital.
Those organs can be transplanted from living donors, and so cells from the donor are available to use in an attempt to train the transplant patient’s immune system.
Far more people need kidneys than need any other organ — there are about 19,500 kidney transplants a year, compared with 8,000 transplanted livers. And those transplanted kidneys rarely last a lifetime of battering with immunosuppressive drugs.
“If you are 30 or 40 and get a kidney transplant, that is not the only kidney you will need,” said Dr. Joseph R. Leventhal, who directs the kidney and pancreas transplant programs at Northwestern University.
Another reason to focus on kidneys: “If something goes wrong, it’s not the end of the world,” Dr. Markmann said. If an attempt to wean patients from immunosuppressive drugs fails, they can get dialysis to cleanse their blood. Rejection of other transplanted organs can mean death.
The liver intrigues researchers for different reasons. It is less prone to rejection by the body’s immune system. When rejection does occur, there is less immediate damage to the organ.
And sometimes, after people have lived with a transplanted liver for years, their bodies simply accept the organ. A few patients discovered this by chance when they decided on their own to discard their anti-rejection drugs, generally because of the expense and side effects.
An estimated 15 to 20 percent of liver transplant patients who have tried this risky strategy have succeeded, but only after years of taking the drugs.
In one trial, Dr. Alberto Sanchez-Fueyo, a liver specialist at King’s College London, reported that as many as 80 percent could stop taking anti-rejection drugs. In general, those patients were older — the immune system becomes weaker with age. They had been long-term users of immunosuppressive drugs and had normal liver biopsies.
But the damage caused by immunosuppressive drugs is cumulative and irreversible, and use over a decade or longer can cause significant damage. Yet there is no way to predict who will succeed in withdrawing.
Tricking the immune system
The more researchers learned about the symphony of white blood cells that control responses to infections and cancers — and transplanted organs — the more they began to see hope for modifying the body’s immune system.
Many types of white blood cells work together to create and control immune responses. A number of researchers, including Dr. Markmann and his colleague, Dr. Eva Guinan of the Dana-Farber Cancer Institute, chose to focus on cells called regulatory T lymphocytes.
These are rare white blood cells that help the body identify its own cells as not foreign. If these regulatory cells are missing or impaired, people can develop diseases in which the body’s immune system attacks its own tissues and organs.
The idea is to isolate regulatory T cells from a patient about to have a liver or kidney transplant. Then scientists attempt to grow them in the lab along with cells from the donor.
Then the T cells are infused back to the patient. The process, scientists hope, will teach the immune system to accept the donated organ as part of the patient’s body.
“The new T cells signal the rest of the immune system to leave the organ alone,” said Angus Thomson, director of transplant immunology at the University of Pittsburgh Medical Center.
Dr. Markmann, working with liver transplant patients, and Dr. Leventhal, working with kidney transplant patients, are starting studies using regulatory T cells.
At Pittsburgh, the plan is to modify a different immune system cell, called regulatory dendritic cells. Like regulatory T cells, they are rare and enable the rest of the immune system to distinguish self from non-self.
One advantage of regulatory dendritic cells is that researchers do not have to isolate them and grow them in sufficient quantities. Instead, scientists can prod a more abundant type of cell — immature white blood cells — to turn into dendritic cells in petri dishes.
“It takes one week to generate dendritic cells,” Dr. Thomson said. In contrast, it can take weeks to grow enough regulatory T cells.
The regulatory T cells also have to remain in the bloodstream to control the immune response, while dendritic cells need not stay around long — they control the immune system during a brief journey through the circulation.
“Each of us is taking advantage of a different approach,” Dr. Markmann said. “It is not clear yet which is best. But the field is at a fascinating point.”
What about patients who already had an organ transplant? Is it too late for them?
“I get asked that question almost every day I am seeing patients,” Dr. Leventhal said.
For now, the answer is that it is too late. These patients are not candidates for these new strategies to modify the immune system. But researchers hope that situation will change as they learn more.
‘Somebody has to be first’
When Michael Schaffer, the Pittsburgh patient, was told that he needed a liver and that he could be the first patient in the group’s clinical trial, he shrugged. “Someone has to be first,” he said.
Mr. Schaffer began a search to find a living donor, a close relative willing to undergo a major operation to remove a lobe of liver — or a stranger whose cells were compatible and who was willing to donate.
The Pittsburgh scientists told him how to proceed. Ask immediate family, then relatives, friends and colleagues. If that failed, he would have to start advertising with fliers and posts on Facebook.
Mr. Schaffer is one of eight brothers. Four were older than 55, too old to safely undergo removal of part of their liver. The three younger brothers were in poor health.
He moved on to nieces and nephews. Three agreed to donate, and one, Deidre Cannon, 34, who was a good match, went forward with the operation.
ARTIFICIAL KIDNEY
From CBC Canada
Artificial kidney in development by Kitchener startup
Morteza Ahmadi holds up one of the first prototypes his company developed for an implantable kidney. (Peggy Lam/CBC)
Qidni Labs wants to improve the lives and survival rate of patients with kidney failure.
Qidni Labs, a startup company based in downtown Kitchener, is building an artificial kidney and portable dialysis machine to help improve the lives and survival rates of kidney failure patients.
The artifical kidney is an implantable device that can operate like a human kidney and remove toxins and excess water from blood.
One of the ways they're attempting to do this is through decellurization — removing the old cells from donated pig kidneys — leaving a "scaffold" on which new cells can be grown.
"You end up with a kidney that can hopefully be transplated in the patient without rejection," said Morteza Ahmadi, a doctorate gradute from the University of Waterloo and founder of Qidni Labs.
The wait list to get a kidney transplant is long; for every 100,000 people waiting for a kidney donor, only 20,000 are available for implantation.
"This is such a huge problem with just the small number of supply for just transplantation," Ahmadi said.
A wearable dialysis machine
In addition to an artificial kidney, Qidni Labs is also building a wearable dialysis machine.
Typically, patients with end stage renal disease, or kidney failure, have to be hooked to a dialysis machine for four hours three times a week to have their blood filtered.
"The biggest thing patients want is the freedom to travel, that's what they talk about most," said Clarence Graansma, who worked in dialysis at Grand River Hospital for 30 years before moving to Qidni Labs.
"They want to move around while they dialyze, rather than sit in a chair all the time," Graansma said.
"They can probably work, go out for a walk, be more mobile," Ahmadi said.
"Hopefully in a few years we can commercialized the product, change the whole industry and remove some pain for families and patients."
Qidni Labs is currently testing their products on animals. Ahmadi said within 20 months, they should be able to test the artifical kidney on human patients.
BioEthics
From BioEdge by Xavier Symons
Should we allow an organ market?
Academics have discussed the ethics of selling organs for several decades. Yet the idea is now gaining traction in the popular media.
The Washington Post published an opinion piece earlier this month defending the introduction of a regulated organ market in the United States.
Washington Post columnist Megan McArdle argued that the “utilitarian calculus” in favour of an organ market “seems overwhelming”:
“Of 126,000 people diagnosed annually with end-stage renal disease, only 20,000 will eventually receive a donated kidney…the government could compensate donors handsomely while still saving money. And because kidney failure disproportionately affects the poor, they would be better off, not worse off”.
McArdle acknowledged the risk exploitation of vulnerable populations, yet suggested that “[the] risk still seems preferable to leaving so many desperate dialysis patients dependent on the kindness of strangers”.
Others argue that it would be in the government’s financial interest to establish an organ market. In a letter to the Washington Post in December, Ike Brannon of the Organ Reform Group and Network argued that “paying $50,000 to a donor would not only provide a healthy, viable kidney for everyone who needs one but would also save the government more than $100 billion over the next decade [in dialysis costs]”.
Yet not everyone has responded enthusiastically to the idea of a regulated market. University of Pennsylvania medical ethicist Emily Largent noted in a blog post that there is a federal prohibition on the sale of organs. She also said that there needed to be a controlled “real-world test of regulated payments … to show definitively whether this is a viable method of increasing the supply of kidneys for transplantation or not”.
Some ethicists question whether an organ market would provide meaningful choices to persons who are from lower socio-economic backgrounds. Still others have argued that the commercial sale of human body parts would erode altruistic sentiment in society and undermine the gift relationship that is an important characteristic of community life.
At the very least, there is always a possibility that things will go horribly wrong in an organ market. Media around the world reported early this month on the case of a Chinese man who in his teens sold his kidney on an underground market so that he could buy new IPhone and IPad. The operation to harvest his kidney was botched, and the man, now 25, is permanently bedbound.
PKDF Chief Science Officer Dr. David Baron co-authors new paper with FDA and top nephrologists
Only a few new drugs for chronic kidney disease (CKD) have been approved in the last several decades because drug companies have shied away from the renal “space.” The need for novel therapies for CKD is compelling, especially because they might mitigate the need for renal replacement therapy, i.e., dialysis or transplant. The drug companies (Pharma) recognize this, but they face a challenge: what clinical trial result would be satisfactory to the FDA, EMA (European Medicines Agency), and other regulatory agencies to actually approve such drugs?
The currently acknowledged conventional endpoints for CKD clinical studies are time to end-stage renal disease (ESRD), doubling of creatinine, or a 30-40% decline in renal function measured as the estimated glomerular filtration rate (eGFR). These are meaningful clinical endpoints; however, they may take many years to reach, especially in patients with early-stage renal disease—a time when treatment could be most beneficial. Most pivotal clinical drug trials for any disease are at most two to three years long. For CKD, studies would have to be much longer to achieve the conventional endpoints. Pharma would lose money conducting such long clinical trials. Therefore, endpoints that could be significant in a two- or three-year pivotal clinical trial are desperately needed. This, of course, applies to PKD, as well as the other nephropathies.
The PKD Foundation in collaboration with the Critical Path Institute (C-Path) sponsored the ADPKD Summit Meeting on July 14, 2016. It was organized by the PKD Outcomes Consortium (PKDOC) of which I am a member. On behalf of our constituency, I spoke at the Summit, which was attended by multiple regulatory agencies, including the FDA, EMA, and Health Canada. Representatives from the National Institutes of Health (NIH), academia, and Pharma were also in attendance. The purpose of the meeting was to define clinical endpoints in earlier stages of ADPKD when patients have preserved eGFR and are still mostly asymptomatic.
The Summit was highly productive and we discussed various biomarkers such as total kidney volume (TKV), which is unique to ADPKD. Dr. Ron Perrone at Tufts, who has had a long relationship with the Foundation, was pivotal in the formal acceptance by the FDA of TKV as prognostic biomarker. My hope is that TKV will become a widely accepted surrogate endpoint as well. Such a surrogate endpoint would certainly facilitate greater interest by Pharma in developing novel therapies for ADPKD. This is already happening—more companies than ever are working in the PKD “space.” Several major clinical trials are underway.
Finally, I am pleased to share with you the publication that resulted from the ADPKD Summit that was just published in the American Journal of Kidney Diseases: “Addressing the Need for Clinical Trial End Points in Autosomal Dominant Polycystic Kidney Disease: A Report From the Polycystic Kidney Diseases Outcomes Consortium (PKDOC)”. I am pleased to be a co-author along with the FDA, C-Path, and Dr. Perrone. The article has been published electronically and will appear in print soon. I am proud of the Foundation’s role in making this happen and I hope to see many more novel drugs entering clinical trials as a result of the progress we’ve made.
David Baron, Ph.D., Chief Scientific Officer
David Baron’s background in the biomedical sciences and drug development will keep us moving forward with progress in research. Dr. Baron is particularly interested in the Foundation’s work as he has PKD, along with several family members. He received a kidney transplant in 2009. Also, his main research focus has been salt and water transport and the translation of basic science into novel therapeutics for the treatment of PKD and other diseases. He has also regularly interacted with the FDA and EMA (European Medicines Agency) during the development and approval of numerous new drugs.
From CBC Canada
Artificial kidney in development by Kitchener startup
Morteza Ahmadi holds up one of the first prototypes his company developed for an implantable kidney. (Peggy Lam/CBC)
Qidni Labs wants to improve the lives and survival rate of patients with kidney failure.
Qidni Labs, a startup company based in downtown Kitchener, is building an artificial kidney and portable dialysis machine to help improve the lives and survival rates of kidney failure patients.
The artifical kidney is an implantable device that can operate like a human kidney and remove toxins and excess water from blood.
One of the ways they're attempting to do this is through decellurization — removing the old cells from donated pig kidneys — leaving a "scaffold" on which new cells can be grown.
"You end up with a kidney that can hopefully be transplated in the patient without rejection," said Morteza Ahmadi, a doctorate gradute from the University of Waterloo and founder of Qidni Labs.
The wait list to get a kidney transplant is long; for every 100,000 people waiting for a kidney donor, only 20,000 are available for implantation.
"This is such a huge problem with just the small number of supply for just transplantation," Ahmadi said.
A wearable dialysis machine
In addition to an artificial kidney, Qidni Labs is also building a wearable dialysis machine.
Typically, patients with end stage renal disease, or kidney failure, have to be hooked to a dialysis machine for four hours three times a week to have their blood filtered.
"The biggest thing patients want is the freedom to travel, that's what they talk about most," said Clarence Graansma, who worked in dialysis at Grand River Hospital for 30 years before moving to Qidni Labs.
"They want to move around while they dialyze, rather than sit in a chair all the time," Graansma said.
"They can probably work, go out for a walk, be more mobile," Ahmadi said.
"Hopefully in a few years we can commercialized the product, change the whole industry and remove some pain for families and patients."
Qidni Labs is currently testing their products on animals. Ahmadi said within 20 months, they should be able to test the artifical kidney on human patients.
BioEthics
From BioEdge by Xavier Symons
Academics have discussed the ethics of selling organs for several decades. Yet the idea is now gaining traction in the popular media.
The Washington Post published an opinion piece earlier this month defending the introduction of a regulated organ market in the United States.
Washington Post columnist Megan McArdle argued that the “utilitarian calculus” in favour of an organ market “seems overwhelming”:
“Of 126,000 people diagnosed annually with end-stage renal disease, only 20,000 will eventually receive a donated kidney…the government could compensate donors handsomely while still saving money. And because kidney failure disproportionately affects the poor, they would be better off, not worse off”.
McArdle acknowledged the risk exploitation of vulnerable populations, yet suggested that “[the] risk still seems preferable to leaving so many desperate dialysis patients dependent on the kindness of strangers”.
Others argue that it would be in the government’s financial interest to establish an organ market. In a letter to the Washington Post in December, Ike Brannon of the Organ Reform Group and Network argued that “paying $50,000 to a donor would not only provide a healthy, viable kidney for everyone who needs one but would also save the government more than $100 billion over the next decade [in dialysis costs]”.
Yet not everyone has responded enthusiastically to the idea of a regulated market. University of Pennsylvania medical ethicist Emily Largent noted in a blog post that there is a federal prohibition on the sale of organs. She also said that there needed to be a controlled “real-world test of regulated payments … to show definitively whether this is a viable method of increasing the supply of kidneys for transplantation or not”.
Some ethicists question whether an organ market would provide meaningful choices to persons who are from lower socio-economic backgrounds. Still others have argued that the commercial sale of human body parts would erode altruistic sentiment in society and undermine the gift relationship that is an important characteristic of community life.
At the very least, there is always a possibility that things will go horribly wrong in an organ market. Media around the world reported early this month on the case of a Chinese man who in his teens sold his kidney on an underground market so that he could buy new IPhone and IPad. The operation to harvest his kidney was botched, and the man, now 25, is permanently bedbound.
PKD Research
From PKD Foundation Blog
Only a few new drugs for chronic kidney disease (CKD) have been approved in the last several decades because drug companies have shied away from the renal “space.” The need for novel therapies for CKD is compelling, especially because they might mitigate the need for renal replacement therapy, i.e., dialysis or transplant. The drug companies (Pharma) recognize this, but they face a challenge: what clinical trial result would be satisfactory to the FDA, EMA (European Medicines Agency), and other regulatory agencies to actually approve such drugs?
The currently acknowledged conventional endpoints for CKD clinical studies are time to end-stage renal disease (ESRD), doubling of creatinine, or a 30-40% decline in renal function measured as the estimated glomerular filtration rate (eGFR). These are meaningful clinical endpoints; however, they may take many years to reach, especially in patients with early-stage renal disease—a time when treatment could be most beneficial. Most pivotal clinical drug trials for any disease are at most two to three years long. For CKD, studies would have to be much longer to achieve the conventional endpoints. Pharma would lose money conducting such long clinical trials. Therefore, endpoints that could be significant in a two- or three-year pivotal clinical trial are desperately needed. This, of course, applies to PKD, as well as the other nephropathies.
The PKD Foundation in collaboration with the Critical Path Institute (C-Path) sponsored the ADPKD Summit Meeting on July 14, 2016. It was organized by the PKD Outcomes Consortium (PKDOC) of which I am a member. On behalf of our constituency, I spoke at the Summit, which was attended by multiple regulatory agencies, including the FDA, EMA, and Health Canada. Representatives from the National Institutes of Health (NIH), academia, and Pharma were also in attendance. The purpose of the meeting was to define clinical endpoints in earlier stages of ADPKD when patients have preserved eGFR and are still mostly asymptomatic.
The Summit was highly productive and we discussed various biomarkers such as total kidney volume (TKV), which is unique to ADPKD. Dr. Ron Perrone at Tufts, who has had a long relationship with the Foundation, was pivotal in the formal acceptance by the FDA of TKV as prognostic biomarker. My hope is that TKV will become a widely accepted surrogate endpoint as well. Such a surrogate endpoint would certainly facilitate greater interest by Pharma in developing novel therapies for ADPKD. This is already happening—more companies than ever are working in the PKD “space.” Several major clinical trials are underway.
Finally, I am pleased to share with you the publication that resulted from the ADPKD Summit that was just published in the American Journal of Kidney Diseases: “Addressing the Need for Clinical Trial End Points in Autosomal Dominant Polycystic Kidney Disease: A Report From the Polycystic Kidney Diseases Outcomes Consortium (PKDOC)”. I am pleased to be a co-author along with the FDA, C-Path, and Dr. Perrone. The article has been published electronically and will appear in print soon. I am proud of the Foundation’s role in making this happen and I hope to see many more novel drugs entering clinical trials as a result of the progress we’ve made.
David Baron, Ph.D., Chief Scientific Officer
David Baron’s background in the biomedical sciences and drug development will keep us moving forward with progress in research. Dr. Baron is particularly interested in the Foundation’s work as he has PKD, along with several family members. He received a kidney transplant in 2009. Also, his main research focus has been salt and water transport and the translation of basic science into novel therapeutics for the treatment of PKD and other diseases. He has also regularly interacted with the FDA and EMA (European Medicines Agency) during the development and approval of numerous new drugs.
