Sunday, October 29, 2017

PKD Research: Tolvaptan Phase 3 Web Briefing, Tolvaptan safety profile, Transplantation Effective for Long Term Dialysis Users

PKD Research

From Business Wire, Invitation to Pre-Register for Briefing 

Otsuka to Host Web Briefing on Tolvaptan Phase 3 Trial Results in Polycystic Kidney Disease


TOKYO & PRINCETON, N.J.--(BUSINESS WIRE)--Otsuka Pharmaceutical Co., Ltd. (OPCJ) and its affiliate Otsuka Pharmaceutical Development & Commercialization, Inc. (OPDC) are pleased to invite investors and media to a November 4 web briefing on in-depth results from the REPRISE phase 3 trial for tolvaptan, a drug candidate for the treatment of patients in the U.S. with autosomal dominant polycystic kidney disease (ADPKD).

To participate in the web briefing, kindly pre-register at:
http://event.on24.com/wcc/r/1534382-1/77E66445B009CE3491DBB035504DCF69

Confirmation of registration and information on how to access the web briefing on November 4 will be sent to registrants by email.

An archived version of the webcast will be accessible on the website of Otsuka Pharmaceutical Company’s parent company, Otsuka Holdings Co., Ltd., within 24 hours after the web briefing.

The REPRISE phase 3 trial data will also be presented earlier in the day on November 4 in a late breaking oral abstract session at American Society of Nephrology (ASN) Kidney Week 2017, in New Orleans (Abstract# SA-OR128). Attendees of Kidney Week 2017 are invited to attend the session, between 10:30 AM and 12:30 PM in Hall J.

The REPRISE trial was completed to supply confirmatory data to the previous studyi to address the Complete Response Letter issued by the U.S. FDA in 2013 for a New Drug Application for tolvaptan in the treatment of adults with ADPKD.

About Tolvaptan
Tolvaptan is a selective vasopressin V2-receptor antagonist. By selectively blocking vasopressin at the V2-receptor, tolvaptan has been shown to decrease cyst-cell proliferation and fluid secretion in subjects with ADPKD, ultimately reducing cyst development.iiIn a previous Phase 3 clinical trial, tolvaptan was associated with reduced kidney growth and slowed decline of kidney function.i




From Dove Medical Press, by: Satoru Muto,1 Tadashi Okada,2 Moriyoshi Yasuda,3 Hidetsugu Tsubouchi,4 Koji Nakajima,4 Shigeo Horie1,5
Long-term safety profile of tolvaptan in autosomal dominant polycystic kidney disease patients: TEMPO Extension Japan Trial

1Department of Advanced Informatics for Genetic Disease, Juntendo University Graduate School of Medicine, Tokyo, 2Department of Clinical Development, 3Pharmacovigilance Department, 4Department of Medical Affairs, Otsuka Pharmaceutical Co, Ltd, 5Department of Urology, Juntendo University Graduate School of Medicine, Tokyo, Japan

Aim: The aim of this trial (ClinicalTrials.gov identifier: NCT01280721) was to investigate the long-term safety profile of tolvaptan in Japanese patients with autosomal dominant polycystic kidney disease (ADPKD).

Methods: This open-label multicenter trial was conducted to examine adverse drug reactions (ADRs) related to tolvaptan up to an additional 3 years in 135 Japanese patients who participated in the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes (TEMPO) 3:4 trial at doses of 60–120 mg/d. Blood samples were collected at baseline; at weeks 1, 2, and 3; at month 3; and every 3 months thereafter.

Results
: In total, 134/135 (>99%) patients experienced ADRs. The most frequent ADRs were thirst (77.0%), pollakiuria (57.0%), polyuria (37.8%), and hyperuricemia (14.8%). Any unexpected ADRs were not reported in this trial. Most ADRs occurred early during treatment. Fourteen patients (10.4%) experienced hepatic events, and 8 (5.9%) experienced >3-fold increases above the upper limits of normal in serum alanine aminotransferase or aspartate aminotransferase levels between 3 and 9 months following tolvaptan initiation, which recovered after drug interruption. Of the 8 patients, 7 (5.2%) were previously allocated to the placebo arm in the TEMPO 3:4 trial and 4 (3.0%) discontinued due to the hepatic events. One patient (0.7%) was previously allocated to tolvaptan and experienced similar events in the TEMPO 3:4 trial. None of the hepatic ADRs met Hy’s Law laboratory criteria.

Conclusion: ADRs observed in this extension trial were similar to those identified in the TEMPO 3:4 trial and hepatic events were not progressive.




From News-Medical

Kidney transplantation may offer survival benefit for patients on long-term dialysis

A new study finds that kidney transplantation prolongs the lives of not only patients who have recently initiated dialysis, but also those who have been undergoing dialysis for more than a decade. The findings, which appear in an upcoming issue of the Clinical Journal of the American Society of Nephrology (CJASN), indicate that patients who may not have been referred for transplantation should be reevaluated.

In individuals with kidney failure, kidney transplantation is associated with longer survival than dialysis; however, this information comes from studies during an era in which patients received transplants relatively rapidly. Today, 13% of the nearly 100,000 wait-listed kidney transplant candidates in the United States have had kidney failure for more than 11 years.

John Gill, MD, MS (University of British Columbia and Vancouver's Providence Health Care) and his colleagues examined whether patients who receive transplants after prolonged treatment with dialysis derive a similar survival benefit as those who undergo transplantation earlier. "Because of recent changes in allocation policy, patients not previously wait-listed for many years can rapidly access transplantation if they are referred for transplantation and accepted onto a waiting list. We wanted to determine if these 'forgotten' patients might still benefit from transplantation despite being treated with dialysis for a very long period of time," said Dr. Gill. The researchers suspected that the benefit might not be the same because pre-transplant dialysis exposure is associated with inferior post-transplant kidney survival.

The team's study of 5365 patients in the Scientific Registry of Transplant Recipients determined the risk of death in recipients of a deceased donor kidney transplant after 10 or more years of dialysis treatment compared with wait-listed patients who continued to undergo dialysis. Patients were followed for at least 5 years.

The overall death rate for patients who underwent transplantation was 3.9 per 100 patient-years, compared with 5.8 per 100 person-years for patients who continued on dialysis. (A person-year is the number of years of follow-up multiplied by the number of people in the study.) After adjustments, transplant recipients had a 40% lower risk of dying than patients on dialysis who had equal lengths of follow-up from their 10-year dialysis anniversary. This benefit was observed in a variety of patient sub-groups, including patients ≥65 years of age and patients with diabetes. Transplant recipients were at higher risk of death for 180 days after transplantation, however, and they did not derive survival benefit until 657 days after transplantation, despite receiving good quality kidneys.

"Because transplantation is associated with longer survival in patients who have more than 10 years of dialysis treatment, patients who might not have been referred for transplantation should be reevaluated, as they might benefit," said Dr. Gill.




From MedScape, by Pam Harrison

MENTOR Results, New Trial Design Pitches at Kidney Week



NEW ORLEANS — Results from the MENTOR trial, a randomized comparison of rituximab and cyclosporine for the treatment of membranous nephropathy, will be in the spotlight here at Kidney Week 2017.

The noninferiority study looked at the long-term remission of proteinuria in patients with this challenging disease.

Also of interest will be a pragmatic clinical trial demonstration project from the National Institutes of Health, said Patrick Nachman, MD, from the University of North Carolina Kidney Center in Chapel Hill, who is chair of the ASN postgraduate education committee.


The "results may give us an idea of how we can think about clinical trials differently than the traditional randomized trial, which of course has benefits, but also some limitations," he told Medscape Medical News.

During the high-impact clinical trials session, studies will be presented on a new candidate molecule for the prevention of acute kidney injury after cardiac surgery; the use of ultrasound-guided percutaneous arteriovenous fistula to improve hemodialysis access; and whether or not tolvaptan (Samsca, Otsuka Pharmaceutical), a vasopressin receptor 2 antagonist, can slow the inevitable decline in kidney function in patients with later-stage autosomal dominant polycystic kidney disease.

And new analyses of data from big name clinical trials — such as the EMPA-REG OUTCOME trial and the Peritoneal Dialysis Outcomes and Practice Patterns Study — will be presented.

The effective prevention of kidney injury after the use of either intravenous or intracoronary contrast agents during coronary angiography will be addressed in an industry-independent phase 3 clinical trial.

Sunday, October 22, 2017

PKD Discrimination Update, Sell Your Kidney, Dialysis Research, PKD Complications

PKD Discrimination

From JD Supra, by Baker Donelson

EEOC Filed More than 80 Lawsuits this Summer – Why Employers Should Pay Attention

Indeed, the EEOC filed far more than 80 lawsuits during July, August, and September 2017 – the last quarter of its fiscal year. Approximately 50 percent of those lawsuits targeted employers for alleged individual and, more significantly, systemic violations of the Americans with Disabilities Act (ADA). No doubt, the EEOC is continuing its targeted, systemic focus on ADA violations, and employers should be concerned.

In 2016, the EEOC updated its strategic systemic initiative, which reiterated the EEOC's Strategic Enforcement Plan (SEP) issued on December 17, 2012. In that update, the EEOC highlighted that the SEP emphasizes coordinated strategies across the EEOC to leverage the agency's resources and promote good government and that "an integrated approach promotes broad sharing and consideration of ideas, strategies, and promising practices and furthers collaboration and coordination throughout the agency." This means the EEOC is seeking out employers who maintain policies and/or practices that disparately impact several or large groups of employees – in such cases, the EEOC "leverages" its resources to get the most bang for its buck.

That SEP identified six nationwide priorities for targeted enforcement:

  Eliminating systemic barriers to recruitment and hiring;
  Protecting immigrant, migrant, and other vulnerable workers;
  Addressing emerging issues such as ADA issues, LGBT coverage under Title VII, pregnancy-       related discrimination, and the aging workforce among other issues;
  Enforcing equal pay laws;
  Preserving access to the legal system; and
  Preventing harassment through systemic investigations and litigation and a targeted outreach   campaign to deter harassment in the workplace.

Notably, the EEOC's Compliance Manual describes its selection standard for systemic cases as those cases involving "systemic discrimination" where the "patterns of employment discrimination are the most severe, and where maintenance of a successful 'systemic case' will have a significant positive impact on the employment opportunities available to minorities and women." EEOC Comp. Man. § 16.1.

So, how did that selection standard play out regarding ADA lawsuits filed in the last quarter of the EEOC's 2016-17 fiscal year? For certain, the EEOC has doubled-down on employers who allegedly have failed to comply with the ADA. Failure to accommodate, failure to engage in the interactive process, failure to extend leave beyond FMLA entitlement, and the application of maximum leave and "100 percent healed" policies remain a high priorities for the EEOC and those issues led the way in the suits filed by the EEOC. Here a just a few of ADA suits recently filed by the EEOC:

Failure to Accommodate: The EEOC alleges that a grocery chain denied a reasonable accommodation to a cashier with polycystic kidney disease and then fired her because of her disability. The EEOC alleges that the employee missed work on two occasions because she had been hospitalized and needed to visit the doctor because of her kidney. Although she allegedly informed the company she needed time off due to her kidney impairment, the EEOC alleges that the company terminated her because of her absences and, therefore, failed to accommodate her.

To read more about these suits and more filed by the EEOC, click here. The cases listed above, are just a small sample of the issues raised in suits filed by the EEOC in final quarter of its fiscal year. But, those cases demonstrate that the EEOC is determined to "leverage" its limited resources to send a clear message to employers – the ADA is high on the EEOC's priority list.



Kidney Transplant

From The Guardian, University of California, San Diego, Opinion by Suzanne Golshanara

I’m Not Kidding, Sell Your Kidney

Kidneys toil away on a daily basis regulating everything from blood pressure to pH and excreting one’s bodily wastes and toxins. In spite of all the work that kidneys do, a majority of the population can survive perfectly fine with just one. This should be great news for the over 100,000 people in the United States who are waiting for a kidney transplant.

However, the National Kidney Foundation states that 13 people die everyday waiting for a kidney transplant. A majority of this deficit in kidneys comes from the 1984 National Organ Transplant Act, a well-meaning piece of legislation that established a national organ-matching registry and prohibited the sale of organs. The penalty for any parties caught doing so is a fine that can cost up to $50,000, up to five years of imprisonment, or both.

As a society, we have deemed it perfectly legal for a person to sell their eggs or sperm. Yet when it comes to kidneys, people are expected to donate their vital organs solely out of pure altruism. In fact, in America, donors are expected to shoulder all their travel and caretaker costs and the four to six weeks taken off of work to recover: an unfeasible financial obligation for most. Instead, a regulated market for kidneys needs to be legalized so kidneys can be freely bought and sold.

A year of dialysis costs approximately $88,000, which is about the same cost as a kidney transplant. If Medicare, which covers the costs of dialysis for a patient of any age for an unspecified number of years, simply reallocated its funds from paying for years of dialysis to paying for individual transplants, thousands of lives and large amounts of money would be saved. A government-run system would also prevent the rich from monopolizing the kidney market by simply bidding up prices.

Many people worry that opening kidneys up to the capitalistic system of supply and demand would disproportionately lead the poor to sell their organs. Frankly, it probably would. However, a piece in the New York Times argues that “people, especially poor people, take risks for money all the time” that are statistically far more dangerous than donating a kidney, like “accepting money for being a policeman or miner or soldier.” Of course, the interests of potential living organ donors should be protected through processes such as interviews to make sure that individuals are making completely independent, informed decisions, payment for all medical and nonmedical related expenses, and follow-up health care. Countries, including Saudi Arabia, Israel, Singapore, and the United Kingdom with similar programs have seen a direct correlation between such compensation and a rise in donations.

It’s easy for people to become sentimental over major societal shifts when their own lives are not at stake. For those in the United States who do not have the fortune of getting a living donor, a long and uncertain future of dialysis and deteriorating health often lies ahead. The organ shortage we have is self-inflicted, and thus solvable. Controversial or not, the legalization of kidney sales is a step that needs to be taken in order to save real lives.





Living with PKD

From Active Beat, by Emily Lockhart



Although it’s not a particularly well-known illness, polycystic kidney disease, or PKD, is very serious and in some situations may prove fatal. The disease involves the development of non-cancerous cysts within the kidneys, causing them to grow larger and, in time, become significantly less functional. These cysts, although not cancerous, can become filled with liquid and grow to the point where the kidneys no longer function as they should.

Failure to treat PKD can lead to cysts developing in other parts of the body, such as the liver. However, this isn’t the only serious complication presented by polycystic kidney disease; in fact, there are a number of complications that can lead to health decline and even death. If you or someone you know has developed PKD, it’s important you’re aware of these complications and their consequences.

1. High Blood Pressure

The development of polycystic kidney disease can lead directly to a spike in blood pressure. In time, higher blood pressure could result in the worsening of kidney damage in addition to the emergence of other serious side effects, including heart disease and stroke.
In essence, polycystic kidney disease presents the patient with a wide variety of significant health challenges. Together, these challenges threaten to rob the patient of his or her physical and mental well-being. Should you or someone you know be diagnosed with polycystic kidney disease, it’s critical that the patient be regularly monitored for high blood pressure.


2. Reduced Kidney Functionality

One of the more obvious side effects of polycystic kidney disease, which involves the development of fluid-filled sacs around the kidneys, is significantly reduced kidney functionality. The impact of this reduced functionality depends in large part on the age of the patient — if they’re young, there’s a good change they will face kidney failure by the time they reach their 60s.
Should kidney failure occur, an individual will need to undergo dialysis until a new kidney can be found and transplanted into the patient. This can be a long and stressful wait, particularly if undergoing dialysis — which can last for hours at a time several days a week — presents logistical problems for the patient.


3. Uremia

Uremia occurs when the toxicity of a individual rises to life-threatening levels; it is usually caused by the kidneys suffering from some kind of damage preventing them from functioning as they should. In essence, the onset of polycystic kidney disease can lead to the kidneys failing to prevent the body from becoming toxic and threatening the life of the patient.
For those monitoring patients with polycystic kidney disease, uremia is a strong sign that the kidneys are no longer functioning properly and that they may soon fail altogether. This will result in physicians putting the patient on dialysis until a new kidney can be found for the patient.

[Read more]




Dialysis Research

From Digital Journal, BY TIM SANDLE

New medical technology for kidney dialysis

The company Kibow Biotech has undertaken further validation of Its "Enteric Dialysis®" Technology, and Renadyl™ Product Formulation, designed for maintaining healthy kidney function.

The biotechnology is designed and sold to hospitals and medical centers and it is an example of important developments within the biotech space. Renadyl is the only kidney health supplement formulated to maintain healthy kidney function.

Kibow Biotech began developing genetically engineered probiotics. These are used to address the toxins that build up due to reduced kidney function (such as indoles, phenols and amines). This probiotic forms part of the concept of "Enteric Dialysis®", which was set out in a 1996 research paper titled "Will the Bowel be the Kidney of the Future?" This paper looked at the Gut-Kidney connection and the role of microorganisms.

Kibow moved away from genetically engineered probiotics and began to use three strains of bacteria that serve as probiotics capable of carrying out the same function. These viable organisms were incorporated into the kidney health supplement called Renadyl. The concept behind this is that these intestinal microbiota provide essential functions which the human body, by itself, is unable to supply. The probiotic has the ability to target and help reduce the buildup of uremic toxins in the body, thus helping to maintain healthy kidney function.

The Renadyl supplement was then subjected to assessment, which consisted of SHIME machine in vitro studies; nephrectomized animal studies in rats and retired zoo animals. The test animals had moderate to severe kidney failure. This was then followed by safety dose-escalation clinical trials in humans. Finally, efficacy clinical trials in dialysis patient populations were performed.
The success of Kibow Biotech is within the context of nine out of ten biotech companies failing within the first five years of business. Kibow has now been operating for twenty-years. Tis success rests on remaining innovative.

For further verification, the company has undertaken a series of customer surveys which chows a positive impact upon the user's quality of life. The most recent survey, showed stabilization of kidney function measured by Glomerular Filtration Rate (GFR). GFR is a key metric for assessing kidney function, and is used to classify stages of chronic kidney disease.
A further study will be held. This is the placebo controlled, large-scale clinical trial titled "Hope Study”, designed as a multi-site Health Economics and Outcomes Research (HEOR) clinical trial.



Sunday, October 15, 2017

Knowing About PKD, Dialysis Research: AVF Implants & Blood Flow Modeling

Living with PKD 

From KERA-News, Dallas, TX, By SAM BAKER

This Kidney Disease Runs In The Family, But You Might Not Know You Have It For Decades


Polycystic kidney disease — or PKD — causes numerous cysts to grow on the kidneys. It's the fourth leading cause of kidney failure. There is no cure, but a researcher at UT Southwestern Medical Center believes treatments are about 10 years away.

A genetic condition, polycystic kidney disease runs in families from one generation to the next.

Dr. Vishal Patel, an assistant professor of internal medicine at UT Southwestern, is one of several researchers at various institutions working to find a way to slow progression of the disease.

Interview Highlights

About PKD: The clinical hallmark of this disease is the massive enlargement of both kidneys. A normal person's kidney should be the size of their fist. In people with polycystic kidney disease, each kidney can grow to be as large as a football.


You can have PKD and not know it: The most common variety is adult-onset. Even though the patients are born with the mutation, they don’t feel any symptoms. The disease actually can go undetected for years until people reach their 40s or their 50s.

About PKD and kidney failure: Not everybody who inherits the mutation will develop kidney failure. About 50 percent of people with the mutated genes end up getting kidney failure, requiring dialysis or transplant. The other 50 percent will have cysts in their kidneys, but their kidneys will continue to have some level of function, not requiring dialysis or kidney transplant.

Treatments for PKD: We instruct our patients to maintain a generally healthy lifestyle, which includes adequate hydration, nutrition, not smoking, exercise - the usual things. Unfortunately, in the United States there isn’t any approved treatment specifically for polycystic kidney disease.

One possibility: Recent clinical research data shows a drug called tolvaptan seems to slow polycystic kidney disease growth in patients. Authorities in Japan, Canada and the E.U. have approved this medication. The Food and Drug Administration in the United States has not approved the medication yet because of concerns that it may have side effects. Additional research on tolvaptan is going on, and in a couple of years after reviewing newer data, the FDA will probably approve this medication for treatment of PKD in the U.S.




Dialysis Research

From Phys.Org, by Colin Smith

AI and aerospace models used to optimise blood flow in veins

AI and aerospace models used to optimise blood flow in veins

This model shows an improvement in blood flow, thanks to Imperial prototype technology. Credit: Imperial College London

Artificial intelligence has been trained to use aerospace simulation software to design a device that may ultimately improve dialysis for patients.

The team from Imperial College London and their colleagues have used computer modelling techniques - normally employed to simulate how unsteady air pockets flow over a plane - to model how unsteady currents in blood flows in the veins of patients undergoing dialysis.

The study, published in the journal Physics of Fluids, was carried out in conjunction with researchers from Hammersmith Hospital, Northwick Park Hospital, and St Mary's Hospital.

When the kidneys stop working properly dialysis can be used to remove waste products and excess fluid from the blood by diverting it to a machine to be cleaned. To connect this machine to the patient a special junction must be formed between an artery and a vein in the patient's wrist or upper arm. This junction is called an arterio-venous fistulae (AVF).

However, due to abnormal and very unsteady blood flow patterns, approximately 50 per cent of AVFs block up and fail within months of their creation because the artery walls inflame, which is known as intimal hyperplasia. This means patients have to undergo another procedure and in some cases repeated procedures. Often patients can run out of regions on the arm where AVF can be carried out, preventing them from using the lifesaving dialysis procedure.

The team have used modelling techniques from the aerospace industry to train a computer, using machine learning algorithms. Machine learning is an application of artificial intelligence (AI) that provides systems the ability to automatically learn and improve from experience without being explicitly programmed.

The AI then went ahead and optimised the shape of an AVF so that the unsteadiness in the blood flow could be suppressed. The prototype device that they have developed to hold the AVF in the optimal shape has so far undergone preliminary tests in pigs, which have been successful.

The next step will involve carrying out trials with pigs for several months at a time to further test the effectiveness of the AVF device. Even if these trials are a success they will be several years away from carrying out clinical trials with patients.




PKD Research

From John Hopkins Institute NanoBio Technology

Sean Sun Receives Award to Support Research in Polycystic Kidney Disease


Chodhury’s organ-on-a-chip device.

Sean Sun, INBT core faculty member and professor and vice-chair of mechanical engineering at the Whiting School of Engineering, was awarded funding from The Baltimore PKD Research and Clinical Core Center at the University of Maryland School of Medicine for their Pilot and Feasibility Program to study polycystic kidney disease (PKD), a common hereditary disorder affecting every 1 in 1,000 persons worldwide.

PKD causes uncontrollable growth of fluid filled cysts, ultimately leading to kidney failure. However, the underlying disease mechanisms are unclear and no well-established medical treatments exists. The award will help Sun and Ikbal Choudhury, 2nd year PhD student, study fluid pumping mechanisms of kidney cells in the early stages of PKD. Choudhury created an organ-on-a-chip device that simulates fluid pumping in the same manner as specific kidney cells reabsorb important nutrients such as ions and water. This research could provide direct insights about the disease and therefore create more efficient treatment methods and a way to test new drugs.


Sunday, October 8, 2017

PKD Research: Lab Grown Kidneys Show Cysts, Drug Lixivaptan considered for ADPKD Treatment, Silicone based Artificial Kidneys

PKD Research

From MedicalXpress

Mini-kidneys grown in lab reveal renal disease secrets

Mini-kidneys grown in lab reveal renal disease secrets


Kidney organoids grown in the lab and suspended in a lab dish show the formation of cysts (right) in the disease model of polycystic kidney disease. Normal kidney organoids are on the left. Credit: Freedman Lab/UW Medicine


Polycystic kidney disease affects 12 million people. Until recently, scientists have been unable to recreate the progression of this human disease in a laboratory setting.

That scientific obstacle is being overcome. A report coming out next week shows that, by substituting certain physical components in the organoid environment, cyst formation can be increased or decreased.

Benjamin Freedman, assistant professor of medicine in the Division of Nephrology at the UW School of Medicine, and his team at the Kidney Research Institute, led these studies in conjunction with scientists at other institutions in the United States and Canada. Freedman and his group also are investigators at the UW Medicine Institute for Stem Cell and Regenerative Medicine

They outlined their methods and results in a paper to be published Oct. 2 in Nature Materials

"Beforehand, we had shown that these organoids could form PKD-like cysts, but what's new here is that we've used the model to understand something fundamental about that disease," said Freedman.

As one example, the team found that PKD mini-kidneys grown in free-floating conditions formed hollow cysts that were very large. These cysts could easily be seen. In contrast, PKD mini-kidneys attached to plastic dishes stayed small.

According to Nelly Cruz, the lead author of the paper, other manipulations to the organoid also affect the progression of polycystic kidney disease.

"We've discovered that polycystin proteins, which are causing the disease, are sensitive to their micro-environment," she explained. "Therefore, if we can change the way they interact or what they are experiencing on the outside of the cell, we might actually be able to change the course of the disease." Cruz is a research scientist in the Freedman lab.

In another paper to be published in Stem Cells, Freedman and his team discuss how podocytes, which are specialized cells in the body that filter blood plasma to form urine, can be generated and tracked in a lab environment. Study of gene-edited human kidney organoids showed how podocytes form certain filtration barriers, called slit diaphragms, just as they do in the womb. This might give the team insight into how to counter the effects of congenital gene mutations that can cause glomerulosclerosis, another common cause of kidney failure.

aken together, these papers are examples of how medical scientists are making progress toward developing effective, personalized therapies for polycystic kidney disease and other kidney disorders.

"We need to understand how PKD works," Freedman said. "Otherwise, we have no hope of curing the disease."

"And our research," he added, "is telling us that looking at the outside environment of the kidney may be the key to curing the disease. This gives us a whole new interventional window.




From Business Wire

Palladio Biosciences Receives Orphan Drug Designation from the U.S. FDA for Lixivaptan for the Treatment of Autosomal Dominant Polycystic Kidney Disease

(Palladio), a privately held biopharmaceutical company founded to develop medicines that make a meaningful impact on the lives of patients with orphan diseases of the kidney, announced today that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation to lixivaptan for the treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD).

There are currently no drug treatments approved for ADPKD in the United States.

The FDA’s Office of Orphan Drug Products grants orphan drug designation to support the development of drugs and biologics intended for the safe and effective treatment, diagnosis or prevention of diseases or disorders that affect fewer than 200,000 people in the U.S., or that affect more than 200,000 people but are not expected to recover the costs of drug development and marketing. Orphan drug designation provides eligibility for certain benefits, including seven years of market exclusivity following receipt of regulatory approval, tax credits for qualified clinical trials, and exemption from FDA application fees.

“ADPKD is a serious progressive, inherited disease that typically affects multiple generations of entire families. Lixivaptan has the potential to slow the progression of ADPKD and possibly delay the need for dialysis or a kidney transplant,” said Lorenzo Pellegrini, Ph.D., Founder and Chief Executive Officer of Palladio. “The granting of orphan drug designation is an important milestone in the lixivaptan development program.”

About Lixivaptan:

Lixivaptan is a potent, selective vasopressin V2 receptor antagonist. This mechanism of action has clinical proof of concept to delay the progression of the autosomal dominant form of PKD. Lixivaptan was previously administered to 1,673 subjects across 36 clinical studies as part of a prior clinical development program for the treatment of hyponatremia. Palladio expects to leverage lixivaptan’s large body of data generated in the hyponatremia clinical program to repurpose lixivaptan and advance its development for the treatment of ADPKD.

About Polycystic Kidney Disease (PKD) – Key Facts and Figures:

PKD is an inherited genetic disease that affects thousands of people in the United States and millions globally. ADPKD is the most common type of PKD. A person with ADPKD has a 50 percent chance of passing the disease on to each of his or her children. The disease is characterized by uncontrolled growth of fluid-filled cysts in the kidney, which can each grow to be as large as a football. Symptoms often include kidney infections and chronic pain. The continued enlargement of cysts and replacement of normal kidney tissue causes irreversible loss of renal function. In the United States, approximately 2,500 new people with PKD require dialysis or a kidney transplant every year, making PKD the 4th leading cause of kidney failure. There is no cure for PKD.





From Wired Magazine, by Megan Molteni

SILICON ISN'T JUST FOR COMPUTERS. IT CAN MAKE A PRETTY GOOD KIDNEY, TOO


EVERY WEEK, TWO million people across the world will sit for hours, hooked up to a whirring, blinking, blood-cleaning dialysis machine. Their alternatives: Find a kidney transplant or die.

In the US, dialysis is a roughly 40-billion-dollar business keeping 468,000 people with end-stage renal disease alive. The process is far from perfect, but that hasn't hindered the industry's growth. That's thanks to a federally mandated Medicare entitlement that guarantees any American who needs dialysis—regardless of age or financial status—can get it, and get it paid for.

The legally enshrined coverage of dialysis has doubtlessly saved thousands of lives since its enactment 45 years ago, but the procedure’s history of special treatment has also stymied innovation. Today, the US government spends about 50 times more on private dialysis companies than it does on kidney disease research to improve treatments and find new cures. In this funding atmosphere, scientists have made slow progress to come up with something better than the dialysis machine-filled storefronts and strip malls that provide a vital service to so many of the country's sickest people.

Now, after more than 20 years of work, one team of doctors and researchers is close to offering patients an implantable artificial kidney, a bionic device that uses the same technology that makes the chips that power your laptop and smartphone. Stacks of carefully designed silicon nanopore filters combine with live kidney cells grown in a bioreactor. The bundle is enclosed in a body-friendly box and connected to a patient’s circulatory system and bladder—no external tubing required.

The device would do more than detach dialysis patients—who experience much higher rates of fatigue, chronic pain, and depression than the average American—from a grueling treatment schedule. It would also address a critical shortfallof organs for transplant that continues despite a recent uptick in donations. For every person who received a kidney last year, 5 more on the waiting list didn’t. And 4,000 of them died.

There are still plenty of regulatory hurdles ahead—human testing is scheduled to begin early next year1—but this bioartificial kidney is already bringing hope to patients desperate to unhook for good.

Innovation, Interrupted

Kidneys are the body’s bookkeepers. They sort the good from the bad—a process crucial to maintaining a stable balance of bodily chemicals. But sometimes they stop working. Diabetes, high blood pressure, and some forms of cancers can all cause kidney damage and impair the organs' ability to function. Which is why doctors have long been on the lookout for ways to mimic their operations outside the body.

The first successful attempt at a human artificial kidney was a feat of Rube Goldberg-ian ingenuity, necessitated in large part by wartime austerity measures. In the spring of 1940, a young Dutch doctor named Willem Kolff decamped from his university post to wait out the Nazi occupation of the Netherlands in a rural hospital on the IJssel river. There he constructed an unwieldy contraption for treating people dying from kidney failure using some 50 yards of sausage casing, a rotating wooden drum, and a bath of saltwater. The semi-permeable casing filtered out small molecules of toxic kidney waste while keeping larger blood cells and other molecules intact. Kolff's apparatus enabled him to draw blood from his patients, push it through the 150 feet of submerged casings, and return it to them cleansed of deadly impurities.

In some ways, dialysis has advanced quite a bit since 1943. (Vaarwel, sausage casing, hello mass-produced cellulose tubing.) But its basic function has remained unchanged for more than 70 years.

Not because there aren’t plenty of things to improve on. Design and manufacturing flaws make dialysis much less efficient than a real kidney at taking bad stuff out of the body and keeping the good stuff in. Other biological functions it can’t duplicate at all. But any efforts to substantially upgrade (or, heaven forbid, supplant) the technology has been undercut by a political promise made four and a half decades ago with unforeseen economic repercussions.

In the 1960s, when dialysis started gaining traction among doctors treating chronic kidney failure, most patients couldn't afford its $30,000 price tag—and it wasn’t covered by insurance. This led to treatment rationing and the arrival of death panels to the American consciousness. In 1972, Richard Nixon signed a government mandate to pay for dialysis for anyone who needed it. At the time, the moral cost of failing to provide lifesaving care was deemed greater than the financial setback of doing so.

But the government accountants, unable to see the country’s coming obesity epidemic and all its attendant health problems, greatly underestimated the future need of the nation. In the decades since, the number of patients requiring dialysis has increased fiftyfold. Today the federal government spends as much on treating kidney disease—nearly $31 billion per year—as it does on the entire annual budget for the National Institutes of Health. The NIH devotes $574 million of its funding to kidney disease research to improve therapies and discover cures. It represents just 1.7 percent of the annual total cost of care for the condition.

But Shuvo Roy, a professor in the School of Pharmacy at UC San Francisco, didn’t know any of this back in the late 1990s when he was studying how to apply his electrical engineering chops to medical devices. Fresh off his PhD and starting a new job at the Cleveland Clinic, Roy was a hammer looking for interesting problems to solve. Cardiology and neurosurgery seemed like exciting, well-funded places to do that. So he started working on cardiac ultrasound. But one day, a few months in, an internal medicine resident at nearby Case Western Reserve University named William Fissell came up to Roy and asked: “Have you ever thought about working on the kidney?”

Roy hadn’t. But the more Fissell told him about how stagnant the field of kidney research had been, how ripe dialysis was for a technological overhaul, the more interested he got. And as he familiarized himself with the machines and the engineering behind them, Roy began to realize the extent of dialysis' limitations—and the potential for innovation.

Limitations like the pore-size problem. Dialysis does a decent job cleansing blood of waste products, but it also filters out good stuff: salts, sugars, amino acids. Blame the polymer manufacturing process, which can’t replicate the 7-nanometer precision of nephrons—the kidney's natural filters. Making dialysis membranes involves a process called extrusion, which yields a distribution of pore sizes—most are about 7nm but you also get some portion that are much smaller, some that are much larger, and everything in between. This is a problem because that means some of the bad stuff (like urea and excess salts) can sneak through and some of the good stuff (necessary blood sugars and amino acids) gets trapped. Seven nanometers is the size of albumin—a critical protein that keeps fluid from leaking out of blood vessels, nourishes tissues, and transports hormones, vitamins, drugs, and substances like calcium throughout the body. Taking too much of it out of the bloodstream would be a bad thing. And when it comes to the kidney’s other natural functions, like secreting hormones that regulate blood pressure, dialysis can’t do them at all. Only living cells can.

“We were talking about making a better Bandaid,” Roy says. But as he and Fissell looked around them at the advances being made in live tissue engineering, they started thinking beyond a better, smaller, faster filter. “We thought, if people are growing ears on the backs of mice, why can’t we grow a kidney?”

It turned out, someone had already tried. Sort of. [Read more]

Sunday, October 1, 2017

PKD: Whole Foods Sued for Discrimination; Gift of Life: Royal to Giant; Vouchers Save 25 Lives

Living with PKD

From JD Supra

Whole Foods Market Sued by EEOC for Disability Discrimination

Grocery Store Fired Employee for Missing Work Due to Kidney Impairment, Federal Agency Charges


RALEIGH, N.C. - "America's Healthiest Grocery Store," Whole Foods Market Group, Inc. dba Whole Foods Market, headquartered in Austin, Texas, denied a reasonable accommodation to a cashier with polycystic kidney disease and then fired her because of her disability, the U.S. Equal Employment Opportunity Commission (EEOC) charged in a lawsuit filed today.

According to the EEOC's suit, Whole Foods hired Diane Butler in 2005 as a cashier for a facility in Raleigh, N.C. Butler has polycystic kidney disease, a genetic disease causing uncontrolled growth of cysts in the kidney, eventually leading to kidney failure. In 2009, while working for Whole Foods, Butler had a kidney transplant. In December 2015, Butler missed work on two occasions because she had been hospitalized and needed to visit the doctor because of her kidney. Although Butler informed the company she needed time off due to her kidney impairment, Whole Foods terminated Butler because of her absences.

Such alleged conduct violates the Americans with Disabilities Act (ADA), which requires employers to offer reasonable accommodations to employees with disabilities. The EEOC filed suit in the U.S. District Court for the Eastern District of North Carolina, Western Division (Equal Employment Opportunity Commission v. Whole Foods Market Group, Inc. d/b/a Whole Foods Market; Civil Action No_5:17-cv-00494-FL) after first attempting to reach a pre-litigation settlement through its conciliation process. The agency seeks back pay for Butler along with compensatory damages, punitive damages, and injunctive relief.

"Employees with disabilities are entitled to reasonable accommodations, including modification of an employer's absenteeism policy, unless making the accommodation would be an undue hardship on the employer," said Lynette A. Barnes, regional attorney for EEOC's Charlotte District Office. "An employer who is on notice that an employee's absences are related to that employee's disability must comply with the ADA's mandate to reasonably accommodate workers with such needs."




Gift of Life

From Kansas City Star, BY LISA GUTIERREZ

Royals fan rises above the World Series thing to donate ‘Royal kidney’ to Giants fan

kelly dugout
San Francisco Giants fan Kelly van den Berghe will receive a kidney on Wednesday from her friend Josh Harrold, a Royals fan.
Kelly Castro Courtesy of Josh Harrold

He is a Royals fan, lifelong.
She roots for the San Francisco Giants, the team that crushed Kansas City’s soul when it won the 2014 World Series at Kauffman Stadium.

Turns out, they’re a good match.

And on Wednesday, Giants fan Kelly van den Berghe will become forever Royal when her friend, 38-year-old Hutchinson, Kan., native Josh Harrold, gives her one of his kidneys.

They both live in California, he in Orange County, she in Santa Cruz. The operation will take place at Stanford Hospital.

Because Josh is the kind of guy who believes in and earns a living making grand gestures, he worked with the Royals and Giants to create a moment his friend would not forget — the day he told her she was getting a “Royal kidney,” as he calls it.

It happened last November at AT&T Park in San Francisco.

It was epic: He got a Giants fan to wear a Royals jersey.

(Now she thinks she jinxed the Giants, currently last place in the NL West.)

Harrold and others close to van den Berghe have known she has PKD  —  polycystic kidney disease. The chronic, genetic disease causes cysts to grow uncontrollably in the kidneys, eventually leading to kidney failure, according to the PKD Foundation, based in Kansas City.

Van den Berghe’s grandmother, mother and brother had PKD. Transplants. Dialysis. Her family has been down this road before.

But her personal nightmare has been lack of appetite, painful leg cramps, mood swings, holding water in her belly, trouble sleeping, unquenchable thirst, panic, anxiety, lower back pain and unrelenting tiredness that banishes her to bed for 18 hours at a time.

“I knew this was going to happen someday,” van den Berghe said. “I just enjoyed all the things I could do now that I knew I wasn’t going to be able to do later.

“It was just a matter of time. And it’s my time.”

Her friends didn’t know how sick she’d become until last August when she got honest and blunt and told her Facebook family she needed a kidney.

“Asking someone for a kidney is not an easy thing to do,” van den Berghe said. “For example, I have a stepsister who would have been a really, really good match. But she has two small children and she just wasn’t ready for it. You can’t be angry at someone for not doing it.

“I just put it out there, once. And just through the chain of social media lots of people went and got tested.”

She had a big pool to fish in. She is a retired roller derby queen, a star in Santa Cruz where she skated as “Roxy Scarmichael” and her jersey hangs from the rafters.

And then there was the juggernaut family of “Survivor” fans. Her husband, Lex van den Berghe, competed on “Survivor: Africa” and “Survivor: All Stars.”

The transplant folks told her they’d never seen so many people sign up to be tested as a possible donor for one person, van den Berghe said.

People have also donated $24,000 to a GoFundMe campaign set up to pay what insurance won’t cover. [Read more]




From UCLA NewsRoom, by Enrique Rivero

How first ‘vouchers’ in UCLA kidney donation program led to 25 lifesaving transplants

Broadman family


Howard Broadman approached UCLA with the concept of donating a kidney so that his grandson Quinn would be eligible to receive one in the future.


In 2014 a former judge from San Diego County approached the UCLA Kidney Transplant Program with an unusual request: If the judge donated a kidney to a stranger now, could his then-4-year-old grandson, who suffered from chronic kidney disease, receive priority for a future kidney transplant if needed later in life?

The suggestion from Howard Broadman, then 64 years old, initiated the kidney “voucher” program, an innovative system allowing living donors to donate a kidney now, or at some time in the near future, allowing a family member or friend to be given priority for a kidney transplant in the future if needed.

A new UCLA-led study published in the September issue of the peer-reviewed journal Transplantation traces how the first three “voucher cases” led to 25 lifesaving kidney transplants across the United States.

“Some potential kidney donors are incompatible with their intended recipient based on blood type; others may be incompatible based on time,” said lead author Dr. Jeffrey Veale, associate clinical professor of urology at the David Geffen School of Medicine at UCLA, and director of the UCLA Kidney Exchange Program. “The voucher program resolves this time incompatibility between the kidney transplant donor and recipient.”

The program works like this: The voucher donor gives a kidney to a stranger on dialysis. Often that recipient had a friend or family member who had wanted to be a donor but couldn’t due to incompatibility. Now that the person in need of a kidney has received the transplant and has been freed from dialysis, the friend or family member instead donates a kidney to another stranger, launching multiple transplant “chains” that essentially mix and match incompatible recipient/donor pairs with compatible ones. These chains are frequently initiated by altruistic donors who give a kidney to a stranger out of simple generosity.

While not guaranteed a kidney, the voucher recipient gets priority in being matched with a donor from the end of a future transplant chain.

The researchers outline three kidney voucher cases that led to 25 transplants across the United States.
Broadman’s grandson has kidney disease that is expected to lead to kidney failure in 10 to 15 years, requiring a transplant. By that time, Broadman would be about 80 years old, too old to qualify as a donor. Broadman’s December 2014 donation initiated a chain with three recipients, who were removed from a wait list for a kidney from a deceased person.
A 52-year-old father of a young woman who had undergone a transplant in 2007 at age 10 wanted to donate a “backup” kidney in case his daughter’s transplanted organ eventually failed. So in August 2015 he donated a kidney at New York Presbyterian-Weill Cornell Medical Center, which started an eight-transplant chain.
Doctors for the same young woman in the case above say they believe she will eventually need a third transplant. To boost her chances of getting a kidney, her 60-year-old aunt donated in May 2016 on her behalf at Weill-Cornell. This donation provided a second voucher for the woman and triggered a chain of 14 kidney transplants.

The researchers say the program is a “game-changer” because it enables someone to donate now before becoming ineligible because of advancing age or unexpected life events. There are now 30 transplant centers that have joined the program as part of the National Kidney Registry.

Study co-authors are Dr. Gabriel Danovitch, Dr. H. Albin Gritsch, Amy Waterman, Marek Pycia and Suzanne McGuire of UCLA; Alexander Capron and Dr. Nima Nassiri of USC; and Dr. Joseph Del Pizzo, Dr. Jim Hu, Marian Charlton and Dr. Sandip Kapur of New York Presbyterian-Weill Cornell Medical Center.




PKD Research

From Eureka Alert, Indiana University

NSF awards Indiana University $4 million to advance medical nanotechnology

Fight against cancer among applications for devices that merge nanotechnology and biotechnology

Only a year after establishing the intelligent systems engineering program in the Indiana University School of Informatics, Computing and Engineering, the university has been awarded a five-year, $4 million grant from the National Science Foundation to advance nanoscale devices to improve human health, including fighting cancer.

The grant will create the Engineered nanoBIO Hub at IU, one of three "nodes" under the NSF's Network for Computational Nanotechnology nanoHUB project, which provides scientists access to advanced tools for complex research problems. The node at IU will focus on simulating the interactions between nanoscale devices -- which operate at the level of a nanometer, or one-billionth of a meter -- and biological cells and tissues.

The grant is led by Geoffrey C. Fox, IU Distinguished Professor and interim associate dean for intelligent systems engineering at the IU School of Informatics, Computing and Engineering.

"We're living in a world where people are increasingly 'instrumented' with wearable devices and implanted devices within the body," Fox said. Examples include ingestible pills that allow doctors to remotely monitor a patient's vital signs, microscopically small machines to continuously monitor blood sugar in people with diabetes, and customized nanoscale medical devices that offer physicians the unprecedented ability to detect and infiltrate cancer cells to destroy them -- or even potentially "reprogram" them to behave like normal cells.

"This award is a real vote of confidence in the school and an acknowledgement of the fact that our people are conducting extremely relevant, exciting work," added Fox, who also directs the Digital Science Center at IU. "To receive a grant of this magnitude only one year after officially launching an engineering department with programs in bioengineering and nanoengineering is a major achievement."

The ultimate goal of the project is to support the development of medical devices that "operate at the intersection of nanotechnology and biotechnology," he said.

Such devices will require extremely complex software to design and run. It's also important that researchers can simulate their function inside a computer program prior to using them in people to ensure the devices work correctly and efficiently and don't cause harm.

The grant supports efforts to develop, and provide wider access to, tools that simulate these nanoparticle-based devices' physical design; simulate and fine-tune their interaction with tissues in the body; and improve their effectiveness. IU researchers will also work to advance the platform through which scientists and medical researchers beyond the university can access the tools -- and the vast computing power required to run the simulations -- in a relatively user-friendly format within a web browser.

The project's leaders note that IU students will benefit from the project as the first people in the world to gain hands-on experience with these simulation technologies. The grant will also fund six Ph.D. students.

"This work puts our intelligent systems engineering program at the forefront of an extremely exciting, emerging field," said Raj Acharya, dean of the IU School of Informatics, Computing and Engineering. "The efforts led by Geoffrey Fox and colleagues will advance IU's reputation as a world leader in the design of these extremely complex devices with vast potential to benefit human health."

Other leaders of the project are IU School of Informatics, Computing and Engineering faculty members Vikram Jadhao, an expert in the simulation of the materials used in nanoscale devices; Paul Macklin, an expert in the simulation of cancer tissue; and James A. Glazier, an expert in the simulation of physical systems in the body. As director of the IU Biocomplexity Institute, Glazier led the development of a software program called CompuCell3D, which has been used to simulate systems such as tumor growth in polycystic kidney disease and the absorption of painkillers in the liver. The first phase of the grant-funded project will expand access to these and other tools developed in-house at IU. Later, the researchers aim to integrate tools from the wider scientific community into the platform so they will also be more widely available.

An additional lead researcher on the project is Trevor Douglas, a professor in the IU College of Arts and Sciences' Department of Chemistry, whose lab will help conduct tests of nanoscale devices in biological conditions to confirm the accuracy of the team's computational models and software simulations. An expert in biomimetic nanomaterials, Douglas focuses on work involving engineering systems inspired by nature.

The IU Pervasive Technology Institute is also a partner on the project. As a part of the NSF's Science Gateways Community Institute, the institute will facilitate the worldwide scientific community's access to the nanotechnology and biotechnology simulation tools supported under the grant.