Sunday, November 26, 2017

Kidney Donation by Tri-athlete, An 8 Person Gift of Life Chain

Kidney Donation

From The Bellingham Herald, via Bend, Oregon

Kidney donation doesn't stop Bend triathlete from competing


Greg Sabin isn't afraid to admit it. He's not exactly the most patient person. So when his doctor told him it'd be at least six weeks after he donated a kidney before he could crank up his workout routine to its usual intensity, he wasn't thrilled.

"I want to be good as gold straight out of the gate," said the 56-year-old Bend resident. "I never really had surgery before, so I didn't really know what to expect."

Sabin didn't swim for a while. He kept his runs short and not too fast. Then, exactly five months after the surgery, he completed a triathlon in Sunriver: a 1.2-mile swim, 58-mile bike ride and 13-mile run.

In January, Sabin donated one of his kidneys to his wife, Stacey, who has a genetic condition called polycystic kidney disease. It causes water-filled cysts to crowd the kidneys and liver, eventually impairing their function. Both of their recoveries have gone smoothly.

Now that Sabin is back in his normal routine — not to mention training for another triathlon — he hopes his experience can be a lesson for others who are hesitant about kidney donation, perhaps fearing it will hamper their athletic performance.

"There was never even a second that I thought that I would accept being less active than I was before," he said, "and I still won't."

Transplant specialists say there's no reason living kidney donors can't continue being competitive athletes, including running in marathons or even ultramarathons.

Dr. Charles Modlin, a kidney transplant surgeon with the Cleveland Clinic, said that's an important message to get out, as living donors are crucial. Not only are there not enough kidneys to go around from deceased donors, transplants from living donors typically have the best outcomes.

"There are a lot of misconceptions that if you donate a kidney, you can't live out your life normally, and you're going to be infirm," Modlin said. "That's just not the case."

'Drink to thirst'

There are, however, important caveats to consider.

Dr. Kayvan Roayaie, an assistant professor of surgery in the division of abdominal organ transplantation at Oregon Health & Science University, said after someone donates a kidney, it's "critically important" to preserve their remaining kidney function.

That means if people plan to engage in intense exercise, they should make sure they're staying hydrated and allowing time for their incisions to heal. Roayaie, who removed Sabin's kidney, said he typically counsels people to wait at least six weeks before vigorous exercise to allow the scar over the abdominal wall — where the surgeon enters to remove the kidney — to develop adequate scar tissue.

Working those muscles too hard before the incision heals enough can lead to hernias, which is when an organ pushes through an opening in the muscle that holds it in place. Abdominal hernias are the most common type.

Sabin said he's noticed he's had to drink more water after the surgery compared with before to avoid cramping during exercise. He also drinks more water over the course of a normal day.

Doctors interviewed for this article said they don't necessarily recommend kidney donors increase their water intake beyond normal, unless they were dehydrated before the surgery. In follow-up exams, Roayaie said doctors will check the moisture of donors' mucous membranes and the turgor of their skin.

After someone donates a kidney, the remaining kidney actually enlarges to compensate and provides between 70 to 80 percent of the total function both kidneys previously contributed together, Modlin said.

"So they don't have to drink an excessive amount of fluid," he said. "Just drink to thirst."

'Extreme stress on the body'

One of the big differences Sabin said he noticed between the triathlon he performed in June and previous races was his energy level wasn't as high as it used to be. As a result, his time was slower than he would have liked.

Fatigue is almost a universal experience for kidney donors, Roayaie said. Typically, they're back to their usual energy levels about a month after the surgery.

"Surgery, even for a healthy person, is an extreme stress on the body," Roayaie said. "The body is pouring a lot of that energy into healing and creating new scar tissue, and that all of that contributes to the fatigue."

As far as completing a triathlon five months after the surgery, Roayaie said he's not surprised Sabin noticed the effects. There are still changes happening in the body within the first year after donation, he said.

It takes four to eight months for the remaining kidney to enlarge to compensate for the missing one, so it's possible that put a damper on Sabin's performance, Modlin said. It could also be he wasn't able to train as hard as he usually does, he said.

"It's remarkable that he was able to do it," Modlin said.

OHSU performs extensive testing on living donor candidates to ensure their bodies can handle the shock. Diabetes and hypertension are the most common conditions that disqualify people from donating, Roayaie said.

Before he was approved to donate, Sabin said doctors were alarmed by his scores on some of their tests. When his heart rate came up as 43, for example, they suspected a heart condition. He was able to convince them that's just his normal resting heart rate.

"They didn't know what to do with it," he said.

Risk low, but not zero

While extensive research has been done on how transplant recipients fare after getting a new kidney, less is known about living donors.

The United Network for Organ Sharing, a nonprofit organization that manages the nation's organ transplant system through a contract with the federal government, requires all transplant centers, like those at OHSU and Cleveland Clinic, for example — to follow up with living organ donors for at least two years. Hospitals are required to send UNOS data on donors' kidney function and whether they had any hospitalizations, organ failures or deaths. Providing the information is voluntary on the patient end.

The risk to donors is low, but it's not zero, said Dr. David Klassen, UNOS' chief medical officer. In the same way as getting one's appendix removed, there's always a small risk of death. For kidney donors, the risk of death is about three in 10,000 people, he said. Another roughly 30 in 10,000 people develop kidney failure after donating a kidney.

"That's fairly small," said Klassen, also a nephrologist. "But again, there have been lots of living donors over the years. To the extent we've been successful in collecting that information, we have a fairly solid understanding of what the risks are."

A partner organization to UNOS, the Scientific Registry of Transplant Recipients, is creating a living donor registry in hopes of tracking donors longterm.

'You can still participate'

For her part, Stacey Sabin said with a laugh that getting her husband's kidney hasn't motivated her to get out and do a triathlon. Her goal for 2018 is to exercise more.

"I live with an Ironman, so I hear it all the time," she said, referring to the Ironman competitions her husband has participated in.

Insomnia is one of the side effects of the medications she takes to prevent her body from rejecting the kidney, so gathering the energy to exercise has been a challenge. She relies on Facebook groups and other online networks to learn about other people's post-transplant experiences. She's been relieved to learn her side effects are normal.

As for her husband, he's in the throes of training for a half-Ironman competition in St. George, Utah, in May, the same one he did in 2014. His goal is to match his 2014 time. The paved course, which features steep hills carved into the red rock canyon, is the toughest he's ever done.

"I'd like to bring awareness to the fact that you can still participate — and hopefully somewhat competitively — in this stuff after such a thing," he said.





From U.S. News and World Report, By Michael Morella, Staff Writer

U.S. News Sits In as Surgeons Carry Out an 8-Person Kidney Exchange

Four people received new leases on life via the transplant 'chain' at Chicago's Northwestern Memorial Hospital.



Four Chicago-area residents needed kidney transplants but did not have matching donors. At Northwestern Memorial Hospital, they got the organs the required from willing strangers through a kidney transplant chain. (BRETT ZIEGLER FOR USN&WR)


Today, Kevin Condreva will receive a new kidney at Northwestern Memorial Hospital. All told, his transplant will involve surgery on eight people.

Condreva, 22, and his aunt, Donna Spans, 63, are two links in a transplant "chain" that by the end of the day tomorrow will give a new lease on life to four people from the Chicago area. Condreva is actually undergoing his second transplant; he was just 15 when he first noticed blood in his urine and was diagnosed with IgA nephropathy, a common kidney disease that damages the organ's ability to filter waste from the blood. When he was 17, his mom was his donor, but the disease came back. That kidney failed, too.

Spans, who is not a match for her nephew, undergoes surgery here as well – ready to trade one of her kidneys to a stranger so that Condreva can receive one from another stranger and be freed from nightly dialysis. She and the other members of the group won't know who donates to whom as they head into surgery, but Spans' kidney will go to Patricia Tripolitakis, 51, who has polycystic kidney disease. Her husband, Leo, 51, is donating to Lee Jenkins, 53, whose wife, Lorretta, 46, is giving a kidney to Steven Boone, 46. Condreva's donor, a good Samaritan who prefers to remain anonymous, turned up as a match for him just a few weeks earlier and set the chain in motion. Later, Maggie Swanson, a friend of Boone's who wanted to help him but wasn't a match, will donate a kidney to someone else in need – potentially starting a new chain.

Such "paired exchanges," first performed in the U.S. at Rhode Island Hospital in 2000, have taken off in the last seven years or so as a way to shorten what can otherwise be a long wait for a healthy kidney. Some 97,000 people are now on the waiting list maintained by the United Network for Organ Sharing, a nonprofit that manages the federal organ transplant system; the average wait time is generally about three to five years. That's too long for many people: About 12 die each day as they hope for a kidney to turn up. A swap like this one effectively fast-tracks the process. At Northwestern, the period between joining the exchange program and surgery typically varies from about two to six months depending on the difficulty of matching.

Today, 20 to 30 percent of living donor kidney transplants here are done through the paired exchange program, mostly in four- to eight-person swaps. Each week, clinicians run a computer program to explore potential matches from among the incompatible pairs in the system. "There are actually multiple potential solutions that we can look through," says John Friedewald, a transplant nephrologist and medical director of the kidney transplant program. Northwestern also participates in the UNOS kidney paired donation program, which includes roughly 250 paired donors and candidates across the country. The National Kidney Registry, another nonprofit organization, facilitates hundreds of exchanges a year nationwide. In 2015, the NKR organized the longest swap to date, a 70-person chain involving teams at 26 hospitals.

By about 7:30 a.m. on the morning of the surgery, Condreva's donor and Spans are in separate operating rooms. Surgeons use a minimally invasive approach, making a series of incisions about the size of a centimeter through which they insert instruments and a tiny camera to guide their work; the kidneys are extracted through a slightly larger cut. The minimally invasive technique has "made the idea of donating a less scary undertaking" because it's safer than open surgery and recovery is much more rapid, says Joseph Leventhal, who directs the kidney and pancreas transplant programs and is performing several of this week's procedures.

By late morning, Condreva and Patricia Tripolitakis are sedated and in the OR. Their surgeons make a long incision across their lower abdomens and patch each new kidney into its blood supply and the ureter, the tube that moves urine from the kidney to the bladder. Before long, the transplanted organs are working fine. Later that day, Condreva and Tripolitakis are up and moving gingerly around the hospital floor.

A match depends largely on blood type and the presence of antibodies, proteins in a recipient's immune system that guard against foreign viruses and bacteria and can cause the system to reject a kidney even from a donor whose blood type matches. Such was the case for Condreva and Spans, who both have Type A blood and initially were a match. They became incompatible because Condreva developed resistance to his aunt – likely a result of several blood transfusions and the transplant from his mom, Patricia, who is Spans' sister. [Read more]

Sunday, November 19, 2017

PKD Impact Scale, Artificial Kidney Update, Tesevatinib Phase 2 Clinical Trial

Artificial Kidney

From Wonderful Engineering, by Ali Vaqar





It is estimated by The National Kidney Foundation that over 100,000 patients are on the waiting list for kidney donors. A further 3,000 names are added to the list every year. An average patient has to wait for 3.6 years for a viable transplant. The patients are treated with dialysis while they are waiting for a transplant and only one in three patients survive for more than five years without a transplant. All that could change as scientists have developed the world’s first artificial kidney.

This bio-hybrid uses living kidney cells along with a series of specialized microchips powered by the human heart to filter waste from the blood-stream. The artificial kidney can bypass the complication of matching donors and tissue rejection. To address this unmet need, William Fissell from Vanderbilt and Shuvo Roy from the University of California, San Francisco (UCSF) launched The Kidney Project.

“We can leverage Mother Nature’s 60 million years of research and development and use kidney cells that fortunately for us grow well in the lab dish, and grow them into a bioreactor of living cells,” explained Fissell in a recent article published by Research News Vanderbilt. Fissel claims that it can reliably distinguish between waste chemicals and the nutrients that need to be reabsorbed by the body.

The artificial kidney can be inserted into the body by a common surgery and has been proved to work efficiently. This kidney has several microchips which are controlled by the heart and removes the toxins from the blood the same way a normal kidney does.

The artificial kidney has 15 microchips built one atop the other and they act as filters. They will hold living renal cells which will eventually grow around the microchips and mimic a real kidney. Engineers are currently working and testing every single detail of the device to make sure the device can safely let the blood run through without the formation of clots or damaging the kidney in any way.

This solution has been working so far and the rejection rate has been zero. The human trials are yet to commence but the research shows promising results and everybody is hoping it might eliminate the need for dialysis.


Slight changes to the system for allocating deceased-donor kidneys could result in higher rates of organ procurement and lead to more kidney transplants across the country, according to new research co-authored by an Indiana University Kelley School of Business professor.

"Any increase in supply will result in saved lives," said Rodney P. Parker, an associate professor of operations management at Kelley. "The lists of patients awaiting a kidney transplantation are lengthy and growing. Many of these patients undergo expensive and inconvenient dialysis treatment while waiting."

Parker and three other researchers studied three risk factors that explain the geographic differences in procuring deceased-donor kidneys across the United States: organ quality, the median wait time for donation and the degree of competition between transplantation centers in the area.

They found an expected annual increase in procured organs ranges from 58 (an increase of 0.5 percent of all procured kidneys) to 174 (an increase of 1.2 percent), depending on regional or national sharing.

In 2015, 87,538 patients with end-stage renal disease died while on dialysis (16.3 percent of all dialysis patients are awaiting kidney transplants), and 18,805 kidney transplantations were performed that same year. The majority, 13,132, came from cadaveric donors.

More than 100,000 people are waiting for a kidney transplant in the U.S, with more than 3,000 patients added to the list each month, according to the National Kidney Foundation.

This study, which appears in the journal Production and Operations Management, is among the first to consider how to increase the supply of procured kidneys, rather than changing demand or considering different ways of allocating a fixed supply.

The researchers analyzed the effects of a 2014 policy change that allows lower-quality kidneys—considered the bottom 15 percent of available organs—to be immediately offered more widely in a region without seeking patients only in the local area.

They found that expanding the geographic range also could save lives of many who currently are less likely to receive a kidney based on where they live.

"The increase in supply is induced by the disparity in patient waiting times across different geographies," Parker said. "Thus, patients in areas with longer waiting times will benefit from this increase without adversely affecting the waiting times in the source areas. Overall, the gap in median waiting times between areas will narrow."

Parker and his colleagues concluded that transplant candidates living in less-populated areas may be more selective about the organ quality because waiting times are relatively short.

"When some cadaveric kidneys of lower quality become available, these kidneys may not be procured since the local patients can simply wait a short period for a superior quality kidney," he said. "However, those lower-quality kidneys would be highly sought in other areas where the waiting times are much longer, such as in California and New York.

"Patients already at the top of the list in the more congested areas (which have longer median waiting times) will already likely have a short time for the next available kidney, so they will likely not accept a poorer quality kidney," he added. "However, someone who is further down the list in these areas may recognize that they face a lengthy wait and be willing to accept such a kidney rather than face the grim prospect of a four-hour dialysis treatment three times per week, not to mention the expense and diminished health."

Cadaveric kidneys are initially made available to those living in one of 58 donor service areas around the country, before being then offered to those in a broader region of several donor service areas and, finally, nationally. Competition among 272 transplant programs across the country also contributes to outcomes.

Fourteen of the 58 donor service areas offered 129 or fewer kidneys in 2009, so if some organs are shared more broadly, then the expected increase in transplants could represent the addition of a small- to medium-sized donor service area. [Read more]



Living with PKD

From American Journal of Kidney Diseases

Development of the Autosomal Dominant Polycystic Kidney Disease Impact Scale: A New Health-Related Quality-of-Life Instrument

Portions of full article.

Background
The impact of autosomal dominant polycystic kidney disease (ADPKD) on health-related quality of life (HRQoL) is not well understood due to a lack of instruments specific to the condition.

Study Design
Content for a new self-administered patient-reported outcome (PRO) questionnaire to assess ADPKD-related HRQoL was developed through clinical expert and patient focus group discussions. The new PRO instrument was administered to study patients with ADPKD to evaluate its reliability and validity.

Setting & Participants
1,674 adult patients with ADPKD participated in this research: 285 patients in focus groups to generate questionnaire content, 15 patients in debriefing interviews to refine the PRO questionnaire, and 1,374 patients to assess the performance and measurement properties of the PRO questionnaire.

Outcome
A new PRO questionnaire.

Results
The ADPKD Impact Scale (ADPKD-IS), consisting of 14 items representing 3 conceptual domains (physical, emotional, and fatigue) plus 4 additional questions, was developed. The instrument’s reliability (regarding internal consistency and test-retest consistency) and validity (content and construct) were supported.

Limitations
Need for more responsiveness testing when more data from clinical use become available over time. Complex concepts such as ADPKD-related pain and impact on a patient's HRQoL need further evaluation.

Conclusions
The ADPKD-IS is a new patient-centric tool that reliably and validly provides a standardized method for assessing HRQoL and overall disease burden in patients with ADPKD.


Discussion
At the outset of our research, we were faced with discrepant reports of disease burden in ADPKD and its onset based on literature and physician reports versus anecdotal reports through patient foundations and patients. This discrepancy was also observed in the feedback from clinical experts, who may not be aware of patients’ early concerns due to the very intermittent visit schedules in the earlier disease stages, and patients, who may not bring concerns to physicians because they have adjusted to the disease impact on their lives and experiences with trivialization of these concerns by physicians.9 Lack of patient-centric tools to assess ADPKD-related disease burden has led to a knowledge gap for disease stages, giving the impression that the burden of patients with ADPKD is no different from that of the general population (Fig 4).9, 12, 19 New initiatives for further understanding of priorities for different stakeholders, including patients, caregivers, physicians, and researchers (such as Standardized Outcomes in Nephrology [SONG]), have been initiated since we started our research, but to date, they focus on other areas in nephrology, and ADPKD-specific outcome measures have yet to emerge.

The ADPKD-IS is a new tool with support for its reliability (internal consistency and test-retest) and validity (content and construct). The ADPKD-IS is useful for assessing ADPKD-related disease burden across all CKD stages in a cross-sectional cohort, but also tracking disease burden long term.

The physical domain includes 5 items measuring impact on the ability to perform various activities and 2 items measuring impact of disease-associated pain on daily activities. Identification of 3 distinct types of pain led to retention of the existing pain questions as descriptive of the overall pain concept. However, we also proceeded to develop an additional questionnaire specific to ADPKD-related pain.36, 37 The fatigue domain assesses 3 specific features of ADPKD-associated fatigue: general fatigue, tiredness while driving, and fatigue after a good night’s sleep. Items within this domain exhibited higher intradomain correlations than interdomain correlations (Table S3). Therefore, fatigue among patients with ADPKD appears likely to encompass aspects of both emotional and physical burden. The emotional domain assesses the emotional impact of ADPKD via 3 concepts common to many instruments (acceptance, anxiety, and sadness) and a fourth disease-specific item (feeling full before appetite is satisfied).

The ADPKD-IS covers the entire range of health burdens associated with ADPKD across CKD stages in a single instrument, which is not the case for any other PRO instruments. All items were non-normally distributed, and most patients reported at the lower (less affected) end of the range, consistent with the natural history progression of the disease, for which hyperfiltration can compensate for the early loss of kidney tissue, leading to little change in kidney function until decades after birth.1, 2 Individual items also showed limited ceiling effects, indicating the ability of the ADPKD-IS to differentiate between health burdens as patients progress to later stages of the disease, in which HRQoL is more dramatically affected. Consistent with its predicted ability to assess HRQoL across the entire disease spectrum, the ADPKD-IS can show differentiation between disease stages with more sensitivity than general instruments.

Use of properly developed PRO instruments is a key element of drug development programs using patient-focused end points and for characterization of disease-specific burden with increasing importance given the 21st Century Cures Act requirements. We also see the ADPKD-IS as a tool for researchers and health care providers to better understand ADPKD-specific patient burden with potential use as a patient management tool in clinical practice. Access to the full US-English ADPKD-IS questionnaire, its user manual, and other language versions are available via Mapi Research Trust at https://eprovide.mapi-trust.org/.



PKD Research

From Business Wire

Kadmon Initiates Phase 2 Placebo-Controlled Clinical Trial of Tesevatinib in Autosomal Dominant Polycystic Kidney Disease

Kadmon Holdings, Inc. (NYSE:KDMN) today announced that the first patient has been dosed in a Phase 2 clinical trial of tesevatinib in autosomal dominant polycystic kidney disease (ADPKD), an inherited disorder that frequently leads to end-stage renal disease. Tesevatinib is the company’s tyrosine kinase inhibitor.

The randomized, double-blind, placebo-controlled trial builds on findings from Kadmon’s open-label, dose-finding Phase 2a study of tesevatinib in ADPKD, which demonstrated that the 50 mg once daily (QD) dose had an encouraging safety profile and was well tolerated in this population.

The new study is enrolling up to 100 patients, randomized 1:1 to receive tesevatinib 50 mg QD or placebo. The primary endpoint is the change from baseline in height-adjusted total kidney volume at 12 months.

In addition to the ADPKD trial, in September 2017, the first patient was dosed in Kadmon’s Phase 1 dose-finding clinical trial of tesevatinib in patients with autosomal recessive polycystic kidney disease (ARPKD), a rarer, more severe form of the disease affecting newborns and children. There are no FDA-approved therapies for ARPKD and there are no other candidates in clinical trials for ARPKD in the United States.

“Tesevatinib has been shown to inhibit molecular pathways central to the progression of PKD—mediated by its inhibition of the epidermal growth factor receptor (EGFR) and Src family kinases—and also accumulates in the kidneys, making it a promising therapeutic candidate for this disease,” said Harlan W. Waksal, M.D., President and CEO at Kadmon. “We are encouraged by the safety and tolerability findings from our open-label study, and the initiation of these trials signifies an important step in our effort to address this unmet medical need.”

Sunday, November 12, 2017

PKD Research: Phase 3 Trial shows Tolvaptan slows decline in kidney function

PKD Research

From Eureka Alert

New findings on tolvaptan as autosomal dominant polycystic kidney disease treatment


Vicente Torres, M.D., Ph.D., discusses new findings on tolvaptan as autosomal dominant polycystic kidney disease treatment

ROCHESTER, Minn. - A phase 3 trial studying the effects of tolvaptan has found that the drug slowed the rate of decline in kidney function in patients with the most common form of polycystic kidney disease, a condition with no cure. The results are published today in the New England Journal of Medicine.

Autosomal dominant polycystic kidney disease is an inherited condition that affects 1 in every 500 to 1,000 individuals in the U.S. This disease is found in all races and sexes.

Autosomal dominant polycystic kidney disease, which is the fourth most common cause of end-stage kidney disease, requires dialysis or kidney transplant.

The disease causes a slow but relentless growth of cysts that damage the kidneys. In addition to negatively affecting quality of life, the condition also causes hypertension and painful complications. The cysts, which can damage kidneys with their size, can develop in other organs, especially the liver.

Approximately half of individuals with autosomal dominant polycystic kidney disease eventually will require dialysis or kidney transplant by age 60. The results of the trial demonstrated tolvaptan's ability to intervene in a way that slows kidney function decline in this population.

"This is the first treatment that targets a mechanism that directly contributes to the development and growth of the kidney cysts in autosomal dominant polycystic kidney disease," says Vicente Torres, M.D., Ph.D., director of Mayo Clinic's Translational Polycystic Kidney Disease Center. "This in effect means it may delay the need for a kidney transplant or dialysis in patients with this disease."

As lead investigator of the trial, Dr. Torres is available for media interviews to discuss these findings and their significance for those facing autosomal dominant polycystic kidney disease.




From Medical Research.com

Vasopressin-Inhibitor Tolvaptan Reduces Kidney Function Decline in Polycystic Kidney Disease

MedicalResearch.com Interview with:

Vicente E. Torres, M.D., Ph.D.
Director of the Mayo Clinic Translational Polycystic Kidney Disease (PKD) Center

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Experimental work pioneered by Dr. Jared Grantham showed that cyclic AMP, an intracellular signaling molecule, promotes the development and growth of cysts. Vasopressin, a hormone produced by the pituitary gland, stimulates the production of cyclic AMP in the collecting ducts, from which most cysts derive in autosomal dominant polycystic kidney disease (ADPKD). While this effect of vasopressin is necessary for the kidneys to concentrate and reduce the volume of urine, it promotes the development and growth of cysts in patients with ADPKD. Dr. Vincent Gattone realized that inhibiting the action of vasopressin could be protective in polycystic kidney disease. Work in our and other laboratories confirmed that suppression of vasopressin production, release or action reduces cyst burden, protects kidney function, and prolongs survival in rodent models of the disease.

This experimental work provided a strong rationale for clinical trials of tolvaptan, a vasopressin V2 receptor antagonist. Tolvaptan reduced the rate of kidney growth in the TEMPO 3:4 trial, in patients with early ADPKD. It also reduced the rate of decline in kidney function, measured by the estimated glomerular filtration rate (eGFR), from 10.1 to 6.8 mL/min/1.73 m2 over three years. The eGFR benefit was maintained during two additional years when all the patients were treated with tolvaptan in an open label extension of the TEMPO 3:4 trial (TEMPO 4:4). Safety laboratory tests performed every four months showed elevations of liver transaminases in blood in 4.4% of tolvaptan and 1% of placebo-treated patients. Three of 1,271 tolvaptan-treated patients during TEMPO 3:4 and TEMPO 4:4 had evidence of potentially serious drug-induced liver injury. These abnormalities occurred all within the first 18 months of exposure to tolvaptan.

Based on the TEMPO 3:4 results, tolvaptan was approved for the treatment of rapidly progressive ADPKD in Japan, Canada, European Union, Switzerland and South Korea. In the United States, the Food and Drug Administration requested additional data to further evaluate the efficacy and safety of this drug. The REPRISE trial was performed to determine the efficacy and safety of tolvaptan in patients with later stage ADPKD.

What are the main findings?

Tolvaptan reduced the decline in eGFR from 3.61 to 2.34 mL/min/1.73 m2 over one year.
The effectiveness of tolvaptan in lowering the rate of decline in kidney function in REPRISE, in patients with later stage ADPKD (mean age 47 years, mean eGFR of 41 mL/min/1.73 m2), was similar to that previously observed in TEMPO 3:4 in patients with early stage ADPKD (mean age 39 years, mean eGFR 81 mL/min/1.73 m2).
The frequency of liver enzyme elevations was also similar, but there no cases of potentially serious drug inducer liver injury occurred in REPRISE, likely due to more frequent monitoring and earlier interruption or discontinuation of the drug.

MedicalResearch.com: What should readers take away from your report?

Response: The results of REPRISE in patients with later stage ADPKD, together with those of TEMPO 3:4 and TEMPO 4:4 over five years in early stage disease, show that tolvaptan is effective over a broad range of disease and may delay the need for dialysis or kidney transplantation.

Assuming that tolvaptan treatment would continue to slow the decrement in estimated eGFR by 1.27 mL/min/1.73 m2 per year, the time from an eGFR of 41 mL/min/1.73 m2 (average baseline eGFR in REPRISE) to CKD 5 (eGFR of mL/min/1.73 m2) would be extended from 6.2 years to 9.0 years. A larger benefit might be expected if treatment were started earlier.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Post-marketing registries in the countries where tolvaptan has been approved for the treatment of ADPKD to confirm its long-term safety and effectiveness.
Research to understand the mechanisms of the liver toxicity and to test or develop similar drugs without this problem.
New tolvaptan formulations or combinations with other drugs to enhance its efficacy.
New pharmacological strategies targeting cyclic AMP signaling.

Sunday, November 5, 2017

PKD Treatment Research: Tolvaptan & Lixivaptan, New tissue-engineered blood vessel replacements

PKD Research

From New England Journal of Medicine

Vicente E. Torres, M.D., Ph.D., Arlene B. Chapman, M.D., Olivier Devuyst, M.D., Ph.D., Ron T. Gansevoort, M.D., Ph.D., Ronald D. Perrone, M.D., Gary Koch, Ph.D., John Ouyang, Ph.D., Robert D. McQuade, Ph.D., Jaime D. Blais, Ph.D., Frank S. Czerwiec, M.D., Ph.D., and Olga Sergeyeva, M.D., M.P.H., for the REPRISE Trial Investigators*

November 4, 2017DOI: 10.1056/NEJMoa1710030
Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is the fourth leading cause of end-stage kidney disease in adults.1-3 When the genes encoding polycystin 1 (PKD1) and polycystin 2 (PKD2) are disrupted, tubular epithelial cells in vasopressin-sensitive distal nephrons and collecting ducts show enhanced proliferation, chloride-driven fluid secretion, and expression of proinflammatory cytokines, resulting in cyst development and the destruction of renal parenchyma.4

Vasopressin promotes kidney-cyst cell proliferation and fluid secretion by means of up-regulation of adenosine-3′,5′-cyclic monophosphate (cAMP).5,6 The suppression of vasopressin production, release, or action by means of hydration,7,8 V2-receptor blockade,9-14 or genetic mutation15 has been shown to reduce cyst burden, protect kidney function, and prolong survival in rodent models.

In the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO) 3:4 trial, which involved patients with early ADPKD (estimated creatinine clearance, ≥60 ml per minute), tolvaptan reduced kidney growth and the decline in the estimated glomerular filtration rate (GFR).16 The benefit with regard to the estimated GFR was maintained after 2 additional years of open-label treatment (TEMPO 4:4 study).17 Idiosyncratic hepatocellular toxic effects were unanticipated.18 With monitoring occurring once every 4 months, two patients in the TEMPO 3:4 trial and one in the TEMPO 4:4 study had evidence of potentially serious drug-induced liver injury. We conducted the Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD (REPRISE) trial, a phase 3, randomized withdrawal, multicenter, placebo-controlled, double-blind trial involving patients with ADPKD who had late chronic kidney disease of stage 2 to early stage 4, in order to ascertain the efficacy and safety of tolvaptan in patients with more advanced ADPKD with the use of more frequent monitoring for toxic effects in the liver.19

METHODS

Trial Design and Oversight

The institutional review board at each site approved the protocol and the informed-consent form. A steering committee that comprised investigators and representatives of the sponsor (Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercialization) oversaw the trial design and conduct with the assistance of an independent data and safety monitoring committee and a hepatic adjudication committee. The sponsor collected and analyzed the data. The first author wrote the manuscript with substantial contributions from the coauthors (including authors who are employees of the sponsor) and assumes responsibility for its content and integrity. The sponsor had no other role in writing or reviewing the manuscript. All the authors had access to the analyzed data, jointly decided to submit the manuscript for publication, and vouch for the accuracy and completeness of the reported data and for fidelity of the trial to the protocol. The trial protocol, which is available with the full text of this article at NEJM.org, has been published previously.19

From May 2014 through March 2016, patients were enrolled at 213 sites globally. Eligible persons were either 18 to 55 years of age with an estimated GFR of 25 to 65 ml per minute per 1.73 m2 of body-surface area or 56 to 65 years of age with an estimated GFR of 25 to 44 ml per minute per 1.73 m2. Patients in the older age group also had to have historical evidence of a decline in the estimated GFR of more than 2.0 ml per minute per 1.73 m2 per year.20

The trial consisted of an 8-week prerandomization period that was divided into a screening phase, a single-blind placebo run-in phase, and a single-blind tolvaptan period that comprised a dose-adjustment phase and a run-in phase (Fig. S1 in the Supplementary Appendix, available at NEJM.org). Patients who could take tolvaptan at daily morning and afternoon doses of 60 mg and 30 mg, respectively, or 90 mg and 30 mg, respectively, were randomly assigned in a 1:1 ratio, in a double-blind fashion, to receive tolvaptan or matching placebo for 12 months. Randomization was stratified according to the baseline estimated GFR (≤45 or >45 ml per minute per 1.73 m2), age of the patient (≤55 or >55 years), and total kidney volume (≤2000 ml, >2000 ml, or unknown).21 The maximal dose of tolvaptan that could be taken without an unacceptable level of side effects during the run-in period, or the equivalent as matching placebo, was dispensed according to the randomization assignment. Adjustment of the dose down to morning and afternoon doses of 45 mg and 15 mg, respectively, or of 30 mg and 15 mg, respectively, was permitted during the trial period.

Serum creatinine levels were measured centrally with the use of the isotope dilution mass spectrometry–traceable enzymatic method and were reported to two decimal points.19,22Determinations of the estimated GFR were made with the use of the Chronic Kidney Disease Epidemiology Collaboration equation.23

Trial Assessments

Evaluations were performed at baseline (during the screening and placebo run-in phases) and during the single-blind tolvaptan period (Fig. S1 in the Supplementary Appendix). Patients underwent monthly laboratory testing and reported to the trial sites every 3 months. Three follow-up laboratory visits occurred between days 7 and 40 after the receipt of the last dose of the assigned trial regimen. For patients who did not complete the trial, the follow-up period started after the discontinuation of the trial regimen and included a final follow-up at the originally scheduled 12-month visit.

Outcome Measures

Primary End Point

The primary end point was the change in the estimated GFR from baseline (before the receipt of any placebo or tolvaptan) to follow-up (after the 1-year trial period had been completed), with adjustment for the time each patient was in the trial and with interpolation to 1 year. Without this adjustment, the trial group that had more withdrawals or earlier withdrawals would have had an advantage because patients who withdrew early would have had less time for renal-function deterioration. The GFR values that were obtained before and after the receipt of any placebo or tolvaptan were estimated from the mean of three baseline serum creatinine values (two obtained during screening and one during the placebo run-in phase) and from the mean of three follow-up values that were obtained after the 1-year trial period was completed. The trial duration for each patient was defined as the interval between the median timings of the baseline observations and the follow-up observations. These estimated GFR measurements were not affected by the acute hemodynamic effect of tolvaptan, which is rapidly reversible when the drug is not being taken.24-26Vasopressin acting on V2-receptors increases the glomerular filtration rate by means of the activation of tubuloglomerular feedback and afferent vasodilation and by means of renin release and efferent vasoconstriction27,28; tolvaptan counteracts these effects. [Read more]




From Business Wire

Palladio Biosciences Announces Presentations of New Data for Lixivaptan and Polycystic Kidney Disease during the American Society of Nephrology 2017 Annual Meeting


Palladio Biosciences, Inc. (Palladio) http://palladiobio.com/, 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, today announced that new data for lixivaptan for the treatment of polycystic kidney disease (PKD) will be presented in two poster sessions during the American Society of Nephrology 2017 annual meeting, to be held in New Orleans, LA on November 2-5.

Briefly, the first poster presents results of an experiment that investigated the effect of lixivaptan in the PCK rat, a validated, orthologous animal model of human PKD. In this study, a beneficial effect of lixivaptan was observed consistently across all aspects of disease tested, including biochemical markers, renal morphology, and renal function.

In the second presentation, data from a large body of existing clinical and preclinical work were used to evaluate whether lixivaptan has safety and efficacy characteristics that suggest a favorable risk-benefit profile for the treatment of Autosomal Dominant Kidney Disease (ADPKD). To explore efficacy, the effect of lixivaptan on accepted pharmacodynamic markers of efficacy in ADPKD was investigated. To explore safety, a DILIsym simulation, a predictive, multiscale computational model of drug-induced liver injury, was conducted to assess the potential for hepatocellular injury compared to tolvaptan. Results supported the potential efficacy of lixivaptan for ADPKD and indicated that lixivaptan was not associated with hepatocellular toxicity at doses expected for ADPKD. Lixivaptan thus has the potential to become a safe and effective therapy for the treatment of ADPKD in a broad patient population.

Details for the accepted poster abstracts are listed below. They can be accessed online on the conference website at: https://www.asn-online.org/education/kidneyweek/2017/program-search-abstract.aspx
Effects of a Novel Vasopressin V2 Receptor Antagonist on Cystic Disease Progression in the PCK Rat
Poster Number: TH-PO574
Presentation date/time: November 02, 2017 / 10:00 AM – 12:00 PM
Location: Hall G
Lixivaptan, a Novel Vasopressin V2 Receptor Antagonist in Development for the Treatment of Autosomal Dominant Polycystic Kidney Disease
Poster Number: FR-PO326
Presentation date/time: November 03, 2017 / 10:00 AM – 12:00 PM
Location: Hall G

About Lixivaptan:

Lixivaptan was granted orphan designation by FDA for the treatment of ADPKD. It is a potent, selective vasopressin V2 receptor antagonist, a mechanism of action that has clinical proof of concept to delay the progression of ADPKD. 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.





From MedicalXpress

New tissue-engineered blood vessel replacements one step closer to human trials

New tissue-engineered blood vessel replacements one step closer to human trials


Researchers at the University of Minnesota have created a new lab-grown blood vessel replacement that is the first-of-its-kind nonsynthetic, decellularized graft that becomes repopulated with cells by the recipient's own cells when implanted. Credit: University of Minnesota

Researchers at the University of Minnesota have created a new lab-grown blood vessel replacement that is composed completely of biological materials, but surprisingly doesn't contain any living cells at implantation. The vessel, that could be used as an "off the shelf" graft for kidney dialysis patients, performed well in a recent study with nonhuman primates.

It is the first-of-its-kind nonsynthetic, decellularized graft that becomes repopulated with cells by the recipient's own cells when implanted. The discovery could help tens of thousands of kidney dialysis patients each year. The grafts could also be adapted in the future for use as coronary and peripheral bybass blood vessels and tubular heart valves.

The research was published today as the cover story in Science Translational Medicine. The University of Minnesota has also licensed the technology.

More than 100,000 people in the United States begin hemodialysis each year to treat kidney disease and more than 400,000 people are being treated with life-saving hemodialysis nationwide, according to the U.S. Renal Data System Annual Data Report. An arteriovenous fistula, which connects an artery to a vein in the arm, is currently the preferred mode of blood vessel access for hemodialysis. However, 30-50 percent of patients experience complications and need to connect the vein and artery using an artificial tube, called an arteriovenous graft.

Currently, these artificial grafts are made of synthetic materials that are prone to clotting, infection and other complications. Grafts grown in the lab from cells and biological materials could cause fewer adverse reactions, but living tissues aren't stable for long-term storage and could induce an immune response unless the patient's own cells were used, both being barriers to commercialization and clinical use.

In this pre-clinical study, University of Minnesota researchers generated vessel-like tubes in the lab from post-natal human skin cells that were embedded in a gel-like material made of cow fibrin, a protein involved in blood clotting. Researchers put the cell-populated gel in a bioreactor and grew the tube for seven weeks and then washed away the cells over the final week. What remained was the collagen and other proteins secreted by the cells, making an all-natural, but non-living tube for implantation.

"We harnessed the body's normal wound-healing system in this process by starting with skin cells in a fibrin gel, which is Nature's starting point for healing," said University of Minnesota Department of Biomedical Engineering Professor Robert Tranquillo who led the study. "Washing away the cells in the final step reduces the chance of rejection. This also means the vessels can be stored and implanted when they are needed because they are no longer a living material. In the future, thousands of the lab-grown vessels could be made from a small skin biopsy from one donor and then stored on the shelf for when they are needed by patients."

To test the vessels, the researchers implanted the 15-centimeter-long (about 5 inches) lab-grown grafts into adult baboons donated by Mayo Clinic as it was closing down its primate facility. Six months after implantation, the grafts grossly appeared like a blood vessel and the researchers observed healthy cells from the recipients taking up residence within the walls of the tubes. None of the grafts calcified and only one ruptured, which was attributed to inadvertent mechanical damage with handling. The grafts after six months were shown to withstand almost 30 times the average human blood pressure without bursting. The implants showed no immune response and resisted infection. In addition, the grafts withstood repeated needle punctures by self-healing, which would be a necessary process for patients undergoing long-term dialysis.

"This pre-clinical trial was extremely important to us," Tranquillo said. "In previous studies, we implanted vessels in sheep, but we needed to test them in a more human-like model before risking human lives because the success of our material depends on the ability of the recipient to recellularize it into a living tissue without immune response, which might have failed in a human even though it succeeded in a sheep."

With the success of this study, Tranquillo and the team will seek FDA approval for clinical trials in children with pediatric heart defects since they recently reported a study in Nature Communications that this material is also capable of growing.