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

Artificial Kidney

From Wonderful Engineering, by Ali Vaqar

This Artificial Kidney Eliminates The Need For Kidney Dialysis

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.

From Medical Xpress

Small changes to organ procurement system could lead to more life-saving transplants

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.”