PKD Research: New Drug Shows Promise, Walk for PKD: Registration is Now Open!

PKD Research

From Big Stamp of Approval, Sheffield, UK

New drug compound could tackle major life-limiting kidney disease

Scientists from the University of Sheffield are part of an international collaboration to develop a new class of drugs to treat a common genetic kidney disease which is a major cause of kidney failure.

Working with Glasgow-based biotech company Mironid and colleagues in the US, the Sheffield researchers have carried out successful laboratory tests of a compound developed by Mironid to treat autosomal dominant polycystic kidney disease (ADPKD), a hereditary, progressive disease which affects over 60,000 people in the UK and around 12 million people worldwide.

ADPKD is caused by a genetic fault that disrupts the normal development of kidney cells and causes cysts to form inside the kidneys. The cysts, which are like fluid-filled blisters, grow and eventually destroy normal kidney tissue causing the kidneys to stop working properly. This leaves patients needing life-saving treatments, such as dialysis or a kidney transplant.

In ADPKD cells, cysts develop and grow because they express higher than normal levels of a ‘messenger molecule’ called cyclic AMP (or cAMP). One of the many known functions of cAMP is to tell cells when to divide and when to secrete fluid.

The new compound discovered by Mironid activates an enzyme called PDE4, whose natural role is to break down cAMP. Researchers at Mironid Ltd describe how the novel small molecule activators of PDE4 enzymes act to supress disease driving cAMP signalling.

Using cell lines and patient tissues derived from ADPKD patient kidneys, researchers at Sheffield and in the US confirmed that when the Mironid compound switched PDE4 on, levels of cAMP in the disease cells were reduced and the number and growth of the cysts were suppressed. The findings are published today (18 June 2019) in the prestigious US journalProceedings of the National Academy of Sciences (PNAS).

Moreover, the reversible nature of the compound means that PDE4 activity may be rapidly and accurately controlled in patients, according to the dose decided by the clinician. This suggests that a future treatment for ADPKD could be tailored to an individual patients’ needs and the severity of their disease without the side effects seen with other approaches. In theory, the compound could also suppress cyst formation due to ADPKD in other organs apart from the kidney, especially in the liver.

Professor Albert Ong, a consultant nephrologist and professor of renal medicine who led the experiments conducted at the University of Sheffield said: “Drug development usually focuses on looking for ways to block molecular and chemical processes, not switch them on, so this is a rare mode of action. As a researcher, it’s very exciting to be involved in the early stage development of a completely new class of drugs.

“It’s also very heartening for me as a clinician since like most genetic diseases, ADPKD cannot be cured. This discovery gives me hope for the many patients I see in my clinics that there could be another effective new treatment in the future to keep the disease in check for much longer, either on its own or in combination with other drugs such as tolvaptan.

“I would love to think that ADPKD could one day be a disease that people can successfully manage throughout their natural lives, rather than one that could shorten their lives.”

Mironid’s next step is to refine the compounds in anticipation of being able to develop a new medicine to treat ADPKD patients.

Dr David Henderson, Senior Investigator at Mironid added: “This exciting publication highlights the innovative science behind our LoAc® PDE4 activator technology. These first-in-class small molecules have the potential to address unmet clinical need in Autosomal Dominant Polycystic Kidney Disease (ADPKD), and potentially have further utility across different therapeutic areas where unbalanced cellular signalling drives disease progression. Looking to the future, we are excited and enthusiastic in our continued collaboration to translate this novel approach into real therapeutic benefit.”

Kidney Research UK has funded work on ADPKD at the University of Sheffield for several years, helping to develop vital knowledge on the mechanism of the disease and ways in which it might be managed.

Chief executive of the charity, Sandra Currie, said: “We are proud to have supported several ADPKD studies led by Professor Ong and his team at Sheffield over the years. Most recently, we funded Professor Ong’s investigations into how to control the ‘messenger molecule’, cyclic AMP, which affects the rate at which cysts grow and expand in the kidneys.

“It is really encouraging news that this collaboration with Mironid has now successfully laboratory-tested a compound which reduces levels of the cyclic AMP molecule. This could bring new hope to the 12 million people living with ADPKD worldwide – we look forward to further developments.”

Walk for PKD

From PKD Foundation

Registration is now open! Find a walk near you.

PKD Treatment: Bardoxolone receives orphan drug status for ADPKD; WavelinQ™ : Improved dialysis access procedure

PKD Treatment

From Yahoo Finance

Reata's (RETA) Kidney Candidate Gets Orphan Drug Status

Reata Pharmaceuticals, Inc. RETA announced that the FDA has granted an orphan drug designation to its pipeline candidate, bardoxolone methyl (bardoxolone), for the treatment of autosomal dominant polycystic kidney disease (ADPKD), an inherited form of kidney disease.

Notably, the orphan drug designation is granted to drugs capable of treating rare diseases that affect less than 200,000 people in the United States. The designation also makes the company entitled to certain other benefits including tax credits related to clinical trial expenses and exemption from the FDA user fee. The status also makes bardoxolone eligible for seven years of marketing exclusivity in the United States.

Shares of Reata Pharmaceuticals have soared 56.6% so far this year, outperforming the industry’s increase of 1%.

Last year, the company announced encouraging data from the phase II PHOENIX study on bardoxolone in the ADPKD cohort. Notably, the phase II study is evaluating bardoxolone for four rare forms of chronic kidney disease (CKD). Patients treated with bardoxolone for 12 weeks, experienced a mean increase from baseline in estimated glomerular filtration rate (eGFR) of 9.3 mL/min/1.73 m2, a measure of the kidney function. Moreover, 96% of the subjects showed an improvement in eGFR after a 12-week regimen.

Following positive results from the PHOENIX program, Reata Pharmaceuticals started the phase III FALCON study for treating patients with ADPKD. Last week, the company enrolled the first patient for the evaluation. The primary efficacy endpoint of this study is to see the change from baseline in eGFR as compared to placebo after 48 weeks of treatment followed by a 4-week drug withdrawal period.

ADPKD is a common form of inherited CKD, caused by mutations in PKD1 and PKD2 genes. Despite the standard of care treatment, it often causes end-stage kidney disease and almost 50% patients require dialysis or kidney transplant by the age of 60. Notably, this is the third orphan drug designation for bardoxolone to address kidney ailment distinguished by mitochondrial dysfunction and inflammation and the second designation for the treatment of patients with rare forms of CKD.

On approval, bardoxolone may provide an important new treatment option for ADPKD patients.




Dialysis

From KPLR, Channel 11, St Louis, MO

SSM Health Medical Minute: Breakthrough procedure for patients with kidney disease


ST. LOUIS - More than 460,000 people in the U.S. are living with End-Stage Renal Disease, the most severe form of chronic kidney disease. A brand-new option is now available for patients suffering from kidney disease. It’s the first innovative breakthrough for patients who require dialysis treatment in 50 years.

SSM Health St. Mary’s Hospital is the first hospital in the Midwest to offer a new, minimally invasive procedure to establish vascular access for patients suffering from kidney disease who require dialysis treatment. The procedure, known as WavelinQ™ (Wave-link) is the first innovative breakthrough in creating arteriovenous fistula (AVF), rather than a surgical fistula.

WavelinQ™ has reduced recovery time in half, allowing patients to go home the same day and start dialysis treatment sooner. It has also reduced infection rates and lowered the risk for painful inflammation.

Dr. Alejandro Alvarez, who helped to pioneer this new procedure and offers one of two training sites in the country at SSM Health St. Mary’s Hospital. “It’s going to have a big impact on our patients by reducing the risk of catheters, infection and even future procedures, as well as increasing recovery time so they can begin dialysis treatment faster.”

The new, minimally invasive WavelinQ™ procedure offers the same benefits as surgery as well as lower infection rates, plus lower the cost of delivery, without the painful inflammation and long recovery. In most cases, patients are able to go home and return to normal activity the next day. Furthermore, the time from fistula creation to first use for dialysis treatment is usually six weeks or less.

Surgical fistula creation has been the preferred technique for these patients. However, the surgery causes painful swelling that can last for weeks. Additionally, it increases the chances of a hospital stay, and the national average from creation to first use is 12 weeks.

“Our patients go through so much – they are tied to a dialysis machine three days a week – they deserve an alternative, more advanced option,” says Dr. Alvarez, MD. “As physicians and leaders in the community, it is our job to try to bring access to these kinds of procedures to our patients and to continue learning and innovating. We are proud to be one of the first hospitals in the area to offer the WavelinQ™ procedure.”

For more information about WavelinQ, click here.

PKD Webinar: Post-Transplant Expectations, Pay for Kidneys? Dialysis and Politics, PKD Awareness: Bowling Green, PKD and interorganellar contact

Kidney Transplants

From PKD Foundation, Webinar

Having a kidney transplant? What to expect post surgery

June 25, 2019 | 7 p.m. CDT

Register for Webinar

Preparing for a kidney transplant can be overwhelming. Once you get through the evaluation process and are ready for surgery, you may be thinking of questions about what to expect after your transplant. Join us to get answers to some of the most common questions transplant recipients have about what to expect when it is time to leave the hospital, recover from surgery and get used to the new normal of living with a kidney transplant.


Mandy Riester, RN BSN
Renal/Pancreas Transplant Nurse Coordinator | University of Kansas Health System

Mandy Riester has worked with transplant patients for almost 7 years. For the last 4 years she’s been the inpatient kidney nurse coordinator at University of Kansas Health System, teaching new kidney and pancreas patients how to care for themselves immediately following transplant. Mandy has a passion for transplant and for PKD patients.

From Forbes, by Robert Pearl, M.D., Contributor

Should The US Government Pay People For Their Kidneys?

These are trying times for healthcare optimists. Despite all the hype surrounding breakthroughs in clinical practice and technology, American medicine is stuck in in neutral. Though the engine is revving loudly, little progress is being made.

This unfortunate truth came into clearer light last week when I was preparing lesson plans for the healthcare strategy course I teach at the Stanford Graduate School of Business. During the first class of the semester, I offer a summary of healthcare-system successes over the previous year. This year, the pickings were slim: New developments in artificial intelligence and progress with Haven, the much-discussed Amazon-Berkshire-Chase venture, offered some glimmers.

The bulk of industry movement, however, was heading in the wrong direction. Dozens of scandals, from generic-drug price fixing to gross conflicts of interest, plagued some of healthcare’s biggest players. Even more discouraging, there was no concrete evidence that U.S. medical care has become more affordable, more accessible, more convenient or better (as measured in quality outcomes) since this time last year. Life expectancy in the United States fell for an unprecedented third year in a row. Americans still spend 50% more on healthcare than any other nation (as a percentage of GPD). And, to rub salt in the wound, the United States slipped again in the latest global health rankings.

Wanting to introduce a ray of optimism, and to stoke the possibility of positive change, I thought about the following question.

What could our nation realistically do to improve patient health and reduce medical costs in the next year?

With the operative word being “realistically,” this query proved difficult to answer.

Congress could cap drug prices or legalize the importation of effective biosimilars like insulin. But how likely is either action, given that the pharmaceutical industry spends hundreds of millions each year to influence legislation?

What about healthcare’s outdated information technology platforms? Six in 10 physicians think electronic health records (EHR) need a complete overhaul. That could achieved if the leading manufacturers were forced to open their application processing interfaces (APIs) to third party developers. But, once again, how likely is that? EHR vendors are just as protective of their profits as drug industry reps.

One solution: Pay people for their kidneys

The idea of paying people for their organs is not new but it is currently illegal. Back in 1984, the National Organ Transplant Act (NOTA) outlawed the buying and selling of human organs.

Prior to the U.S. government’s involvement in the transfer and transplantation of organs, one doctor in Virginia had attempted to establish a company for the express purpose of buying and selling kidneys commercially. And because there were no laws in place to stop him, NOTA made sense. Today, it doesn’t.

We should let the government purchase kidneys and continue to use an independent agency to decide exactly which individuals should receive these organs.

To understand why this solution makes sense now, it’s helpful to look at how far we’ve come in the past 35 years. In the 1980s, transplantation was an inexact science and often dangerous. At the time NOTA was signed into law, only 80% of kidney transplant recipients survived the operation and the associated immunosuppression. Today, transplant success rates exceed 95% among experienced surgeons and transplant teams.

Back in the ‘80s, the lack of diagnostic tests for infectious diseases like AIDS and hepatitis stoked fears that people might lie about their health status to sell an organ, thus increasing the risk of disease transmission for organ recipients.

Finally, proponents of NOTA felt an ethical obligation to uphold the goodwill of organ donation. They didn’t want to see it tainted by those seeking personal, financial gain. In 1983, Dr. David A. Ogden, president of the National Kidney Foundation, told The New York Times, “It is immoral and unethical to place a living person at risk of surgical complication and even death for a cash payment to that person.”

With advances in both science and society, NOTA needs to be modernized for the 21st century. We can realistically save tens of thousands of lives and billions of dollars if Medicare were allowed to purchase kidneys for appropriate recipients and if it paid for transplantation, rather than dialysis.

To highlight the benefits of this approach, two sets of numbers are worth considering. The first set pertains to the discrepancy between kidney need and availability, courtesy of “The Kidney Project” at the University of California in San Francisco (UCSF):

More than 100,000 patients in the United States are currently waiting on the kidney transplant list.

Just over 21,000 donor organs were available for transplant last year.

The need for donor kidneys in the United States is rising at 8% per year.

The other important set of numbers, also from UCSF, are financial:

Americans living with end-stage renal disease (ESRD) comprise 1% of the U.S. Medicare population but account for 7% of the Medicare budget.

Dialysis comes with an average treatment cost of $89,000 per patient annually.

The average cost of a kidney transplant is $32,000 for the surgery and $25,000 per year in post-surgery care.

Armed with these numbers, let’s calculate how much money would be saved by providing 100,000 people on the kidney transplant list with new kidneys, versus keeping approximately 100,000 people on dialysis.

Knowing the annual dialysis expense for this population is $89,000 per patient, the total expense for all 100,000 people over the next five years would be $44.5 billion.

The expense for this same population to receive new kidneys would be $32,000 for the procedure itself, plus $25,000 for post-op care annually, which over the same five-year period would equal $15.7 billion.

That’s a savings of nearly $25 billion.

Of course, these latter calculations assume we can find 100,000 new kidneys donors. Finding living donors would be best for a couple of reasons. First, kidney transplantations that involve “living” donors are more successful than when organs are harvested from the deceased. And second, there are millions of Americans who could contribute.

To find 100,000 donors, the United States government could offer to pay $50,000 for a kidney (plus all surgical costs and follow-up care expenses) for about $5 billion. Doing so would not only improve the health and life-expectancy of the recipients, it would still result in a total healthcare savings of $20 billion over the next five years.

The savings could then be used to fund programs that improve medical prevention, help manage the nation’s high blood pressure problem and lower the rates of adult-onset diabetes—all of which would go a long way toward preventing kidney disease and lowering future healthcare costs.

So, if the proposal has the potential to improve American health, lower medical costs and fund future programs to help more Americans avoid kidney failure, what are the potential pitfalls?

Legalizing the sale of organs, some say, would lead to the wealthy taking advantage of the poor. This concern, however, isn’t based in fact. According to UCSF data, kidney disease disproportionately affects the nation’s minority and low-income patients. Therefore, a government-run kidney purchasing program would disproportionately benefit the poor, not the rich.

Others fear that amending NOTA would create a black market. In fact, implementing this proposal would eliminate the need for a black market, since organs would be readily available and controlled by a federal agency.

There’s also the concern that low-income individuals would be coerced by economic factors to donate kidneys at the expense of their personal health. Here too, the argument is specious. Science has proven that a donor’s remaining organ compensates for the loss. Following removal, the twin kidney enlarges and becomes just effective as when there were two.

Furthermore, science has mastered screening for communicable diseases, rendering historical concerns that poor people might lie about their existing diseases for the donor money both outdated and culturally insensitive.

Finally, what about the risk of the donor losing the remaining kidney from trauma or cancer? Currently, people who anonymously donate kidneys are automatically placed at the top of the transplant list should they need one in the future. By making this same promise to the paid donors, the small risk associated with having a single kidney would be offset by the certainty of receiving immediate access to transplantation should it prove necessary.

There is no silver bullet for solving our nation’s healthcare crisis, and every solution has its risks and downsides.

Using money to incentivize kidney donations carries certain dangers, but also tremendous upside. Those willing to donate would earn $50,000, which would go a long way toward a college education, a home or other family expenses. And those receiving the organs would have a better and more productive life. This solution is realistic. And, done well, the program’s biggest problem might be having to turn away potential donors due to popular demand.

I look forward to hearing what the students think of this idea come September. And please share your thoughts with me on Twitter and LinkedIn.

Dr. Robert Pearl is a former healthcare CEO who teaches at Stanford. More than 10,000 people subscribe to his "Monthly Musings on American Healthcare." Follow him @RobertPearlMD

Dialysis Issues

From Los Angeles Times, By DUC DANG

Assembly bill could make it harder for some dialysis patients to receive treatment

The California Assembly recently voted on a matter of life and death for me and thousands of other Californians living with failed kidneys.

If it sounds dramatic, it is because it is.

At age 50, I depend on a charitable financial grant from the nonprofit American Kidney Fund to help pay for my daily at-home dialysis. Without the grant, I cannot afford the treatment. Without the treatment, I will die. Assembly Bill 290, supported by California’s health insurance companies, will force AKF to cease operating its program in California, hurting me and the more than 3,700 Californians who rely on its financial assistance.

This is because provisions in AB 290 conflict with the strict federal guidelines under which AKF operates and, rather than risk its operations nationwide, AKF will simply stop offering assistance in California. The bill recently passed the Assembly and is headed to the Senate.

When I was 30 and first suffered kidney failure as a result of hypertension, my brother gave me one of his kidneys. I lived a healthy life for 19 years after the successful transplant, working in the mortgage business. But that kidney failed in 2017, forcing me back on dialysis. I lost 30 pounds and was so sick for six months I could not work. Even after returning to work, I soon got laid off because my illness prevented me from bringing in business.

Today the AKF’s charitable premium assistance, along with COBRA from my previous job, combine to pay for expensive dialysis treatment that cleans my blood and removes toxins from my body. This treatment keeps me alive.

AB 290, as the insurance companies designed it, means I will lose my financial assistance and I will be unable to pay my insurance premiums. I will be forced on to Medicare which I don’t want. It will not provide the medical coverage that is best for me.

I’m not alone. There are more than 3,700 dialysis patients in California who will lose financial assistance if AB 290 passes and AKF is forced to stop offering its services in California.

By forcing dialysis patients on to government-funded health care plans, AB 290 will threaten the long-term viability of dialysis clinics since government reimbursements don’t cover the cost of care. If dialysis clinics are forced to cut back services or close because they can’t cover their costs, patients will end up in emergency rooms where care is up to eight times more expensive. The health care system as a whole, and taxpayers, will bear the burden of higher costs.

Not surprisingly, AB 290 also allows insurance companies to pay less to dialysis providers as reimbursement for dialysis treatments. Of course that’s why the insurance industry is supporting the bill. But it doesn’t force insurers to pass any of their savings to consumers. A win-win for insurance companies, but not for patients.

I am trying to do my part to contribute to my health care; working part time and awaiting a kidney transplant on the UC Irvine Medical Center donor list. But it will be years, most likely, before I can get another kidney.

If AB 290 passes, it would cruelly revoke my insurance, right when I need it the most. Dialysis that keeps me alive might be pulled away from me before I even get a chance for my name to come up on the transplant list. I will be forced to either live so far in debt I won’t be able to afford food or shelter, or I will die.

This bill, quite literally, is targeting some of California’s poorest and sickest residents.

It is that simple, and that sad.

PKD Research

From Science Signaling, by Isotta Lorenzi and Luca Scorrano

Too close not to encyst: Polycystic kidney disease and interorganellar contact sites

Abstract

Mitofusin 2 (MFN2) tethers mitochondria to the endoplasmic reticulum (ER). In the 7 May 2019 issue of Science Signaling, Kuo et al. report that polycystin 2 (PC2), encoded by a gene mutated in type 2 autosomal dominant polycystic kidney disease (ADPKD), contributes to cystogenesis by affecting MFN2, thus extending the role of mitochondria-ER contact sites to a common genetic disorder.

Fig. 1The connection between PC2 and mitochondria-ER tethering.

In normal cells, endogenous PC2 resides in the ER and associates with VDAC, an ion channel localized to the outer mitochondrial membrane. In PC2-depleted cells, MFN2 abundance is increased, resulting in greater ER-mitochondria apposition, increased mitochondrial Ca2+ flux, and enhanced mitochondrial metabolism. IP3R [IP3 (inositol 1,4,5-trisphosphate) receptor] and the MCU (mitochondrial Ca2+uniporter) complex are located in the ER and in the inner mitochondrial membrane, respectively. TCA, tricarboxylic acid; WT, wild type.
CREDIT: A. KITTERMAN/SCIENCE SIGNALING

Within the cell, interorganelle communication is often mediated at membrane contact sites, where two heterotypic membranes are in close proximity but do not fuse. The endoplasmic reticulum (ER)–mitochondria contact sites (MERCs) are one of the best-characterized examples of such contacts. MERCs, also known as mitochondria-associated membranes (MAMs), are patches of ER associated with mitochondria. They are crucial for the regulation of several cellular processes, including Ca2+ homeostasis, the transfer of lipids, ER stress, apoptosis, and autophagy. Alteration of the ER-mitochondria juxtaposition indeed impacts on mitochondrial metabolism and cellular response to Ca2+-mediated cell apoptosis (1). Despite the importance of such interface, only a handful of different proteins have been placed at MERCs and unambiguously identified to play a role in tethering or modulating ER-mitochondria proximity in mammalian cells. These include the mitochondrial fusion protein mitofusin 2 (MFN2) (2, 3) and its modulator trichoplein (also known as mitostatin) (4); the phosphofurin acidic cluster sorting protein (PACS-2) (5); the functional complex composed of the inositol 1,4,5-trisphosphate receptor (IP3R), the glucose-regulated protein 75 (Grp75), and the voltage-dependent anion channel (VDAC) (6); and the interaction between the vesicle-associated membrane protein–associated protein B (VAPB) and the protein tyrosine phosphatase–interacting protein 51 (PTPIP51) (7). Most of these genes are mutated in genetic disorders: MFN2 is associated with Charcot-Marie-Tooth disease, type 2a, VAPB is associated with amyotrophic lateral sclerosis type 8, and PACS-2 is associated with early infantile epileptic encephalopathy-66. These disease-associated mutations further substantiate the importance of MERCs in cell physiology. In the 7 May 2019 issue of Science Signaling, Kuo et al.nominate type 2 autosomal dominant polycystic kidney disease (ADPKD) as another MERC disorder.

ADPKD is an autosomal dominant form of polycystic kidney disease characterized by renal and liver cysts and intracranial aneurysms and often leads to end-stage renal disease. Type 2 ADPKD is caused by mutations in PKD2, which encodes polycystin 2 (PC2), a transient receptor potential (TRP) superfamily of large-conductance, nonselective cation channels involved in Ca2+ signaling. Classically, PC2 has been localized in cilia, but the PC2-PC1 (which is encoded by PKD1) complex has been placed in MERCs, and loss of PKD1 results in lower mitochondrial Ca2+ uptake and impaired mitochondrial respiration (8). The connection between PC2 and mitochondria is poorly characterized. Kuo and colleagues (9) determine a novel functional role of PC2 in the modulation of MERCs. They showed that endogenous PC2 was located at the MAM and it associated with VDAC, which helps to transfer Ca2+ between ER and mitochondria (6). Loss of PKD2 indeed led to enhanced mitochondrial Ca2+ influx and altered mitochondrial metabolism (Fig. 1). To rationalize these physiological findings, Kuo and colleagues explored the extent of ER-mitochondrial tethering in PKD2-depleted cells, where they found increased MFN2 protein levels. Accordingly, they reported, using various approaches, that in cells lacking PKD2, ER-mitochondria tethering was increased. They therefore propose a model in which increased MFN2 levels sustain MERCs formation and higher mitochondrial Ca2+ uptake. To test this possibility, Kuo and colleagues turned to an in vivo cystic mouse model in which they modulated MFN2 levels. Several studies on animal models have proposed a role for dysregulated Ca2+, and cyclic adenosine 3′,5′-monophosphate (cAMP) signaling in ADPKD cystogenesis and treatment strategies lowering cAMP levels in cystic tissues have proven beneficial. However, treatments of ADPKD cysts by restoring intracellular contact site levels had not been previously attempted. Cyst formation was strikingly dependent on the amount of MFN2 and hence on mitochondria-ER contacts. Tissue-specific deletion of MFN2 in cystic cells decreased cell proliferation and curtailed the increased mitochondrial Ca2+ uptake, ultimately blunting cyst formation and expansion. Because of the causal relationship between MFN2 levels and cyst formation in this ADPKD model, the study of Kuo et al. (9) opens to the exciting possibility that cyst formation in ADPKD patients harboring PKD2 mutations might be prevented by treatments that target MFN2, for example, by using small-molecule or peptide MFN2 inhibitors (10). Although these MFN2 inhibitors primarily affect MFN2 fusion, tethering function remains to be addressed, calling for the development of small-molecule inhibitors that can differentially target the two different functions of this pleiotropic molecule.

The catalog of diseases associated with changes in ER-mitochondria contact sites is long. Most of them, however, can be classified as diseases of reduced juxtaposition. The Kuo et al. paper raises the possibility that increased tethering between these two organelles can be regarded as a crucial pathogenic event at least in one disease, with the exciting corollary that specific MFN2 inhibition can curtail cyst formation. Besides the therapeutic possibility, another implication of the Kuo et al.work is to nominate MERCs as sites also for cAMP signaling. Although they did not specifically measure the influence of MFN2 deletion on cAMP levels in PKD2-deleted cells, it is tempting to speculate that correction of the exaggerated tethering might also affect local cAMP concentrations. Future research will be needed to decode local cAMP sensors at MERCs and their role in cell biology and signaling to other cellular components and to the nucleus to orchestrate complex processes such as cyst formation and maintenance.

PKD Awareness

From WNKY TV

Jackrabbit Jog returns to raise awareness for polycystic kidney disease

BOWLING GREEN, Ky. – Several Kentuckians kicked off their Memorial Day with a morning run.

A run that supports and raises awareness of individuals with polycystic kidney disease and to also raise money for an undeveloped cure.

This was all during the 4th annual Jackrabbit Jog 5K run/walk at Kerieakes Park.

People of all ages endured the heat to participate in a variety of events.

Including the 5-mile solo run and the 1-mile kids race called the “Bunny Hop.”

All of the proceeds from the running events go directly to the Polycystic Kidney Disease Foundation (PKD).

The PKD Foundation is still working to find a cure for polycystic kidney disease.

The Jackrabbit Jog 5K has raised over $10,000 so far in its three years running.

Even though event coordinator Ryan Dearbone lost his mother to the disease, he hasn’t lost hope.

Hope that one day the run won’t be needed anymore, but wanted to celebrate the disease being cured for good.

Dearbone anticipates that Monday’s run raised around $3,000 alone towards finding the cure.

Mom with PKD needs Kidney, New PKD Research Strategy, Imaging PKD, Kidney Failure Symptoms

PKD Research

From Yale News, By Ziba Kashef

New strategy for untreatable kidney disease: targeting cell energy

The best hope for people with an inherited form of kidney disease that causes kidney failure is dialysis or a kidney transplant. But a study led by Yale researchers reveals a potential strategy for developing new drug therapies for these patients.

Senior author Barbara Ehrlich and her team used mouse models and human tissue samples to study one of the two mutated genes that lead to autosomal dominant polycystic kidney disease (ADPKD). This form of kidney disease is the most commonly inherited type and difficult to treat. The researchers focused their investigation on measuring the production of energy in kidney cells affected by the disease. They discovered that when the gene for the protein called Polycystin 2 is turned off or missing, cellular energy ramps up, leading to the formation of cysts that damage the kidneys.

With this insight, the researchers have identified a promising approach for treating the condition by targeting the abnormal increase in kidney cell energy and growth. Having this novel target for drugs opens the door for developing new therapies that will benefit patients, they said.

The study, co-authored by Allison Brill working in Ehrlich’s lab, was published in Science Signaling.





From Science Signaling

Polycystin 2 regulates mitochondrial Ca2+ signaling, bioenergetics, and dynamics through mitofusin 2

PC2 separates mitochondria from the ER

Patients with loss-of-function mutations in polycystin (PC) 1 or 2 develop fluid-filled cysts due to excessive proliferation of kidney epithelial cells. Kuo et al. found that loss of the ER cation channel PC2 led to increased abundance of the mitochondrial fusion factor MFN2 and enhanced tethering of mitochondria to the ER. The increased mitochondria-ER association resulted in greater mitochondrial Ca2+ influx, biogenesis, and respiration and cellular proliferation, which in cultured cells and mouse models of polycystic kidney disease was rescued by deficiency in MFN2. These results show that PC2 acts to restrict mitochondrial tethering to the ER in kidney cells to prevent inappropriate Ca2+-dependent increases in mitochondrial function and cellular proliferation.

Abstract

Mitochondria and the endoplasmic reticulum (ER) have an intimate functional relationship due to tethering proteins that bring their membranes in close (~30 nm) apposition. One function of this interorganellar junction is to increase the efficiency of Ca2+ transfer into mitochondria, thus stimulating mitochondrial respiration. Here, we showed that the ER cation-permeant channel polycystin 2 (PC2) functions to reduce mitochondria-ER contacts. In cell culture models, PC2 knockdown led to a 50% increase in mitofusin 2 (MFN2) expression, an outer mitochondrial membrane GTPase. Live-cell super-resolution and electron microscopy analyses revealed enhanced MFN2-dependent tethering between the ER and mitochondria in PC2 knockdown cells. PC2 knockdown also led to increased ER-mediated mitochondrial Ca2+signaling, bioenergetic activation, and mitochondrial density. Mutation or deletion of the gene encoding for PC2 results in autosomal dominant polycystic kidney disease (ADPKD), a condition characterized by numerous fluid-filled cysts. In cell culture models and mice with kidney-specific PC2 knockout, knockdown of MFN2 rescued defective mitochondrial Ca2+transfer and diminished cell proliferation in kidney cysts. Consistent with these results, cyst-lining epithelial cells from human ADPKD kidneys had a twofold increase in mitochondria and MFN2 expression. Our data suggest that PC2 normally serves to limit key mitochondrial proteins at the ER-mitochondrial interface and acts as a checkpoint for mitochondrial biogenesis and bioenergetics. Loss of this regulation may contribute to the increased oxidative metabolism and aberrant cell proliferation typical of kidney cysts in ADPKD.




Living with PKD

From Post-Journal, Jamestown, NY, by JORDAN PATTERSON

Regaining Life  Falconer Resident In Need Of Kidney Donation

Ginger Blair-Farmer, pictured with her family, is in need of a kidney. The Falconer resident, in association with The Kidney Connection, is searching for a donor within the surrounding community.

Ginger Blair-Farmer just wants her normal life back.

Diagnosed with polycystic kidney disease, Blair-Farmer is scheduled to begin dialysis treatment if a donor fails to come forward before her kidney essentially shuts down.

“I would be getting back life,” she said of receiving a transplant. “I’d be getting back a life, a quality of life that I wouldn’t be able to have without a kidney donor.”

At the time she spoke to The Post-Journal, her kidney was functioning at 14 percent. She expects that within six months she will her kidney will need the dialysis treatment as functionality will have reached a critical percentage.

While dialysis is a viable option, she hopes a donor will come forward soon.

The Kidney Connection, a locally managed curator of donors, is again asking for the community’s help to provide Blair-Farmer with an organ she desperately needs.

Currently, she is on two transplant lists, but maintained the chances of finding a successful donor increases as she continues to promote herself. A main reason she reached out to The Kidney Connection was to simply do something rather than “do nothing.”

Blair-Farmer is the mother of five children. Diagnosed with polycystic kidney disease at the age of 21, it slowly began shutting down her kidney. Over the last four years, she said her kidney’s decline as increased more rapidly.

Blair-Farmer will soon turn 43 and hopes that a potential transplant can be organized this year. Her father, who was diagnosed with the same disease, had his first transplant at 44.

Now with hopes of getting a transplant of her own around the same age when her father underwent the same process, her oldest daughter, Gabrielle Blair, was recently diagnosed with the kidney-deteriorating disease.

“She’s close to the age I was when I found out and my dad was going through it,” Blair-Farmer said.” “Now she knows and I’m going through it.”

While she understands what her daughter is going through, her hope is to receive a kidney transplant to allow her to become a fully-functioning member of her family again.

The disease, especially in the last few years, generally makes her fatigued much easier than normal. Blair-Farmer, an avid hiker, runner and cyclist said the sickness has taken much of what she loves away from her.

If she does, in fact, find a donor, she looks forward to, “just being a fun mom and not having life revolve around (her).”

“I want to be a part of the family instead of being a part of the family from the background,” she said.

Asked what she would tell potential donors, Blair-Farmer said interested individuals should visit The Kidney Connection website.

Even if people decide to not donate to her specifically, she encouraged people to browse the sight to possibly donate to the other individuals on the site as some people have been waiting “a really long time.”

For anyone considering donating an organ, she said, “the difference you make in someone else’s life is tremendous. It’s a small sacrifice but comes with big changes for other person.”

Blair-Farmer’s story, as well as others, can be found at kidneyconnection.org.

From Cleveland Clinic

5 Kidney Failure Symptoms to See Your Doctor About

Plus, two easy-to-spot kidney disease risk factors

Your kidneys are like the technical crew from the latest “Avengers” movie. They may not be the flashy superheroes, but without their unsung work, you don’t have a blockbuster.

Your kidneys have the thankless but critical job of getting rid of waste and extra fluid. Plus, they keep your organs working. Nephrologist Juan Calle, MD, explains how to look for early signs of kidney disease so you can keep your kidney crew as healthy as possible.
When kidneys aren’t doing their jobs

Renal failure, also called kidney failure or kidney disease, happens when the kidneys are not working efficiently or effectively. An estimated 37 million U.S. adults are living with chronic kidney disease, according to the U.S. Centers for Disease Control and Prevention.

Even more shocking? Nine in ten adults who have it don’t even know it.

How could that be? “People don’t usually have noticeable signs of kidney failure until it is very advanced,” says Dr. Calle.


This sneak attack is why kidney failure is known as a “silent killer.”

By the time it’s diagnosed, dialysis and kidney transplant usually have unwelcome seats at the table. So it’s critical to catch any problems before kidney dysfunction passes the point of no return.
Get to know the signs of kidney failure

So how do you turn up the volume on this silent killer? Dr. Calle says to pay attention to these five signs of kidney failure:

1. High blood pressure: Kidneys help regulate blood pressure by releasing hormones. When they are damaged, they can’t do their job effectively.

2. Changes in your urination habits: You may be urinating less frequently or not at all. Your urine may appear frothy or darker (think the color of tea or cola). “Even a little blood can change the color of urine dramatically.”

3. Swelling, or edema: This goes beyond the bloating some of us experience after a salty meal. “The swelling can happen anywhere. But people usually notice it more in their legs, lower back, face and eyelids.”

4. Nausea, vomiting and a decreased appetite: Too much waste in your body affects everything, including your stomach.

5. Brain fog: Excess waste can make it hard to concentrate. Your brain may feel “fuzzy.” You may also have less energy and feel unsteady or light-headed.

But here’s the problem (as if we didn’t just list five): These symptoms seem to appear with no rhyme or reason. “You could have all the symptoms at the same time or intermittently, or you may have one but not the others,” Dr. Calle explains. It can feel like playing symptom Russian roulette.

To play it safe, see your doctor even if just one of these symptoms makes an appearance.
Watch out for these two risk factors

Two risk factors may rear their ugly heads before you notice any kidney failure symptoms, giving you a head start to get on top of this disease.

The first one to watch for is high blood pressure (again). “High blood pressure may be a sign of kidney disease, or it may cause it. It’s the chicken-or-egg dilemma,” Dr. Calle says.

Diabetes is another key risk factor. “Anyone who has high blood pressure and diabetes needs to be screened for kidney diseases.”

Other important risk factors include:
Family history of kidney disease
Regularly taking nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen and naproxen as well as proton pump inhibitors (PPIs) such as omeprazole (Prilosec OTC®) that treat reflux and other GI issues
A past acute kidney injury, which is when your kidneys are damaged or fail suddenly
Certain chemotherapy regimens

And when in doubt, check it out. Dr. Calle recommends taking any questions or concerns to a primary care physician, internist or nephrologist.

“Don’t rely on your Internet research,” he says. “Some websites are not reputable and can needlessly scare you.”

From Renal and Urology News

Most Common ADPKD Imaging Modality Is Computed Tomography

Nearly half of patients with autosomal dominant polycystic kidney disease receive at least 1 CT scan over 2 years, study finds.

Investigators who studied a national sample of patients with autosomal dominant polycystic kidney disease (ADPKD) found that computed tomography (CT) was the most common imaging modality.

Nearly half of patients received at least 1 abdominal CT scan over 2 years, Myrlene Sanon, MPH, of Otsuka Pharmaceutical Development & Commercialization, Inc., of Princeton, New Jersey, and colleagues reported in a poster presentation.

Sanon’s team used the IBM MarketScan Commercial and Medicare Supplemental databases to identify patients with ADPKD. A total of 4637 patients with a mean age of 51.2 years met study enrollment criteria. The mean follow-up time was 21.29 months. During the observation period, 46.5% of patients had CT scans, 25.06% had ultrasound examinations, and 9.79% underwent magnetic resonance imaging, according to the investigators.

Of the 37.8% of patients who had information on chronic kidney disease (CKD) stage, the frequency of CT imaging was higher among those with later stage (31%, 37%, 42%, 51%, and 69% of those with stage 1, 2, 3, 4, and 5 CKD, respectively.

Overall, 12.9% of patients had a scan during an emergency department (ED) visit leading to hospitalization and 28% had a scan during an ED visit without subsequent hospital admission. In addition, results showed that without a prior ED visit, 30.7% of patients had a scan during inpatient hospitalization and 51% had scans as outpatients.

Read more of Renal & Urology News’ coverage of NKF’s 2019 Spring Clinical Meetings by visiting the conference page.

KidneyX Awards: Wearable Dialysis and More, PKD Research: Octreotide-LAR, PKD Foundation Award, PKD Discrimination Lawsuit Settled

Kidney Dialysis

From University of Washington Medicine Newsroom

Contest award validates ideas for wearable kidney dialysis

A conceptual illustration of the wearable dialysis unit being developed by the CDI.

In 2014, Chuck Lee of Bothell, Washington, was among seven subjects in a clinical trial of a “Wearable Artificial Kidney.” The proof-of-concept dialysis device was an exciting idea for patients like Lee who have irreversible kidney failure and whose survival depends on thrice-weekly clinic visits to be tethered to a large blood-cleansing machine for four or five hours.

At 11 pounds, the prototype trial device was clunky, and it had technical challenges. But Lee loved it because it allowed him to consume tomato juice, Cheetos and other favorites long gone from his diet, and it gave him freedom to walk around the hospital unit as dialysis took place.

The device represented the first significant innovation for those patients since the 1960s, when the University of Washington pioneered dialysis as a life-sustaining therapy.

Eager to pursue the idea of wearable dialysis, the UW Center for Dialysis Innovation (CDI) launched in 2017. It’s composed of doctors and engineers who are rethinking the dialysis circuit and hoping to make wearable dialysis a reality for kidney-failure patients.

Today the CDI was honored as two of its ideas were chosen as finalists in the KidneyX Redesign Dialysis competition, a national contest. Contest sponsors are the U.S. Department of Health and Human Services and the American Society of Nephrology.

“We’re excited to be recognized. It was competitive – over 160 submissions, from which 16 were selected,” said Kassandra Thomson, who directs the CDI’s efforts to translate research into clinical practice. Today she is in Washington, DC, presenting concepts along with other contest honorees.

Today’s winners are invited to develop their ideas into prototypes and to compete in the second phase of the competition, in which up to three winners will be awarded $500,000 each next year.

Thomson described the CDI’s two submissions. One described the vision for a next-generation wearable dialyzer, depicted as a compact device that will allow patients to receive dialysis 24/7. It will be water-efficient, enable complication-free blood access, and more fully model kidney function. Mostly, the device would afford mobility and allow patients to live lives more fully.

The other submission is a new vascular access graft. Blood-vessel access has been called the Achilles’ heel of hemodialysis. Current vascular-access technologies have a finite lifespan; patients suffer repeated needle sticks and, after many repetitions, the points of access can fail and complications can ensue.

“The new arteriovenous (AV) graft we are designing will be resistant to repeated needle punctures, reduce blood clots that might form inside the graft, and induce blood vessels to grow into the graft, so that it becomes more like a piece of living tissue," Thomson said. “The goal is to dramatically improve outcomes and the patient experience with their vascular access, addressing unsolved problems that have plagued patients for decades."

Kidney disease has become a staggering health burden in the United States, affecting 40 million people. More than 700,000 of them have kidney failure, which means being on dialysis, getting a transplant, or dying.

“It’s time for the next big advance,” Thomson said, “and we want it to happen here.”

From healio.com

Innovators at KidneyX competition: Award winners look at access, hemodialysis process

WASHINGTON — HHS awarded more than $1 million in prize money last week during its first KidneyX Summit. Here is a summary of the recipients and their projects.


Vascular access

Researchers/Developers: Mohammad R. Haider, PhD, and Steven D. Gardner

Department of electrical and computer engineering, The University of Alabama at Birmingham

Device: A non-invasive, wearable telehealth device to detect thrombosis and monitor the health of arteriovenous fistulas and grafts in patients on hemodialysis. It uses a small sensor to monitor the patient’s vascular access in real time and sends the acquired data to a local microcontroller for signal processing. A machine learning algorithm then classifies the input data to identify hemodialysis vascular access clotting and automatically alerts patients and their health care teams.

Researchers/Developers: Dimitri Augustin, MD

Stanford University Nephrology fellow and Stanford Biodesign alumnus

Racquel Redwood Meng

Stanford Biodesign alumnus

Device: A wearable, real-time monitor of arteriovenous fistula attributes that identifies failing or properly maturing arteriovenous fistulas. Patients will benefit from real-time arteriovenous fistula data immediately postoperatively without requiring significant time, skills of a health care professional or concurrent connection to a hemodialysis machine. When early arteriovenous fistula maturation failures are identified, providers will be notified in order to evaluate if early interventions are necessary.

Researchers/Developers: Access for Life Inc., Daniel Nadis, Roger Mason, MD

Device: This smart sensor-enhanced needle guide is implanted in the subcutaneous tissue. It directs a blunt needle through an opening in the skin to an underlying fistula, reducing pain from large bore needles. A biosensor on the JEM cylinder with an audio-visual alarm will reduce risks of back wall perforation and needle dislodgement. The sensors also measure blood flow, allowing nephrologists to identify increased stenosis risk.

Researchers/Developers: Yael Vin, MD, MPH, FACS; and Matthew Phaneuf

Beth Israel Deaconess Medical Center in Boston

BioSurfaces LLC in Ashland, Mass.

Device: Beth Israel and BioSurfaces LLC are developing a drug-eluting electrospun hemodialysis graft. “We have the technology to incorporate drugs that reduce neointimal hyperplasia into the electrospun fibers and localize this attachment to a certain segment (venous edge) and layers of choice (inner layer, mid layer),” the researchers wrote.

Hemodialysis

Researchers/Developers: Outset Medical Inc. in San Jose, Calif.

Device: The proposed innovation provides for an integrated, automated means of monitoring of important physiological parameters during hemodialysis, including blood volume status (absolute and relative), vascular access function (flow rate and circulation) and ultrafiltration rate. “This is especially impactful in care settings such as in-home or in-center self-care hemodialysis, where patients take on greater ownership of their therapy,” the researchers wrote.

Researchers/Developers: Christian Schafmeister, PhD

Department of chemistry, College of Science and Technology, Temple University

Device: Schafmeister and colleagues are developing atomically precise membranes for high-flux and selective removal of blood toxins during hemodialysis. “We propose a solution to the problem of replicating kidney functions by creating chemically synthesized, atomically precise membranes that can be as thin as a single-molecule that mimic the highly permeable and selective membrane channels present in human cells,” Schafmeister wrote. “ ... This will open the door for renal replacement therapy to personalized/precise medicine beyond simple dialysis.”

Researchers/Developers: Peter Kotanko, MD; Stephan Thijssen, MD; Xia Tao, MD, PhD;

and Vaibhav Maheshwari, PhD

Renal Research Institute LLC in New York

Device: Kotanko and colleagues are developing a device to improve the intradialytic removal of protein-bound uremic toxins using binding competitors. Hemodialysis can remove uremic toxins, but protein-bound uremic toxins are the most difficult, the researchers wrote. They are infusing a displacer substance into the dialysis machine’s blood tubing upstream of the artificial kidney. The displacer binds to the same binding sites on albumin as the toxins. “Thus, it quite effectively competes with the toxins for their albumin binding, displaces them from the albumin molecule, and, once they are free, they can then be easily removed in the artificial kidney,” wrote the researchers. “In laboratory experiments, we have seen up to a three-fold increase in the removal rate of these toxins.” The plan with KidneyX funding is to develop an ideal displacer (or a combination of displacers) that can be used routinely in hemodialysis and study the impact on toxin removal.

Researchers/Developers: Ira Kurtz, MD, David Geffen School of Medicine at University of California, Los Angeles

Roland Ludlow, CEO and founder, Curion Research Corporation

Jamie Hestekin, MD, professor, department of chemical engineering, University of Arkansas

Device: The group is developing dialysate- and cell-free renal replacement technology that would not require the use of an external dialysate solution to drive the flux of ions and water across a membrane. The device couples multiple wafer electro deionization technology with pressure-driven ultrafiltration, nanofiltration and reverse osmosis modules specifically developed for this project.

CKD

Researchers/Developers: Kirby Binayao, RN, MBA; Karl Quint, MD; and Karen Naranjo

Renal Tracker, the Netherlands

Device: Renal Tracker delivers new or existing CKD self-management programs via digital platforms and uses behavior change elements to help patients modify progression risks.

Home dialysis

Researchers/Developers: Janelle Kaneda, Alisha Birk and Mark Buckup

Bioengineering department, Stanford University

Device: This device utilizes optical interrogation methods for early diagnosis of peritonitis.

The OpticLine will use spectrophotometry to analyze the optical density of whole blood counts (WBCs) in the dialysis waste fluid to gauge for infection. With a prototype, various WBC concentrations in Dulbecco’s phosphate-buffered saline were measured. “Our results from our works-like spectrophotometer prototype experiment indicate that we detect a significant difference in optical density between our two WBC concentrations of interest: 10 WBC/mm3 (normal) and 1,000 WBC/mm3 (infected) (P value = 1.47E-07),” the researchers wrote.

Infection control

Researchers/Developers: Alexander Yevzlin, MD

Director of interventional nephrology, division of nephrology

University of Michigan in Ann Arbor

Device: This is a nitric oxide-eluting, disposable hemodialysis catheter insert aimed at preventing infection and thrombosis. Nitric oxide (NO) is an endogenously formed gaseous molecule that is well known to play a key role in preventing infection and thrombosis. The disposable NO release insert will be replaced at each dialysis session (every 2 to 3 days).

Artificial kidney

Researchers/Developers: Shuvo Roy, PhD; William H. Fissell, MD; and Charles Blaha, MS

University of California, San Francisco; Vanderbilt University Medical Center in Nashville;

Silicon Kidney

Device: The researchers are developing a hemodialysis system (iHemo) that involves implanting a compact hemodialyzer (HemoCartridge) that creates a permanent internal vascular connection. “The iHemo will improve dialysis patient outcomes and their quality of life by eliminating risk of accidental blood disconnect and encouraging frequent and prolonged hemodialysis treatments, especially within the home setting,” they wrote.

Researchers/Developers: Jonathan Himmelfarb, MD; Buddy Ratner, PhD; Larry Kessler, ScD; Kassandra Thomson, PhD; Glenda V. Roberts; and Anna Galperin, PhD

University of Washington Center for Dialysis Innovation in Seattle

Device: The UW Center for Dialysis Innovation is developing the Ambulatory Kidney to Improve Vitality (AKTIV): a wearable, miniaturized dialysis system that “is low-cost, water-efficient, requires minimal anticoagulation, offers complication-free blood access and is patient-friendly,” the researchers wrote. “The AKTIV will provide sustained life, and higher quality, more productive lives for patients worldwide, allowing almost unlimited mobility, dramatically reduce pharmaceutical burden and reduce dietary restrictions.”

Researchers/Developers: Qidni Labs Inc.

Device: This is a project to develop an automatic air removal system that can be used safely in a wearable renal therapy device with minimal user intervention. This system uses an air removal filter of the design used in cardiopulmonary bypass and extracorporeal membrane oxygenation systems. This system can also determine and signal the patient with an alarm if the hydrophobic isolation filter element has been wetted and thus has reduced the accuracy of the integrated return blood pressure monitor.

Transplantation

Researchers/Developers: Jeff Ross; Joseph Uzarski

Miromatrix Medical Inc., Eden Prairie, Minn.

Device: Using multiple patented technologies, Miromatrix is working to bioengineer new kidney grafts that consist of human cells grown in pig extracellular matrix scaffolds. “Perfusion decellularization removes the native cells from pig kidneys while leaving behind a transplantable scaffold that provides the framework needed to grow a new kidney graft,” the developers wrote. Miromatrix’s perfusion software drives cells to regenerate kidney structures, including blood vessels and nephrons, in laboratory bioreactors. As an initial step, Miromatrix has developed a process to revascularize kidney grafts with consistent performance in vivo. Revascularized kidney grafts have shown sustained vascular patency on follow-up angiographies in chronic pig transplantation models without evidence of blood clotting.

Reference:

www.kidneyx.org/WhatWeDo/PrizeCompetitions/redesigndialysisphasei

PKD Research

From MD Linx

Octreotide-LAR in later-stage autosomal dominant polycystic kidney disease (ALADIN 2): A randomized, double-blind, placebo-controlled, multicenter trial

In this randomized and placebo-controlled trial, researchers assessed the renoprotective effect of octreotide long-acting release (octreotide-LAR) in autosomal dominant polycystic kidney disease (ADPKD), the most frequent genetically determined renal disease, patients at high risk of ESRD due to later-stage ADPKD. For this investigation, 100 patients with estimated glomerular filtration rate (GFR) 15–40 ml/min/1.73 m2 were randomized to receive two 20-mg intramuscular injections of octreotide-LAR (n = 51) or sodium chloride (placebo; n = 49) every 28 days for 3 years. Investigators found that 3-year octreotide-LAR treatment did not significantly affect the decline in GFR vs placebo, but significantly slowed cyst growth and progression to end-stage kidney failure, especially in patients with more severe kidney failure (stage 4) to begin with, and was safe and well tolerated. Overall, the authors concluded that octreotide-LAR was well tolerated and during the study, there was no patient requiring interruption of treatment or even transient dose down-titration





Living with PKD

From JD Supra

Remedy Intelligent Staffing and Lornamead to Pay $50,000 to Settle EEOC Disability Discrimination Suit

Staffing Agency and Manufacturer Failed to Accommodate and Instead Fired Long-Term Temporary Worker With Kidney Condition, Agency Charged

BUFFALO, N.Y. - Remedy Intelligent Staffing, LLC, a California-based staffing firm, and Lornamead, Inc., a manufacturer headquartered in New York City, will pay $50,000 and furnish other relief to settle a disability discrimination lawsuit filed by the U.S. Equal Employment Opportunity Commission (EEOC), the federal agency announced today. The EEOC charged that Remedy and Lornamead violated federal law when they refused to provide a reasonable accommodation to a long-term temporary employee that would have enabled him to continue to work after his kidney condition worsened, and instead ended his employment.

According to the EEOC's suit, David Gaiser II was hired by Remedy and assigned to work as a general laborer at Lornamead's Tonawanda, N.Y., facility in June 2013. During his employment, Gaiser was diagnosed with autosomal dominant polycystic kidney disease, a chronic condition characterized by the growth of multiple cysts in the kidneys. In June 2016, Gaiser was assigned to run a machine that re­quired continual bending and twisting, which aggravated his kidney condition and caused him severe pain. Gaiser suggested several accommodations that could enable him to perform his job duties. Instead, Lornamead directed Remedy to end Gaiser's three-year assignment at Lornamead. Remedy failed to place Gaiser at another job with a different client.

Such alleged conduct violates the Americans with Disabilities Act (ADA), which prohibits discrimination based on disability and requires employers to provide a reasonable accommodation to individuals with disabilities. The EEOC filed suit (EEOC v. Lornamead, Inc. and Remedy Intelligent Staffing, Inc., Civil Action No. 1:18-cv- 00841) in U.S. District Court for the Western District of New York, Buffalo Division, after first attempting a pre-litigation settlement through the EEOC's conciliation process.

In addition to the $50,000 in monetary relief, the three-year consent decree settling the suit requires Lornamead to adopt new policies and procedures on disability discrimination and on providing accommodations to employees with disabilities. The decree also requires the company to train all supervisors, managers, and human resources personnel at the Tonawanda facility on Lornamead's obligations under the ADA. The company will also provide training to non-supervisory employees, including temporary employees placed by Remedy, on their rights under the ADA. Remedy will distribute its new policies explaining the ADA's prohibition against disability discrimination and Remedy's duty to provide reasonable accommodations to all employees and newly hired employees. Remedy will also provide training to all supervisors, managers, and human resources personnel responsible for temporary employees assigned to Lornamead's Tonawanda facility. The decree further subjects both employers to reporting, monitoring and record-keeping requirements.

"As joint employers, Remedy and Lornamead share a legal duty to provide reasonable accom­modations to people with disabilities," said Jeffrey Burstein, regional attorney for the EEOC's New York District Office. "We appreciate both employers' willingness to resolve this case without protracted litigation."

Kevin Berry, district director of the New York District Office, said, "The purpose of the ADA is to ensure equal employment opportunities to qualified people with disabilities. Firing a person because he or she needs an accommodation due to a disability is against the law, and the EEOC will continue to hold employers accountable."

Elizabeth Fox-Solomon was the EEOC's lead trial attorney for this case.

The EEOC's New York District Office is responsible for processing discrimination charges, administrative enforcement, and the conduct of agency litigation in Connecticut, Maine, Massachusetts, New Hampshire, New York, northern New Jersey, Rhode Island, and Vermont. The Buffalo Local Office conducted the investigation resulting in this lawsuit.

PKD Foundation

From healio.com

Researchers of polycystic kidney disease honored with Kaplan International Prize for Advancement

York Pei, MSc, MD, FRCPC, and Bradley Yoder, PhD, were presented with the Lillian Jean Kaplan International Prize for Advancement at the World Congress of Nephrology in Melbourne, Australia, according to a press release from the PKD Foundation.

The Lillian Jean Kaplan International Prize recognizes individuals whose scientific work results in improving the knowledge and treatment of polycystic kidney disease.


“It is my distinct honor to present both Pei and Yoder with the Lillian Jean Kaplan International Prize for their most significant research in the polycystic kidney field. And, we deeply appreciate Mr. Kaplan’s generous commitment in recognizing researchers in their quest to advance treatments for PKD,” Andy Betts, CEO of the PKD Foundation, said in the release. “The pioneering studies of these researchers provide great hope for the future for all PKD patients.”

According to the release, both researchers were awarded $50,000, a sculpture, a citation depicting their work and an opportunity to lecture during the World Congress of Nephrology about their research. Pei, a professor of medicine at the University of Toronto, focused on genetic, genomic, clinical and translational research and has made a significant contribution to advance diagnosis, prognosis and development of novel treatment in autosomal dominant polycystic kidney disease.

As professor and chair of the department of cell, developmental, and integrative biology at the University of Alabama at Birmingham Medical School, Yoder has spent 2 decades focused on understanding the function of the primary cilium in multiple tissues and during development, with a long-standing interest in how loss of cilia function contributes to cyst development in the kidney. His recent research has uncovered roles for primary cilia in regulating innate immune responses following renal injury that accelerates cyst progression.

PKD Modeling with Kidney Organiods, Kidney Pain Signs, Medicare Rules Modification Could Lead to Dialysis Care Innovation, Kidney Delivery by Drone

Living with PKD

From Medical Daily, By Leian Naduma

Kidney Pain Signs, Symptoms And Causes

Renal or kidney pain is associated with several malfunctions of the organs or recurring infection. Sometimes, it is a mere urinary tract infection that can be remedied by lifestyle changes or prescription medication. Other times, it is a symptom of a serious mental condition. Here are the most common signs, symptoms and causes to help you identify if what you are going through is a mild or serious case of kidney pain.

Your kidneys are bean-shaped organs located on either side of your spine. They filter the blood and balance the number of fluids and electrolytes in your body. The level of pain you experience also depends on whether the cause is prerenal or related to another organ located near it, intrinsic or caused by the kidneys themselves or postrenal, which is typically due to an obstruction below the organs. Thus, the common triggers of kidney pain are an infection, obstruction, growth or trauma, as per VeryWell Health.

Trauma

Kidneys are placed at a vulnerable position in the abdomen which may easily be affected by a blunt force impact or a penetrating wound. If you have abdominal injuries, there is a 10 percent chance that you will also sustain damage to your kidneys. Events such as physical assaults and vehicular accidents result in renal trauma. You can distinguish this cause from others by pressing the kidney area and note a painful sensation. It may also be associated with fever, hematuria, urinary retention, rapid heart rate, decreased alertness and abdominal swelling. These symptoms require emergency treatment.

Renal Obstruction

This is a result of urinary blockage and it is an intrinsic type of kidney pain. The renal obstruction causes unilateral or bilateral pain due to affected ureters. This type of pain is also called obstructive uropathy which is caused by kidney stones, bladder stones, urinary tract infection, an enlarged prostate, pregnancy, long-term catheterization, a blood clot in the kidney, nerve-related bladder weakness, cancer, or vesicoureteral reflux. These cause your kidneys to swell and is referred to as hydronephrosis. You are most likely to experience pain in the groin, flak or abdominal area and may be associated with urinary urgency, fever, nausea and dysuria. Kidney stones cause higher pain levels while the others are gradual when left untreated.

Growth or Cysts

Renal tumors also cause pain and its intensity depends on the growth. The three most common growth abnormalities are renal adenoma, renal cell carcinoma and polycystic kidney disease (PKD). Larger ones do not cause pain until they disturb the architecture of the kidney. When this happens, the pain is persistent and worsens over time. If the tumor is cancerous, you may also experience unexplained weight loss, which suggests an advanced malignancy. PKD is also associated with headaches, high blood pressure, abdominal pain and swelling, hematuria and renal failure.

Infection

Kidney infection is treated with prescription antibiotics. This is caused by viral or fungal exposure that adversely affects the body’s immune system. Patients who have advanced HIV or underwent organ transplants are more vulnerable to this condition.

Prevention And Cure

As per Medicine.Net, most kidney pains can be relieved by drugs like ibuprofen, ketorolac and acetaminophen, which are common medications for pain. Antibiotics are recommended by doctors in infections while those who have kidney stones may need surgery.

Kidney pains caused by infections can be prevented by drinking sufficient amounts of water per day, wearing loose pants, following proper hygiene and refraining from holding your urine for long periods. Kidney stones and abdominal cancers, on the other hand, may be prevented by eating a healthy diet and avoiding salty and fatty foods.

From Health Care Finance, by Jeff Lagasse, Associate Editor

Modifications to Medicare rules could support care innovation for dialysis

Medicare spends approximately $35 billion annually on care for beneficiaries with end-stage renal disease.

In a commentary published in the American Journal of Kidney Diseases, public health researchers suggest adjustments to recently proposed rule changes on how Medicare pays for dialysis services.

Medicare spends approximately $35 billion annually on care for beneficiaries with end-stage renal disease, or kidney failure. That's more than 7 percent of Medicare's total paid claims. Over half a million people receive regular dialysis treatments to manage this condition, with treatment costs averaging about $85,000 a year, according to the study.

IMPACT

Rule changes were proposed about a year ago that would limit the number of dialysis treatments per week that would be paid for by Medicare. Interest groups including nephrologists and patients themselves were concerned that this would limit patient access to innovative treatment options, such as frequent hemodialysis.

Under the current system, Medicare covers three hemodialysis treatments weekly per patient, but it will often pay for additional treatments when the treating nephrologist provides sufficient medical justification.

The recently proposed rule changes would limit such additional payments to exceptional circumstances -- for example, patients with temporary, acute kidney treatment needs. Although nephrologists would not be prevented from providing any "extra" treatments they believe are needed, they would typically bear the costs of doing so.

The researchers discussed the limitations of the current evidence on frequent dialysis treatment, which to date has yielded mixed conclusions. Their suggested changes to Medicare's dialysis payment system were designed to account for these limitations and give Medicare the flexibility to further modify the system in the future as new evidence comes to light.

Under their main proposal, Medicare would establish a new, separate prospective payment system for frequent hemodialysis treatment.

In that way, they said, nephrologists would have greater clarity about how their dialysis care would be paid for, and free them up to pinpoint better ways to treat their patients.

THE TREND

In the first three years of Medicaid expansion due to the Affordable Care Act, the number of patients with end-stage kidney disease who died within a year of starting dialysis decreased in states that expanded Medicaid, compared to non-expansion states, found research published in October.

The adjusted absolute reduction in mortality in expansion states versus non-expansion states was 0.6 percentage points. Since end-stage renal disease affects more than 100,000 Americans each year, 0.6 percentage points equals hundreds of deaths annually.

PKD Research

Select Science

Modeling Kidney Disease with Bioengineered Kidney Organoids

Kidney organoid pioneer, Dr. Benjamin Freedman, explains the bioengineering, generation and application of 3D cell culture in studying kidney disease.

Kidney disease, prevalent in about 14% of the American population, lacks much-needed early interventions to prevent disease progression. Current methods that address kidney disease in a more chronic stage endure additional complexities: for example, artificial kidney devices don’t function as well as a human kidney, and renal transplant procedures need the support of anti-rejection medication.

In this article, we interview Dr. Benjamin Freedman, Assistant Professor at the University of Washington, whose goal is to understand kidney disease in its early stages. “In the medical practice, there's a lot of focus on the end stages of kidney disease and on managing that chronic disease. We are more interested in the early stages and all the different things that can go wrong early on,” says Freedman.

A pioneer in the field of kidney organoids, Freedman chose the 3D cell culture system to study kidney disease. “Organoids are great for this because they can show signs of disease,” Freedman explains. “We can then intervene by treating them with any compound that we're interested in.” A robust model for mimicking disease in vitro, kidney organoids didn’t even exist until a few years ago.

Freedman was the first scientist in the western hemisphere to generate a kidney organoid from pluripotent stem cells. “That was a very exciting moment,” Freedman recalls. “As soon as I saw these structures, I knew that there was something interesting about them. I had all the tools at my disposal to test whether they were indeed kidney.”

And they were.

Bioengineering kidney organoids

Developing and maintaining kidney organoids requires bioengineering capabilities. While the organoids grow and self-assemble from stem cells, their in vitro development deprives them of the vascular perfusion otherwise available in vivo. Tiny microfluidic tubules pass through the kidneys in our bodies, enabling the inlet and outlet of fluid, a resource that kidney organoids grown on a dish don’t receive.

“The kidneys in the body get about 20–25% of the cardiac output at any time point,” explains Freedman. “One thing we're missing in an organoid structure is the ability to perfuse the organoids and the tiny tubules.”

Freedman’s lab has a solution to this problem. “We're trying to make the kidney organoid 2.0, which will incorporate not just the stem cells and their natural ability to form the structures but will also impose a bioengineering design on top of those structures to enable them to really form the very complex types of functional tubules that are found in the body.”

Kidney organoids cultured in the Freedman lab. Images from left to right; blood vessels joining kidney organoids; grown from reprogrammed skin cells; showing cyst growth from tubules; kidney podocytes. Image courtesy of the Freedman lab.

Mimicking in vivo environments

The kidney organoid 2.0 grows on a kidney-on-a-chip device incorporated with extracellular matrix in scaffolded arrangements. By seeding the stem cell-derived kidney cells on this matrix-coated chip, the cells can be grown into controlled shapes and arrangements. “It's a fusion between stem cell and bioengineering fields,” explains Freedman. “The chip, about the size of a credit card, has a tiny tubule structure through which we can perfuse liquid. We can then observe the absorption of solutes such as glucose and ions and see how they're transported from one side of the tubule to the other side.”

The procedure to generate organoids uses a thin layer of Corning® Matrigel® matrix at the bottom of the tissue culture dish. The cells are plated on top of this layer, followed by a second thin layer of Matrigel. “This enables the cells to fold up and create more three-dimensional types of structures which are about 200 microns in diameter,” says Freedman. “These contain all the key lineages of the kidney tissue that we're interested in.”

The Matrigel matrix forms a crucial component of the kidney organoid generation process from pluripotent stem cells. “Matrigel matrix helps the cells to survive. They need a malleable support that they can grow into and form more three-dimensional structures in; something that they can actually change and remodel as they're growing,” Freedman explains.

For the kidney-on-a-chip protocol, the Freedman lab uses a relatively strong and stiff extracellular matrix. “We use Corning Collagen I, a highly concentrated form of collagen because these gels need to be stiff for the cells to take on the right shape that we’re interested in,” says Freedman. “If it’s too soft, the whole thing just falls apart, especially because we have fluid running through it.”

Alternatively, after the organoids have formed, they are placed inside larger Corning Collagen I droplets to stimulate the cells to grow out and populate. “This way, we study the ability of these cells to migrate out of the organoid, which has ramifications for certain disease processes,” says Freedman. “The tubular cells, which are normally sedentary, can actually migrate out when you give them an environment like that.”

Better detached than attached

One of the projects in the Freedman lab involves studying polycystic kidney disease using the kidney organoid model. “In polycystic kidney disease, the tubules, which are normally very narrow, swell up to form large balloon-life structures. They eventually crowd out and destroy all the healthy kidney tissue,” explains Freedman. “We’ve been able to get this to actually happen in our kidney organoids by mutating a gene in the stem cells and derive organoids that are mutants. The organoids swell just like the kidney tubules in the disease.”

This swelling process, however, depends on the microenvironment the organoid finds itself in. Freedman adds: “If you grow the organoids in a condition where they’re essentially floating in media, then it accelerates and exacerbates the disease process.” The lab uses Corning ultra-low attachment plates to grow the organoids detached. “They make these big balloon-like cyst structures very well in the ultra-low attachment plates,” notes Freedman. “They don’t do as well when grown in normal tissue culture conditions.”
The next big thing for 3D cell culture

High-throughput chemical and genetic screening are soon making their way into 3D cell culture biology. “We’re going to move from a phase where we study one drug and its effects at a time to a stage where we’re interrogating the organoids with thousands of compounds,” says Freedman.

“This is something you can’t do in the mammalian animal model, so it’s an exciting time for unbiased discovery using organoids. The big data phase is upon us.”

Kidney Transplant News

From Yahoo Finance

Pioneering Breakthrough: Unmanned Aircraft Delivers Organ for Successful Kidney Transplant in Maryland

COLLEGE PARK and BALTIMORE, Md., April 26, 2019 /PRNewswire/ -- In a first-ever advancement in human medicine and aviation technology, a University of Maryland (UMD) unmanned aircraft has delivered a donor kidney to surgeons at the University of Maryland Medical Center (UMMC) in Baltimore for successful transplantation into a patient with kidney failure. This successful demonstration illustrates the potential of unmanned aircraft systems (UAS) for providing organ deliveries that, in many cases, could be faster, safer, and more widely available than traditional transport methods.

The momentous flight was a collaboration between aviation and engineering experts at the University of Maryland; transplant physicians and researchers at the University of Maryland School of Medicine (UMSOM) in Baltimore; and collaborators at the Living Legacy Foundation of Maryland.

"This whole thing is amazing. Years ago, this was not something that you would think about," said the kidney recipient, a 44-year-old Baltimore resident who spent eight years on dialysis before undergoing the transplant procedure.The patient was discharged from UMMC on Tuesday.

Maryland faculty and researchers believe this prototype organ transport blazes a trail for the use of UAS to expand access to donated organs, improving outcomes for more people in need of organ transplants.

"This history-making flight not only represents a breakthrough from a technological point of view, but provides an exemplary demonstration of how engineering expertise and ingenuity ultimately serve human needs—in this case, the need to improve the reliability and efficiency of organ delivery to hospitals conducting transplant surgery," said Darryll J. Pines, Ph.D., UMD, dean of the A. James Clark School of Engineering and Nariman Farvardin Professor of Aerospace Engineering. "As astonishing as this breakthrough is from a purely engineering point of view, there's a larger purpose at stake. It's ultimately not about the technology; it's about enhancing human life."

Added Joseph Scalea, MD, assistant professor of surgery at UMSOM, project lead, and one of the surgeons who performed the transplant at UMMC, "As a result of the outstanding collaboration among surgeons, engineers, the Federal Aviation Administration (FAA), organ procurement specialists, pilots, nurses, and, ultimately, the patient, we were able to make a pioneering breakthrough in transplantation."

The many technological firsts of this effort include: a specially designed, high-tech apparatus for maintaining and monitoring a viable human organ; a custom-built UAS with eight rotors and multiple powertrains to ensure consistently reliable performance, even in the case of a possible component failure; the use of a wireless "mesh" network to control the UAS, monitor aircraft status, and provide communications for the ground crew at multiple locations; and aircraft operating systems that combined best practices from both UAS and organ transport standards.

"We had to create a new system that was still within the regulatory structure of the FAA, but also capable of carrying the additional weight of the organ, cameras, and organ tracking, communications and safety systems over an urban, densely populated area—for a longer distance and with more endurance," said Matthew Scassero, MPA, director of UMD's UAS Test Site, part of the A. James Clark School of Engineering. "There's a tremendous amount of pressure knowing there's a person waiting for that organ, but it's also a special privilege to be a part of this critical mission."