PKD Research: Bioartifical Kidney; Stem Cells, Living with PKD: Mandy in Huddersfield, UK

PKD Research

From iTech Post, by Christie Abagon

Bioartificial Kidney May Become A Reality Soon

Dutch scientists and engineers have taken a big step towards developing a bionic kidney that could one day potentially replace the need for dialysis or transplantation. They have tested a "living membrane" made with human cells that would be at the heart of a functional artificial kidney implant.

The Device Filtered Out Waste, The Same Way As A Real Kidney

The team presented the advancement at at ASN Kidney Week 2016 November 15-20 at McCormick Place in Chicago, IL. They demonstrated this activity by attaching human renal proximal tubular epithelial cells on the surfaces of artificial hollow structures. These cultured cells indeed function as a living membrane and are able to actively remove the waste products.

"This study shows the successful development of a living membrane consisting of a reproducible ciPTEC monolayer on hollow fiber membranes, an important step towards the development of a bioartificial kidney device," said Professor Dimitrios Stamatialis from University of Twente in Netherlands.


The Bioartificial Kidney Could Replace The Painful Process Of A Dialysis

In the U.S., kidney is one of the commonly transplanted organs, wherein thousands of patients are put on a waiting list for a suitable kidney donor. Another treatment for kidney disease is Dialysis, where it takes over the job of kidney if the organ fails to filter harmful wastes, salt and excessive fluids from the blood. The treatment itself does not hurt, but the needles going in can be painful.

The goal of the Bioartificial kidney is to eliminate the need of dialysis or transplant in millions of people with kidney failure, and hopefully pave the way to similar developments for bioartificial devices for other organs as well.

"The strategies and methods of this work could be relevant to development of other bioartifical organs, such as bioartificial liver or bioartificial pancreas and organs on chips - such as kidney on chip, a lung on chip or a liver on chip," Stamatialis said.

From MedicalResearch.com

Kidney Organoids Derived from Human Pluripotent Stem Cells Model Polycystic Disease

MedicalResearch.com Interview with:

Dr. Ryuji Morizane MD, PhD
Associate Biologist, Renal Division
Brigham and Women’s Hospital
Affiliated Faculty, Harvard Stem Cell Institute
Instructor, Harvard Medical School

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

Response: Polycystic kidney disease (PKD) accounts for 10% of end-stage kidney disease (ESKD), and there is currently no curable treatment available for patients with PKD.

The adult onset form of PKD, the most common type of PKD, takes 30 years to form cysts in humans; therefore, it is difficult to study mechanisms of PKD to find novel therapeutics for patients.


MedicalResearch.com: What are the main findings?

Response: Last year, we developed a novel tool, a kidney organoid to study kidney diseases in culture plates. The kidney organoid is a 3-dimensional kidney tissue converted from human skin cells. This time, we have generated kidney organoids from patients with Polycystic kidney disease. The kidney organoids generated from PKD patients exhibited severe cyst formation with clinically relevant characteristics in 4 weeks of experiments.


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

Response: These results are encouraging, as they indicate that the kidney organoid can be used to study PKD in a realistic time course of experiments to elucidate mechanisms of the disease and to find novel therapeutics in the future.

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

Response: These results indicated that the kidney organoid can be used as a novel tool to study PKD. We recommend that mechanisms of cyst formation in the kidney organoid continue to be investigated ultimately to find new therapeutic approaches for patients with PKD.

MedicalResearch.com: Thank you for your contribution to the MedicalResearch.comcommunity.

Citation:

November 2016ASN Abstract 2139

Kidney Organoids Derived from Human Pluripotent Stem Cells Contain Multiple Kidney Compartments and Model Polycystic Kidney Disease

Living with PKD

From BBC.com/News/magazine By Claire Bates

My kidneys have failed, and I know my kids face the same fate

Mandy was born with a disease that caused both her kidneys to fail

After years of pain and dialysis, she has just had a kidney transplant

Her mother, brother and two sisters have the same condition

Mandy found out her two youngest children have inherited the disease

Mandy Littlewood is sitting on a park bench with her husband John, their two small dogs are chasing each other up and down the sloping field.

"The kids love to come down and play here as soon as they get home from school," Mandy says.

"It's so convenient as it's just down the road from our house."

But she knows the days of playing carefree in the park are numbered. Millie, 10 and Zac, nine, have inherited a life-threatening disease from her.

Mandy has polycystic kidney disease. It causes fluid-filled cysts to grow in the kidneys over several years. Symptoms, such as chronic pain in the abdomen and urinary tract infections, usually appear between the ages of 30 and 40 but can appear as early as childhood. Sufferers are placed on dialysis and eventually need an organ transplant.

The disease is hereditary and affects Mandy's mother, her sister and two or her aunts and uncles. Her grandmother died from the disease. Someone affected by the condition has a 50% chance of passing it on to their children.

"I've never felt angry about having it as it isn't anyone's fault - it's just something that happens."

Mandy didn't realise she could pass the condition on when she had her first son, Callum, at 19. However she and her husband John knew of the risk before having Millie and Zac.

"John and I had discussed the possibility of passing on the condition but we knew we wanted kids together. I had hoped they would have been spared like my youngest sister. I felt horrendous and so guilty when they were diagnosed.

"I'm glad we got them tested though because now we know to watch their blood pressure and be extra careful if they get infections."

Mandy says the condition only really started to impact on her life six years ago when she was 33.

"I had sharp stabbing pains in my back and side almost constantly. It was too much to cope with and I was prescribed anti-depressants to help with my mood."

She had her first kidney removed in 2011 and was placed on the transplant list in 2012. A year later she was placed on dialysis, which left her feeling exhausted.

"It's taken over my life," she says.

"I had to stop working as a learning disability nurse in 2013 and then stop driving at the start of this year. I didn't like to make plans to go out, in case I had to cancel because I felt rubbish."

Mandy and her family live in Huddersfield - two taxis and a train ride from specialist kidney services in Leeds. It's an issue many people who live far from a larger teaching hospital face.

"John gave up his job as a floorer to take care of me and the kids so we have struggled financially. It costs £30 in taxis and train fare for John to come with me to a hospital appointment."

The NHS first provided patient transport to take Mandy to Leeds for dialysis as it was the closest place with a spot available. She later received dialysis at Wakefield.

"The travel was always a nightmare," says Mandy.

"The patient transport turned the four-hour session into a day-long ordeal. I would be picked up hours before my appointment and then have to wait around after it had finished. As I went three times a week I felt like I was spending my life in hospital."

After two years a spot opened up at the local satellite dialysis unit in Huddersfield. It was a great relief to Mandy. Dialysis left her feeling sick and she was given meal replacements after losing a lot of weight.

"Everything tasted metallic. The kids would come in for their tea and I would have forgotten about it because I wasn't hungry."

This summer there were 141 people in West Yorkshire and 5,066 in the UK waiting for a kidney-only transplant. Waiting times vary due to clinical need and matching between patient and donor. The average waiting time for a kidney-only transplant is 944 days.

In July this year, Mandy finally got the call that there was a possible match.

"They rang early in the morning. I had to wake John and the kids and called my mum to come and take care of them while we rushed to Leeds General Hospital."

The mother-of-three was told she would have a long wait when she arrived at hospital because it was a 'heart-beating' donor. She was then left for hours in a small TV room in St James' Hospital in Leeds.

"I know they were busy but I found that very upsetting. I later found out a lot about my donor's health problems in case I didn't want the organ. It made me feel very sad for him. He had given me such a gift."  [Read more]

What is polycystic kidney disease?

About 70,000 adults and children in the UK have Polycystic Kidney Disease

It causes fluid-filled cysts to grow and multiply in both kidneys, eventually causing them to fail

More than half of sufferers will have kidney failure by the time they are 60 years old

High-blood pressure, pain and urinary tract infections are common symptoms

The form Mandy has is the world's most common inherited life-threatening condition

For more information visit the PKD charity website

PKD Research: Treating ADPKD with Tesevatinib, PKD Pipeline Review, PKD Mechanisms, New Kidney Organoids Methods, Pasireotide LAR: Slow ADPKD Kidney Volume Growth

PKD Research

From Business Wire

Kadmon to Present Additional Data Demonstrating Tesevatinib Safety for the Treatment of Polycystic Kidney Disease at ASN Kidney Week 2016

Kadmon Holdings, Inc. (NYSE:KDMN) (“Kadmon” or the “Company”) today announced additional data from its ongoing Phase 2a clinical study demonstrating the safety of tesevatinib, the Company’s oral tyrosine kinase inhibitor, for the treatment of autosomal dominant polycystic kidney disease (ADPKD). The data will be presented in a poster session on Saturday, November 19 at the American Society of Nephrology (ASN) Kidney Week 2016 in Chicago, IL.

Recent findings from Kadmon’s ongoing Phase 2a study in patients with ADPKD have demonstrated that tesevatinib is well tolerated and have also identified tesevatinib 50 mg once daily (QD) as the optimal dose to treat ADPKD.

New data reported in the poster indicate that tesevatinib is a new member of a group of drugs known as MATE 1/2-K transporter inhibitors, such as cimetidine, which mildly increase levels of serum creatinine. Normally, an increase in serum creatinine can be used to indicate kidney damage, but in the case of MATE 1/2-K inhibitors, these serum creatinine increases occur without clinically meaningful alterations in renal function.

Specifically, new data demonstrated that serum creatinine levels in tesevatinib patients increased by 10% to 14% during the first 28 days of treatment and reversed upon treatment discontinuation. Importantly, levels of cystatin C, another measure of renal function, were relatively unchanged during the same period. In vitro studies demonstrated that tesevatinib potently inhibits MATE1/2-K transporters at tesevatinib concentrations achieved with the 50 mg QD dose. Therefore, MATE inhibition by tesevatinib may explain mild serum creatinine increases associated with tesevatinib treatment.

“Kadmon has identified a contradiction in PKD drug development: MATE transporters such as tesevatinib increase levels of creatinine, the standard measure of PKD drug efficacy, but without clinically relevant effects on kidney function,” said James Tonra, Ph.D., Senior Vice President, Nonclinical Development at Kadmon and first author of the poster. “These findings further characterize the safety of tesevatinib while highlighting the need for alternative methods to evaluate kidney function in PKD drug development.”

“We believe these findings support the continued development of tesevatinib for PKD,” said John Ryan, M.D., Ph.D., Executive Vice President and Chief Medical Officer at Kadmon. “Kadmon has had discussions with the FDA to develop innovative methods to demonstrate drug safety and efficacy in PKD, a major unmet medical need. These discussions will have important implications for clinical trial designs for tesevatinib as well as other therapies in development for renal diseases, especially MATE inhibitors.”

From WhaTech

Recent report on polycystic kidney disease - pipeline review, H2 2016 just published

Polycystic Kidney Disease - Pipeline Review, H2 2016 is a new market research publication announced by Reportstack. This report provides an overview of the Polycystic Kidney Disease (Genetic Disorders) pipeline landscape.

Polycystic kidney disease (PKD) is a disorder in which clusters of cysts develop primarily within kidneys. Polycystic kidney disease symptoms may include high blood pressure, back or side pain, headache, blood in urine, frequent urination and kidney failure.

The predisposing factors include age and family history. Treatment includes antihypertensive drugs and diuretics.

Report Highlights

This report Pharmaceutical and Healthcare latest pipeline guide Polycystic Kidney Disease - Pipeline Review, H2 2016, provides comprehensive information on the therapeutics under development for Polycystic Kidney Disease (Genetic Disorders), complete with analysis by stage of development, drug target, mechanism of action (MoA), route of administration (RoA) and molecule type. The guide covers the descriptive pharmacological action of the therapeutics, its complete research and development history and latest news and press releases.

The Polycystic Kidney Disease (Genetic Disorders) pipeline guide also reviews of key players involved in therapeutic development for Polycystic Kidney Disease and features dormant and discontinued projects. The guide covers therapeutics under Development by Companies /Universities /Institutes, the molecules developed by Companies in Pre-Registration, Phase III, Phase II, Phase I, Preclinical and Discovery stages are 1, 1, 2, 1, 11 and 2 respectively for Similarly, the Universities portfolio in Preclinical and Discovery stages comprises 2 and 2 molecules, respectively for Polycystic Kidney Disease.

Polycystic Kidney Disease (Genetic Disorders) pipeline guide helps in identifying and tracking emerging players in the market and their portfolios, enhances decision making capabilities and helps to create effective counter strategies to gain competitive advantage. The guide is built using data and information sourced from a proprietary databases, company/university websites, clinical trial registries, conferences, SEC filings, investor presentations and featured press releases from company/university sites and industry-specific third party sources.

Additionally, various dynamic tracking processes ensure that the most recent developments are captured on a real time basis.

From Nephrology News

Method to create kidney organoids from patient cells provides insights into polycystic kidney disease

Scientists have developed a method to coax human pluripotent stem cells to mature into cells that go on to form the functional units of the kidney and demonstrated how the method can be used to study human kidney diseases

A new method to create kidney organoids from patient cells may provide insights into how kidney diseases arise and how they should be treated. The research is presented at ASN Kidney Week 2016 November 15-20 in Chicago.

Previously, Ryuji Morizane, MD, PhD, from Brigham and Women’s Hospital, and his colleagues developed a method to coax human pluripotent stem cells (hPSCs) to mature into cells that go on to form the functional units of the kidney.

In their latest work, they show how their method can be used to study human kidney diseases. Researchers used hPSCs derived from patients with autosomal recessive polycystic kidney disease (ARPKD) to generate kidney organoids that possessed tubules with large cysts like those seen in patients with the disease.

“Establishment of a novel platform to model ARPKD using human kidney organoids will facilitate studies on mechanisms of cyst formation and contribute to the development of chemical screening systems to find potential therapeutic agents for polycystic kidney disease,” said Morizane. “Also, our organoid system enables in vitro studies of kidney pathophysiology, nephrotoxicity assays, and disease modeling, and ultimately will lead to development of bioengineered kidneys for regenerative medicine.”

Study: “Kidney organoids derived from human pluripotent stem cells contain multiple kidney compartments and model polycystic kidney disease” (Abstract 2139)

From Northwestern Medicine, BY SARAH PLUMRIDGE

New Insights Into Mechanisms Behind Polycystic Kidney Disease

A new study published in the journal Cell provides insight into potential mechanisms for the activation of a mutated gene in autosomal dominant polycystic kidney disease (ADPKD), a life-threatening genetic disorder that afflicts more than 600,000 Americans and more than 12 million people worldwide.

The gene, named polycystic kidney disease 2 (PKD2), codes for a protein that is a part of a large ion channel and sits on the membrane of cells. A team of scientists, including co-author Paul DeCaen, PhD, assistant professor of Pharmacology, used a type of microscopy called single-particle electron cryo-microscopy combined with nanodisc technology to determine the structure of the PKD2 ion channel.

The structure described in the paper establishes the molecular basis for the majority of disease-causing mutations in PKD2-related ADPKD. They show how the extracellular domain (outside of the cell) of PKD2 — a hotspot for mutations — contributes to channel assembly and may serve as a location for extracellular stimuli to bind to and affect the function of the channel’s gates, which monitor ion flow.

They further uncovered details of the channel’s current and regulation of the flow of ions, or the permeation pathway, using electrophysiology methods.

“Although we know the PKD2 dysfunction leads to ADPKD, we don’t know how to treat patients,” DeCaen said. “This work provides a structural template for drug design, which is an exciting possibility since none currently exist.”

Currently, there are no treatments for ADPKD; right now, treatment can only alleviate some symptoms of the disease. A better understanding of PKD2 structure and function could further the development of better treatments, according to the authors.

The study was supported by the National Institutes of Health NIDDK Pathway to Independence (PI) Award (K99/R00), Howard Hughes Medical Institute, and National Institutes of Health grant R01 DK110575-01A1.

From EMPR.com, Boston, MA

Pasireotide LAR Slows Liver, Kidney Volume Increase in PLD, ADPKD

The investigative agent, pasireotide LAR (SOM230) was found to delay the progressive increase in liver volume and total kidney volume in patients with polycystic liver disease (PLD) and autosomal dominant polycystic kidney disease (ADPKD), in a study presented at The Liver Meeting® 2016.

Octreotide LAR, a somatostatin receptor analog, has been reported to reduce liver volume, improve quality of life in symptomatic PLD and slow glomerular filtration rate (GFR) decline in ADPKD. Maria V. Irazabal, MD, and colleagues from the Mayo Clinic, Rochester, MN, aimed to assess the safety and efficacy of pasireotide LAR in severe PLD and ADPKD. Pasireotide, a novel multi-receptor ligand somatostatin analog, possesses a "broader binding profile and higher affinity to known somatostatin receptors with potential for greater efficacy."

In the 1-year, double-blind randomized trial, 48 study patients were assigned 2:1 to receive pasireotide LAR 60mg or placebo every 28 days; patients were stratified by ADPKD and ADPLD.

"Primary endpoint was change in liver volume; secondary endpoints were change in kidney volume, estimated GFR [eGFR], and quality of life [QOL]," explained Dr. Irazabal. Forty patients completed liver volume measurements at 12 months.

The researchers reported a 3.3% decrease in annualized change in liver volume (4271 ± 2373mL to 4104 ± 2265mL) in the pasireotide LAR group vs. a 6.3% increase in liver volume (4047 ± 1298mL to 4294 ± 1314mL) in the placebo group (P=0.001).

Regarding kidney volume, researchers reported a 1.1% decrease in the pasireotide LAR group vs. a 3.9% increase in the placebo group (P=0.024).

"Changes in eGFR were not different between groups," noted Dr. Irazabal.

Pasireotide LAR the target dose, was reached in 87.5% of patients within the first year. Patients in the pasireotide LAR group, however, experienced a higher incidence of adverse events such as hyperglycemia (73% vs. 20%; P=0.003) and diabetes (30% vs. 0%; P=0.042) compared to the placebo group.

Overall, pasireotide LAR slowed the progressive growth in both liver and total kidney volume in patients with PLD and ADPKD. Bigger studies are warranted to determine the impact of somatostatin receptor analogs on eGFR decline, concluded study authors.

From News-Medical

Fruit flies can be powerful model for unraveling cellular, molecular bases of damaging cold perception

The tiny fruit fly can help humans investigate the genetic and neural bases of detecting painful or harmful cold stimuli and offer intriguing, potential implications for human health, according to a new study.

A team of researchers led by Dr. Daniel N. Cox, associate professor of neuroscience at Georgia State University, has discovered that fruit flies have cold-sensing neurons that when activated drive specific, aversive behaviors to damaging cold, which requires the function of evolutionarily conserved ion channels known as Transient Receptor Potential (TRP) channels.

In the journal Current Biology, the researchers establish the fruit fly, Drosophila melanogaster, as a powerful genetic and behavioral model for unraveling questions about the cellular and molecular bases of damaging cold perception, which have not been well understood.

The study explores the concept of nociception, the peripheral and central nervous systems' perception of painful or potentially tissue damaging stimuli, which is generated by activating sensory nerve cells called nociceptors. This evolutionarily conserved process is critically important for survival.

Nociception, coupled with pain sensation, alerts an organism to possible environmental dangers and allows it to execute behavioral responses to protect against incipient damage. Acute and chronic pain can manifest as altered nociception in neuropathic pain states.

The study found that one of the implicated TRP channel genes called Pkd2 has been causally linked to autosomal dominant polycystic kidney disease (PKD), the most common monogenic disease in humans. Pkd2 ion channels appear to function as cold sensors and misexpression of Pkd2 can confer cold sensitivity to normally insensitive neurons. While it is not yet known if PKD patients have cold nociception defects, these new findings suggest this merits further investigation as a potential non-invasive diagnostic.

These same cold-sensing neurons also function as mechanosensors for touch, revealing that they, as well as the TRP channels identified in this study, are multimodal and raising the question of how neurons and ion channels distinguish between harmless and harmful stimuli to drive specific behavioral responses. Using sophisticated optical assays of neural activation by touch versus cold stimuli, the researchers demonstrate that these sensory neurons have different activation thresholds, with touch having a low threshold and cold having a high threshold, that ultimately determine the appropriate behavioral response.

"This new model sets the stage for uncovering evolutionarily conserved molecular control of nociception," said Cox. "It also provides a powerful genetic platform for unraveling the neural circuitry and molecular mechanisms that integrate multimodal sensory input to produce specific behaviors in response to diverse environmental stimuli."

The research team included Kevin Armengol, Atit A. Patel, Nathaniel J. Himmel, Luis Sullivan, Dr. Srividya C. Iyer and Dr. Eswar P.R. Iyer of the Cox Lab at Georgia State's Neuroscience Institute and Center for Behavioral Neuroscience, and collaborators Heather N. Turner and Michael J. Galko from MD Anderson Cancer Center.

The next steps will be to dissect the neural circuitry, additional molecular players and synaptic mechanisms that modulate cold nociception and multimodal sensory processing.

Need Kidney: Sky High Help, Walk for PKD: Philadelphia, PKD Biomarker

PKD Need Kidney

From Channel 10, Columbus, Ohio, by KARINA NOVA

Man flies his phone number over Ohio State tailgaters to find kidney donor

Fans tailgating near Ohio State’s campus for the Nebraska game may have seen a phone number flying high above.
A man desperate to save his own life is hoping someone will call it.
After being diagnosed with polycystic kidney disease 7 years ago, Thom Kent tells 10TV’s Karina Nova what he's hoping for is the gift of life.
Kent says his wife Karen is a life saver. With her help, he uses a dialysis machine 2 hours a day, five days a week.
But ultimately his goal is to have a kidney transplant.

He says it’s a matter of life and death for him.
He's one of about 100 thousand people waiting for a kidney in the United States.
Kent is on a waiting list, after unsuccessfully finding a match within his family.

“They encouraged me to find my own living donor. Otherwise I'd have to wait 2-5 years for a cadaver to come up,” Kent explains.
That's when he realized he'd have to reach out to more people.
Kent hired an airplane to fly over the massive tailgating crowd before the Nebraska game.

The sign flown in the sky reads “Need kidney call 614-805-8466.”

“A tailgating scenario with a young crowd and alcohol, who knows what kind of calls I'm going to get. But all it takes is one,” Kent says.

He’s optimistic his phone number in the sky is the lifeline to his willing donor.

“There are living donors out there that don't know someone who needs a kidney, but they want to donate a kidney to somebody,” Kent says.

Thom already has big plans for his wife and granddaughter Amelia for when he's healthy. He plans to go to Disney World.
He says his insurance covers everything and there is no cost to the donor.
The Ohio State University performs more than 200 kidney transplants per year.


According to OSU's living kidney donor program:
- People able to donate are usually between 18 and 65-years-old
- Gender and race are not factors for a successful match

- The person should be good in overall physical and mental health.

For more information click here.

PKD Research

From BioPharmaDive.com

Gaining FDA support for a prognostic biomarker, giving patients hope

The lack of a validated prognostic biomarker impedes developing new treatments for rare diseases. Certara Strategic Consulting worked with the Critical Path Institute (C-Path) Polycystic Kidney Disease (PKD) Outcomes Consortium to identify a prognostic biomarker for a debilitating genetic rare disease, autosomal dominant polycystic kidney disease (ADPKD). Having a validated biomarker will help spur new research and clinical trials to find a treatment for ADPKD.

What is Autosomal Dominant Polycystic Kidney Disease?

Normal kidneys are fist-sized and weigh about a third of a pound. ADPKD patients develop cysts that cause the kidneys to enlarge over the course of decades. Renal enlargement leads to severe pain, increasing abdominal girth, hypertension, hematuria, kidney stones, and kidney infection. Many ADPKD patients develop end stage kidney disease (ESRD), which then requires either renal transplantation or dialysis. No medications can slow or stop the progression of ADPKD. Current treatments manage symptoms.

Developing a disease progression model for ADPKD

The lack of understanding of disease progression has hindered developing ADPKD treatments. Common renal function endpoints change late in the course of the disease. Thus, assessing the effectiveness of investigational drugs using these endpoints is difficult. Validating a biomarker that could predict disease progression earlier when patients are more likely to respond to medication was critical to enabling the development of treatments.

Certara Strategic Consulting won a bid to work with the C-Path Institute’s Polycystic Kidney Disease Outcomes Consortium to develop ADPKD disease progression models. The Consortium is a collaboration between C-Path, the PKD Foundation, Clinical Data Interchange Standards Consortium (CDISC), four academic medical centers, and three pharmaceutical companies. The consortium investigated Total Kidney Volume (TKV) as a prognostic biomarker for worsening kidney function and response to therapy in ADPKD patients.

Qualification of this novel biomarker involved multiple steps. First, data from patient registries and observational clinical trial data needed harmonization. To do this, C-Path worked with CDISC to create a data standard for ADPKD. Next, the data standard was used to remap the data into a single database. Then, Certara and the C-Path data management team curated the database for modeling. Finally, the data analysis and modeling strategies were discussed with the FDA pharmacometrics and biostats teams as well as clinicians to elucidate the role of age and glomerular filtration rate (eGFR) on the trajectory of TKV.

Model building and validation

Briefly, a key clinical outcome such as ESRD needed to be linked to the trajectory of TKV. Two additional endpoints were chosen— 30% and 57% worsening of renal function— since they occur in a shorter timeframe and predict the longer term outcome, ESRD. To identify potential confounding effects between the various predictors, Multivariate Cox models were used. Then, a simultaneous joint modeling framework of TKV and the time-to-event outcome was leveraged to account for TKV. A parametric survival submodel was used to simulate the probability of avoiding the clinical outcome according to a given baseline eGFR, TKV, and age. The final model was validated using a standard 5‑fold cross validation strategy.

The model will support ADPKD drug development in several ways. For example, it can simulate clinical trials to determine feasible trial durations. Likewise, the analysis results showed that longitudinal TKV, eGFR and age could predict the likelihood of developing the clinical outcome.

This complex project posed numerous challenges. For example, the database was continually updated. Thus, data analysis was an iterative process where outputs were generated as the dataset matured. Another challenge was finding a technology that facilitated working with busy clinicians. To obtain their critical input, they viewed project results via mobile devices that could be checked in the clinic. Certara’s technological infrastructure was indispensable to completing the project in record time.

Gaining regulatory support for a novel biomarker for ADPKD

In early 2015, the FDA issued a Biomarker Letter of Support for TKV. This biomarker will inform ADPKD clinical trial designs. Optimizing patient selection for clinical trials is an ethical imperative. It also increases the likelihood of the drug program’s success. Likewise, sponsors can use this biomarker to support regulatory decision making for drug development programs. The identification and validation of a prognostic biomarker for ADPKD should support developing new treatments that improve the lives of patients suffering from this devastating disease.

Walk for PKD

From CustomInk.com, Philadelphia, PA

2016 PKD WALK

"This is the second year the AECI Tigers are raising awareness on Polycystic Kidney Disease (PKD) among other charities we walk in to raise awareness. The event took place at the Pier 84 on a bright, crisp morning of Oct. 23. Working with CustomInk to produce all our school's t-shirts for charity event has been prompt and excellent quality. Thank you CustomInk!" - http://www.aecicharterhs.com/ - AECI Tigers (Nov 08, 2016)

Gift of Life: Saving Mother-In-Law, Help from Employee, Risk of Cancer for PKD Patients

Gift of Life

From Wall Street Journal, By STEVEN RUSSOLILLO

My Wife’s Mother Needed a Kidney, and I Was a Match

I married my wife on May 29. Three weeks later, I was lying in a New York City hospital recovery room. My new mother-in-law was a few beds away, my kidney flushing toxins from her body.

When my wife, Shelly Banjo, and I began dating six years ago, I learned that polycystic kidney disease ran in her family. It is a genetic disease where cysts grow on kidneys, eventually destroying them. Shelly’s mother, Batya Banjo, would eventually need a kidney transplant. Some day, Shelly also might need one.

Now, Batya refers to me affectionately as her new son and “kidney buddy.” I’ll be thinking about her, recovering back at her home in Texas, as I run the New York City Marathon on Sunday.

A year and a half ago, I proposed to Shelly on a bench in Central Park, where we have trained together for marathons. Soon after, I decided to get tested to see if her mother and I were the same blood type, the first round in qualifying as a kidney donor.

Batya is 69 years old and grew up in Israel. She met her husband, Chaim, at Hebrew University, where they were biochemistry lab partners. They got married, moved to Canada for medical school and then to Dallas, where they started a medical practice and raised three daughters.

In the summer of 2013, the whole family flew to Israel, where we piled in a van and toured the state for two weeks. Only then did I truly understand who kept the family ticking. Batya chimed in when Shelly’s dad forgot the punch line of a joke, sewed torn backpacks and jeans for her daughters, and never ceased giving her family advice—even when it wasn’t sought. That trip was the last time Batya felt healthy. Soon after, her kidneys started failing.

Currently about 120,000 Americans are on the waiting list for a new organ, according to the U.S. Department of Health & Human Services’ Organ Procurement and Transplantation Network. The majority of them need kidneys. More than 4,000 people died while waiting for a new kidney last year.

Finding a willing, qualified donor is difficult. Living donation rates have fallen steadily for the past decade, according to a study in the American Journal of Transplantation. Roughly half of all living donations in 2014 were from blood relatives.

Shelly and her family worked for three years to find a kidney donor. For a while, I mostly did what any supportive partner would do: I tried to be a good listener and provide comfort. At first, a handful of close friends came forward, but none qualified. We widened the search on Facebook and Twitter. My aunt graciously agreed to be tested, insisting her nephew’s children grow up with all their grandparents. She also didn’t qualify.

By the middle of 2015, Batya’s kidneys were functioning at only around 10%. Complete strangers volunteered to donate. That prompted me to step up. If someone could elect to give a kidney to a stranger, I could at least try to give my kidney to the woman who would soon be my new mother-in-law.

In June 2015, Shelly’s sister Hili got married, but Batya was too sick to walk her daughter down the aisle. Soon after, I got the results back from my first round of tests. My blood type, A-positive, was compatible with Batya’s. I could go on to round two.

A frustrating quirk of the hospital system is that only one potential donor at a time can go through the second qualification round. Several candidates were in the pipeline for further testing at that point. I stood down. [Read more]

From The Sentinel, Hanford, CT, by Cassandra Sandoval

Lemoore man receives kidney from employee

Roger Dudley, owner of R & J’s Machine Shop in Lemoore, and his smog technician Rich Hines have more in common than just working together.

Hines, 44, donated a kidney to Dudley, 69, earlier this year. Dudley has polycystic kidney disease, a genetic disease where a group of cysts develop in the kidneys over time and cause major damage.

“I knew early in life that I needed a kidney,” Dudley said. “I’m thankful to the man upstairs that I never had to go on dialysis.

According to the National Kidney Foundation, people with kidney failure will either need dialysis or a kidney transplant.

Last summer, Dudley was placed on a waiting list for a kidney transplant. The wait time was estimated to be seven years.

Hines decided to undergo tests to determine if he was able to donate one of his kidneys to Dudley. Hines went to the California Pacific Medical Center in San Francisco and found out he was a perfect match after two days of testing. Dudley's two sons had undergone testing and were not matches for their father.

Hines said he gave one of his kidneys to Dudley “because [he] needed one” adding that he believes peoples' paths cross for a reason and helping Dudley was the right thing to do.

“We are both veterans,” Hines said. “We take care of our own.”

Dudley served in the U.S. Army during the Vietnam War, and Hines served in the U.S. Navy around the time of the Gulf War.

Hines has been working for Dudley for six years.

“I’m not that type or person to ask for anything,” Dudley said. “[Hines] was a perfect match which I’m very thankful for.”

After finding out the good news, Dudley had to get a coronary angiogram to ensure his heart was strong enough for surgery which was planned for August 2015. The transplant was postponed after the cardiologist found three blocked arteries.

Dudley had a triple bypass surgery a week later which improved his kidney function to the point where he was no longer eligible for a kidney transplant.

His kidney started to fail again a few months later and the transplant was rescheduled for Feb. 24 in San Francisco.

Dudley and Hines both said they had a positive mindset on the day of the transplant.

“Our faith in God is very strong,” said Dudley's wife, Jana. “He had led us to this point. We sat in the lobby with the donor’s mom and sister and we just all prayed together.”

She said Dudley and Hines were in the hospital for five days.

“The surgeon told us that he literally took the kidney out of Rich’s body and later put it in Roger’s body and it started right up,” she said.

Hines said he does not feel any different and is glad that he was able to do something good for someone.

“Rich, he’s just a fantastic guy,” Roger Dudley said. “He didn’t have to do this, but I am glad he did.”

Dudley said he is doing great and is “still kicking.”

Living with PKD

From The Lancet

Risk of cancer in patients with polycystic kidney disease

Tung-Min Yu and colleagues1 showed, in a large cohort study, an increased incidence of kidney cancer in patients with autosomal dominant polycystic kidney disease (ADPKD) without end-stage renal disease and an increased incidence of extra-renal cancers, especially colon and liver cancer.

The link between ADPKD and cancer was first raised in the 1990s.2 In the subsequent decades, several insights into the pathogenesis of ADPKD were derived from molecular investigations. These findings highlighted a notable similarity between ADPKD and solid neoplasms. In a recent review, Seeger-Nukpezah and colleagues3 analysed similarities on a molecular level between ADPKD and pathological features frequently found in cancer. They raised “the interesting possibility that patients with mutations in PKD1 or PKD2 might be predisposed to kidney cancer” and also described differences in alterations of ciliary signalling and intracellular calcium and cAMP. Gargalionis and colleagues4 showed that an overexpression of non-mutated PKD1 and PKD2 genes are implicated in increased aggressiveness of colorectal cancer.

PKD1 and PKD2 encode polycystin 1 and polycystin 2, which are present not only in renal tubules. In ADPKD, mutations of PKD1 and PKD2 partly account for renal and extra-renal features of the disease,5potentially involving the kidneys, liver, seminal vesicles, pancreas, arachnoid membrane, vascular system, mitral valve, and abdominal wall.

These concepts lead us to ask if there could be an association between the presence of renal and extra-renal manifestations, secondary to ciliopathy, and the development of tumours. Yu and colleagues’ study provides an opportunity to explore a similar correlation. We suggest collecting data about the presence of phenotypical features of ciliopathy (extra-renal cysts, total kidney volume, intracranial aneurysms, mitral valve prolapse, aortic root dilatation and aneurysms, and abdominal wall hernias). Analysis of these data would reveal whether or not there is an association between degree of phenotypical expression of ciliopathy and oncogenesis in patients with ADPKD.

We declare no competing interests.