Five Upsides of PKD; CRISPR Model of PKD; Tiny Cell Bubbles; HALT-PKD Trial; PKD & Medical Marijuana

Living with PKD

From Huffington Post, by Bill Brazell

5 Upsides of a Chronic Disease

At my 25th college reunion, a classmate whom I hadn't met kindly asked me to talk about some of the positive things that had come out of inheriting a disease. This is what I said:

TRANSCRIPT

That's my grandmother Ann on her wedding day. Her husband would die in front of her when he was 44 years old. My poor Nana would later attend the funerals of both of her children, and her oldest grandchild. Three of those four sudden deaths had a single cause: polycystic kidney disease, or PKD -- a disease that was passed down to five or her six grandchildren, including me.

This is a normal kidney. It's the size of a fist.

That on the right is a polycystic kidney. "Polycystic" means "many pockets of fluid."

A healthy kidney weighs about five ounces. [Polycystic kidneys] can weigh 40 pounds each. Carriers are prone to high blood pressure and aneurysms. Along with some height and intelligence, I inherited those kidneys from my dad.

But I'm here to talk about the upside -- the good that has come of our family's history with these vile organs.

The first upside is that because he knew he might die young, my dad bought a lot of life insurance. I'm afraid that some of you may regret your laugh when I tell you what happened next. In 1984, my father drowned at the age of 42. He drowned. He certainly hadn't expected to die like that. But the insurance money put all four of his kids through college. And by the way, I don't hold it against anybody for laughing, believe me.

First Upside: Dad believed in life insurance. Which came in handy.

Two years after my father died, I needed a physical to maintain my spot as the worst rower on the freshman heavyweight crew. I asked the doctor at Holyoke Center to check for PKD. He found it.

Shaken, I walked back to my dorm. Alone, I looked out the window at the students, professors and tourists ambling through the Yard and I thought, "They can expect a full life. Mine may be half over."

Fourteen years passed, and I did very little about the disease.

Then my cousin Mike died. That's Mike and his dad, my Uncle Dick. Both would die of PKD, but Mike died first. He was just 35 when an aneurysm killed him, leaving two young kids behind.

Mike's death shocked me. We had grown up together, sneaking into movies, teasing each other about sports and politics. His death also brought my life into focus. I vowed to do all I could to help cure this disease before it took more of us.

Upside #2: A greater sense of purpose.

By telling Mike's story in email, I raised more than $10,000 for the following year's Walk for PKD. That brought me to the attention of a PKD Foundation volunteer who told me about a promising experimental drug.

As part of an ongoing trial, I've been taking that drug, tolvaptan, for 10 years. Its existence convinced me that it would be ethical for me to get married and have kids -- even though each of my kids would have a 50 percent chance of inheriting these kidneys.

Which leads me to upside #3: My wife, Victoria, who's up there with our little 5-month-old. She's sort of back in the shadows trying to keep the baby from being too loud. By our fourth date, I knew that I liked Victoria a lot, and so I knew I had to tell her about the disease. She took it extremely well. That was a lot for us to learn about each other on date #4. Usually fourth dates focus on... other things.

Upside #3: Learned something great, early, about future spouse.

Upside #4 is the deep generosity that I have received from just about everyone else.

When I email people about this, I'm asking somebody who has nothing to do with my disease -- and no chance of ever getting it -- to donate money to help cure it. What's in it for them? Here are four people, among many, who help anyway.

This is Steve Buchman. Each year he donates a large sum to support my Walk. The last time, I thanked him, and he said, "Look. For some reason, Bill, I get selfish pleasure from doing this. So you don't need to thank me. [Pause.] But you're welcome."

Angela Olivo is part-owner of Select Office Suites, which rents office space to small businesses in New York. It's been years since I was her tenant. Yet Angela and SOS generously support my Walk every year. She is a lovely woman. And I would never have known how lovely if I hadn't asked her for help.

That's my friend David Simons and me. When that photo was taken, David knew that he was dying of colon cancer. He died a few weeks after that photo was taken -- six years ago today, in fact. In his will he left $10,000 to the PKD Foundation in my name -- to cure a disease that he did not have. There are no words for how it felt when I learned that, that he had done that. And this past January, David's mom, Pat Bonardi, without my asking her, donated to my upcoming PKD Walk. Now this is a woman who has had the worst loss any parent can have -- but it was to cancer, not PKD. Yet she is supporting us, without ever being asked.

If I didn't have PKD, I would never have asked these people for support. And I probably would never have imagined that anyone could give as generously as these four people, and so many others, including some in this room, have done.

Upside #4: People have been so generous. How can I ever be cynical again?

Then the PKD helped me experience something very unexpected: I found out what it must feel like to be Brad Pitt.

Some friends made me a kidney costume. I first wore it to an evening benefit at a Manhattan museum where nobody knew me.

En route to the benefit, alone in a cab at night, I felt very anxious and insecure. I wasn't sure it was a good idea at all, and I expected some attendees to ridicule me. And then I thought about my young nieces, who may develop this disease as well. I knew that the costume would make them smile, and I told myself I was wearing it for them.

When I walked in, feeling odd, three lovely young women ran toward me, and said, "Oh, please, please -- will you please take a picture with us?"

A gorgeous woman said to me, "What are you?" I said, "I'm a kidney, darling, what are you?" She said, "I'm just a girrrrl."

And as I was leaving, another beautiful woman took off her heels, ran barefoot on cobblestones, crashed into my foam and said, "You have to come to our afterparty. I don't know you, but you're the only real thing here."

Upside #5: Got to feel like a sex symbol.

I skipped the afterparty. I went home and, like Cinderella, became normal again. I'm a happily married father of three lovely girls, and I never need to feel like Brad Pitt again.

I swear.

Thank you, Kim Harris Gardner, for inviting me to focus on the good things that have come out of this disease. And thank you all for listening. When I had just been diagnosed, and was looking out the dorm window, I may have seen some of you walking by. I didn't think then that I would be able to see you again, when I was 47 years old. But I'm seeing you now. Thank you for being here.

I welcome your help at support.pkdcure.org/goto/billbrazell. To learn more about PKD and join the fight, please visit The PKD Foundation. Thank you.

From Medical Marijuana Inc

Polycystic Kidney Disease – Medical Marijuana Research Overview

Polycystic kidney disease is an inherited kidney disorder that causes abnormal cysts to develop and grow. Studies have shown cannabis reduces kidney damage and helps manage side effects like high blood pressure and pain.
Overview of Polycystic Kidney Disease

Polycystic kidney disease (PKD) is an inherited disorder that causes clusters of cysts to grow in the kidneys. The cysts are filled with fluid and can enlarge the kidneys, replacing much of their normal structure. The abnormal shape leads to chronic kidney disease, which can then over time lead to reduced kidney function and even kidney failure. While most cysts develop in the kidneys, PKD cysts can also develop in the liver and elsewhere throughout the body.

Polycystic kidney disease is caused by genetic defects that are inherited. In rare cases, a mutated gene can be the cause of the disease. There are two types of polycystic kidney disease, each of which is caused by different genetic flaws. The most common type is autosomal dominant polycystic kidney disease (ADPKD), which typically develops between the ages of 30 and 40 and requires only one parent to have the abnormal gene. Autosomal recessive polycystic kidney disease (ARPKD) is a less common type of PKD that typically develops shortly after birth or during childhood. Both parents must have abnormal genes for this type of disease.

PKD commonly causes high blood pressure. Other symptoms caused by the disease include back or side pain, headaches, blood in urine, an increase in abdomen size, frequent urination, kidney stones, urinary tract or kidney infections and kidney failure. Brain aneurysms, heart valve abnormalities, colon problems and chronic pain can also develop from the disease.

There is no cure for polycystic kidney disease, but lifestyle changes and medical treatments can help reduce kidney damage and manage blood pressure. By controlling high blood pressure, the progression of the disease and subsequent kidney damage can be delayed. Medication is often used to manage chronic pain. Additional treatments are necessary if bladder or kidney infections, blood in the urine, kidney failure or aneurysms, develop.
Findings: Effects of Cannabis on Polycystic Kidney Disease

While clinical studies on cannabis’ effect on polycystic kidney disease are lacking, findings in preclinical studies suggest cannabinoids found in cannabis could offer therapeutic benefits for treating kidney disease. One animal study found that a major cannabinoid found in cannabis, cannabidiol (CBD) effectively reduced oxidative stress, inflammation and cell death in the kidney and improved renal function, causing the researchers to conclude CBD may be effective at preventing kidney disease (Pan, et al., 2009). These protective effects of CBD are likely due to its activation of the endocannabinoid system’s CB2 receptors, which another study found was effective at protecting the kidney from damage by minimizing inflammation and oxidative stress (Mukhopadhyay, et al., 2010).

Cannabis may also limit kidney damage caused by polycystic kidney disease by potentially lowering blood pressure. Both animal and human studies have found that cannabinoids cause blood vessels to vasodilate, which in turn improves blood flow and reduces blood pressure (Stanley & O’Sullivan, 2014a) (Stanley & O’Sullivan, 2014b) (Herradon, Martin & Lopez-Miranda, 2007) (Batkai, et al., 2004). CBD specifically has shown provide vasodilation, which researchers found allowed for greater blood flow and reduced damage (Stanley, Hind & O’Sullivan, 2013).

In addition, cannabis can help polycystic kidney disease patients manage their chronic pain levels. Cannabis has been shown to significantly lower both neuropathic and nociceptive pain; even managing chronic pain that had previously proven refractory to other treatments (Boychuck, Goddard, Mauro & Orellana, 2015) (Wallace, et al., 2015) (Lynch & Campbell, 2011). Because of cannabis’ effectiveness, surveys have found that use is prevalent among those experiencing chronic pain (Ware, et al., 2003). In one study, 12 of 15 chronic pain patients who smoke herbal cannabis reported an improvement in pain (Ware, Gamsa, Persson & Fitzcharles, 2002). Cannabis has also been shown to offer a therapeutic role for headaches, which are common in those with polycystic kidney disease (Baron, 2015).
States That Have Approved Medical Marijuana for Polycystic Kidney Disease

Currently, no states have approved medical marijuana specifically for the treatment of polycystic kidney disease. However, in Washington DC, any condition can be approved for medical marijuana as long as a DC-licensed physician recommends the treatment. In addition, a number of other states will consider allowing medical marijuana to be used for the treatment of polycystic kidney disease with the recommendation from a physician. These states include: California (any debilitating illness where the medical use of marijuana has been recommended by a physician), Connecticut (other medical conditions may be approved by the Department of Consumer Protection), Massachusetts (other conditions as determined in writing by a qualifying patient’s physician), Nevada (other conditions subject to approval), Oregon (other conditions subject to approval), Rhode Island (other conditions subject to approval), and Washington (any “terminal or debilitating condition”).

Also, 14 states have approved medical marijuana specifically to treat “chronic pain,” a symptom commonly associated with polycystic kidney disease. These states include: Alaska, Arizona, California, Colorado, Delaware, Hawaii, Illinois (Chronic Post-Operative Pain), Maine, Maryland, Michigan, Montana, New Mexico, Oregon, and Rhode Island. The states of Nevada, New Hampshire and Vermont allow medical marijuana to treat “severe pain.” The state of Washington has approved cannabis for the treatment of “intractable pain.”.

PKD Research

From The American Society for Cell Biology

A new gene editing technique turns human pluripotent stem cells into a model system for polycystic kidney disease

CRISPR/Cas9 is hot. News of the revolutionary gene editing technique that is already shaking up bioscience has finally reached the news media and the public. Now comes a first rate example of how CRISPR is changing the pace of biomedical research by linking up with another cutting edge technology—human pluripotent stem cells (hPSCs). Benjamin S. Freedman, now at the University of Washington, and his colleagues in Joseph Bonventre’s lab at Harvard Medical School, have used CRISPR/Cas9 to guide hPSCs into becoming a human cell-based lab model system for polycystic kidney disease (PKD). The most common inherited kidney disorder, affecting one in 500 Americans, PKD currently is not curable and, without long-term dialysis or kidney transplant, can be fatal. Freedman will speak about the PKD model at ASCB 2015 in San Diego on Monday, December 14, following its earlier publication in Nature Communications.

PKD’s hallmark is the formation of damaging, balloon-like cysts in kidney tubules. In the early 2000s, cell biologists linked cyst formation to gene mutations that affect the primary cilia, hair-like projections from cells that seem to act as sensory antennae. These fundamental discoveries were made in non-human organisms such as the algae,Chlamydomonas reinhardtii, and the zebrafish, Danio rerio. But the exact disease mechanism in humans is still not well understood in part because there hasn’t been a good human model of PKD in kidney cells.

CRISPR gave Freedman et al. a more precise tool to remodel the hPSC genome to include PKD mutations in the disease-linked genes, PKD1 and PKD2. The researchers then used a 3-D cell culture system to coax their mutant and healthy hPSCs down the differentiation pathway into becoming kidney progenitor cells and finally the proximal tubule cells found in kidney nephrons. In the mutant tubule cells, they observed the formation of large, translucent cyst-like structures but not in their healthy controls. These observations and others have convinced the researchers that their CRISPR/Cas9 and hPSC system produces a stable, biologically accurate human model for a common genetic disease where new understanding and new therapies are desperately needed.

From Rutgers University, By Robin Lally

Healthy or Sick? Tiny Cell Bubbles May Hold the Answer

Rutgers researchers provide insight into genes that can spread cancer or heal wounds


Rutgers scientists have uncovered biological pathways in the roundworm that provide insight into how tiny bubbles released by cells can have beneficial health effects, like promoting tissue repair, or play a diabolical role and carry disease signals for cancer or neurodegenerative diseases like Alzheimer’s.

In a new study, published in Current Biology, Rutgers scientists isolated and profiled cells releasing these sub-micron sized bubbles, known as extracellular vesicles (EVs), in adult C. elegans and identified 335 genes that provide significant information about the biology of EVs and their relationship to human diseases.

They and colleagues from Princeton University, the University of Oxford and Albert Einstein College of Medicine, determined that 10 percent of the 335 identified genes in the roundworm regulate the formation, release, and possible function of the EVs. Understanding how EVs are made, dispersed and communicate with other cells can shed light on the difference between EVs carrying sickness or health.

“These EV’s are exciting but scary because we don’t know what the mechanisms are that decide what is packaged inside them,” said Maureen Barr, lead author and a professor in the Department of Genetics in Rutgers’School of Arts and Sciences. "It’s like getting a letter in the mail and you don’t know whether it’s a letter saying that you won the lottery or a letter containing anthrax.”

For decades scientists believed that the EV material released by some human cells – which can only be seen through high-tech electron microscopes – was nothing more than biological debris.

While this theory has changed – with researchers now having a better understanding of the role these EVs play in cancer, infectious diseases and neurodegenerative disorders – scientists still aren’t certain how they are made or why the same parcels can result in different outcomes.

But Barr said by using C. elegans, which have many genes similar to humans, Rutgers scientists have identified new pathways that could control the production of EVs and the cargo they carry, including the proteins responsible for polycystic kidney disease, the most commonly inherited disease in humans. The polycystic kidney disease gene products are secreted in tiny EVs from both humans and worms and no one knows why these proteins are in the EVs, she said.

“The knowledge gained from this tiny worm is essential for determining the biological significance of EVs, for understanding their relationship to human diseases like polycystic kidney disease, and for harnessing their potential therapeutic uses, “Barr said.

Because EVs are found in bodily fluids like urine, blood and cerebral spinal fluid, Barr said it is nearly impossible to determine the cellular source from which they are derived. This is why very little is known about how EVs are made and how the molecular cargo is released.

By understanding how a cell makes and packages proteins, lipids and nucleic acids into EVs, Barr said, pharmaceutical treatments and therapies could be developed, for instance, that would prevent cancer cells from producing EVs carrying cargo necessary for tumor growth.

“When we know exactly how they work, scientists will be able to use EVs for our advantage,” said Barr. “This means that pathological EVs that cause disease could be blocked and therapeutic EVs that can help heal can be designed to carry beneficial cargo.”

From Renal and Urology News, by Jody A. Charnow, Editor

Severe Hyperkalemia Rare Despite Dual RAAS Blockade

Severe hyperkalemia rarely occurs as a result of dual blockade of the renin-angiotensin-aldosterone system (RAAS) or intensive blood pressure (BP) control, according to a study.

Ronald D. Perrone, MD, of Tufts Medical Center in Boston, and colleagues analyzed the frequency and severity of hyperkalemia in the HALT-PKD trial, a prospective, randomized study designed to determine the effects of dual RAAS blockade and BP reduction on progression of autosomal dominant polycystic kidney disease.

The trial had 2 study groups. Study A participants had an estimated glomerular filtration rate (eGFR) greater than 60 mL/min/1.73 m2. These patients were randomly assigned to receive lisinopril plus placebo or lisinopril plus telmisartan, with 2 levels of BP control: standard BP (SBP, 120–130/70–80 mm Hg or low BP (LBP, 95–110/65–75 mm Hg). Study B included patients with an eGFR of 25–60 mL/min/1.73 m2 randomized to lisinopril plus placebo or lisinopril plus telmisartan, with SBP control only.

Hyperkalemia rarely developed in study A participants. Mild hyperkalemia (potassium levels higher than 5.5 but not more than 6 mEq/L) occurred in 3%, 1%, 3%, and 2% of subjects in the lisinopril/telmisartan, lisinopril/placebo, SBP, and LBP arms, respectively, Dr. Perrone's group reported at Kidney Week 2015 in San Diego. Moderate hyperkalemia (potassium levels higher than 6 but not more than 6.5 mEq/L) developed in 2%, 0.4%, 1%, and 1%, respectively. Severe hyperkalemia (potassium levels above 6.5 mEq/L) developed in 0.4%, 0%, 0%, and 0.4%.

Mild hyperkalemia was more common among study B participants, but it was easily managed, according to the investigators. It occurred in 17% of the lisinopril/telmisartan arm and 16% of the lisinopril/placebo arm. Moderate hyperkalemia developed in 4% and 12%, respectively, and severe hyperkalemia developed in 0% and 0.4%, respectively.

“With careful management, dual RAAS blockade and intensive BP control were safe in the HALT PKD trial,” the researchers concluded in their study abstract.

Gift of Life

From Tap Into Morristown, Summit, NJ, By GREG ELLIOTT

Summit Man's Selfless Act Gives New Hope, Gift of Life to Girlfriend's Mother

Hilltop City resident Dana Henderson and Lauren Karsen have been a couple for just over a year now.

Henderson — a Summit High School Class of 2000 alum — is giving a unique anniversary present to Karsen, who is a records clerk with the Summit Police Department.

Henderson's gesture of love to his significant other?

Flowers? No. A heart-shaped box of chocolates? Uh-uh.

Henderson is donating a kidney to Lauren's mom, Karen, who has Polycystic Kidney Disease (PKD), a hereditary disease that, according to atlantichealth.org, is passed down through families and in which many cysts form in the kidneys, causing them to become enlarged.

Symptoms often do not appear until middle age, with statistics showing 1 in 1,000 Americans are affected with PKD, however the actual number may be more, because some people do not have symptoms.

Persons with PKD have many clusters of cysts in the kidneys. What exactly triggers the cysts to form is unknown. The disease is associated with the aortic aneurysms, brain aneurysms, cysts in the liver, pancreas, and testes, and diverticulaof the colon.  Currently, no preventative treatment can prevent the cysts from forming or enlarging, and the disease gets worse slowly. Eventually it leads to end-stage kidney failure, the treatments for which may include dialysis or a kidney transplant.

Henderson, a Muhlenberg College nursing student with two semesters remaining, works full-time as a patient care technician at Overlook Medical Center in Summit. He also volunteers one day each week at the Summit Volunteer First Aid Squad.  His passion for, and proximity to, the medical profession is allowing him to face what is undeniably an emotional and personal journey with a high degree of logic. "I am pretty confident, I have a lot of faith in modern medicine, and transplants in particular."

One of the body's miraculous capabilities is that the lone remaining kidney essentially takes on twice the functioning capacity, making up for the organ that was removed.  When Karen was diagnosed this past February she, like many who find out they have the disease, had no symptoms. At 61, she is in otherwise good health, which makes transplant an more viable option.

"It's all been crazy," said Henderson. "Once we found out, it was like 'who's gonna step up?" Tested for compatibility, Henderson was not the lone option, but assumed that role once another compatible donor was ruled out for health reasons.

Further, If one parent carries the gene, their children have a 50% chance of developing PKD. Once her mother was diagnosed, Lauren and her sister had to get tested. Lauren does not have PKD however, unfortunately, her sister tested positive. Lauren will likely eventually be her sister's donor.

The procedure involving Henderson and Karen will be performed at St. Barnabas Medical Center in Livingston on December 1, appropriately a day that has been designated at #GivingTuesday and calls for folks to help causes and those less fortunate post-Black Friday and after Cyber Monday.

Assuming all goes smoothly, Henderson will be in the hospital for two to three days, and then face another 4-6 weeks of monitored recovery before being able to assume his normal routine.

Henderson's impending, amazing act of selfless giving does not, however, overshadow the fact that his rehab time will place him in some real financial hardship, as his full-time work schedule allows him to pay for his schooling.  Prodded by others, the low-key Henderson finally relented and established a gofundme page, which is collecting donations to make up for his lost wages. In true form, Henderson placed a goal figure on the page of $1,500, which will not be enough to cover the wages he is foregoing. [Read more]