PKD Research
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.
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
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
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.
