Sunday, June 25, 2017

PKD Research: Controlling Cysts with Peptides from Green Mamba Snake Venom, Being a Kidney Donor

PKD Research

From Proceedings of National Academy of Sciences, USA

Green mamba peptide targets type-2 vasopressin receptor against polycystic kidney disease


Significance

Polycystic kidney diseases (PKDs) are genetic disorders in which multiple cysts grow in kidneys, leading to end-stage renal failure. Vasopressin antagonists (vaptans) currently used to treat PKDs have side effects due to liver toxicity. We report the characterization of Mambaquaretin-1, a Kunitz-fold polypeptide isolated from mamba venom that selectively and fully inhibits three major signaling pathways of the vasopressin type-2 receptor. Mambaquaretin-1 induces a purely aquaretic effect on mice and reduces cyst development in a mouse model. We produced mambaquaretin-1 by peptide synthesis and determined its X-ray structure, its binding mode, and functional properties. With high selectivity and without toxic metabolic byproducts associated with its peptidic nature, mambaquaretin-1 could become the preferential treatment for these disorders.

Abstract

Polycystic kidney diseases (PKDs) are genetic disorders that can cause renal failure and death in children and adults. Lowering cAMP in cystic tissues through the inhibition of the type-2 vasopressin receptor (V2R) constitutes a validated strategy to reduce disease progression. We identified a peptide from green mamba venom that exhibits nanomolar affinity for the V2R without any activity on 155 other G-protein–coupled receptors or on 15 ionic channels. Mambaquaretin-1 is a full antagonist of the V2R activation pathways studied: cAMP production, beta-arrestin interaction, and MAP kinase activity. This peptide adopts the Kunitz fold known to mostly act on potassium channels and serine proteases. Mambaquaretin-1 interacts selectively with the V2R through its first loop, in the same manner that aprotinin inhibits trypsin. Injected in mice, mambaquaretin-1 increases in a dose-dependent manner urine outflow with concomitant reduction of urine osmolality, indicating a purely aquaretic effect associated with the in vivo blockade of V2R. CD1-pcy/pcy mice, a juvenile model of PKD, daily treated with 13 μ𝝁g of mambaquaretin-1 for 99 d, developed less abundant (by 33%) and smaller (by 47%) cysts than control mice. Neither tachyphylaxis nor apparent toxicity has been noted. Mambaquaretin-1 represents a promising therapeutic agent against PKDs.




From Live Science, By Agata Blaszczak-Boxe, Contributing Writer

Snake Solution: Dangerous Venom Could Fight Kidney Disease





The venom of the green mamba — one the most dangerous snakes in Africa — might one day help to treat people who have a genetic disorder that affects the kidneys, according to a new study conducted in mice.

The disorder, called polycystic kidney disease, causes numerous cysts to grow in the kidneys. The disorder may lead to kidney damage, according to the National Kidney Foundation. But for babies born with a severe form of the disorder, the condition can also be deadly, according to the National Institute of Diabetes and Digestive and Kidney Diseases.

However, the new study was done in mice, and it is not clear yet if the venom compound may work to treat this disease in people who have the condition, said study author Nicolas Gilles, a venom researcher at the University of Paris-Saclay in France. Further studies are needed to look at this, he said.

Treatments that are currently available for polycystic kidney disease may help to alleviate some of its symptoms, such as high blood pressure, but there is currently no cure for the disease, the National Kidney Foundation says.

Green mamba bites may cause dizziness, nausea and irregular heartbeat, and can be fatal. In the new study, the researchers first extracted one compound from the venom, called mambaquaretin-1, according to the study, published today (June 19) in the journal Proceedings of the National Academy of Sciences.

The researchers then administered the venom compound to six mice with the kidney disease every day for 99 days. The study also included a group of control mice with the condition, which were instead given saline solution every day for 99 days. The mice that were given the compound seemed to tolerate it well, as the animals did not change their behavior during the experiment, the researchers said.

At the end of the experiment, the researchers measured the levels of markers for kidney function in all of the mice. Based on these measurements, the researchers concluded that the mice treated with the venom compound had better kidney function than the mice in the control group.

The number of cysts in the mice treated with the compound was reduced by one-third, the researchers found. The researchers also found that the ratio of cyst area to normal kidney tissue area decreased by 28 percent in the mice treated with the compound. Moreover, the total area of kidney cysts was reduced by 47 percent after the treatment, the scientists found. [Pick Your Poison: 7 Ways Venom Can Be Healing]

The compound seems to work by targeting the action of a receptor called the type-2 vasopressin receptor, which is involved in the disease, the researchers said.

So far, researchers have not looked at using venom from this snake to treat any other condition, Gilles told Live Science. However, based on this and other research, it is becoming more and more clear that, besides being rich in toxins, venoms are also a source of molecules that can target certain receptors in the body that are involved in human health, he said.




Making a Gift of Life

From The Conversation

A quarter of kidney donors are living: what you need to know to be a donor


At any one time, more than 1,400 Australians are on an organ transplant waiting list. The most common organs in demand are kidneys, followed by the liver and lung.

While the number of deceased organ donors in Australia has doubled since 2009, rates of live donor transplantation – where a person donates one kidney or, rarely, a portion of their liver – are relatively static.

In 2016, 265 Australians donated a kidney to a friend or relative, making up about a quarter of all kidney transplants. Live donor liver transplants are rare (only two occurred in Australia last year) and often donated from a parent to a child.

Who needs a kidney?

Kidneys filter toxins from the blood and regulate fluid balance. When kidneys are functioning so poorly a person needs dialysis to do the work for them, we say the person has “end stage kidney disease”.

In 2015, there were nearly 12,500 Australians undergoing dialysis. End stage kidney disease often occurs gradually and is commonly a result of diabetes, high blood pressure and types of autoimmune kidney disease called glomerulonephritis.

Many patients with end stage kidney disease would live longer and have a better quality of life following a kidney transplant compared to staying on dialysis. But the shortage of donor organs means preference is given to those likely to have better outcomes and reasonable life expectancy after transplantation.

Australian guidelines require patients have an 80% likelihood of survival at five years after transplantation to be eligible for the wait list. Tests are done to ensure the potential transplant recipient has acceptable heart health to undergo the operation, and that there are no cancers or infections that will be made worse by medications that suppress the immune system (“anti-rejection drugs”).

The donor’s kidney function is assessed, and the risk of them developing a kidney disease in future is evaluated. This is both to ensure the donor enjoys good kidney function after removal of their kidney, and that the recipient receives a well-functioning kidney. Donors also routinely undergo psychological evaluation.

Where do donors come from?

A potential recipient is encouraged to ask friends and family if they would be willing to donate a kidney. If not, the potential recipient can go on the deceased donor list to wait for a compatible kidney.

People often donate organs to their blood relatives, but it’s also possible to give a kidney to someone who is not related, such as a spouse or close friend. Some people use social media to solicit organ donations, and some have been successful. Specific matching sites also exist in countries such as the US, with the aim of getting healthy volunteers to altruistically donate a kidney.

But methods of acquiring a donor who is previously unknown to the recipient are controversial and generally discouraged in Australia for ethical reasons. In Australia, a person could donate a kidney altruistically to someone on the waiting list. In this situation, the donor and recipient do not find out each other’s identity.

The Australian paired-exchange program allows greater numbers of live donor transplants to occur through paired kidney donor swaps. For example, if Jane’s potential donor John is unsuitable to give her a kidney because of matching issues, and Bob’s potential donor Barbara is unsuitable to give him a kidney, Barbara can donate a kidney to Jane, and John can donate a kidney to Bob.

Last year, an altruistic donation kicked off a domino chain of six paired-exchange donations, with the final kidney from a paired exchange donor going to a patient on the deceased donor waiting list.

Live donors must be over 18, but it’s preferable if they are over 30 as older age at donation minimises their chance of developing an unexpected condition that threatens their kidney health down the track.

Do you need to be a ‘match’?

Different people have different combinations of proteins on the surface of their cells that allow the immune system to determine what is part of the body (self) and what are foreign agents (non-self). These proteins are determined by genes called human leukocyte antigens (HLA).

The immune system is designed to recognise self HLA so it doesn’t target its own tissues. It is advantageous to have high degrees of HLA match (also called tissue match) between a donor and recipient, but it’s not absolutely necessary. A closer degree of HLA match means the immune system is less likely to reject the kidney.

Usually people need to be the same blood group to donate a kidney. But some living donor transplants can occur across different blood groups. These are called ABO incompatible transplantation. For this to happen, the recipient must undergo plasmapheresis – a process in which antibodies (proteins that attack foreign invaders) are removed from their blood and they are given strong medication to suppress the immune system.

Only people with end stage kidney disease can be listed for deceased donor transplantation. But living donor transplants can be “pre-emptive”, taking place before the need for dialysis.

This has advantages, such as not having to take time away from work or study to do dialysis. People who undergo pre-emptive transplantion have a lower risk of death and loss of kidney transplant function compared to people who spend time on dialysis before getting a transplant.

Are there risks to donors?

Kidney donors usually remain in hospital for a few days after surgery, which is usually conducted as “keyhole surgery”. This involves a camera and instruments being inserted through a small incision and the kidney being pulled out through it.

Full recovery time is around six to eight weeks. Complications, such as bleeding or blood clots, related to the operation are rare. There is a very small risk of death around the time of the operation, estimated at 3.1 in 10,000 donors, or 0.031%. Although the patient populations differ, this is less than for other minor operations such appendicectomy (estimated in a recent study at 0.21%).

There is no long-term increased risk of death or heart disease. Donating a kidney is likely to cause a slight increase in blood pressure over time.

After donation, the remaining kidney increases its capacity to filter blood, and kidney function usually returns to 70-80% of the previous level. This is adequate, and does not result in any symptoms related to kidney disease.

Studies comparing kidney donors to equivalently healthy non-donors found kidney donation increases risk of end stage kidney disease about three- to five-fold. But the risk is very low to begin with (around 0.06% for a white US man and 0.04% for a white US woman).

The kidney donation experience is usually positive. In one study, 95% of kidney donors in the US rated their experience as good to excellent. They reported an improvement in their sense of meaning in life and self-esteem. But a degree of psychological stress related to donation was common, and 20% reported a financial burden.

The Australian government gives A$4.1 million to run the Supporting Living Organ Donors program. This scheme includes reimbursing employers for sick leave for those who donate an organ, as well as other initiatives that aim to remove financial barriers to organ donation.

More information about living kidney donation is available at Donate Life, Kidney Health Australia, and the Supporting Living Organ Donors program.

Sunday, June 11, 2017

PKD and Coffee Consumption, Seeking PKD Charity Chair in UK

Living with PKD

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

Coffee Consumption Does Not Worsen ADPKD


Coffee consumption does not worsen the course of autosomal dominant polycystic kidney disease (ADPKD), researchers reported online ahead of print in the Journal of Nephrology.

Prior in vitro studies of human PKD cells identified caffeine as a risk factor for promoting cyst enlargement in ADPKD patients.

In a prospective longitudinal study of 151 ADPKD patients with a median follow-up time of 4.38 years, Laura Girardat-Rotar, of the University of Zurich in Switzerland, and colleagues found that coffee drinkers did not have a statistically significant difference in kidney size or estimated glomerular filtration rate compared with those who did not drink coffee.





From Charity Job UK

Chair of the Board of Trustees


Job Description

The role

The Polycystic Kidney Disease Charity is seeking to appoint a new Chair of Trustees to lead a dedicated and friendly Board and support our Chief Executive in delivering the Charity’s strategic aims. We need someone who shares our outward looking ethos and our commitment to collaborative working and is able to support this by representing us at appropriate events, meetings and functions.

A general background in strategy, governance, finance, HR or fundraising would be welcome, as would previous experience as a Chair or trustee.

About Us

The Polycystic Kidney Disease Charity is the only UK charity solely dedicated to the concerns of people affected by PKD - Polycystic Kidney Disease - a range of incurable, inherited, long-term, chronic conditions that can cause kidney failure and affect other organs in the body. We support those affected, their families and carers. We raise awareness and fund research.

We are a growing charity with an income of £204,000 in the last financial year to 31 March 2016. We have reserves of over £280,000, of which approximately 40% is restricted or designated for research.

The Charity is presently supported by a board of nine trustees and three professional contractors: one primary contractor provides chief executive services, acting as Chief Executive Officer (CEO), plus administrative and company secretarial services; the two others provide fundraising and support services, reporting to the CEO. The Charity additionally contracts out some ad hoc project work, for example medical writing and bookkeeping.

We are in the final stages of reviewing our Strategic Plan, based on information obtained via a survey of our supporters and stakeholders carried out in 2016. This will set out the Charity’s priorities for delivery over the next three years.

Role Profile

Overall Purpose of Role:
Provide leadership and direction to the Board of Trustees, including planning and chairing trustee meetings, and enable the Board to fulfil its responsibilities for the overall governance and strategic direction of the charity.
Ensure that the charity pursues its objects as defined in its governing document, charity law, company law and other relevant legislation/regulations.
Manage primary contractor providing Chief Executive services.
Represent the Charity at appropriate events, meetings and functions.

Responsibilities:

In relation to the Board
In conjunction with the Board of Trustees and CEO, formulate strategic plans and regular review of long-term strategic aims of the charity.
In conjunction with the Board of Trustees and CEO, develop organisational policies, define goals, targets and evaluate performance against agreed targets.
Approve the annual cycle of the board meetings, meeting agendas, chair and facilitate meetings, monitor decisions taken at meetings and ensure they are implemented.
Liaise regularly with the Treasurer to maintain a clear grasp of the charity’s financial position and to ensure full and timely financial transparency and information disclosure to the Board.
Lead and mentor other Board members to fulfil their responsibilities and enable access to training/coaching/information to enhance the overall contribution of the board.
Review as necessary the Board structure, role, contractor agreements and ensure implementation of agreed changes/developments.
Encourage team working among Board members and encourage them to identify and recruit new trustees as required.
Create an effective working relationship with trustees through review and evaluation of contributions and effectiveness of the Board.

Sunday, June 4, 2017

PKD Kidney Secret Search, PKD Effects on Heart and Brain

Living with PKD

From NBC Channel 10, Philadelphia, PA, By Megan Holmes

Mom, Daughter Secretly Search for Kidney for Dad


The Lewis family. Melissa is on the top left and Savannah is on the bottom right. Jay is found on the bottom left.

A secret search for a kidney is the journey Savannah Lewis and her mom Melissa Lewis are on. This mother-daughter duo is using social media to get the word out that Savannah’s father needs a new kidney without him knowing their plan.

Jason “Jay” Lewis, a 39-year-old father of six and a husband of 10 years to Melissa, 38, has stage five kidney failure due to polycystic kidney disease. Jay discovered he had polycystic kidney disease when he was 16. The disease is genetic and Melissa says unfortunately each kid has a 50-50 shot of getting it.

"I always pray that none of mine (kids) have it," she said.

Recently Savannah, 8, one of the couple's six children, made a video aiming to get “one million likes and shares” hoping to spread the word of the family's search for a "gift of life" as they call it.

The Scranton, Pennsylvania-based family has two different Facebook platforms they are using to get the word out, and Melissa’s husband still doesn’t know they’re “on the search for a living kidney donor.”

Originally, Melissa began the Kidney For Jay Give the Gift of Life Today Facebook page in March 2017. Her daughter Savannah wanted to help out. Savannah created her own Facebook page called Savannah’s Secret Gift of Life Search.

"We are searching the world for an extra special amazing person to give my husband his life back and be able to have the energy to watch our six kids grow up,” Melissa said.

Jay's has type B blood but can accept from an O. He is on transplant list at The Hospital of the University of Pennsylvania.

Although their search is a secret for now, Melissa was willing to risk it to get the word out there.

“For a great cause and if it will get the word out so it helps us to find a living kidney donor, I say go for it," she said.

Jay's mother, Cate, is also in need of a kidney transplant.

"I asked his mother if I can do the same (search through Facebook) for her and she wants to hold off on herself until her son gets one," Melissa said. "We all work for Davita dialysis -- me, my mother-in-law, and my husband."

Jay has been a biomed tech for over 20 years and has worked his way up.

“All of the units that Jay goes to... everybody at work has managed to keep it a secret," Melissa said.

While secret-keeping is doing well at home, there are plans to publicize even more out of view from Jay. Melissa's brother Scott Brunnenmeyer is putting up a billboard in Philadelphia off the turnpike in mid-June.

“It’s hard trying to keep one of the biggest secrets of a lifetime from your best friend," Melissa said. "But, so far, the world and I aren’t doing such a bad job at it.”





PKD Research

From Cleveland Clinic Journal of Medicine

Vinod Krishnappa, MBBS
Department of Nephrology, Cleveland Clinic Akron General/Akron Nephrology Associates, Akron, OH

Poornima Vinod, MD
Cleveland Clinic Akron General, Akron, OH

Divya Deverakonda
Biomolecular Science, NYU Tandon School of Engineering, Brooklyn, NY

Rupesh Raina, MD, FAAP, FACP, FASN, FNKF
Consultant Nephrologist, Adult-Pediatric Kidney Disease/Hypertension, Department of Nephrology, Cleveland Clinic Akron General and Akron Children’s Hospital, Akron, OH

Address: Rupesh Raina, MD, Cleveland Clinic Akron General, 1 Akron General Avenue, Akron, OH 44307; rraina@chmca.org; raina@akronnephrology.com

Autosomal dominant polycystic kidney disease and the heart and brain


ABSTRACT

Autosomal dominant polycystic kidney disease (ADPKD) has numerous systemic manifestations and complications. This article gives an overview of hypertension, cardiac complications, and intracranial aneurysms in ADPKD, their pathophysiology, and recent developments in their management.

KEY POINTS

Hypertension and left ventricular hypertrophy are common complications of ADPKD.
Cardiovascular disease is a major cause of morbidity and death in ADPKD.
Early diagnosis and aggressive management of high blood pressure, specifically with agents that block the renin-angiotensin-aldosterone system, are necessary to prevent left ventricular hypertrophy and progression of renal failure in ADPKD.
Timely screening and intervention for intracranial aneurysm would lessen the rates of morbidity and death from intracranial hemorrhage.


Autosomal dominant polycystic kidney disease (ADPKD) has significant extrarenal manifestations. Hypertension is a common complication, arises early in the course of the disease, and is implicated in the development of left ventricular hypertrophy. Patients with ADPKD are also at risk of other cardiovascular complications (Table 1).

This article reviews the timely diagnosis of these common ADPKD complications and how to manage them.


ADPKD ACCOUNTS FOR 10% OF END-STAGE RENAL DISEASE

ADPKD is a genetic condition characterized by multiple renal cysts.1Progressive enlargement of these cysts leads to a gradual decline in kidney function and eventually end-stage renal disease by the fifth or sixth decade of life.2 Worldwide, about 12.5 million people have ADPKD, and it accounts for about 10% of cases of end-stage renal disease.1,3,4

ADPKD has a variety of clinical presentations, including (in decreasing order of frequency) hypertension, flank pain, abdominal masses, urinary tract infection, renal failure, renal stones, and cerebrovascular accidents.2

Extrarenal complications are common and include hepatic cysts, hypertension, left ventricular hypertrophy, valvular heart disease, intracranial and extracranial aneurysms, pancreatic cysts, and diverticulosis.1–5

Less-common complications are dissection of the aorta and the internal carotid, vertebral, and iliac arteries6–10; aneurysm of the coronary, popliteal, and splenic arteries11–14; atrial myxoma15; cardiomyopathy16; pericardial effusion17; intracranial arterial dolichoectasia18; arachnoid cysts2; and intraoperative inferior vena cava syndrome (normally in ADPKD patients, pressure on the inferior vena cava results in compensatory sympathetic overactivity to maintain blood pressure), which occurs due to reduced sympathetic output under the influence of epidural or general anesthesia.19

Cardiovascular complications, especially cardiac hypertrophy and coronary artery disease, are now the leading cause of death in patients with ADPKD, as renal replacement therapy has improved and made death from end-stage renal disease less common.20,21


HYPERTENSION IN ADPKD

Hypertension is the most frequent initial presentation of ADPKD, occurring in 50% to 75% of cases and usually preceding the onset of renal failure.2,22 Hypertension is more common in male ADPKD patients, begins early in the course of the disease, and is diagnosed around the fourth decade of life.21

In a study in 2007, de Almeida et al23 used 24-hour ambulatory blood pressure monitoring early in the course of ADPKD and found significantly higher systolic, diastolic, and mean 24-hour blood pressures in ADPKD patients who had normal in-office blood pressure than in normotensive controls. In addition, nighttime systolic, nighttime diastolic, and nighttime mean blood pressures were significantly higher in the ADPKD group.

Hypertension is strongly associated with an accelerated decline in renal function to end-stage renal disease, development of left ventricular hypertrophy, and cardiovascular death.20,24

Although a prospective study25 showed a strong association between renal stones and hypertension in ADPKD, the relation between them is not clear. The incidence of renal stones is higher in hypertensive than in normotensive ADPKD patients, although evidence has to be established whether nephro­lithiasis is a risk factor for hypertension or the other way around.25

Hypertension in ADPKD is multifactorial (Figure 1). The major factors associated with its development are increased activation of the renin-angiotensin-aldosterone system (RAAS); overexpression of endothelin receptor subtype A (ET-A) in cystic kidneys; increased production of endothelin 1 (ET-1); and sodium retention.26–31
The renin-angiotensin-aldosterone system

Activation of the RAAS plays a major role in the development and maintenance of hypertension in ADPKD. This is thought to be mainly due to progressive enlargement of renal cysts, which causes renal arteriolar attenuation and ischemia secondary to pressure effects, which in turn activates the RAAS.26,30,32–34 Two studies in patients with normal renal function found that cyst growth and increasing kidney volume have a strong relationship with the development of hypertension and declining kidney function.35,36

Ectopic secretion of RAAS components in polycystic kidneys has also been implicated in the development of hypertension, whereby renin, angiotensinogen, angiotensin-converting enzyme (ACE), angiotensin II, and angiotensin II receptors are produced in the epithelium of cysts and dilated tubules in polycystic kidneys.37–39 Proximal renal cysts and tubules produce ectopic angiotensinogen, which is converted to angiotensin I by renin in distal renal cysts. Angiotensin I is converted to angiotensin II by ACE in distal tubules, which in turn stimulates angiotensin II receptors, causing sodium and water retention in distal tubules.37 This may be responsible for hypertension in the initial stages; however, RAAS hyperactivity due to renal injury may predominate during later stages.37

Increased RAAS activity also increases sympathetic output, which in turn raises catecholamine levels and blood pressure.34 A study showed higher levels of plasma catecholamines in ADPKD hypertensive patients irrespective of renal function than in patients with essential hypertension.40
ET-A receptor and ET-1

A few studies have shown that in ADPKD patients, increased density of ET-A receptors and overproduction of ET-1, a potent vasoconstrictor, play a significant role in the development of hypertension and gradual loss of kidney function due to cyst enlargement and interstitial scarring.28,29Ong et al29 found that expression of ET-A receptors is increased in smooth muscle cells of renal arteries, glomerular mesangial cells, and cyst epithelia in ADPKD.