From Eureka Alert, MEDICAL UNIVERSITY OF SOUTH CAROLINA
Polycystic kidney disease develops when the message to generate cilia is 'lost in the mail'
IMAGE: KNOCKDOWN OF DYNAMIN-BINDING PROTEIN OR TUBA RESULTS IN ABNORMAL KIDNEY DEVELOPMENT AND OTHER ABERRANT PHENOTYPES IN ZEBRAFISH MODELS (MIDDLE AND RIGHT PANELS) COMPARED WITH CONTROLS (LEFT PANEL). view more
CREDIT: IMAGE COURTESY OF JOSHUA LIPSCHUTZ, M.D., OF THE MEDICAL UNIVERSITY OF SOUTH CAROLINA
In an article published online ahead of print on Feb. 19, 2015 in the Journal of Biological Chemistry (JBC), investigators at the Medical University of South Carolina (MUSC) and the Ralph H. Johnson VA Medical Center report findings from in vitro and in vivo studies that elucidate the mechanisms underlying the impaired ciliogenesis and abnormal kidney development characteristic of polycystic kidney disease (PKD). Depletion of dynamin-binding protein or Tuba, a guanine nucleotide exchange factor, disrupted renal ciliogenesis in cell culture and led to abnormal kidney morphology in a Tuba knockdown zebrafish model of PKD.
Currently, no drug has been approved by the U.S. Food and Drug Administration to treat autosomal dominant PKD, which affects a half million Americans and more than 12 million people worldwide. The disease is characterized by the development of fluid-filled cysts in both kidneys, leading to end-stage renal disease, usually around age 50 to 60. In PKD, it is speculated that dysfunctional cilia are unable to detect the presence of urine flow, triggering reactivation of developmental pathways, which lead to the uncontrolled production of cysts that eventually destroy the kidney.
Cilia, the finger-like protrusions on most epithelial cells, were not so long ago thought to be as irrelevant to cell biology as the appendix is to physiology, a vestigial remnant of a long ago evolutionary past. Today, they are recognized as essential chemo-mechanical sensors that monitor and regulate what crosses into and out of a cell.
Dysfunctional cilia are now known to be implicated in not only PKD but a wide range of diseases affecting the eyes, ears, heart, and other organs. Understanding how cilia become dysfunctional in these diseases could provide insight into how to better treat or prevent them.
"How are cilia made? If you know that, you can figure out what goes wrong in ciliopathies, including polycystic kidney disease," says nephrologist Joshua H. Lipschutz, M.D., the senior author on the article, who holds a dual appointment at MUSC and the Ralph H. Johnson VA Medical Center.
Much must go right for ciliogenesis to occur. Proteins necessary for ciliogenesis are manufactured in the endoplasmic reticulum before traveling to the trans-Golgi network to be sorted into "zip-coded packages" or vesicles for transport to the cilia. Lipschutz and others previously showed that the exocyst, a protein targeting complex, plays a crucial role in receiving these "zip-coded packages" containing ciliary proteins. The GTPase Cdc42 regulates the exocyst, which is the mailbox where these "packages" are received in the kidney. Renal ciliogenesis occurs only when the packaged proteins are delivered to the Cdc42-activated exocyst complex. Depleting either the exocyst or Cdc42 disrupts renal ciliogenesis.
In the JBC article, Lipschutz and his MUSC coauthors go a step further -- showing in cell culture and a zebrafish model that depletion of Tuba, a guanine nucleotide exchange factor required for Cdc42 activation, also disrupts renal ciliogenesis. Tuba is thought to ensure that the Cdc42/exocyst mailbox is in place at the base of the cilia and ready to receive the packaged proteins. Without Tuba, Cdc42 is not appropriately activated, and the exocyst is mislocalized, so the undelivered packages continue to pile up, perhaps playing a role in the uncontrolled production of renal cysts in PKD.
When grown in a collagen gel, Madin-Darby canine kidney (MDCK) cells form into cysts, and the orientation of proteins, called polarity, are abnormal following Tuba knockdown. Specifically, apical proteins that would normally face the urinary space are mislocalized throughout the cell.
In zebrafish, injection of low doses of both Tuba and Cdc42 antisense morpholinos, which had no effect when administered separately, led to severe phenotypes similar to those seen following knockdown of other ciliary proteins. This is called genetic synergy and provides further evidence that both Tuba and Cdc42 are part of the same pathway. Because knockdown of Tuba in zebrafish affects cilia in a number of organs, including the brain, a variety of aberrant phenotypes were seen in the Tuba knockdown zebrafish model.
Lipschutz, who directs the zebrafish core at MUSC along with co-author Seok-Hyung Kim, Ph.D., is well aware of the advantages of the zebrafish for research -- its genome is well characterized, it can be bred rapidly and inexpensively, and its transparent body enables easy visualization of aberrations under microscopy. However, the next step in this line of research will be to study the effects of Tuba depletion in the kidneys of mice, since murine kidneys are more like human kidneys than those of zebrafish.
Once the pathways underlying impaired ciliogenesis in PKD are more fully understood, therapeutic interventions can be designed to disrupt those pathways. As Lipschutz notes, "We do this research to help our patients. Further elucidating the pathways that underlie impaired ciliogenesis is an essential step in beginning to develop treatment options for PKD and other ciliopathies."
Living with PKD
From Daily Mail, United Kingdom, By CHLOE LYME FOR MAILONLINE
Yu Gongmao from Wuhan city was diagnosed with polycystic kidney disease at the age of 30, over the years his health has deteriorated and he developed uraemia, reports the People's Daily Online.
Despite having to undergo intense treatment three times a week, he continues to teach sitting on his knees as he is too weak to stand. The 41-year-old was pictured giving classes at Wuhan University on March 11.
In 2012 professor Yu passed out in class and was immediately rushed to hospital where doctors found a tumour in is brain. He was operated on which was successful, but his health continued to worsen.
Unfortunately he was left with bad eyesight in his left eye, a result of the operation.
After relapsing in 2014 he was told his kidneys were failing, he is now awaiting a kidney transplant.
He receives dialysis three times a week, both of his kidneys have problems leading to uraemia.
Speaking to the People's Daily, professor Yu said he will 'keep teaching until I collapse in class'.
Since he became ill, professor Yu - who works at the Department of English at the university - has suffered from severe weight loss, dropping to around 120 pounds.
In a week, professor Yu teaches more than ten classes on his knees as he is too weak to stand. He even works as a translator and a tour guide when he is not teaching.
He said he loves to interact with his students, but the disease makes it difficult to give them the physical support they need. [Read more]
Dialysis does not significantly improve survival for elderly kidney failure patients, a new study indicates.
The findings suggest that conservative care may be a reasonable option for some kidney failure patients over 80.
The researchers don't say that dialysis treatment should not be given to anybody older than 80 or with severe co-occurring conditions. "But we show that the treatment is on average of little advantage regarding survival," said study co-leader Dr. Wouter Verberne of St. Antonius Hospital in Nieuwegein, the Netherlands.
The findings were published online March 17 in the Clinical Journal of the American Society of Nephrology.
"Our next task is to predict who benefits and who does not," Verberne said in a journal news release. "Until we are able to give a better prediction of the results of dialysis treatment at high age, we can merely suggest that conservative management is an option which should honestly be discussed when [kidney failure] is approaching."
Conservative therapy includes controlling fluid and electrolyte balance, treating anemia, and offering suitable comfort and end-of-life care.
In this study, researchers examined outcomes among older kidney failure patients in the Netherlands who received either dialysis (204 patients) or conservative care (107 patients). Among those over age 80, the investigators found no statistically significant difference in survival between dialysis and conservative care.
Overall, patients with other health problems died sooner than those without additional medical issues, the study authors reported.
Further research is needed to assess how different treatment options affect patients in other ways, such as quality of life and severity of symptoms, Verberne concluded in the news release.
Kidney Transplant
Incompatibility between donor and recipient is the biggest barrier to successful transplants. If the recipient’s immune system attacks the organ, then the transplant fails. Finding a successful match between non-related people is a one in 100,000 chance, according to Popular Science.
Desensitization works by filtering antibodies from the patient’s blood, which suppresses the immune response against the foreign kidney. During the eight-year study from Johns Hopkins University School of Medicine, patients undergoing desensitization treatments were pitted against folks who received kidneys from compatible donors, and those who remained on dialysis. The results were telling: About 76% of desensitization patients were still alive after eight years compared to 44% of those who stayed on dialysis. The desensitization process even beat out compatible donations—only 63% of those receiving a compatible organ survived.
This is significant because at any given time there are around 20,000 people waiting for kidneys who are "highly sensitized and for whom finding a compatible donor is nearly impossible," says the study’s lead author Dorry Segev. "That’s a lot of people who could have a better chance at surviving if they are allowed to move forward with incompatible live donor transplantation."
The process has been in experimental use for 15 years, but this is the first nationwide study to assess the benefit to patients. The idea is to push the process into regular use. One barrier to this might be cost. Desensitization, as an ongoing process, is expensive. But not, crucially, as expensive as dialysis. "Incompatible transplantation is essentially one-tenth of the price of dialysis for a patient stuck on the wait list," Segev says in a news release.
Also, by essentially making incompatible organs compatible, waiting times can be cut. "During the wait for a compatible organ, the patient gets sicker and sicker. This can become costly—physically, emotionally and financially—for the patient and his or her loved ones," says Segev.
What the study shows is that transplant recipients are twice as likely to survive using desensitization than with their next best option. Those are convincing numbers, and because they are gathered from multiple facilities across the country, they make a good case for more widespread use of the technique.
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