Researchers at Harvard Medical School and Joslin Diabetes Center have discovered that high levels of tumor necrosis factor (TNF) receptors found in the blood of patients with Type 1 and Type 2 diabetes may predict incidence of chronic kidney disease and kidney failure years later. TNF proteins can trigger inflammation, which has been linked to the development and progression of diabetic kidney disease, but the researchers don’t know if this is the reason why TNF receptors are increased in some patients. They hope to learn more about the connection, which could result in a diagnostic test and improved therapies for high-risk diabetes patients.

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Proteins May Warn of Diabetic Kidney Disease Risk, Science News, February 11, 2012

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Scientists from Singapore and China studying people of Han Chinese descent have identified genes and regions in the human genome that increase susceptibility to IgA nephropathy.  The researchers believe the genes could also play a role in the development of clinical symptoms and their severity. Lead scientist, Dr. Yu Xueqing said, “These findings offer us opportunities to identify important biological pathways involved in IgAN development and further explore novel approaches to intervene and thus prevent affected patients from developing severe kidney damage.”

IgA nephropathy occurs when immunoglobin A, an antibody that helps fight infections, builds up inside the blood vessels of the kidney, causing inflammation. The disease affects people differently. Some experience occasional blood in the urine, while others suffer decreased kidney function and often kidney failure. IgAN is a leading cause of kidney failure among Asian populations and usually affects males in their teens to late 30′s.

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Scientists Unravel Kidney Disease Susceptibility Genes in Asian Genomic Study, Asian Scientist, January 4, 2012

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Researchers at the University of Texas Health Science Center San Antonio may have discovered an important medical use for hydrogen sulfide, the toxic, colorless gas that smells of rotten eggs. Their experiment focused on kidney cells exposed to high glucose levels. In diabetes patients, prolonged, uncontrolled blood glucose levels can lead to scarring of the kidneys. The UT researchers found that introducing hydrogen sulfide to the kidney cells resulted in decreased production of damaging proteins that cause kidney scarring. Interestingly, the human body produces small amounts of hydrogen sulfide naturally. The researchers reported that mice with Type 1 and Type 2 diabetes produce fewer kidney enzymes known to aid in the production of hydrogen sulfide. Future research will be needed to determine whether the gas, which is poisonous in higher concentrations, can be used safely and effectively in animals and humans.

Source:

Hydrogen Sulfide Reduces Glucose-Induced Injury in Kidney Cells, Science Daily, January 3, 2012

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This has been a big week for stories about innovative approaches to organ donation. Last Sunday, the New York Times featured an amazing story about 60 people linked by a transplant chain that changed the lives of 30 patients with kidney disease. It all began with one man inspired by an acquaintance who had recently donated a kidney to a friend. – Lives Forever Linked Through Kidney Transplant Chain

A new program in Israel will give transplant priority to patients who are signed up to be organ donors. – In Israel, A New Approach to Organ Donation

Some transplant hospitals are using “less than perfect” organs to save lives. “When so many people are waiting, we need to be more creative in our use of organs,” says Dr. Darla Granger, transplant surgeon at St. John Hospital and Medical Center in Detroit. – Organs From Less-Than-Ideal Donors Are Saving Patients’ Lives

Another New York Times story contains fascinating insight into the current state of transplantion in the United States. Experts agree a national registry would maximize the number of kidney transplants through donation chains. But will we ever have one?  – Lack of Unified System Hampers Kidney Transplants

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Scientists studying the mechanisms behind cell adhesion have made some significant discoveries about the factors that influence podocyte survival. The kidney filter barrier is made up of podocyte cells with long foot-like projections that wrap around the capillaries of the glomerulus. The slits between these projections allow smaller molecules like salts, water and sugar to pass, while preventing larger molecules such as proteins from leaving the blood stream. Podocytes undergo significant physical stress as blood is pushed through the filter barrier. A receptor called integrin a3ß1 ensures that podocyte cells remain tightly bound to the glomerular basement membrane.

Researchers from the Netherlands Cancer Institute in Amsterdam explored the link between a3ß1 and a protein called CD151, which is strongly expressed in podocytes.  They showed that CD151 and a3ß1 interact and that CD151 is involved in adhesion strengthening.  They studied mice lacking CD151 in podocytes and discovered that the mice developed glomerulosclerosis. They also suffered from kidney abnormalities, including unusually broad foot processes and irregular thickening of the glomerular basement membrane. They found that mice lacking global CD151 were not necessarily susceptible to renal disease unless they had a genetic predisposition. They reasoned that because the mice lacked CD151, their podocytes would be more loosely bound and unable to withstand increased mechanical stress. They proved the theory by increasing blood pressure and filtration pressure, which induced nephropathy in the mice.  Treating the mice with an ACE inhibitor drug reduced blood pressure as well as pressure within the glomerulus and prolonged their life span. The scientists determined that the reduction in glomerular pressure was key to preserving podocytes and slowing down glomerulosclerosis in the mice.

Source:

Blood Pressure Influences End Stage Renal Disease of CD151 Knockout Mice, Journal of Clinical Investigation, January 3, 2012

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Researchers at Stanford School of Medicine have discovered that the podocyte cells that make up the kidney filter membrane may be able to regenerate during normal kidney function. Scientists have long believed that these cells, which suffer damage in more than 90 percent of chronic kidney diseases, such as FSGS and diabetic nephropathy, could not renew themselves. Researcher Steven Artandi, M.D., Ph.D., said, “It used to be thought that you were born with podocytes, and died with the same podocytes—you don’t make any more during your lifetime.”

In this study, Artandi and fellow scientists found that the over-expression of TERT, a protein component of the enzyme telomerase, causes podocytes to de-differentiate and divide, and the glomeruli to collapse as a result. A similar scenario occurs in patients with HIV-associated nephropathy or HIVAN. Interestingly, examination of the glomeruli of HIVAN patients revealed increased expression of TERT. Experiments in lab mice showed that increasing the expression of TERT produced the same result as in humans; once over-expression ceased, the cells stopped dividing and began acting like specialized podocyte cells again. The researchers also found that the Wnt signaling pathway is activated in patients with HIVAN. Wnt proteins are important to embryonic development and cell differentiation. The scientists were able to block Wnt signaling in mice with HIVAN to stop podocyte division and improve function. They now hope to discover if podocyte regeneration occurs during healthy kidney function. Dr. Artandi said, “If we can harness this regeneration, we may one day be able to treat people with chronic kidney disease.”

Source:

Regeneration of Specialized Cells Offers Hope for Treating Chronic Kidney Disease, Researchers Say, Stanford School of Medicine, December 4, 2011

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Researchers at University of Miami Miller School of Medicine and Harvard Medical School have discovered an important molecular mechanism behind worsening kidney disease. In a disease such as FSGS, for example, the kidney filter membrane (also known as the slit diaphragm) is damaged, allowing proteins to leak into the urine. The initial damage causes further injury to the podocyte cells, which make up the filter membrane. The podocytes die, resulting in more proteinuria and scarring of the kidneys.  The researchers found that when filter membrane injury occurs, CD2AP—a protein important for podocyte survival and proper signaling in the filter membrane—splits and releases the protein dendrin. This increases activity of protease cathepsin L, or Catl, which then degrades CD2AP, continuing the cycle of damage.

The study’s senior author, Jochen Reiser, M.D., Ph.D., explained, ““We knew that proteinuria is a risk for more and progressive renal disease, but now we understand a mechanism for how this is occurring. A healthy filter membrane regulates a healthy transcriptional program—both of which are altered in disease. The idea to improve not only proteinuria by rebuilding the slit diaphragm of podocytes, but also improve podocyte survival opens novel concepts for nephroprotection in otherwise progressive renal diseases, such as FSGS.”

Sources:

Nephrologists Discover Key to Kidney Disease Progression, University of Miami Miller School of Medicine, September 12, 2011

CD2AP in Mouse and Human Podocytes Controls a Proteolytic Program That Regulates Cytoskeletal Structure and Cellular Survival, JCI, The Journal of Clinical Investigation, October 3, 2011

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Some of our favorite actors, composers, writers, musicians, and athletes have died from kidney disease—many of them, far too soon. Mozart’s death is a fascinating medical mystery, to be explored in a future blog post.

Wolfgang Amadeus Mozart, composer, died 1791 of nephrotic syndrome (or rheumatic fever)

Emily Dickinson, poet, died 1886 of Bright’s disease

Sarah Bernhardt, actress, died 1923 of  kidney failure

Buffalo Bill Cody, Wild West show entertainer, died 1917 of kidney failure

Cole Porter, composer, died 1964 of kidney failure

Marlene Dietrich, actress, died 1992 of kidney failure

Edgar Bergen, ventriloquist, died 1978 of kidney diease

James A. Michener, author, died 1997 of kidney failure

Jean Harlow, actress, died 1937 of kidney failure and uremic poisoning

Julia Child, chef, died 2004 of kidney failure

Dexter Gordon, jazz musician, died 1990 of cancer and kidney failure

Oscar Peterson, jazz musician, died 2007 of kidney failure

Art Buchwald, columnist and writer, died 2007 of kidney failure and diabetes

Erma Bombeck, columnist and writer, died 1996 of PKD and transplant complications

Bobby Fischer, chess master, died 2008 of kidney failure

Barry White, singer, died 2003 of kidney failure

Billy Preston, singer, died 2006 of kidney failure

Manute Bol, basketball player, died 2010 of acute kidney failure

Gary Coleman, actor, died 2010 of FSGS

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Let’s wipe out kidney disease together!

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