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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Researchers at Johns Hopkins have discovered that, contrary to long-held beliefs, not all African American dialysis patients fare as well as their white counterparts. After studying 1.3 million ESRD patients, they found that young African Americans under 50 actually do much worse. The news comes as a surprise because earlier studies had never analyzed outcomes based on age. The new study shows that African Americans over 50 still do have a slight advantage over white patients. However, according to Johns Hopkins, African Americans “…between the ages of 18 and 30 are twice as likely to die on dialysis than their white counterparts; and those ages 31 to 40 are 1.5 times as likely to die.” The researchers believe that the disparity could be due to a lack of access to healthcare or poor healthcare in the early stages of CKD, or perhaps a physiological reason involving high blood pressure, which is very common in the African American community. They hope that this study will change the way young African American patients are counseled regarding the importance of transplantation and that it will lead to more kidney transplants for these patients.

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Conventional Wisdom Unwise: Study Shows Young Black Patients on Kidney Dialysis Do Much Worse—Not Better—Than White Counterparts, Johns Hopkins Medicine, August 9, 2011

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Researchers at Stanford University School of Medicine have identified a drug called STF-31 that starves and kills some kidney cancer cells by cutting off their energy supply of glucose. STF-31 works by binding to a particular glucose transporter. Testing in mice inhibited glucose transport by about half and resulted in slowed tumor growth with limited side effects and no negative impact on the brain, which also uses glucose for fuel. STF-31 may prove effective in fighting other cancers which require the same glucose transporter for energy production.

Source:

Potential Anti-Cancer Therapy That Starves Cancer Cells of Glucose Identified, ScienceDaily, August 4, 2011

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A team of nephrologists and researchers at University of Miami Miller School of Medicine have discovered a factor in the blood that may be responsible for up to two-thirds of the cases of focal segmental glomerulosclerosis or FSGS. They found that an excess of serum soluble urokinase receptor (suPAR) activates a protein in the kidney podocytes called ß3 integrin. The podocytes, which serve as a filtration barrier, begin to move and allow protein to pass into the urine. The process leads to breakdown and fusing of the podocytes, impaired filtration, and glomerular scarring. The scientists found that many patients with FSGS have elevated levels of suPAR in the blood. Therapies to reduce suPAR levels or stop the suPAR-ß3 interaction could prove beneficial. Tests for suPAR levels in the blood could also identify patients at risk of developing recurring FSGS after kidney transplantation.

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Nephrologists Discover Cause of Common Kidney Disease, University of Miami Miller School of Medicine, July 31, 2011

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Researchers at University of Tokyo Graduate School of Medicine have uncovered a new mechanism behind salt-sensitive hypertension. They found that a high-salt diet fed to salt-sensitive rats activates a gene called Rac1 in the kidneys; this leads to increased activity of the MR (Mineralocorticoid Receptor) protein and causes elevated blood pressure and kidney damage. Their study showed that Rac1 is regulated by both salt and aldosterone, a hormone that helps control blood pressure. They found that inhibiting Rac1 prevents high blood pressure as well as injury to the glomeruli of the kidney. Rac1 appears to be a major factor in determining salt sensitivity and could prove to be a beneficial target for preventing salt-sensitive hypertension and resultant kidney injury in humans.

Sources:

New Mechanistic Insight Into Salt-Induced High Blood Pressure, University of Tokyo Graduate School of Medicine, July 18, 2011

Abstract:

Rac1 GTPase in Rodent Kidneys Is Essential for Salt-Sensitive Hypertension Via a Mineralocorticoid Receptor-Dependent Pathway

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Researchers from Oregon Health and Science University Knight Cancer Institute have found that a gene called Src plays a role in helping some kidney cancers grow. The researchers are now looking at existing, approved drugs that may inhibit Src activity in cancer cells.  In addition, they have developed a method of identifying patients that could benefit from such drugs. This discovery could expand kidney cancer drug treatments beyond therapies that slow tumor growth, but fail to provide a cure, and don’t work for all patients.

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Kidney Cancer Discovery Could Expand Treatment Options, Science Daily, July 7, 2011

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Dopamine, an important neurotransmitter that helps to control the brain’s reward and pleasure centers, is often studied in connection with neurological disorders like Parkinson’s disease.  Now researchers at Vanderbilt University Medical Center have discovered that dopamine produced within the kidneys, rather than the brain, is critical to maintaining normal blood pressure and salt and water balance. They showed that mice with impaired kidney dopamine production developed hypertension and died sooner than ordinary mice, despite having normal brain and plasma dopamine levels. Although dopamine has previously been associated with hypertension, this study pinpoints the important role of dopamine made in the kidneys.

Sources:

Long Live Dopamine Production by the Kidneys, Vanderbilt University Medical Center, June 23, 2011

Intrarenal Dopamine Deficiency Leads to Hypertension and Decreased Longevity in Mice, Journal of Clinical Investigation, June 23, 2011

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Results of a year-long drug trial conducted by researchers from UT Southwestern Medical Center show that the experimental drug bardoxolone methyl improves estimated glomerular filtration rates in Type 2 diabetic patients with moderate to severe CKD. Lab tests for those patients revealed decreased blood urea nitrogen, serum phosphorus, uric acid, and magnesium. The new phase 3 trial of bardoxolone is expected to be complete in 2013.

Source:

Drug Shows Improved Kidney Function for Patients with Type 2 Diabetes, UT Southwestern Researchers Report, UT Southwestern Medical Center, June 24, 2011

Bardoxolone Improves eGFR Out to One Year in Advanced CKD, By Daniel M. Keller, Ph.D., Renal and Urology News, June 24, 2011

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Researchers from UC San Diego, the National Institutes of Health, and the Mayo Clinic have shown that an experimental drug called pirfenidone can stop damage and improve kidney function in diabetic patients. Study participants treated with a small amount of the drug for one year showed improved glomerular filtration rates.

Pirfenidone, an anti-inflammatory and anti-fibrotic or anti-scarring drug, targets transforming growth factor beta (TGF-ß), a protein that contributes to kidney scarring.  Prolonged, elevated blood sugar levels lead to over-expression of TGF-ß, but pirfenidone appears to block the protein. The drug has already been used to slow the progression of FSGS and may be an option for treating other fibrotic conditions, such as pulmonary fibrosis.

Source:

Drug Effective in Treating Kidney Disease in Diabetic Patients, By Debra Kain, UC San Diego, April 21, 2011

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