Although much more study is needed, CFTR inhibitors could provide a useful new approach for the treatment of PKD. "The CFTR inhibitors could be the basis of a lifelong treatment to slow renal cyst growth and decline in renal function, prolonging dialysis-free patient survival," comments Dr. Alan S. Verkman of University of California, San Francisco, School of Medicine.
Patients with PKD develop cysts on the kidneys, which progressively increase in size and number. The kidneys become enlarged, eventually leading to kidney failure. Previous research has suggested that the buildup of fluid in the cysts is related to chloride secretion, which is affected by the CFTR (cystic fibrosis transmembrane conductance regulator) gene. The researchers used automated "high-throughput" screening techniques to identify CFTR inhibitors that might affect cyst growth.
These screening studies identified two classes of small-molecule CFTR inhibitors that slowed the growth of renal cysts. The best inhibitor of each class was identified and shown to reduce the number and growth of cysts by more than 80 percent.
The inhibitors were then tested in mice that had been genetically altered to produce a condition similar to PKD. Animals treated with CFTR inhibitors for up to seven days had significantly slower cyst expansion and kidney enlargement, and better preservation of kidney function. There was no evidence of harmful effects on kidney function.
PKD is an incurable condition for which new treatments are urgently needed. If effective medications to reduce the rate of fluid buildup in cysts could be developed, they might provide an entirely new approach to treatment to slowing the progression of the disease.
The results show that CFTR plays a role in the growth of renal cysts, and suggest that CFTR inhibitors have potential as treatments to reduce cyst growth in PKD. However, much more research will be needed to see if drugs based on the CFTR blockers will be useful in human PKD.
"The mouse model of PKD is not the real human disease for many reasons, such as the more rapid progression of disease in mice," says Dr. Verkman. "Clinical trials will be needed to determine the efficacy of these compounds in human PKD."
ScienceDaily (June 26, 2009) — Medical scientists at the University of Leicester are investigating how a species of fish from the Pacific Ocean could help provide answers to tackling chronic conditions such as hereditary high blood pressure and kidney disease.
They are examining whether the Goby fish can help researchers locate genes linked to high blood pressure. This is because a protein called Urotensin II, first identified in the fish, is important for regulating blood pressure in all vertebrates- from fish to humans.
The study is being carried out in the University’s Department of Cardiovascular Sciences. Researcher Dr Radoslaw Debiec said: “The protein found in the fish has remained almost unaltered during evolution".
“This indicates that the protein might be of critical importance in regulation of blood pressure and understanding the genetic background of high blood pressure.
“Uncovering the genetic causes of high blood pressure may help in its better prediction and early prevention of its complications. My research at the University of Leicester has shown how variation in the gene encoding the protein may influence risk of hypertension.”
Dr Debiec will be presenting his research at the Festival of Postgraduate Research which is taking place on the 25th June at the University of Leicester.
He added: “Drugs affecting the protein might be a novel alternative to the available therapies in particular in those patients who have chronic kidney disease coexisting with high blood pressure.
“Analysis of large cohort of families has provided us with evidence that genetic information encrypted in the protein travels together with the risk of high blood pressure across generations. Furthermore, the same genetic variant responsible for elevated blood pressure is responsible for the development of chronic kidney disease in this group of patients.
“The present findings may have an impact on the development of new blood pressure-lowering medications.”
ScienceDaily (June 17, 2009) — The most popular type of gastric bypass surgery appears to nearly double the chance that a patient will develop kidney stones, despite earlier assumptions that it would not, Johns Hopkins doctors report in a new study. The overall risk, however, remains fairly small at about 8 percent.
As rates of morbid obesity have climbed in recent years, so has the popularity of various weight-loss operations, with more than 200,000 patients expected to have one of these procedures this year. The most common type of weight loss, or bariatric, surgery, called Roux-en-Y in a nod to the Y-shape of the surgical connections that go around part of the bowel, accomplishes weight loss by decreasing the size of the stomach and allowing food to bypass part of the small intestine.
While other bariatric procedures have been shown to decrease calcium absorption and increase the risk of kidney stones, doctors have long assumed that the Roux-en-Y procedure did not.
To test the assumption, researchers led by Brian Matlaga, M.D., assistant professor of urology at the Johns Hopkins University School of Medicine and director of stone diseases and ambulatory care at Hopkins' James Buchanan Brady Urological Institute, used an insurance claims database to identify 4,639 patients who had undergone Roux-en-Y surgery between 2002 and 2006. The researchers identified a second set of 4,639 patients who had similar characteristics—including age, gender, and body mass indices that indicate obesity—but not the surgery.
Using medical information encoded in the database for both patient populations, the researchers looked to see which patients were either diagnosed with kidney stones or had treatment for this condition. Their results showed that while only 8 percent of the Roux-en-Y patients developed kidney stones, they were nearly twice as likely to get this condition as the patients with similar characteristics who didn't have weight loss surgery. The researchers published these findings in the June Journal of Urology.
"Our study is not an indictment of bariatric surgery—the benefits of this surgery are well known," says Matlaga. "Rather, we'd like to help physicians understand that their bariatric patients could be at risk for kidney stones, a condition that could be avoidable with proper preventative care."
Matlaga explains that kidney stones are often caused by an excess of a dietary component known as oxalate, which normally binds with calcium and is flushed out of the body. Roux-en-Y surgery might reduce the amount of calcium that patients absorb, contributing to kidney stone formation. Consequently, Matlaga adds, doctors may be able to help patients avoid kidney stones through calcium supplements or other interventions.
Kidney stones are solid mineral crystals that form within the kidneys and can cause pain that is frequently severe. Each year, people make almost 3 million visits to health care providers and more than half a million people go to emergency rooms for kidney stone problems.
ScienceDaily (June 5, 2009) — Fox Chase Cancer Center investigators report that a two-drug blockade of mTOR signaling appears safe in metastatic kidney cancer in a phase I trial. Early data suggests that a combination of temsirolimus and bryostatin may be active in patients with rare forms of renal cell cancer, which are less likely to respond to other targeted therapies.
Elizabeth Plimack, M.D., M.S., a medical oncologist and attending physician at Fox Chase will report the trial results on Sunday, May 31 at the annual meeting of the American Society of Clinical Oncology.
"We have certainly seen sustained responses with this combination which are encouraging," Plimack says.
One of the patients with an extended response has papillary renal cell cancer, which is a rare form of the disease that does not respond well to standard therapies. "Patients with non-clear cell renal cell cancer, including papillary renal cancer, don't respond as well to tyrosine kinase inhibitors, such as sunitinib and sorafenib, as patients with clear cell renal cell. So there is an unmet need for therapy for these patients. We've seen that this combination may be active to some degree for them."
mTOR signaling promotes tumor cell proliferation and blood vessel development. Temsirolimus (Torisel), blocks signaling through one portion of the mTOR signaling complex, called TORC1, and slows tumor progression in patients with advanced kidney cancer. However, a second portion of the complex, called TORC2, is unaffected by temsirolimus and continues to promote cell proliferation. Therefore, Plimack and colleagues suspect that blocking TORC2 signaling activity could improve patient outcomes. Bryostatin blocks a downstream effector of TORC2, called protein kinase C.
Plimack and colleagues designed the phase I trial to test the safety of the bryostatin-temsirolimus combination. Twenty-five patients enrolled in the trial, including 20 patients with renal cell carcinoma. The phase I trial tested a combination of 20 micrograms/m2 bryostatin weekly plus one of the following temsirolimus doses, 10, 15, 25, or 37.5 mg, every 28 days.
The combination appears to be well tolerated in renal cell patients. Two patients developed dose limiting toxicities (one with renal toxicity and one with neutropenia) at the highest temsirolimus dose. Enrollment is now continuing with patients receiving 25 mg temsirolimus. (Two of the non-renal cell cancer patients developed dose-limiting toxicities early in the trial, after which point the investigators limited enrollment to patients who had not received prior chemotherapy.)
Early responses in renal cell cancer patients are promising, according to Plimack. Three patients have had durable partial responses to therapy. Two of those individuals are off therapy and have partial responses continuing at 3+ years and 12+ months, and a third patient continues on therapy with a partial response extending beyond 22 months.
ScienceDaily (May 6, 2009) — Moderate kidney disease increases an older man's risk of developing certain cancers, according to a new study. Given that chronic kidney disease (CKD) affects about a third of older men, maintaining kidney function could help prevent cancer in the general population.
People with end-stage renal disease (ESRD) and kidney transplant recipients are at increased risk of developing cancer, but little is known about the cancer risks of individuals with milder kidney dysfunction. To investigate, Germaine Wong, MD (Children's Hospital at Westmead, Australia), and her colleagues studied data from 3654 Australians aged 49 to 97 years who were followed for an average of 10 years. They observed individuals who had decreased kidney function for an increased risk of developing cancer.
The researchers discovered that men with moderate kidney dysfunction had a 39% increased risk of developing cancer over the risk seen in men with normal kidney function. Risk increased as kidney function declined, and men with significant kidney dysfunction had a three-fold increased risk above normal. The risk for lung and urinary tract cancers, but not prostate cancer, was higher among men with kidney disease.
Some evidence suggests that inflammation caused by CKD may contribute to the development of cancer. Other studies have found an association between Vitamin D deficiency, which is highly prevalent among people with moderately reduced kidney function, and increased cancer risk. Additional research is needed to uncover the underlying mechanisms involved in the cancer-kidney disease link found in this study and to explain why a link was not found in women.
According to Dr. Wong, "Men with CKD should be aware of cancer prevention and screening for early detection," she said. "CKD prevention may be a worthwhile strategy for preventing and reducing cancer risk in the general population
ScienceDaily (June 11, 2008) — Many patients with chronic kidney disease (CKD) have mild reductions in thyroid function, or subclinical hypothyroidism--a condition that becomes more common as kidney function declines, according to a new study
"Although no recommendations are available regarding the treatment of mild abnormalities of thyroid hormone levels in patients with CKD not requiring dialysis, these abnormalities could represent a risk factor for cardiovascular disease and might also be implicated in kidney disease progression," comments lead authors Dr. Michel Chonchol of University of Colorado Health Sciences Center and Dr. Giovanni Targher of University of Verona, Italy.
The researchers analyzed routine blood test results in more than 3,000 patients with CKD who were not receiving dialysis. Patients with CKD have loss of kidney function that, in many cases, progresses to end-stage renal disease (ESRD)--permanent loss of kidney function requiring dialysis or transplantation.
Overall, 9.5 percent of patients with CKD had subclinical hypothyroidism. This means reductions in thyroid hormone levels that are detected on blood tests with no abnormal signs or symptoms.
The lower the patients' kidney function, the higher their risk of subclinical hypothyroidism. Seven percent of patients with mild CKD had low thyroid function, compared to 18 percent of those with moderate CKD. After adjustment for other factors, patients with moderate CKD were 73 percent more likely to have subclinical hypothyroidism.
As laboratory tests become more sophisticated, the ability to detect subtle changes in thyroid function has improved. Regardless of the cause, subclinical hypothyroidism is linked to an increased risk of cardiovascular disease and reduced heart function. Patients with CKD are at greatly increased risk of cardiovascular disease.
Subclinical hypothyroidism is common, especially among older adults; lab tests show low thyroid function in four to 10 percent of the general population. Although increased rates of thyroid abnormalities have been reported in patients with ESRD, the new study is the first to show an increased rate of subclinical hypothyroidism in CKD patients not requiring chronic dialysis.
The nature and consequences of the link between CKD and low thyroid function are not yet clear. When hypothyroidism becomes more severe, it can cause reduced heart function, which can lead to progressively worsening kidney function. Thus the presence of subclinical hypothyroidism in patients with CKD might be a risk factor for both cardiovascular disease and progressive kidney disease.
Because of the lack of follow-up data, the study cannot determine whether there is any causal relationship between subclinical hypothyroidism and CKD. "Further studies should evaluate if mild elevations of the thyroid hormone are harmful for patients with kidney disease and explore the possibility of treating mild abnormalities of thyroid function with thyroid hormone replacement," according to Drs. Chonchol and Targher.
ScienceDaily (May 22, 2009) — A group led by Drs. Erwin P. Böttinger of the Mount Sinai School of Medicine and Matthias Kretzler at the University of Michigan have established novel markers of kidney disease progression.
Chronic kidney disease may affect up to 16.8% of the US population. Only a minority of patients with chronic kidney disease progress to end-stage renal disease. However, current clinical markers are not sufficient to reliably predict chronic kidney disease progression, which would allow for targeted treatment of high-risk patients.
To identify markers of chronic kidney disease progression, Ju et al screened a mouse model of progressive renal disease to identify genes whose expression correlated with renal disease severity. They then examined human versions of these genes, and found that a subset of these candidates were associated with disease progression and glomerular filtration rate in human patients.
The biomarkers identified by Dr. Böttinger, Dr. Kretzler, and colleagues "predict progressive renal fibrosis in mice and may [therefore] be useful molecular predictors of [chronic kidney disease] progression in humans."
ScienceDaily (June 19, 2009) — Scientists in Israel have identified the key substances in exhaled breath associated with healthy and diseased kidneys — raising expectations, they say, for development of long-sought diagnostic and screening tests that literally sniff out chronic renal failure (CRF) in its earliest and most treatable stages.
In the new study, Hossam Haick and colleagues point out that the blood and urine tests now used to diagnose CRF can be inaccurate and may come out "normal" even when patients have lost 75 percent of their kidney function. The most reliable test, a kidney biopsy, is invasive and may result in infections and bleeding. Doctors have long hoped for better tests for early detection of kidney disease.
The scientists describe tests of an experimental "electronic nose" on exhaled breath of laboratory rats with no kidney function and normal kidney function. The device identified 27 so-called volatile organic compounds that appear only in the breath of rats with CRF.
The results presented in this study "raise expectations for future capabilities for diagnosis, detection, and screening various stages of kidney disease," they said, noting that the tests could detect patients with early disease who could be treated in ways that could slow its progression.
ScienceDaily (Nov. 17, 2008) — Kidney stones may damage the kidneys and lead to chronic kidney disease (CKD), according to a paper being presented at the American Society of Nephrology's 41st Annual Meeting and Scientific Exposition in Philadelphia, Pennsylvania. In extreme cases, individuals with CKD caused by kidney stones may even need dialysis or kidney transplants.
Kidney stones lead to CKD in patients with rare genetic diseases, but it is unclear if they also are an important risk factor for CKD in the general population. In general, researchers have thought that complications of kidney stones can only rarely cause CKD, but studies that have looked at this potential link have been small or have had limited follow-up.
To get a better sense of the role that kidney stones may play in the development of CKD, John Lieske, MD, and his colleagues at the Mayo Clinic in Rochester, Minnesota, studied records of all residents of Olmsted County, MN, over a 20 year span (1984-2003). These data are available through the Rochester Epidemiology Project, a unique and extensive medical documentation system that combines clinical records from the Mayo Clinic and other community providers in the county.
The investigators compared residents diagnosed with kidney stones with individuals without stones, noting who went on to develop CKD as determined by diagnosis codes and laboratory tests. Those with kidney stones were matched 1:3 to controls in the general population so that a total of 4424 stone formers and 10995 controls were identified and followed up, on average, for more than eight years.
The researchers discovered that individuals diagnosed with kidney stones were significantly more likely to subsequently develop CKD. Specifically, stone formers had a 60% greater risk of developing CKD and a 40% increased risk of developing end-stage renal disease (ESRD), the most severe form of CKD.
The study indicates that patients with kidney stones should be carefully evaluated for CKD and its risk factors, and they should be appropriately treated for any that are identified, said Lieske.
Additional studies are needed to determine why patients with kidney stones are at increased risk for CKD. Studies on potential treatment options also are needed, such as studies to determine whether treatments to prevent stone recurrence would reduce risk of further CKD progression.
While researchers and clinicians consider cognitive decline to be a common occurrence in patients with chronic kidney disease, it is unclear if this impairment is due to patients' advanced age, their chronic health conditions, or potential treatment-related factors. In addition, the effects of surgery and immunosuppressant medications on memory and overall cognitive performance have been poorly studied, but previous research suggests that kidney transplantation may have a beneficial effect on patients' mental function.
To investigate this further, Mark Unruh, MD, and his colleagues at the University of Pittsburgh in Pittsburg, Pennsylvania, assessed kidney disease patients' cognitive performance before and after kidney transplantation. They did so by using neuropsychological tests related to language, learning and memory, attention, and other brain processes involved with thought and behavior.
The researchers compared test scores of 37 patients before and after they received transplants. A control group of 13 patients who did not receive kidney transplants but received dialysis was also followed over the same period of time.
Dr. Unruh and his team found a statistically significant improvement in performance on tests of verbal learning and memory, attention, and language after patients received kidney transplants. They found no such improvement in patients not undergoing this surgical procedure. In fact, test scores declined in these patients over time.
When comparing the differences of scores between the two groups adjusted to their original scores, transplanted patients performed particularly well on tests of learning and memory compared with dialysis patients.
ScienceDaily (Mar. 1, 2009) — For patients with type two diabetes, a combination of two blood-pressure-lowering drugs reduces the risk of kidney disease by about 20 percent—even in patients who don't have high blood pressure, reports a study in the April 2009 issue of the Journal of the American Society of Nephrology (JASN).
The analysis was based on the randomized ADVANCE study, which included 11,140 patients with type two diabetes. One group received a combination of two antihypertensive (blood pressure-lowering) drugs: the angiotensin-converting enzyme (ACE) inhibitor perindopril and the diuretic drug indapamide. The other group received inactive placebos.
Although most of the patients had hypertension, 20 percent had normal blood pressure: less than 130/80 millimeters of mercury (mm Hg).
"This research demonstrated that lowering blood pressure with an ACE inhibitor/diuretic combination prevents kidney complications, and even cause some early manifestations of kidney disease in people with diabetes regardless of whether their blood pressure is normal or elevated," comments Vlado Perkovic, MBBS, PhD, of The George Institute for International Health in Sydney, Australia, one of the study authors.
The two groups were followed up to compare their rates of kidney disease events, ranging from a drop in kidney function to kidney failure. An average of four years later, the rate of kidney disease was significantly lower for patients receiving the combination drug therapy—21 percent lower than in the placebo group. In some patients who previously had early signs of diabetes-related kidney disease, kidney function returned to normal during treatment with blood pressure-lowering drugs.
The drug combination reduced kidney disease events even in patients who did not initially have high blood pressure. The lower the blood pressure level, the lower the risk of kidney disease—even at blood pressures below the currently accepted normal level (130/80 mm Hg).
Although more research is needed, these results raise the possibility that patients with type two diabetes should be considered for antihypertensive treatment even if they have normal blood pressure.
The study has some important limitations, including the fact that it was a post-hoc analysis of a previous clinical trial. "Most of the findings related to early manifestations of kidney disease (albuminuria) and the study was not large enough to assess the impact of the intervention directly on the risk of kidney failure," Perkovic adds. "We could not separate out the impact of the blood pressure lowering combination used, or prove whether it had any effects beyond its blood pressure-lowering effects."
ScienceDaily (Oct. 2, 2008) — A study of almost 1,500 kidney cancer patients treated at Memorial Sloan Kettering Cancer Center suggests that surgery to spare as much kidney tissue as possible may improve overall survival in patients who also have reduced kidney function at the time their cancer is diagnosed. The finding is significant because both kidney cancer and decreased kidney function appear to be increasing.
"In patients who have the combination of kidney cancer and lowered kidney function, doctors should consider tissue-sparing surgery – versus complete removal – whenever it is technically feasible," said Joseph Pettus, M.D., lead author and now an assistant professor of urology at Wake Forest University School of Medicine. "Currently this option is significantly underused."
Reporting in the Mayo Clinic Proceedings, a peer-reviewed medical journal, researchers found that among patients having surgery for kidney cancer, those who also had severely impaired kidney function were almost three times more likely to die than patients with normal kidney function.
Impaired kidney function can sometimes be related to the cancer itself. But impaired function can also be caused or compounded by a variety of other factors, including diabetes, hypertension and vascular disease. Impaired kidney function itself – even without a diagnosis of cancer – is related to increased risk of death and hospitalization.
Surgery to remove a malignant tumor can further impair kidney function because the loss of kidney tissue affects kidney function over time. Researchers at Memorial Sloan Kettering had previously found that patients whose kidneys were completely removed were almost 12 times more likely to develop significantly impaired function in the remaining kidney than patients whose organs were partially removed.
The study involved an analysis of data from kidney cancer patients treated during a 10-year period. Pettus conducted the research with colleagues at Sloan Kettering before moving to Wake Forest.
The research was based on the hypothesis that kidney cancer patients with reduced kidney function prior to surgery would have lower survival rates than cancer patients with normal kidney function. The researchers excluded patients whose disease had spread to the lymph nodes or other parts of the body.
They found that median beginning levels of kidney function in all patients decreased during the 10-year period by about 10 percent. Compared to those with normal kidney function, patients who began with moderately reduced function were 150 percent more likely to die from any cause. Those with severely reduced function were almost three times (280 percent) more likely to die.
Pettus said the findings suggest that obesity and related diseases that affect kidney function may be contributing to the rising death rates from kidney cancer. Overall death rates increased 323 percent among kidney cancer patients between 1983 and 2002 – despite the fact that the disease is being detected earlier. He said that rising rates of kidney cancer – combined with a decline in kidney function – is almost a "perfect storm" scenario which may explain the decrease in survival, even among patients with early stages of kidney cancer.
"These findings underscore the importance of considering baseline kidney function when devising treatment plans for patients with kidney tumors," said Pettus.
He said the findings raise concerns that surgery may result in more medical harm than benefit to treating the cancer.
"Our data beg the question of whether patients with moderate to severe kidney disease and small tumors might be better managed through tissue-sparing techniques or a 'watchful waiting' approach," said Pettus. "Completely removing the kidney may result in more harm than good, particularly in elderly patients with small tumors and other medical problems. For these patients, careful surveillance may be a legitimate option with surgery reserved for cases where the tumor increases in size."
Research has shown that for tumors that are 7 cm or less, partial removal of the kidney provides equal cancer control to total removal. However, partial removal accounted for only 7.5 percent of kidney surgeries between 1988 and 2002. And for smaller tumors, only 20 percent were treated with partial removal of the kidney.
ScienceDaily (Feb. 13, 2009) — On Thursday, February 5, 2009, surgeons at the University of California, San Diego Medical Center removed a patient’s diseased kidney through one incision hidden in the belly button. No other incisions were used. This groundbreaking procedure is the 15th in a series of single-incision clinical trial surgeries performed by the UC San Diego Center for the Future of Surgery.
“The successful removal of a kidney containing a seven centimeter tumor, with a single incision, is a pivotal advancement in cancer care,” said Ithaar H. Derweesh, MD, associate professor of surgery for the Division of Urology and urologic oncologist at UC San Diego Medical Center and Moores UCSD Cancer Center. “This less invasive approach offers patients a shorter recovery time, less need for pain medication, and an improved cosmetic outcome.”
During a traditional laparoscopic surgery, three to five small abdominal incisions would be made to insert a camera and instruments to remove the kidney. This novel surgery required one incision in the navel.
“The idea of being able to perform a surgery with fewer incisions and requiring a shorter hospital stay is particularly attractive to cancer patients who may face repeated surgeries,” said Santiago Horgan, MD, professor of surgery, and Director of the Center for the Future of Surgery at UC San Diego. “We are currently testing these scarless procedures for the treatment of cancer, obesity and other digestive disorders.”
According to the American Cancer Society, kidney cancer is an expanding cancer, increasing at a rate of two to three percent each year and affecting approximately 55,000 patients in the United States. Risk factors for developing kidney cancer include smoking, obesity and hypertension.
“Kidney cancer is among the 10 most common cancers in men and women,” said Derweesh, an expert in kidney-preserving surgeries and a member of the American Urological Association’s Guideline Committee for the treatment of kidney tumors. “The combination of kidney cancers being diagnosed at earlier stages and smaller sizes, and the ability perform less invasive surgeries, presents a new horizon of care for these patients.”
ScienceDaily (Mar. 1, 2009) — Patients with reduced kidney function require lower doses of the anticoagulant drug warfarin, and may need closer monitoring to avoid serious bleeding complications, suggests a new study.
Among patients who take blood thinner there is a high prevalence of reduced kidney function, ranging from mild to severe. "Although warfarin is very effective in protecting against blood clots it can also cause serious bleeding complications," commented lead author Nita A. Limdi, PharmD, PhD, of the University of Alabama at Birmingham. "The information in our study may help doctors customize warfarin management in patients with kidney failure and lower the risk of complications," commented Michael Allon, MD, also of the University of Alabama at Birmingham.
The researchers evaluated responses to warfarin, the most widely used oral anticoagulant drug, in 578 patients. about 60 percent of the patients had normal or mildly reduced kidney function. Another 30 percent had moderate reductions in kidney function, common in older adults. The remaining patients, nearly ten percent, had kidney failure requiring dialysis.
Warfarin dose was significantly affected by kidney function. The influence of kidney function remained significant even after accounting for medications and the two genes (CYP2C9 and VKORC1) that have been shown to influence warfarin dose. For dialysis patients with kidney failure, a lower dose of warfarin achieved the desired blood-thinning effect. Patients with kidney failure were also more likely to develop serious bleeding complications related to warfarin, regardless of other risk factors. "Patients with renal failure may require closer monitoring to maintain their warfarin in the desired range," said Dr. Limdi.
Even moderately reduced kidney function affected patients' response to blood thinner. These patients also required a lower dose of warfarin, although they were not at increased risk of serious bleeding. The results have important implications for a large proportion of patients who take warfarin. "Warfarin therapy is prescribed and managed similarly in patients with reduced kidney function as in the general medical population," according to Dr. Allon. "However, in our study patients with reduced renal function and renal failure required lower doses. Forty percent of study participants fell into these categories. This highlights that kidney function may be an important factor to consider in patients being prescribed warfarin," said Dr. Limdi.
Patients with kidney failure are at higher risk of serious bleeding. "Further studies are required to understand the harm and benefit associated with warfarin therapy in patients with kidney failure," said Dr. Limdi.
The study had some important limitations, including a lack of data on patients who developed blood clots despite being on warfarin. "Therefore we hesitate to recommend the use of kidney function in making treatment decisions," Dr. Limdi added. "Perhaps ongoing and future research efforts evaluating both clotting and bleeding events will enable more balanced clinical decision making in this unique and medically challenging patient population."
ScienceDaily (Sep. 24, 2008) — Kidneys from older donors often do not survive long after transplantation because of certain structural dysfunctions that can occur as the kidney ages, according to a new study. The findings indicate that the number of functioning glomeruli—the filtering units of the kidney—drops significantly with age, leading to a self-perpetuating injury in the rest of the kidney.
Thousands of individuals are on the waiting list for kidney transplants in the United States, and the average waiting time is more than three years. One response to the donor deficit has been to increase the number of transplants from older deceased donors. However, these kidneys exhibit a striking reduction in the 5-year graft survival rate. "We need to understand the process of renal senescence better in order to better select older donor organs that are likely to function well after transplantation," said Jane C.Tan, MD, of the Stanford University Medical Center in Stanford, California.
To understand the aging-related changes in the kidney that account for the shortened survival of older organs, Dr. Tan and her colleagues analyzed the structures of kidneys from 20 aging (>55 years) and 23 youthful (<40 years) deceased donors. They also looked specifically at the glomeruli of a subset of 13 aging and 12 youthful deceased donors that were taken prior to transplantation.
The investigators found a 32% depression of the glomerular filtration rate, a measure of the kidneys' ability to filter and remove waste products, in the aging vs youthful groups. In addition, the number of functioning glomeruli was profoundly depressed in older kidneys compared with younger kidneys. The authors proposed that this could lead to a "remnant kidney" phenomenon, whereby a self-perpetuating injury to the remaining kidney tissue occurs, ultimately contributing to shortened survival of the transplanted organ.
Information from this study might be useful for selecting kidneys from older donors when younger organs are not available. Kidneys with a greater number functioning glomeruli would clearly be better suited for transplantation than those with fewer glomeruli.
ScienceDaily (Feb. 13, 2009) — Measuring the amount of protein lost in the urine can identify individuals at risk of developing kidney disease, according to a new study. The results suggest that a simple and low-cost urine screen is a promising way to address the epidemic of chronic kidney disease (CKD).
More and more individuals are diagnosed with CKD each year, but many people are unaware of their risks of developing the disease. Researchers have been looking for ways to screen the population to identify people at high risk for kidney function loss at an early stage so that preventive measures can be taken. Now investigators have found that screening urine samples is a promising strategy.
In a study led by Ronald T. Gansevoort, MD, PhD, of the University Medical Center Groningen in the Netherlands, more than 40,000 individuals of the general population were asked to collect a urine sample in a plastic test tube. Samples were sent to a central laboratory where their protein concentrations were measured. The investigators continued to follow these individuals and noted who developed end-stage kidney disease over the next nine years. A subgroup of 8,592 subjects visited an outpatient department once every three years allowing a detailed study of the rate of kidney function decline during follow-up.
Subjects from the general population that were found to have increased urinary protein levels were shown to represent more than half of the patients who started dialysis or had a kidney transplant during follow-up. Restricting screening to those individuals with hypertension, diabetes, cardiovascular disease history, or age >55 years having increased urinary protein levels identified nearly all cases needing kidney disease treatment during follow-up.
The researchers concluded that individuals with high urinary protein levels are at high risk for losing their kidney function and needing dialysis or a kidney transplant. The higher the level of proteins in the urine, the higher the risk of needing dialysis or a kidney transplant and the more rapid the rate of kidney function decline.
"Our findings suggest that subjects with a high amount of urinary protein loss should be invited to a medical center for further investigation and for start of preventive treatment to protect the kidney," said Dr. Gansevoort. While our group already showed this approach to be cost-effective to prevent cardiovascular events, additional studies are needed to determine if performing urine screens in the general population (or in certain high-risk groups of individuals) would even be more cost-effective because need for dialysis may also be prevented.
ScienceDaily (Apr. 8, 2009) — For men with Fabry disease, enzyme replacement therapy (ERT) with agalsidase alfa slows deterioration of kidney function, reports a new study. "The results provide further evidence that ERT with agalsidase alfa may slow the progression of kidney disease, provided that ERT is initiated early in the disease process," comments Michael L. West, MD (Dalhousie University, Canada).
The researchers pooled the results of three previous clinical trials of ERT with agalsidase alfa in 108 men with Fabry disease—a rare genetic disorder. Without treatment, Fabry disease causes progressive loss of kidney function, eventually leading to end-stage renal disease.
During treatment with an inactive placebo, kidney function declined rapidly. By comparison, during treatment with agalsidase alfa (1 to 4.5 years), the rate of decline slowed considerably. The response to treatment was not as good for patients with lower initial kidney function. "This underlines the importance of prompt diagnosis and intervention in patients with Fabry disease," adds Dr. West.
The study was one of the largest ever of men with Fabry disease and included the most accurate techniques of measuring kidney function. The study also had important limitations: it used data from different studies performed at different times; it represented a relatively narrow range of patient characteristics, specifically excluding children and women; and it lacked adequate data for full statistical analysis.
While not approved for use in the US, Agalsidase alfa is approved for use in over 40 countries including Canada, European countries, Argentina, Australia, and Japan. A related drug called agalsidase beta is approved in the US
ScienceDaily (Apr. 28, 2009) — HIV-1–associated nephropathy (HIVAN) is a kidney disease that occurs commonly in individuals infected with HIV-1. Several studies have linked variants of genes expressed in kidney cells known as podocytes to HIVAN.
Using a genetic analysis approach known as expression quantitative trait locus analysis, Ali Gharavi and colleagues, at Columbia University College of Physicians and Surgeons, New York, have now identified new genetic regions associated with kidney disease in a mouse model of HIVAN. As noted by Susan E. Quaggin, at the University of Toronto, Toronto, analysis of corresponding regions of the human genome may well shed new light on genetic susceptibility to HIVAN in humans.
In the study, the initial genetic analysis revealed two new genetic regions associated with kidney disease in the mouse model of HIVAN, HIVAN2 and HIVAN3. Analysis of genes expressed by podocytes indicated that HIVAN2 and HIVAN1 (a genetic region previously associated with HIVAN in mice) markedly affected the levels of expression of Nphs2.
Surprisingly, HIVAN1 and HIVAN2 did not contain Nphs2, but regulated the expression of networks of genes expressed by podocytes, thereby impacting expression of Nphs2. As the gene networks modified by these two genetic regions were not completely identical, the authors suggest that the affected genes in HIVAN1 and HIVAN2 impact different points within the network.
ScienceDaily (Oct. 22, 2008) — Modification of the current screening criteria are needed for diagnosing patients with autosomal dominant polycystic disease (ADPKD), according to a new study. The results suggest that some patients with a milder form of the disease may otherwise be misdiagnosed
ADPKD, a genetic disorder characterized by the growth of numerous cysts in the kidneys, can lead to reduced kidney function and kidney failure. It is the most common inherited disorder of the kidney, occurring in approximately 1 in 500 births, and symptoms usually develop between the ages of 30 and 40 years.
Individuals at risk for developing ADPKD are commonly screened by imaging techniques such as ultrasound. Diagnosis can also be made with a genetic test that detects mutations in the two genes that cause the disease, called PKD1 and PKD2. However, gene-based diagnosis is expensive and detects definitive mutations in only 41% to 63% of cases. In many clinical settings, it is rarely performed.
Testing for ADPKD in individuals whose families have a history of the disease is important. Young people who know they are affected may be able to better preserve their kidney function through diet, life style modification and blood pressure control. Testing also can be used to determine whether an at-risk individual can safely donate a kidney to a family member with the disease.
Ultrasound screening for ADPKD is based on diagnostic criteria developed to detect cases caused by mutations in the PKD1 gene. This form of the disease is more common and more severe than the form caused by mutations in the PKD2 gene. Therefore, there may be a need for different diagnostic criteria for patients with the milder, less common form of autosomal dominant polycystic disease.
To test whether this is the case, York Pei, MD, of the University of Toronto, in Ontario, Canada, and his colleagues performed kidney ultrasounds and genetic tests on 577 and 371 at-risk individuals from 58 PKD1 and 39 PKD2 families, respectively.
The researchers found that the ultrasound diagnostic criteria currently in use may misdiagnose individuals with mutations in the PKD2 gene. Therefore, the investigators designed new ultrasound criteria that could accurately detect the disease in individuals with mutations in either PKD1 or PKD2 gene. They determined that in families of unknown gene type, the presence of three or more kidney cysts is sufficient for establishing the diagnosis in individuals aged 15 to 39 years, two or more cysts in each kidney is sufficient for individuals aged 40 to 59 years, and four or more cysts in each kidney is required for subjects ≥60 years. Also, fewer than two kidney cysts in at-risk individuals aged ≥40 years is sufficient to exclude the disease. For at-risk individuals aged 30 to 39 years, the absence of any kidney cysts provides almost certainty that the disease is not present.
"For the first time we have derived a set of highly predictive criteria for ultrasound diagnosis of ADPKD that is suitable for test subjects with either gene type," said Pei. "These unified diagnostic criteria will be useful for genetic counseling and for evaluation of at-risk subjects as living-related kidney donors for their affected relatives," he added.
ScienceDaily (Apr. 10, 2009) — A novel hemodialysis procedure helps restore kidney function and increases lifespan in patients with multiple myeloma, according to a new study.
Multiple myeloma is a form of cancer that causes severe kidney failure. Once multiple myeloma patients require dialysis to treat their kidney failure, most live less than a year. Unfortunately, there are no effective treatments to help these cancer patients.
However, researchers have suspected that a procedure called high cut-off hemodialysis, which removes large immunological proteins that cause kidney damage in myeloma patients, might improve patients' health and allow them to live longer (when used in combination with chemotherapy). To test high cut-off hemodialysis' potential, Colin Hutchison, MD (University Hospital Birmingham, United Kingdom), and his colleagues studied 19 individuals with multiple myeloma who underwent the procedure while receiving chemotherapy. Thirteen of the 19 patients completed the full treatment protocol, and in all 13 immunological proteins were reduced. In addition, kidney function was restored in all 13 patients.
"This study saw over 70% of patients becoming independent of dialysis, which is greatly above the rate expected in this setting," said Dr. Hutchison. "High cut-off hemodialysis is exciting because it offers a novel way of treating this group of patients who have historically done very poorly," he added.
The study was a pilot study and therefore not controlled. Thus, it cannot be used to change medical practice. The EuLITE trial (European trial of free light chain removal by extended haemodialysis) is a randomized control trial designed to further evaluate this treatment.
ScienceDaily (May 5, 2009) — When Lisa Garnes received a call from her daughter’s daycare saying that 3-year-old Emma was complaining of back pain, she never dreamt the cause would be a condition often associated with middle aged men: kidney stones.
“They said that Emma was doubled over in pain and saying that her back hurt her,” says Garnes.
Garnes took her to the pediatrician, who suggested it was a urinary tract infection. A half hour later, she called again to tell her doctor that her daughter couldn’t keep anything down. The doctor suggested taking her to the ER.
After a battery of tests, including an ultrasound, the doctor returned with the news: she had kidney stones.
“It was quite hard to believe,” Garnes says.
The growing incidence of kidney stones in children can be linked to the modern diet and lifestyle, says Gary Faerber, MD, a urologist at the University of Michigan Health System.
“I am seeing more and more children who have kidney stones,” says Faerber. “It’s a real phenomenon.”
To treat Emma, urologists performed two lithotripsies to break up the stones and performed surgery on a tough one she couldn’t pass. Doctors said she had high levels of oxalates (found in many fruits and vegetables) in her system, which required putting her on a low oxalate diet. Oxalates can be found in strawberries, blueberries, raspberries, chocolate, peanut butter and nuts. Doctors also suggested she spike up her water intake.
Typically, kidney stones are found in adults between the ages of 35 and 60 but children can get them, too. A family history of kidney stones is also a significant risk factor.
Children today seem to live a lifestyle that puts them at risk of kidney stones, meaning they consume sugar-filled drinks and a fast-food diet that is high in sodium, a known risk factor in the formation of kidney stones, says Faerber.
“The sedentary lifestyle we’re starting to see in the younger age group and the pediatric group is also a risk factor because we know that obesity increases the risk of forming kidney stones,” he adds.
The most common kidney stones in the U.S. are calcium oxalate stones.
Oxalates are found in high concentration in fruits and vegetables such as leafy green vegetables and strawberries.
Recent research has shown a link between global warming and dehydration.
The more dehydrated one becomes, the more concentrated the urine becomes, which forms crystals and crystals form into kidney stones, Faerber adds.
Recent studies in global warming indicate that the number of patients yearly who are treated for kidney stones is going to increase from 1 million to 2 million.
The most common reason people have kidney stones is that the urine becomes super saturated and it doesn’t take much for a small crystal to form in the urine. Crystal can grow into stones and get larger and larger as long as they sit in the super saturated fluid. This is why it’s really important for kidney stone patients to make sure they keep their urine really diluted, Faerber says.
The most common symptoms in children with kidney stones are back and abdominal pain. Parents may often mistake their child's symptoms for appendicitis or gastritis. Kidney stones tend to be way down on the list of possible problems.
Doctors recommend for children between the ages of 5 and 10 who have kidney stones to drink six glasses of water a day and those kids over 10, to drink 10 glasses.
“The main takeaway is to get your child to stay away from sugar filled drinks, sodas, colas and go to something natural like plain old water,” he says.
ScienceDaily (Feb. 12, 2009) — Women who drink two or more cans of soda pop per day are nearly twice as likely to show early signs of kidney disease, a recent study has found.
However, researchers did not find an elevated risk for men, or for people who drink diet soda, said lead researcher David Shoham of Loyola University Health System.
Researchers examined data from a representative sample of 9,358 U.S. adults in the National Health and Nutrition Examination Survey. The NHANES survey included urine samples and a questionnaire about dietary habits.
Women who reported drinking two or more sodas in the previous 24 hours were 1.86 times more likely to have albuminuria, a sensitive marker for early kidney damage. Albuminuria is an excess amount of a protein called albumin in the urine. Since healthy kidneys filter out large molecules such as albumin, an excess amount can be a sign of damage to the kidneys.
about 11 percent of the population has albuminuria. Among those who drink two or more cans of soda per day, 17 percent have this early marker of kidney disease, the study found. It's unclear why drinking soda increased the risk only in women, Shoham said. There may be an unknown underlying cause that is linked to both soda consumption and kidney damage, he said. Shoham is an assistant professor in the Department of Preventive Medicine and Epidemiology.
In recent years, diabetes, obesity and kidney disease have been increasing, along with consumption of high fructose corn syrup, the sweetener used in most sodas.
But what's most important is the amount of sugar, not the type, Shoham said. "I don?t think there is anything demonic about high fructose corn syrup per se," Shoham said. "People are consuming too much sugar. The problem with high fructose corn syrup is that it contributes to over consumption. It's cheap, it has a long shelf life and it allows you to buy a case of soda for less than $10."
Shoham and colleagues concluded that additional studies are needed to determine whether the elevated risk of kidney disease is due to high fructose corn syrup itself, an overall excess intake of sugar, unmeasured lifestyle factors or other causes.
A recent pilot study by other researchers, reported in the journal Environmental Health, found that nine of 20 commercial samples of high fructose corn syrup from three manufacturers contained detectable levels of mercury. "This adds the intriguing possibility that it is not just the sugar itself in high fructose corn syrup that is harmful, because mercury is harmful to kidneys as well," Shoham said.
about 26 million American adults have chronic kidney disease, according to the National Kidney Foundation. Advanced kidney disease causes such symptoms as fatigue, poor appetite, trouble sleeping and concentrating and swollen feet. Kidney disease can lead to high blood pressure, anemia, nerve damage, weak bones and cardiovascular disease.
ScienceDaily (Feb. 22, 2009) — Taking a much higher than recommended dose of the hypertension drug candesartan cilexetil effectively lowered the amount of protein excreted in the urine of patients with kidney disease, according to a new study. By reducing such proteinuria, the drug could potentially prevent the development of serious complications such as end-stage kidney disease and therefore save many patients' lives.
Many research efforts are focused on finding ways to lower urinary protein excretion in patients with kidney disease because doing so may postpone kidney failure and prevent the development of cardiovascular disease. Investigators in Canada recently reported the results of a multicenter trial that evaluated whether high doses of the hypertension drug candesartan cilexetil could reduce proteinuria better than the maximum approved dose. This drug is an angiotensin receptor blocker, an agent that reduces blood pressure by blocking several of the effects of the hormone angiotensin II, including tightening and thickening of the arteries, secretion of the hormone aldosterone, and reabsorption of sodium by the kidney. Because angiotensin receptor blockers also have effects on fibrosis and inflammation in the kidney, these drugs are also used to prevent or slow the progression of kidney failure.
The trial, led by Ellen Burgess, MD, of the University of Calgary in Alberta, Canada, enrolled 269 patients who had persistent proteinuria despite treatment with the highest approved dose of candesartan (16 mg daily at the time the study was initiated). Patients were randomized to receive 16, 64, or 128 mg daily of candesartan for 30 weeks.
The investigators found that patients taking 128 mg of candesartan experienced more than a 33% reduction in proteinuria compared with those receiving 16 mg candesartan by the end of the study. This reduction was in addition to the reduction in proteinuria that the patients would have had when they first started taking candesartan at 16 mg daily.
"We were surprised to see such a dramatic effect since, in the end, several other studies using higher-than-approved doses of angiotensin receptor blockers were not able to show benefit," said Dr. Burgess.
Additional research is needed to determine the optimal dose of candesartan for lowering proteinuria. However this study proves that "proteinuria that persists despite treatment with the maximum recommended dose of candesartan can be reduced by increasing the dose of candesartan further," the authors wrote. While high dose therapy with candesartan was well-tolerated, 11 patients dropped out of the study due to high blood potassium levels. Therefore, the researchers recommend that potassium levels be monitored during treatment with this drug.
ScienceDaily (Feb. 20, 2009) — Advanced kidney disease patients have a list of foods they know to avoid because they naturally contain a high level of the mineral phosphorus, which is difficult for their compromised kidneys to expel. But researchers from MetroHealth Medical Center and Case Western Reserve University School of Medicine in Cleveland have discovered that a great deal of processed and fast food actually contains phosphorus additives which can be just as dangerous for these patients.
High blood levels of phosphorus can lead to heart disease, bone disease, and even death among patients with advanced kidney disease. This is why these patients must avoid foods with naturally high levels of phosphorus – such as certain meats, dairy products, whole grains, and nuts. The research team discovered that it has become an increasingly common practice by food manufacturers to include phosphorus additives, such as sodium phosphate or pyrophosphate, to processed foods. The additives are used to enhance flavor and shelf life –particularly in meats, cheeses, baked goods, and beverages – and it is very difficult for American consumers to know whether or not these additives are present in products.
"Calories, fat, and sodium content are required to be listed on nutrition labels, but phosphorus is not," says Catherine Sullivan, M.S., R.D., lead researcher from the Center for Reducing Health Disparities, a joint center created and operated by MetroHealth and Case Western Reserve University. "This makes it impossible for kidney disease patients to know how much phosphorus they are eating. For example, we discovered that while chicken is often on dialysis patients' 'Safe List' of foods to eat, chicken from fast food and sit down restaurants often contains this phosphorus additive."
The researchers found they were able to significantly lower phosphorus levels among advanced kidney disease patients once they were taught to avoid foods containing phosphorus additives.
The investigators randomly assigned 279 advanced kidney disease patients receiving dialysis treatment to a control group that received usual care or to an intervention group that was taught to avoid additive-containing foods when purchasing groceries or eating at fast food restaurants. After three months, phosphorus levels declined two and a half times more in the intervention group than in the control group (0.4 vs. 1.0 mg/dL).
The study findings are most relevant to the half a million Americans with advanced kidney disease and the 10 million more with moderate kidney disease. However, the study authors note that even people with normal kidney function may be affected by these additives since previous research has found that high phosphorus diets appear to lower bone density and increase fracture risk as well.
"Phosphorus is already abundant in naturally-occurring foods," says study co-investigator Srilekha Sayre, M.D., M.S., MetroHealth and Case Western Reserve University. "By adding even more phosphorus to our food supply, we may be exceeding the body's regulatory ability, especially for those with kidney disease. We need to limit the use of these additives until their impact is better understood or at least encourage the Food and Drug Administration to require food manufacturers to report phosphorus content on nutrition food labels."
ScienceDaily (Dec. 17, 2008) — Researchers at the University of Warwick have discovered high doses of thiamine – vitamin B1 – can reverse the onset of early diabetic kidney disease.
Kidney disease, or diabetic nephropathy, develops progressively in patients with type 2 diabetes. Early development of kidney disease is assessed by a high excretion rate of the protein albumin from the body in the urine, known as microalbuminuria.
The research is led by Dr Naila Rabbani and Professor Paul J Thornalley at Warwick Medical School, University of Warwick, in collaboration with researchers at the University of Punjab and Sheik Zaid Hospital, Lahore, Pakistan.
The team has discovered taking high oral doses of thiamine can dramatically decrease the excretion of albumin and reverse early stage kidney disease in type 2 diabetes patients.
In a paper published online in the journal Diabetologia, the team show 300 mg of thiamine taken orally each day for three months reduced the rate of albumin excretion in type 2 diabetes patients. The albumin excretion rate was decreased by 41% from the value at the start of the study. The results also showed 35% of patients with microalbuminuria saw a return to normal urinary albumin excretion after being treated with thiamine.
Forty patients with type 2 diabetes aged between 35 and 65 years old took part in the trial. They were randomly assigned a placebo or 3 x 100mg tablets of thiamine a day for three months.
The Warwick research group has already conclusively proven that type 2 diabetes patients have a thiamine deficiency. In an earlier study led by Professor Paul Thornalley at Warwick Medical School, the research team showed that thiamine deficiency could be key to a range of vascular problems for diabetes patients.