RxPG News : Nephrology

Belatacept may preserve renal function better than calcineurin inhibitors in kidney transplantation

Tue, 09 Mar 2010 14:29:51 PST

( from http://www.rxpgnews.com ) Initial results of a study conducted at 100 centers worldwide indicate that belatacept, a first-in-class costimulation blocker can prevent the immune system rejecting new organs. The results also suggest that it may provide similar patient and graft survival to cyclosporine but with fewer side effects and superior kidney function after 12 months. The study, published in the American Journal of Transplantation, provides the first findings to come from BENEFIT (Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial).

Although advances in transplantation have reduced rates of organ rejection and improved outcomes after one-year, corresponding improvements in long-term survival rates have not been observed. The kidney allograft (transplant from another human donor with different genes) survival rate is 95% for transplants from living donors and 89% for transplants from deceased donors during the first year. BENEFIT is a three-year, randomized, active-controlled, parallel-group, set up to evaluate the efficacy of belatacept for post-transplant maintenance immunosuppressive management.

"Our findings show that this will be a novel and more specific way of suppressing the immune system with less toxicity," said lead researcher Dr. Flavio Vincenti, of the University of California, San Francisco Medical Center. "It will target the specific responses that cause rejection of transplanted organs with less damage to other systems of the body."

Belatacept is different from calcineurin inhibitors (CNI), such as cyclosporine, which is the class of drugs most commonly used to suppress the immune system in transplant patients, because it does not cause the toxicities associated with CNI – such as nephrotoxicity and aggravating cardiovascular risk factors. Belatacept selectively blocks T-cell activation (which plays a key part in immune response) and the results suggest that this selectivity allows effective immunosuppression, better preservation of renal function and an improved cardiovascular/metabolic risk profile.

The researchers found that treatment with belatacept was generally safe, although there was a higher incidence of post-transplant lymphoproliferative disorder in belatacept patients with known risk factors.

686 patients 18 years or older who were expected to receive a kidney transplant from a standard criteria donor were included in BENEFIT, and were randomized into three groups; more or less intensive regimens of belatacept, or cyclosporine. 666 patients eventually received a transplant and of these, 527 patients completed the initial 12 month treatment phase, with an even spread of discontinuation between the groups.

"Although belatacept was associated with a higher early rejection rate than patients treated with cyclosporine, it was also associated with better kidney function and thus has the potential of extending the life of the renal graft," added Vincenti. "Of course, only time will tell how many patients may benefit from this new drug."

Alongside the BENEFIT study is BENEFIT-EXT, which included 543 recipients of extended criteria donors (defined as donors over 60 years old, over 50 years and with two other risk factors, or donation after cardiac death, or more than 24 hours with no blood supply to the organ). 394 patients completed the initial 12 months of this trial with similar results. The initial results of this study are also published in the American Journal of Transplantation.

Bone mineral density loss faster in those with kidney disease

Sat, 06 Feb 2010 15:20:08 PST

( from http://www.rxpgnews.com ) Even slight kidney impairment can speed up the loss of bone mineral density (BMD) among older people, putting them at risk of potentially disabling fractures, new research shows.

“Our findings highlight the importance of estimating kidney function when evaluating patients for fracture risk,” Sophie A. Jamal, MD, PhD, of the University of Toronto and her colleagues say in the February issue of the American Journal of Kidney Diseases, the official journal of the National Kidney Foundation.

Most people who have chronic kidney disease (CKD), or who are at risk for this condition, don’t know it, points out Dr. Kerry Willis, senior vice president for scientific activities at the National Kidney Foundation. “The new findings show the potential impact of early identification of kidney disease in preventing complications that can cause disability and premature death,” Dr. Willis said.

When a person’s kidney function is completely lost—a condition known as end-stage renal disease—he or she is at much greater risk of sustaining a hip fracture, Dr. Jamal and her colleagues explain in their report.

To better understand the relationship between more modest kidney impairment and bone loss, the researchers followed 191 men and 444 women age 50 and older for five years. They used two different techniques—estimated creatinine clearance and estimated glomerular filtration rate—to gauge patients’ kidney function at the beginning of the study. The first test measures how quickly the kidneys clear creatinine (a waste product), from the blood, and the second gauges the speed at which fluid flows through the kidney. Study participants also had their BMD measured at the beginning of the study and five years later.
Dr. Jamal and her team found that the people with impaired kidney function lost BMD faster than those whose kidneys were working normally. For example, the study participants with the worst kidney function showed a 9.3 percent greater decrease in their lower spine BMD over a five-year period compared to those with normally functioning kidneys. The results were basically the same with either kidney function measure.

“Not only is this a substantial loss, but equally concerning is that the bone loss occurs with even modest impairment of kidney function,” Dr. Jamal and her colleagues say.

To date, the National Kidney Foundation’s Kidney Early Evaluation Program (KEEP) has screened 130,000 high-risk individuals for CKD, Dr. Willis said. Anyone 18 and older who has high blood pressure, diabetes or a family history of kidney disease should be screened for CKD, she added, which can be done with three simple tests: blood pressure measurement, a urine test for the presence of a protein called albumin, and a blood test for creatinine.

“Osteoporosis can lead to potentially disabling fractures of the spine and hip,” she added. “Physicians should understand that even a slight decline of kidney function in their older patients could mean an increased risk of osteoporosis.”

Proteinuria, in addition to decreased glomerular filtration rate, has adverse outcomes

Tue, 02 Feb 2010 14:12:50 PST

( from http://www.rxpgnews.com ) Patients with high levels of proteinuria (protein in urine) in addition to another marker of reduced kidney function had an associated increased risk of all-cause death, heart attack or progression to kidney failure, according to a study in the February 3 issue of JAMA.

As many as 26 million Americans have chronic kidney disease (CKD). The current system for determining the stage of CKD is based primarily on the estimated rate of glomerular filtration (eGFR; measure of the kidneys' ability to filter and remove waste products) with lower eGFR associated with higher risk of adverse outcomes. "… the guidelines have been criticized because they do not incorporate information about the presence and severity of proteinuria an important marker of CKD that is associated with adverse outcomes," the authors write.

Brenda R. Hemmelgarn, M.D., Ph.D., of the University of Calgary, Alberta, Canada, and colleagues examined the association between reduced eGFR, proteinuria, and adverse clinical outcomes, including all-cause death, heart attack, and progression to kidney failure. The researchers analyzed data from a province-wide (Alberta) laboratory registry that included eGFR and proteinuria measurements for 2002 to 2007.

The researchers found that within each level of eGFR, there was substantial variability in risk with participants who had greater amounts of proteinuria having increased adjusted rates of all 4 adverse outcomes (all-cause death, heart attack, end-stage renal disease, and the doubling of serum creatinine measurement [corresponding to a 50 percent decline in kidney function]). Patients with heavy proteinuria but without overtly abnormal eGFR appeared to have worse clinical outcomes than those with moderately reduced eGFR but without proteinuria. Significant interactions between eGFR and proteinuria were observed for death, initiation of renal replacement, and doubling of serum creatinine.

"These findings are important because current guidelines for the classification and staging of CKD are based on eGFR without explicit consideration of the severity of concomitant proteinuria. In addition, computerized reporting of eGFR (generally without consideration of proteinuria) is increasingly used to assist physicians in identifying patients at high risk of adverse outcomes—or those who might benefit from specialist care. Although our findings do not directly address which patients would benefit from referral to a nephrologist, they do suggest that risk stratification performed in terms of eGFR alone is relatively insensitive to clinically relevant gradients in risk," the authors write. "These findings suggest that future revisions of the classification system for CKD should incorporate information from proteinuria."

Hypertension often missed in children with renal disease

Sun, 22 Nov 2009 08:57:10 PST

( from http://www.rxpgnews.com ) Blood pressure readings in children with chronic kidney disease often fail to detect hypertension – even during doctor’s office visits — increasing a child’s risk for serious heart problems, according to research from Johns Hopkins Children’s Center and other institutions. A report of the findings appears online in the Journal of American Society of Nephrology.

Researchers compared blood pressure measurements obtained during regular doctor visits to readings obtained via a special device the children wore at home that automatically recorded their blood pressure every 20 minutes.
Of the 198 children in the study, nearly 40 percent had “masked” hypertension, meaning their blood pressure was normal at the doctor’s office, but spiked outside of it.

An even more disturbing finding: Children with masked hypertension were four times more likely to have a form of hypertension-related heart damage called left ventricular hypertrophy (LVH) than children with normal blood pressure, researchers report. LVH is a common consequence of untreated hypertension that results in a thickening of the left chamber of the heart and that over time can lead to heart failure and heart rhythm disturbances.

“Taking blood pressure at the doctor’s office clearly misses many cases of masked hypertension,” says Susan Furth, M.D., Ph.D., a pediatric nephrologist at Hopkins Children’s and one of the study’s principal investigators. “This means children with chronic kidney disease should have their blood pressure taken at home several times a day and regularly reported to their doctors.” An overnight monitor, like the one used in the study, that automatically takes a child’s blood pressure every 20 minutes is great, but some insurance companies won’t pay for it, investigators say.

“Our findings are a sobering reminder of something we have long known: Blood pressure changes constantly throughout the day,” says study lead author Mark Mitsnefes, M.D., M.S., from the Division of Nephrology and Hypertension at Cincinnati Children’s. “We really can’t rely on a single measurement as a valid indicator.”

Investigators recommend that all children with chronic kidney disease get regular at-home readings of their blood pressure in addition to those taken during their visits to the doctor. Even though they used a different device in the study, researchers say many blood pressure monitors sold at drug stores are reliable but urge parents to talk to a doctor before choosing one.

Children who have repeated episodes of high blood pressure, researchers say, should also get a baseline echocardiogram, an ultrasound picture of the heart to evaluate heart muscle and function, and to get them every year thereafter.

This study was part of an ongoing NIH-funded research of chronic kidney disease in children, the largest to date, and involving more than 500 patients from 57centers. Hopkins Children’s is one of two clinical coordinating sites, along with the Children’s Hospital at the University of Missouri-Kansas City. The Johns Hopkins Bloomberg School of Public Health is the study’s data coordinating center.

Kidney disease in children tends to start and evolve silently. More than one-third (37 percent) of kidney transplant patients in 2001 were between the ages of 20 and 44, and the majority of them likely developed the disease in childhood, researchers say. Researchers estimate that 650,000 Americans will develop end-stage renal disease by 2010, costing the health care system $28 billion a year.

Eculizumab prevents kidney transplant rejection by inhibiting activation the complement system

Tue, 02 Jun 2009 14:25:35 PST

( from http://www.rxpgnews.com ) Early results from a Mayo Clinic research study demonstrate the effectiveness of a new approach to blocking an important part of the immune system that causes severe damage to some kidney transplants. Historically, these patients have been very difficult to treat successfully because their immune systems are already primed with antibodies to destroy the donor organ. These findings were presented today at the American Transplant Congress.

Results show that the drug under study, called eculizumab, prevents antibody-mediated kidney transplant rejection by inhibiting the immune system's activation of one of the body's important defense mechanisms -- the complement system. Antibody-mediated rejection is a major barrier to transplant in patients with antibodies against their living donors sometimes called "positive crossmatch kidney transplants."

Though the results are preliminary and the study is ongoing, Mayo Clinic's lead author, Mark Stegall, M.D., said the data suggest that eculizumab therapy may be a turning point for this select group of high risk kidney transplantation patients. "This innovative approach has the potential to make this type of high risk transplant possible for more people while improving outcomes," he says

Background

Positive crossmatch patients have antibodies in their blood against foreign "tissue types" that are present on donor kidneys. These tissue types, termed Human Leukocyte Antigens (HLA), are the reason the transplant patient's body perceives the donated kidney as "non-self" tissue. These antibodies result from previous transplants, blood transfusions or pregnancies.

Increasingly recognized as a major problem, high levels of these antibodies delay transplantation, as evidenced by the approximately 7,000 people on the United Network for Organ Sharing (UNOS) kidney waiting list who are still looking for a match. Mayo Clinic has long been a leader in devising innovative approaches to help this challenging group of kidney patients, and these latest findings about eculizumab add to the expertise and options offered to patients.

Significance of the Mayo Clinic research

This work suggests a novel way to block antibody-mediated tissue injury. The Mayo team showed that eculizumab blocks the part of the immune system known as the complement system, which initiates tissue destruction. In this study, 10 positive crossmatch kidney transplant patients were treated with eculizumab. None of the treated patients developed antibody-mediated rejection compared to historical controls in which 60 percent with similar levels of antibody would have developed antibody-mediated rejection.

"These results are great news because they mean that none of the treated patients developed the most serious complication that normally threatens the transplant. This represents a quantum leap in this area," explains Dr. Stegall.

Research rationale

High levels of antibodies were once considered an absolute contraindication to kidney transplantation; however, Mayo Clinic researchers and other groups have developed new protocols to successfully overcome antibody barriers -- mostly in the setting of living donation. Without such protocols, most of these patients would die without ever receiving a kidney transplant. Despite their general success, these protocols, which have been in use for almost a decade, have been complicated by a high rate of antibody-mediated damage which can lead to early graft injury that shortens the lifespan of the transplant. Preventing antibody-mediated rejection has been difficult. This new therapy may be a first step toward improved outcomes in these high-risk recipients.

Endothelial involvement

In addition to the 10-sample study in which tissue destruction was prevented in all patients, the Mayo team presented a related, more detailed analysis of the ability of eculizumab to prevent kidney damage at the microscopic level. This study involved 62 tissue biopsies from 50 kidney transplant patients. The biopsies were analyzed using the electron microscope for evidence of the mechanism and process of tissue destruction.

Results showed that when acute antibody-mediated rejection occurs, it involves changes observable by electron microscope in the endothelial cells lining the kidney blood vessels. These changes correspond with high levels of antibodies against the donor circulating in the patient's blood serum. And importantly, by blocking a specific part of the immune system with eculizumab, doctors prevented endothelial activation. These results suggest the endothelial lining may be a potential target for developing new drugs to stop antibody-mediated tissue destruction so that more positive crossmatch patients can be successfully transplanted. More research is needed to confirm these findings.

Three-variable and five-variable equations for eGFR recommended for pre-operative patients

Sun, 24 May 2009 10:25:46 PST

( from http://www.rxpgnews.com ) Although creatinine clearance (Ccr) has been measured clinically by a simple method as a preoperative renal function test, Ccr is not strictly equal to glomerular filtration rate (GFR). Recently, an equation for estimated GFR (eGFR) for Japanese individuals has been postulated, and eGFR has been accepted as equal to measured GFR in chronic kidney disease. However, there have been no previous studies regarding the reliability of eGFR as a preoperative renal function test.

A research article to be published on May 14, 2009 in the World Journal of Gastroenterology addresses this question. The research team led by Dr. Tokihiko Sawada from Dokkyo Medical University, Japan retrospectively calculated the preoperative three-variable and five-variable equations for eGFR, and compared the results with Ccr in patients undergoing hepatectomy.

One hundred and ninety seven patients undergoing hepatectomy between August 2006 and August 2008 were enrolled in this study. Preoperative Ccr, a three-variable equation for eGFR (eGFR3) and a five-variable equation for eGFR (eGFR5) were calculated. Abnormal values were defined as Ccr < 50 mL/min, eGFR3 and eGFR5 < 60 mL/min/1.73 m2. The maximum increases in the postoperative serum creatinine (post Cr) level and postoperative rate of increase in the serum Cr level (post Cr rate) were compared. There were 37 patients (18.8%) with abnormal Ccr, 31 (15.7%) with abnormal eGFR3, and 40 (20.3%) with abnormal eGFR5. Although there were no significant differences in the post Cr rate between patients with normal and abnormal Ccr, eGFR3 and eGFR5 values, the post Cr level was significantly higher in patients with eGFR3 and eGFR5 abnormality than in normal patients (P < 0.0001). Post Cr level tended to be higher in patients with Ccr abnormality (P = 0.0936 and P = 0.0875, respectively).

They concluded that eGFR5 and the simpler eGFR3, rather than Ccr, are recommended as a first-choice preoperative renal function test in patients undergoing hepatectomy.

Nephrologist care prior to starting dialysis reduces risk of death

Wed, 25 Mar 2009 16:13:34 PST

( from http://www.rxpgnews.com ) For patients with end-stage renal disease (ESRD), receiving care from a nephrologist in the months before starting dialysis reduces the risk of death during the first year on dialysis, reports a study in the May 2009 issue of the Journal of the American Society of Nephrology (JASN). The study also shows geographic "clusters" where pre-dialysis care for patients with advanced chronic kidney disease (CKD) is not optimal. "Assistance to improve pre-dialysis care might be profitably targeted to specific treatment centers and the health care systems they serve," comments William McClellan, MD (Emory University School of Medicine, Atlanta, GA).

Dr. McClellan and colleagues analyzed data on more than 30,000 patients starting dialysis in five of the 18 US ESRD Network regions. The researchers evaluated the quality of the patients' medical care in the months before their CKD progressed to ESRD, and how that affected the patients' outcomes on dialysis.

Just over half of the patients received at least six months of pre-dialysis care from a nephrologist, as recommended by current guidelines. For these patients, the chances of surviving the first year on dialysis were about 50 percent higher than for patients who did not receive at least six months of nephrologist care. Survival rates were higher at dialysis centers where more patients received recommended care.

The researchers also unexpectedly discovered that dialysis centers with the lowest rates of recommended pre-dialysis care tended to be "clustered geographically." For example, there was a "significant circular cluster" of low pre-dialysis care centers located in Alabama and Mississippi.

Although the reasons for the geographic variations in care are unclear, the results identify specific regions that might benefit from efforts to improve care for advanced CKD patients. "The Centers for Medicare & Medicaid Services are currently conducting a pilot quality improvement initiative in ten states to determine the feasibility of such efforts," says Dr. McClellan

Women drinking 2 or more cans of soda are at risk of albuminuria

Mon, 09 Feb 2009 11:52:10 PST

( from http://www.rxpgnews.com ) 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.

The study was published in PLoSONE, a peer-reviewed journal of science and medical research published by the Public Library of Science.

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.

Lower death rate in dialysis patients living at higher altitude

Tue, 03 Feb 2009 23:15:38 PST

( from http://www.rxpgnews.com ) Compared to dialysis patients living near sea level, dialysis patients living at an altitude higher than 4,000 feet have a 12-15 percent lower rate of death, according to a study in the February 4 issue of JAMA.

A recent study found that patients with end-stage renal (kidney) disease (ESRD) living at higher altitude achieved greater hemoglobin concentrations (a protein in red blood cells that primarily transports oxygen from the lungs to the rest of the body) while receiving lower doses of erythropoietin (a hormone that stimulates the production of red blood cells). Increased iron availability caused by activation of hypoxia-induced (oxygen deficiency) factors at higher altitude may explain this finding, according to background information in the article.

Wolfgang C. Winkelmayer, M.D., Sc.D., of Brigham and Women's Hospital and Harvard Medical School, Boston, and colleagues examined whether increased altitude would be associated with a reduced rate of death for patients initiating chronic dialysis. Using a comprehensive dialysis registry, the researchers identified 804,812 patients with ESRD who initiated dialysis between 1995 and 2004 and who met the study entry requirements. Most patients resided below an altitude of 250 ft. (40.5 percent) or between 250-1,999 ft. (54.4 percent). Only 1.9 percent of incident dialysis patients lived between 4,000 and 5,999 ft. and 0.4 percent higher than 6,000 ft. Patients were stratified by the average elevation of their residential zip code.

Compared with patients living at lower altitudes (less than 250 ft.), the rate of death was reduced for patients living from 250-1,999 ft. by 3 percent; from 2,000 through 3,999 ft. by 7 percent; from 4,000 to 5,999 ft. by 12 percent; and higher than 6,000 ft. by 15 percent.

Actuarial 5-year survival was 34.8 percent for patients living at or near sea level but was 42.7 percent among those living at an altitude higher than 6,000 ft.; patients in the highest elevation group experienced a 7.9 percent greater absolute or 22.7 percent greater relative 5-year survival. Median (midpoint) survival after initiation of dialysis was 3.1 years for those living lower than 250 ft. but was 4.0 years for those living at an altitude higher than 6,000 ft., for a difference in median survival of 0.9 years between these 2 groups.

While a decrease in age- and sex-standardized mortality at higher altitude was also observed in the general population, the magnitude of the risk reduction was half of that observed in the ESRD population.

"In conclusion, we found a graded reduction in mortality from any cause in ESRD patients residing at greater altitude, a finding that was not explained by differences in observed patient characteristics. The magnitude of this observation was markedly greater than the observed small reduction in mortality at higher altitude in the general population. We propose that hypoxia-inducible factors are persistent at high altitude in patients with ESRD and may confer protective effects," the authors write.

Normograms to predict long-term outcomes in renal transplants

Sat, 24 Jan 2009 16:42:37 PST

( from http://www.rxpgnews.com ) Kidney transplants are the best available therapy for end stage renal disease. Because of the shortage of deceased organ donors, living donor transplantation is rapidly growing and has the advantage of improved outcomes over deceased donor transplants. In fact, a transplant candidate may now have several potential living donors and the clinician may need to identify which donor would yield the best results. In a study published in the March 2009 issue of The Journal of Urology, researchers report on the development and validation of three nomograms that can reliably predict long-term outcomes.

A nomogram is an objective tool that uses an algorithm or mathematical formula to predict the probability of an outcome. Nomograms have been shown to outperform clinicians in predicting oncological outcomes and may be of benefit in certain decision-making settings. Nomograms can sift through the multitude of donor and recipient parameters that impact transplant outcome and help transplant physicians to better counsel their patients.

Using records from over 20,000 living donor transplant cases taken from the United Network for Organ Sharing (UNOS) registry, investigators from the Renal Transplantation Program, Glickman Urological & Kidney Institute at the Cleveland Clinic identified 18 characteristics, such as donor and recipient ages, donor serum creatinine levels and the cause of the recipient's renal failure. By using the value of each factor to determine a point score and totaling all of the points, the nomograms were able to predict kidney function 1 year after transplant and 5-year transplant survival. By adding 3 additional factors obtained 6 months after surgery, another nomogram was developed to refine the 5-year survival prediction.

Writing in the article, D. A. Goldfarb states, "Our work is consistent with the transplant physician community's efforts to develop better predictive tools...the nomograms developed in this study take this effort a step further by using a greater number of variables including early posttransplant information for better predictability and by attempting to predict specific outcome measures of renal function in addition to long term graft survival... These models can help to optimize the selection of living kidney donors. The prognostic information these models provide can help improve patient care."

Clear advantage of high efficacy Haemodiafiltration over conventional hemodialysis

Sat, 29 Nov 2008 03:18:57 PST

( from http://www.rxpgnews.com ) Suffering from end-stage renal disease (ESRD), a growing number of patients at the Centre hospitalier de l'Université de Montréal (CHUM), have become the beneficiaries of a North American breakthrough: high efficacy hemodiafiltration (HDF).

An extracorporeal blood purification technique, HDF is indicated for ESRD patients. Since the HDF unit was introduced in CHUM's Nephrology section, preliminary results show a clear advantage of high efficacy HDF over conventional hemodialysis in several areas, including the following:

Improved removal of uremic toxins;
Decreased number of hospitalization days;
A better tolerance for patients;
Minimizes the state of chronic inflammation that too often may lead to complications over a long course of dialysis;
Diminished need for certain medications.
Increased biocompatibility across the blood-dialysis system interface.

"Conventional hemodialysis continues to save lives, but we now have the technology to improve the lot of dialysis patients," says Dr. Rénee Lévesque, nephologist and lead physician in the HDF program at CHUM, and a professor with the medical faculty of the Université de Montréal. "At CHUM, we're proud to soon be accepting a cohort of forty patients undergoing HDF." Dr. Lévesque added that the CHUM Nephrology section is putting much efforts behind the new process, and hopes that one day soon all dialysis patients will be treated in this fashion.

Recent retrospective clinical data indicate 1, 2 that HDF reduces the mortality rates of dialysis patients and randomized studies are under way to provide clear proof of increased survival rates for patients. Among these, the CONTRAST3 study compares hemodialysis with online hemodiafiltration HDF in overall performance relative to cardiovascular morbidity and mortality. The study seeks to recruit seven hundred test subjects and follow them over a three-year period. CHUM is the only medical centre in North America to take part in this study, currently the largest in terms of the size of the randomized cohort.

Hemodiafiltration : the best of both worlds

HDF combines the elements of two processes, conventional hemodialysis (HD) and hemofiltration (HF). Renal replacement therapy for ESRD is based on two processes: diffusion and convection.

Conventional HD is diffusive; blood is circulated in an artificial kidney machine on one side of a semi-permeable membrane, while a special dialysis fluid is circulated on the other side. Small molecules of metabolic waste seep out into a dialysis solution flowing in the opposite direction on the other side of the membrane, mimicking the kidneys and washing wastes and toxins out of the bloodstream. One major toxin is urea. HD is the most widely used renal replacement function technology for ESRD.

Hemofiltration (HF) or ultrafiltration is exclusively convective, forcing blood through a filter under high pressure. The principle consists of applying a hydrostatic pressure gradient (high pressure on one side, low pressure on the other) across the membrane or filter. This results in an ultrafiltrate (water and electrolytes) on the other side. The quantity of ultrafiltrate lost in this process must be compensated by a matching infusion of replacement fluid. HF is used primarily in continuous mode and in acute care or intensive care.

In HDF, the diffusive component of HD is combined with the convective component of HF. As is the case in HF, the excessive loss of liquid must be compensated by the reinfusion of a sterile and apyrogenic fluid. Recent developments have led to the "on-line" production of large volumes of ultrapure liquid of high quality. This has led to higher quality physicochemical and microbiological properties in these solutions, in comparison with HD.

Atlas of kidney genome created

Thu, 13 Nov 2008 10:43:03 PST

( from http://www.rxpgnews.com ) A comprehensive genome-based atlas, created by researchers, would help shed light on healthy and abnormal kidney development and disease. The atlas shows how the entire genome is regulated to produce thousands of specific genes that are mixed and re-mixed to form genetic teams.

It is the joint outcome of the work by Cincinnati Children's Hospital Medical Centre, Institute for Molecular Bioscience - University of Queensland - and Harvard University researchers.

The teams jointly directed formation of 15 embryonic sections in developing kidney - from the earliest phases when stem cells are told how to differentiate into specific kidney cells, to the development of nephrons, the kidney's primary functioning unit.

Given that about one in every 500 births results in a kidney development abnormality, the study is a beginning for providing new insight into genes and genetic programmes that are critical to determining how kidney stem cells develop into structures in the adult kidney.

'Researchers can refer to the atlas to see the gene expression patterns in a normal developing kidney,' said Melissa Little, a professor who led the Australian team.

'It will provide a basis of comparison for scientists studying abnormal kidney development, so they can see where gene interactions have gone awry to produce the abnormality.'

Researchers created the atlas by analysing mouse embryonic kidneys aged 15.5 days, according to a University of Queensland release.

One of the more unexpected discoveries was the observation of new domains of gene expression that marked clusters of cells not previously known to be distinct.

The data has been released as an open-access resource for researchers around the world as part of the GenitoUrinary Development Molecular Anatomy Project.

NICE issues guidelines for chronic kidney disease- early identification and management

Sat, 27 Sep 2008 08:17:35 PST

( from http://www.rxpgnews.com ) The new National Institute for Health and Clinical Excellence (NICE) guidelines for the management of early kidney disease were issued on the 24th of September 2008. It focuses on the early identification of renal disease in high risk individuals (i.e. in patients with diabetes mellitus, hypertension, multisystem disorders, cardiovascular disease and those with family history of kidney disease), management of risk factors and early kidney disease and appropriate referral for specialist care.

Dr Gillian Leng, NICE Deputy Chief Executive, and Executive Lead for this guideline said: "Chronic kidney disease often has no symptoms so can go undetected, potentially leading to serious health problems. This new guideline will help save lives and prevent ill-health by advising how to identify people at risk of CKD at an early stage. The guideline recommends offering people a simple test for CKD if they have risk factors like diabetes, high blood pressure, cardiovascular disease and a family history of kidney failure. This will ensure that they get advice and treatment as quickly as possible, which in most cases will allow them to stay healthy."

There has been an emphasis placed on using urine albumin–creatinine ratio (ACR) for detecting proteinuria as it is more sensitive than a protein–creatinine ratio. Subsequently, physicians may choose to quantify or follow up proteinuria with PCR monitoring. ACR is the preferred method in patients with diabetes.

A lot of emphasis has been placed on the monitoring of the GFR (glomerular filtration rate). Stages of chronic kidney disease has been updated to the following

Stage GFR (ml/min/1.73m2) Description
1 ≥ 90 Normal or increased GFR, with other evidence of kidney damage
2 60–89 Slight decrease in GFR, with other evidence of kidney damage
3A 45–59 Moderate decrease in GFR, with or without other evidence of kidney damage
3B 30–44
4 15–29 Severe decrease in GFR, with or without other evidence of kidney damage
5 < 15 Established renal failure
Use the suffix (p) to denote the presence of proteinuria when staging CKD

Particularly useful is the section which deals with criteria for referral to a nephrologist. It is recommended that the following groups of patients be refered to the specialist.
1)stage 4 and 5 CKD (with or without diabetes)
2)higher levels of proteinuria (ACR 70 mg/mmol or more, approximately equivalent to PCR 100 mg/mmol or more, or urinary protein excretion 1 g/24 h or more) unless known to be due to diabetes and already appropriately treated
3)proteinuria (ACR 30 mg/mmol or more, approximately equivalent to PCR 50 mg/mmol or more, or urinary protein excretion 0.5 g/24 h or more) together with haematuria
4) rapidly declining eGFR (more than 5 ml/min/1.73 m2 in 1 year, or more than 10 ml/min/1.73 m2 within 5 years)
5) hypertension that remains poorly controlled despite the use of at least four antihypertensive drugs at therapeutic doses
6)people with, or suspected of having, rare or genetic causes of CKD
7)suspected renal artery stenosis.
Furthermore patients with chronic kidney disease and renal outflow obstruction should normally be referred to urological services.

Lifestyle advice and patient education has been dealt with. Health professionals should work with people who are more likely to have progressive kidney disease to maintain the best possible health, and check their kidney function regularly. This includes people who: have cardiovascular disease, diabetes, proteinuria,are of African-Caribbean or Asian ethnicity; smoke; take long-term non-steroidal anti-inflammatory medicines or have chronic urinary tract obstruction. Blood pressure targets are to keep the systolic pressure below 140 mm Hg and diastolic pressure below 90 mm Hg for patients with CKD in keeping with previous NICE hypertension guidelines. Blood pressure targets for CKD patients with diabetes mellitus or patients with ACR equal to or greater than 70 mg/mmol are to keep the systolic pressure below 130 mm Hg and diastolic pressure below 80 mm Hg. ACE inhibitors and ARBs should be the first choice of antihypertensives for patients with CKD and diabetes or ACR of 70 mg/mmol or more. Statin use and treatment of renal bone disease has been covered for early kidney disease. Treatment of anaemia has not been covered as there is a separate NICE guideline for that.

Finally it is worth noting that it does not cover patient with end stage renal disease on renal replacement therapy, renal dysfunction in pregnant women, short lasting renal dysfunction or renal disease in children under 16 years of age.

Night-time kidney transplants less successful

Tue, 15 Jul 2008 12:37:15 PST

( from http://www.rxpgnews.com ) Kidney transplants should be carried out during the day if possible. At least this is the conclusion suggested by a survey just published by urologists and internists at the University of Bonn (Transplantation Proceedings, vol. 40, p. 1341 ff.). Hence operations carried out at night require a further operation more than twice as often as other operations. Moreover, the risk of premature failure of the transplant is higher with operations taking place at night. The reason is probably that the surgeon is more alert and focused during the day. Particularly with a complicated procedure such as a transplant, surgical skill is a critical factor for success. Still, currently every third kidney transplant is performed at night, as donor organs should be as fresh as possible.

The medics from Dr. Guido Fechner and Professor Stefan Müller's Bonn team scrutinised a total of 260 kidney transplants. Over 60 per cent had been carried out during the day, the remainder between eight in the evening and eight o'clock in the morning. More than 16 per cent of all the 'night kidneys' had to be operated on a second time in the month following the transplant due to surgical complications. With the 'day kidneys', the complications rate was significantly less, being over six per cent.

On average transplanted kidneys last nine years, but there are also transplants that still work well after more than 20 years. The time when the operation took place here too seems to be a critical factor. 'For "day kidneys" there is a higher than 90 per cent chance that they will function flawlessly even five years after the transplant,' Dr. Guido Fechner explains. 'With "night kidneys" the figure is only 80 per cent.'

The reason presumed for this is that kidney transplants are comparatively complicated procedures. Accordingly, they require a brain that is alert. However, the donated organs are often transplanted during the night shift. 'It was long believed that kidneys had to be as fresh as possible, at all cost, for the transplant to be successful,' Guido Fechner says. It is currently perceived as ideal if the organ is reinserted 18 hours after its removal at the latest. 'Rescheduling a kidney transplant within this time frame, say from 5 a.m. to 8 a.m., without the transplant suffering, is definitely feasible,' he emphasises. 'Instead operations are performed as early as possible, even if that means the urologist has to work at night.'

An alternative is a living kidney donation during which the kidney is taken from a living donor and is immediately inserted into the recipicent. This always happens during the day.

AVOID study shows Aliskiren decreasing albuminuria

Thu, 12 Jun 2008 11:35:08 PST

( from http://www.rxpgnews.com ) The much awaited results of the AVOID (Aliskiren in the eValuation of prOteinuria In Diabetes) study were published in the June 5th edition of the New England Journal of Medicine. It is the first study which looked at the kidney-protective benefits of Aliskiren, independent of its proven blood pressure reductions.

About the study
The AVOID study is one of the trials in the landmark ASPIRE HIGHER clinical trial program, the largest ongoing cardio-renal outcomes program involving more than 35,000 patients in 14 trials. The ASPIRE HIGHER program is studying the effect of direct renin inhibition in a variety of cardiac and renal conditions.

Mechanism of action
Aliskiren is an oral renin inhibitor. Renin is secreted by the kidney in response to decreases in blood volume and low renal perfusion. Renin cleaves the peptide angiotensinogen to the inactive decapeptide angiotensin I. Angiotensin I is converted to the active octapeptide angiotensin II by angiotensin-converting enzyme (ACE) produced in the lungs. Angiotensin II is a vasoconstrictor and also promotes aldosterone secretion and sodium reabsorption, which increases blood pressure. It provides a negative feedback to decrease the production of renin. This cycle is known as the renin-angiotensin-aldosterone system. Thus, as a direct renin inhibitor, aliskiren disrupts the RAAS process by decreasing plasma renin activity (PRA).

Method and findings
599 patients were involved in this multinational, randomized, double-blind study. Initially all patients received 100 mg of losartan daily and then they were randomly assigned to receive 6 months of treatment with aliskiren (initially 150 mg and then increased to 300 mg) or placebo, in addition to losartan. The primary outcome seen was a reduction in albuminuria by an additional 20% in type 2 diabetic patients with kidney disease who also had a diagnosis of high blood pressure. These patients were already taking the maximum dose of the angiotensin-receptor blocker (ARB) losartan.As far as side effects were concerned, hyperkalemia reported as an adverse event was seen in 5% of patients taking Aliskiren in addition to losartan, compared to 5.7% of those taking placebo plus losartan. Hyperkalemia as a laboratory abnormality was seen in 13.7% of patients on aliskiren and losartan, compared to 10.8% of the patients taking placebo and losartan.

It, therefore, appears that aliskiren in addition to optimising blood pressure treatment, has additional benefits. But whether a decrease in albuminuria will translate into slowing the decline of renal function is still to be seen . Perhaps, the ALTITUDE study, which is planning to enroll 8500 patients in 36 countries and is due to report results in 2011, will provide the answer.

ASTRAL Trial-Angioplasty and stenting offer no benefit over medical therapy

Tue, 01 Apr 2008 13:44:05 PST

( from http://www.rxpgnews.com ) The largest-ever randomized study to evaluate the effectiveness of catheter-based interventions in patients with narrowing of the renal artery has shown that angioplasty and stenting offer no benefit over medical therapy. Among patients who completed one year of follow-up, there were no differences in the change in kidney function, blood pressure control or the rates of major cardiovascular illness, according to the Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) trial.

The ASTRAL trial is being reported today in a Late-Breaking Clinical Trials session at the SCAI Annual Scientific Sessions in Partnership with ACC i2 Summit (SCAI-ACCi2) in Chicago. SCAI-ACCi2 is a scientific meeting for practicing cardiovascular interventionalists sponsored by the Society for Cardiovascular Angiography and Interventions (SCAI) in partnership with the American College of Cardiology (ACC).

The study also found that 3 percent of patients who underwent renal artery intervention experienced a serious procedural complication, including poorly positioned stents and perforation and dissection of the renal artery.

“For 15 years we’ve had the wherewithal to fix renal artery stenosis and restore patency of the renal artery,” said Philip A. Kalra, MD, a consultant nephrologist at Hope Hospital, Salford, and lecturer at the University of Manchester, both in the United Kingdom. “Thousands of patients have had this procedure, but no one has ever demonstrated any benefit in randomized control trial testing.”

About 7 percent of people over age 65—and about 10 percent of people with chronic kidney disease who eventually need dialysis—have narrowing, or stenosis, of the renal artery. There are several links between renal artery stenosis and cardiovascular disease. For example, in nine out of 10 cases renal artery stenosis is caused by the build-up of atherosclerotic plaque. Many patients with renal artery stenosis also have coronary and peripheral arterial disease; indeed, these conditions share common risk factors. At least 30 percent of older patients with chronic congestive heart failure have renal artery stenosis. Perhaps most important, uncontrolled high blood pressure often prompts physicians to suspect renal artery stenosis—and to treat it with angioplasty and stenting.

To evaluate the clinical effectiveness of renal artery stenting, Dr. Kalra and his colleagues recruited 806 patients with atherosclerotic renal vascular disease (ARVD) from 54 medical centers in the United Kingdom, and four in Australia and New Zealand. Patients had renal failure, with an average serum creatinine of about 2.0 mg/dL. Baseline blood pressure averaged 151/76 mm Hg. More than half were current or ex-smokers, nearly one-third had diabetes and nearly half had coronary artery disease. The degree of renal artery stenosis at baseline was 76 percent, on average.

The researchers randomly assigned patients to catheter-based intervention plus medical therapy or medical therapy alone. Renal artery stenting was successful in widening the renal artery, achieving a residual stenosis of less than 50 percent in 88 percent of patients.

After one year of follow-up, however, there were no differences in the change in serum creatinine—it rose by 0.2 mg/dL in both groups—or in rates of renal events, including acute renal failure. Even in the highest-risk patients—those with a baseline creatinine in the highest third, or who had experienced a rapid deterioration in kidney function in the preceding year—renal artery angioplasty and stenting offered no significant renal functional benefit at one year, but patient numbers in these sub-groups were fairly small.

Blood pressure fell slowly over time, and by four years, averaged 146/74 mm Hg in both groups. At one year, there was no significant difference in the rates of heart attack, stroke, hospitalization for chest pain or heart failure or the need for coronary intervention or bypass surgery. Risk-adjusted mortality was the same in the two groups.

“In this study we were looking at the majority of patients with renal artery stenosis—those in whom there is substantial uncertainty about whether to revascularize,” Dr. Kalra said. “The message is, you don’t put a stent in these patients without more careful evaluation. More often than not, it will make no difference whatsoever in clinical outcomes. However, some patients with renal artery stenosis have more definite indications for revascularization, such as acute renal failure or severe acute heart failure, and they should continue to receive this therapy.”

Dr. Kalra will present the results of the "Angioplasty and Stenting for Renal Artery Lesions” (ASTRAL) study on Tuesday, April 1 at 10:45 a.m. CDT in the Grand Ballroom, S100.

Renal patients still being referred late

Sun, 02 Mar 2008 03:09:27 PST

( from http://www.rxpgnews.com ) Some patients with kidney disease aren’t referred to kidney specialists in time to delay disease progression and improve their prognosis for a variety of reasons, according to researchers at Wake Forest University School of Medicine and colleagues.

An analysis of 18 separate studies found that overall, being older, belonging to a minority group, being uninsured and suffering from multiple health problems are patient characteristics associated with late referral. In addition, a lack of communication between referring physicians and nephrologists also contribute to the problem. The findings were published online this week by BioMed Central Nephrology.

Research has shown that the progression from chronic to end-stage kidney disease, which requires dialysis treatments, can be slowed if kidney damage is detected and treated early. Care by nephrologists, who specialize in treating kidney disease, is associated with reduced rates of hospitalization and death. However, studies indicate that up to 80 percent of patients who start dialysis are referred late to nephrologists.

“Late referral has been documented as a problem for more than 15 years and, according to recent studies, is not declining,” said Sonal Singh, M.D., senior author and an assistant professor of general internal medicine. “Finding ways to address the problem has been hampered by a lack of understanding of the factors responsible.”

About 26 million Americans suffer from chronic kidney disease and it is estimated that there will be 700,000 cases of end-stage kidney disease by 2015. The National Kidney Foundation recommends that patients with kidney disease be referred to nephrologists when they reach stage 4, which is a severe decrease in kidney function.

The researchers analyzed 18 studies on late referrals and looked for trends in results. They included studies that used the National Kidney Foundation’s definition of “late” as well as studies using earlier definitions, such as referrals that were one, three or six months before dialysis was initiated.

Singh and colleagues found that in North America, increasing age was associated with late referral, with several studies showing that being over age 75 resulted in a late referral.

“One study showed that even being older than 55 is associated with late referral so it is prudent to assume the risk for delayed referral increases with age,” said Singh.

The researchers said that lack of provider knowledge about the appropriate timing of referral may account for more than 25 percent of late referrals.

“The study has important implications for both clinicians and policy makers,” said Singh. “In the future, referral guidelines should be prepared in collaboration with primary care physicians, and co-management approaches for chronic kidney disease need to be explored.”

Tushar Vachharajani, M.D., an interventional nephrologist at Wake Forest Baptist who was not involved in the study, said there are multiple benefits of early referral. Early treatment by a nephrologist can help slow disease progression, but even if dialysis is inevitable, an early referral gives patient and family time to plan for the treatment.

“Patients need time to prepare mentally and physically for dialysis,” he said. “Dialysis requires a 360-degree change in lifestyle.”

He also noted that end-stage kidney disease is among the most expensive to treat on a per-capital basis. “Growing health care costs makes it mandatory to practice prevention before treating a problem whenever possible,” he said.

Emory algorithm helps improve kidney transplant chances

Fri, 02 Mar 2007 11:51:22 PST

( from http://www.rxpgnews.com ) Approximately one-third of the patients on the national waiting list for kidney transplants have only a small chance of receiving a new organ, no matter how long they are on the list. Due to prior transplants, pregnancies or blood transfusions, these patients have developed antibodies that make it very difficult to match them with donor organs.
Researchers at Emory University have developed a decision process, based on innovative technology, that may help to level the transplant playing field and give new hope to these "highly sensitized patients." The Emory Algorithm, as this new method is known, may even change the way kidneys from deceased donors are allocated in the United States.

Sensitized patients have developed antibodies against human leukocyte antigens (HLAs), which play an important role in the body's immune response to foreign tissue. These patients represent one-third of the national waiting list for kidney transplant patients (50 percent in Georgia), but they only receive about 15 percent of deceased-donor kidney transplants each year.

The United Network for Organ Sharing (UNOS) coordinates the nation's transplant system through a point system based primarily on wait time, sensitization and HLA matching. When a "perfect match" occurs, the kidney is offered to the person at the top of the national list. If there are no perfect matches nationally, the kidney becomes available to transplant centers in the region from which it came.

The Emory Algorithm, while still following these guidelines, allows a transplant center to predict which sensitized patients on the list will be compatible with any given donor. A five-year Emory study, published in the October 2006 issue of the American Journal of Transplantation, found the algorithm raised the rate of transplants from 15 percent to 25 percent in sensitized patients by accurately predicting which of these patients would be compatible with the donor kidney. The survival rate of a kidney transplant in sensitized patients in the five-year study was almost identical to that of unsensitized recipients--66 percent vs. 70 percent.

The algorithm was developed by Emory immunologists Robert Bray, PhD, and Howard Gebel, PhD, along with Emory transplant surgeons Christian Larsen, MD, DPhil and Thomas Pearson, MD, DPhil. They used a relatively new technology of single-antigen bead assays, which gives a more specific analysis of HLA antibodies by identifying a single antibody at a time versus general groups of antibodies. The algorithm allows immunologists to inform transplant surgeons with a high degree of confidence whether a kidney from a deceased donor is a compatible match with a recipient.

"Each of us has a constellation of HLAs, with six major ones related to kidney transplantation and dozens of specific HLAs within each of those antigen groups," says Dr. Bray. "Studies show the more antigens a donor and recipient share, the better the survival rate of the transplanted kidney. With the older technique of cross matching HLA cells with the blood of a potential recipient, we couldn't always identify which HLAs the antibodies were targeting. False readings could occur."

A decade ago Drs. Bray and Gebel helped One Lambda, Inc., an HLA diagnostic company in California, develop and test its single-antigen bead assays. Each bead is coated with a single HLA antigen produced by recombinant DNA technology. Different HLA molecules are bound onto different antigen beads. The beads are mixed with the recipient's blood and placed in a flow cytometer. A laser reads which antibodies, if any, are attached to the HLA molecules on the beads. A computer collects and organizes the results.

While some transplant centers use these same single assay tests to identify HLA antibodies, they don't incorporate the data into their cross-matching process. Prior to the Emory Algorithm, highly sensitized patients may have been at a disadvantage due to the time constraints in the organ donor process, which did not allow transplant centers to determine if they could receive the kidney that was available. At Emory, sensitized patients have an increased chance of receiving a transplant.

"Kidney transplantation is the optimal treatment for end-stage renal disease, and being able to offer transplantation to this population is a significant advance," says Dr. Pearson.

Based on results of the Emory study, a UNOS committee is looking at the algorithm as UNOS reevaluates its kidney allocation system. The committee is expected to make recommendations this year, according to Mark Stegall, MD, a transplant surgeon at the Mayo Clinic who chairs this committee. Dr. Pearson also sits on the committee.

"I hope the algorithm process will become national policy as part of an overall kidney allocation policy," Dr. Stegall says. "Eighty percent of transplant programs are using the single-antigen bead technology, but relatively few are using that data as a way to allocate kidneys to sensitized patients." But Dr. Stegall is not ready to commit to a system based only on organ compatibility as determined by antibodies. "Kidneys are a scarce resource," he says. "We have to put sensitization in perspective. There is always an unsensitized patient out there."

The Emory algorithm helps equalize the allocation scheme, Dr. Pearson says. With this system everyone on the waiting list would be considered for an available kidney, but only the best match would receive it. "We have to balance priorities to try and help as many people as possible," he says.

"There is a perception that patients who are highly sensitized have poor outcomes," says Gebel, "but that is not our experience."

Kidney stones? Have some orange juice!!!

Fri, 01 Sep 2006 17:13:37 PST

( from http://www.rxpgnews.com ) A daily glass of orange juice can help prevent the recurrence of kidney stones better than other citrus fruit juices such as lemonade, researchers at UT Southwestern Medical Center have discovered.

The findings indicate that although many people assume that all citrus fruit juices help prevent the formation of kidney stones, not all have the same effect. The study is available online and is scheduled to be published in the Oct. 26 issue of the Clinical Journal of the American Society of Nephrology.

Medically managing recurrent kidney stones requires dietary and lifestyle changes as well as treatment such as the addition of potassium citrate, which has been shown to lower the rate of new stone formation in patients with kidney stones.

But some patients can't tolerate potassium citrate because of gastrointestinal side effects, said Dr. Clarita Odvina, assistant professor of internal medicine at the Charles and Jane Pak Center for Mineral Metabolism and Clinical Research and the study's lead author. In those cases, dietary sources of citrate such as orange juice may be considered as an alternative to pharmacological drugs.

"Orange juice could potentially play an important role in the management of kidney stone disease and may be considered an option for patients who are intolerant of potassium citrate," Dr. Odvina said.

All citrus juices contain citrate, a negatively charged form of citric acid that gives a sour taste to citrus fruits. Researchers compared orange juice and lemonade juices with comparable citrate contents and found that the components that accompany the citrate can alter the effectiveness of the juice in decreasing the risk of developing new kidney stones.

Kidney stones develop when the urine is too concentrated, causing minerals and other chemicals in the urine to bind together. Over time, these crystals combine and grow into a stone.

In the UT Southwestern study, 13 volunteers some with a history of kidney stones and some without underwent three phases, each lasting one week. Chosen in random order, the phases included: a distilled water or control phase; an orange juice phase; and a lemonade phase. There was a three-week interval between phases.

During each phase, volunteers drank 13 ounces of orange juice, lemonade or distilled water three times a day with meals. They also maintained a low-calcium, low-oxalate diet. Urine and blood samples were taken at intervals during each phase. The study was done at UT Southwestern's General Clinical Research Center.

Orange juice, researchers found, boosted the levels of citrate in the urine and reduced the crystallization of uric acid and calcium oxalate the most frequently found ingredient in kidney stones.

But lemonade did not increase the levels of citrate, an important acid neutralizer and inhibitor of kidney stone formation.

"One reason might be the different constituents of various beverages," Dr. Odvina said.

For instance, the citrate in orange and grapefruit juice is accompanied by a potassium ion while the citrate in lemonade and cranberry juice is accompanied by a hydrogen ion. Ions of hydrogen, but not potassium, counteract the beneficial effects of the high citrate content.

"There is an absolute need to consider the accompanying positive charge [of hydrogen ions] whenever one assesses the citrate content of a diet," Dr. Odvina said.

NOTCH2 gene mutations linked to Alagille syndrome

Tue, 01 Aug 2006 13:29:37 PST

( from http://www.rxpgnews.com ) In a finding that may have broader implications for understanding kidney disorders, genetics researchers at The Children's Hospital of Philadelphia have identified a second gene that gives rise to Alagille syndrome, a genetic developmental disease that affects multiple organs. The Children's Hospital team previously discovered the first gene associated with this disease.

The researchers found that mutations in the NOTCH2 gene were linked to kidney abnormalities in patients and families. "While Alagille syndrome is relatively rare, organ diseases are not rare, and our findings suggest that genes on this biological pathway may have a broader role in kidney disorders," said study leader Nancy B. Spinner, Ph.D., a geneticist at The Children's Hospital of Philadelphia.

The study appears in the July issue of the American Journal of Human Genetics.

Dr. Spinner led the Children's Hospital team that identified mutations in the JAG1 gene as a cause of Alagille syndrome in 1997. Like the NOTCH2 gene analyzed in the current study, JAG1 is part of a signaling pathway that governs important processes in early human development.

Alagille syndrome, estimated to occur in one in 20,000 individuals, is a complex disorder, primarily affecting the liver, heart, eyes, face and skeleton. Some patients with Alagille syndrome have very mild symptoms or isolated problems, while others may have severe, life-threatening heart or liver defects.

Both the JAG1 and the NOTCH2 genes participate in the Notch signaling pathway. JAG1 codes for the ligand Jagged1, a signaling protein that triggers receptors in the pathway. The NOTCH2 gene codes for Notch2, which is one of those receptors. The pathway as a whole is active during embryonic development, and transmits signals to cells to develop into specialized organs. Mutations in those genes are thought to disrupt normal development, by, for instance, causing the defective bile ducts found in the livers of many patients with Alagille syndrome.

"Ligands and receptors are like keys and locks," said Dr. Spinner. "If either one is defective, it may interfere with normal growth and development."

Dr. Spinner's team previously determined that 94 percent of patients diagnosed with Alagille syndrome had mutations in the JAG1 gene. In the current study, they analyzed 11 patients with Alagille syndrome who did not have the JAG1 mutation, and found that two of them had mutations in NOTCH2. Furthermore, the patients had three family members, all mildly affected, who also had the same mutation. All five individuals had kidney disease.

Because their study identified only two families with NOTCH2 mutations, said Dr. Spinner, it is not definitive in establishing that those mutations cause a distinct variety of Alagille syndrome. However, it is the first study to report that mutations in the NOTCH2 gene cause human disease. Dr. Spinner is planning further studies to better characterize the role of NOTCH2 mutations and the Notch signaling pathway in the wider population of patients with kidney disorders.

She also will investigate liver involvement in Alagille syndrome under the Rare Diseases Clinical Research Network, recently established by the National Institutes of Health. "Part of the rationale for this research network is that, collectively, relatively rare diseases added together constitute a significant portion of the population," said David A. Piccoli, M.D., chief of Gastroenterology and Nutrition at Children's Hospital and a co-author of the study. "Another rationale is that studying relatively rare diseases may offer insights into more common diseases and into health in general."

Fetal hydronephrosis mystery solved

Wed, 03 May 2006 00:13:37 PST

( from http://www.rxpgnews.com ) Researchers seeking insights into kidney failure in human infants have located the source of a 30-year-old mystery mutation that causes similar problems in a mouse line.

Scientists have known of the mouse line's naturally occurring mutation since the early 1970s. Researchers at Washington University School of Medicine in St. Louis are the first to identify the mutated gene, allowing them to determine the mutation's effects and the origins of the disease.

"The gene codes for a protein that moves water across membranes, and we showed that the mutated form of the protein doesn't get properly distributed in the urinary system," says senior author Feng Chen, Ph.D., assistant professor of medicine. "If something similar happens in human disorders, one way to treat such diseases would be to redirect the protein to its appropriate location."

Results from Chen and his colleagues are published online in the Proceedings of the National Academy of Sciences.

Ultrasonic scans reveal fetal hydronephrosis, or enlargement of the kidney, in approximately 1 in every 100 human fetuses. The condition results from impairment of passage of urine from the kidney to the bladder. About 20 percent of those cases lead to clinical complications that, if left untreated, can include kidney failure and death.

Scientists suspect a variety of environmental and genetic factors contribute to fetal hydronephrosis. However, they frequently cannot tie it to any causative factors, making it difficult to determine how normal molecular and cellular processes in kidney development break down in infants affected by the condition.

Researchers at The Jackson Laboratory first noted the mouse line's mutation in the early 1970s when some of the mice developed enlarged bellies and died within three to four weeks of their birth. Scientists initially assumed that the mutation was causing a form of polycystic kidney disease, but a follow-up study more than a decade later showed that passage of urine from the kidney was blocked, and the condition was renamed congenital progressive hydronephrosis.

With assistance from the mouse genome sequence and Li Ding, Ph.D., a research instructor at the Genome Sequencing Center at Washington University, Chen and his colleagues showed that the protein mutated in the mice is aquaporin 2 (aqp2), which belongs to an important family of proteins that channel water across membranes.

"We knew that the aqp2 protein is found in the principal cells of the collecting duct, the final stretch of the kidney filtration machinery," Chen says. "Water and some other useful components are reabsorbed from the urine here. The concentrated urine is then passed on to the bladder and other downstream parts of the urinary system."

When scientists used an antibody to identify where aqp2 is in the kidneys of the mutant mice, they saw that distribution of the protein was changed. Normally aqp2 is concentrated on the side of collection duct cells that faces the urine, where aqp2 can extract water from the waste stream for recirculation in the body. In the mutant mice, though, aqp2 was scattered around the collection duct cells.

"The protein is still there, but it's not in the right place," Chen says. "To make sure this was the cause and not just a result of the problem, we analyzed the sequence of the aqp2 gene from the mutant mice, comparing it to the gene from other normal mice, and found a single base pair had changed."

The change swaps the amino acid serine for the amino acid leucine at a key position in the protein. Serine can undergo phosphorylation, a form of chemical modification frequently used in biological processes; leucine cannot. This change apparently disrupts the processes that otherwise produce a normal distribution pattern for the protein.

Chen compares the machinery that transfers water from the kidney to a plumbing system. With aqp2 unable to reabsorb water, he says, that results in up to 30 times more urine being dumped into the downstream pipes.

"Eventually, you overwhelm the plumbing system, and it gets backed up to an upstream location: the kidney," Chen says.

Chen plans follow-up studies of aqp2 to determine how important various parts of the protein are to its proper distribution in the kidney collecting duct epithelium. His lab also is looking for other genetic factors that contribute to renal diseases.

Alport Syndrome: From Pathogenesis to a Potential Therapy

Wed, 08 Mar 2006 05:06:37 PST

( from http://www.rxpgnews.com ) In 1927, Cecil Alport described a family in which affected individuals developed progressive kidney failure, deafness, and sometimes eye problems. Alport syndrome, although it affects only one in 50,000 live births in the United States, is the second most commonly inherited reason for kidney failure. It is caused by mutations in the genes that encode type IV collagen, a structural component of the thin, sheet-like basement membrane that covers the glomeruli, the kidney's filtration units. The glomerular basement membrane (GBM) normally filters fluid and small molecules (but not proteins or red blood cells) from the capillaries in the glomeruli into the urine, but in Alport syndrome, the collagen scaffold of the GBM is defective and, over time, the GBM splits and thins. The first symptom of Alport syndrome is blood in the urine (hematuria), followed by proteinuria and progressive renal failure as scar tissue (fibrotic tissue) forms around the glomeruli. The syndrome has no specific treatment, but kidney transplantation is usually successful in patients with end-stage kidney failure.

There are six isoforms of type IV collagenα1(IV) through α6(IV). In immature kidneys, the GBM contains α1(IV) and α2(IV), but these are replaced by α3(IV), α4(IV), and α5(IV) as the kidneys mature. The gene encoding α5(IV) is mutated in patients with X-linked Alport syndrome (85% of cases); mutations in the genes encoding α3(IV) or α4(IV) cause other forms of the syndrome. In all cases, the normal switch in collagen isoforms does not occur as the kidneys mature. Raghu Kalluri and colleagues have been investigating whether this failure to switch might make the GBM more susceptible to proteolytic degradation by matrix metalloproteinases (MMPs). They now report that MMPs have a dual role during disease progression in a mouse model of Alport disease, and suggest that MMP inhibition might be therapeutic during the early stages of the human disorder.

The mouse model used by Raghu Kalluri, Michael Zeisberg, and colleagues to test their ideas about the pathogenesis of Alport syndrome is the α3(IV)−/− mouse, which lacks functional α3(IV) collagen. These mice are born normal, but by four to five weeks old, their GBMs begin to disintegrate and they develop proteinuria. By eight weeks old, fibrotic tissue has formed in the tubulointerstitial compartment of their kidneys, and the mice die by 14 weeks old from kidney failure. The researchers first examined the localization of MMP-2, MMP-3, and MMP-9 (all of which degrade GBM) in α3(IV)−/− mice. Wild-type mice expressed low levels of these MMPs in their kidneys, but α3(IV)−/− mice expressed increased levels of MMP-2 and MMP-3 in their glomeruli at four weeks old, and as their disease progressed, expression of all three MMPs spread to the renal tubulointerstitial compartment. Renal expression of these MMPs was also increased in patients with X-linked Alport syndrome and end-stage renal failure when compared with normal kidneys. Furthermore, GBM from humans with Alport syndrome and from α3(IV)−/− mice was more susceptible to MMP degradation than that from normal humans or mice.

These results support the idea that increased proteolytic degradation of a defective GBM may be responsible for Alport syndrome, but renal disease still occurs in α3(IV)−/− mice when MMP-9 is missing. Could other MMPs compensate for the loss of MMP-9? When the researchers examined renal tissue from α3(IV)−/− mice deficient for MMP-2 and/or MMP-9, they did indeed discover compensatory upregulation of other MMPs. So the researchers then looked to see whether pharmacological agents that inhibit multiple GBM-degrading MMPs could alter disease progression in α3(IV)−/− mice. The researchers report that giving such drugs to four-week-old mice (before proteinuria developed) delayed disease progression and increased their survival by five weeks. However, giving the same drugs to eight-week-old mice (in which there was tubulointerstitial fibrosis) shortened their lives by two to three weeks.

Based on these animal experiments, the researchers suggest that in patients with Alport syndrome, the GBM (unlike GBM in healthy individuals) is susceptible to degradation by the low levels of MMP normally present in the kidney. Partial disruption of the GBM attracts infiltrating monocytes, which increase local MMP concentrations and accelerate GBM destruction. MMP inhibitors during this phase of the syndrome should be protective, suggest the researchers, but once the damage is sufficient to stimulate renal fibrosis, the same drugs will accelerate disease progression by inhibiting the MMPs that normally help to degrade fibrotic tissue. MMP inhibitors are already being developed for other indications and would be worth investigating as preventive drugs in Alport syndrome. But, warn Kalluri and colleagues, these drugs would be a double-edged sword, and could only be used in patients with identified genetic defects and only before the onset of proteinuria.

Meckel-Gruber syndrome gene identified- a help to understand polycystic kidney disease

Tue, 17 Jan 2006 02:09:37 PST

( from http://www.rxpgnews.com ) An international research collaboration led by Mayo Clinic has identified a new gene involved in causing the inherited kidney disorder, Meckel-Gruber syndrome (MKS). Children with MKS have central nervous system deformities as well as abnormal cysts in their kidneys, and usually die shortly after birth. The findings appear in the current edition of Nature Genetics . In addition to Mayo Clinic, the collaboration involved researchers from the Indiana University School of Medicine in Indianapolis, and the University of Birmingham, England.
Significance of the Finding

This news is of immediate importance to MKS families who may now have their blood screened for the defect and seek genetic counseling. The finding also is important for advancing understanding of what goes wrong in common birth defects, such as neural tube defects, as well as for related disorders such as more common forms of polycystic kidney disease (PKD). PKD accounts for more than 5 percent of end-stage kidney disease in the United States and Europe.

"This gene has immediate relevance for a small number of families, but the broader implications are important for the understanding they bring of how cysts develop in the kidney," explains Peter Harris, Ph.D., the Mayo Clinic nephrology researcher who led the research team. "There is a kind of common linkage among these diseases. Our hope is that this new finding will aid us to devise new treatments for a broad category of disabling disease."

Meckel-Gruber kidney disease is separate from, though related to, PKD in that some of the same things go wrong to cause the abnormal formation of cysts that disrupt kidney function. Knowing the identity of one key gene involved in MKS is a first step to understanding the disorder and eventually devising therapies to blunt its effects. Treatments are being developed for the more common forms of polycystic kidney disease.

The current work is an extension of Mayo researchers' groundbreaking work for more than a decade that has helped to reveal the genetic basis of PKD and to develop therapies. In that time, Mayo researchers have identified key genes driving the most common form of the disease in adults and in infants.

Dialysis patients may be overmedicated

Wed, 30 Nov 2005 15:34:38 PST

( from http://www.rxpgnews.com ) Changes in a widely used assay (blood test) for parathyroid hormone (PTH) have made its use with the established guidelines for end stage renal disease clinical management both inappropriate and potentially harmful to patients. This research is published in the journal Seminars in Dialysis.

A PTH assay measures levels of parathyroid hormone, produced by the parathyroid gland, which helps diagnose conditions such as hyperparathyroidism or to determine causes of abnormal regulation of calcium by the bones of patients with renal disease, which can lead to arterial calcification. Levels of PTH that are too high or too low can affect calcium metabolism, bone integrity and cause vascular disease.

In 2003, the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (K/DOQI) published the Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. These guidelines, for both diagnoses and treatments, are based on use of a manual iPTH assay that is not widely used for routine clinical analysis.

According to an editorial in Seminars in Dialysis, the iPTH assay that is now widely used by nephrologists has shifted significantly compared to the assay on which K/DOQI guidelines are based, generating much different results. Currently, almost all testing of dialysis patient specimens in the United States are performed at one of seven centralized labs. None use the PTH test on which the K/DOQI bone metabolism guidelines are based.

As a result, evidence shows that rates of parathyroidectomy may have been increased, patients have been over treated with expensive medications, and adynamic bone disease has become more prevalent, now affecting half of dialysis patients.

Tom Cantor, author of the editorial, and his research team have tracked changes in the most commonly used PTH assay. The team has also developed a more specific assay for PTH.

They have found important inconsistencies in testing results, Cantor states, indicating that "careful attention to the comparability of PTH assays is required by nephrologists and those who serve [patients] in this area."

Mycophenolate mofetil may be more effective in inducing lupus nephritis remission

Fri, 25 Nov 2005 06:21:38 PST

( from http://www.rxpgnews.com ) Treating lupus patients suffering from kidney inflammation with a medicine known as mycophenolate mofetil may be more effective in inducing remission than treating them with the standard regimen of intravenous cyclophosphamide (Cytoxan), a new clinical trial indicates.

The study, published in Thursdays issue (Nov. 24) of the New England Journal of Medicine, also showed that mycophenolate mofetil produced fewer complications, researchers found.

Such results could be an important step forward in protecting patients from Cytoxans side effects, including loss of child-bearing ability, the doctors say. Since 90 percent of lupus patients are women, and the average age when the disease is diagnosed is 32 years old, loss of fertility remains an important concern.

Authors of the report include Drs. Ellen M. Ginzler, chief of rheumatology at SUNY Downstate Medical Center in Brooklyn, and Mary Anne Dooley, associate professor of medicine and a Thurston Arthritis Research Center investigator at the University of North Carolina at Chapel Hill School of Medicine.

"This is the first nationwide randomized clinical trial comparing the newer agent, approved for about 10 years for kidney transplant patients, with the long-time standard of care, which has been Cytoxan," said Dooley, who helped design the FDA orphan disease branch-funded study, get it approved and recruit medical centers and patients. "Our results are very promising, but we need to do longer follow-up to see if the new medicine produces long-lasting improvement."

Oral mycophenolate mofetil worked faster in relieving inflamed kidneys, a condition doctors call nephritis, in half of the 140 patients enrolled in the trial, she said. At the end of the six months, patients taking it were doing significantly better than the other half, who were getting monthly intravenous doses of the standard medication.

"Lupus nephritis is a severe manifestation of lupus, which is an autoimmune disease that affects nine times as many women as men," Dooley said. "It also is three times more likely to occur in African-Americans than in Caucasians, and it is an increasing cause of end-stage renal disease.

"Among African-American patients we see, 40 percent progress to dialysis within five years," she said. "Thats despite being treated with Cytoxan, and so we are very motivated to find new drugs to better treat these patients."

For unknown reasons, blacks tend to get lupus earlier in life and suffer severe kidney damage much more frequently, the UNC physician said. African patients get it, too, but not with nearly the same severity as blacks in the U.S. and Europe.

A major issue for future studies of mycophenolate mofetil will be whether it protects as well as, or better than, Cytoxan does against nephritis relapses among lupus patients, Dooley said.

In an accompanying editorial in the New England Journal of Medicine, Dr. W. Joseph McCune of the University of Michigan said, "In an era of industry-sponsored research, this investigator-initiated and investigator-directed clinical trial makes an important contribution to patient care."

Dialysis patients often have close family members also on dialysis - Study

Wed, 02 Nov 2005 12:11:38 PST

( from http://www.rxpgnews.com ) Nearly one-fourth of all dialysis patients have a close relative on dialysis, researchers at Wake Forest University Baptist Medical Center, and others, report in the current online edition of the American Journal of Nephrology. The researchers suggest screening other relatives for undetected kidney disease.

Barry I. Freedman, M.D., reports that many relatives in these families have silent kidney diseases that can be treated at early stages, leading to slowed progression or prevention of future dialysis treatments or kidney transplants.

"Physicians caring for patients with chronic kidney disease should consider focusing screening efforts on high-risk family members in an attempt to slow the exponential growth rate of kidney failure," said Freedman, nephrology section head.

According to the National Institute of Diabetes and Digestive and Kidney Diseases, the rate of end stage kidney disease jumped from 219 persons per million in 1991 to 334 per million in 2000.

"Family members of individuals with chronic kidney disease also have an increased prevalence of high blood pressure, diabetes, excess protein in the urine, and undetected kidney disease," Freedman said. Excess protein in the urine is a sign that kidney disease is present and also a major risk factor for heart attack and stroke.

The study was based on dialysis patients in North Carolina, South Carolina and Georgia, which comprise End-Stage Renal Disease (ESRD) Network 6 of the Center for Medicare and Medicaid Services, one of 18 ESRD Networks in the United States. As of Dec. 31, 2003, Network 6 had 28,980 patients with end-stage kidney disease, the largest total among all 18 ESRD Networks and "accounting for approximately 7 percent of the U.S. population of individuals receiving renal replacement therapy," Freedman said.

The researchers from Wake Forest, Emory University and ESRD Network 6 undertook the largest study of its type ever performed, collecting family history information from 25,883 newly treated dialysis patients in the region. Of these, 5,901 (22.8 percent) had other close family members also with end-stage kidney failure on dialysis.

"This report demonstrated the strikingly high rates of familial clustering of the severest forms of kidney disease," he said. Patients with kidney disease due to diabetes were most likely to have close relatives with kidney disease, followed by those with kidney disease caused by high blood pressure.

Because of this clustering, "close relatives might be at increased risk for the presence of undetected chronic kidney disease or conditions that predispose to chronic kidney disease," Freedman said. "Periodically screening family members for chronic kidney disease and risk factors may be appropriate."

He said that chronic kidney disease has a long pre-clinical period, during which there are no symptoms, but when it can be easily diagnosed using blood and urine tests and treatment can be started.

"Primary care physicians need to be aware of this familial clustering and consider screening the close relatives of dialysis patients for silent kidney disease," said Freedman, who is the John H. Felts III, M.D., Professor of Internal Medicine and Head of the Section on Nephrology.

Prognosis Improving For Diabetics With End Stage Renal Disease

Fri, 14 Oct 2005 21:54:38 PST

( from http://www.rxpgnews.com ) Diabetic kidney disease is one of the most severe complications of type 1 diabetes, and diabetes is the most important cause of end-stage renal disease (ESRD; severely impaired kidney function, requiring dialysis) in industrialized countries, according to background information in the article. Data on patients' risk of developing ESRD are sparse. Large population-based studies with long-term follow-up have not been performed; therefore, the true incidence and age- and sex-stratified risk estimates of ESRD among patients with type 1 diabetes are not known.

Patrik Finne, M.D., Ph.D., of Helsinki University, Finland, and colleagues estimated the long-term risk of ESRD and death in patients with type 1 diabetes and assessed how age at diagnosis of diabetes, time period of diagnosis, and sex affect these risks. The study included patients younger than 30 years at the time of being diagnosed with type 1 diabetes in Finland in 1965-1999 (n = 20,005), who were identified from the Finnish Diabetes Register. The group was followed from diagnosis of diabetes until development of ESRD (dialysis or kidney transplantation as identified from the Finnish Registry for Kidney Diseases), death, or end of follow-up on December 31, 2001.

The median follow-up time after diagnosis was 16.7 years, with a maximum of 37 years. During the follow-up period, there were 632 cases of ESRD and 1,417 deaths. The researchers found that the cumulative incidence among all type 1 diabetic patients was 2.2 percent at 20 years and 7.8 percent at 30 years after diagnosis. Patients of both sexes diagnosed as having type 1 diabetes before age 5 years had a smaller risk of developing ESRD (3.3 percent after 30 years) than other patients (8.4 percent). The risk of ESRD was lower for patients diagnosed as having type 1 diabetes in later years. The risk did not differ significantly between sexes.

Patients with ESRD had 13.1 times the risk of death compared with other patients with type 1 diabetes when adjusting for age, sex, and time period of diabetes diagnosis. "This emphasizes the severity of ESRD as a complication of diabetes," the authors write. The cumulative death rate was 6.8 percent at 20 years and 15.0 percent at 30 years after diagnosis of type 1 diabetes. The cumulative risk of dying with ESRD was 0.7 percent at 20 years and 3.3 percent at 30 years after diagnosis of type 1 diabetes. The risk of death increased with age at diagnosis. The time period for the diagnosis of diabetes strongly affected survival: patients with diagnosis in 1975-1979 had 48 percent lower risk of dying than those with diagnosis in 1965-1969.

"In conclusion, our data indicate improved prognosis of type 1 diabetes with regard to both ESRD and death," the researchers write. "The overall incidence of ESRD appears to be lower than previously reported."

Osmolytes critical to survival of kidney cells

Sat, 08 Oct 2005 05:39:38 PST

( from http://www.rxpgnews.com ) Researchers at the University of Texas Medical Branch at Galveston (UTMB) have developed a new way to predict the ability of certain small molecules to protect proteins in the cells of a wide variety of organisms living in extreme environments. The technique, described in a paper published online Oct. 7 in the Proceedings of the Natural Academy of Sciences (PNAS), is a method of calculating the stabilizing effect on cellular proteins by small organic molecules called "osmolytes." It could have implications for the study of Alzheimer's disease, cystic fibrosis, kidney disease and stabilizing protein drugs.

Osmolytes, whose effects were first well described in 1982, work to preserve various forms of life under extraordinarily hostile conditions. They keep cells alive in human kidneys, for example, despite high concentrations of the protein-destroying chemical urea; they enable a species of frog found in the Arctic literally to be frozen solid and then thawed without harm; and they make it possible for the remarkable microscopic creatures known as "water bears" to survive complete drying, exposure to intense radiation, and temperatures ranging from a few degrees above absolute zero to that of superheated steam.

In the PNAS paper, Matthew Auton and D. Wayne Bolen describe their application of thermodynamic calculations to successfully predict the ability of a variety of osmolytes to protect proteins in cells under stress. Proteins function as molecular machines, performing tasks essential for cellular survival; extremes of heat and cold and changes in the chemical environment around the cell can cause the proteins to lose their proper shape and prevent them from functioning properly. Osmolytes, however, are able to force proteins to take on the correct shape and stay on the job.

"You can think of protein structure as origami, like strips of paper folded up into unique structures," said Bolen, senior author on the paper and a professor of human biological chemistry and genetics at UTMB. "Understanding how and why they fold or unfold -- they're not very stable, and there's this constant pressure on them to unfold -- is a major goal of biomedical science. What we've done is shown that we can calculate how osmolytes will influence the stability of different proteins, and we've also determined how different parts of the proteins interact with the osmolytes, which can give us significant insights on the protein-folding process."

Protein folding and unfolding, Bolen said, are critical features of disorders like Alzheimer's disease, mad cow disease and cystic fibrosis. Osmolytes perform vital functions in many different locations in the human body, notably the kidneys and the brain. "Without osmolytes, the kidneys wouldn't function at all, and brain tissue wouldn't be able to be as resilient as it is," Bolen said. "Medicine has only really emphasized their role in the kidneys, but they also occur in a lot of other tissues, and this technique should be quite useful for medical researchers looking at osmolytes throughout the body."

Study Examines Global Prevalence Of Kidney Failure Among Critically Ill Patients

Wed, 17 Aug 2005 21:58:38 PST

( from http://www.rxpgnews.com ) A multinational study has found that 5 to 6 percent of patients in intensive care units experience acute kidney failure, and about 60 percent of these patients die in the hospital, according to an article in the August 17 issue of JAMA.

The epidemiology and outcome of acute renal (kidney) failure (ARF) in critically ill patients in different regions of the world have not been well understood, according to background information in the article.

Shigehiko Uchino, M.D., of Austin Hospital, Melbourne, Australia, and colleagues conducted a study to determine the prevalence of ARF in intensive care unit (ICU) patients at 54 hospitals in 23 countries. The ICU patients were either treated with renal replacement therapy (RRT), such as dialysis, or fulfilled at least 1 of the predefined criteria for ARF from September 2000 to December 2001.

Of 29,269 critically ill patients admitted during the study period, 1,738 (5.7 percent) had ARF during their ICU stay, including 1,260 who were treated with RRT. The most common contributing factor to ARF was septic shock (47.5 percent). Approximately 30 percent of patients had preadmission renal dysfunction. The overall hospital death rate was 60.3 percent. Dialysis dependence at hospital discharge was 13.8 percent for survivors. Independent risk factors for hospital death included use of vasopressors (drugs that produce a rise in blood pressure), mechanical ventilation, septic shock, cardiogenic shock, and hepatorenal syndrome (kidney failure combined with severe liver disease).

"In summary, we have conducted a multinational, multicenter, prospective, epidemiological study of ARF that includes the largest and most representative sample of ICUs and ARF patients so far," the authors write. "This information may be helpful in the design of future international interventional trials, which would apply to worldwide practice, in regard to the statistical power and choice of appropriate outcome measures."

"gold standard" of open surgery for kidney tumors should remain the first choice

Wed, 10 Aug 2005 12:21:38 PST

( from http://www.rxpgnews.com ) Urologists often view less-invasive surgery techniques as more desirable for the patient, but in a study of open nephron-sparing surgeries (NSS) from 1985 to 2001 at Mayo Clinic, researchers found that the "gold standard" of open surgery for kidney tumors should remain the first choice for many patients. The study appears online today in The Journal of Urology.
"By comparing the first decade of elective open surgeries with more contemporary ones, we found that patient outcomes have greatly improved," says Michael Blute, M.D., Mayo Clinic urologist and lead investigator of the study. "This leads us to the understanding that while there are some new treatment options out there, what was once the only option (open NSS) is still quite often the best option."

Prior to 1985, open NSS was only done on patients with one kidney while patients with two kidneys and cancer in one automatically had the entire kidney removed. In the mid-1980s, Mayo Clinic began to use open NSS to treat patients who still had a healthy second kidney. This led to increased quality of life and fewer patients who subsequently had to resort to dialysis.

Since then, laparoscopy has evolved as another commonly used treatment, often considered superior in other types of surgery. Initial studies showed that laparoscopic NSS is feasible for small, easily accessible kidney tumors, making it appear the more favorable option. However, Dr. Blute and his colleagues have found that may not be true for many cases, especially when large or complex tumors are involved. "It's very difficult to safely and accurately remove a complex kidney tumor with laparoscopic NSS," explains Dr. Blute, "and if you find some cancer remaining when you look at the tissue under the microscope, it is difficult to remove more tissue like you can when doing an open NSS."

Dr. Blute and his co-investigators reviewed all open NSS procedures performed at Mayo Clinic between 1985 and 1995, and compared them to those performed between 1996 and 2001. They found that the procedure has gotten increasingly better results over time, and attributed this to increased surgeon experience, improved anatomical imaging, and enhanced perioperative care. For example, hospital stay declined from a median of seven days to five days, blood loss and transfused units of blood significantly decreased, early complications declined considerably, and urine leak occurrence was demonstrated in only 0.6 percent (compared to previous reports as high as 17 percent). They also found declines in the rates of dialysis need and other long-term complications.

When studying the more recent surgeries, researchers also found that open NSS showed some benefits compared with laparoscopic NSS. While laparoscopic NSS can often offer patients reduced postoperative pain, shorter hospital stays and smaller scars, it carries some risks that open NSS actually lessens. For example, Mayo Clinic surgeons needed to clamp the renal artery, stopping blood flow to the kidney, in only 50 percent of open NSS surgeries. For the majority of similarly complex laparoscopic NSS, this artery is clamped for durations typically much longer than those required for open NSS. The importance of limiting artery clamp times was indicated by fewer early surgical complications seen in patients with 20 minutes or less of stopped blood flow.

Dr. Blute's team concluded that open NSS remains the standard by which other treatments should be evaluated. "While there is a definite benefit for many patients with tumors on the kidney's surface to have laparoscopy," says primary author R. Houston Thompson, M.D., "we find that NSS via an open approach remains the best option for patients with complex kidney tumors. In addition, we are now performing open NSS through mini-incisions of less than five inches, which reduces pain and helps with a speedy recovery."

Chronic Kidney Disease Associated with "Benign" Prostate Obstruction

Wed, 29 Jun 2005 12:59:38 PST

( from http://www.rxpgnews.com ) Men who experience signs and symptoms of a prostate obstruction resulting from benign prostatic hyperplasia (BPH) are three times more likely than other men to develop chronic kidney disease, according to findings of a Mayo Clinic study published in this month's edition of Kidney International.

"This is the first study on the topic to sample the general community," says Andrew Rule, M.D., the Mayo Clinic kidney specialist who conducted the study with epidemiologist Steven Jacobsen, M.D., Ph.D.

"Symptomatic and non-symptomatic men were compared, unlike clinical trials and studies in a urology practice, which tend to represent only symptomatic men."

BPH and chronic kidney disease pose significant health problems in older men. Chronic kidney disease (CKD) occurs when the kidneys cannot rid metabolic wastes from the body or maintain the proper fluid and chemical balances. Eventually, the waste builds up and becomes poisonous to the body. Kidney disease can develop rapidly - in two to three months - or gradually over decades.

Many risks coincide with the development of CKD. "Several studies show men with chronic kidney disease have increased chance of death, hospitalization and cardiovascular events," says Dr. Rule.

The prostate gland is located just below a male's bladder and surrounds the top portion of the urethra, the tube that drains urine from the bladder. "Growth of the prostate gland can lead to a bladder outlet obstruction," says Dr. Rule. "An obstruction of the bladder can cause inability to or discomfort in emptying the bladder, a slowed stream of urine, frequent urges to void during the night or an enlarged, damaged bladder."

"We were surprised at how much kidney disease can be attributed to BPH," says Dr. Jacobsen. "An obstruction on the urethra is like a dam on a river - men can still void, but the constant buildup and pressure will ultimately cause damage." BPH affects about half of men in their 60s and up to 90 percent of men in their 70s and 80s. It is not related to the development of prostate cancer, although causes of BPH tissue growth inside the prostate later in life is unclear. Researchers believe that with age the prostate becomes more susceptible to the effects of hormones, including testosterone.

The most effective way to treat CKD is to care for and manage the underlying disease. "It has been shown that many patients with kidney disease respond to surgical treatments of BPH," says Dr. Rule. "There are also medications to relieve obstructions, by either shrinking the prostate gland or relaxing muscles that contribute to the obstruction."

The recent study surveyed 476 white men, ages 40-79, randomly selected from Olmsted County, Minn. Eventually, the researchers would like to see if similar findings are reproduced among general populations studied at other research centers. Dr. Jacobsen also suggests further research and testing to determine if treating BPH reverses the progression of kidney disease.

Ultimately, the researchers hope the results of the study will encourage both physicians and patients to consider BPH as a factor in kidney disease. "Men with diagnosed BPH may need to be screened to see if this condition is causing kidney damage," says Dr. Jacobsen.

Unique therapeutic strategy for Chronic Kidney Disease (CKD)

Sun, 12 Jun 2005 05:41:38 PST

( from http://www.rxpgnews.com ) Researchers at Oregon Health & Science University's Doernbecher Children's Hospital have uncovered a unique therapeutic strategy to combat cachexia -- severe malnutrition and physical wasting away -- in children and adults with chronic kidney disease (CKD). The study is published in the June issue of the Journal of Clinical Investigation.

Although the exact cause of cachexia -- a common life-threatening complication of CKD, cancer, AIDS and heart failure patients -- is unknown, Doernbecher researchers found elevated levels of leptin, a hormone that is produced by fat cells and plays a role in weight regulation, may be the cause. Leptin signals through the hypothalamic melanocortin 4 receptor (MC4-R) pathway in the brain, and blocking this pathway may be an important avenue for treatment, they report. The study was conducted in mice.

"Understanding why patients develop cachexia is important because it is associated with very high mortality in patients with chronic kidney disease," said study investigator Robert Mak, M.D., professor of pediatrics in the OHSU School of Medicine and head of pediatric nephrology, Doernbecher Children's Hospital. "Through this research, we have found a novel therapeutic strategy to combat this life-threatening complication of chronic renal disease, which affects more than 10 percent of the population and costs $40 billion each year to treat."

In an accompanying editorial commentary, William Mitch, M.D., past president of the American Society of Nephrology and Edward Randall Distinguished Chairman in Medicine, University of Texas Medical Branch, wrote that this study "provides a quantum increase in our understanding of CKD-associated anorexia."

Hemodialysis causes antioxidant loss leading to long-term complications

Fri, 08 Apr 2005 01:33:38 PST

( from http://www.rxpgnews.com ) An article published in Hemodialysis International discusses the role of oxidative stress (OS) in dialysis patients, an imbalance which can result in long-term health problems. Potential therapeutic options to restore balance in patients are also reviewed.

Oxidative stress, an imbalance between toxic compounds and defense mechanisms, and prevalent in the dialysis process, has been linked to numerous adverse complications in end-stage renal disease (ESRD) patients. The imbalance is caused by the overproduction of reactive oxygen species (ROS), or toxic compounds, and lack of antioxidants to fight these toxins. In fact, the hemodialysis process can cause loss of these necessary antioxidants.

Many ESRD and hemodialysis patients are in a state of chronic inflammation induced by the dialysis process which further enhances oxidative stress. This state is strongly associated with long-term complications such as cardiovascular disease, malnutrition, poor outcome and low survival.

"It is important to prevent reactive oxygen species production by improving the biocompatibility of the hemodialysis system," states Dr. Jean-Paul Cristol, corresponding author. Antioxidant supplementation and ROS modulation by specific or non-specific drugs, such as statins, are possible solutions outlined in the article.

"Correction of OS imbalance appears to be a basic requisite to prevent complications in long-term dialysis patients" and is "a promising avenue of research."

Oxidative Stress in Dialysis Patients can Lead to Long-Term Health Problems

Sun, 03 Apr 2005 10:03:38 PST

( from http://www.rxpgnews.com ) An article published in Hemodialysis International discusses the role of oxidative stress (OS) in dialysis patients, an imbalance which can result in long-term health problems. Potential therapeutic options to restore balance in patients are also reviewed.

Oxidative stress, an imbalance between toxic compounds and defense mechanisms, and prevalent in the dialysis process, has been linked to numerous adverse complications in end-stage renal disease ( ESRD ) patients.

The imbalance is caused by the overproduction of reactive oxygen species ( ROS ), or toxic compounds, and lack of antioxidants to fight these toxins. In fact, the hemodialysis process can cause loss of these necessary antioxidants.

Many ESRD and hemodialysis patients are in a state of chronic inflammation induced by the dialysis process which further enhances oxidative stress. This state is strongly associated with long-term complications such as cardiovascular disease, malnutrition, poor outcome and low survival.

It is important to prevent reactive oxygen species production by improving the biocompatibility of the hemodialysis system, states Dr. Jean-Paul Cristol, corresponding author.

Antioxidant supplementation and ROS modulation by specific or non-specific drugs, such as statins, are possible solutions outlined in the article.

Correction of OS imbalance appears to be a basic requisite to prevent complications in long-term dialysis patients and is a promising avenue of research.

KCP enhances signals from bone morphogenetic proteins that control kidney development and disease

Tue, 29 Mar 2005 15:17:38 PST

( from http://www.rxpgnews.com ) Scientists have identified a new and unusual protein that reduces, in laboratory mice, kidney damage caused by chronic renal disease and acute toxic injuries.

Named KCP, for kielin/chordin-like protein, the new protein is the first of its kind found to directly enhance signals from bone morphogenetic proteins or BMPs, which are vital to the normal development and healthy functioning of the kidney.

"KCP is similar in structure to proteins like chordin, which suppress BMP signals during embryonic development," says Gregory R. Dressler, Ph.D., an associate professor of pathology in the U-M Medical School, who directed the research study. "But instead of suppressing the signal, KCP enhances it by strengthening interactions between the BMP protein and its receptor on kidney cells."

"In two different models of mice with renal injuries, we found that KCP activity was required to slow the progression of kidney disease," Dressler says. "Mice that couldn't secrete KCP protein were more susceptible to renal injuries, had higher mortality rates and showed more fibrosis and scarring than normal mice. Our data suggest that KCP could have the potential to be a therapeutic agent for fibrotic renal disease in humans."

Results of the study were published March 27 by Nature Medicine on its Advance Online Publication Web site.

Developmental biologists like Dressler have been studying bone morphogenetic proteins for decades, because they are so important to the regulation of embryonic development in mammals. BMPs aren't as familiar to clinical scientists, because only a handful of studies, conducted during the last six years, have examined the effects of BMPs on renal disease. BMP7, in particular, plays an essential role in kidney disease and development.

"When BMP7 binds to the type 1 receptor on a kidney epithelial cell, it triggers signaling proteins called Smads, which are inside the cell, to move to the nucleus where they can change the pattern or degree of gene activity," Dressler explains. "In our study, we found that KCP is secreted primarily by tubular epithelial cells in the kidney. When it attaches to BMP7, it increases the stability between BMP7 and the cell's receptor, which gives genes more time to express proteins epithelial cells need to recover from injury."

Like many significant scientific discoveries, U-M researchers discovered the protein by accident while searching a library of DNA clones involved in embryonic kidney development. "We were looking for DNA sequences with cysteine-rich domains, because we knew they were important in BMP signal suppression," Dressler says. "But as we worked with KCP, we realized it's not a suppressor at all."

In initial studies, Dressler and his research team found that cells in cultures containing KCP showed three to ten times the response to signals from BMP7 than similar cell cultures without KCP.

To determine the effects of KCP in experimental animals, Dressler created a strain of knock-out mice that were unable to produce KCP protein, because they lacked the required gene. When he bred the mutant knock-out mice, he was surprised to find they were fertile, with a normal lifespan and no obvious abnormalities.

"Bone morphogenetic proteins have a definite developmental function. If you knock-out BMP7, the kidneys stop developing about 14 days after fertilization," Dressler says. "But KCP doesn't appear to affect embryonic development at all. My interpretation is that this protein may be a stress response gene, which is active in adults."

Jingmei Lin, a U-M graduate student and first author of the study, used two different laboratory procedures designed to produce the effects of human renal disease or injury in experimental animals.

In the first procedure, Lin and Xu Cheng, a U-M research associate, tied off the ureter, or connecting tube leading from one kidney to the bladder, while leaving the other kidney untouched. As a result of this procedure, mice develop a condition called interstitial fibrosis or scarring, which is commonly seen in chronic renal disease in humans. When Lin compared kidneys from the KCP knock-out mice and the control mice, she found significant differences.

Seven days after surgery, kidneys from KCP knock-out mice had twice the amount of fibrosis as kidneys from normal mice. Thirteen days after surgery, knock-out kidneys had 67 percent more interstitial damage than normal kidneys. And what was most surprising was that the knock-out mice developed fibrosis in their unobstructed kidney, while the control mice did not.

"Fibrosis in the control kidney was a surprise, because it's never been reported before," Dressler says. "This could be an indication of increased stress on the remaining functional kidney, or an inflammatory response, but clearly KCP protected the control kidney in normal mice from damage."

To evaluate the impact of KCP on animals after an acute toxic injury to the kidney, Lin and Sanjeevkumar Patel, M.D., a clinical lecturer in internal medicine, injected both sets of mice with folic acid, which causes severe damage to proximal tubular epithelial cells in the kidney. "It's the kidneys' job to filter out toxic substances from blood and urine, and proximal tubule cells are particularly sensitive, because this is an area where toxins are present in high concentrations," Dressler explains. "In people, this is a common cause of renal failure from drug overdoses or exposure to toxic chemicals."

According to Dressler, mice usually recover from this procedure within seven days. But 23 percent of the KCP knock-out mice died from renal failure, while only 2 percent of the normal control mice died. Kidneys from the experimental mice had large amounts of scarring and cysts, while kidneys from the control mice looked normal.

"Our work supports the idea that BMP pathways play an important role in chronic and acute renal disease," Dressler says. "If we can understand and learn to manipulate those pathways, then we may be able to improve patient outcomes."

"My overall goal is to understand the pathways that control the differentiation of cells during development, and apply that knowledge to the disease process, so we can ultimately develop new therapies for kidney disease," he adds.

Sulodexide Gelcaps : An Oral Heparinoid for the Treatment of Diabetic Nephropathy Gets Ready for Phase 3-4 Trial

Thu, 17 Mar 2005 08:02:38 PST

( from http://www.rxpgnews.com ) Keryx Biopharmaceuticals, Inc. announced today that it has finalized a Special Protocol Assessment (SPA) agreement with the Food and Drug Administration (FDA) for the Phase 3 and Phase 4 clinical trials of KRX-101 (sulodexide gelcaps), the Company's drug candidate for the treatment of diabetic nephropathy.

The clinical plan to support an NDA approval for KRX-101 under Subpart H (accelerated approval), as agreed upon with the FDA under an SPA, consists of:

(i) a single Phase 3 trial in patients with microalbuminuria based on the surrogate marker of regression of microalbuminuria as the primary endpoint;

(ii) supportive data from previously conducted clinical studies; and

(iii) substantial recruitment into our Phase 4 confirmatory study that will measure clinical outcomes in patients with overt nephropathy, or macroalbuminuria.

As part of commitment to the FDA, the company plans to commence the Phase 4 trial at approximately the same time as the start of the Phase 3 trial.

The Special Protocol Assessment (SPA) process is a procedure by which the FDA provides official evaluation and written guidance on the design and size of proposed protocols that are intended to form the basis for a new drug application.

Subpart-H guidelines allow for the use of surrogate endpoints in pivotal Phase 3 trials to support NDA approval, with confirmatory studies completed post-approval.

Michael S. Weiss, Chairman and Chief Executive Officer of Keryx, commented, "We would like to thank the FDA for their substantial input and guidance in this process."

Keryx's lead compound under development is KRX-101, a first-in-class, oral heparinoid for the treatment of diabetic nephropathy, a life-threatening kidney disease caused by diabetes. More than 20 studies have been published assessing the safety and efficacy of KRX-101 in diabetic nephropathy and other vascular conditions.

A randomized, double-blind, placebo-controlled, Phase 2 study of the use of sulodexide for treatment of diabetic nephropathy was conducted in 223 patients in Europe, and was published in the June 2002 issue of the Journal of the American Society of Nephrology. The results of this Phase 2 study showed a dose-dependent reduction in proteinuria, or pathological urinary albumin excretion rates.

In the third quarter of 2003, they announced that the Collaborative Study Group (CSG), the world's largest standing renal clinical trial group comprised of academic and tertiary nephrology care centers, would conduct the U.S.-based Phase 2/3 clinical program for KRX-101 for the treatment of diabetic nephropathy.

The CSG has previously conducted multiple large-scale clinical trials resulting in over 40 publications in peer-reviewed journals. In addition, the CSG conducted the pivotal studies for two of the three drugs that are currently approved for treatment of diabetic nephropathy. In the fourth quarter of 2003, Keryx initiated the Phase 2 portion of the Phase 2/3 clinical program for KRX-101, and in the third quarter of 2004, we completed the target enrollment for this Phase 2 portion of the clinical program.

In January 2005, the Company announced that the CSG recommended proceeding to the Phase 3 portion of the Phase 2/3 clinical program of KRX-101, as planned.

This recommendation was based on the completion, by an independent Data Safety Monitoring Committee, or DSMC, on January 4, 2005, of a safety evaluation of the first interim analysis from the approximately 150-patient, randomized, double-blind, placebo-controlled Phase 2 clinical trial of KRX-101, and an efficacy assessment of the same data set conducted by the CSG.

Pursuant to this recommendation, and in accordance with its commitment to the FDA, Keryx expects to commence its pivotal program, including both Phase 3 and Phase 4 studies for KRX-101, in the first half of 2005.

Keryx holds an exclusive license to KRX-101 in the territories of North America, Japan and certain other markets.

Age Should Not Be A Limiting Factor for Kidney Transplantation

Tue, 15 Mar 2005 13:53:38 PST

( from http://www.rxpgnews.com ) Growing evidence suggests that age alone shouldnt prevent older adults from being organ donors or having a kidney transplant themselves according to researchers at Wake Forest University Baptist Medical Center. The findings could help alleviate a serious shortage of organs for transplantation.

A study of 144 kidney transplants found that at least a year after surgery, success rates were comparable, regardless of the age of the donors or recipients. The results were reported today at a meeting of the Central Surgical Association in Tucson, Ariz.

You can no longer make the argument that transplanting a kidney into an older recipient is a wasted organ, said Robert Stratta, M.D., director of Transplantation Services at Wake Forest Baptist.

About 50 percent of the more than 60,000 people on the waiting list for kidney transplants are age 50 or older. Wake Forest Baptist and other centers are grappling with how to best use the limited number of kidneys that are available each year from deceased donors.

There is a critical shortage of kidneys for transplantation, which puts us in the difficult situation of rationing organs, said Stratta. Some physicians have ethical concerns that providing elderly patients with scarce donated kidneys may not represent a worthwhile investment.

Strattas research, however, found that by using newer methods to match the kidney with the recipient, the ages of the donors and recipients did not affect either patient survival or short-term survival of the transplanted kidney. This means both that more organs previously considered unusable might be transplanted and that older patients might be better candidates to donate and receive available organs.

From October 2001 through February 2004, Wake Forest Baptist transplanted 144 kidneys from deceased donors and found that a minimum of one year after surgery, transplant patients who were over age 60 did as well as younger patients, despite the fact that they usually received kidneys from older donors. Stratta had previously reported on success rates in 129 of these patients after six months and will continue to follow them long-term.

We no longer consider chronological age to be a contraindication to either organ donation or organ transplantation, Stratta said.

Of the 144 transplants, about one out of four (26 percent) were in patients age 60 and older. The mean age of this group was 65, and seven kidney recipients were older than 70. Most of the patients (62 percent) in the older group received kidneys from older donors that once would have been discarded.

In comparison, the mean age for the younger patients was 46, and only 32 percent received kidneys from older donors.

At least one year after transplant, survival rates for the transplanted kidneys were 86 percent in the older group of recipients and 87 percent in the younger group. Patient survival was 92 percent in the older patients and 98 percent in the younger group.

Stratta said a key to success is using newer methods to match donated kidneys to recipients. In the past, kidneys were matched exclusively by blood and tissue type. Newer approaches to matching have come about as a result of a system implemented by the United Network for Organ Sharing (UNOS) in October 2002 for allocating higher-risk kidneys that were once considered unsuitable for transplantation and discarded.

These include kidneys from deceased donors over age 60 or those over age 50 with health conditions such as high blood pressure or elevated levels of a protein called creatinine. Levels of creatinine, which is produced by muscle, are used to determine kidney function.

Using kidneys from these donors, which UNOS calls expanded criteria donors (ECDs), permits more patients to benefit from transplantation, Stratta said, but requires careful matching. Wake Forest Baptist has doubled its number of transplants using ECD kidneys.

We are matching based on age, weight and kidney function, said Stratta. An older kidney has less capacity, and someone who weighs less doesnt need as much capacity. It is a concept that is in evolution.

Stratta believes that with careful patient selection, the kidneys from expanded criteria donors may function for as long as kidneys donated under the standard criteria, about eight to 12 years. He cautions, though, that "long-term follow-up is needed to ultimately determine the risks and benefits of kidney transplantation in this setting.

Vitamin D May Significantly Improve Survival in Dialysis Patients

Sun, 13 Mar 2005 08:33:38 PST

( from http://www.rxpgnews.com ) The administration of intravenous vitamin D appears to significantly improve the survival of patients on dialysis, according to a study that will be published in the April Journal of the American Society of Nephrology and has been released ahead of print on the journal's website. Vitamin D injections are currently recommended only for dialysis patients with elevated levels of parathyroid hormone, but the report from a Massachusetts General Hospital (MGH)-based research group suggests that the treatment might help most dialysis patients live longer.

"We've been administering vitamin D injections for decades, but the potential benefit on survival has never been studied," says Ravi Thadhani, MD, MPH, director of clinical research in MGH Nephrology, the study's senior author. "This finding was a surprise and should force us to think more broadly about who should be treated."

Among the approximately 300,000 U.S. patients who receive dialysis for chronic kidney failure, the annual mortality rate is 20 percent, with cardiovascular disease the primary cause of death. In healthy individuals, the kidneys convert vitamin D from food and over-the-counter supplements into an activated form that the body can use.

Kidney failure patient cannot utilize dietary vitamin D and must receive activated forms of the nutrient to avoid deficiency. Currently only 50 percent of kidney failure patients are treated with activated vitamin D, since the therapy is recommended only for those who also have elevated parathyroid levels.

In 2003 the same research group published a study finding that a particular form of activated vitamin D, paricalcitol, was associated with better survival than was calcitriol, previously the standard activated vitamin D therapy. For the current study, the reseachers asked the broader question of whether dialysis patients receiving any form of activated vitamin D therapy would live longer than those who did not.

Working with collaborators from Fresenius Medical Care North America, based in Lexington, Mass., the researchers compiled information on more than 50,000 patients who started dialysis at Fresenius centers across the country between 1996 and 1999 and were followed into 2002. More than 37,000 of those patients received injections of some form of activated vitamin D.

At the end of the two-year study period, 76 percent of those receiving any form of activated vitamin D were still alive, compared with 59 percent of those not receiving the therapy. That more than 20 percent reduction in mortality was seen across all categories of patients in the study - all races, ages and both genders. Even patients with elevated calcium or phosphorus levels, which often lead to the discontinuation of vitamin D therapy, lived longer if they received the treatment.

These results must be confirmed by follow-up studies - including randomized clinical trials - before more precise recommendations for treatment can be made, but the researchers note that even many patients who meet current guidelines for vitamin D therapy are not receiving it.

"While these results need to be verified, we at least need to be more aggressive in treating people that meet the current criteria," Thadhani says. "Thereafter we need to investigate what is the mechanism conferring this survival benefit. We are actively pursuing that with a focus on the effects on cardiovascular disease." Thadhani is an assistant professor of Medicine at Harvard Medical School.

BMP-7 Prevents Renal Osteodystrophy and Vascular Calcification Associated with Chronic Renal Disease

Sun, 13 Mar 2005 08:25:38 PST

( from http://www.rxpgnews.com ) Curis, Inc. highlighted that the recent online issue of the Journal of the American Society of Nephrology contains a preclinical report demonstrating that treatment with BMP-7, a signaling protein that was discovered by scientists from Curis, results in amelioration of two major complications of chronic kidney disease.

The United States Renal Data System estimates that there are currently 423,000 patients in the U.S. with end-stage kidney disease and many more with various stages of chronic kidney disease.

Patients with chronic kidney disease or end-stage kidney disease experience a number of serious metabolic disorders that are associated with the loss of kidney function. Some of these disorders, such as severe anemia, have effective therapeutic treatments, such as erythropoietin.

Other kidney-disease-related disorders, including renal osteodystrophy (a collective name for several forms of metabolic bone disease) and vascular calcification (a form of cardiovascular disease that involves mineralization of the blood vessels), have proven much more difficult to treat successfully.

Cardiovascular mortality in patients with chronic kidney disease is extremely high.

The current report, entitled "Low Turnover Osteodystrophy and Vascular Calcification are Amenable to Skeletal Anabolism in an Animal Model of Chronic Kidney Disease and the Metabolic Syndrome," is authored by researchers from the Washington University School of Medicine in St. Louis, Missouri.

The investigators demonstrate that BMP-7 treatment prevents renal osteodystrophy and vascular calcification by stimulating the rate of skeletal mineralization, thereby diverting mineral that might have been deposited inappropriately in the blood vessels.

LEA29Y (belatacept) effectively preserves kidneys during transplants

Wed, 23 Feb 2005 20:03:38 PST

( from http://www.rxpgnews.com ) Emory University physician-researchers in Atlanta have shown an investigational medication, known as LEA29Y (belatacept), is effective in preserving transplanted kidney function while at the same time avoiding the toxic side effects that are common in the currently used long-term, immunosuppressive transplant medications. The pre-clinical research conducted with nonhuman primates at the Yerkes National Primate Research center was an important step in establishing human clinical trials to develop an effective alternative to current anti-rejection therapies.

More than 23,000 organ transplants are performed each year in the United States. While current immunosuppressant medications have reduced the incidence of early organ failure following transplants, measures to prevent late failure and to halt other diseases that result from toxic side effects of current treatments have been limited.

Cyclosporine, the current standard of care following organ transplantation, prevents initial organ rejection by effectively blocking certain immune system pathways that are activated when the body detects foreign cells. At the same time, though, cyclosporine indiscriminately targets and blocks other cellular signal pathways, causing serious side effects such as high blood pressure and cholesterol, which may lead to cardiovascular disease, and high kidney toxicity that ultimately leads to long-term renal failure. In addition, long-term cyclosporine use damages the body's immune system and prevents it from fighting off other infections following transplant.

"For the past 20 years, transplant patients have been treated with cyclosporine-like medications that effectively suppressed the immune system to prevent the body from rejecting the new organ," said Christian Larsen, MD, DPhil, director of the Emory Transplant Center. "The problem is, the medication not only shuts down the immune system, but has side effects that increase the risk of heart attacks and can damage the kidney. We need to develop a medication as effective as cyclosporine in preventing initial rejection, while at the same time preserving the kidney and providing better patient outcomes."

Dr. Larsen and Thomas Pearson, MD, DPhil, with colleagues at Bristol-Myers Squibb Pharmaceutical Research Institute, developed LEA29Y to selectively block the second of two cellular signals (co-stimulatory signals) the body needs to trigger an immune response. Blocking this co-stimulatory signal prevents organ rejection while allowing the body to continue fighting other infections.

Following in vitro studies, during which the researchers observed LEA29Y was 10 times more effective than cyclosporine in blocking the co-stimulatory immune signal, Drs. Larsen and Pearson tested the drug in nonhuman primates and found that it significantly prolonged survival of transplanted kidneys.

"The studies with nonhuman primates were critical because, while we knew the co-stimulatory blocker was effective in vitro, we needed to study it in a living organism," said Dr. Larsen. "The nonhuman primate studies allowed us to take a bold step toward studying this medication in humans to determine if it is a better choice than the current standard of care. Working with nonhuman primates enabled us to expedite the research process by four or five years."

The research team recently completed a phase II clinical study comparing LEA29Y to cyclosporine in human kidney transplant patients. On behalf of investigators from 22 transplant centers worldwide. Dr. Larsen will present results from the phase II study at the annual American Transplant Congress May 20 25 in Seattle. Multiple phase III studies currently are being planned.

Why Blood Glucose Control Matters for the Kidney

Tue, 22 Feb 2005 21:49:38 PST

( from http://www.rxpgnews.com ) One of the most common and most serious complications of both type 1 and type 2 diabetes is diabetic nephropathy. It occurs in around 30% of patients with type 1 diabetes and 10% to 40% of patients with type 2 diabetes. Diabetic nephropathy is the leading cause of renal failure in the developed world. The main effect of diabetic nephropathy is proteinuria, initially in very small amounts but which increases, leading to nephrotic syndrome and end-stage renal disease in most cases.

Various risk factors in individuals with diabetes are known to increase the chance of developing diabetic nephropathy, including South Asian or African background, male sex, long history of diabetes, poor blood sugar control, high blood pressure, and smoking. One early change associated with diabetic nephropathy is degeneration of the renal tubular epithelium, but the exact cause of this at the cellular level is unclear. Erwin Böttinger and colleagues have dissected out one key point in the progression to diabetic nephropathy. They looked at cell lines of renal tubular cells from humans and mice and kidney biopsies from patients with diabetic nephropathy, patients with non-diabetic renal disease, and mice with genetic and induced diabetes. In the human cell lines they showed that glucose induced the expression of CD36, a receptor known to have a role in adhesion and signal transduction (in addition to being the receptor for malaria-infected erythrocytes). They then went on to show that apoptosis of these cells occurred in the presence of glycated (glucose-modified) albumins or free fatty acids, which are present in increased amounts in patients with diabetes, and that CD36 was essential for the apoptosis to occur. They then examined how CD36 triggered apoptosis and found that it involved src kinase, p38 MAP kinase, and caspase 3.

Comparing mice and humans, the researchers found that the two species are not alike: diabetic mice did not show an increase in tubular expression of CD36even though the gene is present in miceand had normal tubular epithelium and no tubular apoptosis. They confirmed this difference between humans and mice by showing that normal mouse epithelial cell lines were resistant to apoptosis caused by the glycated albumins; however, artificially expressing CD36 in these lines made them susceptible to apoptosis by these modified albumins.

These results provide insight into one of the crucial steps in diabetic nephropathy and, in humans at least, might help to explain why high blood glucose is so damaging to the kidney, hence providing a good reasonif another is neededfor encouraging patients to control blood glucose as tightly as possible.

Amitriptyline to be tested for painful bladder syndrome

Fri, 18 Feb 2005 16:28:38 PST

( from http://www.rxpgnews.com ) A new study will test an FDA-approved antidepressant for its potential to alleviate bladder pain for which there is no known cause and no effective therapy. Thousands, if not millions, of patients may benefit. The study is funded by the National Institutes of Health (NIH).

Ten medical centers in the United States and Canada are recruiting adults newly diagnosed with either painful bladder syndrome (PBS) or interstitial cystitis (IC) to learn if the oral drug amitriptyline (Elavil®) will reduce the pain and frequent urination that are hallmarks of the conditions. The centers make up the Interstitial Cystitis Clinical Research Network, sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at NIH.

PBS is defined by symptoms--frequent urination day and night and increasing pain as the bladder fills--according to the International Continence Society. The syndrome includes IC, which has been estimated to affect as many as 700,000 people, mostly women. Estimates for PBS vary widely, but as many as 10 million people may suffer from this condition.

The 270 participants will be randomly assigned to take up to 75 milligrams of amitriptyline or a placebo each day for 14 to 26 weeks. All will practice suppressing the urge to urinate for increasingly longer stretches until they can wait 3 or 4 hours before going to the bathroom. Participants will also regulate when and how much they drink and avoid bladder irritants such as alcohol, acidic foods and carbonated or caffeinated drinks. Staff and patients will find out who received the amitriptyline when the study is finished. Medications and tests are free to participants. Although amitriptyline is primarily used for depression, the way it works makes it useful for treating the pain of fibromyalgia, multiple sclerosis, and other chronic pain syndromes. Prior small studies in IC suggested the drug may be a wise choice for this syndrome as well, because it blocks nerve signals that trigger pain and may also decrease muscle spasms in the bladder, helping to cut both pain and frequent urination. An average of 75 milligrams of amitriptyline a day may begin relieving IC pain within a week. In contrast, doses in the range of 150 to 300 milligrams are generally used to treat depression.

"Like so many potential treatments tried before it, amitriptyline looks promising. And we are desperate to find a safe and effective treatment for patients. But until the drug is rigorously tested we won't know its true value in these syndromes," said Leroy M. Nyberg Jr., Ph.D., M.D., who oversees IC research sponsored by NIDDK. "And we'll never know if we are raising false hopes for patients, and unnecessarily spending health care dollars on prescriptions, if we don't do this study. It's critical to base our treatment decisions on evidence."

Eligibility criteria for the amitriptyline trial mark a major departure from two prior IC studies supported by NIDDK. The current trial is enlisting newly diagnosed adults and only those who have not yet received treatment.

Following up on earlier promising research supported by NIDDK, participants' urine will be checked for substances that may, ultimately, lead to a definitive test for diagnosing IC and for measuring the effectiveness of potential treatments.

Obese kidney donors are as safe as other donors

Fri, 18 Feb 2005 16:23:38 PST

( from http://www.rxpgnews.com ) Mayo Clinic researchers have found that obese individuals in otherwise good health who donated a kidney had outcomes similar to their non-obese counterparts.

In a retrospective study of more than 500 patients, at an average of eleven months after kidney donation, Mayo doctors found obese donors did not experience more problems than non-obese donors. However, prior to donation, obese patients were at greater risk for cardiovascular disease based on blood pressure and cholesterol levels, compared to normal weight donors. Despite the findings, the study emphasizes the importance of following obese patients for a longer time before drawing any long-term conclusions.

Historically living kidney donation has been restricted to a select donor group in very good health. However, with national trends indicating an increased obese population in the United States, the number of obese individuals offering to donate a kidney to a friend or loved one is rising. Recognizing this trend, Mayo physicians reviewed the extensive living donor experience at Mayo to examine outcomes in obese donors.

"We know that obesity is rising in our population, and while that is not a good trend, we need to see if obesity poses a specific risk for kidney donors," says Sandra Taler, M.D., a Mayo Clinic kidney specialist and a co-author of the study. "We found that short-term outcomes for obese donors did not differ significantly from outcomes experienced by donors of normal weight. Additional follow-up is definitely needed to see if there are long-term differences, but these initial findings are encouraging."

As the largest living donor organ transplant program in the United States, Mayo Clinic encourages live organ donations. Because a typical wait for a kidney from a deceased donor can range from three to five years, many people will not survive long enough on dialysis to reach transplantation.

More than 300,000 Americans suffer from kidney failure requiring dialysis to live. Life expectancies increase from about four years with dialysis, to 15 years with a kidney transplant. Despite the superior survival and better quality of life with a transplant, only about 5 percent of dialysis patients will receive a transplant in the United States, due to a limited supply of donor organs.

Potential therapy may stop Kidney failure

Thu, 17 Feb 2005 21:30:38 PST

( from http://www.rxpgnews.com ) Columbia University Medical Center researchers have identified a protein that may provide a powerful new therapeutic tool for fighting kidney failure.

The research, which is published in the March issue of the Journal of Clinical Investigation, shows that injection of a protein, known as Ngal, can protect mice from renal failure, suggesting its great potential as a therapeutic tool for humans.

Kidney failure is a significant risk for patients undergoing cardiopulmonary bypass surgery, radiologic testing, antibiotic therapy or in patients suffering from severe infections. More than 80 percent of patients with postoperative acute renal failure die.

The study also shows that the protein is highly accumulated in blood, urine and kidney tissue at the onset of acute renal failure, making it an effective marker for diagnosing kidney failure in its initial stages.

"We found that although Ngal exists in high amounts early in failing kidneys, it is still produced too late to prevent the damage," said Jonathan Barasch, M.D., Ph.D., assistant professor of Medicine at Columbia University College of Physicians and Surgeons and the principal investigator on the study. "But if we inject the protein earlier in the process, such as when a patient is starting bypass surgery or using some antibiotics, our study suggests that Ngal can prevent damage from occurring."

Ngal was initially discovered by Dr. Barasch and his colleagues to induce embryonic cells to form kidney tubules.

"When Dr. Devarajan of Cincinnati Children's Hospital identified Ngal in a screen for genes expressed in damaged kidneys, we decided to join forces, because there were theoretical reasons why creation of embryonic kidneys and repair of adult kidneys should be stimulated by the same molecule," said Kiyoshi Mori, M.D., PhD., a post-doctoral research fellow.

The two groups independently showed that Ngal is a sensitive marker of renal failure and after extensive studies with mice, the two independently found that Ngal was protective.

"Given the fact that Ngal expression is conserved in mice, rats, and human kidneys after damage, we are hopeful that the protein will be protective in humans," said Dr. Barasch.

Ngal will be ready for initial human trials after one further confirmation in mouse models.

Second-Generation Lanthanum-Based Phosphate Binders Have Potential Role in Treatment of Hyperphosphatemia in End-Stage Renal Disease

Tue, 01 Feb 2005 09:14:38 PST

( from http://www.rxpgnews.com ) Spectrum Pharmaceuticals,Inc.,announced today that it has acquired worldwide exclusive rights to RenaZorb(TM)(two second-generation lanthanum-based phosphate binding agents) from Altair Nanotechnologies, Inc.

These novel non-aluminum, non-calcium phosphate binders which utilize Altair's proprietary lanthanum nanomaterial technology have the potential to treat hyperphosphatemia, i.e., high phosphorus levels in blood, in patients with end-stage renal disease (ESRD) and chronic kidney disease (CKD), with potentially as little as one tablet per meal while currently approved therapies require as many as several tablets per meal.

There are an estimated 340,000 ESRD patients in the U.S. who are on kidney dialysis, and the market for phosphate binding agents was in excess of $600 million in 2004.

According to the National Kidney Foundation, the number of ESRD patients in the U.S. is expected to double over the next decade. In addition, there are an estimated 8.4 million CKD patients, representing a potential multi-billion dollar market opportunity, who are candidates for phosphate binder therapy under the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (K/DOQI) Clinical Practice Guidelines, issued in 2003.

Under the terms of the agreement, Spectrum acquired an exclusive worldwide license to develop and commercialize these lanthanum-based phosphate binding agents for all human therapeutic and diagnostic uses. Spectrum will pay to Altair an upfront payment of 100,000 shares of restricted Spectrum common stock and will make an equity investment of $200,000 for 38,314 shares of Altair common stock. In addition, Altair is eligible to receive payments upon achievement of a clinical development and certain regulatory and sales milestones, in addition to royalties on potential net sales.

"This in-licensing of these lanthanum-based phosphate binding agents is an important step in our continued effort to build an extensive and well-diversified portfolio of drug product candidates that span all stages of development and address significant unmet medical needs," stated Rajesh Shrotriya, M.D., Chairman of the Board, Chief Executive Officer and President of Spectrum Pharmaceuticals, Inc. "We are extremely pleased to establish this alliance with Altair. We look forward to advancing these lanthanum-based phosphate binding agents into clinical trials, and pursuing the appropriate regulatory strategy to maximize its potential."

"We are delighted to have the opportunity to work with the Altair team and look forward to developing and commercializing these lanthanum-based phosphate binding agents," stated Luigi Lenaz, M.D., of Spectrum Pharmaceuticals, Inc. "We believe there is a significant unmet medical need for the treatment of hyperphosphatemia, a condition that leads to significant bone disorders and cardiovascular disease, and is associated with a significantly higher death risk in patients with chronic and end-stage kidney disease.

According to K/DOQI Guidelines, fewer than 30 percent of dialysis patients are able to achieve and maintain serum phosphorus levels in the optimal range, despite dietary phosphorus restriction and treatment with currently marketed phosphate binders.

As a non-aluminum, non-calcium phosphate binder, these lanthanum-based phosphate binding agents has the potential to become one of the preferred first-line treatment options for hyperphosphatemia under the new K/DOQI Guidelines because it has the potential to significantly improve patient compliance by lowering the daily pill burden to the lowest-in-class dosage, namely one tablet per meal, and smaller-sized tablets, in addition to a potentially more favorable safety and efficacy profile."

"We are delighted to have a collaborator for the first of our Life Sciences initiatives, these lanthanum-based phosphate binding agents, with the drug development, regulatory and commercialization expertise of Spectrum's management," stated Alan J. Gotcher, Ph. D., Chief Executive Officer of Altair Nanotechnologies, Inc. "We look forward to working with Spectrum to enhance and expedite the development of this promising compound."

"These lanthanum-based phosphate binding agents represents a new generation of high performance phosphate binding drugs that have significant promise in terms of dose and compliance," stated Dr. Ravi Thadhani, M.D., M.P.H. Department of Medicine and Renal Unit, Massachusetts General Hospital, Boston, MA. "The partnership between Altair and Spectrum is an excellent complementary marriage of leaders in their respective fields."

Understanding acid sensing in the kidney

Thu, 16 Dec 2004 17:52:38 PST

( from http://www.rxpgnews.com ) The normal daily diet generates volatile acid (carbon dioxide) and nonvolatile acid (hydrogen ions) from carbohydrate and protein metabolism, respectively, and the kidney is responsible for maintaining an acid-base balance by excreting these acids. In this issue of the Journal of Clinical Investigation, Patricia Preisig and colleagues from the University of Texas Southwestern Medical Center have identified the kidney's elusive acid sensor. The authors examined opossum kidney cells cultured under acidic conditions and found that a 24-hour exposure to acid activates the enzyme Pyk2, which then binds to the proto-oncogene c-Src, causing c-Src activation and subsequent activation of signaling pathways that increase production of NHE3, the molecule at the surface of renal proximal tubule cells in the kidney that release hydrogen ions from the cell.

In an accompanying commentary, Steven Gluck from the University of California San Francisco discusses the broader role of Pyk2 in acid-base balance in bone and other tissues beyond the kidney.