Alfacalcidol Does Not Lower CV Risk in Dialysis, Trial Suggests


Alfacalcidol does not reduce the risk for cardiovascular events in patients without secondary hyperparathyroidism undergoing maintenance hemodialysis compared with usual care, the Japan Dialysis Active Vitamin D (J-DAVID) trial has found. But experts question the generalizability of the findings.

During a median of 4 years, the composite outcome of select cardiovascular events was 21.1% in those who took oral alfacalcidol, a vitamin D receptor agonist (VDRA), compared with 17.9% in the usual-care group, a difference that was not statistically different.

“[O]ral alfacalcidol compared with usual care did not reduce the risk of a composite measure of select cardiovascular events. These findings do not support the use of vitamin D receptor activators for patients such as these,” the researchers write.

The study, by Tetsuo Shoji, MD, PhD, from the Department of Vascular Medicine, Osaka City University Graduate School of Medicine, Japan, and colleagues, was published online December 10 in JAMA.

The study was conducted in Japan, and the results are not generalizable to other countries, Rasheeda K. Hall, MD, MBA, MHS, and Julia J. Scialla, MD, MHS, from the Department of Medicine, Duke University School of Medicine, Durham, North Carolina, write in an accompanying editorial.

“Although the use of phosphate binders, VDRAs, and cinacalcet in Japan are comparable to the use in the United States, dialysate calcium and selection of calcium-based vs non–calcium-based phosphate binders tends to be higher in Japan. These patterns were observed in the J-DAVID trial, with approximately 70% of participants using dialysate calcium of 3.0 mEq/L and approximately 80% using calcium-based phosphate binders,” Hall and Scialla explain.

“These practices may be so different from those in the United States and internationally that generalization is not feasible,” they continue.

No Difference in Cardiovascular Outcomes

Vitamin D activation is impaired and cardiovascular risk is elevated in patients with chronic kidney disease. Observational studies have suggested that VDRAs reduce this risk, but the approach had not been tested in randomized trials.

Therefore, Shoji and colleagues conducted a randomized, open-label, blinded endpoint trial that compared the effect of the oral VDRA alfacalcidol with usual care (no VDRAs) on cardiovascular events in patients without secondary hyperparathyroidism receiving maintenance hemodialysis at 108 dialysis centers. For the patients in the study, serum intact parathyroid hormone levels were ≤180 pg/mL.

The investigators randomly assigned 976 patients to receive either alfacalcidol, beginning at a dose of 0.5 μg per day (n = 495) or usual care (n = 481). The intention-to-treat analysis included 964 patients, of whom 944 (97.9%) completed the trial. The median age of the participants was 65 years, and 386 were women (40.0%).

“All participants were eligible to receive any medications other than VDRAs, including phosphate binders and cinacalcet, for standard medical care as recommended by the JSDT [Japanese Society for Dialysis Therapy] Clinical Practice Guidelines,” the researchers explain.

Cardiovascular events, the primary composite outcome, occurred in 103 of 488 patients (21.1%) in the alfacalcidol group, compared with 85 of 476 patients (17.9%) in the usual-care group (absolute difference, 3.25%; 95% confidence interval [CI], −1.75% to 8.24%; hazard ratio [HR], 1.25; 95% CI, 0.94 – 1.67; P = .13). This difference was not statistically significant.

The secondary outcome of all-cause mortality did not differ significantly between the groups (18.2% vs 16.8%, respectively; HR, 1.12; 95% CI, 0.83 – 1.52; P = .46).

Among those in the alfacalcidol group, 76.0% experienced serious adverse events (SAEs), including cardiovascular-related (40.8%), infection-related (13.1%), and malignancy-related SAEs (4.5%).

Among those in the usual-care group, 79.2% experienced SAEs, including events that were cardiovascular- (40.1%), infection- (13.2%), and malignancy-related (4.4%).

“The number of cardiovascular SAEs was higher than the number of occurrences of the primary outcome because some participants had more than 2 cardiovascular SAEs,” the researchers explain.

Predefined laboratory abnormalities differed between the two groups. Corrected serum calcium levels >10.0 mg/dL and phosphate levels >6.0 mg/dL occurred more frequently in the group that received alfacalcidol compared with the control group. Intact parathyroid hormone levels >240 pg/mL occurred less commonly, especially during the first year of follow-up.

Generalizability May Be Limited

“[T]he results cannot be generalized to patients with secondary hyperparathyroidism or to non-Japanese populations, particularly not to US patients undergoing hemodialysis, who have much higher levels of intact PTH [parathyroid hormone] than the participants of this trial,” the researchers note.

Hall and Scialla reiterate that point. “As the J-DAVID investigators acknowledge, VDRAs may plausibly yield different results when accompanied by less calcium loading in the form of dialysate and exogenous calcium,” they write.

The editorialists say that although the researchers excluded patients “with clear indications or contraindications for VDRAs,” approximately one third of participants crossed over during the study; 35% of patients in the usual-care group and 32% of those in the alfacalcidol group dropped out of their assigned treatment. The study did not account for this in power calculations, they explain.

“In addition, the composite cardiovascular end point in the J-DAVID trial was broad. Although this broad end point may improve power for the study, the pathophysiology of many of the end point components, such as sudden cardiac death, peripheral amputation, and stroke, including hemorrhagic stroke, may be heterogeneous and not clearly modified by 1,25[OH]2D-responsive pathways,” Hall and Scialla observe.

“Future studies are needed, both observational and randomized, to understand who should be treated with VDRAs, to what biochemical target levels patients should be treated, and what therapeutic combinations of VDRAs and mineral metabolism cointerventions should be used to prevent CVD in patients with ESKD [end-stage kidney disease] undergoing hemodialysis,” they conclude.

No more dialysis, Scientists Have Developed A Bionic Kidney! 


Natural remedies are indeed very powerful, but there are times when we have to turn to modern technology. Dialysis patients can’t live without the treatment, but their suffering is enormous.

Many of them must wait for years to get a kidney transplant and live normally, with seemingly no other solution on the horizon. However, there’s finally a light in the dark tunnel – scientists from the University of California at San Francisco, USA, have developed the world’s first bionic kidney which can replace damaged kidneys easily and effectively.

Natural remedies are indeed very powerful, but there are times when we have to turn to modern technology. Dialysis patients can’t live without the treatment, but their suffering is enormous.

Many of them must wait for years to get a kidney transplant and live normally, with seemingly no other solution on the horizon. However, there’s finally a light in the dark tunnel – scientists from the University of California at San Francisco, USA, have developed the world’s first bionic kidney which can replace damaged kidneys easily and effectively.

The bionic kidney is a perfect replica of our kidneys. It consists of numerous microchips and is moved by the heart. Like the normal kidneys, it is able to filter waste and toxins from the bloodstream.

The project was unveiled by Willian Vanderbilt Fissels and Shuvo Roy from the University of California, offering renewed hope for millions of kidney dialysis patients. Now, some of you may be wondering “But, what if the body rejects it?”, but, the scientists assure us that the chances of rejection are zero! Incredible, right?

This is because the bionic kidney is made from renal cells. The first prototype is the size of a coffee cup and can balance the levels of sodium and potassium in the body while regulating blood pressure.

The project is wonderful news for any dialysis patient. In the beginning (November 2015), the scientists received $6 million from the Institute of Biomedical Imaging and Bioengineering, and it’s safe to say that the money were well spent.

The scientists have high hopes for the bionic kidney, and the lead researcher, Dr. Victor Gura, says that the device will be available for sale in only 2 years.

The bionic kidney is a perfect replica of our kidneys. It consists of numerous microchips and is moved by the heart. Like the normal kidneys, it is able to filter waste and toxins from the bloodstream.

  The project was unveiled by Willian Vanderbilt Fissels and Shuvo Roy from the University of California, offering renewed hope for millions of kidney dialysis patients. Now, some of you may be wondering “But, what if the body rejects it?”, but, the scientists assure us that the chances of rejection are zero! Incredible, right?

This is because the bionic kidney is made from renal cells. The first prototype is the size of a coffee cup and can balance the levels of sodium and potassium in the body while regulating blood pressure.

The project is wonderful news for any dialysis patient. In the beginning (November 2015), the scientists received $6 million from the Institute of Biomedical Imaging and Bioengineering, and it’s safe to say that the money were well spent.

The scientists have high hopes for the bionic kidney, and the lead researcher, Dr. Victor Gura, says that the device will be available for sale in only 2 years.

Source:medicalonline1.com

Could wearable ‘artificial kidney’ change dialysis?


A small, experimental wearable device has moved a step closer to helping patients who rely on kidney dialysis, according to a report.

Victor Gura fits a "wearable artificial kidney," which filters a patient's blood continuously.

For patients with kidney failure, the common treatment is to be hooked up to a dialysis machine at a hospital or clinic several times a week. In addition to the inconvenience, patients develop buildup of fluids and minerals between dialysis sessions, which can result in high blood pressure and breathing problems and require severe dietary restrictions.

“I was very frustrated — I still am — because for decades, we’ve been doing dialysis with big machines that prolong the life of the patient a little bit … and in addition, they have a lousy quality of life,” said Victor Gura, an associate clinical professor of medicine at the David Geffen School of Medicine at the University of California, Los Angeles.

Gura and his colleagues are developing the Wearable Artificial Kidney, or WAK, which would filter a patient’s blood continuously, instead of a few times a week. “This is to reduce a lot of the complications that make patients sick … (and) to give patients back their life,” such as allowing them to have jobs again, he said.

The researchers presented the results of a small trial of the device on Saturday at Kidney Week, the annual meeting of the American Society of Nephrology. The trial involved seven patients in Seattle with end-stage kidney disease who wore the device for 24 hours. During that time, the device removed water and salts from the blood at the same rate as healthy kidneys, and patients did not complain of discomfort or experience side effects, Gura said.

New rules give hope to people waiting for donated kidneys

The current research has not been published in a peer-reviewed journal and should be considered preliminary; however, Gura and his colleagues have previously published studies of patients wearing WAK devices for up to eight hours.

Participants in the current and previous trials were able to sleep with the devices, and should be able to take showers and carry out other normal activities, Gura said.

“We encouraged patients to eat bananas and mashed potatoes and drink orange juice, (and) they enjoyed ice cream and cheesecake, which they couldn’t before,” Gura said. Normally, these foods would be off-limits because they can lead to a dangerous buildup of potassium and phosphorus between dialysis sessions.

However, the device had one important pitfall: Two of the seven patients stopped wearing it before the 24 hours were up because it stopped working properly. Gura and his colleagues are working to correct technical problems before they start their next trial, which will probably involve a group of patients wearing the device for a week.

“Getting the machine to be reliable and consistent is going to be (Gura’s) greatest challenge. … I’ll be convinced when they can keep patients stable for seven or 14 days,” said Leslie Spry, medical director for the Dialysis Center of Lincoln in Lincoln, Nebraska, and spokeswoman for the National Kidney Foundation, a patient advocacy organization.

The WAK device weighs 10 pounds, though Gura and his colleagues are working to get it down to 5 pounds, and patients in the study wore them on their belts. The device connects to a large vein in the body via a catheter and, similar to a conventional dialysis machine, contains filters that separate water, salts and minerals out of the blood.

Users would have to remove the WAK from the catheter once a week to replace the filter and add chemicals once per day to purify the water that is filtered out. Other than those steps, the device would take care of itself, running on 9-volt batteries.

“Anytime you maintain a connection with a machine to your blood vessel system, infection is going to be your No. 1 enemy,” Spry said, adding that he will be interested to see whether patients in longer-lasting trials develop infections. However, it would be “very possible” to teach patients to maintain their devices properly, just as those with home dialysis machines do, he added.

Home dialysis machines have alleviated some of the burden of treatment, allowing patients to receive dialysis up to seven days a week, Spry said. He has helped develop these machines and is a part-time employee of Nx Stage, which makes dialysis machines. However, these machines do not allow continuous dialysis, and patients use them for only up to eight hours a day (in the case of nocturnal machines), he added.

Although other wearable dialysis devices have been researched over the years, the WAK is the only one for which there are published clinical trials, Gura said.

If the researchers continue to receive funding to conduct clinical trials and further develop the technology, Gura estimates that WAK devices could be available for patients in two years.

The U.S. Food and Drug Administration announced last month that it would expedite the approval of the device once studies are able to demonstrate safety and efficacy.

Bone Loss May Indicate Poor Heart Health in Dialysis Patients


High parathyroid hormone levels and bone loss may predict progression of coronary artery calcification (CAC) in patients receiving dialysis, according to a study published online April 2 in the Journal of the American Society of Nephrology.

“We discovered that high parathyroid hormone and the consequential bone loss are major risk factors for progression of vascular calcifications,” Hartmut H. Malluche, MD, from the Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Lexington, commented in a news release.

“These two factors were heretofore not appreciated and were independent from traditional known risk factors,” he added.
Elevated parathyroid hormone levels cause the release of calcium from bone, leading to bone loss and thinning. Most patients receiving dialysis for chronic kidney disease have CAC. CAC increases the risk for cardiovascular events, which in turn cause the majority of deaths in patients with CKD, the authors note.

Therefore, Dr Malluche and colleagues recommend monitoring bone loss with measurements of parathyroid hormone or bone mineral density (BMD) as a way to predict progression of CAC in patients receiving dialysis.

Between August 2009 and April 2013, the researchers enrolled 213 participants from 38 dialysis centers in Kentucky. Participants underwent measurement of routine laboratory tests, serum markers of bone metabolism, and CAC at baseline and 1 year. The researchers also evaluated BMD at both points using dual-energy X-ray absorptiometry scans and quantitative computed tomography. They assessed CAC using multislide computed tomography of the heart and CAC square root of coronary artery calcification volume, an analytic technique that accounts for variability in scanning.

About 80% of participants had CAC at baseline, and almost 50% of these had measurements suggesting high risk for cardiovascular events. One third of participants had osteoporosis.

Independent positive predictors of baseline CAC included coronary artery disease, diabetes, length of time receiving dialysis, age, and concentration of fibroblast growth factor 23, which regulates serum phosphate levels and helps maintain bone strength. In contrast, BMD of the spine inversely predicted baseline CAC.
CAC progression at 1 year occurred among three quarters of the 122 patients who completed the study. Independent risk factors for CAC progression included age, osteoporosis (β = 4.6; 95% confidence interval, 1.8 – 7.5; P = .002), and baseline total or whole parathyroid hormone more than nine times the normal value, after adjusting for age (β = 6.9; 95% confidence interval, 2.4 – 11.4; P = .003).

The researchers note several limitations for the study, including exclusion of about 20% of screened patients because of severe comorbidities or impaired mental status. In addition, the prospective, short-term nature of the study precluded determination of disease mechanisms and long-term relationships.

Dr Malluche noted in the press release that important links may exist between the level of calcification in bones and calcifications in blood vessels.

“Studies need to be done to find out whether prevention of bone loss will reduce progression of vascular calcifications,” he emphasized.

Defer dialysis in ESRD: New guidelines.


New clinical practice guidelines from the Canadian Society of Nephrology recommend deferred – over early – initiation of dialysis in patients with end-stage renal disease (ESRD).

With the deferred strategy, patients with an estimated glomelular filtration rate (eGFR) of <15 mL/min per 1.73 m2 need to be closely monitored by a nephrologist. Dialysis is initiated only when uremic symptoms (fluid overload, refractory hyperkalemia or acidosis) emerge or when the eGFR drops to ≤6 mL/min per 1.73m2. [CMAJ 2014;186:112-117]

The updated recommendation was based on a review of 23 studies, including the Initiating Dialysis Early and Late (IDEAL) study, a large clinical trial which showed that early dialysis did not improve survival, quality of life, or hospital admission rates in patients with chronic kidney disease (CKD) compared with late or deferred strategy. The findings start to reverse a trend toward early initiation of dialysis.

There is a lack of compelling benefit for early initiation of dialysis in CKD, said guideline chair Professor Louise M. Moist from the Western University in London, Ontario, Canada. Veering away from the practice will avoid the burden and inconvenience of an early start, which has been associated with longer time on dialysis and greater resource use, she added.

The new guideline covers adult patients (age >18 years) with ESRD (stage 5 CKD) initiating chronic hemodialysis or peritoneal dialysis. It does not consider the timing of pre-emptive transplantation, dialysis for acute kidney injury, pediatric patients, or those electing conservative management without dialysis.

The Canadian guidance does not recommend earlier initiation of dialysis in higher-risk subgroups, such as patients with diabetes. It also dropped previous recommendations to initiate dialysis based only on a decline in nutritional status (as measured by serum albumin, lean body mass, etc). The recommendation differs from that of the National Kidney Foundation’s Kidney Disease Quality Outcomes Initiative (KDOQI), which calls for nephrologists to evaluate the benefits, risks and disadvantages of beginning kidney replacement therapy at eGFR <15 mL/min and the Caring for Australians with Renal Impairment (CARI) guidelines which recommend initiation of dialysis at eGFR <10 mL/min or if uremic symptoms or signs of malnutrition occur.

The guideline is intended not only for nephrologists but for primary care physicians, other internal medicine subspecialties, and nursing specialists caring for, referring, or co-managing treatment for patients with CKD.

Improved detection of PTH imbalance may benefit dialysis patients.


New data demonstrate an association between lower levels of non-oxidized biologically active parathyroid hormone and increased mortality in hemodialysis patients, suggesting the need for improved assays.

“The current tests for parathyroid hormone levels overlook a key factor. When parathyroid hormone interacts with oxygen under conditions of stress such as end-stage kidney disease, it becomes biologically inactive,” researcherBerthold Hocher, MD, PhD, of the University of Potsdam in Germany, said in a press release.

Researchers conducted a prospective cohort study of 340 hemodialysis patients (224 men, 116 women; median age, 66 years) with end-stage CKD. They measured parathyroid hormone (PTH) levels using a third-generation intact parathyroid hormone electrochemiluminescence immunoassay system (ECLIA; Roche iPTH, Roche Diagnostics) directly and after prior removal of oxidized biologically inactive PTH using an antihuman oxidized parathyroid monoclonal antibody (Immundiagnostik AG).

During 5-year follow-up, 50% of the patients died. Cardiovascular diseaseaccounted for 60% of the deaths, according to the researchers, followed by infections (23%), cancer (11%) and unknown causes (6%).

Results revealed higher median non-oxidized biologically active PTH levels in those who survived (7.2 ng/L) vs. those who did not (5 ng/L; P=.002).

Survival was increased among patients in the highest tertile of non-oxidized biologically active PTH compared with the lowest (P=.0008). Additionally, in the highest tertile, median survival was 1,702 days compared with 453 days in the lowest tertile.

Data also showed that, after multivariable adjustment, older age appeared to increase risk for death, but higher levels of non-oxidized biologically active PTH decreased risk for death.

In an analysis of a subgroup of patients with intact PTH levels above the upper normal range of 70 ng/L at baseline, mortality appeared to be associated with oxidized biologically inactive PTH levels but not non-oxidized biologically active PTH levels.

“With more precise parathyroid hormone testing, health care professionals will have the information they need to improve clinical outcomes,” Hocher said. “The nephrology community has long recognized there is an issue with current testing approaches, and now we can solve this problem and improve patient care.”

The calcified abdominal cocoon.


A 45-year-old man with end-stage renal failure secondary to Alport syndrome, who had received maintenance peritoneal dialysis for 19 years, presented with abdominal pain and haemodynamic instability.

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His abdomen was tender and 500 mL of fresh blood was drained from the peritoneal dialysis catheter. Following resuscitation, an abdominal CT scan showed thickened bowel wall and extraordinary calcification of abdominal viscera .At laparotomy, exploration of the abdomen was precluded by severe calcification of the abdominal wall and bowel loops . Blood was arising from the pelvis, which was subsequently packed with gauze, arresting the haemorrhage. The packs were removed after 72 h and the patient was transferred to haemodialysis. He was discharged home on day 36. The radiographic and intraoperative appearances were typical of advanced, sclerosing, encapsulating peritonitis,1 or so-called abdominal cocoon, a well recognised complication of long-term peritoneal dialysis, with ectopic calcification secondary to tertiary hyperparathyroidism. Sclerosing encapsulating peritonitis is one of the most serious complications of peritoneal dialysis and is associated with a high mortality rate, even if peritoneal dialysis is discontinued. Patients usually present with symptoms of bowel obstruction. Unfortunately, there is no reliable therapy, although tamoxifen and surgery are used.

Source: Lancet

Kidney Injuries Requiring Dialysis on the Rise in the U.S.


The incidence of acute renal failure (also called acute kidney injury, or AKI) is now higher than that of end-stage renal disease in the U.S., according to statistics presented in the Journal of the American Society of Nephrology.

On the basis of a representative sample of hospitalizations from 2000 to 2009, the incidence of AKI requiring dialysis has been increasing at the rate of about 10% annually. Risk for dialysis-requiring AKI was higher with older age, among men, and among non-Hispanic blacks. Inpatient deaths associated with the condition more than doubled over the 10-year span of the sample, from 18,000 to 39,000 a year.

The authors say they were unable to explain the observed increase, but speculate that contrast procedures outside of cardiac catheterization labs may have a role. They also say that more liberal use of acute dialysis is an unlikely explanation.

Source: Journal of the American Society of Nephrology