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National Kidney Foundation (NKF): Spring Clinical Meetings
Hemodialysis patients forget to take metabolic bone disease medications
LAS VEGAS – The most common reason why end-stage-renal disease patients missed doses of their metabolic bone disease medications was that they forgot to take them, a multicenter study showed.
"Medication adherence is a constant struggle for patients with end-stage renal disease," Maureen McKinley, M.S.W., said in an interview after a meeting sponsored by the National Kidney Foundation, where the study was presented. "Dialysis patients are prescribed an average of 21 pills a day which would be difficult for even a healthy person to track and manage. The average dialysis patient misses one out of every two medication doses, which has a direct impact on their health, frequency of hospitalizations and, in turn, on costs to our health care system."
Ms. McKinley, a clinical social worker at Irvine, Calif.–based DaVita HealthCare Partners, and her associates interviewed 50 patients across 17 hemodialysis clinics over a period of 12 weeks to determine root causes of missed metabolic bone disease (MBD) medication doses. Of the 50 patients, 70% reported having missed doses of their MBD medication over the 12-week period. Of these, 66% missed a dose fewer than five times while 10% missed doses five times or more.
The most frequent reason for missing doses was "forgot to take" (41%), followed by "ill and not eating that many meals" (10%), "don’t understand importance" (7%), and "difficulty swallowing" (7%). Other reasons included "side effects" (6%), "forgot to refill" (4%), and financial barriers (3%).
"From my background as a social worker, I was expecting financial reasons to be the most common cause for patients not taking all their prescribed medication," Ms. McKinley said. "After years of sitting with families struggling to make ends meet and stay on top of payments, I know the burden that dialysis can place on a patient and their loved ones. Yet, 41% of respondents cited "forgot to take" as the reason for not taking medications."
With the complexity of so many medications and the reality of the disease, "it’s all about keeping it simple and as easy as possible for our patients," Ms. McKinley continued. "Trying to assist with simple reminders, setting an alarm, putting pills where you can see them or carrying your phosphate binders with you. Having a support system is such a help for patients on dialysis. As clinicians, we try to assist in these ways, but having the support of loved ones is a huge benefit for these daily struggles."
The study was supported by DaVita Rx. Ms. McKinley is an employee of DaVita HealthCare Partners.
LAS VEGAS – The most common reason why end-stage-renal disease patients missed doses of their metabolic bone disease medications was that they forgot to take them, a multicenter study showed.
"Medication adherence is a constant struggle for patients with end-stage renal disease," Maureen McKinley, M.S.W., said in an interview after a meeting sponsored by the National Kidney Foundation, where the study was presented. "Dialysis patients are prescribed an average of 21 pills a day which would be difficult for even a healthy person to track and manage. The average dialysis patient misses one out of every two medication doses, which has a direct impact on their health, frequency of hospitalizations and, in turn, on costs to our health care system."
Ms. McKinley, a clinical social worker at Irvine, Calif.–based DaVita HealthCare Partners, and her associates interviewed 50 patients across 17 hemodialysis clinics over a period of 12 weeks to determine root causes of missed metabolic bone disease (MBD) medication doses. Of the 50 patients, 70% reported having missed doses of their MBD medication over the 12-week period. Of these, 66% missed a dose fewer than five times while 10% missed doses five times or more.
The most frequent reason for missing doses was "forgot to take" (41%), followed by "ill and not eating that many meals" (10%), "don’t understand importance" (7%), and "difficulty swallowing" (7%). Other reasons included "side effects" (6%), "forgot to refill" (4%), and financial barriers (3%).
"From my background as a social worker, I was expecting financial reasons to be the most common cause for patients not taking all their prescribed medication," Ms. McKinley said. "After years of sitting with families struggling to make ends meet and stay on top of payments, I know the burden that dialysis can place on a patient and their loved ones. Yet, 41% of respondents cited "forgot to take" as the reason for not taking medications."
With the complexity of so many medications and the reality of the disease, "it’s all about keeping it simple and as easy as possible for our patients," Ms. McKinley continued. "Trying to assist with simple reminders, setting an alarm, putting pills where you can see them or carrying your phosphate binders with you. Having a support system is such a help for patients on dialysis. As clinicians, we try to assist in these ways, but having the support of loved ones is a huge benefit for these daily struggles."
The study was supported by DaVita Rx. Ms. McKinley is an employee of DaVita HealthCare Partners.
LAS VEGAS – The most common reason why end-stage-renal disease patients missed doses of their metabolic bone disease medications was that they forgot to take them, a multicenter study showed.
"Medication adherence is a constant struggle for patients with end-stage renal disease," Maureen McKinley, M.S.W., said in an interview after a meeting sponsored by the National Kidney Foundation, where the study was presented. "Dialysis patients are prescribed an average of 21 pills a day which would be difficult for even a healthy person to track and manage. The average dialysis patient misses one out of every two medication doses, which has a direct impact on their health, frequency of hospitalizations and, in turn, on costs to our health care system."
Ms. McKinley, a clinical social worker at Irvine, Calif.–based DaVita HealthCare Partners, and her associates interviewed 50 patients across 17 hemodialysis clinics over a period of 12 weeks to determine root causes of missed metabolic bone disease (MBD) medication doses. Of the 50 patients, 70% reported having missed doses of their MBD medication over the 12-week period. Of these, 66% missed a dose fewer than five times while 10% missed doses five times or more.
The most frequent reason for missing doses was "forgot to take" (41%), followed by "ill and not eating that many meals" (10%), "don’t understand importance" (7%), and "difficulty swallowing" (7%). Other reasons included "side effects" (6%), "forgot to refill" (4%), and financial barriers (3%).
"From my background as a social worker, I was expecting financial reasons to be the most common cause for patients not taking all their prescribed medication," Ms. McKinley said. "After years of sitting with families struggling to make ends meet and stay on top of payments, I know the burden that dialysis can place on a patient and their loved ones. Yet, 41% of respondents cited "forgot to take" as the reason for not taking medications."
With the complexity of so many medications and the reality of the disease, "it’s all about keeping it simple and as easy as possible for our patients," Ms. McKinley continued. "Trying to assist with simple reminders, setting an alarm, putting pills where you can see them or carrying your phosphate binders with you. Having a support system is such a help for patients on dialysis. As clinicians, we try to assist in these ways, but having the support of loved ones is a huge benefit for these daily struggles."
The study was supported by DaVita Rx. Ms. McKinley is an employee of DaVita HealthCare Partners.
AT SCM 14
Key clinical point: Discuss simple reminders, such as setting an alarm, to improve medication adherence for dialysis patients.
Major finding: Over a period of 12 weeks, 76% of patients being treated at hemodialysis clinics reported missing doses of their metabolic bone disease medications.
Data source: A survey of 50 patients at 17 hemodialysis clinics.
Disclosures: The study was supported by DaVita Rx. Ms. McKinley is an employee of DaVita HealthCare Partners.
Primary Prevention of Diabetic Kidney Disease: Thumbs Up/Down
LAS VEGAS – Contrary to conventional wisdom, neither ACE inhibitors nor angiotensin receptor blockers have any role to play in primary prevention of diabetic kidney disease, according to Dr. Robert C. Stanton, chief of nephrology at the Harvard University’s Joslin Diabetes Center, Boston.
"I don’t see any unique indication for ACE inhibitors and ARBs for the primary prevention of kidney disease in diabetic patients, especially given that around 70% of diabetes patients will never develop kidney disease. They’re perfectly fine blood pressure pills. But as a magic kidney disease prevention drug, I don’t see any evidence for that. Of course, patients with proteinuria are another issue entirely. Those drugs absolutely are beneficial in that setting," he said at a meeting sponsored by the National Kidney Foundation.
When Dr. Stanton polled his audience electronically during the course of his talk, however, the majority of physicians indicated that they believe ACE inhibitors and ARBs are indeed useful for primary prevention of diabetic kidney disease. The evidence, Dr. Stanton emphasized, shows otherwise.
For example, a well-conducted, randomized, multicenter, placebo-controlled, 5-year clinical trial showed no benefit for enalapril or losartan in preventing kidney disease in patients with type 1 diabetes (N. Engl. J. Med. 2009;361:40-51). And three randomized controlled trials showed no primary preventive benefit for candesartan in more than 5,000 patients with type 1 or type 2 diabetes (Ann. Intern. Med. 2009;151:11-20).
Dr. Stanton noted that lots of other interventions have been proposed for the primary prevention of kidney disease in diabetes patients. Some are supported by solid evidence of benefit, others are not.
Here is his view of the preventive landscape:
• Intensive blood glucose control. "This is the easy one," he said. "A lot of us in the diabetes world feel that a hemoglobin A1c of 7% is the appropriate target for preventing many complications. It’s a reasonable target and should be achieved whether you’re talking about type 1 or type 2 patients."
The nephrologist noted that recent 25-year follow-up data from the landmark Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study showed that fully 18 years after the intervention ended, patients assigned to intensive blood glucose control still showed highly impressive 50% reductions in the cumulative incidence of both microalbuminuria and end-stage renal disease compared with patients placed on less intensive control (Diabetes Care 2014;37:24-30).
• Smoking cessation. Smoking has been linked to a several-fold increased risk of diabetic kidney disease. "I think of diabetes as an endothelial cell disease, and smoking is the greatest endothelial cell poison we’ve come up with. So stopping smoking is something well worth doing," Dr. Stanton said.
• Blood pressure control. No question exists regarding its renoprotective effect. But recent guidelines are dizzyingly all over the map in terms of target pressure recommendations.
"I’m getting a major headache reading these articles right now. I can show you the data. Good luck! I personally like a target of 130/80 mm Hg or less, particularly when it’s not that hard to get there. But I’d let you decide what particular target you favor," he said.
He prefers 130/80 mm Hg as a target blood pressure for primary prevention of diabetic kidney disease in large part because of a meta-analysis showing that it was associated with a 10% reduction in the risk of developing microalbuminuria and an 11% decrease in end-stage renal disease (PloS Med 2012;9(8):e1001293).
• Weight loss. The growing bariatric surgery literature supports weight loss as a primary preventive strategy.
• Protein intake. There is no role for a low-protein diet – say, less than 0.8 g/kg per day – for primary prevention of kidney disease in diabetes patients. And Dr. Stanton believes a high-protein diet in the range of more than 1.5 or 2 g/kg per day is best avoided in patients with diabetes, although he stressed that the evidence on this score remains sketchy.
Still, "I would not go on a body-building diet or an Atkins-type diet," he cautioned.
• Targeting glomerular hyperfiltration. Studies have shown conflicting results. "For me, there’s no clear role for targeting hyperfiltration," said Dr. Stanton, who cited a comprehensive review that he finds persuasive (Diabetologia 2010;53:2093-104).
The key to developing more effective primary prevention strategies, according to Dr. Stanton, will be first to establish markers that clearly identify the 30% or so of diabetes patients who will go on to develop renal disease, then test novel interventions specifically in that high-risk group.
Promising biomarkers include circulating tumor necrosis factor alpha receptor levels, von Willebrand factor, monocyte chemoattractant factor, asymmetrical dimethylarginine, interleukin-6 and -8, and Fas receptor.
For example, one study showed that patients with type 2 diabetes in the top quartile for circulating TNF receptor 1 had a cumulative 12-year incidence of end-stage renal disease of 54%, compared to just 3% in patients in the other quartiles (J. Am. Soc. Nephrol. 2012;23:507-15).
"Lots of companies are looking at these now. These markers may be coming our way as indicators of people with diabetes who are likely to progress to kidney disease," Dr. Stanton said.
He reported serving as a consultant to Boehringer Ingelheim.
LAS VEGAS – Contrary to conventional wisdom, neither ACE inhibitors nor angiotensin receptor blockers have any role to play in primary prevention of diabetic kidney disease, according to Dr. Robert C. Stanton, chief of nephrology at the Harvard University’s Joslin Diabetes Center, Boston.
"I don’t see any unique indication for ACE inhibitors and ARBs for the primary prevention of kidney disease in diabetic patients, especially given that around 70% of diabetes patients will never develop kidney disease. They’re perfectly fine blood pressure pills. But as a magic kidney disease prevention drug, I don’t see any evidence for that. Of course, patients with proteinuria are another issue entirely. Those drugs absolutely are beneficial in that setting," he said at a meeting sponsored by the National Kidney Foundation.
When Dr. Stanton polled his audience electronically during the course of his talk, however, the majority of physicians indicated that they believe ACE inhibitors and ARBs are indeed useful for primary prevention of diabetic kidney disease. The evidence, Dr. Stanton emphasized, shows otherwise.
For example, a well-conducted, randomized, multicenter, placebo-controlled, 5-year clinical trial showed no benefit for enalapril or losartan in preventing kidney disease in patients with type 1 diabetes (N. Engl. J. Med. 2009;361:40-51). And three randomized controlled trials showed no primary preventive benefit for candesartan in more than 5,000 patients with type 1 or type 2 diabetes (Ann. Intern. Med. 2009;151:11-20).
Dr. Stanton noted that lots of other interventions have been proposed for the primary prevention of kidney disease in diabetes patients. Some are supported by solid evidence of benefit, others are not.
Here is his view of the preventive landscape:
• Intensive blood glucose control. "This is the easy one," he said. "A lot of us in the diabetes world feel that a hemoglobin A1c of 7% is the appropriate target for preventing many complications. It’s a reasonable target and should be achieved whether you’re talking about type 1 or type 2 patients."
The nephrologist noted that recent 25-year follow-up data from the landmark Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study showed that fully 18 years after the intervention ended, patients assigned to intensive blood glucose control still showed highly impressive 50% reductions in the cumulative incidence of both microalbuminuria and end-stage renal disease compared with patients placed on less intensive control (Diabetes Care 2014;37:24-30).
• Smoking cessation. Smoking has been linked to a several-fold increased risk of diabetic kidney disease. "I think of diabetes as an endothelial cell disease, and smoking is the greatest endothelial cell poison we’ve come up with. So stopping smoking is something well worth doing," Dr. Stanton said.
• Blood pressure control. No question exists regarding its renoprotective effect. But recent guidelines are dizzyingly all over the map in terms of target pressure recommendations.
"I’m getting a major headache reading these articles right now. I can show you the data. Good luck! I personally like a target of 130/80 mm Hg or less, particularly when it’s not that hard to get there. But I’d let you decide what particular target you favor," he said.
He prefers 130/80 mm Hg as a target blood pressure for primary prevention of diabetic kidney disease in large part because of a meta-analysis showing that it was associated with a 10% reduction in the risk of developing microalbuminuria and an 11% decrease in end-stage renal disease (PloS Med 2012;9(8):e1001293).
• Weight loss. The growing bariatric surgery literature supports weight loss as a primary preventive strategy.
• Protein intake. There is no role for a low-protein diet – say, less than 0.8 g/kg per day – for primary prevention of kidney disease in diabetes patients. And Dr. Stanton believes a high-protein diet in the range of more than 1.5 or 2 g/kg per day is best avoided in patients with diabetes, although he stressed that the evidence on this score remains sketchy.
Still, "I would not go on a body-building diet or an Atkins-type diet," he cautioned.
• Targeting glomerular hyperfiltration. Studies have shown conflicting results. "For me, there’s no clear role for targeting hyperfiltration," said Dr. Stanton, who cited a comprehensive review that he finds persuasive (Diabetologia 2010;53:2093-104).
The key to developing more effective primary prevention strategies, according to Dr. Stanton, will be first to establish markers that clearly identify the 30% or so of diabetes patients who will go on to develop renal disease, then test novel interventions specifically in that high-risk group.
Promising biomarkers include circulating tumor necrosis factor alpha receptor levels, von Willebrand factor, monocyte chemoattractant factor, asymmetrical dimethylarginine, interleukin-6 and -8, and Fas receptor.
For example, one study showed that patients with type 2 diabetes in the top quartile for circulating TNF receptor 1 had a cumulative 12-year incidence of end-stage renal disease of 54%, compared to just 3% in patients in the other quartiles (J. Am. Soc. Nephrol. 2012;23:507-15).
"Lots of companies are looking at these now. These markers may be coming our way as indicators of people with diabetes who are likely to progress to kidney disease," Dr. Stanton said.
He reported serving as a consultant to Boehringer Ingelheim.
LAS VEGAS – Contrary to conventional wisdom, neither ACE inhibitors nor angiotensin receptor blockers have any role to play in primary prevention of diabetic kidney disease, according to Dr. Robert C. Stanton, chief of nephrology at the Harvard University’s Joslin Diabetes Center, Boston.
"I don’t see any unique indication for ACE inhibitors and ARBs for the primary prevention of kidney disease in diabetic patients, especially given that around 70% of diabetes patients will never develop kidney disease. They’re perfectly fine blood pressure pills. But as a magic kidney disease prevention drug, I don’t see any evidence for that. Of course, patients with proteinuria are another issue entirely. Those drugs absolutely are beneficial in that setting," he said at a meeting sponsored by the National Kidney Foundation.
When Dr. Stanton polled his audience electronically during the course of his talk, however, the majority of physicians indicated that they believe ACE inhibitors and ARBs are indeed useful for primary prevention of diabetic kidney disease. The evidence, Dr. Stanton emphasized, shows otherwise.
For example, a well-conducted, randomized, multicenter, placebo-controlled, 5-year clinical trial showed no benefit for enalapril or losartan in preventing kidney disease in patients with type 1 diabetes (N. Engl. J. Med. 2009;361:40-51). And three randomized controlled trials showed no primary preventive benefit for candesartan in more than 5,000 patients with type 1 or type 2 diabetes (Ann. Intern. Med. 2009;151:11-20).
Dr. Stanton noted that lots of other interventions have been proposed for the primary prevention of kidney disease in diabetes patients. Some are supported by solid evidence of benefit, others are not.
Here is his view of the preventive landscape:
• Intensive blood glucose control. "This is the easy one," he said. "A lot of us in the diabetes world feel that a hemoglobin A1c of 7% is the appropriate target for preventing many complications. It’s a reasonable target and should be achieved whether you’re talking about type 1 or type 2 patients."
The nephrologist noted that recent 25-year follow-up data from the landmark Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study showed that fully 18 years after the intervention ended, patients assigned to intensive blood glucose control still showed highly impressive 50% reductions in the cumulative incidence of both microalbuminuria and end-stage renal disease compared with patients placed on less intensive control (Diabetes Care 2014;37:24-30).
• Smoking cessation. Smoking has been linked to a several-fold increased risk of diabetic kidney disease. "I think of diabetes as an endothelial cell disease, and smoking is the greatest endothelial cell poison we’ve come up with. So stopping smoking is something well worth doing," Dr. Stanton said.
• Blood pressure control. No question exists regarding its renoprotective effect. But recent guidelines are dizzyingly all over the map in terms of target pressure recommendations.
"I’m getting a major headache reading these articles right now. I can show you the data. Good luck! I personally like a target of 130/80 mm Hg or less, particularly when it’s not that hard to get there. But I’d let you decide what particular target you favor," he said.
He prefers 130/80 mm Hg as a target blood pressure for primary prevention of diabetic kidney disease in large part because of a meta-analysis showing that it was associated with a 10% reduction in the risk of developing microalbuminuria and an 11% decrease in end-stage renal disease (PloS Med 2012;9(8):e1001293).
• Weight loss. The growing bariatric surgery literature supports weight loss as a primary preventive strategy.
• Protein intake. There is no role for a low-protein diet – say, less than 0.8 g/kg per day – for primary prevention of kidney disease in diabetes patients. And Dr. Stanton believes a high-protein diet in the range of more than 1.5 or 2 g/kg per day is best avoided in patients with diabetes, although he stressed that the evidence on this score remains sketchy.
Still, "I would not go on a body-building diet or an Atkins-type diet," he cautioned.
• Targeting glomerular hyperfiltration. Studies have shown conflicting results. "For me, there’s no clear role for targeting hyperfiltration," said Dr. Stanton, who cited a comprehensive review that he finds persuasive (Diabetologia 2010;53:2093-104).
The key to developing more effective primary prevention strategies, according to Dr. Stanton, will be first to establish markers that clearly identify the 30% or so of diabetes patients who will go on to develop renal disease, then test novel interventions specifically in that high-risk group.
Promising biomarkers include circulating tumor necrosis factor alpha receptor levels, von Willebrand factor, monocyte chemoattractant factor, asymmetrical dimethylarginine, interleukin-6 and -8, and Fas receptor.
For example, one study showed that patients with type 2 diabetes in the top quartile for circulating TNF receptor 1 had a cumulative 12-year incidence of end-stage renal disease of 54%, compared to just 3% in patients in the other quartiles (J. Am. Soc. Nephrol. 2012;23:507-15).
"Lots of companies are looking at these now. These markers may be coming our way as indicators of people with diabetes who are likely to progress to kidney disease," Dr. Stanton said.
He reported serving as a consultant to Boehringer Ingelheim.
EXPERT ANALYSIS FROM SCM 14
Chronic kidney disease brings often subtle cognitive impairment
LAS VEGAS – Patients on dialysis for end-stage renal disease have a high burden of impaired executive function that’s typically missed by clinicians, Dr. Daniel E. Weiner said at a meeting sponsored by the National Kidney Foundation.
Vascular dementia, which is much more common than Alzheimer’s disease in patients with chronic kidney disease (CKD), impairs executive function and is associated with anatomic white matter brain disease. Executive function is the cognitive domain concerned with attention, processing speed, reasoning, planning, and problem solving. Clinicians tend to miss the presence of cognitive impairment in patients with CKD because they typically rely upon the Mini-Mental State Examination (MMSE) to screen for impaired cognition. And the MMSE focuses on memory difficulties, which are more common in Alzheimer’s disease, rather than the more subtle domain of executive function, he explained.
"We’re trying to teach (CKD patients) about complex topics such as fluid restriction, medication management, and salt intake, and you wonder if it just goes in one ear and out the other because they’re not able to process these complicated issues," observed Dr. Weiner, a nephrologist at Tufts University, Boston.
Dr. Weiner was coauthor of a recent cross-sectional cohort study in which 314 hemodialysis patients at six Boston-area hemodialysis units completed a comprehensive battery of neuropsychological tests assessing memory and executive function. The patients scored markedly worse than general population norms on executive function, but not on memory performance. Moreover, impaired executive function was highly prevalent even in patients with a normal MMSE of 24 or more. The take-home message: be cautious in using an MMSE score of less than 24 to screen for cognitive impairment in dialysis patients (Neurology 2013;80:471-80).
Moderate to severe cognitive impairment is also prevalent in patients on peritoneal dialysis, as shown by investigators at the University of Minnesota. They gave a battery of nine validated neuropsychological tests to 51 peritoneal dialysis patients, 338 hemodialysis patients, and 101 controls without CKD who were matched for age and comorbid conditions. Of the peritoneal dialysis cohort, 31% had severe cognitive impairment, as did 37% of the hemodialysis group and 13% of controls. In an adjusted logistic regression model, peritoneal dialysis was associated with a 2.5-fold increased risk of moderate to severe global cognitive impairment, compared with the no-CKD controls, while hemodialysis patients had a similar 3.16-fold increased risk (Am. J. Kidney Dis. 2011;57:612-20).
"That’s a remarkably high prevalence: one-third of dialysis patients in a moderately well educated Minnesota population with access to medical care performed poorly enough on a neurocognitive battery to be classified as severely cognitively impaired, meaning they flubbed on two different domains of cognitive function," Dr. Weiner commented.
The effect of dialysis itself upon cognition is a matter of continuing controversy. Although some nephrologists posit that a more intensive dialysis regimen would result in improved cognitive performance, that hasn’t been borne out in analyses to date (Kidney International 2011;79:14-22).
"This suggests that the cognitive impairment we see in dialysis patients isn’t related to the dialysis dose. It’s not related to retained solutes, but is more related to the – for lack of a better word – bad humors patients have been exposed to for many years and which have put them into a situation where they require dialysis," according to Dr. Weiner.
"We have patients that drop their systolic blood pressure by 20, 30, 40, even unfortunately 80 mm Hg during dialysis. You can’t imagine that this is good for you. We’re inducing transient microvascular ischemia, which is ultimately manifest structurally: in the kidney we get fibrosis, in the brain we get white matter disease," he continued.
Cognitive dysfunction is associated with increased mortality risk even in CKD patients who are not dialysis dependent. In an analysis of National Health and Nutrition Examination Survey III data, non–dialysis dependent CKD patients in the lowest quartile in terms of cognitive score had a twofold increased risk of mortality, compared with those in the highest quartile (Am. J. Nephrol. 2012;35:49-57).
Chronic kidney disease as defined by an estimated glomerular filtration rate below 60 mL/min/1.73 m2 is also a cardiovascular disease risk equivalent for stroke. Dr. Weiner and coworkers showed that the stroke rate in patients with CKD but no known cardiovascular disease is elevated to roughly the same extent as in patients with known cardiovascular disease but no CKD (Am. J. Kidney Dis. 2006;48:392-401).
More recently, Dr. Weiner and his colleagues showed in a brain MRI study that hemodialysis patients not only have far more white matter disease and cerebral atrophy than controls without kidney disease, they also have a high prevalence of previously unrecognized strokes. The cross-sectional study involved 45 hemodialysis patients and 67 controls, all without a history of stroke. Impressively, 18% of the hemodialysis patients had evidence of a small-vessel infarct on MRI and another 8% had a large-vessel infarct (Am. J. Kidney Dis. 2013;61:271-8).
The high rate of often subtle cognitive impairment among dialysis patients points to the need for alternative patient education strategies. In order to reinforce his educational messages, Dr. Weiner makes an effort to convey the same extensive information to family members and other primary caregivers that he provides to the patients themselves.
He reported having no financial conflicts.
LAS VEGAS – Patients on dialysis for end-stage renal disease have a high burden of impaired executive function that’s typically missed by clinicians, Dr. Daniel E. Weiner said at a meeting sponsored by the National Kidney Foundation.
Vascular dementia, which is much more common than Alzheimer’s disease in patients with chronic kidney disease (CKD), impairs executive function and is associated with anatomic white matter brain disease. Executive function is the cognitive domain concerned with attention, processing speed, reasoning, planning, and problem solving. Clinicians tend to miss the presence of cognitive impairment in patients with CKD because they typically rely upon the Mini-Mental State Examination (MMSE) to screen for impaired cognition. And the MMSE focuses on memory difficulties, which are more common in Alzheimer’s disease, rather than the more subtle domain of executive function, he explained.
"We’re trying to teach (CKD patients) about complex topics such as fluid restriction, medication management, and salt intake, and you wonder if it just goes in one ear and out the other because they’re not able to process these complicated issues," observed Dr. Weiner, a nephrologist at Tufts University, Boston.
Dr. Weiner was coauthor of a recent cross-sectional cohort study in which 314 hemodialysis patients at six Boston-area hemodialysis units completed a comprehensive battery of neuropsychological tests assessing memory and executive function. The patients scored markedly worse than general population norms on executive function, but not on memory performance. Moreover, impaired executive function was highly prevalent even in patients with a normal MMSE of 24 or more. The take-home message: be cautious in using an MMSE score of less than 24 to screen for cognitive impairment in dialysis patients (Neurology 2013;80:471-80).
Moderate to severe cognitive impairment is also prevalent in patients on peritoneal dialysis, as shown by investigators at the University of Minnesota. They gave a battery of nine validated neuropsychological tests to 51 peritoneal dialysis patients, 338 hemodialysis patients, and 101 controls without CKD who were matched for age and comorbid conditions. Of the peritoneal dialysis cohort, 31% had severe cognitive impairment, as did 37% of the hemodialysis group and 13% of controls. In an adjusted logistic regression model, peritoneal dialysis was associated with a 2.5-fold increased risk of moderate to severe global cognitive impairment, compared with the no-CKD controls, while hemodialysis patients had a similar 3.16-fold increased risk (Am. J. Kidney Dis. 2011;57:612-20).
"That’s a remarkably high prevalence: one-third of dialysis patients in a moderately well educated Minnesota population with access to medical care performed poorly enough on a neurocognitive battery to be classified as severely cognitively impaired, meaning they flubbed on two different domains of cognitive function," Dr. Weiner commented.
The effect of dialysis itself upon cognition is a matter of continuing controversy. Although some nephrologists posit that a more intensive dialysis regimen would result in improved cognitive performance, that hasn’t been borne out in analyses to date (Kidney International 2011;79:14-22).
"This suggests that the cognitive impairment we see in dialysis patients isn’t related to the dialysis dose. It’s not related to retained solutes, but is more related to the – for lack of a better word – bad humors patients have been exposed to for many years and which have put them into a situation where they require dialysis," according to Dr. Weiner.
"We have patients that drop their systolic blood pressure by 20, 30, 40, even unfortunately 80 mm Hg during dialysis. You can’t imagine that this is good for you. We’re inducing transient microvascular ischemia, which is ultimately manifest structurally: in the kidney we get fibrosis, in the brain we get white matter disease," he continued.
Cognitive dysfunction is associated with increased mortality risk even in CKD patients who are not dialysis dependent. In an analysis of National Health and Nutrition Examination Survey III data, non–dialysis dependent CKD patients in the lowest quartile in terms of cognitive score had a twofold increased risk of mortality, compared with those in the highest quartile (Am. J. Nephrol. 2012;35:49-57).
Chronic kidney disease as defined by an estimated glomerular filtration rate below 60 mL/min/1.73 m2 is also a cardiovascular disease risk equivalent for stroke. Dr. Weiner and coworkers showed that the stroke rate in patients with CKD but no known cardiovascular disease is elevated to roughly the same extent as in patients with known cardiovascular disease but no CKD (Am. J. Kidney Dis. 2006;48:392-401).
More recently, Dr. Weiner and his colleagues showed in a brain MRI study that hemodialysis patients not only have far more white matter disease and cerebral atrophy than controls without kidney disease, they also have a high prevalence of previously unrecognized strokes. The cross-sectional study involved 45 hemodialysis patients and 67 controls, all without a history of stroke. Impressively, 18% of the hemodialysis patients had evidence of a small-vessel infarct on MRI and another 8% had a large-vessel infarct (Am. J. Kidney Dis. 2013;61:271-8).
The high rate of often subtle cognitive impairment among dialysis patients points to the need for alternative patient education strategies. In order to reinforce his educational messages, Dr. Weiner makes an effort to convey the same extensive information to family members and other primary caregivers that he provides to the patients themselves.
He reported having no financial conflicts.
LAS VEGAS – Patients on dialysis for end-stage renal disease have a high burden of impaired executive function that’s typically missed by clinicians, Dr. Daniel E. Weiner said at a meeting sponsored by the National Kidney Foundation.
Vascular dementia, which is much more common than Alzheimer’s disease in patients with chronic kidney disease (CKD), impairs executive function and is associated with anatomic white matter brain disease. Executive function is the cognitive domain concerned with attention, processing speed, reasoning, planning, and problem solving. Clinicians tend to miss the presence of cognitive impairment in patients with CKD because they typically rely upon the Mini-Mental State Examination (MMSE) to screen for impaired cognition. And the MMSE focuses on memory difficulties, which are more common in Alzheimer’s disease, rather than the more subtle domain of executive function, he explained.
"We’re trying to teach (CKD patients) about complex topics such as fluid restriction, medication management, and salt intake, and you wonder if it just goes in one ear and out the other because they’re not able to process these complicated issues," observed Dr. Weiner, a nephrologist at Tufts University, Boston.
Dr. Weiner was coauthor of a recent cross-sectional cohort study in which 314 hemodialysis patients at six Boston-area hemodialysis units completed a comprehensive battery of neuropsychological tests assessing memory and executive function. The patients scored markedly worse than general population norms on executive function, but not on memory performance. Moreover, impaired executive function was highly prevalent even in patients with a normal MMSE of 24 or more. The take-home message: be cautious in using an MMSE score of less than 24 to screen for cognitive impairment in dialysis patients (Neurology 2013;80:471-80).
Moderate to severe cognitive impairment is also prevalent in patients on peritoneal dialysis, as shown by investigators at the University of Minnesota. They gave a battery of nine validated neuropsychological tests to 51 peritoneal dialysis patients, 338 hemodialysis patients, and 101 controls without CKD who were matched for age and comorbid conditions. Of the peritoneal dialysis cohort, 31% had severe cognitive impairment, as did 37% of the hemodialysis group and 13% of controls. In an adjusted logistic regression model, peritoneal dialysis was associated with a 2.5-fold increased risk of moderate to severe global cognitive impairment, compared with the no-CKD controls, while hemodialysis patients had a similar 3.16-fold increased risk (Am. J. Kidney Dis. 2011;57:612-20).
"That’s a remarkably high prevalence: one-third of dialysis patients in a moderately well educated Minnesota population with access to medical care performed poorly enough on a neurocognitive battery to be classified as severely cognitively impaired, meaning they flubbed on two different domains of cognitive function," Dr. Weiner commented.
The effect of dialysis itself upon cognition is a matter of continuing controversy. Although some nephrologists posit that a more intensive dialysis regimen would result in improved cognitive performance, that hasn’t been borne out in analyses to date (Kidney International 2011;79:14-22).
"This suggests that the cognitive impairment we see in dialysis patients isn’t related to the dialysis dose. It’s not related to retained solutes, but is more related to the – for lack of a better word – bad humors patients have been exposed to for many years and which have put them into a situation where they require dialysis," according to Dr. Weiner.
"We have patients that drop their systolic blood pressure by 20, 30, 40, even unfortunately 80 mm Hg during dialysis. You can’t imagine that this is good for you. We’re inducing transient microvascular ischemia, which is ultimately manifest structurally: in the kidney we get fibrosis, in the brain we get white matter disease," he continued.
Cognitive dysfunction is associated with increased mortality risk even in CKD patients who are not dialysis dependent. In an analysis of National Health and Nutrition Examination Survey III data, non–dialysis dependent CKD patients in the lowest quartile in terms of cognitive score had a twofold increased risk of mortality, compared with those in the highest quartile (Am. J. Nephrol. 2012;35:49-57).
Chronic kidney disease as defined by an estimated glomerular filtration rate below 60 mL/min/1.73 m2 is also a cardiovascular disease risk equivalent for stroke. Dr. Weiner and coworkers showed that the stroke rate in patients with CKD but no known cardiovascular disease is elevated to roughly the same extent as in patients with known cardiovascular disease but no CKD (Am. J. Kidney Dis. 2006;48:392-401).
More recently, Dr. Weiner and his colleagues showed in a brain MRI study that hemodialysis patients not only have far more white matter disease and cerebral atrophy than controls without kidney disease, they also have a high prevalence of previously unrecognized strokes. The cross-sectional study involved 45 hemodialysis patients and 67 controls, all without a history of stroke. Impressively, 18% of the hemodialysis patients had evidence of a small-vessel infarct on MRI and another 8% had a large-vessel infarct (Am. J. Kidney Dis. 2013;61:271-8).
The high rate of often subtle cognitive impairment among dialysis patients points to the need for alternative patient education strategies. In order to reinforce his educational messages, Dr. Weiner makes an effort to convey the same extensive information to family members and other primary caregivers that he provides to the patients themselves.
He reported having no financial conflicts.
EXPERT ANALYSIS FROM SCM 14
Look for nephrotoxicity in adult survivors of childhood cancer
LAS VEGAS – Adult survivors of childhood cancer treated with high-dose cisplatin or high-dose ifosfamide are at markedly increased risk for chronic renal impairment, according to a large Dutch study with a median 18.3-year follow-up.
Long-term treatment-related nephrotoxicity was also seen in the adult survivors of childhood cancer who underwent unilateral nephrectomy combined with abdominal radiation therapy.
"This study is perhaps a warning to us when we’re seeing these adult survivors of childhood cancer in clinic, particularly if they have a history of ifosfamide or cisplatin use, to pay closer attention to the development of chronic kidney disease so they can be managed better in the future," Dr. Anushree C. Shirali said at a meeting sponsored by the National Kidney Foundation.
Drug-induced acute kidney injury is a common event during cancer therapy. Its mechanisms and treatments are well studied. In contrast, the long-term nephrotoxicity of the powerful therapies used in treating childhood cancers has received much less scrutiny. But it’s an increasingly relevant issue because childhood cancer survival rates have improved substantially. Indeed, as the Dutch investigators observed, today 1 in 570 young adults is a childhood cancer survivor (Clin. J. Am. Soc. Nephrol. 2013;8:922-9).
Dr. Shirali, a nephrologist at Yale University in New Haven, Conn., highlighted the Dutch study of 763 adult survivors of childhood cancer because of its unusually long and complete follow-up. The investigators included nearly 90% of all adult survivors treated at Erasmus University in Rotterdam, the Netherlands, during 1964-2005.
High-dose ifosfamide was associated with a 6.2-fold greater likelihood of an increased urinary beta2-microglobulin/creatinine ratio indicative of persisting tubular dysfunction, compared with cancer survivors not receiving that therapy. High-dose cisplatin was associated with a 5.2-fold increased risk of albuminuria. The estimated glomerular filtration rate in adult survivors who had received high-dose ifosfamide was 88 mL/min per 1.73 m2, significantly lower than the 98 mL/min per 1.73 m2 in others. Similarly, patients who had received high-dose cisplatin had an average estimated glomerular filtration rate of 83 mL/min per 1.73 m2, compared with 101 mL/min per 1.73 m2 in survivors not treated with high-dose cisplatin.
In contrast to ifosfamide, its isomer cyclophosphamide was not associated with long-term nephrotoxicity; neither was carboplatin, a cisplatin analogue, or methotrexate. Although methotrexate is known to cause acute nephrotoxicity, this phenomenon appears to be completely reversible, since methotrexate-treated, long-term cancer survivors didn’t develop tubular or glomerular dysfunction.
This long-term study was supported by the Dutch Kidney Foundation. Dr. Shirali, who was not involved in the study, reported having no financial conflicts.
LAS VEGAS – Adult survivors of childhood cancer treated with high-dose cisplatin or high-dose ifosfamide are at markedly increased risk for chronic renal impairment, according to a large Dutch study with a median 18.3-year follow-up.
Long-term treatment-related nephrotoxicity was also seen in the adult survivors of childhood cancer who underwent unilateral nephrectomy combined with abdominal radiation therapy.
"This study is perhaps a warning to us when we’re seeing these adult survivors of childhood cancer in clinic, particularly if they have a history of ifosfamide or cisplatin use, to pay closer attention to the development of chronic kidney disease so they can be managed better in the future," Dr. Anushree C. Shirali said at a meeting sponsored by the National Kidney Foundation.
Drug-induced acute kidney injury is a common event during cancer therapy. Its mechanisms and treatments are well studied. In contrast, the long-term nephrotoxicity of the powerful therapies used in treating childhood cancers has received much less scrutiny. But it’s an increasingly relevant issue because childhood cancer survival rates have improved substantially. Indeed, as the Dutch investigators observed, today 1 in 570 young adults is a childhood cancer survivor (Clin. J. Am. Soc. Nephrol. 2013;8:922-9).
Dr. Shirali, a nephrologist at Yale University in New Haven, Conn., highlighted the Dutch study of 763 adult survivors of childhood cancer because of its unusually long and complete follow-up. The investigators included nearly 90% of all adult survivors treated at Erasmus University in Rotterdam, the Netherlands, during 1964-2005.
High-dose ifosfamide was associated with a 6.2-fold greater likelihood of an increased urinary beta2-microglobulin/creatinine ratio indicative of persisting tubular dysfunction, compared with cancer survivors not receiving that therapy. High-dose cisplatin was associated with a 5.2-fold increased risk of albuminuria. The estimated glomerular filtration rate in adult survivors who had received high-dose ifosfamide was 88 mL/min per 1.73 m2, significantly lower than the 98 mL/min per 1.73 m2 in others. Similarly, patients who had received high-dose cisplatin had an average estimated glomerular filtration rate of 83 mL/min per 1.73 m2, compared with 101 mL/min per 1.73 m2 in survivors not treated with high-dose cisplatin.
In contrast to ifosfamide, its isomer cyclophosphamide was not associated with long-term nephrotoxicity; neither was carboplatin, a cisplatin analogue, or methotrexate. Although methotrexate is known to cause acute nephrotoxicity, this phenomenon appears to be completely reversible, since methotrexate-treated, long-term cancer survivors didn’t develop tubular or glomerular dysfunction.
This long-term study was supported by the Dutch Kidney Foundation. Dr. Shirali, who was not involved in the study, reported having no financial conflicts.
LAS VEGAS – Adult survivors of childhood cancer treated with high-dose cisplatin or high-dose ifosfamide are at markedly increased risk for chronic renal impairment, according to a large Dutch study with a median 18.3-year follow-up.
Long-term treatment-related nephrotoxicity was also seen in the adult survivors of childhood cancer who underwent unilateral nephrectomy combined with abdominal radiation therapy.
"This study is perhaps a warning to us when we’re seeing these adult survivors of childhood cancer in clinic, particularly if they have a history of ifosfamide or cisplatin use, to pay closer attention to the development of chronic kidney disease so they can be managed better in the future," Dr. Anushree C. Shirali said at a meeting sponsored by the National Kidney Foundation.
Drug-induced acute kidney injury is a common event during cancer therapy. Its mechanisms and treatments are well studied. In contrast, the long-term nephrotoxicity of the powerful therapies used in treating childhood cancers has received much less scrutiny. But it’s an increasingly relevant issue because childhood cancer survival rates have improved substantially. Indeed, as the Dutch investigators observed, today 1 in 570 young adults is a childhood cancer survivor (Clin. J. Am. Soc. Nephrol. 2013;8:922-9).
Dr. Shirali, a nephrologist at Yale University in New Haven, Conn., highlighted the Dutch study of 763 adult survivors of childhood cancer because of its unusually long and complete follow-up. The investigators included nearly 90% of all adult survivors treated at Erasmus University in Rotterdam, the Netherlands, during 1964-2005.
High-dose ifosfamide was associated with a 6.2-fold greater likelihood of an increased urinary beta2-microglobulin/creatinine ratio indicative of persisting tubular dysfunction, compared with cancer survivors not receiving that therapy. High-dose cisplatin was associated with a 5.2-fold increased risk of albuminuria. The estimated glomerular filtration rate in adult survivors who had received high-dose ifosfamide was 88 mL/min per 1.73 m2, significantly lower than the 98 mL/min per 1.73 m2 in others. Similarly, patients who had received high-dose cisplatin had an average estimated glomerular filtration rate of 83 mL/min per 1.73 m2, compared with 101 mL/min per 1.73 m2 in survivors not treated with high-dose cisplatin.
In contrast to ifosfamide, its isomer cyclophosphamide was not associated with long-term nephrotoxicity; neither was carboplatin, a cisplatin analogue, or methotrexate. Although methotrexate is known to cause acute nephrotoxicity, this phenomenon appears to be completely reversible, since methotrexate-treated, long-term cancer survivors didn’t develop tubular or glomerular dysfunction.
This long-term study was supported by the Dutch Kidney Foundation. Dr. Shirali, who was not involved in the study, reported having no financial conflicts.
AT SCM 14
Key clinical point: Today 1 in 570 young adults is a childhood cancer survivor, and many are on the road to chronic kidney disease.
Major finding: Adult survivors of childhood cancer treated with high-dose cisplatin or high-dose ifosfamide had a significantly lower estimated glomerular filtration rate than those who were not.
Data source: This was a retrospective, single-center study involving 763 adult survivors of childhood cancer with a median 18.3 years of follow-up.
Disclosures: This long-term study was supported by the Dutch Kidney Foundation. Dr. Shirali, who was not involved in the study, reported having no financial conflicts.
Primary prevention of diabetic kidney disease: Thumbs up/down
LAS VEGAS – Contrary to conventional wisdom, neither ACE inhibitors nor angiotensin receptor blockers have any role to play in primary prevention of diabetic kidney disease, according to Dr. Robert C. Stanton, chief of nephrology at the Harvard University’s Joslin Diabetes Center, Boston.
"I don’t see any unique indication for ACE inhibitors and ARBs for the primary prevention of kidney disease in diabetic patients, especially given that around 70% of diabetes patients will never develop kidney disease. They’re perfectly fine blood pressure pills. But as a magic kidney disease prevention drug, I don’t see any evidence for that. Of course, patients with proteinuria are another issue entirely. Those drugs absolutely are beneficial in that setting," he said at a meeting sponsored by the National Kidney Foundation.
When Dr. Stanton polled his audience electronically during the course of his talk, however, the majority of physicians indicated that they believe ACE inhibitors and ARBs are indeed useful for primary prevention of diabetic kidney disease. The evidence, Dr. Stanton emphasized, shows otherwise.
For example, a well-conducted, randomized, multicenter, placebo-controlled, 5-year clinical trial showed no benefit for enalapril or losartan in preventing kidney disease in patients with type 1 diabetes (N. Engl. J. Med. 2009;361:40-51). And three randomized controlled trials showed no primary preventive benefit for candesartan in more than 5,000 patients with type 1 or type 2 diabetes (Ann. Intern. Med. 2009;151:11-20).
Dr. Stanton noted that lots of other interventions have been proposed for the primary prevention of kidney disease in diabetes patients. Some are supported by solid evidence of benefit, others are not.
Here is his view of the preventive landscape:
• Intensive blood glucose control. "This is the easy one," he said. "A lot of us in the diabetes world feel that a hemoglobin A1c of 7% is the appropriate target for preventing many complications. It’s a reasonable target and should be achieved whether you’re talking about type 1 or type 2 patients."
The nephrologist noted that recent 25-year follow-up data from the landmark Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study showed that fully 18 years after the intervention ended, patients assigned to intensive blood glucose control still showed highly impressive 50% reductions in the cumulative incidence of both microalbuminuria and end-stage renal disease compared with patients placed on less intensive control (Diabetes Care 2014;37:24-30).
• Smoking cessation. Smoking has been linked to a several-fold increased risk of diabetic kidney disease. "I think of diabetes as an endothelial cell disease, and smoking is the greatest endothelial cell poison we’ve come up with. So stopping smoking is something well worth doing," Dr. Stanton said.
• Blood pressure control. No question exists regarding its renoprotective effect. But recent guidelines are dizzyingly all over the map in terms of target pressure recommendations.
"I’m getting a major headache reading these articles right now. I can show you the data. Good luck! I personally like a target of 130/80 mm Hg or less, particularly when it’s not that hard to get there. But I’d let you decide what particular target you favor," he said.
He prefers 130/80 mm Hg as a target blood pressure for primary prevention of diabetic kidney disease in large part because of a meta-analysis showing that it was associated with a 10% reduction in the risk of developing microalbuminuria and an 11% decrease in end-stage renal disease (PloS Med 2012;9(8):e1001293).
• Weight loss. The growing bariatric surgery literature supports weight loss as a primary preventive strategy.
• Protein intake. There is no role for a low-protein diet – say, less than 0.8 g/kg per day – for primary prevention of kidney disease in diabetes patients. And Dr. Stanton believes a high-protein diet in the range of more than 1.5 or 2 g/kg per day is best avoided in patients with diabetes, although he stressed that the evidence on this score remains sketchy.
Still, "I would not go on a body-building diet or an Atkins-type diet," he cautioned.
• Targeting glomerular hyperfiltration. Studies have shown conflicting results. "For me, there’s no clear role for targeting hyperfiltration," said Dr. Stanton, who cited a comprehensive review that he finds persuasive (Diabetologia 2010;53:2093-104).
The key to developing more effective primary prevention strategies, according to Dr. Stanton, will be first to establish markers that clearly identify the 30% or so of diabetes patients who will go on to develop renal disease, then test novel interventions specifically in that high-risk group.
Promising biomarkers include circulating tumor necrosis factor alpha receptor levels, von Willebrand factor, monocyte chemoattractant factor, asymmetrical dimethylarginine, interleukin-6 and -8, and Fas receptor.
For example, one study showed that patients with type 2 diabetes in the top quartile for circulating TNF receptor 1 had a cumulative 12-year incidence of end-stage renal disease of 54%, compared to just 3% in patients in the other quartiles (J. Am. Soc. Nephrol. 2012;23:507-15).
"Lots of companies are looking at these now. These markers may be coming our way as indicators of people with diabetes who are likely to progress to kidney disease," Dr. Stanton said.
He reported serving as a consultant to Boehringer Ingelheim.
LAS VEGAS – Contrary to conventional wisdom, neither ACE inhibitors nor angiotensin receptor blockers have any role to play in primary prevention of diabetic kidney disease, according to Dr. Robert C. Stanton, chief of nephrology at the Harvard University’s Joslin Diabetes Center, Boston.
"I don’t see any unique indication for ACE inhibitors and ARBs for the primary prevention of kidney disease in diabetic patients, especially given that around 70% of diabetes patients will never develop kidney disease. They’re perfectly fine blood pressure pills. But as a magic kidney disease prevention drug, I don’t see any evidence for that. Of course, patients with proteinuria are another issue entirely. Those drugs absolutely are beneficial in that setting," he said at a meeting sponsored by the National Kidney Foundation.
When Dr. Stanton polled his audience electronically during the course of his talk, however, the majority of physicians indicated that they believe ACE inhibitors and ARBs are indeed useful for primary prevention of diabetic kidney disease. The evidence, Dr. Stanton emphasized, shows otherwise.
For example, a well-conducted, randomized, multicenter, placebo-controlled, 5-year clinical trial showed no benefit for enalapril or losartan in preventing kidney disease in patients with type 1 diabetes (N. Engl. J. Med. 2009;361:40-51). And three randomized controlled trials showed no primary preventive benefit for candesartan in more than 5,000 patients with type 1 or type 2 diabetes (Ann. Intern. Med. 2009;151:11-20).
Dr. Stanton noted that lots of other interventions have been proposed for the primary prevention of kidney disease in diabetes patients. Some are supported by solid evidence of benefit, others are not.
Here is his view of the preventive landscape:
• Intensive blood glucose control. "This is the easy one," he said. "A lot of us in the diabetes world feel that a hemoglobin A1c of 7% is the appropriate target for preventing many complications. It’s a reasonable target and should be achieved whether you’re talking about type 1 or type 2 patients."
The nephrologist noted that recent 25-year follow-up data from the landmark Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study showed that fully 18 years after the intervention ended, patients assigned to intensive blood glucose control still showed highly impressive 50% reductions in the cumulative incidence of both microalbuminuria and end-stage renal disease compared with patients placed on less intensive control (Diabetes Care 2014;37:24-30).
• Smoking cessation. Smoking has been linked to a several-fold increased risk of diabetic kidney disease. "I think of diabetes as an endothelial cell disease, and smoking is the greatest endothelial cell poison we’ve come up with. So stopping smoking is something well worth doing," Dr. Stanton said.
• Blood pressure control. No question exists regarding its renoprotective effect. But recent guidelines are dizzyingly all over the map in terms of target pressure recommendations.
"I’m getting a major headache reading these articles right now. I can show you the data. Good luck! I personally like a target of 130/80 mm Hg or less, particularly when it’s not that hard to get there. But I’d let you decide what particular target you favor," he said.
He prefers 130/80 mm Hg as a target blood pressure for primary prevention of diabetic kidney disease in large part because of a meta-analysis showing that it was associated with a 10% reduction in the risk of developing microalbuminuria and an 11% decrease in end-stage renal disease (PloS Med 2012;9(8):e1001293).
• Weight loss. The growing bariatric surgery literature supports weight loss as a primary preventive strategy.
• Protein intake. There is no role for a low-protein diet – say, less than 0.8 g/kg per day – for primary prevention of kidney disease in diabetes patients. And Dr. Stanton believes a high-protein diet in the range of more than 1.5 or 2 g/kg per day is best avoided in patients with diabetes, although he stressed that the evidence on this score remains sketchy.
Still, "I would not go on a body-building diet or an Atkins-type diet," he cautioned.
• Targeting glomerular hyperfiltration. Studies have shown conflicting results. "For me, there’s no clear role for targeting hyperfiltration," said Dr. Stanton, who cited a comprehensive review that he finds persuasive (Diabetologia 2010;53:2093-104).
The key to developing more effective primary prevention strategies, according to Dr. Stanton, will be first to establish markers that clearly identify the 30% or so of diabetes patients who will go on to develop renal disease, then test novel interventions specifically in that high-risk group.
Promising biomarkers include circulating tumor necrosis factor alpha receptor levels, von Willebrand factor, monocyte chemoattractant factor, asymmetrical dimethylarginine, interleukin-6 and -8, and Fas receptor.
For example, one study showed that patients with type 2 diabetes in the top quartile for circulating TNF receptor 1 had a cumulative 12-year incidence of end-stage renal disease of 54%, compared to just 3% in patients in the other quartiles (J. Am. Soc. Nephrol. 2012;23:507-15).
"Lots of companies are looking at these now. These markers may be coming our way as indicators of people with diabetes who are likely to progress to kidney disease," Dr. Stanton said.
He reported serving as a consultant to Boehringer Ingelheim.
LAS VEGAS – Contrary to conventional wisdom, neither ACE inhibitors nor angiotensin receptor blockers have any role to play in primary prevention of diabetic kidney disease, according to Dr. Robert C. Stanton, chief of nephrology at the Harvard University’s Joslin Diabetes Center, Boston.
"I don’t see any unique indication for ACE inhibitors and ARBs for the primary prevention of kidney disease in diabetic patients, especially given that around 70% of diabetes patients will never develop kidney disease. They’re perfectly fine blood pressure pills. But as a magic kidney disease prevention drug, I don’t see any evidence for that. Of course, patients with proteinuria are another issue entirely. Those drugs absolutely are beneficial in that setting," he said at a meeting sponsored by the National Kidney Foundation.
When Dr. Stanton polled his audience electronically during the course of his talk, however, the majority of physicians indicated that they believe ACE inhibitors and ARBs are indeed useful for primary prevention of diabetic kidney disease. The evidence, Dr. Stanton emphasized, shows otherwise.
For example, a well-conducted, randomized, multicenter, placebo-controlled, 5-year clinical trial showed no benefit for enalapril or losartan in preventing kidney disease in patients with type 1 diabetes (N. Engl. J. Med. 2009;361:40-51). And three randomized controlled trials showed no primary preventive benefit for candesartan in more than 5,000 patients with type 1 or type 2 diabetes (Ann. Intern. Med. 2009;151:11-20).
Dr. Stanton noted that lots of other interventions have been proposed for the primary prevention of kidney disease in diabetes patients. Some are supported by solid evidence of benefit, others are not.
Here is his view of the preventive landscape:
• Intensive blood glucose control. "This is the easy one," he said. "A lot of us in the diabetes world feel that a hemoglobin A1c of 7% is the appropriate target for preventing many complications. It’s a reasonable target and should be achieved whether you’re talking about type 1 or type 2 patients."
The nephrologist noted that recent 25-year follow-up data from the landmark Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study showed that fully 18 years after the intervention ended, patients assigned to intensive blood glucose control still showed highly impressive 50% reductions in the cumulative incidence of both microalbuminuria and end-stage renal disease compared with patients placed on less intensive control (Diabetes Care 2014;37:24-30).
• Smoking cessation. Smoking has been linked to a several-fold increased risk of diabetic kidney disease. "I think of diabetes as an endothelial cell disease, and smoking is the greatest endothelial cell poison we’ve come up with. So stopping smoking is something well worth doing," Dr. Stanton said.
• Blood pressure control. No question exists regarding its renoprotective effect. But recent guidelines are dizzyingly all over the map in terms of target pressure recommendations.
"I’m getting a major headache reading these articles right now. I can show you the data. Good luck! I personally like a target of 130/80 mm Hg or less, particularly when it’s not that hard to get there. But I’d let you decide what particular target you favor," he said.
He prefers 130/80 mm Hg as a target blood pressure for primary prevention of diabetic kidney disease in large part because of a meta-analysis showing that it was associated with a 10% reduction in the risk of developing microalbuminuria and an 11% decrease in end-stage renal disease (PloS Med 2012;9(8):e1001293).
• Weight loss. The growing bariatric surgery literature supports weight loss as a primary preventive strategy.
• Protein intake. There is no role for a low-protein diet – say, less than 0.8 g/kg per day – for primary prevention of kidney disease in diabetes patients. And Dr. Stanton believes a high-protein diet in the range of more than 1.5 or 2 g/kg per day is best avoided in patients with diabetes, although he stressed that the evidence on this score remains sketchy.
Still, "I would not go on a body-building diet or an Atkins-type diet," he cautioned.
• Targeting glomerular hyperfiltration. Studies have shown conflicting results. "For me, there’s no clear role for targeting hyperfiltration," said Dr. Stanton, who cited a comprehensive review that he finds persuasive (Diabetologia 2010;53:2093-104).
The key to developing more effective primary prevention strategies, according to Dr. Stanton, will be first to establish markers that clearly identify the 30% or so of diabetes patients who will go on to develop renal disease, then test novel interventions specifically in that high-risk group.
Promising biomarkers include circulating tumor necrosis factor alpha receptor levels, von Willebrand factor, monocyte chemoattractant factor, asymmetrical dimethylarginine, interleukin-6 and -8, and Fas receptor.
For example, one study showed that patients with type 2 diabetes in the top quartile for circulating TNF receptor 1 had a cumulative 12-year incidence of end-stage renal disease of 54%, compared to just 3% in patients in the other quartiles (J. Am. Soc. Nephrol. 2012;23:507-15).
"Lots of companies are looking at these now. These markers may be coming our way as indicators of people with diabetes who are likely to progress to kidney disease," Dr. Stanton said.
He reported serving as a consultant to Boehringer Ingelheim.
EXPERT ANALYSIS FROM SCM 14
Polymyxin use generates flood of acute kidney injuries
LAS VEGAS – Polymyxins are back on the scene due to the worrisome increase in multidrug-resistant gram-negative bacterial infections.
"These drugs were taken off the shelf many years ago because of their severe nephrotoxicity, but they’ve entered the arena again because they’re very effective – and their toxicity has reemerged as well," Dr. Mark A. Perazella warned at a meeting sponsored by the National Kidney Foundation.
Drug-induced renal injury accounts for 18%-27% of all acute kidney injury in hospital cases. Antimicrobial agents are among the top causes of drug-related nephropathy, particularly in the hospitalized population, he added.
The incidence of acute kidney injury associated with polymyxin B and polymyxin E (colistin) in contemporary practice is a whopping 30%-60%, depending upon the cumulative dose and duration of therapy, comorbid conditions, and whether other nephrotoxic medications are being used concomitantly. Often an individual’s risk of acute kidney injury is at the high end of this range because the polymyxins are viewed as agents of last resort, and vancomycin – a nephrotoxin in its own right, albeit a less potent one – is commonly on board.
Plus, patients with a serious multidrug-resistant gram-negative infection often have multiple comorbidities and are in a weakened state, further predisposing them to acute kidney injury upon exposure to a nephrotoxin, added Dr. Perazella, professor of medicine and director of the acute dialysis unit at Yale University in New Haven, Conn.
There are no randomized trial data to define polymyxin dosing parameters that maximize efficacy and minimize renal risk, which is clearly dose and duration dependent. For example, in a retrospective study of 173 adults on polymyxin B, the incidence of acute kidney injury was 60%; 10% required dialysis, and 14% had to discontinue treatment because of nephrotoxicity. The median cumulative dose of polymyxin B in patients with acute kidney injury was 1,578 mg, as compared with 800 mg in those without acute kidney injury. Concomitant vancomycin was used by 82% of patients with and by 55% without acute kidney injury (J. Infect. 2012;65:80-7).
The reported incidence of acute kidney injury in patients on vancomycin is most often in the 10%-20% range. Risk is higher in patients with multiple comorbidities and increases with higher cumulative doses and longer-duration therapy. In an effort to improve cure rates, the target vancomycin trough level has increase from 10-20 mg/dL to 15-20 mg/dL. That higher trough level means more cases of acute kidney injury, according to Dr. Perazella.
The randomized prospective ZEPHYR study highlighted fixed-dose linezolid as an attractive alternative to dose-optimized vancomycin for treatment of hospital-acquired methicillin-resistant Staphylococcus aureus pneumonia. In a randomized study of 165 participants, the clinical cure rate was significantly better with linezolid by a margin of 58%-47%. The incidence of nephrotoxicity was 8% in the linezolid group, compared with 18% with vancomycin.
Dr. Perazella reported having no financial conflicts.
LAS VEGAS – Polymyxins are back on the scene due to the worrisome increase in multidrug-resistant gram-negative bacterial infections.
"These drugs were taken off the shelf many years ago because of their severe nephrotoxicity, but they’ve entered the arena again because they’re very effective – and their toxicity has reemerged as well," Dr. Mark A. Perazella warned at a meeting sponsored by the National Kidney Foundation.
Drug-induced renal injury accounts for 18%-27% of all acute kidney injury in hospital cases. Antimicrobial agents are among the top causes of drug-related nephropathy, particularly in the hospitalized population, he added.
The incidence of acute kidney injury associated with polymyxin B and polymyxin E (colistin) in contemporary practice is a whopping 30%-60%, depending upon the cumulative dose and duration of therapy, comorbid conditions, and whether other nephrotoxic medications are being used concomitantly. Often an individual’s risk of acute kidney injury is at the high end of this range because the polymyxins are viewed as agents of last resort, and vancomycin – a nephrotoxin in its own right, albeit a less potent one – is commonly on board.
Plus, patients with a serious multidrug-resistant gram-negative infection often have multiple comorbidities and are in a weakened state, further predisposing them to acute kidney injury upon exposure to a nephrotoxin, added Dr. Perazella, professor of medicine and director of the acute dialysis unit at Yale University in New Haven, Conn.
There are no randomized trial data to define polymyxin dosing parameters that maximize efficacy and minimize renal risk, which is clearly dose and duration dependent. For example, in a retrospective study of 173 adults on polymyxin B, the incidence of acute kidney injury was 60%; 10% required dialysis, and 14% had to discontinue treatment because of nephrotoxicity. The median cumulative dose of polymyxin B in patients with acute kidney injury was 1,578 mg, as compared with 800 mg in those without acute kidney injury. Concomitant vancomycin was used by 82% of patients with and by 55% without acute kidney injury (J. Infect. 2012;65:80-7).
The reported incidence of acute kidney injury in patients on vancomycin is most often in the 10%-20% range. Risk is higher in patients with multiple comorbidities and increases with higher cumulative doses and longer-duration therapy. In an effort to improve cure rates, the target vancomycin trough level has increase from 10-20 mg/dL to 15-20 mg/dL. That higher trough level means more cases of acute kidney injury, according to Dr. Perazella.
The randomized prospective ZEPHYR study highlighted fixed-dose linezolid as an attractive alternative to dose-optimized vancomycin for treatment of hospital-acquired methicillin-resistant Staphylococcus aureus pneumonia. In a randomized study of 165 participants, the clinical cure rate was significantly better with linezolid by a margin of 58%-47%. The incidence of nephrotoxicity was 8% in the linezolid group, compared with 18% with vancomycin.
Dr. Perazella reported having no financial conflicts.
LAS VEGAS – Polymyxins are back on the scene due to the worrisome increase in multidrug-resistant gram-negative bacterial infections.
"These drugs were taken off the shelf many years ago because of their severe nephrotoxicity, but they’ve entered the arena again because they’re very effective – and their toxicity has reemerged as well," Dr. Mark A. Perazella warned at a meeting sponsored by the National Kidney Foundation.
Drug-induced renal injury accounts for 18%-27% of all acute kidney injury in hospital cases. Antimicrobial agents are among the top causes of drug-related nephropathy, particularly in the hospitalized population, he added.
The incidence of acute kidney injury associated with polymyxin B and polymyxin E (colistin) in contemporary practice is a whopping 30%-60%, depending upon the cumulative dose and duration of therapy, comorbid conditions, and whether other nephrotoxic medications are being used concomitantly. Often an individual’s risk of acute kidney injury is at the high end of this range because the polymyxins are viewed as agents of last resort, and vancomycin – a nephrotoxin in its own right, albeit a less potent one – is commonly on board.
Plus, patients with a serious multidrug-resistant gram-negative infection often have multiple comorbidities and are in a weakened state, further predisposing them to acute kidney injury upon exposure to a nephrotoxin, added Dr. Perazella, professor of medicine and director of the acute dialysis unit at Yale University in New Haven, Conn.
There are no randomized trial data to define polymyxin dosing parameters that maximize efficacy and minimize renal risk, which is clearly dose and duration dependent. For example, in a retrospective study of 173 adults on polymyxin B, the incidence of acute kidney injury was 60%; 10% required dialysis, and 14% had to discontinue treatment because of nephrotoxicity. The median cumulative dose of polymyxin B in patients with acute kidney injury was 1,578 mg, as compared with 800 mg in those without acute kidney injury. Concomitant vancomycin was used by 82% of patients with and by 55% without acute kidney injury (J. Infect. 2012;65:80-7).
The reported incidence of acute kidney injury in patients on vancomycin is most often in the 10%-20% range. Risk is higher in patients with multiple comorbidities and increases with higher cumulative doses and longer-duration therapy. In an effort to improve cure rates, the target vancomycin trough level has increase from 10-20 mg/dL to 15-20 mg/dL. That higher trough level means more cases of acute kidney injury, according to Dr. Perazella.
The randomized prospective ZEPHYR study highlighted fixed-dose linezolid as an attractive alternative to dose-optimized vancomycin for treatment of hospital-acquired methicillin-resistant Staphylococcus aureus pneumonia. In a randomized study of 165 participants, the clinical cure rate was significantly better with linezolid by a margin of 58%-47%. The incidence of nephrotoxicity was 8% in the linezolid group, compared with 18% with vancomycin.
Dr. Perazella reported having no financial conflicts.
EXPERT ANALYSIS FROM SCM 14
ZS-9 may be a safer hyperkalemia therapy
LAS VEGAS – A novel, highly selective, oral potassium ion–binding agent called ZS-9 effectively reversed hyperkalemia in patients with underlying diabetes, heart failure, or chronic kidney disease.
ZS-9’s safety and tolerability matched those of placebo in the double-blind trial, which was the largest phase III treatment trial ever conducted in patients with hyperkalemia, Dr. Bhupinder Singh said at a meeting sponsored by the National Kidney Foundation.
ZS-9 is an inorganic, microporous crystal composed of zirconium silicate. It is insoluble, highly stable, and not systemically absorbed. In vitro it is more than 125 times more selective for potassium ions than is sodium polystyrene sulfate (SPS, brand name Kayexalate), the resin-based therapy traditionally used in hyperkalemia. ZS-9 also has nine times greater potassium ion binding capacity than SPS, according to Dr. Singh, of Apex Research in Riverside, Calif.
He reported on 753 patients with serum potassium levels of 5.0-6.5 mEq/L; 60% had chronic kidney disease, 40% had heart failure, and 60% had diabetes. Two-thirds of the patients were on an ACE inhibitor or an angiotensin receptor blocker (ARB). Importantly, 28% of subjects had an estimated glomerular filtration rate below 29 mL/min per 1.73 m2.
Subjects were randomized to one of four dosing regimens of ZS-9 or to placebo. For the first 48 hours of the study, patients received oral ZS-9 at doses of 1.25, 2.5, 5, or 10 g t.i.d. or placebo. Patients whose serum potassium levels normalized after 48 hours were then switched to once-daily doses of the same strengths or to placebo for 12 days in order to evaluate ZS-9’s safety and efficacy as a maintenance therapy.
The average reduction from baseline at 48 hours in serum potassium (as measured 14 hours after the last dose) was 0.46 mEq/L in the 2.5-g t.i.d. group, 0.54 mEq/L in 5-mg t.i.d. group, and 0.73 mEq/L in the 10-mg t.i.d. group. Normokalemia was attained at a similar rate in all patient subgroups, regardless of their underlying hyperkalemia-promoting disease. ZS-9 at 1.25 g t.i.d. wasn’t significantly more effective than placebo.
The higher a patient’s baseline serum potassium, the larger the absolute drop in response to a given dose. At 10 mg t.i.d., for example, patients with a baseline serum potassium level of 5.3 mEq/L or less averaged a 0.58-mEq/L reduction. Those who started at 5.4-5.5 mEq/L averaged a 0.98-mEq/L decrease, and patients with a baseline serum potassium level in excess of 5.5 mEq/L had a 1.10-mEq/L reduction.
Of patients who were on ZS-9 at 10 mg t.i.d. for the acute phase of the study, 99% were normokalemic at 48 hours.
All told, 542 patients entered the 12-day maintenance therapy phase. The two higher dosing regimens – 5 and 10 mg once daily – provided clinically and statistically significant benefit, with serum potassium levels remaining flat throughout the study period. Those who were switched double-blind to placebo after 12 days on ZS-9 immediately experienced a rise in their serum potassium. For example, patients with a serum potassium at 4.6 mEq/L during 12 days on ZS-9 at 10 mg climbed on average to a serum potassium of 5.0 mEq/L after 1 week on placebo.
Serum sodium, magnesium, and calcium did not change, nor did blood pressure or body weight in ZS-9-treated patients. There were no cases of significant hypokalemia (values below 3.0 mEq/L) in the study. Two of 11,000 serum potassium measures were less than 3.5 mEq/L. The side-effect profile of ZS-9 was basically the same as that of placebo. The incidence of nausea, vomiting, and other gastrointestinal adverse effects was actually more than twice as high with placebo than it was with active therapy, according to Dr. Singh.
Ongoing and planned studies of ZS-9 include an open-label, 12-month study and a 1-month, randomized treatment withdrawal with long-term extension.
Dr. Singh cited two major candidates for ZS-9 in clinical practice. One is in the large subgroup of patients with heart failure, diabetic kidney disease, or proteinuric nephropathy who become hyperkalemic on optimal doses of guideline-recommended therapy with an ACE inhibitor or ARB. The other potential beneficiaries are patients who would like to follow a healthy diet emphasizing vegetables, fruits, and low-fat dairy products, many of which are quite high in potassium content.
Dr. Singh reported serving as a consultant to ZS Pharma, which is developing ZS-9, as well as to Keryx Biopharmaceuticals and Concert.
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The phase III ZS-9 results are extremely encouraging. There is a major unmet need for a safe and effective agent for acute and chronic management of hyperkalemia. Concern is mounting regarding chronic use of sodium polystyrene sulfate. A systematic review of published reports highlighted the risk of potentially fatal colonic necrosis and other gastrointestinal injuries with this traditional therapy (Am. J. Med. 2013;126:264.e9-e.24).
This information calls into question the use of SPS as a chronic therapy. So we need other options, and we perhaps have some on the horizon with ZS-9. Patiromer is another novel therapy well along in the developmental pipeline. This high-capacity, nonabsorbed, oral ion-exchange polymer also performed well in a phase III randomized trial presented by Dr. Matthew Weir of the University of Maryland, Baltimore, last fall at the annual meeting of the American Society of Nephrology.
Dr. John P. Middleton, a nephrologist at Duke University in Durham, N.C., made these remarks in a separate presentation at the meeting. Dr. Middleton reported having no financial conflicts.
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The phase III ZS-9 results are extremely encouraging. There is a major unmet need for a safe and effective agent for acute and chronic management of hyperkalemia. Concern is mounting regarding chronic use of sodium polystyrene sulfate. A systematic review of published reports highlighted the risk of potentially fatal colonic necrosis and other gastrointestinal injuries with this traditional therapy (Am. J. Med. 2013;126:264.e9-e.24).
This information calls into question the use of SPS as a chronic therapy. So we need other options, and we perhaps have some on the horizon with ZS-9. Patiromer is another novel therapy well along in the developmental pipeline. This high-capacity, nonabsorbed, oral ion-exchange polymer also performed well in a phase III randomized trial presented by Dr. Matthew Weir of the University of Maryland, Baltimore, last fall at the annual meeting of the American Society of Nephrology.
Dr. John P. Middleton, a nephrologist at Duke University in Durham, N.C., made these remarks in a separate presentation at the meeting. Dr. Middleton reported having no financial conflicts.
|
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The phase III ZS-9 results are extremely encouraging. There is a major unmet need for a safe and effective agent for acute and chronic management of hyperkalemia. Concern is mounting regarding chronic use of sodium polystyrene sulfate. A systematic review of published reports highlighted the risk of potentially fatal colonic necrosis and other gastrointestinal injuries with this traditional therapy (Am. J. Med. 2013;126:264.e9-e.24).
This information calls into question the use of SPS as a chronic therapy. So we need other options, and we perhaps have some on the horizon with ZS-9. Patiromer is another novel therapy well along in the developmental pipeline. This high-capacity, nonabsorbed, oral ion-exchange polymer also performed well in a phase III randomized trial presented by Dr. Matthew Weir of the University of Maryland, Baltimore, last fall at the annual meeting of the American Society of Nephrology.
Dr. John P. Middleton, a nephrologist at Duke University in Durham, N.C., made these remarks in a separate presentation at the meeting. Dr. Middleton reported having no financial conflicts.
LAS VEGAS – A novel, highly selective, oral potassium ion–binding agent called ZS-9 effectively reversed hyperkalemia in patients with underlying diabetes, heart failure, or chronic kidney disease.
ZS-9’s safety and tolerability matched those of placebo in the double-blind trial, which was the largest phase III treatment trial ever conducted in patients with hyperkalemia, Dr. Bhupinder Singh said at a meeting sponsored by the National Kidney Foundation.
ZS-9 is an inorganic, microporous crystal composed of zirconium silicate. It is insoluble, highly stable, and not systemically absorbed. In vitro it is more than 125 times more selective for potassium ions than is sodium polystyrene sulfate (SPS, brand name Kayexalate), the resin-based therapy traditionally used in hyperkalemia. ZS-9 also has nine times greater potassium ion binding capacity than SPS, according to Dr. Singh, of Apex Research in Riverside, Calif.
He reported on 753 patients with serum potassium levels of 5.0-6.5 mEq/L; 60% had chronic kidney disease, 40% had heart failure, and 60% had diabetes. Two-thirds of the patients were on an ACE inhibitor or an angiotensin receptor blocker (ARB). Importantly, 28% of subjects had an estimated glomerular filtration rate below 29 mL/min per 1.73 m2.
Subjects were randomized to one of four dosing regimens of ZS-9 or to placebo. For the first 48 hours of the study, patients received oral ZS-9 at doses of 1.25, 2.5, 5, or 10 g t.i.d. or placebo. Patients whose serum potassium levels normalized after 48 hours were then switched to once-daily doses of the same strengths or to placebo for 12 days in order to evaluate ZS-9’s safety and efficacy as a maintenance therapy.
The average reduction from baseline at 48 hours in serum potassium (as measured 14 hours after the last dose) was 0.46 mEq/L in the 2.5-g t.i.d. group, 0.54 mEq/L in 5-mg t.i.d. group, and 0.73 mEq/L in the 10-mg t.i.d. group. Normokalemia was attained at a similar rate in all patient subgroups, regardless of their underlying hyperkalemia-promoting disease. ZS-9 at 1.25 g t.i.d. wasn’t significantly more effective than placebo.
The higher a patient’s baseline serum potassium, the larger the absolute drop in response to a given dose. At 10 mg t.i.d., for example, patients with a baseline serum potassium level of 5.3 mEq/L or less averaged a 0.58-mEq/L reduction. Those who started at 5.4-5.5 mEq/L averaged a 0.98-mEq/L decrease, and patients with a baseline serum potassium level in excess of 5.5 mEq/L had a 1.10-mEq/L reduction.
Of patients who were on ZS-9 at 10 mg t.i.d. for the acute phase of the study, 99% were normokalemic at 48 hours.
All told, 542 patients entered the 12-day maintenance therapy phase. The two higher dosing regimens – 5 and 10 mg once daily – provided clinically and statistically significant benefit, with serum potassium levels remaining flat throughout the study period. Those who were switched double-blind to placebo after 12 days on ZS-9 immediately experienced a rise in their serum potassium. For example, patients with a serum potassium at 4.6 mEq/L during 12 days on ZS-9 at 10 mg climbed on average to a serum potassium of 5.0 mEq/L after 1 week on placebo.
Serum sodium, magnesium, and calcium did not change, nor did blood pressure or body weight in ZS-9-treated patients. There were no cases of significant hypokalemia (values below 3.0 mEq/L) in the study. Two of 11,000 serum potassium measures were less than 3.5 mEq/L. The side-effect profile of ZS-9 was basically the same as that of placebo. The incidence of nausea, vomiting, and other gastrointestinal adverse effects was actually more than twice as high with placebo than it was with active therapy, according to Dr. Singh.
Ongoing and planned studies of ZS-9 include an open-label, 12-month study and a 1-month, randomized treatment withdrawal with long-term extension.
Dr. Singh cited two major candidates for ZS-9 in clinical practice. One is in the large subgroup of patients with heart failure, diabetic kidney disease, or proteinuric nephropathy who become hyperkalemic on optimal doses of guideline-recommended therapy with an ACE inhibitor or ARB. The other potential beneficiaries are patients who would like to follow a healthy diet emphasizing vegetables, fruits, and low-fat dairy products, many of which are quite high in potassium content.
Dr. Singh reported serving as a consultant to ZS Pharma, which is developing ZS-9, as well as to Keryx Biopharmaceuticals and Concert.
LAS VEGAS – A novel, highly selective, oral potassium ion–binding agent called ZS-9 effectively reversed hyperkalemia in patients with underlying diabetes, heart failure, or chronic kidney disease.
ZS-9’s safety and tolerability matched those of placebo in the double-blind trial, which was the largest phase III treatment trial ever conducted in patients with hyperkalemia, Dr. Bhupinder Singh said at a meeting sponsored by the National Kidney Foundation.
ZS-9 is an inorganic, microporous crystal composed of zirconium silicate. It is insoluble, highly stable, and not systemically absorbed. In vitro it is more than 125 times more selective for potassium ions than is sodium polystyrene sulfate (SPS, brand name Kayexalate), the resin-based therapy traditionally used in hyperkalemia. ZS-9 also has nine times greater potassium ion binding capacity than SPS, according to Dr. Singh, of Apex Research in Riverside, Calif.
He reported on 753 patients with serum potassium levels of 5.0-6.5 mEq/L; 60% had chronic kidney disease, 40% had heart failure, and 60% had diabetes. Two-thirds of the patients were on an ACE inhibitor or an angiotensin receptor blocker (ARB). Importantly, 28% of subjects had an estimated glomerular filtration rate below 29 mL/min per 1.73 m2.
Subjects were randomized to one of four dosing regimens of ZS-9 or to placebo. For the first 48 hours of the study, patients received oral ZS-9 at doses of 1.25, 2.5, 5, or 10 g t.i.d. or placebo. Patients whose serum potassium levels normalized after 48 hours were then switched to once-daily doses of the same strengths or to placebo for 12 days in order to evaluate ZS-9’s safety and efficacy as a maintenance therapy.
The average reduction from baseline at 48 hours in serum potassium (as measured 14 hours after the last dose) was 0.46 mEq/L in the 2.5-g t.i.d. group, 0.54 mEq/L in 5-mg t.i.d. group, and 0.73 mEq/L in the 10-mg t.i.d. group. Normokalemia was attained at a similar rate in all patient subgroups, regardless of their underlying hyperkalemia-promoting disease. ZS-9 at 1.25 g t.i.d. wasn’t significantly more effective than placebo.
The higher a patient’s baseline serum potassium, the larger the absolute drop in response to a given dose. At 10 mg t.i.d., for example, patients with a baseline serum potassium level of 5.3 mEq/L or less averaged a 0.58-mEq/L reduction. Those who started at 5.4-5.5 mEq/L averaged a 0.98-mEq/L decrease, and patients with a baseline serum potassium level in excess of 5.5 mEq/L had a 1.10-mEq/L reduction.
Of patients who were on ZS-9 at 10 mg t.i.d. for the acute phase of the study, 99% were normokalemic at 48 hours.
All told, 542 patients entered the 12-day maintenance therapy phase. The two higher dosing regimens – 5 and 10 mg once daily – provided clinically and statistically significant benefit, with serum potassium levels remaining flat throughout the study period. Those who were switched double-blind to placebo after 12 days on ZS-9 immediately experienced a rise in their serum potassium. For example, patients with a serum potassium at 4.6 mEq/L during 12 days on ZS-9 at 10 mg climbed on average to a serum potassium of 5.0 mEq/L after 1 week on placebo.
Serum sodium, magnesium, and calcium did not change, nor did blood pressure or body weight in ZS-9-treated patients. There were no cases of significant hypokalemia (values below 3.0 mEq/L) in the study. Two of 11,000 serum potassium measures were less than 3.5 mEq/L. The side-effect profile of ZS-9 was basically the same as that of placebo. The incidence of nausea, vomiting, and other gastrointestinal adverse effects was actually more than twice as high with placebo than it was with active therapy, according to Dr. Singh.
Ongoing and planned studies of ZS-9 include an open-label, 12-month study and a 1-month, randomized treatment withdrawal with long-term extension.
Dr. Singh cited two major candidates for ZS-9 in clinical practice. One is in the large subgroup of patients with heart failure, diabetic kidney disease, or proteinuric nephropathy who become hyperkalemic on optimal doses of guideline-recommended therapy with an ACE inhibitor or ARB. The other potential beneficiaries are patients who would like to follow a healthy diet emphasizing vegetables, fruits, and low-fat dairy products, many of which are quite high in potassium content.
Dr. Singh reported serving as a consultant to ZS Pharma, which is developing ZS-9, as well as to Keryx Biopharmaceuticals and Concert.
AT SCM 14
Key clinical point: ZS-9 may become a safer treatment alternative to sodium polystyrene sulfate.
Major finding: After 48 hours on the investigational selective potassium ion trapper known as ZS-9 at 10 mg t.i.d., 99% of initially hyperkalemic patients with chronic kidney disease, diabetes, and/or heart failure were normokalemic.
Data source: This phase III, double-blind trial included 753 hyperkalemic patients randomized to one of four doses of ZS-9 or to placebo.
Disclosures: The study was sponsored by ZS Pharma. Dr. Singh reported serving as a consultant to ZS Pharma, which is developing ZS-9.
Depression linked to increased mortality in dialysis patients
LAS VEGAS – Depression in patients with chronic kidney disease is common, underrecognized, and undertreated, Dr. Daniel E. Weiner asserted at a meeting sponsored by the National Kidney Foundation.
Moreover, a recent meta-analysis by University of Toronto researchers demonstrated that the presence of depressive symptoms in patients on long-term dialysis was independently associated with a 51% increase in mortality, noted Dr. Weiner, a nephrologist at Tufts University, Boston.
The meta-analysis included 12 observational studies in which formal depression scales were utilized in more than 21,000 dialysis patients. Even after adjusting for potential publication bias, the presence of depressive symptoms was associated with a 45% increased risk of mortality (Am. J. Kidney Dis. 2014;63:623-35).
The prevalence of depression is elevated among patients across the spectrum of chronic kidney disease (CKD) severity. This was highlighted in a study in which 272 consecutive non–dialysis dependent patients with stage 2-5 CKD underwent screening for depression using the structured Mini International Neuropsychiatric Interview. One in five met criteria for an ongoing major depressive episode. The prevalence of depression didn’t vary significantly by CKD stage (Am. J. Kidney Dis. 2009;54:424-32).
Depression is even more common among patients on dialysis for end-stage renal disease, with prevalence rates of up to 42% reported, Dr. Weiner continued.
He urged physicians to routinely screen for depression in patients with CKD. Studies indicate that’s not widely being done at present, probably in part because the evidence for therapeutic benefit is spotty because the large randomized controlled trials of antidepressant medications have generally excluded patients with advanced CKD.
Dr. Weiner, however, argued that routine screening in patients with CKD is warranted given that the yield is markedly higher than in the general population, depression is associated with increased mortality in dialysis-dependent patients, and it is a treatable disorder. There is evidence from small studies that the selective serotonin reuptake inhibitors (SSRIs) are safe in patients with CKD. Cognitive-behavioral therapy and exercise-based treatment regimens also are backed by supporting evidence.
Dr. Weiner reported having no financial conflicts regarding his presentation.
LAS VEGAS – Depression in patients with chronic kidney disease is common, underrecognized, and undertreated, Dr. Daniel E. Weiner asserted at a meeting sponsored by the National Kidney Foundation.
Moreover, a recent meta-analysis by University of Toronto researchers demonstrated that the presence of depressive symptoms in patients on long-term dialysis was independently associated with a 51% increase in mortality, noted Dr. Weiner, a nephrologist at Tufts University, Boston.
The meta-analysis included 12 observational studies in which formal depression scales were utilized in more than 21,000 dialysis patients. Even after adjusting for potential publication bias, the presence of depressive symptoms was associated with a 45% increased risk of mortality (Am. J. Kidney Dis. 2014;63:623-35).
The prevalence of depression is elevated among patients across the spectrum of chronic kidney disease (CKD) severity. This was highlighted in a study in which 272 consecutive non–dialysis dependent patients with stage 2-5 CKD underwent screening for depression using the structured Mini International Neuropsychiatric Interview. One in five met criteria for an ongoing major depressive episode. The prevalence of depression didn’t vary significantly by CKD stage (Am. J. Kidney Dis. 2009;54:424-32).
Depression is even more common among patients on dialysis for end-stage renal disease, with prevalence rates of up to 42% reported, Dr. Weiner continued.
He urged physicians to routinely screen for depression in patients with CKD. Studies indicate that’s not widely being done at present, probably in part because the evidence for therapeutic benefit is spotty because the large randomized controlled trials of antidepressant medications have generally excluded patients with advanced CKD.
Dr. Weiner, however, argued that routine screening in patients with CKD is warranted given that the yield is markedly higher than in the general population, depression is associated with increased mortality in dialysis-dependent patients, and it is a treatable disorder. There is evidence from small studies that the selective serotonin reuptake inhibitors (SSRIs) are safe in patients with CKD. Cognitive-behavioral therapy and exercise-based treatment regimens also are backed by supporting evidence.
Dr. Weiner reported having no financial conflicts regarding his presentation.
LAS VEGAS – Depression in patients with chronic kidney disease is common, underrecognized, and undertreated, Dr. Daniel E. Weiner asserted at a meeting sponsored by the National Kidney Foundation.
Moreover, a recent meta-analysis by University of Toronto researchers demonstrated that the presence of depressive symptoms in patients on long-term dialysis was independently associated with a 51% increase in mortality, noted Dr. Weiner, a nephrologist at Tufts University, Boston.
The meta-analysis included 12 observational studies in which formal depression scales were utilized in more than 21,000 dialysis patients. Even after adjusting for potential publication bias, the presence of depressive symptoms was associated with a 45% increased risk of mortality (Am. J. Kidney Dis. 2014;63:623-35).
The prevalence of depression is elevated among patients across the spectrum of chronic kidney disease (CKD) severity. This was highlighted in a study in which 272 consecutive non–dialysis dependent patients with stage 2-5 CKD underwent screening for depression using the structured Mini International Neuropsychiatric Interview. One in five met criteria for an ongoing major depressive episode. The prevalence of depression didn’t vary significantly by CKD stage (Am. J. Kidney Dis. 2009;54:424-32).
Depression is even more common among patients on dialysis for end-stage renal disease, with prevalence rates of up to 42% reported, Dr. Weiner continued.
He urged physicians to routinely screen for depression in patients with CKD. Studies indicate that’s not widely being done at present, probably in part because the evidence for therapeutic benefit is spotty because the large randomized controlled trials of antidepressant medications have generally excluded patients with advanced CKD.
Dr. Weiner, however, argued that routine screening in patients with CKD is warranted given that the yield is markedly higher than in the general population, depression is associated with increased mortality in dialysis-dependent patients, and it is a treatable disorder. There is evidence from small studies that the selective serotonin reuptake inhibitors (SSRIs) are safe in patients with CKD. Cognitive-behavioral therapy and exercise-based treatment regimens also are backed by supporting evidence.
Dr. Weiner reported having no financial conflicts regarding his presentation.
EXPERT ANALYSIS FROM SCM 14
New definition of clinically meaningful CKD progression
LAS VEGAS – A landmark study has provided physicians with an improved definition of clinically significant progression of chronic kidney disease for use as a major endpoint in clinical trials as well as in daily medical practice.
Specifically, it’s now clear from the study conducted by the global CKD Prognosis Consortium that a 30% decline in estimated glomerular filtration rate (eGFR) over the course of 2 years portends a 5- to 6-fold increased risk of developing end-stage renal disease (ESRD) during the next 2-3 years, Dr. Josef Coresh reported at a meeting sponsored by the National Kidney Foundation.
The magnitude of increased risk of ESRD in patients with a 30% 2-year decline in eGFR was similar regardless of their baseline stage of CKD. That is, patients with a low baseline eGFR of less than 60 mL/min per 1.73 m2 had an adjusted 5.4-fold increased risk if they had a 30% drop in eGFR, compared with those whose eGFR remained unchanged over a 2-year period, while those with a 30% eGFR drop starting from a higher baseline of 60 mL/min per 1.73 m2 or more had a 6-fold increased risk, said Dr. Coresh, professor of epidemiology and director of the George W. Comstock Center for Public Health Research and Prevention at Johns Hopkins University, Baltimore.
He presented an individual-level meta-analysis of 1.5 million participants in 28 cohorts. Among roughly half a million patients in the 19 cohorts with an initial eGFR below 60 mL/min per 1.73 m2, there were 7,523 ESRD events during a mean 2.4 years of follow-up beginning at the close of the 2-year baseline period. An additional 1,009 ESRD events occurred during the follow-up period in participants with an initial eGFR of 60 mL/min per 1.73 m2 or more.
This study grew out of a collaboration between the National Kidney Foundation and the Food and Drug Administration. Officials at the regulatory agency now accept that the established endpoint used to document CKD progression in clinical trials – that is, a doubling of serum creatinine concentration from baseline – has held back therapeutic progress in the field. That’s because this FDA-mandated surrogate endpoint is a late event and thus requires studies with large sample sizes and long follow-up times. The agency is eager for evidence in support of a better surrogate endpoint, explained Dr. Coresh, who is also director of the cardiovascular epidemiology training program at Johns Hopkins.
The new meta-analysis confirmed that a doubling of serum creatinine concentration over the course of 2 years is indeed a valid endpoint for CKD progression. It was associated with a 32-fold increased risk of developing ESRD in patients who started with an eGFR below 60 mL/min per 1.73 m2 and a 57-fold increased risk in patients with a higher starting eGFR. However, a doubling of serum creatinine in a 2-year time frame was also a rare outcome, occurring in less than 1% of patients with a low initial eGFR and in 0.1% of those with a higher initial value. In contrast, a 30% drop in eGFR over a 2-year period was 10 times more common.
"A doubling of serum creatinine captures only 10% of the excess or population-attributable risk of ESRD during follow-up, whereas a 30% decline in eGFR captures 44% of the population with ESRD in the baseline low-eGFR group and 28% in those with a baseline eGFR of 60 mL/min per 1.73 m2 or greater," Dr. Coresh said.
An impressive level of consistency in the results was seen across the 28 studies included in the meta-analysis, which featured adjustment for confounders.
"I think this level of remarkable consistency makes it safer to think that in many settings, if you have a 30% decline in eGFR over 2 years, you will have a substantially increased risk of ESRD of approximately 5-fold," according to the physician.
He stressed that the meta-analysis demonstrated that it’s not just the change in eGFR over the course of 2 years that’s important in determining risk, but that the starting eGFR level and duration of follow-up are also key in determining absolute risk.
"For example, someone who starts at 50 mL/min per 1.73 m2 and is stable for 2 years has a subsequent risk of ESRD 10 years later of only 5%. If, on the other hand, that patient had a 30% decline in eGFR during 2 years, the 10-year risk becomes 21%. And if you start out at an eGFR of 35 mL/min per 1.73 m2, your 10-year risk of ESRD goes from 18% if your eGFR is unchanged for 2 years to 64% if your eGFR falls by 30%. So within the first 2 years, you have the ability to detect things that will happen a long time from now, with pretty good power," Dr. Coresh said.
The findings held true regardless of patient age, the presence or absence of diabetes, and albuminuria.
This meta-analysis, which was supported by the National Kidney Foundation and the National Institute of Diabetes and Digestive and Kidney Diseases, will result in six publications during the next year. The first was published online on June 3 (JAMA 2014 [doi:10.1001/jama.2014.6634]). The JAMA report goes beyond Dr. Coresh’s time-limited Las Vegas presentation in that it also includes data on all-cause mortality risk according to change in eGFR. He noted this is important because the majority of patients with CKD die of cardiovascular and other causes without ever reaching ESRD. In the meta-analysis, a 30% decline in eGFR over the course of 2 years was associated with an 80% increased risk in all-cause mortality.
Dr. Coresh reported having no relevant financial conflicts.
LAS VEGAS – A landmark study has provided physicians with an improved definition of clinically significant progression of chronic kidney disease for use as a major endpoint in clinical trials as well as in daily medical practice.
Specifically, it’s now clear from the study conducted by the global CKD Prognosis Consortium that a 30% decline in estimated glomerular filtration rate (eGFR) over the course of 2 years portends a 5- to 6-fold increased risk of developing end-stage renal disease (ESRD) during the next 2-3 years, Dr. Josef Coresh reported at a meeting sponsored by the National Kidney Foundation.
The magnitude of increased risk of ESRD in patients with a 30% 2-year decline in eGFR was similar regardless of their baseline stage of CKD. That is, patients with a low baseline eGFR of less than 60 mL/min per 1.73 m2 had an adjusted 5.4-fold increased risk if they had a 30% drop in eGFR, compared with those whose eGFR remained unchanged over a 2-year period, while those with a 30% eGFR drop starting from a higher baseline of 60 mL/min per 1.73 m2 or more had a 6-fold increased risk, said Dr. Coresh, professor of epidemiology and director of the George W. Comstock Center for Public Health Research and Prevention at Johns Hopkins University, Baltimore.
He presented an individual-level meta-analysis of 1.5 million participants in 28 cohorts. Among roughly half a million patients in the 19 cohorts with an initial eGFR below 60 mL/min per 1.73 m2, there were 7,523 ESRD events during a mean 2.4 years of follow-up beginning at the close of the 2-year baseline period. An additional 1,009 ESRD events occurred during the follow-up period in participants with an initial eGFR of 60 mL/min per 1.73 m2 or more.
This study grew out of a collaboration between the National Kidney Foundation and the Food and Drug Administration. Officials at the regulatory agency now accept that the established endpoint used to document CKD progression in clinical trials – that is, a doubling of serum creatinine concentration from baseline – has held back therapeutic progress in the field. That’s because this FDA-mandated surrogate endpoint is a late event and thus requires studies with large sample sizes and long follow-up times. The agency is eager for evidence in support of a better surrogate endpoint, explained Dr. Coresh, who is also director of the cardiovascular epidemiology training program at Johns Hopkins.
The new meta-analysis confirmed that a doubling of serum creatinine concentration over the course of 2 years is indeed a valid endpoint for CKD progression. It was associated with a 32-fold increased risk of developing ESRD in patients who started with an eGFR below 60 mL/min per 1.73 m2 and a 57-fold increased risk in patients with a higher starting eGFR. However, a doubling of serum creatinine in a 2-year time frame was also a rare outcome, occurring in less than 1% of patients with a low initial eGFR and in 0.1% of those with a higher initial value. In contrast, a 30% drop in eGFR over a 2-year period was 10 times more common.
"A doubling of serum creatinine captures only 10% of the excess or population-attributable risk of ESRD during follow-up, whereas a 30% decline in eGFR captures 44% of the population with ESRD in the baseline low-eGFR group and 28% in those with a baseline eGFR of 60 mL/min per 1.73 m2 or greater," Dr. Coresh said.
An impressive level of consistency in the results was seen across the 28 studies included in the meta-analysis, which featured adjustment for confounders.
"I think this level of remarkable consistency makes it safer to think that in many settings, if you have a 30% decline in eGFR over 2 years, you will have a substantially increased risk of ESRD of approximately 5-fold," according to the physician.
He stressed that the meta-analysis demonstrated that it’s not just the change in eGFR over the course of 2 years that’s important in determining risk, but that the starting eGFR level and duration of follow-up are also key in determining absolute risk.
"For example, someone who starts at 50 mL/min per 1.73 m2 and is stable for 2 years has a subsequent risk of ESRD 10 years later of only 5%. If, on the other hand, that patient had a 30% decline in eGFR during 2 years, the 10-year risk becomes 21%. And if you start out at an eGFR of 35 mL/min per 1.73 m2, your 10-year risk of ESRD goes from 18% if your eGFR is unchanged for 2 years to 64% if your eGFR falls by 30%. So within the first 2 years, you have the ability to detect things that will happen a long time from now, with pretty good power," Dr. Coresh said.
The findings held true regardless of patient age, the presence or absence of diabetes, and albuminuria.
This meta-analysis, which was supported by the National Kidney Foundation and the National Institute of Diabetes and Digestive and Kidney Diseases, will result in six publications during the next year. The first was published online on June 3 (JAMA 2014 [doi:10.1001/jama.2014.6634]). The JAMA report goes beyond Dr. Coresh’s time-limited Las Vegas presentation in that it also includes data on all-cause mortality risk according to change in eGFR. He noted this is important because the majority of patients with CKD die of cardiovascular and other causes without ever reaching ESRD. In the meta-analysis, a 30% decline in eGFR over the course of 2 years was associated with an 80% increased risk in all-cause mortality.
Dr. Coresh reported having no relevant financial conflicts.
LAS VEGAS – A landmark study has provided physicians with an improved definition of clinically significant progression of chronic kidney disease for use as a major endpoint in clinical trials as well as in daily medical practice.
Specifically, it’s now clear from the study conducted by the global CKD Prognosis Consortium that a 30% decline in estimated glomerular filtration rate (eGFR) over the course of 2 years portends a 5- to 6-fold increased risk of developing end-stage renal disease (ESRD) during the next 2-3 years, Dr. Josef Coresh reported at a meeting sponsored by the National Kidney Foundation.
The magnitude of increased risk of ESRD in patients with a 30% 2-year decline in eGFR was similar regardless of their baseline stage of CKD. That is, patients with a low baseline eGFR of less than 60 mL/min per 1.73 m2 had an adjusted 5.4-fold increased risk if they had a 30% drop in eGFR, compared with those whose eGFR remained unchanged over a 2-year period, while those with a 30% eGFR drop starting from a higher baseline of 60 mL/min per 1.73 m2 or more had a 6-fold increased risk, said Dr. Coresh, professor of epidemiology and director of the George W. Comstock Center for Public Health Research and Prevention at Johns Hopkins University, Baltimore.
He presented an individual-level meta-analysis of 1.5 million participants in 28 cohorts. Among roughly half a million patients in the 19 cohorts with an initial eGFR below 60 mL/min per 1.73 m2, there were 7,523 ESRD events during a mean 2.4 years of follow-up beginning at the close of the 2-year baseline period. An additional 1,009 ESRD events occurred during the follow-up period in participants with an initial eGFR of 60 mL/min per 1.73 m2 or more.
This study grew out of a collaboration between the National Kidney Foundation and the Food and Drug Administration. Officials at the regulatory agency now accept that the established endpoint used to document CKD progression in clinical trials – that is, a doubling of serum creatinine concentration from baseline – has held back therapeutic progress in the field. That’s because this FDA-mandated surrogate endpoint is a late event and thus requires studies with large sample sizes and long follow-up times. The agency is eager for evidence in support of a better surrogate endpoint, explained Dr. Coresh, who is also director of the cardiovascular epidemiology training program at Johns Hopkins.
The new meta-analysis confirmed that a doubling of serum creatinine concentration over the course of 2 years is indeed a valid endpoint for CKD progression. It was associated with a 32-fold increased risk of developing ESRD in patients who started with an eGFR below 60 mL/min per 1.73 m2 and a 57-fold increased risk in patients with a higher starting eGFR. However, a doubling of serum creatinine in a 2-year time frame was also a rare outcome, occurring in less than 1% of patients with a low initial eGFR and in 0.1% of those with a higher initial value. In contrast, a 30% drop in eGFR over a 2-year period was 10 times more common.
"A doubling of serum creatinine captures only 10% of the excess or population-attributable risk of ESRD during follow-up, whereas a 30% decline in eGFR captures 44% of the population with ESRD in the baseline low-eGFR group and 28% in those with a baseline eGFR of 60 mL/min per 1.73 m2 or greater," Dr. Coresh said.
An impressive level of consistency in the results was seen across the 28 studies included in the meta-analysis, which featured adjustment for confounders.
"I think this level of remarkable consistency makes it safer to think that in many settings, if you have a 30% decline in eGFR over 2 years, you will have a substantially increased risk of ESRD of approximately 5-fold," according to the physician.
He stressed that the meta-analysis demonstrated that it’s not just the change in eGFR over the course of 2 years that’s important in determining risk, but that the starting eGFR level and duration of follow-up are also key in determining absolute risk.
"For example, someone who starts at 50 mL/min per 1.73 m2 and is stable for 2 years has a subsequent risk of ESRD 10 years later of only 5%. If, on the other hand, that patient had a 30% decline in eGFR during 2 years, the 10-year risk becomes 21%. And if you start out at an eGFR of 35 mL/min per 1.73 m2, your 10-year risk of ESRD goes from 18% if your eGFR is unchanged for 2 years to 64% if your eGFR falls by 30%. So within the first 2 years, you have the ability to detect things that will happen a long time from now, with pretty good power," Dr. Coresh said.
The findings held true regardless of patient age, the presence or absence of diabetes, and albuminuria.
This meta-analysis, which was supported by the National Kidney Foundation and the National Institute of Diabetes and Digestive and Kidney Diseases, will result in six publications during the next year. The first was published online on June 3 (JAMA 2014 [doi:10.1001/jama.2014.6634]). The JAMA report goes beyond Dr. Coresh’s time-limited Las Vegas presentation in that it also includes data on all-cause mortality risk according to change in eGFR. He noted this is important because the majority of patients with CKD die of cardiovascular and other causes without ever reaching ESRD. In the meta-analysis, a 30% decline in eGFR over the course of 2 years was associated with an 80% increased risk in all-cause mortality.
Dr. Coresh reported having no relevant financial conflicts.
AT SCM 14
Key clinical point: A decline of 30% in eGFR over the course of 2 years helps identify those who will progress to end-stage renal disease in the next 2-3 years.
Major finding: Patients with a 30% drop in estimated glomerular filtration rate during a 2-year period had a 5- to 6-fold increased risk of developing end-stage renal disease during a subsequent mean 2.4 years of follow-up, compared with patients whose eGFR remained unchanged.
Data source: An individual-level meta-analysis of 28 studies involving roughly 1.5 million patients with chronic kidney disease.
Disclosures: The study was supported by the National Kidney Foundation and the National Institute of Diabetes and Digestive and Kidney Diseases. The presenter reported having no relevant financial conflicts.
Efforts to improve screening, detection of CKD needed
LAS VEGAS – Many barriers to chronic kidney disease detection and screening exist in today’s health care landscape, according to Dr. Georges Saab.
For one thing, patient have a lack of knowledge about chronic kidney disease (CKD) and receive very little education about it, explained Dr. Saab of the department of medicine at Case Western Reserve University and MetroHealth Medical Center, Cleveland.
Patients lack education about CKD "because they don’t ask about it," Dr. Saab said at a meeting sponsored by the National Kidney Foundation. "They know about their hypertension, diabetes, and cholesterol, but they don’t know about kidney disease; they don’t take medications for kidney disease, so they fail to recognize it as a distinct entity."
He noted that some primary care physicians feel they lack the knowledge and skills to educate patients on CKD. Thus, measures to enhance these skills are needed. Others are not familiar with published CKD screening guidelines, and among those that are, the recommendations are not consistent in whom to screen.
Dr. Saab called for ways to improve physician and patient education on risk factors for CKD and on the impact of the disease. Such information is available from the National Kidney Foundation and the National Kidney Disease Education Program. Recently, the National Kidney Foundation launched the CKD Primary Care Initiative to identify and overcome barriers to CKD testing, detection, and management in the primary care setting. The NKF’s CKD Primary Care Initiative will disseminate CKD guidelines to PCPs around the United States through education programs, symposia, and practical implementation tools.
Other strategies that could be used include implementing clinical reminders to screen for CKD in high-risk groups, routine reporting of estimated glomerular filtration rate (eGFR), incentivizing providers for higher-quality care, including screening for CKD, and providing patients with access to their laboratory data. He notes that patients themselves may initiate the process of referral to a nephrologist if given access to their results.
Community-based screening also has the potential to eliminate or mitigate some of the patient and physician barriers to screening. Dr. Saab cited the NKF’s Kidney Early Evaluation Program (KEEP) as an example. Between 2000 and 2013, KEEP reached more than 185,000 individuals at increased risk for developing CKD. The KEEP program "is free, it’s in a nonmedical location, such as a church or town hall, and it’s managed by a trained staff and nephrologists," Dr. Saab said of the program. "It’s also short in duration – it only takes about 45 minutes – and it’s focused on CKD and related issues."
Of KEEP data collected through 2010, roughly 20% of participants were found to have CKD (Am. J. Kidney Dis. 2012;60:692-3. At the time of screening, patients are asked if they’re aware if they have any kidney problems or not. Awareness increased from 8.8% in 2000-2002 to 16.6% in 2009-2011, "which means that the message is getting out there, and patients are getting screened a little more commonly than they were before," he said.
Community screening for CKD appears to increase patient awareness of chronic kidney disease, "and it may indirectly lead to increased screening in clinical encounters," Dr. Saab said. "For example, KEEP reports sent to PCPs may influence screening and detection, and friends and family members of those screened may also seek screening."
Another community-based initiative is the NKF’s KEEP Healthy program, designed to educate people about the kidneys and risk factors for kidney disease. A check-up for participants includes a risk survey, body mass index, blood pressure check, free educational materials, and an opportunity to speak with a health care professional.
"Awareness of CKD is low," Dr. Peter A. McCullough, chair of the NKF’s Kidney Early Evaluation Program Steering Committee, said during a separate presentation at the meeting. "We have to get to levels of awareness of diabetes, heart disease, and cancer. In kidney disease, we haven’t gotten there yet. I haven’t seen a single data set where [awareness] is more than 50%."
In his opinion, clinicians should screen for CKD with KEEP Healthy and other clinical and community approaches, "because it raises awareness for risk factors and CKD, it potentially triggers better risk factor control, it potentially helps avoid additional insults along the way, and it readies for the next steps."
Dr. Saab acknowledged limitations of community-based screening, including the fact that isolated measurements may lead to misclassification. "But that is usually the case in all screening processes," he added. "It also requires external funding, and it does attract patients who are motivated to be screened, so you may not necessarily be catching the people who aren’t aware of CKD."
Electronic health records also have the potential to improve CKD screening and detection, he said. For example, a record query can be designed to extract variables that may impact detection or screening, including those at the patient, physician, or institutional level.
"You can also identify potential patients to be screened who don’t have eGFR or albuminuria assessment," Dr. Saab said, including the elderly and those with cardiovascular disease or obesity.
The remedy for improving current shortfalls in CKD screening and detection is likely to involve some combination of amendments to clinical encounters, community-based screening, and electronic health record queries, Dr. Saab predicted.
Dr. Saab said that he had no relevant financial disclosures.
hypertension, diabetes, cholesterol,
LAS VEGAS – Many barriers to chronic kidney disease detection and screening exist in today’s health care landscape, according to Dr. Georges Saab.
For one thing, patient have a lack of knowledge about chronic kidney disease (CKD) and receive very little education about it, explained Dr. Saab of the department of medicine at Case Western Reserve University and MetroHealth Medical Center, Cleveland.
Patients lack education about CKD "because they don’t ask about it," Dr. Saab said at a meeting sponsored by the National Kidney Foundation. "They know about their hypertension, diabetes, and cholesterol, but they don’t know about kidney disease; they don’t take medications for kidney disease, so they fail to recognize it as a distinct entity."
He noted that some primary care physicians feel they lack the knowledge and skills to educate patients on CKD. Thus, measures to enhance these skills are needed. Others are not familiar with published CKD screening guidelines, and among those that are, the recommendations are not consistent in whom to screen.
Dr. Saab called for ways to improve physician and patient education on risk factors for CKD and on the impact of the disease. Such information is available from the National Kidney Foundation and the National Kidney Disease Education Program. Recently, the National Kidney Foundation launched the CKD Primary Care Initiative to identify and overcome barriers to CKD testing, detection, and management in the primary care setting. The NKF’s CKD Primary Care Initiative will disseminate CKD guidelines to PCPs around the United States through education programs, symposia, and practical implementation tools.
Other strategies that could be used include implementing clinical reminders to screen for CKD in high-risk groups, routine reporting of estimated glomerular filtration rate (eGFR), incentivizing providers for higher-quality care, including screening for CKD, and providing patients with access to their laboratory data. He notes that patients themselves may initiate the process of referral to a nephrologist if given access to their results.
Community-based screening also has the potential to eliminate or mitigate some of the patient and physician barriers to screening. Dr. Saab cited the NKF’s Kidney Early Evaluation Program (KEEP) as an example. Between 2000 and 2013, KEEP reached more than 185,000 individuals at increased risk for developing CKD. The KEEP program "is free, it’s in a nonmedical location, such as a church or town hall, and it’s managed by a trained staff and nephrologists," Dr. Saab said of the program. "It’s also short in duration – it only takes about 45 minutes – and it’s focused on CKD and related issues."
Of KEEP data collected through 2010, roughly 20% of participants were found to have CKD (Am. J. Kidney Dis. 2012;60:692-3. At the time of screening, patients are asked if they’re aware if they have any kidney problems or not. Awareness increased from 8.8% in 2000-2002 to 16.6% in 2009-2011, "which means that the message is getting out there, and patients are getting screened a little more commonly than they were before," he said.
Community screening for CKD appears to increase patient awareness of chronic kidney disease, "and it may indirectly lead to increased screening in clinical encounters," Dr. Saab said. "For example, KEEP reports sent to PCPs may influence screening and detection, and friends and family members of those screened may also seek screening."
Another community-based initiative is the NKF’s KEEP Healthy program, designed to educate people about the kidneys and risk factors for kidney disease. A check-up for participants includes a risk survey, body mass index, blood pressure check, free educational materials, and an opportunity to speak with a health care professional.
"Awareness of CKD is low," Dr. Peter A. McCullough, chair of the NKF’s Kidney Early Evaluation Program Steering Committee, said during a separate presentation at the meeting. "We have to get to levels of awareness of diabetes, heart disease, and cancer. In kidney disease, we haven’t gotten there yet. I haven’t seen a single data set where [awareness] is more than 50%."
In his opinion, clinicians should screen for CKD with KEEP Healthy and other clinical and community approaches, "because it raises awareness for risk factors and CKD, it potentially triggers better risk factor control, it potentially helps avoid additional insults along the way, and it readies for the next steps."
Dr. Saab acknowledged limitations of community-based screening, including the fact that isolated measurements may lead to misclassification. "But that is usually the case in all screening processes," he added. "It also requires external funding, and it does attract patients who are motivated to be screened, so you may not necessarily be catching the people who aren’t aware of CKD."
Electronic health records also have the potential to improve CKD screening and detection, he said. For example, a record query can be designed to extract variables that may impact detection or screening, including those at the patient, physician, or institutional level.
"You can also identify potential patients to be screened who don’t have eGFR or albuminuria assessment," Dr. Saab said, including the elderly and those with cardiovascular disease or obesity.
The remedy for improving current shortfalls in CKD screening and detection is likely to involve some combination of amendments to clinical encounters, community-based screening, and electronic health record queries, Dr. Saab predicted.
Dr. Saab said that he had no relevant financial disclosures.
LAS VEGAS – Many barriers to chronic kidney disease detection and screening exist in today’s health care landscape, according to Dr. Georges Saab.
For one thing, patient have a lack of knowledge about chronic kidney disease (CKD) and receive very little education about it, explained Dr. Saab of the department of medicine at Case Western Reserve University and MetroHealth Medical Center, Cleveland.
Patients lack education about CKD "because they don’t ask about it," Dr. Saab said at a meeting sponsored by the National Kidney Foundation. "They know about their hypertension, diabetes, and cholesterol, but they don’t know about kidney disease; they don’t take medications for kidney disease, so they fail to recognize it as a distinct entity."
He noted that some primary care physicians feel they lack the knowledge and skills to educate patients on CKD. Thus, measures to enhance these skills are needed. Others are not familiar with published CKD screening guidelines, and among those that are, the recommendations are not consistent in whom to screen.
Dr. Saab called for ways to improve physician and patient education on risk factors for CKD and on the impact of the disease. Such information is available from the National Kidney Foundation and the National Kidney Disease Education Program. Recently, the National Kidney Foundation launched the CKD Primary Care Initiative to identify and overcome barriers to CKD testing, detection, and management in the primary care setting. The NKF’s CKD Primary Care Initiative will disseminate CKD guidelines to PCPs around the United States through education programs, symposia, and practical implementation tools.
Other strategies that could be used include implementing clinical reminders to screen for CKD in high-risk groups, routine reporting of estimated glomerular filtration rate (eGFR), incentivizing providers for higher-quality care, including screening for CKD, and providing patients with access to their laboratory data. He notes that patients themselves may initiate the process of referral to a nephrologist if given access to their results.
Community-based screening also has the potential to eliminate or mitigate some of the patient and physician barriers to screening. Dr. Saab cited the NKF’s Kidney Early Evaluation Program (KEEP) as an example. Between 2000 and 2013, KEEP reached more than 185,000 individuals at increased risk for developing CKD. The KEEP program "is free, it’s in a nonmedical location, such as a church or town hall, and it’s managed by a trained staff and nephrologists," Dr. Saab said of the program. "It’s also short in duration – it only takes about 45 minutes – and it’s focused on CKD and related issues."
Of KEEP data collected through 2010, roughly 20% of participants were found to have CKD (Am. J. Kidney Dis. 2012;60:692-3. At the time of screening, patients are asked if they’re aware if they have any kidney problems or not. Awareness increased from 8.8% in 2000-2002 to 16.6% in 2009-2011, "which means that the message is getting out there, and patients are getting screened a little more commonly than they were before," he said.
Community screening for CKD appears to increase patient awareness of chronic kidney disease, "and it may indirectly lead to increased screening in clinical encounters," Dr. Saab said. "For example, KEEP reports sent to PCPs may influence screening and detection, and friends and family members of those screened may also seek screening."
Another community-based initiative is the NKF’s KEEP Healthy program, designed to educate people about the kidneys and risk factors for kidney disease. A check-up for participants includes a risk survey, body mass index, blood pressure check, free educational materials, and an opportunity to speak with a health care professional.
"Awareness of CKD is low," Dr. Peter A. McCullough, chair of the NKF’s Kidney Early Evaluation Program Steering Committee, said during a separate presentation at the meeting. "We have to get to levels of awareness of diabetes, heart disease, and cancer. In kidney disease, we haven’t gotten there yet. I haven’t seen a single data set where [awareness] is more than 50%."
In his opinion, clinicians should screen for CKD with KEEP Healthy and other clinical and community approaches, "because it raises awareness for risk factors and CKD, it potentially triggers better risk factor control, it potentially helps avoid additional insults along the way, and it readies for the next steps."
Dr. Saab acknowledged limitations of community-based screening, including the fact that isolated measurements may lead to misclassification. "But that is usually the case in all screening processes," he added. "It also requires external funding, and it does attract patients who are motivated to be screened, so you may not necessarily be catching the people who aren’t aware of CKD."
Electronic health records also have the potential to improve CKD screening and detection, he said. For example, a record query can be designed to extract variables that may impact detection or screening, including those at the patient, physician, or institutional level.
"You can also identify potential patients to be screened who don’t have eGFR or albuminuria assessment," Dr. Saab said, including the elderly and those with cardiovascular disease or obesity.
The remedy for improving current shortfalls in CKD screening and detection is likely to involve some combination of amendments to clinical encounters, community-based screening, and electronic health record queries, Dr. Saab predicted.
Dr. Saab said that he had no relevant financial disclosures.
hypertension, diabetes, cholesterol,
hypertension, diabetes, cholesterol,
EXPERT ANALYSIS AT SCM 14
