Nephrology

CHICAGO – Treating patients with hepatitis C virus genotype 1a or 1b with 12 weeks of an experimental interferon-free, triple-drug oral regimen produced good sustained virologic response rates with or without the use of ribavirin, but the addition of ribavirin appeared helpful to those with genotype 1a infection, according to results of two separate phase III studies.

Both studies recruited previously untreated patients with no cirrhosis to undergo a regimen of ABT-450 with ritonavir and ombitasvir (ABT-450/r-ombitasvir) plus dasabuvir and either ribavirin or a matching placebo. The PEARL-III study randomized 419 patients with hepatitis C virus genotype 1b, and the PEARL-IV study randomized 305 patients with genotype 1a infection. Patients received a daily dose of 150 mg ABT-450, 100 mg ritonavir, and 25 mg ombitasvir, twice-daily doses of 250 mg dasabuvir, and either placebo or ribavirin dosed according to body weight.

Sherry Boschert/Frontline Medical News

In patients with genotype 1a, 97% who got the regimen plus ribavirin and 90.2% of those who got the regimen plus placebo achieved a sustained virologic response (SVR) 12 weeks after treatment ended (defined as a hepatitis C virus RNA level of less than 25 IU/ml). The difference between those two groups was statistically significant, and the treatment without ribavirin was inferior to the regimen with ribavirin in genotype 1a patients. These response rates were superior, however, to rates in the medical literature for treatment-naive patients who got conventional treatment with telaprevir plus peginterferon-ribavirin, Dr. Peter Ferenci and his associates reported.

Virologic failure was significantly more likely in patients with genotype 1a who got the regimen plus placebo in the current study, compared with those who got ribavirin – 7.8% vs. 2%, respectively, reported Dr. Ferenci of the Medical University of Vienna. Only 2 of the 18 patients with genotype 1a who developed virologic failure received ribavirin.

The findings were published online by the New England Journal of Medicine (N. Engl. J. Med. 2014 May 4 [doi:10.1056/NEJMoa1402338]).

Previous data on treatment with telaprevir plus peginterferon-ribavirin showed sustained virologic response rates of 60%-65%, coinvestigator Dr. David Bernstein said in an interview. With the experimental regimen, "the take-home message is that there are extraordinarily high cure rates for patients with hepatitis C genotype 1," said Dr. Bernstein, chief of hepatology at the Center for Liver Disease, North Shore University Hospital, Manhasset, N.Y. He reported results of the PEARL IV study in a poster presentation at the annual Digestive Disease Week.

Genotype 1b is the most prevalent form of hepatitis C, especially in Europe and East Asia, but genotype 1a is more prevalent in North America.

For patients with genotype 1b infection in the study, 99.5% who received the regimen with ribavirin and 99% who got placebo achieved SVR at 12 weeks.

ABT-450/4, ombitasvir, and dasabuvir are not yet approved for treatment, but approval is expected later this year, Dr. Bernstein said.

Fewer than 1% of patients discontinued treatment due to adverse events. "The second take-home message is that it’s a 12-week course of therapy and the overall side effect profile is minimal," he said. "We will be using these therapies once they become available."

ABT-450 inhibits the hepatitis C virus nonstructural 3/4A protease and is given with ritonavir to increase ABT-450 plasma levels and half-life. Ombitasvir inhibits the hepatitis C virus NS5A replication complex. Dasabuvir is a nonnucleoside NS5B polymerase inhibitor.

AbbVie, which is developing the new drugs, funded the study. Dr. Ferenci reported financial associations with 10 companies and his coinvestigators reported financial associations with dozens of companies.

[email protected]

On Twitter @sherryboschert

CHICAGO – Treating patients with hepatitis C virus genotype 1a or 1b with 12 weeks of an experimental interferon-free, triple-drug oral regimen produced good sustained virologic response rates with or without the use of ribavirin, but the addition of ribavirin appeared helpful to those with genotype 1a infection, according to results of two separate phase III studies.

Both studies recruited previously untreated patients with no cirrhosis to undergo a regimen of ABT-450 with ritonavir and ombitasvir (ABT-450/r-ombitasvir) plus dasabuvir and either ribavirin or a matching placebo. The PEARL-III study randomized 419 patients with hepatitis C virus genotype 1b, and the PEARL-IV study randomized 305 patients with genotype 1a infection. Patients received a daily dose of 150 mg ABT-450, 100 mg ritonavir, and 25 mg ombitasvir, twice-daily doses of 250 mg dasabuvir, and either placebo or ribavirin dosed according to body weight.

Sherry Boschert/Frontline Medical News

In patients with genotype 1a, 97% who got the regimen plus ribavirin and 90.2% of those who got the regimen plus placebo achieved a sustained virologic response (SVR) 12 weeks after treatment ended (defined as a hepatitis C virus RNA level of less than 25 IU/ml). The difference between those two groups was statistically significant, and the treatment without ribavirin was inferior to the regimen with ribavirin in genotype 1a patients. These response rates were superior, however, to rates in the medical literature for treatment-naive patients who got conventional treatment with telaprevir plus peginterferon-ribavirin, Dr. Peter Ferenci and his associates reported.

Virologic failure was significantly more likely in patients with genotype 1a who got the regimen plus placebo in the current study, compared with those who got ribavirin – 7.8% vs. 2%, respectively, reported Dr. Ferenci of the Medical University of Vienna. Only 2 of the 18 patients with genotype 1a who developed virologic failure received ribavirin.

The findings were published online by the New England Journal of Medicine (N. Engl. J. Med. 2014 May 4 [doi:10.1056/NEJMoa1402338]).

Previous data on treatment with telaprevir plus peginterferon-ribavirin showed sustained virologic response rates of 60%-65%, coinvestigator Dr. David Bernstein said in an interview. With the experimental regimen, "the take-home message is that there are extraordinarily high cure rates for patients with hepatitis C genotype 1," said Dr. Bernstein, chief of hepatology at the Center for Liver Disease, North Shore University Hospital, Manhasset, N.Y. He reported results of the PEARL IV study in a poster presentation at the annual Digestive Disease Week.

Genotype 1b is the most prevalent form of hepatitis C, especially in Europe and East Asia, but genotype 1a is more prevalent in North America.

For patients with genotype 1b infection in the study, 99.5% who received the regimen with ribavirin and 99% who got placebo achieved SVR at 12 weeks.

ABT-450/4, ombitasvir, and dasabuvir are not yet approved for treatment, but approval is expected later this year, Dr. Bernstein said.

Fewer than 1% of patients discontinued treatment due to adverse events. "The second take-home message is that it’s a 12-week course of therapy and the overall side effect profile is minimal," he said. "We will be using these therapies once they become available."

ABT-450 inhibits the hepatitis C virus nonstructural 3/4A protease and is given with ritonavir to increase ABT-450 plasma levels and half-life. Ombitasvir inhibits the hepatitis C virus NS5A replication complex. Dasabuvir is a nonnucleoside NS5B polymerase inhibitor.

AbbVie, which is developing the new drugs, funded the study. Dr. Ferenci reported financial associations with 10 companies and his coinvestigators reported financial associations with dozens of companies.

[email protected]

On Twitter @sherryboschert

CHICAGO – Treating patients with hepatitis C virus genotype 1a or 1b with 12 weeks of an experimental interferon-free, triple-drug oral regimen produced good sustained virologic response rates with or without the use of ribavirin, but the addition of ribavirin appeared helpful to those with genotype 1a infection, according to results of two separate phase III studies.

Both studies recruited previously untreated patients with no cirrhosis to undergo a regimen of ABT-450 with ritonavir and ombitasvir (ABT-450/r-ombitasvir) plus dasabuvir and either ribavirin or a matching placebo. The PEARL-III study randomized 419 patients with hepatitis C virus genotype 1b, and the PEARL-IV study randomized 305 patients with genotype 1a infection. Patients received a daily dose of 150 mg ABT-450, 100 mg ritonavir, and 25 mg ombitasvir, twice-daily doses of 250 mg dasabuvir, and either placebo or ribavirin dosed according to body weight.

Sherry Boschert/Frontline Medical News

In patients with genotype 1a, 97% who got the regimen plus ribavirin and 90.2% of those who got the regimen plus placebo achieved a sustained virologic response (SVR) 12 weeks after treatment ended (defined as a hepatitis C virus RNA level of less than 25 IU/ml). The difference between those two groups was statistically significant, and the treatment without ribavirin was inferior to the regimen with ribavirin in genotype 1a patients. These response rates were superior, however, to rates in the medical literature for treatment-naive patients who got conventional treatment with telaprevir plus peginterferon-ribavirin, Dr. Peter Ferenci and his associates reported.

Virologic failure was significantly more likely in patients with genotype 1a who got the regimen plus placebo in the current study, compared with those who got ribavirin – 7.8% vs. 2%, respectively, reported Dr. Ferenci of the Medical University of Vienna. Only 2 of the 18 patients with genotype 1a who developed virologic failure received ribavirin.

The findings were published online by the New England Journal of Medicine (N. Engl. J. Med. 2014 May 4 [doi:10.1056/NEJMoa1402338]).

Previous data on treatment with telaprevir plus peginterferon-ribavirin showed sustained virologic response rates of 60%-65%, coinvestigator Dr. David Bernstein said in an interview. With the experimental regimen, "the take-home message is that there are extraordinarily high cure rates for patients with hepatitis C genotype 1," said Dr. Bernstein, chief of hepatology at the Center for Liver Disease, North Shore University Hospital, Manhasset, N.Y. He reported results of the PEARL IV study in a poster presentation at the annual Digestive Disease Week.

Genotype 1b is the most prevalent form of hepatitis C, especially in Europe and East Asia, but genotype 1a is more prevalent in North America.

For patients with genotype 1b infection in the study, 99.5% who received the regimen with ribavirin and 99% who got placebo achieved SVR at 12 weeks.

ABT-450/4, ombitasvir, and dasabuvir are not yet approved for treatment, but approval is expected later this year, Dr. Bernstein said.

Fewer than 1% of patients discontinued treatment due to adverse events. "The second take-home message is that it’s a 12-week course of therapy and the overall side effect profile is minimal," he said. "We will be using these therapies once they become available."

ABT-450 inhibits the hepatitis C virus nonstructural 3/4A protease and is given with ritonavir to increase ABT-450 plasma levels and half-life. Ombitasvir inhibits the hepatitis C virus NS5A replication complex. Dasabuvir is a nonnucleoside NS5B polymerase inhibitor.

AbbVie, which is developing the new drugs, funded the study. Dr. Ferenci reported financial associations with 10 companies and his coinvestigators reported financial associations with dozens of companies.

[email protected]

On Twitter @sherryboschert

LAS VEGAS – Consuming less than one glass of wine per day may help keep the kidneys healthy and may protect the heart in patients who already have chronic kidney disease, according to an analysis of data from the National Health and Nutrition Examination Survey.

In this video interview from a meeting sponsored by the National Kidney Foundation, Dr. Tapan Mehta, a renal fellow at the University of Colorado, Aurora, highlights the findings and discusses the potential clinical implications.

[email protected]

On Twitter @dougbrunk

LAS VEGAS – Consuming less than one glass of wine per day may help keep the kidneys healthy and may protect the heart in patients who already have chronic kidney disease, according to an analysis of data from the National Health and Nutrition Examination Survey.

In this video interview from a meeting sponsored by the National Kidney Foundation, Dr. Tapan Mehta, a renal fellow at the University of Colorado, Aurora, highlights the findings and discusses the potential clinical implications.

[email protected]

On Twitter @dougbrunk

LAS VEGAS – Consuming less than one glass of wine per day may help keep the kidneys healthy and may protect the heart in patients who already have chronic kidney disease, according to an analysis of data from the National Health and Nutrition Examination Survey.

In this video interview from a meeting sponsored by the National Kidney Foundation, Dr. Tapan Mehta, a renal fellow at the University of Colorado, Aurora, highlights the findings and discusses the potential clinical implications.

[email protected]

On Twitter @dougbrunk

VANCOUVER – Two years of low-dose trimethoprim-sulfamethoxazole prophylaxis halved the risk of recurrent urinary tract infections, but did not prevent renal scarring in a trial of 607 children with vesicoureteral reflux that was published online May 4 in the New England Journal of Medicine, and presented concurrently at the annual meeting of the Pediatric Academic Societies.

Within 112 days of their first or second febrile or symptomatic urinary tract infection (UTI), 302 young children diagnosed with vesicoureteral reflux (VUR) by voiding cystourethrogram were randomized to 3 mg of trimethoprim plus 15 mg of sulfamethoxazole per kilogram; and 305 other VUR children were randomized to placebo.

Alexander Otto/Frontline Medical News

Thirty-nine (13%) children who received antimicrobial prophylaxis developed a recurrent febrile or symptomatic UTI, compared with 72 (24%) who received a placebo (hazard ratio for risk of recurrence, 0.50; 95% confidence interval, 0.34-0.74). Prophylaxis was particularly effective in children whose index UTI was febrile (HR, 0.41; 95% CI, 0.26-0.64) and in those with baseline bladder and bowel dysfunction (HR, 0.21; 95% CI, 0.08-0.58).

Nuclear imaging showed no significant between-group differences in the incidence of renal scarring (11.9% in the treated group vs. 10.2% in the placebo group; P = 0.55), severe renal scars (4.0% vs. 2.6%; P = 0.37), or new renal scars since baseline (8.2% vs. 8.4%; P = 0.94) at trial completion (N. Eng. J. Med. 2014 May 4 [doi: 10.1056/NEJMoa1401811]).

"This study showed unequivocal evidence that antimicrobial prophylaxis reduced at least in half the likelihood of children having recurrent UTIs. Rates of renal scarring ... were low and not reduced by prophylaxis, perhaps because most children were enrolled after their first infection and because parents, instructed to be vigilant, sought early medical attention," said Dr. Alejandro Hoberman, a professor of pediatrics at the University of Pittsburgh and lead investigator in the multicenter study, dubbed the RIVUR (Randomized Intervention for Children with Vesicoureteral Reflux) trial.

"As long as evidence supporting the benefit of prophylaxis was dubious, the recommendation of a watchful-waiting approach, without performance of a voiding cystourethrographic study, seemed reasonable, because the imaging findings would not affect the nature of treatment. However, our finding that antimicrobial prophylaxis was associated with a reduced risk of recurrence may warrant reconsideration of that recommendation," the investigators said.

Eight children would have had to be treated for 2 years to prevent one case of febrile or symptomatic UTI. Several audience members, after hearing the results, wondered if the benefits of prophylaxis outweighed the costs, given that there was no effect on the incidence of renal scarring in the short term, and the difficulty and expense of performing voiding cystourethrographic studies, among other concerns.

Dr. Hoberman plans to investigate the cost-effectiveness implications of the findings, and, in the meantime, he noted that the study offers proof that prophylaxis helps prevent recurrent UTIs, something that was uncertain in the past. Also, he noted, the study was not powered to detect a difference in renal scarring as a primary outcome.

The children were aged 2-71 months (median age, 12 months), and 92% were girls. Eighty percent had grade II or III vesicoureteral reflux, and 48% had bilateral reflux.

Among 87 children with a first recurrence caused by Escherichia coli, the proportion of isolates that were resistant to trimethoprim-sulfamethoxazole was 63% in the prophylaxis group and 19% in the placebo group. "Not unexpectedly, recurrences that did occur in children who received prophylaxis were more likely to have been caused by a resistant pathogen," the investigators said.

Parents of 77% of the children reported that they had given the study medication at least 75% of the time, and parents of 85% reported administering it at least 50% of the time. There was no significant difference in reported adherence between the study groups.

Dr. Hoberman had no disclosures. The work was funded by the National Institute of Diabetes and Digestive and Kidney Diseases.

[email protected]

VANCOUVER – Two years of low-dose trimethoprim-sulfamethoxazole prophylaxis halved the risk of recurrent urinary tract infections, but did not prevent renal scarring in a trial of 607 children with vesicoureteral reflux that was published online May 4 in the New England Journal of Medicine, and presented concurrently at the annual meeting of the Pediatric Academic Societies.

Within 112 days of their first or second febrile or symptomatic urinary tract infection (UTI), 302 young children diagnosed with vesicoureteral reflux (VUR) by voiding cystourethrogram were randomized to 3 mg of trimethoprim plus 15 mg of sulfamethoxazole per kilogram; and 305 other VUR children were randomized to placebo.

Alexander Otto/Frontline Medical News

Thirty-nine (13%) children who received antimicrobial prophylaxis developed a recurrent febrile or symptomatic UTI, compared with 72 (24%) who received a placebo (hazard ratio for risk of recurrence, 0.50; 95% confidence interval, 0.34-0.74). Prophylaxis was particularly effective in children whose index UTI was febrile (HR, 0.41; 95% CI, 0.26-0.64) and in those with baseline bladder and bowel dysfunction (HR, 0.21; 95% CI, 0.08-0.58).

Nuclear imaging showed no significant between-group differences in the incidence of renal scarring (11.9% in the treated group vs. 10.2% in the placebo group; P = 0.55), severe renal scars (4.0% vs. 2.6%; P = 0.37), or new renal scars since baseline (8.2% vs. 8.4%; P = 0.94) at trial completion (N. Eng. J. Med. 2014 May 4 [doi: 10.1056/NEJMoa1401811]).

"This study showed unequivocal evidence that antimicrobial prophylaxis reduced at least in half the likelihood of children having recurrent UTIs. Rates of renal scarring ... were low and not reduced by prophylaxis, perhaps because most children were enrolled after their first infection and because parents, instructed to be vigilant, sought early medical attention," said Dr. Alejandro Hoberman, a professor of pediatrics at the University of Pittsburgh and lead investigator in the multicenter study, dubbed the RIVUR (Randomized Intervention for Children with Vesicoureteral Reflux) trial.

"As long as evidence supporting the benefit of prophylaxis was dubious, the recommendation of a watchful-waiting approach, without performance of a voiding cystourethrographic study, seemed reasonable, because the imaging findings would not affect the nature of treatment. However, our finding that antimicrobial prophylaxis was associated with a reduced risk of recurrence may warrant reconsideration of that recommendation," the investigators said.

Eight children would have had to be treated for 2 years to prevent one case of febrile or symptomatic UTI. Several audience members, after hearing the results, wondered if the benefits of prophylaxis outweighed the costs, given that there was no effect on the incidence of renal scarring in the short term, and the difficulty and expense of performing voiding cystourethrographic studies, among other concerns.

Dr. Hoberman plans to investigate the cost-effectiveness implications of the findings, and, in the meantime, he noted that the study offers proof that prophylaxis helps prevent recurrent UTIs, something that was uncertain in the past. Also, he noted, the study was not powered to detect a difference in renal scarring as a primary outcome.

The children were aged 2-71 months (median age, 12 months), and 92% were girls. Eighty percent had grade II or III vesicoureteral reflux, and 48% had bilateral reflux.

Among 87 children with a first recurrence caused by Escherichia coli, the proportion of isolates that were resistant to trimethoprim-sulfamethoxazole was 63% in the prophylaxis group and 19% in the placebo group. "Not unexpectedly, recurrences that did occur in children who received prophylaxis were more likely to have been caused by a resistant pathogen," the investigators said.

Parents of 77% of the children reported that they had given the study medication at least 75% of the time, and parents of 85% reported administering it at least 50% of the time. There was no significant difference in reported adherence between the study groups.

Dr. Hoberman had no disclosures. The work was funded by the National Institute of Diabetes and Digestive and Kidney Diseases.

[email protected]

VANCOUVER – Two years of low-dose trimethoprim-sulfamethoxazole prophylaxis halved the risk of recurrent urinary tract infections, but did not prevent renal scarring in a trial of 607 children with vesicoureteral reflux that was published online May 4 in the New England Journal of Medicine, and presented concurrently at the annual meeting of the Pediatric Academic Societies.

Within 112 days of their first or second febrile or symptomatic urinary tract infection (UTI), 302 young children diagnosed with vesicoureteral reflux (VUR) by voiding cystourethrogram were randomized to 3 mg of trimethoprim plus 15 mg of sulfamethoxazole per kilogram; and 305 other VUR children were randomized to placebo.

Alexander Otto/Frontline Medical News

Thirty-nine (13%) children who received antimicrobial prophylaxis developed a recurrent febrile or symptomatic UTI, compared with 72 (24%) who received a placebo (hazard ratio for risk of recurrence, 0.50; 95% confidence interval, 0.34-0.74). Prophylaxis was particularly effective in children whose index UTI was febrile (HR, 0.41; 95% CI, 0.26-0.64) and in those with baseline bladder and bowel dysfunction (HR, 0.21; 95% CI, 0.08-0.58).

Nuclear imaging showed no significant between-group differences in the incidence of renal scarring (11.9% in the treated group vs. 10.2% in the placebo group; P = 0.55), severe renal scars (4.0% vs. 2.6%; P = 0.37), or new renal scars since baseline (8.2% vs. 8.4%; P = 0.94) at trial completion (N. Eng. J. Med. 2014 May 4 [doi: 10.1056/NEJMoa1401811]).

"This study showed unequivocal evidence that antimicrobial prophylaxis reduced at least in half the likelihood of children having recurrent UTIs. Rates of renal scarring ... were low and not reduced by prophylaxis, perhaps because most children were enrolled after their first infection and because parents, instructed to be vigilant, sought early medical attention," said Dr. Alejandro Hoberman, a professor of pediatrics at the University of Pittsburgh and lead investigator in the multicenter study, dubbed the RIVUR (Randomized Intervention for Children with Vesicoureteral Reflux) trial.

"As long as evidence supporting the benefit of prophylaxis was dubious, the recommendation of a watchful-waiting approach, without performance of a voiding cystourethrographic study, seemed reasonable, because the imaging findings would not affect the nature of treatment. However, our finding that antimicrobial prophylaxis was associated with a reduced risk of recurrence may warrant reconsideration of that recommendation," the investigators said.

Eight children would have had to be treated for 2 years to prevent one case of febrile or symptomatic UTI. Several audience members, after hearing the results, wondered if the benefits of prophylaxis outweighed the costs, given that there was no effect on the incidence of renal scarring in the short term, and the difficulty and expense of performing voiding cystourethrographic studies, among other concerns.

Dr. Hoberman plans to investigate the cost-effectiveness implications of the findings, and, in the meantime, he noted that the study offers proof that prophylaxis helps prevent recurrent UTIs, something that was uncertain in the past. Also, he noted, the study was not powered to detect a difference in renal scarring as a primary outcome.

The children were aged 2-71 months (median age, 12 months), and 92% were girls. Eighty percent had grade II or III vesicoureteral reflux, and 48% had bilateral reflux.

Among 87 children with a first recurrence caused by Escherichia coli, the proportion of isolates that were resistant to trimethoprim-sulfamethoxazole was 63% in the prophylaxis group and 19% in the placebo group. "Not unexpectedly, recurrences that did occur in children who received prophylaxis were more likely to have been caused by a resistant pathogen," the investigators said.

Parents of 77% of the children reported that they had given the study medication at least 75% of the time, and parents of 85% reported administering it at least 50% of the time. There was no significant difference in reported adherence between the study groups.

Dr. Hoberman had no disclosures. The work was funded by the National Institute of Diabetes and Digestive and Kidney Diseases.

[email protected]

LAS VEGAS – Treatment with ferric citrate coordination complex conferred multiple benefits with cardioprotective implications in non–dialysis-dependent chronic kidney disease patients with elevated serum phosphate and iron-deficiency anemia in a randomized trial.

Ferric citrate coordination complex (FCCC), an investigational oral product also known as Zerenex, effectively lowered patients’ elevated serum phosphate into normal range while repleting iron stores, boosting hemoglobin, and reducing levels of the cardiotoxic protein fibroblast growth factor 23 (FGF23), Dr. Geoffrey A. Block reported at a meeting sponsored by the National Kidney Foundation.

"We are quite happy with these results and the implications they may have in trying to address cardiovascular risk at multiple levels in chronic kidney disease," declared Dr. Block of Denver Nephrology, who was principal investigator in the phase II study.

FCCC is currently under Food and Drug Administration review for potential marketing approval as a treatment in patients with end-stage renal disease complicated by iron-deficiency anemia and elevated serum phosphate. However, the phase II study led by Dr. Block focused on the much larger patient population with non–dialysis-dependent chronic kidney disease (CKD) with elevated serum phosphate and iron-deficiency anemia. Experience has shown it is far more difficult to lower serum phosphate in such patients than in those with end-stage renal disease, the nephrologist noted.

The 12-week, double-blind clinical trial included 141 subjects with an estimated glomerular filtration rate below 60 mL/min per 1.73 m², a serum phosphate in excess of 4.0 mg/dL, a transferrin saturation below 30%, a hemoglobin level of 9-12 g/dL, and a serum ferritin below 300 ng/mL. Participants were not permitted to use intravenous iron or an erythropoietin-stimulating agent in the months prior to or during the trial. They were randomized to FCCC titrated to achieve a serum phosphate below 3.5 mg/dL or to placebo.

The coprimary endpoints were changes from baseline through 12 weeks in serum phosphate and transferrin saturation. The FCCC-treated patients fared significantly better than controls on those endpoints as well as the secondary outcomes (see chart).

• FGF23: The FCCC group’s 40% drop in C-terminal FGF23 over the course of the 12-week study, while levels remained static in the control group, was particularly noteworthy, according to Dr. Block. In several observational studies, including the Heart and Soul Study (Ann. Intern. Med. 2010;152:640-8), elevated FGF23 levels have been associated with significantly increased risk of cardiovascular events and all-cause mortality.

Elevated FGF23 levels appear to promote left-ventricular hypertrophy, while hyperphosphatemia promotes vascular calcification. Through these different mechanisms, both abnormalities increase the risk of cardiovascular events. Both abnormalities are common in patients with CKD. And FCCC resulted in significant reductions in both FGF23 and serum phosphate, he noted.

A prespecified safety feature of the phase II trial was that any participant whose hemoglobin fell below 9.0 g/dL or whose serum phosphate climbed above 6.0 mg/dL would have to be taken out of the study. One patient on FCCC and nine controls were withdrawn from the study for low hemoglobin. No patients in the FCCC group and two controls were removed due to an excessive phosphate level.

The safety profile of FCCC was essentially the same as for placebo with two exceptions: 20% of the FCCC group reported diarrhea, compared with 6% of controls; and one-third of the FCCC group reported discolored feces as a consequence of iron utilization.

• Serum phosphate: Dr. Block said that "reasonably solid evidence" from observational studies, clinical trials, and animal studies indicates that a serum phosphate level greater than 4.0 mg/dL leads to faster progression of kidney disease and an increase in cardiovascular events. For example, in a fully adjusted reanalysis of data from the randomized prospective REIN (Ramipril Efficacy in Nephropathy) trial, patients with a baseline serum phosphate above 4.0 mg/dL were at greatly increased risk for the combined endpoint of a doubling of serum creatinine or progression to end-stage renal disease (J. Am. Soc. Nephrol. 2011;22:1923-30).

Moreover, the renoprotective effect of ramipril decreased as baseline serum phosphate increased: While the ACE inhibitor reduced the risk of the combined endpoint by 85%, compared with placebo, in subjects with a serum phosphate less than 3.45 mg/dL and by 63% in those with a level of 3.45-4.0 mg/dL, ramipril wasn’t significantly more effective than placebo in those with a serum phosphate above 4.0 mg/dL.

Dietary phosphorus intake, which is high in the United States, has also come under scrutiny as a public health concern. A recent prospective cohort study in 9,686 healthy U.S. adults concluded that consumption of more than 1,400 mg daily – the median intake in this representative study population was 1,166 mg per day – was independently associated with higher all-cause mortality. Those with a phosphorus density greater than 0.35 mg/kcal, a statistic derived by dividing phosphorus intake by energy intake – had a significantly increased risk of cardiovascular mortality (Am. J. Clin. Nutr. 2014;99:320-7). And in an analysis of 4,494 participants in MESA (Multi-Ethnic Study of Atherosclerosis), dietary phosphorus intake was independently associated with greater left-ventricular mass such that subjects in the top dietary phosphorus quintile had a 6.1-g greater left-ventricular mass than those in the lowest quintile (Kidney Intl. 2013;83:707-14).

The three phosphate binders currently on the market for reduction of elevated serum phosphate in CKD patients are "really marginal treatments," according to Dr. Block. He was first author on a study in which 148 patients with moderate CKD were randomized to 9 months of calcium acetate, sevelamer carbonate, lanthanum carbonate, or placebo. Serum phosphorus inched lower over the 9 months from a baseline of 4.2 mg/dL to 3.9 mg/dL with active therapy, which was only 0.2 mg/dL better than with placebo. In contrast, serum phosphate fell by an average of 0.6 mg/dL during 3 months on FCCC in the phase II study. Moreover, active therapy with the commercially available phosphate binders had no effect upon FGF23 levels, and it significantly increased coronary artery and abdominal aorta calcification by a median of 18% and 15%, respectively (J. Am. Soc. Nephrol. 2012;23:1407-15).

• Iron-deficiency anemia: The Kidney Dialysis International Guideline Organization defines iron deficiency warranting iron supplementation in CKD patients as a transferrin saturation of 30% or less and a serum ferritin of 50 ng/mL or less. By those criteria, it is estimated that nearly 70% of CKD patients are iron deficient. So there is a large unmet need for iron repletion therapies that avoid the use of erythropoietin-stimulating agents and intravenous iron, Dr. Block noted.

The FCCC trial was sponsored by Keryx Biopharmaceuticals. Dr. Block serves as a consultant to the company and was principal investigator in the study.

[email protected]

LAS VEGAS – Treatment with ferric citrate coordination complex conferred multiple benefits with cardioprotective implications in non–dialysis-dependent chronic kidney disease patients with elevated serum phosphate and iron-deficiency anemia in a randomized trial.

Ferric citrate coordination complex (FCCC), an investigational oral product also known as Zerenex, effectively lowered patients’ elevated serum phosphate into normal range while repleting iron stores, boosting hemoglobin, and reducing levels of the cardiotoxic protein fibroblast growth factor 23 (FGF23), Dr. Geoffrey A. Block reported at a meeting sponsored by the National Kidney Foundation.

"We are quite happy with these results and the implications they may have in trying to address cardiovascular risk at multiple levels in chronic kidney disease," declared Dr. Block of Denver Nephrology, who was principal investigator in the phase II study.

FCCC is currently under Food and Drug Administration review for potential marketing approval as a treatment in patients with end-stage renal disease complicated by iron-deficiency anemia and elevated serum phosphate. However, the phase II study led by Dr. Block focused on the much larger patient population with non–dialysis-dependent chronic kidney disease (CKD) with elevated serum phosphate and iron-deficiency anemia. Experience has shown it is far more difficult to lower serum phosphate in such patients than in those with end-stage renal disease, the nephrologist noted.

The 12-week, double-blind clinical trial included 141 subjects with an estimated glomerular filtration rate below 60 mL/min per 1.73 m², a serum phosphate in excess of 4.0 mg/dL, a transferrin saturation below 30%, a hemoglobin level of 9-12 g/dL, and a serum ferritin below 300 ng/mL. Participants were not permitted to use intravenous iron or an erythropoietin-stimulating agent in the months prior to or during the trial. They were randomized to FCCC titrated to achieve a serum phosphate below 3.5 mg/dL or to placebo.

The coprimary endpoints were changes from baseline through 12 weeks in serum phosphate and transferrin saturation. The FCCC-treated patients fared significantly better than controls on those endpoints as well as the secondary outcomes (see chart).

• FGF23: The FCCC group’s 40% drop in C-terminal FGF23 over the course of the 12-week study, while levels remained static in the control group, was particularly noteworthy, according to Dr. Block. In several observational studies, including the Heart and Soul Study (Ann. Intern. Med. 2010;152:640-8), elevated FGF23 levels have been associated with significantly increased risk of cardiovascular events and all-cause mortality.

Elevated FGF23 levels appear to promote left-ventricular hypertrophy, while hyperphosphatemia promotes vascular calcification. Through these different mechanisms, both abnormalities increase the risk of cardiovascular events. Both abnormalities are common in patients with CKD. And FCCC resulted in significant reductions in both FGF23 and serum phosphate, he noted.

A prespecified safety feature of the phase II trial was that any participant whose hemoglobin fell below 9.0 g/dL or whose serum phosphate climbed above 6.0 mg/dL would have to be taken out of the study. One patient on FCCC and nine controls were withdrawn from the study for low hemoglobin. No patients in the FCCC group and two controls were removed due to an excessive phosphate level.

The safety profile of FCCC was essentially the same as for placebo with two exceptions: 20% of the FCCC group reported diarrhea, compared with 6% of controls; and one-third of the FCCC group reported discolored feces as a consequence of iron utilization.

• Serum phosphate: Dr. Block said that "reasonably solid evidence" from observational studies, clinical trials, and animal studies indicates that a serum phosphate level greater than 4.0 mg/dL leads to faster progression of kidney disease and an increase in cardiovascular events. For example, in a fully adjusted reanalysis of data from the randomized prospective REIN (Ramipril Efficacy in Nephropathy) trial, patients with a baseline serum phosphate above 4.0 mg/dL were at greatly increased risk for the combined endpoint of a doubling of serum creatinine or progression to end-stage renal disease (J. Am. Soc. Nephrol. 2011;22:1923-30).

Moreover, the renoprotective effect of ramipril decreased as baseline serum phosphate increased: While the ACE inhibitor reduced the risk of the combined endpoint by 85%, compared with placebo, in subjects with a serum phosphate less than 3.45 mg/dL and by 63% in those with a level of 3.45-4.0 mg/dL, ramipril wasn’t significantly more effective than placebo in those with a serum phosphate above 4.0 mg/dL.

Dietary phosphorus intake, which is high in the United States, has also come under scrutiny as a public health concern. A recent prospective cohort study in 9,686 healthy U.S. adults concluded that consumption of more than 1,400 mg daily – the median intake in this representative study population was 1,166 mg per day – was independently associated with higher all-cause mortality. Those with a phosphorus density greater than 0.35 mg/kcal, a statistic derived by dividing phosphorus intake by energy intake – had a significantly increased risk of cardiovascular mortality (Am. J. Clin. Nutr. 2014;99:320-7). And in an analysis of 4,494 participants in MESA (Multi-Ethnic Study of Atherosclerosis), dietary phosphorus intake was independently associated with greater left-ventricular mass such that subjects in the top dietary phosphorus quintile had a 6.1-g greater left-ventricular mass than those in the lowest quintile (Kidney Intl. 2013;83:707-14).

The three phosphate binders currently on the market for reduction of elevated serum phosphate in CKD patients are "really marginal treatments," according to Dr. Block. He was first author on a study in which 148 patients with moderate CKD were randomized to 9 months of calcium acetate, sevelamer carbonate, lanthanum carbonate, or placebo. Serum phosphorus inched lower over the 9 months from a baseline of 4.2 mg/dL to 3.9 mg/dL with active therapy, which was only 0.2 mg/dL better than with placebo. In contrast, serum phosphate fell by an average of 0.6 mg/dL during 3 months on FCCC in the phase II study. Moreover, active therapy with the commercially available phosphate binders had no effect upon FGF23 levels, and it significantly increased coronary artery and abdominal aorta calcification by a median of 18% and 15%, respectively (J. Am. Soc. Nephrol. 2012;23:1407-15).

• Iron-deficiency anemia: The Kidney Dialysis International Guideline Organization defines iron deficiency warranting iron supplementation in CKD patients as a transferrin saturation of 30% or less and a serum ferritin of 50 ng/mL or less. By those criteria, it is estimated that nearly 70% of CKD patients are iron deficient. So there is a large unmet need for iron repletion therapies that avoid the use of erythropoietin-stimulating agents and intravenous iron, Dr. Block noted.

The FCCC trial was sponsored by Keryx Biopharmaceuticals. Dr. Block serves as a consultant to the company and was principal investigator in the study.

[email protected]

LAS VEGAS – Treatment with ferric citrate coordination complex conferred multiple benefits with cardioprotective implications in non–dialysis-dependent chronic kidney disease patients with elevated serum phosphate and iron-deficiency anemia in a randomized trial.

Ferric citrate coordination complex (FCCC), an investigational oral product also known as Zerenex, effectively lowered patients’ elevated serum phosphate into normal range while repleting iron stores, boosting hemoglobin, and reducing levels of the cardiotoxic protein fibroblast growth factor 23 (FGF23), Dr. Geoffrey A. Block reported at a meeting sponsored by the National Kidney Foundation.

"We are quite happy with these results and the implications they may have in trying to address cardiovascular risk at multiple levels in chronic kidney disease," declared Dr. Block of Denver Nephrology, who was principal investigator in the phase II study.

FCCC is currently under Food and Drug Administration review for potential marketing approval as a treatment in patients with end-stage renal disease complicated by iron-deficiency anemia and elevated serum phosphate. However, the phase II study led by Dr. Block focused on the much larger patient population with non–dialysis-dependent chronic kidney disease (CKD) with elevated serum phosphate and iron-deficiency anemia. Experience has shown it is far more difficult to lower serum phosphate in such patients than in those with end-stage renal disease, the nephrologist noted.

The 12-week, double-blind clinical trial included 141 subjects with an estimated glomerular filtration rate below 60 mL/min per 1.73 m², a serum phosphate in excess of 4.0 mg/dL, a transferrin saturation below 30%, a hemoglobin level of 9-12 g/dL, and a serum ferritin below 300 ng/mL. Participants were not permitted to use intravenous iron or an erythropoietin-stimulating agent in the months prior to or during the trial. They were randomized to FCCC titrated to achieve a serum phosphate below 3.5 mg/dL or to placebo.

The coprimary endpoints were changes from baseline through 12 weeks in serum phosphate and transferrin saturation. The FCCC-treated patients fared significantly better than controls on those endpoints as well as the secondary outcomes (see chart).

• FGF23: The FCCC group’s 40% drop in C-terminal FGF23 over the course of the 12-week study, while levels remained static in the control group, was particularly noteworthy, according to Dr. Block. In several observational studies, including the Heart and Soul Study (Ann. Intern. Med. 2010;152:640-8), elevated FGF23 levels have been associated with significantly increased risk of cardiovascular events and all-cause mortality.

Elevated FGF23 levels appear to promote left-ventricular hypertrophy, while hyperphosphatemia promotes vascular calcification. Through these different mechanisms, both abnormalities increase the risk of cardiovascular events. Both abnormalities are common in patients with CKD. And FCCC resulted in significant reductions in both FGF23 and serum phosphate, he noted.

A prespecified safety feature of the phase II trial was that any participant whose hemoglobin fell below 9.0 g/dL or whose serum phosphate climbed above 6.0 mg/dL would have to be taken out of the study. One patient on FCCC and nine controls were withdrawn from the study for low hemoglobin. No patients in the FCCC group and two controls were removed due to an excessive phosphate level.

The safety profile of FCCC was essentially the same as for placebo with two exceptions: 20% of the FCCC group reported diarrhea, compared with 6% of controls; and one-third of the FCCC group reported discolored feces as a consequence of iron utilization.

• Serum phosphate: Dr. Block said that "reasonably solid evidence" from observational studies, clinical trials, and animal studies indicates that a serum phosphate level greater than 4.0 mg/dL leads to faster progression of kidney disease and an increase in cardiovascular events. For example, in a fully adjusted reanalysis of data from the randomized prospective REIN (Ramipril Efficacy in Nephropathy) trial, patients with a baseline serum phosphate above 4.0 mg/dL were at greatly increased risk for the combined endpoint of a doubling of serum creatinine or progression to end-stage renal disease (J. Am. Soc. Nephrol. 2011;22:1923-30).

Moreover, the renoprotective effect of ramipril decreased as baseline serum phosphate increased: While the ACE inhibitor reduced the risk of the combined endpoint by 85%, compared with placebo, in subjects with a serum phosphate less than 3.45 mg/dL and by 63% in those with a level of 3.45-4.0 mg/dL, ramipril wasn’t significantly more effective than placebo in those with a serum phosphate above 4.0 mg/dL.

Dietary phosphorus intake, which is high in the United States, has also come under scrutiny as a public health concern. A recent prospective cohort study in 9,686 healthy U.S. adults concluded that consumption of more than 1,400 mg daily – the median intake in this representative study population was 1,166 mg per day – was independently associated with higher all-cause mortality. Those with a phosphorus density greater than 0.35 mg/kcal, a statistic derived by dividing phosphorus intake by energy intake – had a significantly increased risk of cardiovascular mortality (Am. J. Clin. Nutr. 2014;99:320-7). And in an analysis of 4,494 participants in MESA (Multi-Ethnic Study of Atherosclerosis), dietary phosphorus intake was independently associated with greater left-ventricular mass such that subjects in the top dietary phosphorus quintile had a 6.1-g greater left-ventricular mass than those in the lowest quintile (Kidney Intl. 2013;83:707-14).

The three phosphate binders currently on the market for reduction of elevated serum phosphate in CKD patients are "really marginal treatments," according to Dr. Block. He was first author on a study in which 148 patients with moderate CKD were randomized to 9 months of calcium acetate, sevelamer carbonate, lanthanum carbonate, or placebo. Serum phosphorus inched lower over the 9 months from a baseline of 4.2 mg/dL to 3.9 mg/dL with active therapy, which was only 0.2 mg/dL better than with placebo. In contrast, serum phosphate fell by an average of 0.6 mg/dL during 3 months on FCCC in the phase II study. Moreover, active therapy with the commercially available phosphate binders had no effect upon FGF23 levels, and it significantly increased coronary artery and abdominal aorta calcification by a median of 18% and 15%, respectively (J. Am. Soc. Nephrol. 2012;23:1407-15).

• Iron-deficiency anemia: The Kidney Dialysis International Guideline Organization defines iron deficiency warranting iron supplementation in CKD patients as a transferrin saturation of 30% or less and a serum ferritin of 50 ng/mL or less. By those criteria, it is estimated that nearly 70% of CKD patients are iron deficient. So there is a large unmet need for iron repletion therapies that avoid the use of erythropoietin-stimulating agents and intravenous iron, Dr. Block noted.

The FCCC trial was sponsored by Keryx Biopharmaceuticals. Dr. Block serves as a consultant to the company and was principal investigator in the study.

[email protected]

Q) Does anemia in CKD patients affect their A1C? Is A1C accurate in CKD patients?

Tight glycemic control is imperative for patients with chronic kidney disease (CKD), but the management of diabetes in CKD can be complex due to factors including anemia and changes in glucose and insulin homeostasis.

A1C is directly proportionate to the ambient blood glucose concentration and in the general diabetic population has proven to be a reliable marker.¹ However, it may not be valid in patients with diabetes and CKD. Reduced red blood cell (RBC) lifespan, rapid hemolysis, and iron deficiency may lead to falsely decreased results.² Decreased RBC survival results from an increase in hemoglobin turnover, which decreases glycemic exposure time.¹ This process then lowers the amount of nonenzymatic glucose binding to hemoglobin.¹ Folate deficiency caused by impaired intestinal absorption in CKD also affects RBC survival.³ Falsely increased results may be related to carbamylation of the hemoglobin and acidosis, both of which are influenced by uremia.²

Special considerations should be made for dialysis patients with diabetes. In hemodialysis patients, A1C may be falsely decreased due to blood loss, RBC transfusion, and erythropoietin therapy.³ Observational studies have shown that erythropoietin therapy is associated with lower A1C due to the increased number of immature RBCs that have a decreased glycemic exposure time.¹ In peritoneal dialysis patients, A1C may increase after the start of therapy as a result of dialysate absorption.³

Research suggests that glycated albumin (GA) provides a short-term index of glycemic control (typically two to three weeks) and is not influenced by albumin concentration, RBC lifespan, or erythropoietin administration.¹ A clear consensus on optimal levels of GA has not been established, but GA may be a more reliable marker of glycemic control in patients with diabetes and CKD. Further research is needed to establish a target GA level that predicts the best prognosis for patients with both conditions.¹

A1C is the most reliable marker at this time, but special considerations should be made for the patient with CKD. Rather than focus on a single measurement, clinicians need to consider the patient’s symptoms and results from all labwork, along with A1C, to best evaluate glycemic control.⁴ Further research is needed in ­patients with diabetes and CKD to explore other reliable markers to help maintain tight glycemic control.

Continued on next page >>

Q) One of my patients developed severe leg cramps while taking statins. I felt it was questionable rhabdomyolysis and stopped the medication; the leg pain went away. Is there a way to know if the rhabdomyolysis is progressive?

Rhabdomyolysis is a serious condition caused by the breakdown of muscle tissue that leads to the release of myoglobin into the bloodstream. This condition can lead to severe kidney failure and death.

Previously, there has been no easy method to predict progressive rhabdomyolysis. But re­searchers from Brigham and Women’s Hospital recently developed the Rhabdomyolysis Risk Calculator, a prediction score that can help determine whether a patient with rhabdomyolysis is at risk for severe kidney failure or death.

The researchers conducted a retrospective cohort study of 2,371 patients admitted between 2000 and 2011 and examined variables that may be associated with kidney failure and death.⁵ They identified independent predictors for these outcomes, including age; gender; initial levels of phosphate, calcium, creatinine, carbon dioxide, and creatine kinase; and etiology of rhabdomyolysis (myositis, exercise, statin use, or seizure).⁵

This tool can assist providers in developing a patient-specific treatment plan. However, further research is needed to validate the current variables, verify the risk prediction score in other pop­ulations, and examine its ability to guide individualized ­treatment plans.

The Rhabdomyolysis Risk Calculator is available at www.brighamandwomens.org/research/rhabdo/default.aspx

Kristy Washinger, MSN, CRNP
Nephrology Associates of Central PA
Camp Hill, PA

REFERENCES

1. Vos FE, Schollum JB, Walker RJ. Glycated albumin is the preferred marker for assessing glycaemic control in advanced chronic kidney disease. Nephrol Dial Transplant Plus. 2011; 4(6):368-375.

2. National Kidney Foundation Kidney Disease Outcomes Quality Initiative. Clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease. Guideline 2: management of hyperglycemia and general diabetes care in chronic kidney disease. www.kidney.org/professionals/kdoqi/guideline_diabetes/guide2.htm. Accessed April 15, 2014.

3. Sharif A, Baboolal K. Diagnostic application of the A1c assay in renal disease. J Am Soc Nephrol. 2010;21(3):383-385.

4. American Diabetes Association. Standards of medical care in diabetes—2013. Diabetes Care. 2013;36(suppl 1):S11-S66.

5. McMahon GM, Zeng X, Walker SS. A risk prediction score for kidney failure or mortality in rhabdomyolysis. JAMA Intern Med. 2013;173(19):1821-1828.         

Q) Does anemia in CKD patients affect their A1C? Is A1C accurate in CKD patients?

Tight glycemic control is imperative for patients with chronic kidney disease (CKD), but the management of diabetes in CKD can be complex due to factors including anemia and changes in glucose and insulin homeostasis.

A1C is directly proportionate to the ambient blood glucose concentration and in the general diabetic population has proven to be a reliable marker.¹ However, it may not be valid in patients with diabetes and CKD. Reduced red blood cell (RBC) lifespan, rapid hemolysis, and iron deficiency may lead to falsely decreased results.² Decreased RBC survival results from an increase in hemoglobin turnover, which decreases glycemic exposure time.¹ This process then lowers the amount of nonenzymatic glucose binding to hemoglobin.¹ Folate deficiency caused by impaired intestinal absorption in CKD also affects RBC survival.³ Falsely increased results may be related to carbamylation of the hemoglobin and acidosis, both of which are influenced by uremia.²

Special considerations should be made for dialysis patients with diabetes. In hemodialysis patients, A1C may be falsely decreased due to blood loss, RBC transfusion, and erythropoietin therapy.³ Observational studies have shown that erythropoietin therapy is associated with lower A1C due to the increased number of immature RBCs that have a decreased glycemic exposure time.¹ In peritoneal dialysis patients, A1C may increase after the start of therapy as a result of dialysate absorption.³

Research suggests that glycated albumin (GA) provides a short-term index of glycemic control (typically two to three weeks) and is not influenced by albumin concentration, RBC lifespan, or erythropoietin administration.¹ A clear consensus on optimal levels of GA has not been established, but GA may be a more reliable marker of glycemic control in patients with diabetes and CKD. Further research is needed to establish a target GA level that predicts the best prognosis for patients with both conditions.¹

A1C is the most reliable marker at this time, but special considerations should be made for the patient with CKD. Rather than focus on a single measurement, clinicians need to consider the patient’s symptoms and results from all labwork, along with A1C, to best evaluate glycemic control.⁴ Further research is needed in ­patients with diabetes and CKD to explore other reliable markers to help maintain tight glycemic control.

Continued on next page >>

Q) One of my patients developed severe leg cramps while taking statins. I felt it was questionable rhabdomyolysis and stopped the medication; the leg pain went away. Is there a way to know if the rhabdomyolysis is progressive?

Rhabdomyolysis is a serious condition caused by the breakdown of muscle tissue that leads to the release of myoglobin into the bloodstream. This condition can lead to severe kidney failure and death.

Previously, there has been no easy method to predict progressive rhabdomyolysis. But re­searchers from Brigham and Women’s Hospital recently developed the Rhabdomyolysis Risk Calculator, a prediction score that can help determine whether a patient with rhabdomyolysis is at risk for severe kidney failure or death.

The researchers conducted a retrospective cohort study of 2,371 patients admitted between 2000 and 2011 and examined variables that may be associated with kidney failure and death.⁵ They identified independent predictors for these outcomes, including age; gender; initial levels of phosphate, calcium, creatinine, carbon dioxide, and creatine kinase; and etiology of rhabdomyolysis (myositis, exercise, statin use, or seizure).⁵

This tool can assist providers in developing a patient-specific treatment plan. However, further research is needed to validate the current variables, verify the risk prediction score in other pop­ulations, and examine its ability to guide individualized ­treatment plans.

The Rhabdomyolysis Risk Calculator is available at www.brighamandwomens.org/research/rhabdo/default.aspx

Kristy Washinger, MSN, CRNP
Nephrology Associates of Central PA
Camp Hill, PA

REFERENCES

1. Vos FE, Schollum JB, Walker RJ. Glycated albumin is the preferred marker for assessing glycaemic control in advanced chronic kidney disease. Nephrol Dial Transplant Plus. 2011; 4(6):368-375.

2. National Kidney Foundation Kidney Disease Outcomes Quality Initiative. Clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease. Guideline 2: management of hyperglycemia and general diabetes care in chronic kidney disease. www.kidney.org/professionals/kdoqi/guideline_diabetes/guide2.htm. Accessed April 15, 2014.

3. Sharif A, Baboolal K. Diagnostic application of the A1c assay in renal disease. J Am Soc Nephrol. 2010;21(3):383-385.

4. American Diabetes Association. Standards of medical care in diabetes—2013. Diabetes Care. 2013;36(suppl 1):S11-S66.

5. McMahon GM, Zeng X, Walker SS. A risk prediction score for kidney failure or mortality in rhabdomyolysis. JAMA Intern Med. 2013;173(19):1821-1828.         

Q) Does anemia in CKD patients affect their A1C? Is A1C accurate in CKD patients?

Tight glycemic control is imperative for patients with chronic kidney disease (CKD), but the management of diabetes in CKD can be complex due to factors including anemia and changes in glucose and insulin homeostasis.

A1C is directly proportionate to the ambient blood glucose concentration and in the general diabetic population has proven to be a reliable marker.¹ However, it may not be valid in patients with diabetes and CKD. Reduced red blood cell (RBC) lifespan, rapid hemolysis, and iron deficiency may lead to falsely decreased results.² Decreased RBC survival results from an increase in hemoglobin turnover, which decreases glycemic exposure time.¹ This process then lowers the amount of nonenzymatic glucose binding to hemoglobin.¹ Folate deficiency caused by impaired intestinal absorption in CKD also affects RBC survival.³ Falsely increased results may be related to carbamylation of the hemoglobin and acidosis, both of which are influenced by uremia.²

Special considerations should be made for dialysis patients with diabetes. In hemodialysis patients, A1C may be falsely decreased due to blood loss, RBC transfusion, and erythropoietin therapy.³ Observational studies have shown that erythropoietin therapy is associated with lower A1C due to the increased number of immature RBCs that have a decreased glycemic exposure time.¹ In peritoneal dialysis patients, A1C may increase after the start of therapy as a result of dialysate absorption.³

Research suggests that glycated albumin (GA) provides a short-term index of glycemic control (typically two to three weeks) and is not influenced by albumin concentration, RBC lifespan, or erythropoietin administration.¹ A clear consensus on optimal levels of GA has not been established, but GA may be a more reliable marker of glycemic control in patients with diabetes and CKD. Further research is needed to establish a target GA level that predicts the best prognosis for patients with both conditions.¹

A1C is the most reliable marker at this time, but special considerations should be made for the patient with CKD. Rather than focus on a single measurement, clinicians need to consider the patient’s symptoms and results from all labwork, along with A1C, to best evaluate glycemic control.⁴ Further research is needed in ­patients with diabetes and CKD to explore other reliable markers to help maintain tight glycemic control.

Continued on next page >>

Q) One of my patients developed severe leg cramps while taking statins. I felt it was questionable rhabdomyolysis and stopped the medication; the leg pain went away. Is there a way to know if the rhabdomyolysis is progressive?

Rhabdomyolysis is a serious condition caused by the breakdown of muscle tissue that leads to the release of myoglobin into the bloodstream. This condition can lead to severe kidney failure and death.

Previously, there has been no easy method to predict progressive rhabdomyolysis. But re­searchers from Brigham and Women’s Hospital recently developed the Rhabdomyolysis Risk Calculator, a prediction score that can help determine whether a patient with rhabdomyolysis is at risk for severe kidney failure or death.

The researchers conducted a retrospective cohort study of 2,371 patients admitted between 2000 and 2011 and examined variables that may be associated with kidney failure and death.⁵ They identified independent predictors for these outcomes, including age; gender; initial levels of phosphate, calcium, creatinine, carbon dioxide, and creatine kinase; and etiology of rhabdomyolysis (myositis, exercise, statin use, or seizure).⁵

This tool can assist providers in developing a patient-specific treatment plan. However, further research is needed to validate the current variables, verify the risk prediction score in other pop­ulations, and examine its ability to guide individualized ­treatment plans.

The Rhabdomyolysis Risk Calculator is available at www.brighamandwomens.org/research/rhabdo/default.aspx

Kristy Washinger, MSN, CRNP
Nephrology Associates of Central PA
Camp Hill, PA

REFERENCES

1. Vos FE, Schollum JB, Walker RJ. Glycated albumin is the preferred marker for assessing glycaemic control in advanced chronic kidney disease. Nephrol Dial Transplant Plus. 2011; 4(6):368-375.

2. National Kidney Foundation Kidney Disease Outcomes Quality Initiative. Clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease. Guideline 2: management of hyperglycemia and general diabetes care in chronic kidney disease. www.kidney.org/professionals/kdoqi/guideline_diabetes/guide2.htm. Accessed April 15, 2014.

3. Sharif A, Baboolal K. Diagnostic application of the A1c assay in renal disease. J Am Soc Nephrol. 2010;21(3):383-385.

4. American Diabetes Association. Standards of medical care in diabetes—2013. Diabetes Care. 2013;36(suppl 1):S11-S66.

5. McMahon GM, Zeng X, Walker SS. A risk prediction score for kidney failure or mortality in rhabdomyolysis. JAMA Intern Med. 2013;173(19):1821-1828.         

LAS VEGAS – Patients with chronic kidney disease appear to be at increased risk for cancer, a study showed.

A retrospective analysis of data on 31,896 participants in ALLHAT (the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) showed that during a mean 4.9 years of in-trial follow-up, 2,529 subjects were diagnosed with various cancers.

The 5-year rate of incident cancer was 7.24 cases per 100 person-years among subjects with a baseline normal estimated glomerular filtration rate (eGFR) greater than 90 mL/min per 1.73 m². The cancer rate rose with decreasing renal function: 8.38 cases per 100 person-years in patients with a baseline eGFR of 60-89.9, 9.18 per 100 person-years in those with an eGFR of 45-59.9, and 11.58 per 100 person-years in patients with an eGFR below 45 mL/min per 1.73 m², Dr. Dhruti P. Chen reported at a meeting sponsored by the National Kidney Foundation.

An additional 4 years of follow-up for mortality due to cancer was available through national databases after ALLHAT ended. During the mean total 8.9 years of follow-up, there were 2,338 cancer-related deaths. The 10-year rate of cancer mortality was 7.90 cases per 100 person-years in patients with an eGFR greater than 90; 7.71 in those with an eGFR of 60-89.9; 10.11 per 100 person-years with an eGFR of 45-59.9; and 13.19 per 100 person-years in patients with an eGFR below 45 mL/min per 1.73 m², added Dr. Chen of the department of medicine at Case Western Reserve University, Cleveland.

In a multivariate analysis adjusted for demographics, body mass index, diabetes, cardiovascular risk factors, blood glucose level, and the antihypertensive agent to which a patient was randomized, the association between chronic kidney disease and incident cancer was attenuated. Nonetheless, having a baseline eGFR below 45 mL/min per 1.73 m² was independently associated with an adjusted 28% increased risk of incident cancer during 4.9 years of follow-up, compared with those with an eGFR greater than 90, as well as with a 55% increased risk of cancer mortality during 8.9 years of follow-up.

Colon cancer was the only common type of malignancy whose incidence was significantly increased in patients with chronic kidney disease, although Dr. Chen said she didn’t attach much significance to this finding, given the limited number of cancers that accrued.

In an interview, she observed that a post hoc analysis such as this can’t establish causality or the mechanisms involved. She speculated that the most likely explanation for the findings is that patients with impaired kidney function have incomplete removal of various toxins, some of which are oncogenic.

ALLHAT was funded by the National Heart, Lung, and Blood Institute. Dr. Chen reported having no financial conflicts of interest.

[email protected]

LAS VEGAS – Patients with chronic kidney disease appear to be at increased risk for cancer, a study showed.

A retrospective analysis of data on 31,896 participants in ALLHAT (the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) showed that during a mean 4.9 years of in-trial follow-up, 2,529 subjects were diagnosed with various cancers.

The 5-year rate of incident cancer was 7.24 cases per 100 person-years among subjects with a baseline normal estimated glomerular filtration rate (eGFR) greater than 90 mL/min per 1.73 m². The cancer rate rose with decreasing renal function: 8.38 cases per 100 person-years in patients with a baseline eGFR of 60-89.9, 9.18 per 100 person-years in those with an eGFR of 45-59.9, and 11.58 per 100 person-years in patients with an eGFR below 45 mL/min per 1.73 m², Dr. Dhruti P. Chen reported at a meeting sponsored by the National Kidney Foundation.

An additional 4 years of follow-up for mortality due to cancer was available through national databases after ALLHAT ended. During the mean total 8.9 years of follow-up, there were 2,338 cancer-related deaths. The 10-year rate of cancer mortality was 7.90 cases per 100 person-years in patients with an eGFR greater than 90; 7.71 in those with an eGFR of 60-89.9; 10.11 per 100 person-years with an eGFR of 45-59.9; and 13.19 per 100 person-years in patients with an eGFR below 45 mL/min per 1.73 m², added Dr. Chen of the department of medicine at Case Western Reserve University, Cleveland.

In a multivariate analysis adjusted for demographics, body mass index, diabetes, cardiovascular risk factors, blood glucose level, and the antihypertensive agent to which a patient was randomized, the association between chronic kidney disease and incident cancer was attenuated. Nonetheless, having a baseline eGFR below 45 mL/min per 1.73 m² was independently associated with an adjusted 28% increased risk of incident cancer during 4.9 years of follow-up, compared with those with an eGFR greater than 90, as well as with a 55% increased risk of cancer mortality during 8.9 years of follow-up.

Colon cancer was the only common type of malignancy whose incidence was significantly increased in patients with chronic kidney disease, although Dr. Chen said she didn’t attach much significance to this finding, given the limited number of cancers that accrued.

In an interview, she observed that a post hoc analysis such as this can’t establish causality or the mechanisms involved. She speculated that the most likely explanation for the findings is that patients with impaired kidney function have incomplete removal of various toxins, some of which are oncogenic.

ALLHAT was funded by the National Heart, Lung, and Blood Institute. Dr. Chen reported having no financial conflicts of interest.

[email protected]

LAS VEGAS – Patients with chronic kidney disease appear to be at increased risk for cancer, a study showed.

A retrospective analysis of data on 31,896 participants in ALLHAT (the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) showed that during a mean 4.9 years of in-trial follow-up, 2,529 subjects were diagnosed with various cancers.

The 5-year rate of incident cancer was 7.24 cases per 100 person-years among subjects with a baseline normal estimated glomerular filtration rate (eGFR) greater than 90 mL/min per 1.73 m². The cancer rate rose with decreasing renal function: 8.38 cases per 100 person-years in patients with a baseline eGFR of 60-89.9, 9.18 per 100 person-years in those with an eGFR of 45-59.9, and 11.58 per 100 person-years in patients with an eGFR below 45 mL/min per 1.73 m², Dr. Dhruti P. Chen reported at a meeting sponsored by the National Kidney Foundation.

An additional 4 years of follow-up for mortality due to cancer was available through national databases after ALLHAT ended. During the mean total 8.9 years of follow-up, there were 2,338 cancer-related deaths. The 10-year rate of cancer mortality was 7.90 cases per 100 person-years in patients with an eGFR greater than 90; 7.71 in those with an eGFR of 60-89.9; 10.11 per 100 person-years with an eGFR of 45-59.9; and 13.19 per 100 person-years in patients with an eGFR below 45 mL/min per 1.73 m², added Dr. Chen of the department of medicine at Case Western Reserve University, Cleveland.

In a multivariate analysis adjusted for demographics, body mass index, diabetes, cardiovascular risk factors, blood glucose level, and the antihypertensive agent to which a patient was randomized, the association between chronic kidney disease and incident cancer was attenuated. Nonetheless, having a baseline eGFR below 45 mL/min per 1.73 m² was independently associated with an adjusted 28% increased risk of incident cancer during 4.9 years of follow-up, compared with those with an eGFR greater than 90, as well as with a 55% increased risk of cancer mortality during 8.9 years of follow-up.

Colon cancer was the only common type of malignancy whose incidence was significantly increased in patients with chronic kidney disease, although Dr. Chen said she didn’t attach much significance to this finding, given the limited number of cancers that accrued.

In an interview, she observed that a post hoc analysis such as this can’t establish causality or the mechanisms involved. She speculated that the most likely explanation for the findings is that patients with impaired kidney function have incomplete removal of various toxins, some of which are oncogenic.

ALLHAT was funded by the National Heart, Lung, and Blood Institute. Dr. Chen reported having no financial conflicts of interest.

[email protected]

LONDON – Herbal medicines and other home remedies or supplements are a significant cause of hepatotoxicity experts warned recently during a symposium at the International Liver Congress, which unintentionally coincided with World Homeopathy Awareness Week.

Although they are not at the very top of the list when it comes to drug-induced liver injury (DILI) – that accolade being reserved for antimicrobial agents used to treat tuberculosis – the use of homeopathy-based approaches are potentially on the increase in the western world and the use of such substances are often not reported to physicians.

"Herbal medicines represent a significant cause of liver injury," Dr. Dominique Larrey (Central University Hospital, Montpellier, France), said at the meeting that was sponsored by the European Association for the Study of the Liver. "Herbs can cause almost the whole spectrum of hepatic and biliary lesions, acute hepatitis being the most frequent one," he added.

The rise of herbal medicine

Dr. Larrey, who works in the liver and transplantation department of Saint Eloi Hospital, also in Montpellier, noted that the use of herbs in traditional medicine was very important in many parts of the world, notably in Asia, Africa, and Central and South America. They are used for both traditional and cultural reasons, he added, are often easy to access and are low cost in comparison to regulated medicines.

Their use is probably on the increase in western countries for a variety of reasons, Dr. Larrey suggested, such as the migration of people from cultures in which the use of traditional medicines is high, to the thinking that "what is natural can only be good" and "herbal medicines are considered completely innocuous in contrast to classical drugs." Furthermore, the lack of satisfactory treatments for some severe diseases – cancer, multiple sclerosis, AIDS, and hepatitis C virus infection to name a few – mean that people often are willing to try out complementary or alternative medicines (CAM).

In the United States, the total sale of herbal remedies in 2010 was an estimated $5.2 billion per year, having increased around 3% a year over the past decade, Dr. Larrey pointed out.

The problem is that patients do not often tell their doctors about their use of CAM. A staggering 90% of patients taking the anticoagulant drug warfarin – which is renowned for having a very narrow therapeutic window and careful monitoring is required – were taking herbal medicines in one study, he said.

Prospective studies on the use of herbal medicines in western countries are scarce but those that have been conducted specifically in patients with liver disease suggest that as many as one-fifth (Hepatology 2008;47:605-12) to one-third (Gastroenterology 2001;120[Suppl 1]:A228) might be taking herbal remedies unbeknownst to their doctor.

The problem of assessment

There are limited data on how frequently herbal medicines cause liver damage, but estimates range from 2% to 16%, Dr. Larrey observed, adding that reported cases could be just the tip of the iceberg.

"Herbal medicine hepatoxicity is clearly underestimated for many reasons," he suggested. First, their intake is hard to analyze. Second, the mechanism of liver damage is often uncertain, and third, it is hard to confirm causality. Indeed, herbal medicines do not have to undergo the rigorous testing or regulation in the same way that prescribed medicines do, and sales via the Internet make them easily available to all.

There is then the uncertainty of what is really in the preparations, if they contain the right plant at all or the wrong part of it, and then whether or not they have been stored correctly, or if they have been contaminated with other liver-damaging agents or microorganisms.

Advice for physicians

DILI from prescription and nonprescription medicines is an important but rare event in the westernized world, Dr. Robert Fontana of the University of Michigan in Ann Arbor said in an interview. However, because it can bring about very bad and unpredictable liver injury, it is of great importance for hepatologists and general family physicians alike.

"In the United States and I think worldwide, the frequency in use of [herbal treatments] is increasing and as we start to see registry data I think we will start to see more and more cases [of hepatoxicity]," Dr. Fontana said.

Dr. Fontana is part of the National Institutes of Health–funded Drug-Induced Liver Injury Network (DILIN), a multicenter, prospective registry looking at the etiologies, risk factors, and outcomes of DILI in the United States (Drug Saf. 2009;32:55-68). Data from the registry show the prevalence of herbal and dietary supplements is around 9% (n = 300) in confirmed DILI cases.

"Patients need to tell their doctors what they are taking," he advised, adding that, as physicians, "we all need to be aware and maybe ask more questions of our patients."

The LiverTox website – produced by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Library of Medicine – is a valuable online and freely available resource for determining if a medication, herbal, or other supplement is known to cause liver problems. This is going to have a new chapter on herbal medicines, Dr. Fontana said, and is worth using in daily practice to help advise patients on the prescription or CAM they might be taking.

Dr. Larrey and Dr. Fontana had no disclosures relevant to their comments.

New Chinese herbal medicine inhibits HCV activity

A compound named SBEL1 after the laboratory in which it was discovered has multiple effects on the hepatitis C virus (HCV) life cycle, according to data from a late-breaking poster presented at the meeting.

Researchers from the Systems Biology of Epithelia Laboratory at the National Taiwan University, Taipei, screened six herbal medicines and found that one of these – SBEL1 – inhibited HCV activity by about 90% in infected cells.

Cheng-Wei Lin and Ming-Jiun Yu pretreated liver cells with the herbal extract and then infected these cells with HCV. Compared with control cells, SBEL1-treated cells contained 23% less viral protein. This suggested that SBEL1 prevented HCV from entering the pretreated cells.

Their findings also suggested that SBEL1 reduced internal-ribosome entry site–mediated translation, a process vital for viral protein production, and might also have interfered with the RNA replication process.

"SBEL1 has demonstrated significant inhibition of HCV at multiple stages of the viral life cycle," Dr. Markus Peck-Radosavljevic, the secretary-general of the European Association for the Study of the Liver, said in a press release issued by the Society.

Dr. Peck-Radosavljevic (University of Vienna, Austria), who was not involved in the research, added that this "is an exciting discovery because it allows us to gain a deeper understanding of the virus and its interactions with other compounds. Ultimately, this adds to our library of knowledge that may bring us closer to improving future treatment options."

LONDON – Herbal medicines and other home remedies or supplements are a significant cause of hepatotoxicity experts warned recently during a symposium at the International Liver Congress, which unintentionally coincided with World Homeopathy Awareness Week.

Although they are not at the very top of the list when it comes to drug-induced liver injury (DILI) – that accolade being reserved for antimicrobial agents used to treat tuberculosis – the use of homeopathy-based approaches are potentially on the increase in the western world and the use of such substances are often not reported to physicians.

"Herbal medicines represent a significant cause of liver injury," Dr. Dominique Larrey (Central University Hospital, Montpellier, France), said at the meeting that was sponsored by the European Association for the Study of the Liver. "Herbs can cause almost the whole spectrum of hepatic and biliary lesions, acute hepatitis being the most frequent one," he added.

The rise of herbal medicine

Dr. Larrey, who works in the liver and transplantation department of Saint Eloi Hospital, also in Montpellier, noted that the use of herbs in traditional medicine was very important in many parts of the world, notably in Asia, Africa, and Central and South America. They are used for both traditional and cultural reasons, he added, are often easy to access and are low cost in comparison to regulated medicines.

Their use is probably on the increase in western countries for a variety of reasons, Dr. Larrey suggested, such as the migration of people from cultures in which the use of traditional medicines is high, to the thinking that "what is natural can only be good" and "herbal medicines are considered completely innocuous in contrast to classical drugs." Furthermore, the lack of satisfactory treatments for some severe diseases – cancer, multiple sclerosis, AIDS, and hepatitis C virus infection to name a few – mean that people often are willing to try out complementary or alternative medicines (CAM).

In the United States, the total sale of herbal remedies in 2010 was an estimated $5.2 billion per year, having increased around 3% a year over the past decade, Dr. Larrey pointed out.

The problem is that patients do not often tell their doctors about their use of CAM. A staggering 90% of patients taking the anticoagulant drug warfarin – which is renowned for having a very narrow therapeutic window and careful monitoring is required – were taking herbal medicines in one study, he said.

Prospective studies on the use of herbal medicines in western countries are scarce but those that have been conducted specifically in patients with liver disease suggest that as many as one-fifth (Hepatology 2008;47:605-12) to one-third (Gastroenterology 2001;120[Suppl 1]:A228) might be taking herbal remedies unbeknownst to their doctor.

The problem of assessment

There are limited data on how frequently herbal medicines cause liver damage, but estimates range from 2% to 16%, Dr. Larrey observed, adding that reported cases could be just the tip of the iceberg.

"Herbal medicine hepatoxicity is clearly underestimated for many reasons," he suggested. First, their intake is hard to analyze. Second, the mechanism of liver damage is often uncertain, and third, it is hard to confirm causality. Indeed, herbal medicines do not have to undergo the rigorous testing or regulation in the same way that prescribed medicines do, and sales via the Internet make them easily available to all.

There is then the uncertainty of what is really in the preparations, if they contain the right plant at all or the wrong part of it, and then whether or not they have been stored correctly, or if they have been contaminated with other liver-damaging agents or microorganisms.

Advice for physicians

DILI from prescription and nonprescription medicines is an important but rare event in the westernized world, Dr. Robert Fontana of the University of Michigan in Ann Arbor said in an interview. However, because it can bring about very bad and unpredictable liver injury, it is of great importance for hepatologists and general family physicians alike.

"In the United States and I think worldwide, the frequency in use of [herbal treatments] is increasing and as we start to see registry data I think we will start to see more and more cases [of hepatoxicity]," Dr. Fontana said.

Dr. Fontana is part of the National Institutes of Health–funded Drug-Induced Liver Injury Network (DILIN), a multicenter, prospective registry looking at the etiologies, risk factors, and outcomes of DILI in the United States (Drug Saf. 2009;32:55-68). Data from the registry show the prevalence of herbal and dietary supplements is around 9% (n = 300) in confirmed DILI cases.

"Patients need to tell their doctors what they are taking," he advised, adding that, as physicians, "we all need to be aware and maybe ask more questions of our patients."

The LiverTox website – produced by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Library of Medicine – is a valuable online and freely available resource for determining if a medication, herbal, or other supplement is known to cause liver problems. This is going to have a new chapter on herbal medicines, Dr. Fontana said, and is worth using in daily practice to help advise patients on the prescription or CAM they might be taking.

Dr. Larrey and Dr. Fontana had no disclosures relevant to their comments.

New Chinese herbal medicine inhibits HCV activity

A compound named SBEL1 after the laboratory in which it was discovered has multiple effects on the hepatitis C virus (HCV) life cycle, according to data from a late-breaking poster presented at the meeting.

Researchers from the Systems Biology of Epithelia Laboratory at the National Taiwan University, Taipei, screened six herbal medicines and found that one of these – SBEL1 – inhibited HCV activity by about 90% in infected cells.

Cheng-Wei Lin and Ming-Jiun Yu pretreated liver cells with the herbal extract and then infected these cells with HCV. Compared with control cells, SBEL1-treated cells contained 23% less viral protein. This suggested that SBEL1 prevented HCV from entering the pretreated cells.

Their findings also suggested that SBEL1 reduced internal-ribosome entry site–mediated translation, a process vital for viral protein production, and might also have interfered with the RNA replication process.

"SBEL1 has demonstrated significant inhibition of HCV at multiple stages of the viral life cycle," Dr. Markus Peck-Radosavljevic, the secretary-general of the European Association for the Study of the Liver, said in a press release issued by the Society.

Dr. Peck-Radosavljevic (University of Vienna, Austria), who was not involved in the research, added that this "is an exciting discovery because it allows us to gain a deeper understanding of the virus and its interactions with other compounds. Ultimately, this adds to our library of knowledge that may bring us closer to improving future treatment options."

LONDON – Herbal medicines and other home remedies or supplements are a significant cause of hepatotoxicity experts warned recently during a symposium at the International Liver Congress, which unintentionally coincided with World Homeopathy Awareness Week.

Although they are not at the very top of the list when it comes to drug-induced liver injury (DILI) – that accolade being reserved for antimicrobial agents used to treat tuberculosis – the use of homeopathy-based approaches are potentially on the increase in the western world and the use of such substances are often not reported to physicians.

"Herbal medicines represent a significant cause of liver injury," Dr. Dominique Larrey (Central University Hospital, Montpellier, France), said at the meeting that was sponsored by the European Association for the Study of the Liver. "Herbs can cause almost the whole spectrum of hepatic and biliary lesions, acute hepatitis being the most frequent one," he added.

The rise of herbal medicine

Dr. Larrey, who works in the liver and transplantation department of Saint Eloi Hospital, also in Montpellier, noted that the use of herbs in traditional medicine was very important in many parts of the world, notably in Asia, Africa, and Central and South America. They are used for both traditional and cultural reasons, he added, are often easy to access and are low cost in comparison to regulated medicines.

Their use is probably on the increase in western countries for a variety of reasons, Dr. Larrey suggested, such as the migration of people from cultures in which the use of traditional medicines is high, to the thinking that "what is natural can only be good" and "herbal medicines are considered completely innocuous in contrast to classical drugs." Furthermore, the lack of satisfactory treatments for some severe diseases – cancer, multiple sclerosis, AIDS, and hepatitis C virus infection to name a few – mean that people often are willing to try out complementary or alternative medicines (CAM).

In the United States, the total sale of herbal remedies in 2010 was an estimated $5.2 billion per year, having increased around 3% a year over the past decade, Dr. Larrey pointed out.

The problem is that patients do not often tell their doctors about their use of CAM. A staggering 90% of patients taking the anticoagulant drug warfarin – which is renowned for having a very narrow therapeutic window and careful monitoring is required – were taking herbal medicines in one study, he said.

Prospective studies on the use of herbal medicines in western countries are scarce but those that have been conducted specifically in patients with liver disease suggest that as many as one-fifth (Hepatology 2008;47:605-12) to one-third (Gastroenterology 2001;120[Suppl 1]:A228) might be taking herbal remedies unbeknownst to their doctor.

The problem of assessment

There are limited data on how frequently herbal medicines cause liver damage, but estimates range from 2% to 16%, Dr. Larrey observed, adding that reported cases could be just the tip of the iceberg.

"Herbal medicine hepatoxicity is clearly underestimated for many reasons," he suggested. First, their intake is hard to analyze. Second, the mechanism of liver damage is often uncertain, and third, it is hard to confirm causality. Indeed, herbal medicines do not have to undergo the rigorous testing or regulation in the same way that prescribed medicines do, and sales via the Internet make them easily available to all.

There is then the uncertainty of what is really in the preparations, if they contain the right plant at all or the wrong part of it, and then whether or not they have been stored correctly, or if they have been contaminated with other liver-damaging agents or microorganisms.

Advice for physicians

DILI from prescription and nonprescription medicines is an important but rare event in the westernized world, Dr. Robert Fontana of the University of Michigan in Ann Arbor said in an interview. However, because it can bring about very bad and unpredictable liver injury, it is of great importance for hepatologists and general family physicians alike.

"In the United States and I think worldwide, the frequency in use of [herbal treatments] is increasing and as we start to see registry data I think we will start to see more and more cases [of hepatoxicity]," Dr. Fontana said.

Dr. Fontana is part of the National Institutes of Health–funded Drug-Induced Liver Injury Network (DILIN), a multicenter, prospective registry looking at the etiologies, risk factors, and outcomes of DILI in the United States (Drug Saf. 2009;32:55-68). Data from the registry show the prevalence of herbal and dietary supplements is around 9% (n = 300) in confirmed DILI cases.

"Patients need to tell their doctors what they are taking," he advised, adding that, as physicians, "we all need to be aware and maybe ask more questions of our patients."

The LiverTox website – produced by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Library of Medicine – is a valuable online and freely available resource for determining if a medication, herbal, or other supplement is known to cause liver problems. This is going to have a new chapter on herbal medicines, Dr. Fontana said, and is worth using in daily practice to help advise patients on the prescription or CAM they might be taking.

Dr. Larrey and Dr. Fontana had no disclosures relevant to their comments.

New Chinese herbal medicine inhibits HCV activity

A compound named SBEL1 after the laboratory in which it was discovered has multiple effects on the hepatitis C virus (HCV) life cycle, according to data from a late-breaking poster presented at the meeting.

Researchers from the Systems Biology of Epithelia Laboratory at the National Taiwan University, Taipei, screened six herbal medicines and found that one of these – SBEL1 – inhibited HCV activity by about 90% in infected cells.

Cheng-Wei Lin and Ming-Jiun Yu pretreated liver cells with the herbal extract and then infected these cells with HCV. Compared with control cells, SBEL1-treated cells contained 23% less viral protein. This suggested that SBEL1 prevented HCV from entering the pretreated cells.

Their findings also suggested that SBEL1 reduced internal-ribosome entry site–mediated translation, a process vital for viral protein production, and might also have interfered with the RNA replication process.

"SBEL1 has demonstrated significant inhibition of HCV at multiple stages of the viral life cycle," Dr. Markus Peck-Radosavljevic, the secretary-general of the European Association for the Study of the Liver, said in a press release issued by the Society.

Dr. Peck-Radosavljevic (University of Vienna, Austria), who was not involved in the research, added that this "is an exciting discovery because it allows us to gain a deeper understanding of the virus and its interactions with other compounds. Ultimately, this adds to our library of knowledge that may bring us closer to improving future treatment options."

The efficacy and safety of lorazepam were not superior to diazepam in a clinical trial of pediatric status epilepticus, investigators reported online April 22 in JAMA.

Both drugs effectively halted status epilepticus in more than 70% of children and adolescents and caused severe respiratory depression in less than 20%, said Dr. James Chamberlain of the Children’s National Medical Center, Washington, and his associates in the Pediatric Emergency Care Applied Research Network (PECARN).

"Taken together with the results of the RAMPART trial, it would appear that either diazepam, lorazepam, or midazolam could be chosen as a reasonable first-line therapy" for pediatric status epilepticus, the researchers said. Many prehospital systems prefer diazepam because it does not require refrigeration, they noted (JAMA 2014;311:1652-60 [doi:10.1001/jama.2014.2625]).

The multicenter, randomized, double-blind trial included 272 patients aged 3 months to less than 18 years who presented to one of 11 academic pediatric emergency departments with generalized tonic-clonic convulsive status epilepticus. Patients received intravenous diazepam (0.2 mg/kg) or lorazepam (0.1 mg/kg), with half the dose repeated at 5 minutes if needed. If status epilepticus continued at 12 minutes, patients received fosphenytoin or phenytoin.

Status epilepticus ceased by 10 minutes and did not recur for at least 30 minutes in 97 (72.9%) patients given lorazepam and in 101 (72.1%) patients treated with diazepam. The absolute efficacy difference was 0.8% (95% confidence interval, –11.4% to 9.8%). Severe respiratory depression – the primary safety outcome – occurred in 17.6% of lorazepam patients and 16.0% of diazepam patients, for an absolute risk difference of just 1.6% (95% CI, –9.9% to 6.8%), Dr. James Chamberlain and his associates reported.

Rates of secondary outcomes also were similar, except that sedation was more common in the lorazepam group (66.9% vs. 50% for diazepam; absolute risk difference, 16.9%; 95% CI, 6.1% to 27.7%).

The study was a superiority trial, not a noninferiority trial, so the two drugs could not be assumed to be statistically equivalent, the researchers said. "Although the point estimates for both efficacy and safety outcomes are similar in the two groups, the confidence intervals suggest that one medication could be superior in efficacy by as much as approximately 10% to 11% and in safety by approximately 7% to 10%," they wrote. They concluded that new treatment options for pediatric status epilepticus are needed, given the extent of medication failure and respiratory depression observed in both study groups.

The Eunice Kennedy Shriver National Institute of Child Health and Human Development funded the study. Dr. Pamela Okada reported receiving a grant from NICHD during the study. Dr. Prashant Mahajan, Dr. Richard Lichenstein, and Dr. Joseph Grubenhoff reported having received grants from the National Institutes of Health during the study. The remaining authors reported no relevant financial disclosures.

The efficacy and safety of lorazepam were not superior to diazepam in a clinical trial of pediatric status epilepticus, investigators reported online April 22 in JAMA.

Both drugs effectively halted status epilepticus in more than 70% of children and adolescents and caused severe respiratory depression in less than 20%, said Dr. James Chamberlain of the Children’s National Medical Center, Washington, and his associates in the Pediatric Emergency Care Applied Research Network (PECARN).

"Taken together with the results of the RAMPART trial, it would appear that either diazepam, lorazepam, or midazolam could be chosen as a reasonable first-line therapy" for pediatric status epilepticus, the researchers said. Many prehospital systems prefer diazepam because it does not require refrigeration, they noted (JAMA 2014;311:1652-60 [doi:10.1001/jama.2014.2625]).

The multicenter, randomized, double-blind trial included 272 patients aged 3 months to less than 18 years who presented to one of 11 academic pediatric emergency departments with generalized tonic-clonic convulsive status epilepticus. Patients received intravenous diazepam (0.2 mg/kg) or lorazepam (0.1 mg/kg), with half the dose repeated at 5 minutes if needed. If status epilepticus continued at 12 minutes, patients received fosphenytoin or phenytoin.

Status epilepticus ceased by 10 minutes and did not recur for at least 30 minutes in 97 (72.9%) patients given lorazepam and in 101 (72.1%) patients treated with diazepam. The absolute efficacy difference was 0.8% (95% confidence interval, –11.4% to 9.8%). Severe respiratory depression – the primary safety outcome – occurred in 17.6% of lorazepam patients and 16.0% of diazepam patients, for an absolute risk difference of just 1.6% (95% CI, –9.9% to 6.8%), Dr. James Chamberlain and his associates reported.

Rates of secondary outcomes also were similar, except that sedation was more common in the lorazepam group (66.9% vs. 50% for diazepam; absolute risk difference, 16.9%; 95% CI, 6.1% to 27.7%).

The study was a superiority trial, not a noninferiority trial, so the two drugs could not be assumed to be statistically equivalent, the researchers said. "Although the point estimates for both efficacy and safety outcomes are similar in the two groups, the confidence intervals suggest that one medication could be superior in efficacy by as much as approximately 10% to 11% and in safety by approximately 7% to 10%," they wrote. They concluded that new treatment options for pediatric status epilepticus are needed, given the extent of medication failure and respiratory depression observed in both study groups.

The Eunice Kennedy Shriver National Institute of Child Health and Human Development funded the study. Dr. Pamela Okada reported receiving a grant from NICHD during the study. Dr. Prashant Mahajan, Dr. Richard Lichenstein, and Dr. Joseph Grubenhoff reported having received grants from the National Institutes of Health during the study. The remaining authors reported no relevant financial disclosures.

The efficacy and safety of lorazepam were not superior to diazepam in a clinical trial of pediatric status epilepticus, investigators reported online April 22 in JAMA.

Both drugs effectively halted status epilepticus in more than 70% of children and adolescents and caused severe respiratory depression in less than 20%, said Dr. James Chamberlain of the Children’s National Medical Center, Washington, and his associates in the Pediatric Emergency Care Applied Research Network (PECARN).

"Taken together with the results of the RAMPART trial, it would appear that either diazepam, lorazepam, or midazolam could be chosen as a reasonable first-line therapy" for pediatric status epilepticus, the researchers said. Many prehospital systems prefer diazepam because it does not require refrigeration, they noted (JAMA 2014;311:1652-60 [doi:10.1001/jama.2014.2625]).

The multicenter, randomized, double-blind trial included 272 patients aged 3 months to less than 18 years who presented to one of 11 academic pediatric emergency departments with generalized tonic-clonic convulsive status epilepticus. Patients received intravenous diazepam (0.2 mg/kg) or lorazepam (0.1 mg/kg), with half the dose repeated at 5 minutes if needed. If status epilepticus continued at 12 minutes, patients received fosphenytoin or phenytoin.

Status epilepticus ceased by 10 minutes and did not recur for at least 30 minutes in 97 (72.9%) patients given lorazepam and in 101 (72.1%) patients treated with diazepam. The absolute efficacy difference was 0.8% (95% confidence interval, –11.4% to 9.8%). Severe respiratory depression – the primary safety outcome – occurred in 17.6% of lorazepam patients and 16.0% of diazepam patients, for an absolute risk difference of just 1.6% (95% CI, –9.9% to 6.8%), Dr. James Chamberlain and his associates reported.

Rates of secondary outcomes also were similar, except that sedation was more common in the lorazepam group (66.9% vs. 50% for diazepam; absolute risk difference, 16.9%; 95% CI, 6.1% to 27.7%).

The study was a superiority trial, not a noninferiority trial, so the two drugs could not be assumed to be statistically equivalent, the researchers said. "Although the point estimates for both efficacy and safety outcomes are similar in the two groups, the confidence intervals suggest that one medication could be superior in efficacy by as much as approximately 10% to 11% and in safety by approximately 7% to 10%," they wrote. They concluded that new treatment options for pediatric status epilepticus are needed, given the extent of medication failure and respiratory depression observed in both study groups.

The Eunice Kennedy Shriver National Institute of Child Health and Human Development funded the study. Dr. Pamela Okada reported receiving a grant from NICHD during the study. Dr. Prashant Mahajan, Dr. Richard Lichenstein, and Dr. Joseph Grubenhoff reported having received grants from the National Institutes of Health during the study. The remaining authors reported no relevant financial disclosures.