ScienceDaily (May 6, 2010) — Two-year results from phase III clinical trials show the experimental immunosuppressive drug belatacept can better preserve kidney function in kidney transplant recipients while preventing graft rejection when compared with the standard immunosuppressive drug cyclosporine.
UKidney Nephrology News and Insights
Much has been written over the years of a so-called J-point in blood pressure management; that point above which BP is too high and below which BP is too low (if one is arriving there by antihypertensive medications). The late breaking ACCORD BP Study, published online in the New England Journal of Medicine, casts doubt on the benefit of aggressively lowering systolic blood pressure towards 120 mmHg in patients with type 2 diabetes.
However, while much will be written on these very results, I want to issue a cautionary note that this trial not be interpreted as 'strict blood pressure management is unimportant'. Quite the contrary; tight blood pressure control is likely more important that tight glycemic control in patients with type 2 diabetes, but there is a limit to this effect. The ACCORD BP study should be interpreted as nothing more than the demonstration of a J-point in blood pressure management, a finding that actually support current published guidelines in patients with diabetes to target a BP below 130 rather than an even stricter threshold (NB: 130 as a target has not been firmly established by randomized trial data). We now understand however, that 'below' is not a bottomless term and that a range of 120 to 130 is likely appropriate.
Over the past 2 years, considerable excitement has been building over the results of the ACCOMPLISH study. This trial suggested that the combination of benazapril plus amlodipine is superior to benazapril plus hydrochlorothiazide for the prevention of a composite cardiovascular outcome. While there are methodological concerns regarding this trial that make me question its generalizability, it is thought-provoking to consider that one medication combination is superior to another even if blood-pressure between the 2 groups is negligible.
In the latest issue of Lancet, a follow-up paper suggests that benzapril-amlodipine prevented renal outcomes more-so than in the benazapril-hydrochlorothiazide arm. However, as the excellent accompanying editorial points out, all is not as it appears. (continued...)
Hyperphosphatemia has been been linked to poor patient outcomes, including a link to higher mortality. This relationship has been inferred by several retrospective and observational studies. In fact, the relationship between hyperphosphatemia and death is one of the most consistently espoused theories in all of nephrology. There is just problem however; there has never been a randomized trial to confirm this association.
In the latest issue of Nephrology Dialysis and Transplantation, Smith et al cast doubt on this long-held belief. In their retrospective CKD-inception cohort study, there was no association between hyperphosphatemia and death, though there was less risk of renal replacement therapy in patients with better phosphorus control.
This finding is by no means conclusive. I continue to aggressively treat hyperphosphatemia. However, it does lend further support for a large-scale randomized trial to study this seemingly unimpeachable belief.
In a fascinating article from November's Journal of the American Society of Nephrology, researchers present data suggesting that patients returning to dialysis after a transplant fails experience improved survival if the kidney is removed. In this study, despite correction for comorbidities and socioeconomic factors, graft nephrectomy prolonged survival. One explanation of the results might be that nephrectomy removes an inflammatory stimulant and would allow complete withdrawal of immunosuppression and its risks. This finding is somewhat contradictory to current dogma which suggests that immunosuppression should be continued once returning to dialysis in order to preserve residual renal function. This study's finding would need to be reproduced with a prospective randomized trial to reduce bias but in the meantime, is quite compelling.
SAN DIEGO—Dialysis patients with low body fat are at increased risk of death—even compared to patients at the highest level of body fat percentage, according to research being presented at the American Society of Nephrology's 42nd Annual Meeting and Scientific Exposition in San Diego.
"Our study indicates that body fat may be protective in dialysis patients," said Kamyar Kalantar-Zadeh, PhD, of LABioMed at Harbor-UCLA. "The results add to the increasing number of reports about the 'obesity paradox' or 'reverse epidemiology' in patients with chronic kidney disease and other chronic diseases."
Nephrologists have puzzled over the "obesity paradox" in dialysis patients, Kalantar-Zadeh said. "Counter-intuitively, higher body mass index is associated with greater survival in hemodialysis patients. We hypothesized that very low body fat—less than ten percent—would be a strong predictor of mortality."
Using near-infrared interactance technology, the researchers measured body fat percentage in 671 hemodialysis patients from eight California dialysis centers. They then compared five-year mortality rates for patients at different levels of body fat percentage. The mortality rate was highest for dialysis patients with less than 10 percent body fat—2.5 to 3 times higher than for those with body fat of 20 to 30 percent. The increased risk of death for patients with very low body fat remained after adjustment for age, sex, race, other illnesses, and key laboratory results. Further analyses using continuous values of body fat (rather than categories) confirmed a direct, linear relationship between body fat and mortality risk: "The higher the body fat, the greater the survival," said Kalantar-Zadeh. Although more research is needed, the results suggest that the obesity paradox may be explained by an increased risk of death for patients with very low body fat, compared to those with average—or even very high—body fat percentage.
The observational study had the same limitations as other epidemiological studies, Kalantar-Zadeh points out. "In addition, we estimated body fat by measuring the subcutaneous fat of the upper arm, which may be different from the intra-abdominal fat." 10/31/2009
The TREAT Trial was presented at the ASN in San Diego. This much publicized trial examined the role of Aranesp in the management of diabetic patients with CKD. One group was randomized to receive Aranesp with a hemoglobin target of 130 g/l while the control group was given placebo and treated with Aranesp only if their hemoglobin fell below 90 g/l.
There was no advantage to the group given Aranesp and a statistically significant increase in strokes observed in the the treatment group. Below is a link to the article from NEJM and the accompanying editorial written by renowned nephrologist, Dr. Phil Marsden of the University of Toronto.
It is worth noting, that the treatment group was targeted to a higher hemoglobin than we now conventionally use. Furthermore, the dose of Aranesp was more than double the typical dosages used by the majority of my predialysis patients. As has been observed in other studies where high hemoglobin seems harmful, the dose of Aranesp required might explain the observation of harm. Perhaps those patients who respond to lower dosages and those whose hemoglobins remain with target would be perfectly safe to continue.
More study is needed to clarify this and perhaps might be forthcoming from further analysis of the TREAT Study.
No Statistically Significant Difference in Cardiovascular and Renal Composite Endpoints Between Aranesp and Placebo
THOUSAND OAKS, Calif., Aug. 25 /PRNewswire-FirstCall/ -- Amgen (Nasdaq: AMGN) today announced that in a large, randomized, double-blind, placebo-controlled, Phase 3 study of patients with chronic kidney disease (CKD) (not requiring dialysis), anemia and type-2 diabetes (the Trial to Reduce CardiovascularEndpoints with Aranesp((R)) Therapy, or TREAT), treatment of anemia with Aranesp((R) )(darbepoetin alfa) to a hemoglobin target of 13 g/dL had no statistically significant effect on either of two primary endpoints compared with placebo treatment. The two primary endpoints were a composite of time to all-cause mortality or cardiovascular morbidity (including heart failure, heart attack, stroke, or hospitalization for myocardial ischemia) and a composite of time to all-cause mortality or chronic renal replacement therapy. Among the elements that formed these composite endpoints, an excess of stroke events (a labeled risk of Aranesp therapy) occurred in the Aranesp-treated patients compared to those receiving placebo.
These summary results will be followed by full efficacy and safety analyses, which will be shared with global regulatory authorities and presented at an upcoming medical meeting later this year.
"TREAT was designed to answer important questions about the effects of erythropoiesis-stimulating agents (ESAs) on cardiovascular and renal outcomes in patients with renal insufficiency and type-2 diabetes. It is by any measure the most comprehensive analysis that has ever been performed to examine the impact of anemia therapy in patients who do not yet require dialysis. The trial will provide nephrologists with important information as they endeavor to improve renal care," said Roger M. Perlmutter, M.D., Ph.D., executive vice president of Research and Development at Amgen. "In contrast to a recent, smaller study of ESAs in a similar patient population, TREAT did not show a statistically significant adverse effect on all-cause mortality or cardiovascular morbidity when patients were treated to a hemoglobin target of 13 g/dL. We continue to believe that ESAs have a favorable benefit:risk profile when used according to the approved label."
Currently, Aranesp is indicated for the treatment of anemia in patients with chronic renal failure (CRF), including patients on dialysis and patients not on dialysis. The approved label for Aranesp recommends individualizing dosing to achieve and maintain hemoglobin levels within the range of 10 to 12 g/dL. TREAT studied uses for Aranesp in which it is not approved.
TREAT Study Design
TREAT was an international, Phase 3, randomized, double-blind, placebo-controlled study of 4,038 chronic kidney disease (CKD) patients with type-2 diabetes and anemia. It is the largest study of ESA use in CKD patients to date. Patients enrolled in the study were randomized in a one-to-one ratio to receive either treatment with Aranesp to a target hemoglobin of 13 g/dL or placebo. Due to the increased risk of negative outcomes associated with low hemoglobin levels, patients in the control arm whose hemoglobin fell below 9 g/dL were given Aranesp until their hemoglobin level was 9 g/dL. Investigators were blinded to this intervention.
TREAT had two primary endpoints. The first evaluated time to all-cause mortality or cardiovascular morbidity including heart attack (myocardial infarction), congestive heart failure, hospitalization for angina (myocardial ischemia), or stroke (cerebrovascular accident). The second primary endpoint evaluated time to all-cause mortality or chronic dialysis. TREAT was not designed to determine the appropriate hemoglobin target in this patient population.
For patients randomized to the Aranesp group, the starting dose was 0.75 mcg/kg administered subcutaneously every two weeks; subsequent doses were titrated to achieve hemoglobin target of 13.0 g/dL. Once the target hemoglobin was reached, the frequency of administration was extended to once-monthly.
Chronic Kidney Disease: Impact and Prevalence
CKD affects more than 26 million Americans and millions more worldwide. The disease is characterized by progressive kidney damage and impaired kidney function and is most often caused by type-2 diabetes or high blood pressure. When CKD progresses to kidney failure, chronic dialysis or a kidney transplant are required to sustain life. Approximately 350,000 people in the United States are on dialysis today. Anemia is a common complication of CKD that may begin in the early stages of the disease and becomes more common and severe as kidney function declines. Studies have shown that anemia is associated with an increased risk of mortality and cardiovascular morbidity in CKD patients.
Aranesp was approved by the U.S. Food and Drug Administration in 2001 for the treatment of anemia associated with CRF for patients on dialysis and patients not on dialysis. The European Commissiongranted marketing authorization for the same indication in 2001 and subsequently updated it for CRF patients with symptomatic anemia in 2008.
In 2002, the FDA approved the treatment of anemia caused by concomitantly administered chemotherapy in patients with nonmyeloid malignancies. The European Commission authorized the treatment of anemia caused by concomitantly administered chemotherapy in patients with non-haemological malignancies in 2002 and extended it to include non-myeloid malignancies in patients receiving chemotherapy in 2003.
Important Aranesp Safety Information
WARNINGS: INCREASED MORTALITY, SERIOUS CARDIOVASCULAR and THROMBOEMBOLIC EVENTS, and TUMOR PROGRESSION
Renal failure: Patients experienced greater risks for death and serious cardiovascular events when administered erythropoiesis-stimulating agents (ESAs) to target higher versus lower hemoglobin levels (13.5 vs. 11.3 g/dL; 14 vs. 10 g/dL) in two clinical studies. Individualize dosing to achieve and maintain hemoglobin levels within the range of 10 to 12 g/dL.
-- ESAs shortened overall survival and/or time-to-tumor progression in clinical studies in patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers when dosed to target a hemoglobin of greater than or equal to 12 g/dL.
-- To minimize these risks, as well as the risk of serious cardio- and thrombovascular events, use the lowest dose needed to avoid red blood cell transfusions.
-- Use only for treatment of anemia due to concomitant myelosuppressive chemotherapy.
-- ESAs are not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure. (This information is specific to the U.S. prescribing information)
-- Discontinue following the completion of a chemotherapy course.
Aranesp is contraindicated in patients with uncontrolled hypertension.
All patients, including patients with cancer or chronic kidney failure:
-- You may get serious heart problems such as heart attack, stroke, heart failure, and may die sooner if you are treated with Aranesp to a hemoglobin level above 12 g/dL.
-- You may get blood clots at any time while taking Aranesp. If you are receiving Aranesp and you are going to have surgery, talk to your healthcare provider about whether or not you need to take a blood thinner to lessen the chance of blood clots during or following surgery. Clots can form in blood vessels (veins), especially in your leg (deep venous thrombosis or DVT). Pieces of a blood clot may travel to the lungs and block the blood circulation in the lungs (pulmonary embolus).
Amgen discovers, develops, manufactures and delivers innovative human therapeutics. A biotechnology pioneer since 1980, Amgen was one of the first companies to realize the new science's promise by bringing safe and effective medicines from lab, to manufacturing plant, to patient. Amgen therapeutics have changed the practice of medicine, helping millions of people around the world in the fight against cancer, kidney disease, rheumatoid arthritis, and other serious illnesses. With a deep and broad pipeline of potential new medicines, Amgen remains committed to advancing science to dramatically improve people's lives. To learn more about our pioneering science and our vital medicines, visit www.amgen.com.
This news release contains forward-looking statements that are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and assumptions that could cause actual results to differ materially from those described. All statements, other than statements of historical fact, are statements that could be deemed forward-looking statements, including estimates of revenues, operating margins, capital expenditures, cash, other financial metrics, expected legal, arbitration, political, regulatory or clinical results or practices, customer and prescriber patterns or practices, reimbursement activities and outcomes and other such estimates and results. Forward-looking statements involve significant risks and uncertainties, including those discussed below and more fully described in theSecurities and Exchange Commission (SEC) reports filed by Amgen, including Amgen's most recent annual report on Form 10-K and most recent periodic reports on Form 10-Q and Form 8-K. Please refer toAmgen's most recent Forms 10-K, 10-Q and 8-K for additional information on the uncertainties and risk factors related to our business. Unless otherwise noted, Amgen is providing this information as of Aug. 25, 2009 and expressly disclaims any duty to update information contained in this news release.
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The KDIGO guideline group has released its bone and mineral guidelines.
- These can be seen online at this link.
- Alternatively, you may download the .PDF of these guidelines using this link
Dr. Jeff Berns, editor in chief of Medscape Nephrology, had this to say on this development:
In the latest edition of the Journal American Association of Nephrology, investigators report that sodium bicarbonate administration delays the progression of kidney disease to end-stage renal failure. 134 adult patients with CKD (creatinine clearance [CrCl] 15 to 30 ml/min per 1.73 m2) and serum bicarbonate 16 to 20 mmol/L to either supplementation with oral sodium bicarbonate or standard care for 2 yr. With this simple intervention, patients receiving sodium bicarbonate were significantly less likely to experience rapid progression (9 versus 45%; relative risk 0.15; 95% confidence interval 0.06 to 0.40; P < 0.0001). Compared with the control group, decline in CrCl was slower with bicarbonate supplementation (5.93 versus 1.88 ml/min 1.73 m2; P < 0.0001). Nutritional parameters were improved as well. This very simple intervention, practiced variably by nephrologists, shows great promise in the management of patients with chronic kidney disease.