Hemoglobin stability in patients with anemia, CKD, and type 2 diabetes: An analysis of the TREAT (Trial to Reduce Cardiovascular Events With Aranesp Therapy) placebo arm

Authors:  Skali H, Lin J, Pfeffer MA, Chen C-Y, Cooper ME, McMurray JJV, Nissenson AR, Remuzzi G, Rossert J, Parfrey PS, Scott-Douglas NW, Singh AK, Toto R, Uno H, Ivanovich P
Journal Citation:    Am J Kidney Dis. 2012; Epub ahead of print. doi:10.1053/j.ajkd.2012.08.043

The authors describe a post hoc retrospective analysis of the placebo arm of the TREAT study (NCT00093015; Pfeffer MA et al, New Eng J Med. 2009;361:2019-2032), examining the frequency of protocol-directed darbepoetin alfa dosing in 2019 patients with non-dialysis dependent chronic kidney disease, type II diabetes, and moderate anemia who were randomized to the placebo arm. The protocol specified that patients should be administered darbepoetin alfa when hemoglobin (Hb) levels were below 9 g/dL. Most patients (55%) did not receive darbepoetin alfa; however, darbepoetin alfa was administered once (16% of all patients), 2 to 4 times (16% of patients), and 5 or more times (13% of patients) during the 2.3 years of follow-up during the study; these doses may not have been consecutive doses. Generally, compared with patients who received 5 or more doses, the patients who required no darbepoetin alfa support had higher baseline Hb levels, higher glomerular filtration rates (GFRs), less proteinuria, and lower ferritin and tranferrin saturation levels, all indicators of a relatively heathier status. Lower baseline Hb, lower GFR, and higher proteinuria levels were found to be predictors for requiring 5 or more doses of darbepoetin alfa. Further, patients who required 5 or more doses typically received more intravenous iron and more transfusions during the follow-up period, further they were more likely to progress to dialysis. Lastly, patients who required 5 or more doses did not have an increased risk of death.  In summary, the authors found that most patients were able to maintain their Hb levels at or above 9 g/dL; long term erythropoiesis-stimulating agent use was not required.  Read more…

 
Hepcidin-25 is related to cardiovascular events in chronic haemodialysis patients

Authors: van der Weerd NC, Grooteman MPC, Bots ML, van den Dorpel MA, den Hoedt CH, Mazairac AHA, Nubé1 MJ, Penne EL, Wetzels JFM, Wiegerinck ET, Swinkels DW, Blankestijn PJ, ter Wee1 PM, CONTRAST Investigators*
Journal Citation:  Nephrol Dial Transplant. 2012; NDT Advance access published November 11, 2012. doi: 10.1093/ndt/gfs488
Link to Article    http://ndt.oxfordjournals.org/content/early/2012/11/11/ndt.gfs488.abstract

The authors describe a retrospective analysis of data from the CONvective TRAnsport STudy (CONTRAST, NCT00205556), looking at the relationship between baseline hepcidin-25 levels and outcomes after a median of 3 years of follow-up in 405 patients receiving chronic hemodialysis. Hepcidin-25 plays a role in iron homeostasis, and has been reported to be at elevated levels in hemodialysis patients. The authors analyzed the data using multivariate Cox proportional hazard models. During the follow-up period, 39% of patients died, and 32% of patients had a cardiovascular event. Baseline hepcidin-25 levels were associated with fatal and non-fatal cardiovascular events. The association remained even after adjusting for inflammation levels; inflammation was also a confounder in the examination of all cause mortality. One limitation of this study is that the analyses were based on baseline hepcidin-25 levels and there is high intrapatient variability in hepcidin-25 levels (Ford BA et al, Kidney Internat. 2010;78;769-773). Still the findings provide a unique observation that warrants further research:  the potential role for hepcidin-25 as a “novel determinant” of cardiovascular disease in this patient population. Read more…

Effect of Early Initiation of Dialysis on Cardiac Structure and Function: Results From the Echo Substudy of the IDEAL Trial

Authors:  Whalley GA, Marwick TH, Doughty RN, Cooper BA, Johnson DW, Pilmore A, Harris DCH, Pollock CA, Collins JF, IDEAL Echo Substudy Investigators
Journal Citation:  Am J Kidney Dis. 2012; Epub ahead of print doi:10.1053/j.ajkd.2012.09.008

The authors describe a cardiac substudy of the larger Initiating Dialysis Early and Late (IDEAL) study, a study examining whether starting dialysis earlier reduces the rate of death from any cause in people with stage 5 chronic kidney disease (CKD) (Perit Dial Int. 2004;24(2):176-81 and New Eng J Med. 2010;363:609-619. Australian New Zealand Clinical Trials Registry number, 12609000266268). In this study, starting early and late were defined as initiating dialysis when glomerular filtration rate (GFR) was between 10 and 14 mL/min/1.73 m2 and between 5 and 7 mL/min/1.73 m2, respectively; patients were randomly assigned to one of these treatment practices. As a reminder, this study did not detect any benefit with initiating dialysis earlier.

In this substudy, electrocardiograms were performed at baseline and at 12 months after randomization in 182 patients. No changes in cardiac structure and function were detected at 12 months, even in patients with advanced cardiac disease at baseline and regardless of when dialysis was initiated. The authors note these finding were similar to that observed for the larger study, wherein time of dialysis initiation had no notable impact on other clinical outcomes. Read more…

Randomized controlled trial of cholecalciferol supplementation in chronic kidney disease patients with hypovitaminosis D

Authors: Marckmann P, Hanne Agerskov H, Thineshkumar S, Bladbjerg EM, Sidelmann JJ, Jespersen J, Nybo M, Rasmussen LM, Ditte Hansen D, Scholze A.
Journal Citation: Nephrol Dial Transplant. 2012;doi:10.1093/ndt/gfs138. Advance access published July 20, 2012.

Summary
Marckmann et al describe an randomized, placebo-controlled, double-blind, parallel intervention study (NCT00968877; EudraCT: 2008-20090061) of the effects of vitamin D replenishment using 40,000 IU cholecalciferol orally that was conducted in 52 patients with chronic kidney disease, either on hemodialysis or not, being treated for 8 weeks at a single center.  This dose was based on the KDOQI guidelines. Patients had plasma 25-hydroxyvitamin D (25 OHD) levels < 50 nmol/L at screening. Treatment replenished 25-OHD levels in all patients, with patients not on hemodialysis also exhibiting improvements in plasma 1,25 dihydroxyvitamin D and lowering of parathyroid hormone levels.  However, patients also exhibited significant increases in serum calcium and serum fibroblast growth factor-23, signs of potential hypercalcemia.  These results indicate that hypovitaminosis D can be reversed in patients with CKD, regardless of whether they are on hemodialysis or not, but so treated patients also need to be monitored for hypercalcemia. No non-classical effects were observed with treatment, unlike some other small studies.
This study highlights the importance of prospective trials actually being conducted in the dialysis unit as it adds to the clinical importance of the results.  Moving forward, it is increasingly important for dialysis units to be able to conduct analytics on their data to support these types of trials.  Read more…

Effects of Phosphate Binders in Moderate CKD

Authors: Block GA, Wheeler DC, Persky MS, Kestenbaum B, Ketteler M, Spiegel DM, Allison MA, Asplin J, Smits G, Hoofnagle AN, Kooienga L, Thadhani R, Mannstadt M, Wolf M, Chertow GM
Journal Citation:  J Amer Soc Nephrol. 2012;23: doi: 10.1681/ASN.2012030223. Published online before print July 19, 2012,

Summary
The authors describe a single center, placebo-controlled randomized clinical trial to examine the effect of phosphate binders in 148 patients with moderate chronic kidney disease (CKD; GFR = 20-45 ml/min per 1.73 m2) over 9 months. Three phosphate binders were included in the study: calcium acetate, lanthanum carbonate, and sevelamer carbonate.  Phosphate binders attenuated the progression of secondary hyperthyroidism as evident by significantly decreasing both mean serum and mean 24-hour urinary phosphorus levels, whereas both medium serum intact parathyroid hormone and plasma C-terminal fibroblast growth factor 23 levels remained stable in this population.  Patients receiving phosphate binders, however, did exhibit increased calcification of both the coronary arteries and the abdominal aorta, regardless of whether the binder contained calcium. Further, the authors note that the affect on serum phosphorus levels was modest, perhaps suggesting that it may not be the best marker of phosphate binder effect.
It is interesting to note how the results of this study differ from those of previous randomized, controlled trials and of unadjusted observational data in the CKD population. The increased vascular calcification in the intervention arm, both with calcium and non-calcium containing phosphate binder was a surprising observation, which the authors speculated may have arisen due to previously unreported effects on free intestinal calcium.  Findings from this study certainly are hypothesis generating given the implications of its findings regarding use of phosphate binders in dialysis patients. Read more…

Troponin T for the Detection of Dialysis-induced Myocardial Stunning in Hemodialysis Patients

Authors: Breidthardt T, Burton JO, Odudu A, Eldehni MT, Jefferies HJ, McIntyre CW
Journal Citation: Clin J Amer Soc Nephrol. 2012; 7:doi: 10.2215/CJN.00460112. Published ahead of print July 19, 2012

Summary
In this single-center observational cohort study, the authors examine the association between troponin T and the occurrence of myocardial stunning at baseline and after 12 months in 70 prevalent hemodialysis patients receiving dialysis 3-times a week. At baseline, 64% of patients had myocardial stunning, and these patients had significantly higher predialytic troponin T levels compared with patients without myocardial stunning.   After 12 months, when 12 of the 70 patients were not available for follow-up, 9 additional patients had myocardial stunning and statistically significant increases in troponin T levels compared with baseline.  Based on this and additional analyses (both receiver operating characteristic analyses and multivariate analyses) the authors conclude that troponin T levels were statistically significant indicators of myocardial stunning – both in terms of presence and severity.
This research highlights the importance of biomarkers, in this case troponin T, may play in predicting the adverse events among the prevalent hemodialysis population.  Once biomarkers such as these are validated, they may serve to aide nephrologists in individualizing the treatment options to their parents.  Further, these results highlight the importance of predictive analytics in this patient population. Read more…

Inflammation and the Paradox of Racial Differences in Dialysis Survival

Authors: Deidra C. Crews, Stephen M. Sozio, Yongmei Liu, Josef Coresh, and Neil R. Power

Journal Citation: J Am Soc Nephrol 22: , 2011. DOI:  10.1681/ASN.2011030305

Summary

In this prospective study, Crews et al examined the relationship between inflammation and the apparent differences in survival rates between African-Americans and all patients who have end-stage renal disease (ESRD). An apparent inverse relationship exists for African-Americans who develop ESRD. Although the number of African-Americans with ESRD is higher than the general population (32% vs. 12%), African-Americans have a lower mortality rate than the general population (16% vs. 24% for Caucasians). Investigators wanted to study whether or not inflammation, as measured by C-Reactive Protein (CRP), a common marker for inflammatory conditions, is associated with this phenomenon.
The authors observed 554 Caucasian and 262 African-American patients with incident dialysis across 81 clinics for a median 3-year period, with the actual periods of observation ranging from 4 months to 9.5 years. Overall, they found no significant differences in the CRP levels between the 2 patient populations (Americans and Caucasians (3.4 mg/L in African-Americans compared with 3.9 mg/L in Caucasians). However, there was an observed difference in mortality at 5 years:  34% in African Americans vs. 56% in Caucasians, even when adjusted for confounding factors such as age, sex, diabetes, and comorbidities. Notably, the investigators did find differences in survival based on the CRP levels, with no difference in patients who had low CRP (relative hazard ratio = 1.0) but a significant difference in patients with high CRP (relative hazard ratio = 0.5). Thus, the investigators concluded that inflammation may be a possible factor in improved survival rates for African-Americans with ESRD, but that this may be dependent on the level of inflammation observed in the patient.

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Cardiac Biomarkers and Prediction of ESRD

Authors:   Susanne B. Nicholas

Journal Citation:   Am J Kidney Dis. 2011;58(5):689-691. DOI:  10.1053/j.ajkd.2011.08.013

Summary
In this editorial, Susanne Nicholas (UCLA) reviews the prospect of using biomarkers as prognostic and diagnostic tools in the treatment of kidney disease. In particular, she examines results of 2 biomarkers, troponin T (TnT) and N-terminal pro–B-type natriuretic peptide (NT-pro-BNP), from several clinical trials, including the large-scale TREAT and CRIB studies. These biomarkers are normally associated with cardiovascular complications but may also be of value as prognostic indicators of morbidity and mortality in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD). Dr. Nicholas makes a strong argument for recognizing the strong association between cardiovascular and kidney diseases, concluding that “based on the evidence that cardiovascular risk may contribute to CKD risk, targeting cardiovascular disease prevention may potentially target CKD prevention as well.”

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Sudden Cardiac Arrest and Sudden Cardiac Death on Dialysis: Epidemiology, Evaluation, Treatment, and Prevention

Authors:   Martin A. Alpert

Journal Citation: Hemodialysis International 2011; 15:S22–S29

Summary

One of the most common causes of death among dialysis patients is cardiac disease, which can account for up to 50% of deaths observed. In this comprehensive review, Martin A. Alpert (University of Missouri) discusses in detail the problems associated with sudden cardiac death in dialysis patients. He outlines the epidemiologic, diagnostic, treatment, and prevention options for dialysis patients at risk of developing these types of cardiovascular comorbidities.

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Erythropoietin-stimulating Agents in Chronic Kidney Disease:
A Response to Hyporesponsiveness

Author: Patrick S. Parfrey
Journal Citation: Seminars in Dialysis—2011. DOI: 10.1111/j.1525-139X.2011.00949.x

Summary

As the debate around the use of ESAs and anemia treatment continues, one of the main issues under discussion is the hyporesponsive reactions to ESAs in certain patients. In this timely editorial, Dr. Patrick Parfrey of Memorial University in Newfoundland, Canada shares his opinions on the possible causes of ESA hyporesponsiveness and some treatment options. Parfrey’s participation in the major clinical studies assessing ESAs in different patient populations, including the Normal Hematocrit Trial, TREAT, and the Canada‑Europe Trial, gives him a wealth of experience from which to make his recommendations. He suggests that there is a relationship between ESA hyporesponsiveness and an increased risk of cardiovascular events. Rather than any particular ESA being the cause, Dr. Parfrey’s opinion is that this relationship may be due to associated co-morbidities as well as the overall general toxicity of ESAs. He concludes with 3 specific recommendations for treating patients who are hyporesponsive to ESAs:

1.      Determining the cause of the hyporesponsiveness

2.      Personalizing the anemia treatment based on the indications of treatment

3.      Controlling the ESA dosage

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Long interdialytic interval and mortality among patients receiving hemodialysis

Authors: Robert N. Foley, David T. Gilbertson, Thomas Murray, and Allan J. Collins
Journal Citation: N Engl J Med 2011; 365:1099-1107

Summary

For dialysis patients undergoing thrice-weekly hemodialysis sessions, a serious concern has always been deviations from normal metabolic and fluid ranges, which may cause cardiovascular complications. One potential source of such variations is the longer interval (2 day versus 1 day interval) between some hemodialysis sessions. In this study of 32,065 patients in the End-Stage Renal Disease Clinical Performance Measures Project, Foley et al assessed the adverse events associated with death and cardiovascular-related hospitalizations between different interdialytic intervals.

Investigators conducted a retrospective analysis of data from a 3-year period, 2005 through 2008, searching for events that occurred on the day of a hemodialysis session after a 2 day interdialytic interval compared with those events that occurred on other days of the week. They reviewed the databases for differences in overall mortality, cause-specific mortality (including cardiac arrest, withdrawal of treatment or uremia, myocardial infarction, septicemia, and stroke), cardiovascular-related hospitalizations, a composite of first hospitalization for cardiovascular related complications, and the individual cardiovascular-related components of the first hospitalization composite.

Patients in this study averaged 2.2 years on dialysis, with 24.2% having received hemodialysis for < 1 year. Investigators found statistically significantly (p < 0.05) higher rates associated with the 2-day interdialytic interval in most of the variables, including all-cause mortality (22.1 versus 18.0 deaths/100 person-years), admissions for myocardial infarction (6.3 versus 3.9), and any cardiovascular event (44.2 versus 19.7). Based on these observations, the investigators concluded that “the long (2-day) interdialytic interval is a time of heightened risk among patients receiving dialysis.”

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Genomics, Health Care, and Society

Authors :  Kathy L. Hudson
Journal Citation:    N Engl J Med 2011; 365:1033-1041

Summary

In this timely review, Dr. Kathy L. Hudson, the Deputy Director for Science, Outreach, and Policy at the National Institutes of Health, assesses a myriad of issues related to the evolving trend of using genetics and genomics in personalized clinical practice. She discusses policies related to “genetic and genomic research, the integration of genetics into clinical care, and the broader issues raised by genetic technologies and information.”

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