Association Between Serum Albumin and Erythropoietin Sensitivity in Hemodialysis Patients

Recent studies have indicated that higher target hemoglobin (Hb) levels are associated with an increased risk of mortality in patients with chronic kidney disease. Use of high erythropoietin (EPO) doses has been suggested as one factor that might be involved in these observations. A variety of factors appear to influence EPO sensitivity and responsiveness, including iron sufficiency, blood loss, adequacy of dialysis, infection, and inflammatory disorders. Several markers of inflammation have been associated with EPO responsiveness. By analyzing these markers, clinicians may be able to make predictions concerning EPO sensitivity or responsiveness in hemodialysis patients. Recently, a study hypothesized that the changes in white blood cell (WBC) count and serum albumin levels-along with other experimental biomarkers such as monocyte chemoattractant protein 1 (MCP1) and malondialdehyde (MDA)-could predict EPO sensitivity.

In the study, several potential markers of ESA sensitivity - WBC count, serum albumin concentration, levels of MDA and MCP1, and tests of iron status and their changes over time, as well as ESA dose and iron therapy - were recorded over a 3-month period in a population of 82 prevalent hemodialysis patients (mean age 53.3 years). Using a series of covariance models with various fixed parameters, the results showed that patients with higher Hb levels also had higher levels of serum albumin and vice versa. Serum albumin was also a significant predictor of baseline Hb and EPO sensitivity. However, no independent relationships were found between WBC count, MCP1, or MDA levels and EPO sensitivity. Tests of iron sufficiency and use of intravenous iron therapy were also not predictive of EPO responsiveness.

The significant relationship between serum albumin levels and EPO sensitivity is an important finding because albumin is an excellent marker of overall health for patients undergoing dialysis. Observations of increased serum albumin concentrations may indicate improving infection, inflammation, oxidative stress, and nutrition. Clinicians may be able utilize serum albumin as a routine, bedside tool to determine if decreases in Hb are caused by infection, inflammation, or other factors. Future clinical trials on EPO responsiveness with stratification of patient populations according to this biomarker may allow for a better understanding of modifiable risk factors that arise during hemodialysis.

Please reference the source article:
Serum albumin is strongly associated with erythropoietin sensitivity in hemodialysis patients. Agarwal R, Davis JL, Smith L. Clin J Am Soc Nephrol. 2008 Jan;3(1):98-104.

NAAC Expert Commentary:
Much recent research and commentary has focused on outcomes associated with specific Hb target levels (1,2), causes and consequences of Hb variability (3,4), and the relationships between markers of inflammation or nutrition and responsiveness to erythropoiesis stimulating agents (ESAs) and other clinical outcomes (5,6) in patients with CKD. Retrospective, observational cohort studies derived from large administrative data bases, showed us that higher achieved Hb levels in hemodialysis patients were associated with better outcomes (i.e. mortality and hospitalizations) and lower Hb levels with poorer outcomes (7,8). We now have evidence from prospective clinical trials in hemodialysis patients (9) and patients with CKD who are not on dialysis (1,2) that targeting higher Hb levels does not result in better outcomes, and in fact may cause higher mortality risk. The reasons for this are not yet entirely clear. What is emerging is a picture of complex and as of yet still poorly understood interactions between achieved Hb level, nutritional status, inflammatory responses, ESA responsiveness, ESA doses used to achieve (or attempt to achieve) targeted Hb levels, Hb variability, and iron therapies that are intertwined with individual patient characteristics and impact clinical outcomes. It does seem that using ESAs with the intent of achieving the same Hb level in all CKD and dialysis patients is neither possible nor advisable.

In this study by Agarwal et al, all of the patients received erythropoietin (EPO) subcutaneously. There was a relatively high proportion of patients dialyzed with catheters (36%) while use of fistulas was infrequent (27%). Although the authors suggest that patients with extremes of Hb levels tended to have greater Hb variability than those in the middle, this should be treated as a preliminary observation requiring further study and if real, is likely due mostly to efforts to raise the Hb in those with low baseline levels and reduce the Hb in those with high baseline levels. In modeling the relationship between all study parameters and changes in Hb during the 3 months of the study, baseline EPO dose, EPO dose over time, baseline serum albumin, serum albumin over time, and baseline WBC count were predictors of Hb change. After accounting for EPO dose, only serum albumin was related to baseline Hb and predictive of the 3-month change in Hb. As has become reported previously, serum ferritin and transferrin levels were poor predictors of Hg changes (TSAT was not studied).

As the authors suggest, these results might be relevant to patient care because changes in serum albumin may help anticipate changes in ESA responsiveness and provide clues as to the cause of changes in Hb levels. An increasing serum albumin might be used to anticipate an increase in ESA responsiveness and trigger a reduction in ESA dose. A fall in Hb associated with a low or declining albumin suggests an inflammatory and/or infectious process is present, while a fall in Hb with a normal or increasing albumin would be more suggestive of blood loss or iron insufficiency. Recognizing that clinical outcomes in individual patients are perhaps related more to patient-specific factors that influence changes in Hb, serum albumin, and ESA responsiveness than the absolute Hb level itself may help us get out of the trap of mindlessly increasing the ESA dose in hyporesponsive patients in pursuit of a specific Hb level and allow us to focus more on what is actually happening with our patients.

References:

1. Drueke TB, et al. N Engl J Med 2006; 355:2071-84.
2. Singh AK, et al. N Engl J Med 2006; 355:2085-98.
3. Berns JS, et al. Kidney Int 2003; 64:1514-21
4. Brunelli SM, et al Clin J Am Soc Nephrol 2008; 3: 777-82.
5. Locatelli F, et al. Nephrol Dial Transplant 2006; 21: 991-8.
6. Kalantar-Zadeh K, et al. Am J Kidney Dis 42: 761-73
7. Xia A, et al. J Am Soc Nephrol 1999; 10:1309-16.
8. Collins AJ, et al. J Am Soc Nephrol 2001; 12:2465-73.
9. Besarab A, et al. New Engl J Med 1998; 339:584-90.

Darbepoetin Alfa Treatment For Patients With Symptomatic Heart Failure And Anemia

Anemia is common in patients with heart failure and has been shown to be an independent risk factor for severe symptoms in heart failure patients, such as lower functional status, worse exercise capacity, cognitive impairment, and worse quality of life. Because of the detrimental impact of anemia on these patients, anemia has become an important target for heart failure therapy.

Preliminary studies have demonstrated that erythropoiesis-stimulating agents (ESAs) may improve exercise capacity and cardiac and renal function in heart failure patients. Although the studies were not designed to be conclusive, the evidence from preliminary studies suggests that treatment of anemia may lead to improved outcomes in heart failure patients.

The Study of Anemia in Heart Failure Trial was designed to test the efficacy of using a long-acting ESA, darbepoetin alfa, to treat patients with heart failure in a multicenter (65 centers), double-blind, randomized, placebo-controlled, phase II study. Patients in the treatment arm received darbepoetin alfa subcutaneously every two weeks for a total of 52 weeks. The primary endpoint was the change from baseline to week 27 in treadmill exercise time. Secondary endpoints consisted of the change from baseline to week 27 in (1) New York Heart Association functional classification and (2) health-related quality-of-life, measured by the Minnesota Living with Heart Failure Questionnaire. One-year analysis of all cause mortality was also conducted.

The study cohort consisted of 157 patients receiving placebo and 162 patients receiving darbepoetin alfa. Transient ischemic attacks occurred in four patients in the darbepoetin alfa group compared with one in the placebo group. However, patients not treated with darbepoetin had a higher number and frequency of worsening heart failure episodes compared to the placebo group. In 85% of patients treated with darbepoetin alfa, two consecutive hemoglobin levels of 14.0 +/- 1.0 g/dL were achieved, and patients experienced >1.0 g/dL increase in Hb level from baseline.

Neither the exercise capacity nor quality-of-life improved significantly in patients receiving darbepoetin alfa compared with placebo. However, a nonsignificant trend was observed toward a lower risk of all cause mortality or first heart failure hospitalization in patients treated with darbepoetin (hazard ratio, 0.68; 95% CI, 0.43, 1.08; P=0.10).

Please reference the source article:
Randomized double-blind trial of darbepoetin alfa in patients with symptomatic heart failure and anemia. Ghali JK, Anand IS, Abraham WT, Fonarow GC, Greenberg B, Krum H, Massie BM, Wasserman SM, Trotman ML, Sun Y, Knusel B, Armstrong P; Study of Anemia in Heart Failure Trial (STAMINA-HeFT) Group. Circulation. 2008 Jan 29;117(4):526-35.

NAAC Expert Commentary:
The risk of death in heart failure patients increases roughly 12% for each g/dL decrease in Hb level. Whether anemia is merely a marker or a mediator of the risk is uncertain. STAMINA-HF is the first of several clinical trials designed to test the hypothesis that correction of the anemia in heart failure patients will obviate the risk of death associated with anemia. In this trial, patients who were iron replete (iron saturation ?15%) received darbepoetin alpha to correct the anemia. Darbepoetin alpha increased the Hb level by approximately 1.5 g/dL. However, the trial failed to show improvements in heart failure signs and symptoms, or exercise performance. Nevertheless, a post hoc analysis did suggest that patients who had an increase in Hb level, regardless of therapy, had a greater increase in exercise duration. The trial also found a strong trend for survival free of hospitalization at 1 year (hazard ratio 0.68, p=0.10). There was a nonsignificant reduction in mortality (44%) and heart failure related hospitalization (26%).

Treatment with ESAs has come under scrutiny because of association with potential increases in mortality in patients with chronic kidney disease and cancer. Treatment to higher versus lower Hb levels in patients with chronic kidney disease has been associated with harm. However, in this study of patients with heart failure, the trend was the opposite, and results even suggested a potential benefit. Importantly, thrombotic events (MI, TIA, CVA, PE, or DVT) were similar with darbepoetin (7%) and placebo (7%).

Treatment of anemia in heart failure is being approached by two different therapies: intravenous iron or ESA. When the results of these clinical trials are available, we will know if anemia should be treated in heart failure patients and the benefit of these two alternative approaches. It is likely that many heart failure patients will require treatment with both ESA and intravenous iron to correct the anemia as is the current standard for chronic kidney disease patients. We await the results of clinical trials in heart failure patients to determine when we should treat anemia, how to treat it, and what target Hb levels are appropriate. In the mean time, each provider will need to decide how best to treat anemia in heart failure patients.