Experts Explore Role of ESAs Beyond Making Red Blood Cells

For 20 years, the use of erythropoiesis-stimulating agents (ESAs) has improved the health and quality of life for patients with chronic kidney disease (CKD) while reducing the need for blood transfusions. By replacing erythropoietin, a protein made by the kidneys but deficient when the kidneys fail, ESAs help correct the anemia of CKD by stimulating the bone marrow to produce more red blood cells.

Therapy has always been a balancing act. Physicians must weigh the amount of ESA to use, providing enough iron to meet the body’s needs for red blood cell production and setting and achieving hemoglobin goals. Another goal is to balance benefits and risks of ESAs’ nonhematologic effects in the body, effects that are increasingly coming into view through clinical experience and research. Recent studies indicate that more is not always better. A higher hemoglobin level can present problems, and negative outcomes may be related to a multitude of factors, possibly including high doses of ESAs themselves.

Besides their use in CKD, ESAs are also approved for treating the anemia related to cancer chemotherapy. Here, too, their optimal use is still being worked out.

“The mechanism of why some patients fare poorly, I don’t think we understand very well,” said Murat Arcasoy, MD, associate professor of medicine in hematology and oncology at Duke University Medical Center in Durham, N.C. “My feeling is that it’s probably not just the hemoglobin causing adverse effects and potential for decreased tumor responses.”

Typical therapeutic doses of ESAs are much higher than the body’s natural levels, said Anatole Besarab, MD, director of clinical research in the division of nephrology and hypertension at the Henry Ford Health System in Detroit, Mich. “Pharmacological levels where you reach 1, 2, 3, 4 milliunits per mL are concentrations log orders higher than anything that the body normally sees, but that’s part of our problem,” he said during the American Society of Nephrology’s Renal Week in November 2008.

Erythropoietin (Epo) has a multitude of functions and effects besides red blood cell production, or erythropoiesis. In fetal development, it aids brain development and blood vessel formation. A lack of Epo causes fetal death. In the adult, it has the potential to protect tissues, with possible applications in myocardial ischemia, heart attack, stroke, spinal cord injury, wound healing, other conditions of ischemia (lack of blood flow to a tissue), trauma, toxic exposure, inflammation, pathologic blood vessel formation (angiogenesis), and autoimmunity.

Tissue Protective Mechanisms

Epo may have therapeutic potential as a tissue protective agent, Besarab said. Administration of a single dose of recombinant human Epo decreased the degree of infarction to about one-quarter of that in saline-treated controls, he said. In addition, Epo markedly decreased tissue apoptosis. And even when given to rats three weeks after tying off a coronary artery, it induced VEGF, an angiogenic protein that resulted in capillary growth.

Similar effects can occur in the brain. “I think what’s important is what’s going on in the vasculature. We don’t spend enough time about this particular role of Epo, and it can cause proliferation and migration” of cells, he said. He warned that different ESAs may stimulate vessel cells to different degrees, “and it is dose dependent.”

Clinical Implications and Potential

In terms of possible beneficial effects besides red cell production, “the area of research that is most mature at this point in time is the potential neurologic [protective] effect of the medication,” Arcasoy said. In a small study of stroke patients conducted by Ehrenreich and colleagues at the Max-Planck-Institute for Experimental Medicine of the Georg-August-University in Goettingen, Germany, recombinant human Epo or saline placebo was administered for three days to 40 patients, beginning within eight hours of an ischemic stroke.

At one month, the patients who received the active drug had greater improvement on neurologic outcome scales and a “strong trend for reduction in infarct size…compared to controls.” Patients who received the drug had Epo levels in their cerebrospinal fluid that were 60 to 100 times greater than in the saline control group, indicating that Epo reached the brain, suggesting a possible direct effect of the drug on the brain and not just an increase in red blood cell numbers.

The dilemma is to balance the beneficial effects of ESAs with possible detrimental effects, Arcasoy and Besarab said. In stroke, ESA’s tissue protective effects could be offset by increases in red cell mass, increased blood pressure, and an increased propensity for blood clots.

A similar concern exists for the use of ESAs in cancer patients. A side effect of chemotherapy can be anemia, and while giving an ESA may correct the anemia, the potential exists for it to stimulate some tumors.

Another potential concern is stimulating blood vessel formation in the retina of CKD patients with diabetes, a population that often develops retinal problems. Yet in certain situations, Epo can be protective, Arcasoy said.

Lois Smith, MD, PhD, and colleagues at Harvard demonstrated both protective and harmful effects of Epo administration using an animal model and manipulating the amount of oxygen that the retina was exposed to. A critical factor was the timing of Epo administration. So, again, the picture is far from clear, and not only are doses important but so may be the timing of Epo administration.

“Even for the approved indications, we don’t really know optimally how to give the drugs, whether we should use hemoglobin as the target [or] whether we should have other outcome measures,” Arcasoy said. “Typically hemoglobin has been measured, but at least in the renal literature, higher doesn’t necessarily mean better.”

In one trial, Linda Szczech and co-workers at Duke University Medical Center found that significantly more patients randomized to a higher hemoglobin target group were unable to achieve the higher target level and required high-dose Epo compared with patients randomized to a low hemoglobin target. They were also at greater risk of death, heart attack, congestive heart failure, or stroke. However, those patients who did achieve the target level had better outcomes than those who did not, and there was no increased risk associated with the higher hemoglobin goal. The work was conducted as part of a secondary analysis of the Correction of Hemoglobin in the Outcomes in Renal Insufficiency (CHOIR) trial.

The mechanisms of harm with more intensive ESA treatment are not clear. But one approach is to correct the factors that may limit responsiveness to ESAs, possibly allowing lower doses to be used to achieve target hemoglobin levels. Steven Fishbane of the department of neurology at Winthrop University Hospital in Mineola, N.Y., reported on the experience of a group of dialysis clinics in Berlin that “achieved outstanding patient outcomes” while targeting normal hemoglobin levels.

The study addressed ancillary factors such as intensive cardiovascular and antihypertensive treatment, treatments to optimize oxygen utilization (e.g., correction of metabolic acidosis, supplementation with L-carnitine, folic acid, and vitamins B6 and B12), maintainence of sufficient iron stores, and avoidance of excessively high ESA doses. Patients required considerably lower doses of ESA in the Berlin centers than what is typical in the United States, Fishbane said. “This is likely a result of intensive iron treatment and improved ESA responsiveness,” he said. “The reduced ESA dose requirement could relate to the excellent patient outcomes.”

Support for this idea comes from a study by Zhang and colleagues at the Medical Technology and Practice Patterns Institute in Bethesda, MD. Zhang’s group found that ESA dose was an independent predictor of mortality in their study of more than 90,000 hemodialysis patients.

The Berlin results are in contrast to large randomized clinical trials (RCTs) that found trends toward worse outcomes with higher hemoglobin targets. Given the sample sizes, the RCTs carry more weight, Fishbane said. Nonetheless, the Berlin experience demonstrated the possibility of achieving excellent clinical outcomes while maintaining full hemoglobin correction (13.5–14.5 g/dL), he noted. In addition, patients had significant improvements in several measures of cardiac function.

More work is needed to understand the mechanisms of ESA resistance in CKD patients that lead to the need for higher doses associated with adverse effects, Arcasoy said. “We can think about ways to avoid causing problems for our patients if we understand the mechanisms.”

Arcasoy suggested that discovering parameters that predict ESA resistance would be helpful. As in the Berlin experience, correcting the factors that are modifiable could increase patients’ responsiveness to ESAs. For those factors that are not modifiable, “can we select patients who will fare better with ESA therapy?” he asked. The final question would be whether that approach would translate into a patient benefit.