By Peter Laird, MD
Erythropoietin (EPO) is a natural hormone that mediates the production of red blood cells (RBC's) that is primarily produced in the renal cortex and small amounts in the liver. Studies over the last decade evaluated the effects of EPO in diverse populations at risk of anemia outside of the renal dialysis patients, especially in patients undergoing chemotherapy for a variety of cancers. Unfortunately, these studies revealed adverse survival with more rapidly progressive cancers and shortened survival. In addition, in the CKD population, patients were more likely to experience cardiovascular events and death bringing the CHOIR study to an early close as well. The TREAT trial followed shortly with a higher risk of stroke for patients treated with EPO for CKD related anemia.
Many patients sustained with EPO for years on dialysis vocally protested the new FDA labelling changes and the removal of minimum Hb levels in the QIP. Despite the increased risk of cardiovascular outcomes with EPO and the suspected increased cancer risk for chemotherapy trials, the correction of anemia for many patients overcame the potential risks. However, a new study highlighed by Gary Peterson of RenalWEB sheds light on the role of EPO not only in promoting cancer, but it is actually involved in the development of cancers as well:
At the molecular level, we show that the PDGF-BB–PDGFR-bβ signaling system activates the EPO promoter, acting in part through transcriptional regulation by the transcription factor Atf3, possibly through its association with two additional transcription factors, c-Jun and Sp1. Our findings suggest that PDGF-BB–induced EPO promotes tumor growth through two mechanisms: first, paracrine stimulation of tumor angiogenesis by direct induction of endothelial cell proliferation, migration, sprouting and tube formation, and second, endocrine stimulation of extramedullary hematopoiesis leading to increased oxygen perfusion and protection against tumor-associated anemia.
Blood protein EPO involved in origin and spread of cancer
Angiogenesis is the formation of new blood vessels from pre-existing ones, and is one of the most important research fields in the treatment of such diverse conditions as cancer, metastases, obesity, heart disease, stroke, diabetes and chronic inflammation. The process is also important in healthy individuals for wound healing, the menstrual cycle and other normal processes. Professor Yihai Cao and his team are researching into angiogenesis and its links to cancer and other diseases, and in the present study show the significant role played by a growth factor, PDGF-BB.
"It's a member of the PDGF family and significantly contributes to blood vessel development, which is one of the characteristic signs of cancer, says Professor Yihai Cao. Our preclinical findings suggest that PDGF-BB causes systemic effects in the body, which is to say that rather than being active locally it goes into the blood and interferes with the function of several organs so that the entire body is affected."
As a cancer survivor in addition to my IgA nephropathy and dialysis, I have been very leery of EPO right from the time I first started on dialysis in 2007. My first confrontation with my health care team at dialysis came about when I refused to continue EPO shortly after beginning dialysis. In retrospect of current guidelines, I never needed EPO with a Hb over 12.0 with only iron infusions alone. The issue of adverse cardiovascular outcomes and now this new basic science information that EPO is involved in cancer formation leaves dialysis patients with hard choices. EPO prevents the need for blood transfusions and their associated complications, but at what price?
The for-profit dialysis industry made billions of dollars pushing higher and higher dosages of EPO to their patients prior to the bundle. The cardinal duty of physicians is to first do no harm. As we evaluate each and every aspect of dialysis care in America, it keeps coming up short every time. The irony is that we are spending billions of dollars for a genetically engineered medicine that is supposed to reduce pain, suffering and enhance our lives. Instead, the evidence is mounting on the dangers of EPO. The debate will continue especially since many dialysis patients fail to respond to iron supplementation alone. Blood transfusions for many are an unacceptable rescue method. In an era of uncertainty, EPO may be too risky to justify it's continued use. Adding the risks of cardiovascular disease and cancer together may render the issue of informed consent between doctor and patient on whether to use EPO instead in the hands of the FDA and further black box warnings.
EPO is wonderful medicine if used properly. The average dosage in my unit is about 6000 units per patient and week. Most of the patients receive intravenous iron. Average hemoglobin is about 10,8. I don´t believe cancer risk is increased in my patients by this amount of erythropoetin. But the consuption of EPO is much higher due to historical payments in your country.
Patient with HB over 10.0 has never been treated with EPO, unless he or she suffers from ischemic symptoms.
But I can remember the very poor quality of life in the ancient time, when my patients used to have Hb abouT 7.0 and reapeated transufusions were administered, because EPO was not available.
Posted by: Roman Kantor | Thursday, December 08, 2011 at 01:59 PM