Heavy Metal

Aug 22 2010 Published by under [Medicine&Pharma]

Once upon a time in nephrology, iron killed people. Today, it seems patients with kidney disease cannot get enough.

Iron marches on

What changed?

1950-1989

As dialysis became the standard of care for patients with end-stage kidney failure, it soon became obvious that the kidney was important in maintaining red blood cell mass in the body. Erythrocytes or red blood cells carry oxygen to the tissues; when lacking, patients have anemia. The kidneys provide most of the erythropoeitin in the body, the hormone that tells the bone marrow to make erythrocytes.

While dialysis kept patients with kidney failure alive, it could not produce erythropoeitin. Patients required periodic transfusions to avoid severe anemia. Soon it became clear that these infusions of red blood cells were also problematic. Many patients had a build-up of iron in various organs. Hemosiderosis could produce life-threatening toxicities in the heart and liver. To avoid these fatal complications, transfusions were withheld until hemoglobin levels fell quite low, to less than 8 g/dL (lower limit of normal 12-13 usually). If dangerous levels of iron accumulated, agents could be used to chemically bind and attempt to clear the iron with dialysis.

The Science of EPO

Work in the 1970s suggested that the kidneys made a hormone that controlled red blood cell production. The molecular structure of erythropoeitin (EPO) was eventually ascertained, and by 1985 production of the recombinant human hormone was underway. It received FDA approval for the treatment of anemia of end-stage renal disease in 1989.

1989-present

A PubMed search shows that from 1950-1988 there were 702 publications when the terms "iron" and "dialysis" are searched. These focused on treatment of iron overload and various regimens for chelation therapy. When these same terms are searched from 1989 through the present, 2004 articles are found which focus on achieving adequate iron stores.

The majority of patients on chronic dialysis receive hemodialysis, in which blood is run through a pump-driven filter and returned to the body. Small amounts of blood are lost each time a treatment occurs, generally 3 times each week. Once EPO became available, this blood loss became critical. Patients often did not have the stores of iron to respond to EPO. Giving sufficient oral iron to overcome these losses is often impossible; gastrointestinal symptoms and interactions with other drugs get in the way.

Transfusion would be one way to get iron in intravenously; however, then the patient is exposed to the risks of blood. Intravenous iron preparations were dusted off for a new market. Iron cannot be given parenterally; the toxic iron molecule must be coated by a carbohydrate of some sort to prevent fatal toxicity. A number of preparations are on the market, with more on the way.

Clinical Guidelines

Anemia treatment guidelines for chronic kidney disease are undergoing revision; the new statement should be available in 2011.

For now, target hemoglobin levels are 11-13 g/dL; higher levels have been associated with excessive cardiovascular mortality. Transferrin saturation levels should be >20% for all dialysis patients, and ferritin levels should be >100 ng/mL for peritoneal dialysis patients who have minimal ongoing blood loss. Hemodialysis patients should have ferritin levels >200  but <500 ng/mL to allow optimal response to EPO.

Personal Thoughts

I began my nephrology training in 1988, just before the approval of EPO. I saw the ravages of iron overload in my patients. Then EPO came along, and we could not only treat anemia without life-threatening complications, but we could also normalize hemoglobin levels. Patients felt much better, even though most claimed to "feel fine" at hemoglobin levels of 8 or 9.

I never imagined the volume of ads I would eventually see for iron products in my journals. The story of iron provides further proof that physicians have to remain life-long students, able to adjust to the changing body of medical knowledge.

Image courtesy of PhotoXpress.

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