K is for kidney, also Kalamazoo

(An attendee at my talk this week reminded me about the somewhat sketchy history of synthetic erythropoietin.  Aside from its use as an athletic doping agent, I was only vaguely aware of other controversies, including allegations of kickbacks.  I’m excited and horrified to have the chance to read up on this. –PalMD)

A man came to see me in the office recently for a host of problems, especially weight loss, weakness, and fatigue which had become progressively worse over the previous months.  On physical exam, he appeared pale, but there were no outward signs of ongoing blood loss.  As part of the evaluation, I sent his blood off for some specific tests.  His blood count was low.  He had slightly low iron levels, which together with the low blood count suggested he might be slowly losing blood from somewhere.   In men his age, that somewhere is usually the colon, and often due to a colon cancer. (He was also not taking any medicines that might cause stomach ulcers.)  Thankfully, no cancers were found when he underwent a colonoscopy.  I gave him iron supplements, bringing his iron levels to normal, but he remained anemic, with no other blood abnormalities.

Another laboratory finding was reduced kidney function.  Red blood cells are produced in the bone marrow under the control of a hormone called erythropoietin (EPO).  EPO is made in the kidneys, and less kidney tissue equals less EPO. Like most hormones, EPO is regulated by feedback. Normal kidneys produce proteins that aid in the production of EPO, but in the presence of sufficient oxygen, these proteins are broken down rapidly.  As oxygen levels drop, these “transcription factors” are not broken down as quickly, and more EPO is produced.  The EPO travels to red blood cell precursors, telling them to become mature red blood cells.  More red blood cells means better oxygen delivery, which cuts back on EPO production.  But even at low oxygen levels if there isn’t enough kidney tissue, there isn’t enough EPO to tell the marrow to make red blood cells.  Patients with chronic kidney disease will all eventually become anemic.  That’s some fascinating science.

Having grown up near Detroit and having lived in Chicago, I’ve driven by Kalamazoo countless times, but I’ve never stopped there—until today. Today begins the annual meeting of the Michigan chapter of the American College of Physicians.  The meeting is part of the apparatus that keeps doctors up to date.  I was asked by my hospital to help out with one of the learning sessions.

To maintain my status as a board-certified internist, I must participate in the American Board of Internal Medicine’s Maintenance of Certification process.  This process culminates in the board exam, which is taken every ten years.  Leading up to the exam are mandatory learning modules, some of which are a bit like board questions.   For this meeting, I’ve been given a set of these questions (but not the answers) to present as teaching tools.

The first question that I’ll be presenting is about anemia in chronic kidney disease (CKD), which turns out to be a great example of the way science-based medicine works.   To know how to approach a medical problem requires asking the right questions. First, is the anemia of CKD even a problem?  It turns out that it is, causing decreased quality of life through symptoms such as fatigues, weakness, and difficulty breathing.  Does treating the anemia relieve these symptoms?  Yes it does.  Does treating the anemia prolong life?  Well, not so much, and the treatment can, in fact, shorten life.

In the past, the only treatment available was blood transfusion, and multiple blood transfusions come with their own set of risks.  But over the last several years, we’ve learned to make EPO that can be given as an injection.  We’ve found that these injections do indeed lead to increased blood counts and reduced symptoms.  And it seems reasonable to suppose that giving these shots until the blood count is normal is the best way to go about things.

But it’s not.  Studies have found that when EPO is given with a target blood count in the normal range, the rate of serious adverse events is significant (by adverse events, I mean heart attacks, death—you know, serious).  What the studies also found is that aiming a bit lower reduces the symptoms of anemia without killing the patient.

The accumulation of this valuable knowledge has taken decades of bench science and clinical research.  It illustrates one of the most important points in clinical medicine: an idea that makes sense and seems plausible is only a starting point.  If we had continued to aim for normal hemoglobin levels in CKD patients, we would probably have killed people.  By studying the problem systematically, we have created a relatively safe and effective therapy.  That’s also some impressive science.

3 Comments

  1. Fascinating! The next time Hotter complains about his (mild) anemia Imma send him to read this…

  2. It isn’t just low O2 that allows accumulation of the transcription factors that regulate EPO (HIF-1), high NO does too, even under normal O2 levels (the O2 levels they used here are actually somewhat above “normal”, 20% is atmospheric O2 level, in the body O2 is is somewhat lower).

    http://www.molbiolcell.org/cgi/content/full/14/8/3470

    High is relative, high NO can be only a few nM/L (depending on what is being activated). They used GSNO (S-nitrosoglutathione), which is a NO donor but at 1 mM/L levels. The effective NO level from 1 mM/L GSNO is hard to figure, there can be direct NO, but there can also be transnitrosation via protein disulfide isomerase which can produce NO effects without NO being present by transferring NO from GSNO to NO active sites, even through cell membranes.

    Hypoxia does cause nitrite to be reduced to NO. Many enzymes do this in many tissue and cellular compartments.

    In refreshing my look at the literature I found this supplement dedicated to erythropoiesis stimulating agents (available open access).

    http://theoncologist.alphamedpress.org/content/vol14/suppl_1/

    Some of the articles are pretty good. This one has some nice graphs (just the title to not exceed the 2 link limit).

    Anemia management in oncology and hematology.
    Jerry L. Spivak, Pere Gascón, Heinz Ludwig

  3. This story also shows us that the science never ends.
    Kidneys make EPO, and EPO treats anemia of CKD.
    Post-approval monitoring led to observations about target levels that led to more clinical studies.

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