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(00:13): In the episode description, downloadable slides and resources are also available. (00:18): The following presentation
is copyrighted by Medscape. No use, broadcast, or recording of this presentation or any part thereof is permitted without
the written authorization of Medscape. Dr. Jay Wish (00:30): Hello, I'm Dr. Jay Wish, professor of clinical medicine at the
Indiana University School of Medicine in Indianapolis, Indiana. Welcome to this program titled Anemia of CKD: The Science
Beyond the Disease, part of the Updates and Advances in Anemia of Chronic Kidney Disease Series. Joining me today is Dr. Anil
Agarwal, who is professor of medicine at the University of California San Francisco, academy professor at Ohio State University,
and chief of medicine at the VA Central California Health System in Fresno, California. Welcome, Anil. Dr. Anil Agarwal (01:06):
Glad to be here. Dr. Jay Wish (01:09): Anemia is a common complication of chronic kidney disease or CKD. The prevalence of
anemia in patients with CKD increases as the disease progresses and about 50% of all patients with stage 5 CKD have associated
anemia. (01:24): This is episode one in the six part podcast series on understanding and managing anemia in patients with
CKD. In this episode, we'll focus on the pathophysiology of anemia associated with CKD and dive into why new treatment strategies
are needed in managing anemia in these patients. (01:46): Let's start with our first question. Anil, what are the major new
things we've learned about the pathophysiology of CKD anemia since recombinant erythropoietin was approved in 1989? Dr. Anil
Agarwal (02:00): That's a great question. First of all, thank you, Medscape, and thank you, Dr. Wish, for inviting me to talk
about the pathophysiology and the new understanding about pathophysiology in treatment of anemia of CKD. (02:16): As you know,
if you recall from the days of medical school decades ago, you'll remember that we only had couple of different factors that
we understood what caused anemia, and one was the deficient erythropoietin. As the kidney starts losing nephrons and starts
producing less and less erythropoietin, people get become erythropoietin deficient. And once there is erythropoietin deficiency,
there is not enough kick to the bone marrow to produce more red cells. The second thing that we understood at the time was
the deficiency of iron. As you know, there are multiple reasons. The patients are not eating well, they are nutritionally
deficient in general, they lose blood in different ways and there's likelihood of more bleeding and consequently, the patients
are iron deficient. And if you recall, for decades, the only things available to treat anemia of chronic kidney disease was
essentially just the iron and blood transfusions. (03:24): The biggest discovery, as you mentioned, was really the approval
of epoetin back in 1989 for treatment of anemia of CKD, and that changed lives of millions of dialysis patients. Prior to
that, intravenous iron and blood transfusion, as you know, were the most effective therapies, but knowing what we know now
today, none of these really addressed the real pathophysiology. (03:55): What is new now that we are talking about is we have
two very important recent discoveries that have very significantly improved our understanding of anemia of CKD. First, we
know now that that inflammation, working through hepcidin, regulates and restricts absorption and availability of iron for
erythropoiesis. That is very important because if you just think about a CKD patient on any given day, they have a lot of
inflammation going on. Second, we are really thankful to the Nobel Prize-winning discovery of hypoxia-inducible factor that
has really afforded to us invaluable insight into the mechanism of how erythropoietin is produced in response to hypoxia,
and at the same time, both these discoveries have afforded us opportunity to discover some potential breakthroughs in our
knowledge and approach to management of anemia of CKD. Dr. Jay Wish (05:01): So let me pursue this whole issue of inflammation
and hepcidin in the anemia of chronic kidney disease. Please explain what their role is and how they affect red cell production.
Dr. Anil Agarwal (05:13): All right, that's a great question. Well, let's think about how this even evolved. We recognized
inflammation as a contributor to anemia in patients with CKD over decades. We realized that patients are being treated, they're
not responding to management, and now they're getting more and more anemic despite proper treatment. But its exact relationship
to anemia of CKD remained unclear until the turn of this century. It is very interesting to note that hepcidin was discovered
as a liver-expressed antimicrobial peptide or the LEAP peptide, and it is a 25-amino acid peptide that is produced mostly
by the hepatocytes in response to inflammation, as well as due to iron overload. It is considered part of native immunity,
to restrict supply of iron to microbes which may utilize iron as a micronutrient. Now we know and understand the hepcidin
is actually the master regulator of iron absorption and transport. (06:27): How it works then is that hepcidin-25 binds to
ferroportin. Ferroportin is a transmembrane protein that is responsible for efflux of iron from the cell. When ferroportin
is internalized and degraded, release of iron from enterocytes, from macrophages and hepatocytes, all the cells involved in
the turnover of iron and red cells, that is inhibited, which negatively impacts the absorption and availability of iron and
also utilization of iron. Finally, hepcidin is cleared via its internalization and degradation with ferroportin as well as
through its excretion by the kidneys. So it is no surprise to me that when the patients have lower kidney function, there
is a higher level of hepcidin in the blood because they're just simply not able to excrete hepcidin from the system. (07:28):
Production of the hepcidin is regulated by the systemic availability of iron in a feedback mechanism and erythropoietic requirement
also, because when you want to make red cells, you want to have more iron available and less hepcidin. So a state of inflammation,
in other words is a very, very important discovery for us in this era. Dr. Jay Wish (07:54): So it's been shown by some studies
that hepcidin levels do increase almost proportionally to the degree of renal function impairment. And the patients with more
advanced CKD generally have significant elevations of hepcidin, which is fairly consistent with their level of renal sufficiency.
Should we be routinely measuring hepcidin levels in our anemic CKD patients? Dr. Anil Agarwal (08:15): Well, I can understand
the reason why that question is being asked and if you think about it, there has been an eternal desire to have a really perfect
test of iron deficiency. That, unfortunately, remains a fantasy to this day. As you know, a variety of laboratory tests have
been used to assess iron deficiency in patients with anemia, including some of those are ferritin, transferrin saturation,
percent of hypochromic red cells, and soluble transferrin receptor. However, all these current methods of assessing adequacy
of iron stores and iron availability to the intron are grossly inadequate, especially when you throw in the presence of inflammation
into the mix. So these tests are really unable to guide the clinician to formulate a strategy to treat anemia with iron. Association
of hepcidin levels with the stage of CKD and ferritin and its inverse relationship with ESA therapy do support the possibility
that hepcidin could be a good biomarker of iron status. (09:30): But think about it, there is significant intrapatient variability
of hepcidin level measurements. Then, hepcidin is dependent on kidney function for its excretion and for those reasons, the
level of hepcidin can simply be high because of kidney insufficiency. Additionally, hepcidin is dependent on kidney function
for its excretion and the levels increase with the presence of inflammation and are not necessarily different in patients
sensitive or resistant to ESA. When you consider all of these factors, along with the non-harmonization of different hepcidin
assays, the hepcidin levels cannot be considered a good biomarker of iron status in their current form, or even a predictor
of ESA response, at this time. There are also some biological variations. For example, women have a lower level of hepcidin
than men, and there is a diurnal variation, with levels being lower in the morning, higher in the afternoon. Those factors
make it even more difficult to how we even interpret hepcidin levels, leave alone how they help us formulating a strategy
of iron supplementation. Dr. Jay Wish (10:50): So it sounds like the answer to that question is a no, but what can we do diagnostically
and therapeutically to address the role of inflammation in our anemic CKD patients? Dr. Anil Agarwal (11:02): Yes, we have
to have some way of addressing the role of inflammation in anemic CKD patients. And first of all, in any patients with anemia,
especially who is not being so responsive or a so-called erythropoietin resistance, in those patients, we should have a very
high index of suspicion from get-go for inflammation. (11:28): Diagnostically, what you would do is first of all, start with
the basics. Do a good physical examination, look for the source of inflammation. Could it be dental caries? Could it be old
non-functional abscesses that have been shown to be very inflamed? And we should also look for any other apparent source of
inflammation that that might be there. We should remember that the use of non-biocompatible dialysate, both in PD and hemodialysis,
those can be source of inflammation in almost any patient. (12:03): There are other reasons why there could be inflammation.
Think about heart failure. That has been associated with inflammation in patients with kidney disease. Further, once you have
done the examination, the next step would be to do a good laboratory evaluation for functional iron deficiency. You might
find an elevated ferritin level with low transferrin saturation. There may be other measures to look for inflammation including
checking for high sensitivity CRP or C-reactive protein. Also, erythrocyte sedimentation rate. I know that some of these are
very nonspecific, but still those could indicate presence of inflammation. And as I mentioned earlier, hepcidin assay unfortunately
does not help us too much in this regard and probably is not ready for prime time. (12:56): Then, approaching inflammation.
Now we did the exam, we did the testing, we found inflammation. Therapeutically, what do we do in these patients? (13:07):
If you discover a source of inflammation, please treat it promptly and appropriately. Just increasing the dose of iron, increasing
the dose of EPO, may not be beneficial and probably have a potential to cause more damage. Unfortunately at this time, there
are no specific approved therapies to treat elevated hepcidin, although many molecules have been tried in experimental studies,
but those are nowhere close to being in clinical studies yet. Then therapy with hypoxia-inducible factor, that is something
that is being tested and has been in vogue quite a bit lately. That has been shown to be effective even in presence of inflammation
in treating anemia of CKD in randomized controlled trials. So these agents are currently not approved, let me declare that,
disclose that right now that these are not currently approved for treatment of anemia of CKD, at least in the United States.
So there are multiple strategies as you can see, but you have to really start from the very basics. Dr. Jay Wish (14:21):
Briefly, what is the role of hypoxia-inducible factor, or HIF, in the pathophysiology of CKD anemia? Dr. Anil Agarwal (14:30):
So very remarkably, now we have this knowledge of this hypoxia-inducible factor and how it works in the pathophysiology. So
the hypoxia-inducible factor is a transcription factor. It is constantly produced by all somatic cells. It has the potential
of increasing erythropoietin production, in addition to activation of hundreds of other genes. However, under normal oxygen
condition, or under normoxia, HIF is constantly degraded. That occurs through the action of HIF protyl hydroxylase or HIFPHI
enzymes. What they do is they add a hydroxyl group to specific proline residues on HIF. This serves as a tag for proteasomal
degradation, and that's the end of the story for the HIF. (15:27): But in presence of hypoxia, such as a person is at a high
altitude or upon administration of a drug that is a pH antagonist, this protyl hydroxylase enzyme is inactivated that allows
for activation of erythropoietin gene transcription. (15:51): Now it is extremely important. We are all aerobic organisms.
Elucidation of the detailed mechanism by which cells can sense oxygen allows the development of specific molecules that target
specific proteins or processes. It has a potential to treat many diseases, including cancer, stroke, and inflammation, apart
from CKD anemia. And no surprise to me, in 2019, doctors Gregg Semenza, William Kaelin, and Peter Ratcliffe were honored with
the Nobel Prize in physiology or medicine for their work on deciphering the hypoxia mechanism. Dr. Jay Wish (16:34): I should
point out that Dr. Peter Ratcliffe is the only nephrologist ever to have won the Nobel Prize. So we want to make sure that
everybody listening to the podcast appreciates that. (16:44): All right, so just last question. How is this discovery of the
hypoxia-inducible factor system helpful in our management of anemic patients with CKD? Dr. Anil Agarwal (16:55): So again,
just slightly to repeat, the HIF agonist, they block the HIF protyl-hydroxylase enzyme activity. HIF is not degraded but is
stabilized. What happens next is once it is stabilized, the HIF-alpha dimerizes with HIF-beta, and the heterodimer then translocates
to the nucleus, binds to DNA, coordinates transcription of erythropoietic genes, and there is production of erythropoietin
right there. There is also an increase in the number of EPO receptors and these are all further assisted in terms of erythropoiesis
by activation of pro-iron absorption genes which allow more streamlined erythropoiesis. Further, the HIF agonists inhibit
hepcidin, as demonstrated by their efficacy in improving CKD anemia despite high levels of hepcidin and presence of inflammation
demonstrated by high levels of ferritin, low transferrin saturation, and high levels of high sensitivity CRP. Dr. Jay Wish
(18:00): Before we conclude, do you have any comments to wrap things up? Dr. Anil Agarwal (18:05): Well, I would just like
to summarize that this is a really exciting time in nephrology, and CKD anemia, especially. Now we have a better understanding
of pathophysiology of anemia of CKD, and also, it has become very clear to us that the epoetin therapy and iron administration
and blood transfusions that we were using for decades do not really address the entire inflammation and hepcidin pathway that
usually causes hyporesponse. So it is also quite important to screen and stratify patients with CKD anemia according to presence
or absence of adequate iron levels and inflammation to consider potential pathways in treating anemia of CKD. Dr. Jay Wish
(18:53): So we now understand that the pathophysiology of anemia of CKD is much more complicated than a simple inability of
the diseased kidney to make erythropoietin. It's not analogous to the insulin deficiency of a Type 1 diabetic where you could
just replace the insulin and thereby treat the disease. These new insights may provide the foundation for novel therapeutic
approaches to anemia in CKD, whose mechanisms of action directly address the pathophysiology we discussed. (19:22): I'd like
to thank you for this great discussion, Anil. I really appreciate your sharing your expertise, and I'd also like to thank
our audience for participating in this activity. (19:32): Please join us for the remaining five podcasts in this series, Updates
and Advances in Anemia of Chronic Kidney Disease. We hope you enjoy the rest of your day. Please continue on to answer the
questions that follow and complete the evaluation. We really appreciate your feedback as it helps us develop future educational
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