#263 Iron Deficiency and Anemia of CKD (NephMadness 2021)

March 22, 2021 | By Matthew Watto, MD

Dominant iron deficiency and anemia of CKD! We discuss how to interpret iron studies, when and how to start treatment with PO vs. IV iron, and ESAs vs. the new HIF-PHIs! Iron deficiency in chronic kidney disease is common but frequently overlooked in primary care.  This episode features Kashlak Memorial’s own Chief of Nephrology, Dr. Joel Topf (@kidney_boy), joined by NephMadness experts, Dr. Matthew Spark (@Nephro_Sparks), and Dr. Pascale Khairallah (@Khairallah_P)!  Our guests lay out an easy-to-follow framework for primary care and give us some inside information to #Nephmadness! Read the Anemia Region scouting report.

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Credits

• Writer, Producer:  Stuart Brigham, MD
• Cover Art:  Kate Grant MBChB, MRCGP
• Hosts: Stuart Brigham MD; Matthew Watto MD, FACP; Paul Williams MD, FACP   
• Editor: Matthew Watto MD (written materials); Clair Morgan of nodderly.com
• Guest: Joel Topf MD, Matt Sparks MD, Pascale Khairallah MD

Keyword: iron deficiency, anemia of CKD, nephmadness 2021

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Segments

• Intro, disclaimer, guest bio
• Case from Kashlak
• Approaching CKD in Primary Care
• Iron and anemia labs in CKD
• Ferritin Goals in CKD
• Oral Replacement of Iron in CKD
• IV Replacement of Iron in CKD
• Discussing treatment option for Anemia of CKD
• Basic information on HIF Stabilizers / PHIs in CKD
• Take-home points and Outro

Iron Deficiency in CKD Pearls

1. Iron Deficiency in CKD is exceedingly common and presents as either absolute iron deficiency or functional iron deficiency.
2. With CKD Stage 3 or worse, consider searching for iron deficiency.
3. Newer oral iron agents are available, but older oral iron agents may not be as bad as previously thought.
4. IV Iron may be necessary for some circumstances and is not as “scary” as we previously thought.
5. ESAs are not without their side effects and should be approached cautiously (i.e. history of stroke, malignancy, high blood pressure, elevated cardiovascular risk).
6. The newer HIF PHIs under evaluation are promising when compared to ESAs, but long-term data is missing at this time.

Iron Deficiency in CKD Notes

Approaching Iron Deficiency in CKD

The #Nephmadness crew discuss some of the misconceptions about identifying Iron Deficiency in CKD.  Dr. Khairallah identifies both absolute iron deficiency (TSAT <20% or Ferritin <100 ng/mL) and functional iron deficiency (TSAT <20% or Ferritin <500 ng/mL were mentioned by Dr. Khairallah, whereas KDIGO [KDIGO, 2012] states TSAT <30% and Ferritin <500 ng/mL [Para 2.1.2]).  In functional iron deficiency, they have enough iron stores, but the patient cannot incorporate this iron (for example, due to inflammation).  In a patient with functional iron deficiency, treatment should be considered, but the determination of when to initiate treatment varies depending on both the patient and clinician preference.  

There is some debate as to when to check iron stores in patients with CKD.  Since the goal Hb in CKD is >10.0, Dr. Topf notes that he likely would not have even ordered an Iron Panel in the case presented (Hb 12.0) unless the patient endorsed fatigue.  On the other hand, both Dr. Sparks and Dr. Khairallah would likely have checked iron stores in the patient presented.  Ultimately, whether to check iron stores or not should be a shared decision-making process with the patient to improve anemia.

Brigham’s Brief Bombshell

Dr. Brigham, who considers himself an idiot savant for non-anemic iron deficiency, stresses the importance of looking at the RBC indices, specifically RDW.  The presence of Anisocytosis is the first marker seen in iron deficiency (England, 1976).  Specifically, Dr. Brigham is interested in the non-anemic symptoms of iron deficiency as a result of the neurohormonal pathways for which Iron is a required co-factor (the tetrahydrobiopterin reactions):

Figure courtesy Dr. Stuart Kent Brigham and reproduced with his permission.

Iron repletion has been shown to improve the outcomes of several related conditions dependent on these sympathomimetic neurotransmitters (Dopamine, Norepinephrine, Epinephrine, Serotonin, Melatonin), including, but not limited to, RLS (Wang, 2009; Lee, 2014; Zhang, 2015), Pain in Fibromyalgia (Boomershine, 2018), ADHD Outcomes (Konofal, 2008), Sleep Disturbances in ASD (Dosman, 2007), Postpartum Depression (Sheikh, 2017; Holm, 2017), and Heart Failure (Zhou, 2019; Ponikowski, 2015) with iron deficiency.

Treating Iron Deficiency in CKD

In general, oral iron should be trialed in patients with CKD prior to considering IV Iron.  The mainstay of treatment is still Ferrous Sulfate with recent studies suggesting every other day dosing (Stoffel, 2020) may be more beneficial.  While newer formulations do exist (ferric citrate and ferric maltol), they can be cost-prohibitive.  A brief search reveals the costs of ferric citrate ($187/mo) and ferric maltol ($86/mo); on the other hand, ferrous sulfate costs around $7/mo (or $3.5/mo if you dose it every other day).  It is worth noting that ferric citrate was originally studied as a phosphorous binder and can be used for both that and iron deficiency.  Furthermore, these newer formulations of oral iron do seem to be absorbed even in patients with inflammatory conditions.  Lastly, we may be overselling the nocebo effect of constipation; oral iron has an NNC (Number Needed to Constipate) of 10 with around 10% of patients on oral iron developing constipation.  Two newer formulations of iron may be FDA approved soon:  Liposomal iron and sucrosomal iron.

IV iron is considered in those patients who are either (a) resistant to oral iron after 1-3 months, (b) have noted side effects from oral iron, or (c) have severe iron deficiency anemia at presentation.  Patients with heart failure have only been studied with IV Iron, not oral iron, and this may be a consideration to use IV iron.  Newer formulations of IV Iron can be administered in one dosage (ferric carboxymaltose, ferumoxytol, and iron isomaltoside) as compared to older formulations (iron sucrose and iron dextran).  These newer formulations also have relatively few side effects (except ferric carboxymaltose which causes hypophosphatemia) and the decision of which agent to utilize is oftentimes dependent on the institution.  The goal treatment dosage is 1,000mg of IV Iron.

Brigham’s Brief Bonanza

OTC Multivitamins frequently co-administer multiple divalent cations (Zn, Mn, Ca, Mg, Se, Cu, Cr, etc.) that either compete directly with the DMT1 transporter or indirectly (by affecting the transmembrane potential).  This includes every prenatal vitamin that I have been able to find on the market.  The sole supplement that does not co-administer divalent cations is the Flintstones Vitamin (but not the gummi formulation). 

Treating Anemia of CKD

First, once you get to the point of treating anemia in CKD, you should ensure that your patient is seeing your friendly, neighborhood Nephrologist!  Prior to considering treating CKD with ESAs (erythropoiesis-stimulating agents), it is important to assess for symptoms because of the side effects related to these agents.  The newer agents on the market, the hypoxia-induced factor prolyl-hydroxylase inhibitors (HIF PHIs) that are very promising, but we do not have long-term safety data on these agents.  The data, so far, shows that they increase Hb levels by up to 2 g/dL (in placebo trials), reduce transfusion requirement, and show improved effectiveness in inflammatory conditions.  On the other hand, there may be an increase in major adverse cardiovascular events.

For a more in-depth look at iron deficiency and anemia of CKD Read the Anemia Region scouting report.

Links

1. Kidney Failure Risk calculator:  https://kidneyfailurerisk.com/
2. NephMadness 2021 – Anemia region
3. NephMadness 2021 – fill out your bracket here.

Goal

Listeners will gain a better understanding of how to treat iron deficiency in Chronic Kidney Disease.

Learning objectives

After listening to this episode listeners will…  

1. Recognize iron deficiency in CKD
2. Recognize the limitations of diagnostic testing to identify Iron Deficiency
3. Identify the differences between oral and IV iron in the treatment of CKD
4. Develop an approach on how to treat iron deficiency in Chronic Kidney Disease
5. Educate patients on the treatments available for iron deficiency in CKD
6. Identify when a patient should be sent to a Nephrologist to continue treatment for iron deficiency in CKD

Disclosures

Dr. Sparks, and Dr. Khairallah all report no relevant financial disclosures. The Curbsiders report no relevant financial disclosures. 

Dr. Topf has received honoraria from AstraZeneca and Cara Therapeutics. He is a joint venture partner in Davita Dialysis centers receiving dividends. 

Citation

Brigham, SK, Topf J, Sparks M, Khairallah P, Williams PN, Watto MF. “#263 Iron Deficiency and Anemia in CKD with #Nephmadness”. The Curbsiders Internal Medicine Podcast. http://thecurbsiders.com/episode-list Final publishing date, 2021.