Seolhyun Lee @LeeSeolhyun

Dr. Seolhyun Lee is currently a clinical Assistant Professor at Stanford University. He attended medical school at Chungnam National University in South Korea, and completed internal medicine residency at Cooper University Hospital, NJ. During his postdoctoral research fellowship at Stanford University, he studied clearances of uremic solutes and improving those in hemodialysis, which was funded by the American Society of Nephrology. He is one of AJKD’s 2022-23 Editorial Interns. Additionally, he has clinical interests in onco-nephrology. Dr. Lee is a proud father of three children. He shamelessly admits going to work feels like a vacation to him.

“Intravenous (IV) iron can cause clinically significant intra-dialytic hypotension” – many clinicians may believe such a statement. The FDA even labels 36% prevalence of hypotension as a side effect of IV iron sucrose and warns of the risk of significant hypotension following IV iron sucrose administration.

In a recent AJKD article, Singh and colleagues disproved such a statement. They conducted a prospective cohort study of 950 patients who received a total of 135,412 HD sessions. Infusion of IV iron sucrose 100 mg or greater was associated with a 16% lower rate of intradialytic hypotension (incidence rate ratio 0.84 [95% CI, 0.80-0.89]).  Singh and colleagues further showed that IV iron can instead cause hypertension during dialysis; systolic blood pressure was increased 2.5 (95% CI, 2.2 to 2.8) mmHg when IV iron sucrose 100 mg or greater was given. These effects remained significant when adjusted for various risk factors

Hypotension in children secondary to accidental oral iron ingestion, typically greater than 60 g/kg, was traditionally observed in clinical settings, which may have seeded the concept of iron-induced anaphylaxis and hypotension. The pathophysiology of iron-induced hypotension is based on the hypothesis that labile iron can cause hypersensitivity or vascular reaction via oxidative stress and endothelial dysfunction. It has been also supported by clinical studies, such as the systematic review and meta-analysis by Avni and colleagues that demonstrated the association between hypotension and IV iron therapy.

Singh and colleagues suggest two hypothetical mechanisms why IV iron sucrose would prevent hypotension or even cause hypertension during HD. The first mechanism is related to the osmolar effects of IV iron sucrose. Iron sucrose with 100 mg elemental iron, mixed in 100 mL of isotonic saline provides hyperosmolar solution with 404 mOsm/L; hence, a total osmoles contained in a bag of IV iron sucrose infusion is approximately 40 mOsm. Further, IV iron sucrose is not dialyzable, owing to its large mass (34,000–60,000 Da) as a polymer.

The second mechanism is reduced production of nitric oxide, a potent vasodilator, by resolution of iron deficiencies. Although there is evidence of increased nitric oxide production in the setting of iron-deficiency anemia, we do not know whether infusing IV iron would immediately reduce the concentration of nitric oxide and therefore contribute to the hypertension.

In patients with end-stage kidney disease (ESKD) on HD, IV iron is preferred to oral iron, as it is more effective in raising hemoglobin level, more amenable to achieve higher compliance, and more convenient to administer during HD sessions. A consequence of not administering IV iron to a patient with ESKD and severe iron deficiency anemia is a higher chance of requiring blood transfusion, which has a greater risk of adverse outcomes. Based on this study by Singh and colleagues, nephrologists may consider scheduling IV iron infusion specifically on Mondays or Tuesdays for patients on HD if they are on typical thrice weekly HD schedule because those patients may have higher chance of intradialytic hypotension on Mondays or Tuesdays when higher rate of ultrafiltration is required after accumulating significant volume over the weekend.

The least we can learn from the study of Singh and colleagues is that we should not avoid ordering IV iron for patients with ESKD and iron-deficiency anemia just because we fear adverse events, such as intradialytic hypotension. Additionally, we also learned that it makes little sense to start IV iron at a lower dose to avoid possible hypotension as an adverse reaction because only higher dose IV iron sucrose 100 mg or greater significantly reduced the risk of intradialytic hypotension.

Singh and colleagues showed patients with ESKD on HD had a lower prevalence of intradialytic hypotension when they received IV iron sucrose 100 mg or greater. We can use these findings to improve clinical outcome of hemodialysis treatment and inspire future studies to elucidate the mechanisms.

– Post prepared by Seolhyun Lee @LeeSeolhyun

To view Singh et al (subscription required), please visit AJKD.org:
Title: Associations of Iron Sucrose and Intradialytic Blood Pressure
Authors: Anika T. Singh, Timothy E. Yen, Suraj Sarvode Mothi, Sushrut S. Waikar, and Finnian R. Mc Causland
DOI: 10.1053/j.ajkd.2022.11.007