Preventing kidney failure in hemolytic anemias with a novel heme and hemoglobin scavenger

Abstract

Chronic hemolytic conditions, seen in genetic and acquired hemolytic diseases, result in increased levels of circulatory hemoglobin (Hb) released from erythrocytes, free heme, and iron. Cell-free Hb's toxicity arises from the Hb dissociation into dimers that can traverse tissue barriers, impacting crucial compartments like arterial smooth muscle cells and renal glomeruli. Chronic hemolysis leads to vasoconstriction, renal injury, and activates pathways via Hb oxidation and heme-ligation of TLR4 on endothelial cells, as well as leukocytes, affecting adhesion pathways. Hb and heme exposure to the immune system causes phagocyte dysfunction, inflammation suppression, and impaired antigen presentation. Kidneys are particularly susceptible to Hb toxicity due to Hb and dimer penetration into glomeruli and tubules, disrupting filtration forces, elevating the glomerular filtration rate (GFR), and causing acute kidney injury (AKI). To combat this issue, our group developed a novel Hb and heme scavenger based on apohemoglobin-haptoglobin (apoHb-Hp), functioning as both a hemopexin (Hpx) and Hp mimetic to scavenge cell-free Hb and heme during hemolytic states. Our study utilized the dorsal window chamber model in Golden Syrian hamsters, employing FITC-Sinistrin for non-invasive GFR measurement, avoiding the need for blood and urine sampling throughout time to estimate GFR. Two experiments were conducted, volumetric exchange groups with 20% of the animal’s blood volume either with Hb at different concentrations or a combination ApoHb-Hp and Hb. Results showed a significant acute decrease of 35% in half-life of the Hb group at 1.2g/dL and 5g/dL after two hours, and further decrease is seen of 45% at 24hrs. In contrast, the ApoHb-Hp group experienced a 30% decrease at 2hrs but reverted back to baseline at 24hrs, signifying Hb's predominant effect on the acute decrease rather than the volume change. Furthermore, the ApoHb-Hp group demonstrated a quicker return to baseline compared to the Hb group after the 24-hour mark, suggesting prolonged Hb exposure's lasting impact on kidney filtration rate, potentially leading to irreversible damage. Further research is required to comprehend these findings fully and explore ApoHb-Hp's protective role in mitigating Hb-induced kidney damage. Title of the project: Bioengineering a Dual Function Protein Construct to Detoxify Heme and HemoglobinProject number: R01HL159862Title of the project: Bioengineering a novel therapeutic protein complex to minimize the effects of medical device induced hemolysis.Project number: R01HL162120. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.