Preventing Kidney Failure in Hemolytic Anemias with a Novel Heme and Hemoglobin Scavenger

Abstract

Pathophysiological conditions characterized by chronic hemolysis, such as genetic and acquired hemolytic diseases, lead to increased levels of circulatory cell-free hemoglobin (fHb), free heme, and iron. The toxicity of free acellular hemoglobin has been a subject of intense study to understand its impact on the human body. fHb's small size allows it to extravasate into various organs, causing damage. The kidney is particularly vulnerable to Hb toxicity as it can filtrate through the kidneys, affecting glomerular filtration rate and leading to kidney failure. To address this, our group has developed a novel technique using the dorsal window chamber model in Golden Syrian hamsters. This method allows us to non-invasively measure glomerular filtration rate (GFR) using FITC-Sinistrin. The advantage of this approach is that it can assess renal function in awake animals, eliminating the need for anesthesia and minimizing its impact on the assessment. We also tested the function of ApoHb-Hp, a scavenger for Hb and heme, developed by our group, to see how it protects kidney function from mild and severe hemolysis. Our data involved two sets of experiments. In the first set, we injected groups with 10% of their blood volume, either with Hb alone or along with ApoHb-Hp. In the second set, we performed a 20% volumetric exchange of Hb or ApoHb-Hp with Hb. The results indicated that the group infused with Hb showed a sharp 60% decrease in half-life after 2 hours, but it returned to baseline after 24 hours. On the other hand, the group infused with ApoHb-Hp only showed a 30% decrease, suggesting that Hb is responsible for a more pronounced acute decrease, rather than just the volume change. Furthermore, when comparing the exchange data, both the Hb and ApoHb-Hp groups exhibited a 55% decrease in half-life after 2 hours compared to baseline, attributed to the change in volume. However, at the 24-hour mark, the ApoHb-Hp group returned to baseline, while the Hb group's half-life continued to decrease, reaching an 86% decrease compared to baseline. In conclusion, our preliminary data indicates that continuous exposure to Hb has a more prolonged effect on the kidney's filtration rate, potentially causing prolonged kidney impairment and irreversible damage. Further research is needed to understand the full implications of these findings and to explore the protective role of ApoHb-Hp in mitigating Hb-induced kidney damage.