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. Author manuscript; available in PMC: 2021 Mar 1.
Published in final edited form as: Semin Nephrol. 2020 Mar;40(2):148–159. doi: 10.1016/j.semnephrol.2020.01.006

Table 1.

Potential mechanisms of hemoglobin renal toxicity in sepsis-AKI

Tubular obstruction
 Extracellular hemoglobin forms small (32kD) αβ-chain heterodimers that are freely filtered by the glomerulus
 Breakdown of filtered hemoglobin in urinary space releases heme
 Heme accumulation forms pigment casts in urinary space
 Tubular obstruction promotes proximal tubular endocytosis of heme and tubular epithelial injury
Extravascular translocation of hemoglobin
 Hemoglobin αβ-heterodimers can translocate through the vascular walls of peritubular capillaries
 Breakdown of hemoglobin releases free heme and causes iron deposition in the renal interstitium
Reaction with nitric oxide (NO)
 Consumes NO leading to vasoconstriction and endothelial dysfunction
 Reaction of oxyhemoglobin with NO generates ferric (Fe3+) hemoglobin
Generation of reactive oxygen species
 Ferric (Fe3+) and ferryl (Fe4+) iron hemoglobin outside of
 Globin radicals can drive lipid and protein peroxidation
 Free heme oxidizes LDL, promoting inflammation and cytotoxicity
 Increased oxidative stress promotes hemolysis and more CFH release
Heme-mediated immune signaling
 Heme potentiates neutrophilic inflammation and inhibits neutrophil apoptosis
 Heme can bind TLR4 triggering pro-inflammatory signaling