Evaluation of the Renal Toxicity of Heme Proteins and Their Derivatives: A Role in the Genesis of Acute Tubule Necrosis

Abstract

This investigation studies the toxicity of heme proteins and/or their break-down products on renal function. Heme proteinemia precedes acute tubule necrosis at a frequency great enough to suggest a causal relationship between the two events. Physiological and metabolic functions of kidney slices are investigated in several models of acute tubule necrosis. Organic acid and organic base transport is depressed earliest. These alterations in tubule function cannot be explained by ischemia or obstruction alone. Heme proteinemia in rats or incubation of renal slices in medium containing heme proteins yields several interesting observations. Neither in vivo or in vitro do hemoglobin and methemoglobin alone produce a depressive effect on the transport systems studied. However, parallel to many clinical situations, when such secondary insults as hypoxia and elevated ammonia concentrations are included in the experimental design, transport functions are depressed. Ferrihemate, a molecule smaller than hemoglobin or methemoglobin, depresses transport function without secondary insults. From these studies it is concluded that heme proteins play a role in tubule dysfunction seen in acute tubule necrosis. A model is presented that collates these data with other factors known to play a part in the pathogenesis of this renal syndrome.

Inducible heme oxygenase in the kidney: a model for the homeostatic control of hemoglobin catabolism

“…It is apparent, however, that when the filtered load of hemoglobin is increased, this homeostatic mechanism is easily overwhelmed and thus rendered relatively ineffective. The role of the adaptive heme oxygenase system 2048 Pimstone, Engel, Tenhunen, Seitz, Marver, and Schmid of the kidney in the multifactorial pathogenesis of hemoglobinuric nephropathy (33)(34)(35) is unclear.…”

Acute kidney injury caused by intravascular hemolysis after mechanical thrombectomy

“…Experimental studies showed that infusion of hemoglobin after a multifactorial insult predisposed rats to kidney injury, including ischemic damage. 15 In addition, the presence of methemoglobin was associated with severe azotemia and tubular necrosis. 14 Infusion of hemoglobin in rats when the blood is acidemic also caused azotemia, but not as severe as that seen with methemoglobin.…”

Polymerized hemoglobin restores cardiovascular and kidney function in endotoxin-induced shock in the rat.

“…However, this model reflects at least important aspects of the pathophysiological changes seen in human septic shock. The use of hemoglobin solutions prepared by lysis of red blood cells as substitute for blood transfusion was associated with serious side effects including kidney failure, intravascular coagulation, and anaphylactic reactions (28,29). Purification to remove erythrocyte stroma or contaminating lipopolysaccharide reduces but does not prevent toxicity because hemoglobin causes renal failure by intratubular precipitation of methemoglobin and free heme (33).…”

“…Due to its affinity to NO, hemoglobin (Hb) could function as a scavenger to remove exessive amounts of NO and therefore could be of therapeutic use in septic shock (27). However, Hb itself can induce acute renal failure when infused intravenously (28,29). Polymers of Hb were originally developed as substitutes for blood transfusion and to improve tissue perfusion and oxygen delivery in hemorrhagic shock (30).…”