Heme Proteins and Kidney Injury: Beyond Rhabdomyolysis

Abstract

Heme proteins, the stuff of life, represent an ingenious cellular strategy that capitalizes on the biochemical versatility of heme, and yet is one that avoids the inherent risks to cellular vitality posed by unfettered and promiscuously reactive heme. Heme proteins, however, may be a double-edged sword as they can damage the kidney in certain settings. While such injury is often viewed mainly within the context of rhabdomyolysis and the nephrotoxicity of myoglobin, an increasing literature now attests to the fact that involvement of heme proteins in renal injury ranges well beyond the confines of this single disease (and its analogue, hemolysis); indeed, through the release of the defining heme motif, destabilization of intracellular heme proteins may be a common pathway for acute kidney injury, in general, and irrespective of the underlying insult. This brief review outlines current understanding regarding processes underlying such heme protein-induced acute kidney injury (AKI) and chronic kidney disease (CKD). Topics covered include, among others, the basis for renal injury following the exposure of the kidney to and its incorporation of myoglobin and hemoglobin; autooxidation of myoglobin and hemoglobin; destabilization of heme proteins and the release of heme; heme/iron/oxidant pathways of renal injury; generation of reactive oxygen species and reactive nitrogen species by NOX, iNOS, and myeloperoxidase; and the role of circulating cell-free hemoglobin in AKI and CKD. Also covered are the characteristics of the kidney that render this organ uniquely vulnerable to injury following myolysis and hemolysis, and pathobiologic effects emanating from free, labile heme. Mechanisms that defend against the toxicity of heme proteins are discussed, and the review concludes by outlining the therapeutic strategies that have arisen from current understanding of mechanisms of renal injury caused by heme proteins and how such mechanisms may be interrupted.

The Significance of Hematuria in Podocytopathies

“…19 In addition, prior studies support that free heme can lead to tubular injury by various mechanisms, including proximal tubular uptake using the megalin/ cubilin complex, altered cellular cytoskeletal structure because of pro-oxidant properties, impaired cytosolic enzymes, and proinflammatory properties based on in vivo studies. 9,10,20 One intriguing question is whether an underlying genetic polymorphism, such as genes associated with GBM composition and structure, may explain the presence of hematuria in some patients and confer a higher risk of disease progression. In a study of over 3000 patients with mixed etiologies of CKD, including glomerular disease, 66 monogenic disorders were detected in 307 patients, of which 30% were collagen IV gene variants.…”

“…11 Fewer studies in adults reported the prevalence of hematuria by disease. In 410 adult patients in India, hematuria was present in 20 minimal change disease, and 25% (23/92) with membranous nephropathy. 12 Among 95 adults with minimal change disease, 28.9% had hematuria at presentation.…”

“…19 In addition, prior studies support that free heme can lead to tubular injury by various mechanisms, including proximal tubular uptake using the megalin/cubilin complex, altered cellular cytoskeletal structure because of pro-oxidant properties, impaired cytosolic enzymes, and proinflammatory properties based on in vivo studies. 9,10,20…”

Induction of p16Ink4a Gene Expression in Heme Protein–Induced AKI and by Heme: Pathophysiologic Implications

“…[5][6][7][8] Moreover, in virtually all forms of AKI, kidney content of heme may increase because of destabilization of heme proteins (especially p450 cytochromes) in the injured kidney 7,9,10 ; this leads to the release of heme, the latter being a nephrotoxic and proinflammatory metabolite. 7 Heme proteins may thus contribute to diverse types of AKI. 7,8 HP-AKI, induced by the intramuscular injection of hypertonic glycerol (which causes myolysis and hemolysis), has long and widely been studied by our and other laboratories.…”

Evaluating Heme-Oxygenase-1 and Bilirubin Concentration from the Recovered and Glomerulonephritis Patients from Lady Reading Hospital (LRH) District Peshawar, Pakistan

“…The release of excessive amounts of heme from intracellular proteins is inherently dangerous 1 . There are numerous conditions associated with the release of heme, or free heme, which can lead to oxidative and inflammatory harm [2][3] .…”