Nature Reviews Nephrology | 2019
Mechanisms of haemolysis-induced kidney injury
Abstract
Intravascular haemolysis is a fundamental feature of chronic hereditary and acquired haemolytic anaemias, including those associated with haemoglobinopathies, complement disorders and infectious diseases such as malaria. Destabilization of red blood cells (RBCs) within the vasculature results in systemic inflammation, vasomotor dysfunction, thrombophilia and proliferative vasculopathy. The haemoprotein scavengers haptoglobin and haemopexin act to limit circulating levels of free haemoglobin, haem and iron — potentially toxic species that are released from injured RBCs. However, these adaptive defence systems can fail owing to ongoing intravascular disintegration of RBCs. Induction of the haem-degrading enzyme haem oxygenase 1 (HO1) — and potentially HO2 — represents a response to, and endogenous defence against, large amounts of cellular haem; however, this system can also become saturated. A frequent adverse consequence of massive and/or chronic haemolysis is kidney injury, which contributes to the morbidity and mortality of chronic haemolytic diseases. Intravascular destruction of RBCs and the\xa0resulting accumulation of haemoproteins can induce kidney injury via a number of mechanisms, including oxidative stress and cytotoxicity pathways, through the formation of intratubular casts and through direct as well as indirect proinflammatory effects, the latter via the activation of neutrophils and monocytes. Understanding of the detailed pathophysiology of haemolysis-induced kidney injury offers opportunities for the design and implementation of new therapeutic strategies to counteract the unfavourable and potentially fatal effects of haemolysis on the kidney.Intravascular haemolysis and the subsequent release of proinflammatory haemoglobin and haem into the circulation are characteristic of several diseases. This Review discusses the major pathophysiological mechanisms and consequences of intravascular haemolysis with a focus on the kidney, and highlights emerging therapeutic strategies to target haemolysis-related kidney injury.Key pointsSeveral human haemolytic conditions result in the presence of large amounts of haemoglobin and haem in the circulation, which overwhelms endogenous scavengers such as haptoglobin and haemopexin.Free haemoproteins present in plasma are filtered by the kidney, exposing the kidney to the injurious effects of haem and iron.The presence of copious quantities of haem in the kidney necessitates clearance of\xa0haem; induction of haem oxygenase 1 and ferritin in the kidney protects against haem-induced oxidative stress.However, these mechanisms are not sufficient to avoid pathological outcomes instigated by cell-free haemoglobin, haem and iron during haemolytic conditions such as oxidative stress, nitric oxide depletion, inflammation and cell death.Haemoprotein-induced acute kidney injury is a multifactorial process, involving reactive oxygen species, labile iron and inflammation.Two main approaches exist for the treatment of haemolytic anaemias: treating the underlying disease to prevent the disintegration of red blood cells and mitigating the\xa0damage induced by released haemoproteins.