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 resulting 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.
Key points
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Several 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.
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Free haemoproteins present in plasma are filtered by the kidney, exposing the kidney to the injurious effects of haem and iron.
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The presence of copious quantities of haem in the kidney necessitates clearance of haem; induction of haem oxygenase 1 and ferritin in the kidney protects against haem-induced oxidative stress.
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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.
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Haemoprotein-induced acute kidney injury is a multifactorial process, involving reactive oxygen species, labile iron and inflammation.
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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 damage induced by released haemoproteins.
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Glossary
- Sickle cell disease
-
(SCD). A β-globin disorder driven by haemoglobin S polymerization and characterized by recurrent vaso-occlusive episodes, the propensity of red blood cells to sickle and neutrophil recruitment. SCD alters renal function and causes various renal manifestations (sickle cell nephropathy).
- Thalassaemias
-
Common inherited monogenic haemoglobin disorders, characterized by an imbalance in the ratio of α-globin to β-globin chains, chronic haemolytic anaemia, ineffective erythropoiesis, compensatory haematopoietic expansion, a state of hypercoagulability and iron overload.
- Spherocytosis
-
Hereditary spherocytosis is a type of congenital haemolytic anaemia that results from genetic mutations in red blood cell membrane or cytoskeletal proteins involved in morphological stability and affects the ability of red blood cells to maintain their normal biconcave shape. The clinical manifestations vary based on the severity of disease and the type of mutation.
- Paroxysmal nocturnal haemoglobinuria
-
(PNH). A clonal haematopoietic disease caused by expansion of a stem cell that harbours a somatic mutation in PIGA. Red blood cells that harbour the mutation are deficient in the complement regulator proteins CD55 and CD59, increasing their susceptibility to intravascular haemolysis due to a failure to regulate the alternative pathway of complement.
- Autoimmune haemolytic anaemia
-
(AIHA). Caused by autoantibodies against red blood cells that can fix complement on the red blood cell surface and trigger haemolysis at excessive or uncompensated rates.
- Thrombotic microangiopathies
-
(TMA). A diverse group of syndromes that can be hereditary or acquired, characterized by vascular damage and capillary thrombosis with typical abnormalities in the endothelium and vessel wall. Clinical features include microangiopathic haemolytic anaemia and a procoagulant state, with or without damage to the kidneys and other organs.
- Haemolytic transfusion reaction
-
A clinical situation that involves transfusion-related ABO incompatibility with brisk complement-mediated lysis of red blood cells.
- Chemically induced anaemia
-
A form of extracorpuscular haemolytic disorder caused by exposure to chemical substances. Haemolytic anaemia induced by chemical agents might be particularly detrimental for people with hereditable haemolytic disorders (e.g. G6PD deficiency) and for people with pre-existing anaemia.
- Haemoglobin H disease
-
The most severe non-fatal form of α-thalassaemia, which occurs when only one normal α-globin gene has been inherited (compound heterozygosity). An insufficiency of α-globin chains results in inadequate formation of HbA (α2β2), resulting in an excess of β-globin chains, which become unstable and precipitate as HbH (β4), causing haemolysis.
- Schizont
-
A stage of the Plasmodium spp. life cycle that occurs following infection of red blood cells with Plasmodium merozoites. The schizont contains 16–32 merozoites and occurs within 40–48 hours of infection. Red blood cell egress releases merozoites into the bloodstream, where the cycle recommences.
- Haemoproteins
-
Proteins that contain a haem prosthetic group and are responsible for containing more than 80% of bioavailable iron in mammals. Based on the capacity of haem-iron to exchange electrons, haemoproteins play an essential role in a variety of vital cellular functions: the major haemoprotein pool in mammals is formed by haemoglobin in red blood cells and myoglobin in muscle cells. Another important compartment involves ubiquitously expressed cytochromes.
- Fenton reaction
-
A reaction that involves the transition of haem-iron from a ferrous to ferric state, generating Hb-Fe3+ (methaemoglobin) and highly reactive hydroxyl radicals. The participation of iron in the production of free radicals via this reaction is potentially cytotoxic.
- Favism
-
By far the most identifiable cause of acute haemolytic anaemia caused by glucose-6-phosphate dehydrogenase (G6PD) deficiency. Haemolysis of G6PD-deficient red blood cells (RBCs) arises because nicotinamide adenine dinucleotide phosphate (NADPH) generation is insufficient to provide antioxidant defence. Following exposure to highly reactive redox compounds released on ingestion of fava beans, G6PD-deficient RBCs cannot withstand the oxidative attack by fava bean glucosides, causing RBC destruction.
- Haemin
-
Haemin can be generated by haem oxidation, and consists of a protoporphyrin IX ring surrounding a single coordinated ferric iron (Fe3+) moiety instead of Fe2+.
- Ferritin
-
Multimeric complexes (~450 kDa) made of ferritin H (heavy) and ferritin L (light) chains. These heteropolymeric nanocage-like structures have ferroxidase activity that catalyses the conversion of Fe2+ into ferric Fe3+, allowing for intracellular storage and neutralization of inert ferric iron.
- Ferroportin 1
-
A 62 kDa transmembrane iron transporter that exports ferrous iron from cells when it accumulates above a threshold level. It is regulated by the iron regulatory hormone hepcidin, which binds ferroportin and induces its internalization and degradation.
- Haemosiderosis
-
Also known as iron storage disease, characterized by accelerated haemosiderin deposition at high cellular iron storage levels, causing an irreversible iron overload.
- Infiltrating neutrophils
-
In the circulation, neutrophils patrol tissues and drive aggressive responses after exposure to danger signals (sterile or triggered by microorganisms). This is accomplished by swift transmigration into the damaged tissue, where infiltrating neutrophils release reactive chemicals and proteases.
- Marginating neutrophils
-
Although intravascular, this pool of neutrophils remains reversibly but intimately associated with the endothelium, resisting the shearing forces of flowing blood.
- Clonal haematopoiesis
-
Uncontrolled expansion and clonal selection of one or more haematopoietic stem cells results in clonal evolution, which can compete with and — as described for PNH —overcome normal haematopoiesis. Selection for specific clones is most likely related to certain somatic mutations at the stem cell level or to changes in the haematopoietic niche.
- Haemosiderin
-
The non-ferritin constituent of iron stores, which accumulates as insoluble, aggregated deposits as the amount of cellular iron increases. It has no physiological role in iron metabolism but can sequester cellular iron waste.
- Acute chest syndrome
-
A form of acute lung injury and the second most common cause of hospital admission in patients with sickle cell disease, in whom it is associated with high mortality. It is caused by a combination of infection, fat embolism and vaso-occlusion of the pulmonary vasculature with subsequent development of a new alveolar pulmonary infiltrate.
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Van Avondt, K., Nur, E. & Zeerleder, S. Mechanisms of haemolysis-induced kidney injury. Nat Rev Nephrol 15, 671–692 (2019). https://doi.org/10.1038/s41581-019-0181-0
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DOI: https://doi.org/10.1038/s41581-019-0181-0
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