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The role of platelets in acute kidney injury

Nature Reviews Nephrologyvolume 14pages457471 (2018) | Download Citation


Acute kidney injury (AKI), a major public health problem associated with high mortality and increased risk of progression towards end-stage renal disease, is characterized by the activation of intra-renal haemostatic and inflammatory processes. Platelets, which are present in high numbers in the circulation and can rapidly release a broad spectrum of bioactive mediators, are important acute modulators of inflammation and haemostasis, as they are the first cells to arrive at sites of acute injury, where they interact with endothelial cells and leukocytes. Diminished control of platelet reactivity by endothelial cells and/or an increased release of platelet-activating mediators can lead to uncontrolled platelet activation in AKI. As increased platelet sequestration and increased expression levels of the markers P-selectin, thromboxane A2, CC-chemokine ligand 5 and platelet factor 4 on platelets have been reported in kidneys following AKI, platelet activation likely plays a part in AKI pathology. Results from animal models and some clinical studies highlight the potential of antiplatelet therapies in the preservation of renal function in the context of AKI, but as current strategies also affect other cell types and non-platelet-derived mediators, additional studies are required to further elucidate the extent of platelet contribution to the pathology of AKI and to determine the best therapeutic approach by which to specifically target related pathogenic pathways.

Key points

  • Both ischaemia–reperfusion and systemic inflammation lead to alterations in the renal macrocirculation and microcirculation that often result in poorly controlled inflammatory and haemostatic responses, thereby causing irreversible renal tissue damage.

  • Platelets are the first cells to arrive at sites of acute injury, where they interact with endothelial cells and leukocytes.

  • Activation of platelets during acute kidney injury (AKI) may be exaggerated owing to an excess of platelet stimuli in combination with diminished antiplatelet regulation.

  • Platelets are important acute modulators of haemostasis and likely disturb renal haemodynamic processes during AKI, which leads to sustained hypoxaemic renal tissue injury.

  • Platelets facilitate inflammation during the pathophysiology of AKI, mainly by stimulating endothelial cells as well as by recruiting and activating leukocytes during the inflammatory reaction.

  • Early data from animal and human studies and from randomized clinical trials suggest that antiplatelet therapies will reduce the risk of AKI.

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J.J.T.H.R. is supported by The Netherlands Organisation for Health Research and Development (Clinical Fellowship grant #40-00703-97-12480) and by the Dutch Kidney Foundation (grant #KJP10.017).

Reviewer information

Nature Reviews Nephrology thanks B. Kerlin, A. Zarbock and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands

    • Marcel P. B. Jansen
    • , Sandrine Florquin
    •  & Joris J. T. H. Roelofs


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M.P.B.J. researched data for the article and wrote the manuscript. M.P.B.J. and J.J.T.H.R. substantially contributed to the discussion of the content. All authors reviewed and edited the manuscript before submission.

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The authors declare no competing interests.

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Correspondence to Joris J. T. H. Roelofs.



A serine protease that plays a key part in the coagulation cascade. Thrombin is generated from prothrombin by proteolytic cleavage that is mediated by blood coagulation factor X. This activation also releases prothrombin fragment 1.2, which can be used clinically as a coagulation marker.


The most abundant storage platelet granules (50–80 granules per platelet) containing membrane-bound proteins such as P-selectin and soluble proteins such as platelet factor 4 (PF4) that are either expressed on the platelet surface or released into the extracellular space following platelet activation.


A layer of proteoglycans that line the luminal endothelial surface, providing a physical barrier that prevents the adhesion and subsequent activation of platelets by endothelial components.


(PGI2). A prostaglandin member of the eicosanoid family of lipid molecules that is released from the endothelium. PGI2 release inhibits platelet activation and has a role in the maintenance of a nonthrombotic barrier between the vessel wall and the blood. PGI2 is also an effective vasodilator.

Ectonucleoside triphosphate diphosphohydrolase 1

(NTPDase 1). A membrane-anchored glycoprotein with ecto-apyrase activity that rapidly hydrolyses ATP and ADP into AMP.

Weibel–Palade bodies

Endothelial-specific secretory granules that contain a variety of bioactive molecules that play a part in inflammation and haemostasis and are released by exocytosis upon endothelial activation.

Extrinsic coagulation pathway

A branch of the coagulation pathway that begins with initiation of the coagulation cascade in response to tissue factor exposure (for example, as a result of tissue injury), leading to thrombin generation.

Danger-associated molecular patterns

(DAMPs). Molecules released by stressed cells undergoing necrosis that act as endogenous danger signals to promote and exacerbate the inflammatory response.


A process in which particles (such as bacteria) are marked for immune cell destruction through phagocytosis.


A decrease in plasma volume that causes an increase in the concentration of circulating blood cells. Haemoconcentration facilitates the inflammatory process by allowing increased endothelial cell–leukocyte contact.

Caecal ligation and puncture

A method used in animal models to induce polymicrobial sepsis for studying the progression and characteristics of human sepsis.

Chimeric mice

Mice composed of cells with distinct genotypes.

Intravital imaging

A form of microscopy that allows the capture of images of biological processes in vivo at a high resolution.


A family of eicosanoid inflammatory mediators (such as leukotriene B4) that are produced in leukocytes by oxidation of arachidonic acid and the essential fatty acid eicosapentaenoic acid by the enzyme arachidonate 5-lipoxygenase.

Systemic inflammatory response syndrome

(SIRS). An excessive immune response triggered by a non-infectious agent as a result of trauma, burn or acute pancreatitis.

Reactive oxygen species

(ROS). Highly reactive chemical species containing oxygen, which have important roles in processes such as cell signalling, homeostasis and defence against pathogens.

Histone citrullination

An epigenetic post-translational modification in which arginine is converted to citrulline on histones, thereby affecting chromatin structure.

Phosphodiesterase inhibitors

A class of platelet activation inhibitors that interfere with the breakdown of intracellular cyclic nucleotides (cGMP and cAMP) by reversible binding to phosphodiesterases, thereby increasing their concentration.


A class of small-molecule inhibitors that irreversibly bind to the ADP-binding pocket of P2Y purinoreceptor 12 (P2Y12) on platelets.

Thrombotic microangiopathy

A pathology that results in thrombosis in capillaries and arterioles owing to an endothelial injury.


A type of biologically active lipid that forms a subclass of the eicosanoid family. Prostanoids are formed from the metabolism of arachidonic acid by the action of cyclooxygenase (COX) enzymes and include prostaglandin E2 (PGE2), thromboxanes (such as thromboxane A2 (TxA2)), prostacyclin (PGI2), prostaglandin F2A (PGF2A) and prostaglandin D2 (PGD2), each of which is involved in some aspect of the inflammatory response.

Propensity score

A statistical matching technique that attempts to estimate the effect of an intervention by accounting for the covariates that predict receiving the treatment.

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