Intravascular haemolysis in severe
            <i>Plasmodium knowlesi</i>
            malaria: association with endothelial activation, microvascular dysfunction, and acute kidney injury

Barber, Bridget E.; Grigg, Matthew J.; Piera, Kim A.; William, Timothy; Cooper, Daniel J.; Plewes, Katherine; Dondorp, Arjen M.; Yeo, Tsin Wen; Anstey, Nicholas M.

doi:10.1038/s41426-018-0105-2

Cited by 49 publications

(45 citation statements)

References 59 publications

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“…In Malaysia, P. knowlesi now accounts for >90% of all malaria cases (Cooper et al, 2020). Severe P. knowlesi malaria is associated with haemolysis-induced endothelial activation leading to acute kidney injury (Barber et al, 2018a, Grigg et al, 2018. We found that P. knowlesi-infected RBCs exhibit a large increase in volume and a more moderate increase in surface area, resulting in an overall decrease in SA:V ratio and a consequent increase in MCD.…”

Section: Discussionmentioning

confidence: 78%

“…Despite the lack of adhesion, splenic rupture has been observed, suggesting blockage of sinusoidal vessels (Chang et al, 2018) and an autopsy of a fatal human knowlesi malaria case revealed brain capillaries congested with infected RBCs (Menezes et al, 2012). Acute kidney injury, potentially caused by chronic haemolysis, also contributes to severe pathology (Barber et al, 2018a). The molecular basis for the different pathologies remains poorly understood (Renia et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Surface area-to-volume ratio, not cellular rigidity, determines red blood cell traversal through small capillaries

Namvar

Blanch

Dixon

et al. 2020

Preprint

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SummaryThe remarkable deformability of red blood cells (RBCs) depends on the viscoelasticity of the plasma membrane and cell contents and the surface area to volume (SA:V) ratio; however, it remains unclear which of these factors is the key determinant for passage through small capillaries. We used a microfluidic device to examine the traversal of normal, stiffened, swollen, parasitised and immature RBCs. We show that dramatic stiffening of RBCs had no measurable effect on their ability to traverse small channels. By contrast, a moderate decrease in the SA:V ratio had a marked effect on the equivalent cylinder diameter that is traversable by RBCs of similar stiffness. We developed a finite element model that provides a coherent rationale for the experimental observations, based on the nonlinear mechanical behaviour of the RBC membrane skeleton. We conclude that the SA:V ratio should be given more prominence in studies of RBC pathologies.

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Section: Discussionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Surface area-to-volume ratio, not cellular rigidity, determines red blood cell traversal through small capillaries

Namvar

Blanch

Dixon

et al. 2020

Preprint

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“…Human malaria is caused by five different species of Plasmodium-P. falciparum, P. vivax, P. knowlesi, P. malariae and P. ovale. Acute kidney injury (AKI), is a frequent presentation in severe malaria which is associated with mortality [1][2][3][4][5]. Overall, AKI has been shown to have a global prevalence in about 20-50% hospitalized malaria cases [6,7].…”

Section: Introductionmentioning

confidence: 99%

Renal detection of Plasmodium falciparum, Plasmodium vivax and Plasmodium knowlesi in malaria associated acute kidney injury: a retrospective case–control study

et al. 2020

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Objective: Acute kidney injury (AKI) is a frequent presentation in malaria infections. Several cases of AKI that are accompanied by clinical symptoms of malaria infection, such as fever, nausea, respiratory distress, and anemia remain undiagnosed due to challenges in accurate diagnosis using peripheral blood microscopy and rapid diagnostic tests that are currently used in clinical settings. This is particularly true for P. vivax and P. knowlesi infections. As a result, these patients are not able to receive anti-malarial therapy in a timely manner. The objective of the present study was to investigate if patients presenting with AKI harbored any of the five human Plasmodium species (P. falciparum, P. vivax, P. knowlesi, P. malariae, and P. ovale) within their renal tissues. Results: We found that renal biopsies from malaria associated AKI patients harbor the human malaria parasites P. falciparum, P. vivax and P. knowlesi as mono-and mixed species infections. Presence of microvascular injury in a majority of the malaria associated AKI cases suggested vascular involvement of P. vivax and P. knowlesi. This research note also highlights P. knowlesi as an emerging pathogen in the Indian subcontinent.

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“…Pathogenesis of P. falciparum is attributed to its cytoadherence to endothelial cells of tissue capillaries. P.knowlesi-associated severe malaria, specifically AKI, is hypothesized to be due to the haemolysis of RBCs and subsequent release of cell-free haemoglobin leading to oxidative damage [10]. Additionally, P. knowlesi ex vivo cultures have been shown to bind to host endothelial receptors ICAM-1 and VCAM [11].…”

Section: Introductionmentioning

confidence: 99%

Renal Localization of Plasmodium vivax and Zoonotic Monkey Parasite Plasmodium knowlesi in Malaria Associated Acute Kidney Injury

Acharya

Pramanik

Kaur

et al. 2019

Preprint

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ObjectivesAcute kidney injury (AKI) is a frequent clinical manifestation of severe malaria. Although the pathogenesis of P. falciparum severity is attributed to cytoadherence, the pathogenesis due to P. vivax and P. knowlesi are not very well understood and their presence within the host tissue has not been demonstrated. Therefore, the objective of this study was to determine if P. vivax and P.knowlesi interact with host renal tissue in malarial AKI. MethodsArchival FFPE renal biopsies from 16 patients having AKI with suspected or confirmed malaria diagnosis, and 5 patients with non-malarial AKI, were subjected to histopathological analysis and DNA extraction. The total DNA from these renal biopsies was used to investigate the presence of the 5 species of human malaria parasite: P. falciparum, P. vivax, P. knowlesi, P.malariae and, P. ovale. The results of histopathology and PCR analysis were analyzed to understand the pathogenesis of malaria associated AKI. ResultsRenal biopsies from malarial AKI patients were found to harbor DNA from P. vivax (14 of 16), the zoonotic monkey parasite P. knowlesi (7) and P. falciparum (5) in the form of monoinfections as well as mixed infections. Sanger sequencing was used to confirm species identity.Histopathological analysis revealed the presence of microvascular injury as a common feature of P. vivax and P. knowlesi related AKI. Hemozoin could be detected within the renal tissue, which indicated the presence of metabolically active parasites. ConclusionsP. vivax and P. knowlesi associated AKI may involve interaction of the host renal tissue with parasite derived components such as Plasmodium DNA and hemozoin which may lead to innate immune activation and host tissue injury.

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Intravascular haemolysis in severe Plasmodium knowlesi malaria: association with endothelial activation, microvascular dysfunction, and acute kidney injury

Cited by 49 publications

References 59 publications

Surface area-to-volume ratio, not cellular rigidity, determines red blood cell traversal through small capillaries

Surface area-to-volume ratio, not cellular rigidity, determines red blood cell traversal through small capillaries

Renal detection of Plasmodium falciparum, Plasmodium vivax and Plasmodium knowlesi in malaria associated acute kidney injury: a retrospective case–control study

Renal Localization of Plasmodium vivax and Zoonotic Monkey Parasite Plasmodium knowlesi in Malaria Associated Acute Kidney Injury

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