| Summary: | Acute kidney injury (AKI) complicating severe falciparum malaria is an independent predictor of death in children and adults, however the magnitude of the problem in both populations is unclear due to divergent AKI definitions. Late recognition of this serious complication results in a mortality of up to 75% without renal replacement therapy, which is frequently unavailable. The aim of this thesis was to characterise malaria-associated AKI along the spectrum of this syndrome, evaluate the pathophysiology and assess the role of paracetamol as a renoprotective adjunctive therapy for the management of severe and moderately severe falciparum malaria. The main findings of the studies described here include: (1) The incidence of malaria-associated AKI is underrecognised as mild AKI is underreported. AKI defined by the Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition identifies mild AKI and is strongly associated with mortality. (2) Sequestered parasite burden, immune activation, cell-free haemoglobin and lipid peroxidation contribute to the pathophysiology of AKI in severe malaria. The proposed mechanism of kidney injury mediated by cell-free haemoglobin is oxidative damage by ferryl (Fe4+)-haemoglobin, which can be reduced by paracetamol. (3) Paracetamol tablets administered at the maximum recommended adult dose (4 g/day) results in sub-therapeutic steady state concentrations for antipyresis in severe and moderately severe malaria in adults, and simulations suggest a loading dose might be indicated. (4) In a randomised controlled trial, it was shown that paracetamol reduces kidney dysfunction and the odds of developing AKI in severe and moderately severe malaria in adults. The protective effect was particularly prominent in patients with high plasma concentrations of cell-free haemoglobin resulting from pronounced intravascular haemolysis. In conclusion, this thesis shows that AKI defined by the harmonized KDIGO classification system is associated with mortality in falciparum malaria. Multiple mechanisms contribute to the pathophysiology of AKI in malaria and targeted preventative treatment with paracetamol reduces kidney dysfunction associated with high cell-free haemoglobin. The definition of AKI in the WHO malaria guidelines should be reconsidered. A larger trial of the use of paracetamol to reduce kidney dysfunction in severe malaria is warranted.
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