Malaria guidelines fall short in diagnosing acute kidney injury

Abstract

Malaria is responsible for more than 1000 deaths of African children every day and, 95% of all deaths due to malaria occur in Africa.1WHO World malaria report 2022. Geneva, 2022Google Scholar Progress in reducing malaria mortality stalled during the COVID-19 pandemic and additional challenges include emerging resistance to first-line therapies for severe malaria and the discovery of invasive vector species in the horn of Africa.1WHO World malaria report 2022. Geneva, 2022Google Scholar Acute kidney injury is a frequent life-threatening complication of severe malaria that can have major implications for health-care costs—often unaffordable in settings with few health-care resources—resulting in increased risk of death and long-term morbidity.2Daher EF da Silva Jr, GB Trivedi M et al.Kidney complications of parasitic diseases.Nat Rev Nephrol. 2022; 18: 396-406Google Scholar A misconception about severe malaria is that acute kidney injury is a rare complication in young children and more common in older children and adults.3WHO Severe malaria..Trop Med Int Health. 2014; 19: 7-131PubMed Google Scholar This misconception is driven, in part, by the WHO definition of acute kidney injury. WHO severe malaria guidelines, in place since 2014 (last updated October, 20234WHO WHO guidelines for malaria. World Health Organization, Geneva2023Google Scholar), define acute kidney injury or renal impairment as a single serum creatinine threshold of greater than 3 mg/dL (>265 μmol/L) or urea greater than 120 mg/dL (>20 mmol/L).3WHO Severe malaria..Trop Med Int Health. 2014; 19: 7-131PubMed Google Scholar These thresholds are approximately three times higher than the typical values in adults (figure; typical values are substantially lower in children and vary by age, size, and gender)5Pottel H Vrydags N Mahieu B Vandewynckele E Croes K Martens F Establishing age/sex related serum creatinine reference intervals from hospital laboratory data based on different statistical methods.Clin Chim Acta. 2008; 396: 49-55Crossref PubMed Scopus (143) Google Scholar and therefore only detect late-stage, severe acute kidney injury, obviating any opportunity for early diagnosis and intervention. WHO guidelines are the foundation of clinical treatment guidelines in high-burden endemic countries. As shown in the figure, the creatinine threshold in the WHO definition leads to misclassification of acute kidney injury in both adults and children and only allows for the identification of late-stage acute kidney injury. This is concerning, given that early recognition of acute kidney injury can allow interventions to prevent or attenuate kidney injury; that late-stage acute kidney injury can require dialysis for survival, which is often unavailable or unaffordable in regions with high risk of severe malaria; and that the long-term risk of chronic kidney disease and death are both increased with increasing severity of acute kidney injury.6Mehta RL Cerdá J Burdmann EA et al.International Society of Nephrology's 0by25 initiative for acute kidney injury (zero preventable deaths by 2025): a human rights case for nephrology.Lancet. 2015; 385: 2616-2643Summary Full Text Full Text PDF PubMed Scopus (724) Google Scholar There is, therefore, an urgent need to include appropriate acute kidney injury definitions in updated guidelines for the management of severe malaria. Acute kidney injury occurs in up to 45% of adults with severe malaria and is associated with mortality rates up to 75% when dialysis is needed but unavailable.2Daher EF da Silva Jr, GB Trivedi M et al.Kidney complications of parasitic diseases.Nat Rev Nephrol. 2022; 18: 396-406Google Scholar Data suggest an incidence of acute kidney injury in children similar to or higher than that observed in adults, with an estimated 25% of children with acute kidney injury having a clinical indication for dialysis on admission.7Batte A Berrens Z Murphy K et al.Malaria-associated acute kidney injury in African Children: prevalence, pathophysiology, impact, and management challenges.Int J Nephrol Renovasc Dis. 2021; 14: 235-253Crossref PubMed Scopus (25) Google Scholar However, many studies use variable thresholds for acute kidney injury, and therefore the true incidence of acute kidney injury in malaria remains unclear. Perspectives on acute kidney injury in paediatric severe malaria began to change following a study in which the blood urea nitrogen threshold for renal impairment was lowered from 57 mg/dL to 20 mg/dL, and blood urea nitrogen concentration was identified as an independent predictor of mortality in African children.8von Seidlein L Olaosebikan R Hendriksen IC et al.Predicting the clinical outcome of severe falciparum malaria in African children: findings from a large randomized trial.Clin Infect Dis. 2012; 54: 1080-1090Crossref PubMed Scopus (133) Google Scholar Subsequent studies using the broadly established Kidney Disease Improving Global Outcomes (KDIGO) definitions of acute kidney injury reported an acute kidney injury incidence of 25–59% in children with severe malaria.7Batte A Berrens Z Murphy K et al.Malaria-associated acute kidney injury in African Children: prevalence, pathophysiology, impact, and management challenges.Int J Nephrol Renovasc Dis. 2021; 14: 235-253Crossref PubMed Scopus (25) Google Scholar However, when using the WHO threshold in 1078 Ugandan children younger than 13 years, only 2% of children with KDIGO-defined acute kidney injury had a creatinine that surpassed the WHO threshold, meaning that 98% of the children with acute kidney injury would have been missed.7Batte A Berrens Z Murphy K et al.Malaria-associated acute kidney injury in African Children: prevalence, pathophysiology, impact, and management challenges.Int J Nephrol Renovasc Dis. 2021; 14: 235-253Crossref PubMed Scopus (25) Google Scholar KDIGO consensus guidelines define three stages of acute kidney injury on the basis of an increase in serum creatinine greater than or equal to 1∙5 times higher than baseline, or a decrease in urine output (<0∙5 mL/kg per h for at least 6 h).9KDIGO KDIGO clinical practice guideline for acute kidney injury.Kidney Int Suppl. 2012; 2: 1-138Summary Full Text Full Text PDF Scopus (2329) Google Scholar Baseline can be defined with a pre-illness creatinine value, if known, or a population reference. KDIGO guidelines also consider typical age-related changes in serum creatinine and can therefore be used to diagnose acute kidney injury across the lifespan and at early, potentially reversible stages. The 2023 WHO definition of acute kidney injury in severe malaria would therefore only detect stage 3 acute kidney injury; the stage at which acute kidney failure is present or imminent, and dialysis is often required for survival. WHO guidelines recommend routine creatinine testing with frequent monitoring of kidney function in people with evidence of acute kidney injury and early initiation of renal replacement therapy before kidney function is severely compromised.3WHO Severe malaria..Trop Med Int Health. 2014; 19: 7-131PubMed Google Scholar The change in acute kidney injury threshold—a combination of sensitivity and not recognising normal developmental changes in creatinine—is a call for developmentally appropriate definitions to facilitate recognition of acute kidney injury in children, the population most affected by severe malaria. Changes in acute kidney injury thresholds will necessitate updates to national treatment guidelines, and these will, in turn, require appropriate training of health-care workers and appropriate diagnostic capacity.10Mottes T Menon S Conroy A et al.Pediatric AKI in the real world: changing outcomes through education and advocacy–a report from the 26th Acute Disease Quality Initiative (ADQI) consensus conference..Pediatr Nephrol. 2023; (published online Nov 7. https://doi.org/10.1007/s00467-023-06180-w)Google Scholar Although testing for acute kidney injury with the KDIGO criteria is feasible at a primary care level, the necessary diagnostic capacity is not always available11Macedo E Hemmila U Sharma SK et al.Recognition and management of community-acquired acute kidney injury in low-resource settings in the ISN 0by25 trial: a multi-country feasibility study.PLoS Med. 2021; 18: e1003408Crossref PubMed Google Scholar, 12Htay H Alrukhaimi M Ashuntantang GE et al.Global access of patients with kidney disease to health technologies and medications: findings from the Global Kidney Health Atlas project.Kidney Int Suppl (2011). 2018; 8: 64-73Summary Full Text Full Text PDF Scopus (0) Google Scholar despite creatinine being part of the WHO essential in vitro diagnostics list.13WHO The selection and use of essential in vitro diagnostics. World Health Organization, Geneva2023Google Scholar The cost-effectiveness of a comprehensive AKI care programme in countries with high burdens of malaria is unknown, and studies in this area should be prioritised. In 2015, the International Society of Nephrology launched the 0by25 initiative to eliminate avoidable deaths from acute kidney injury by 2025.6Mehta RL Cerdá J Burdmann EA et al.International Society of Nephrology's 0by25 initiative for acute kidney injury (zero preventable deaths by 2025): a human rights case for nephrology.Lancet. 2015; 385: 2616-2643Summary Full Text Full Text PDF PubMed Scopus (724) Google Scholar Given the important prevalence and accompanying morbidity and mortality of acute kidney injury in children with severe malaria and the increasing rates and risks of severe malaria, children are a priority population. Adoption of the KDIGO definition of acute kidney injury by WHO would support early recognition and treatment of acute kidney injury in children and adults with severe malaria. Early treatment through enhanced recognition and initiation of kidney protective measures, and engaging nephrology teams early, has the potential to prevent worsening of acute kidney injury and potentially avert the need for dialysis in settings where access is severely restricted. Efforts to improve recognition and treatment of acute kidney injury in children could translate into improved long-term kidney health in populations affected by malaria. The authors declare no competing interests. This Comment was supported by the National Institutes of Health project grant from the National Institutes of Allergy and Infectious Diseases (R01AI165946) to ALC