Severe malaria is a medical emergency due to vital organ dysfunction resulting from sequestered parasitised red blood cells in the microvasculature. The risk of death is highly dependent on the clinical presentation and the organs affected. Renal impairment is common in adults but was thought to be unusual in children. However, the thresholds used to define severe renal impairment in adults (e.g. a creatinine threshold of 3 mg/dL or 250 mmol/L) are inappropriate for children due to differences in muscle mass. Creatinine values are a function of muscle mass, so the threshold of 3 mg/dL reflects a much greater reduction in glomerular filtration rate (GFR) in children, particularly the youngest children, than it does in adults. We therefore propose to standardise definitions of renal impairments for adults and children by comparing the prognostic values of specific thresholds. This will allow for an evidence-based assessment of optimal thresholds to be used in clinical management to identify children with severe malaria.

Severe falciparum malaria is vital organ dysfunction resulting from parasitised red blood cells and associated with an increased risk of death. It results from a high parasite biomass and vital organ sequestration. Severe malaria is a medical emergency requiring rapid assessment and immediate treatment with artesunate, preferably by the parenteral route. The exact definition of severe malaria depends on the context and purpose of the definition.
 

There are two main purposes for a definition of severe malaria:
1. To guide clinical management (broad, inclusive)
2. To guide clinical, therapeutic, and epidemiologic research (narrower)

One of the key components of severe malaria is renal impairment. Acute kidney injury (AKI) is a common manifestation in adults, often requiring renal replacement therapies, but AKI has been considered rare in children. Recent large clinical studies show that AKI is common in children and may have been underestimated previously because biochemical thresholds are lower in children than in adults.
The current WHO Practical Handbook on the management of severe malaria defines renal impairment using a single creatinine threshold of 3 mg/dL (250μmol/L) for both adults and children. Given that baseline creatinine values are a function of muscle mass, this threshold reflects a much greater reduction in glomerular filtration rate (GFR) in children, particularly the
youngest children, than it does in adults.
We propose standardising definitions of renal impairment for adults and children by comparing the prognostic values of specific thresholds. This will allow for an evidence-based assessment of optimal thresholds to be used in clinical management to identify children with severe malaria. The consensus thresholds will then be used for the update of the WHO Practical Handbook.
 

The goal of this study group is to pool data from severe malaria studies in children and adults in
order to answer the following questions:
1. What are equivalent thresholds (where equivalence is defined in relationship to expected mortality) for creatinine and urea values in children and adults. In particular, what paediatric and adult creatinine (or blood urea) thresholds are associated with greater than 5% mortality in severe malaria? The objective is not to define criteria for renal impairment per-se but to provide
thresholds for increased risk of a fatal outcome to direct appropriate intensive care.
2. What is the comparative prognostic utility of blood/plasma/serum urea (or blood urea nitrogen) versus plasma/serum creatinine concentration? This is important to consider which thresholds are more useful, as both measurements are not always available.
It is acknowledged that other measures of GFR, and access to specialist nephrology support are usually unavailable where severe malaria is first managed.
 

The primary analysis will be a series of univariate regression models examining the relationship between the absolute creatinine and blood urea values measured (with appropriate adjustments) and the expected mortality across studies.
Important meta-data will include patient demographics, clinical manifestations, and other clinical and laboratory measures.
In patients where both urea and creatinine measurements are available, we will assess agreement, and look for systematic differences due to variation in laboratory techniques.
A pooled meta-analysis will add random effect intercept terms. We will also look at the prognostic value of fold changes relative to age-standardised baseline values. Models will be compared and assessed using R2 for logistic regression models.

The Study Group comprises participating investigators who contribute relevant data to the pooled analysis. Data will remain the property of the investigator. The Study Group collectively makes decisions with respect to including additional studies, data analysis and plans for publication, in line with the WWARN Publication Policy of April 2019. The Study Group will identify one or two people to coordinate activities including data analysis, and drafting of publications and reports for group review. The study group statistician(s) will be responsible for statistical analyses.

This research project is funded by the World Health Organisation (WHO) and Wellcome.