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Acute kidney injury (AKI) is emerging as a complication of increasing clinical importance associated with substantial morbidity and mortality in African children with severe malaria. Using the Kidney Disease: Improving Global Outcomes (KDIGO) criteria to define AKI, an estimated 24–59% of African children with severe malaria have AKI with most AKI community-acquired. AKI is a risk factor for mortality in pediatric severe malaria with a stepwise increase in mortality across AKI stages. AKI is also a risk factor for postdischarge mortality and is associated with increased long-term risk of neurocognitive impairment and behavioral problems in survivors. Following injury, the kidney undergoes a process of recovery and repair. AKI is an established risk factor for chronic kidney disease and hypertension in survivors and is associated with an increased risk of chronic kidney disease in severe malaria survivors. The magnitude of the risk and contribution of malaria-associated AKI to chronic kidney disease in malaria-endemic areas remains undetermined. Pathways associated with AKI pathogenesis in the context of pediatric severe malaria are not well understood, but there is emerging evidence that immune activation, endothelial dysfunction, and hemolysis-mediated oxidative stress all directly contribute to kidney injury. In this review, we outline the KDIGO bundle of care and highlight how this could be applied in the context of severe malaria to improve kidney perfusion, reduce AKI progression, and improve survival. With increased recognition that AKI in severe malaria is associated with substantial post-discharge morbidity and long-term risk of chronic kidney disease, there is a need to increase AKI recognition through enhanced access to creatinine-based and next-generation biomarker diagnostics. Long-term studies to assess severe malaria-associated AKI’s impact on long-term health in malaria-endemic areas are urgently needed.
In the past few years, there have been efforts to validate GFR estimating equations within adult populations in sub-Saharan Africa,33–35 but data from pediatric populations are lacking.36 Additional studies to evaluate and standardize approaches to estimate baseline AKI across the pediatric age-spectrum for low-and-middle-income countries are needed to facilitate comparisons across populations and age groups in LMIC and high-income countries (HIC). Adaptations to the KDIGO guidelines have been proposed in situations where it is challenging to define normal creatinine levels because of rapidly changing levels or in situations where estimates of normal creatinine are lacking. For example, creatinine trajectories in neonates are affected by maternal creatinine levels, gestational age, and innate kidney function.37 Thus, within the first week of life, a ≥0.3mg/dL rise in creatinine outperforms a percent creatinine change in predicting mortality in neonates (the Assessment of Worldwide Acute Kidney Epidemiology in Neonates, AWAKEN study).37 While there have been attempts to evaluate normal baseline creatinine in populations of Ugandan children 6 months to 12 years of age,38 additional research is needed to evaluate methods to estimate baseline creatinine across pediatric populations in LMIC, particularly infants <6 months of age. Pre-illness baseline creatinine levels are not available in most—if not all— children. If baseline creatinine is not known in children, it must be estimated. The approach to estimate baseline serum creatinine can lead to substantial differences in AKI incidence and outcome associations.38,39 There are two main approaches to estimate baseline creatinine: i) use a known measure from the child; or ii) use population-based estimates (discussed here40). Patient-specific approaches are best suited in situations where underlying kidney disease is suspected or during a period of rapid changes in creatinine. Examples where patient-specific trajectories in creatinine are most appropriate to estimate baseline include: i) neonates where creatinine levels initially reflect maternal levels, are affected by gestational age, and there are rapid changes in postnatal creatinine levels; ii) children with severe malnutrition where creatinine levels are expected to deviate from population-normal levels; or iii) children with known or suspected chronic kidney disease (CKD). As most AKI in LMIC is community-acquired and present at hospital admission, using the admission creatinine will lead to vast underestimation of AKI. A recent study in Ghana using the admission creatinine as baseline noted an AKI frequency of 2%27 compared to 32–59% using population approaches.13–16 A study in Ugandan children with serial creatinine measurements over the first four days of hospitalization estimated 79% of AKI cases were present on admission.41 Another approach to estimate baseline would be to use the discharge or nadir creatinine measure over hospitalization. However, an estimated 7–25% of children do not recover within 10–50% of baseline creatinine.9,42 Using the discharge creatinine may: i) underestimate AKI, and ii) fail to identify children with persistent kidney injury in need of clinical follow-up. AKI can also be defined using urine output. A large, retrospective study supported the importance of urine output, finding that 67% of patients diagnosed with AKI by urine output criteria would not have been diagnosed if only plasma creatinine criteria was used.43 Furthermore, the adverse outcomes associated with oliguria but not a rise in serum creatinine were comparable to those found in patients who had a rise in serum creatinine alone.43 Notably, in a retrospective study of adults, patients with both oliguria and a rise in serum creatinine had worse outcomes than patients who only met one KDIGO criteria.44 In practice in many LMICs, urine output is often not assessed in hospitalized children and is difficult to quantify in patients without an indwelling catheter. However, given the importance of urine output in defining AKI, efforts should be made to quantify urine output in hospitalized children, particularly as it does not rely on laboratory testing and is a bedside measure. Whenever feasible, urine output should be quantified at the bedside from toilet trained children or by using pre-weighed, absorbent diapers. When using diapers, efforts should be made to avoid stool contamination by frequently changing diapers or using urine bags with adhesive edges to collect urine. The effect of humidity should also be considered. In high humidity environments, urine output may be overestimated, while in low humidity environments, the impact of evaporative loss can lead to underestimation of urine output.45,46 In low-resource settings where limitations in nursing care make assessment of urine output challenging, it may be possible to train caregivers to provide support.
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