Methods to estimate baseline creatinine and define acute kidney injury in lean Ugandan children with severe malaria: a prospective cohort study

Abstract

Background: Acute kidney injury (AKI) is increasingly recognized as a consequential clinical complication in children with severe malaria. However, approaches to estimate baseline creatinine (bSCr) are not standardized in this unique patient population. Prior to wide-spread utilization, bSCr estimation methods need to be evaluated in many populations, particularly in children from low-income countries.

Methods: We evaluated six methods to estimate bSCr in Ugandan children aged 6 months to 12 years of age in two cohorts of children with severe malaria (n = 1078) and healthy community children (n = 289). Using isotope dilution mass spectrometry (IDMS)-traceable creatinine measures from community children, we evaluated the bias, accuracy and precision of estimating bSCr using height-dependent and height-independent estimated glomerular filtration (eGFR) equations to back-calculate bSCr or estimating bSCr directly using published or population-specific norms.

Results: We compared methods to estimate bSCr in healthy community children against the IDMS-traceable SCr measure. The Pottel-age based equation, assuming a normal GFR of 120 mL/min per 1.73m², was the more accurate method with minimal bias when compared to the Schwartz height-based equation. Using the different bSCr estimates, we demonstrated the prevalence of KDIGO-defined AKI in children with severe malaria ranged from 15.6-43.4%. The lowest estimate was derived using population upper levels of normal and the highest estimate was derived using the mean GFR of the community children (137 mL/min per 1.73m²) to back-calculate the bSCr. Irrespective of approach, AKI was strongly associated with mortality with a step-wise increase in mortality across AKI stages (p < 0.0001 for all). AKI defined using the Pottel-age based equation to estimate bSCr showed the strongest relationship with mortality with a risk ratio of 5.13 (95% CI 3.03-8.68) adjusting for child age and sex.

Conclusions: We recommend using height-independent age-based approaches to estimate bSCr in hospitalized children in sub-Saharan Africa due to challenges in accurate height measurements and undernutrition which may impact bSCr estimates. In this population the Pottel-age based GFR estimating equation obtained comparable bSCr estimates to population-based estimates in healthy children.

Keywords: Acute kidney injury; Baseline creatinine; Methods; Mortality; Pediatric; Pottel; Schwartz; Severe malaria; Sub-Saharan Africa; Undernutrition.

Fig. 1

Flow chart of the two study populations. Between 2008 and 2017, 289 community children and 1078 children with severe malaria were enrolled in two severe malaria studies that recruited children from Kampala and Jinja in Uganda. One community child from each cohort with evidence of underlying kidney disease (estimated GFR < 90 mL/min per 1.73m²) was excluded from the study

Fig. 2

Overview of approaches used to evaluate estimates of baseline serum creatinine. a Overview of GFR-based and direct SCr-based methods to estimate baseline serum creatinine (bSCr) in community children. Linear regression models using the height and age of community children were used for direct estimation of ebSCr_heightCC and ebSCr_ageCC. b The estimated bSCr and measured SCr were compared in community children to evaluate the bias, precision and accuracy of methods. c AKI was defined in children with severe malaria using the different approaches to estimate bSCr, and the relationship between AKI and mortality was evaluated

Fig. 3

Estimated GFR and bSCr in healthy community children based on method to estimate bSCr. Graphs showing the GFR calculated off the estimated bSCr using the Bedside Schwartz equation on the left y-axis in black and the estimated bSCr in grey on the right y-axis. The top row represents approaches starting with an assumed GFR and back-calculating bSCr using either the Bedside Schwartz equation (a, c) or the Pottel height-independent equation (b). The bottom row represents approaches to estimate bSCr directly using the upper limit of normal (d) or height (e) and age (f) based estimates from community children. The eGFR for each graph was calculated using the Bedside Schwartz equation using the bSCr and height at enrollment, where eGFR = (0.413*height)/bSCr

Fig. 4

Bland Altman analysis comparing measured SCr in community children versus different methods to estimate bSCr. Graphs show the difference in estimated baseline SCr (bSCr) and measured (mSCr) compared to the average. The top row represents approaches starting with an assumed GFR and back-calculating bSCr using either the Bedside Schwartz equation (a, c) or the Pottel height-independent equation (b). The bottom row represents approaches to estimate bSCr directly using the upper limit of normal (d) or height (e) and age (f) based estimates from the community children. The bias represents the difference between the mSCr and estimated bSCr where the significance of bias was assessed using a one sample t-test comparing the mean bias to 0. The precision is represented as one standard deviation of the mean difference. Proportional bias was evaluated by testing if the slope of the linear regression model of the differences between estimated and measured creatinine against the average of estimated and measured creatinine differed from zero. Proportional bias represents the slope (B1) + SE (standard error) and the asterisks indicate whether the slope is statistically different from zero. Not significant (NS, where p > 0.05), *p < 0.05, **p < 0.001, ***p < 0.0001

Fig. 5

AKI prevalence and mortality across AKI stages and age categories in children with severe malaria. Bar graphs showing the frequency of AKI (a, c) or AKI mortality (b, d) using different approaches to estimate baseline serum creatinine (bSCr). b AKI severity was associated with increased mortality irrespective of method used to estimate bSCr (p < 0.0001 for all, Pearson’s Chi square test). c AKI prevalence differed across age categories when GFR based methods were used to estimate bSCr *p < 0.05. There was no difference in AKI prevalence when using approaches to directly estimate SCr (ns, p > 0.05). d AKI was associated with increased mortality across age categories