WCN24-2067 Regional differences in acute kidney injury in Ugandan children hospitalized for Hypoxemia

Introduction: Acute kidney injury (AKI) is associated with increased mortality in hospitalized patients and incidence is highest in resource limited settings. The objective of this study was to assess sub-National regional differences in the incidence of AKI in children \u3c5 years of age hospitalized with an acute febrile illness and hypoxemia. Methods: This was a secondary analysis of a stepped wedge cluster randomized controlled trial, which enrolled children \u3c5 years of age hospitalized with hypoxemia between 2019 and 2021. At least one measure of kidney function was available in 1452 children. A single creatinine was measured at enrolment in a sub-set of 495 children with serum stored and AKI defined using KDIGO criteria where baseline creatinine was estimated using the age-based Pottel equation assuming a normal glomerular filtration rate of 120mL/min per 1.73m2. Markers were divided into structural (uNGAL positive, proteinuria, hematuria) or functional (AKI, saliva urea nitrogen (SUN)) measures of kidney injury. Results: 1452 children were included in this AKI sub-study (Figure 1). The mean age of participants was 1.49 years (standard deviation (SD), 1.21) and 55.7% were male (809/1452). Overall 2.6% of children died (38/1452). The majority of participants enrolled were from the West (31.3%) followed by the East (25.3%), North (24.1%), and Central (19.4%) regions. In general, 48.5% of children had AKI (240/495), the prevalence was highest in Eastern Uganda with 62.4% of children having AKI compared to 25.0% of children in Western Uganda, 44% in Central region and 53% in Northern region (p\u3c0.001). Over a third of children had urine NGAL levels ≥150ng/mL, a marker of structural damage, irrespective of site and rates comparable across sites (p=0.095). Other measures of functional and structural kidney injury varied across sites, proteinuria ranged from 6.3% to 14.0% with rates lower in Central and Eastern Uganda compared to Northern and Western Uganda. Hematuria was over two times more common in Eastern and Northern Uganda compared to Central and Western Uganda. Of all the children 49.0 % were positive for malaria based on rapid diagnostic test (RDT) either as positive pLDH or both pLDH and HRP-2. The presence of a single band positive RDT for HRP-2 alone was associated with increased risk of AKI, severe AKI, elevated BUN, a positive SUN test and urinalysis positive for hematuria or urobilinogen (unadjusted p\u3c0.05). Children with a 3-band positive RDT were more likely to have proteinuria, hematuria, bilirubinuria and urobilinogen by dipstick (unadjusted p\u3c0.05). Regional differences in AKI persisted after adjusting for malaria, age, and sex. Conclusions: As we move towards the ISN 0by25 initiative which aims to eliminate preventable deaths from AKI worldwide by 2025. This study provides key in-country data from a resource limited setting, demonstrating marked regional differences in the incidence of AKI in children hospitalized with hypoxaemia and malaria remains an important predictor of AKI. The substantial within-country heterogeneity of AKI highlights the need for further studies to evaluate regional contributors to local patterns of AKI

WCN24-931 AKI Phenotypes in Ugandan children hospitalized with Hypoxemia and Malaria

Introduction: Acute kidney injury (AKI) is a frequent life-threatening complication in hospitalized children. Emerging data suggest AKI is a heterogeneous condition that varies based on the underlying cause and is composed of distinct phenotypes. The objective of this study was to define AKI phenotypes using proposed classification systems in Ugandan children hospitalized with hypoxemia and to evaluate differences in phenotypes by malaria infection. Methods: Between 2019 and 2021, 2402 Ugandan children \u3c5 years of age hospitalized with hypoxemia were enrolled in a cluster randomized trial of solar powered oxygen delivery across 20 districts in Uganda. At enrollment, urine NGAL was measured using a point-of-care lateral flow test with a positive test defined as a level ≥150ng/mL. Malaria was assessed using a threeband rapid diagnostic test. In an extended sub-study, 491 children had creatinine measured to define AKI. AKI was defined using a single creatinine measure at enrolment and phenotypically characterized using two acute dialysis quality initiative (ADQI) proposed AKI phenotypes. The AKI biomarker definition incorporated urine NGAL into the KDIGO definition[group 1, no AKI; group 2, subclinical AKI (biomarker positive); group 3, AKI; group 4, biomarker positive AKI]. The ADQI sepsis AKI phenotype groups stage 1 AKI as sepsis phenotype (SP)-1 irrespective of biomarker status and differentiates severe AKI (stage 2/3) based on biomarker positivity where severe AKI that is biomarker negative is (SP2) and severe biomarker positive AKI is SP3. Results: Overall, 491 children were included in the extended study with AKI defined and uNGAL measured. The median age was 1.3 years (interquartile range, 0.7 to 2.3) and 53.8% of children were male. There were 4 deaths (0.8%) and 24 children required transfer to a higher-level health facility (4.9%). Among children included, 91.2% met a clinical definition of pneumonia and 49.5% were positive for malaria. The frequency of creatinine defined AKI was 32.0% (157/491) and 36.5% (179/491) were biomarker positive. AKI was associated with a 3.24-fold increase in mortality (95% CI 0.34 to 31.4) but underpowered to show a difference. In children without malaria, 17.7% were biomarker positive and AKI negative (subclinical AKI, 44/248) while 37.5% of children had AKI (93/284) of whom 39.8% (37/93) were biomarker positive. In children with malaria, 14.0% had subclinical AKI, 34/243), 59.3% had AKI (144/243) with 44.4% of AKI cases biomarker positive (64/144). Children with malaria had a higher frequency of AKI compared to children without malaria (59.6% vs. 37.6%, p\u3c0.001) but comparable frequency of a positive biomarker test (41.3% vs. 36.2%, p=0.10). Using the sepsis phenotype criteria, 16.3% of children had SP1, 17.9% were SP2 and 14.1% were SP3. When evaluating the sepsis phenotype by malaria status, children with malaria were more likely to have SP2 (23.1% vs. 12.9%) and SP3 (18.1% vs.10.1%) compared to children without malaria (p\u3c0.001). Conclusions: In this population of children hospitalized with hypoxemia across 20 health centers in Uganda, KDIGO-defined AKI was more common in children with malaria. While there was no difference in the AKI-biomarker classification based on malaria status, children with malaria were more likely to have severe phenotypes of AKI

Renin as a biomarker of acute kidney Injury and mortality in children with severe malaria or sickle cell disease

Background: Globally, a very high percentage of acute kidney injury (AKI) occurs in low- and middle-income countries (LMICs) where late recognition contributes to increased mortality. There are challenges with using existing biomarkers of AKI in LMICs. Emerging evidence suggests renin may serve as a biomarker of kidney injury that can overcome limitations in creatinine-based diagnostics. Methods: Two study populations in Uganda were assessed. Cohort #1 was a two-site, prospective cohort study enrolling 600 children with severe malaria (SM). Cohort #2 was a prospective cohort study enrolling 185 children with sickle cell disease (SCD) hospitalized with a vaso-occlusive crisis. Plasma or serum renin concentrations were measured in both cohorts of children at the time of hospital admission using Luminex® (Luminex Corporation, Austin, Texas, United States) or enzyme-linked immunosorbent assay (ELISA), respectively. We assessed the ability of renin to discriminate between children with or without AKI and between children who survived and children who died using receiver operating characteristic curves. Results: In both cohorts, renin concentrations were strongly associated with AKI and mortality. Renin was able to discriminate between children with or without AKI with an area under the curve (AUC) of 0.70 (95%CI, 0.65-0.74) in children with SM and 0.72 (95%CI, 0.6co3-0.81) in children with SCD. Renin was able to discriminate between children who survived and children who died with an AUC of 0.73 (95%CI, 0.63- 0.83) in children with SM and 0.94 (95%CI, 0.89-0.99) in children with SCD. In Cohort #2, we compared renin against urine neutrophil gelatinase-associated lipocalin (NGAL) as the leading biomarker of AKI, and it had comparable performance in discriminating AKI and predicting mortality. Conclusions: In two independent populations of children at risk of AKI with key differences in the etiology of kidney injury, renin was strongly associated with AKI and mortality and had moderate to good diagnostic performance to predict mortality

Cerebrospinal fluid biomarkers provide evidence for kidney-brain axis involvement in cerebral malaria pathogenesis

Introduction: Cerebral malaria is one of the most severe manifestations of malaria and is a leading cause of acquired neurodisability in African children. Recent studies suggest acute kidney injury (AKI) is a risk factor for brain injury in cerebral malaria. The present study evaluates potential mechanisms of brain injury in cerebral malaria by evaluating changes in cerebrospinal fluid measures of brain injury with respect to severe malaria complications. Specifically, we attempt to delineate mechanisms of injury focusing on blood-brain-barrier integrity and acute metabolic changes that may underlie kidney-brain crosstalk in severe malaria. Methods: We evaluated 30 cerebrospinal fluid (CSF) markers of inflammation, oxidative stress, and brain injury in 168 Ugandan children aged 18 months to 12 years hospitalized with cerebral malaria. Eligible children were infected with Plasmodium falciparum and had unexplained coma. Acute kidney injury (AKI) on admission was defined using the Kidney Disease: Improving Global Outcomes criteria. We further evaluated blood-brain-barrier integrity and malaria retinopathy, and electrolyte and metabolic complications in serum. Results: The mean age of children was 3.8 years (SD, 1.9) and 40.5% were female. The prevalence of AKI was 46.3% and multi-organ dysfunction was common with 76.2% of children having at least one organ system affected in addition to coma. AKI and elevated blood urea nitrogen, but not other measures of disease severity (severe coma, seizures, jaundice, acidosis), were associated with increases in CSF markers of impaired blood-brain-barrier function, neuronal injury (neuronspecific enolase, tau), excitatory neurotransmission (kynurenine), as well as altered nitric oxide bioavailability and oxidative stress (p \u3c 0.05 after adjustment for multiple testing). Further evaluation of potential mechanisms suggested that AKI may mediate or be associated with CSF changes through blood-brainbarrier disruption (p = 0.0014), ischemic injury seen by indirect ophthalmoscopy (p \u3c 0.05), altered osmolality (p = 0.0006) and through alterations in the amino acids transported into the brain

Autoantibody levels are associated with acute kidney injury, anemia and post-discharge morbidity and mortality in Ugandan children with severe malaria

Autoantibodies targeting host antigens contribute to autoimmune disorders, frequently occur during and after infections and have been proposed to contribute to malaria-induced anemia. We measured anti-phosphatidylserine (PS) and anti-DNA antibody levels in 382 Ugandan children prospectively recruited in a study of severe malaria (SM). High antibody levels were defined as antibody levels greater than the mean plus 3 standard deviations of community children (CC). We observed increases in median levels of anti-PS and anti-DNA antibodies in children with SM compared to CC (p < 0.0001 for both). Children with severe malarial anemia were more likely to have high anti-PS antibodies than children with cerebral malaria (16.4% vs. 7.4%), p = 0.02. Increases in anti-PS and anti-DNA antibodies were associated with decreased hemoglobin (p < 0.05). A one-unit increase in anti-DNA antibodies was associated with a 2.99 (95% CI, 1.68, 5.31) increase odds of acute kidney injury (AKI) (p < 0.0001). Elevated anti-PS and anti-DNA antibodies were associated with post-discharge mortality (p = 0.031 and p = 0.042, respectively). Children with high anti-PS antibodies were more likely to have multiple hospital readmissions compared to children with normal anti-PS antibody levels (p < 0.05). SM is associated with increased autoantibodies against PS and DNA. Autoantibodies were associated with anemia, AKI, post-discharge mortality, and hospital readmission

Acute kidney injury in hospitalized children with sickle cell anemia

Background: Children with sickle cell anemia (SCA) are at increased risk of acute kidney injury (AKI) that may lead to death or chronic kidney disease. This study evaluated AKI prevalence and risk factors in children with SCA hospitalized with a vaso-occlusive crisis (VOC) in a low-resource setting. Further, we evaluated whether modifcations to the Kidney Disease: Improving Global Outcomes (KDIGO) defnition would infuence clinical outcomes of AKI in children with SCA hospitalized with a VOC. Methods: We prospectively enrolled 185 children from 2 – 18 years of age with SCA (Hemoglobin SS) hospitalized with a VOC at a tertiary hospital in Uganda. Kidney function was assessed on admission, 24–48 h of hospitalization, and day 7 or discharge. Creatinine was measured enzymatically using an isotype-dilution mass spectrometry traceable method. AKI was defned using the original-KDIGO defnition as≥1.5-fold change in creatinine within seven days or an absolute change of≥0.3 mg/dl within 48 h. The SCA modifed-KDIGO (sKDIGO) defnition excluded children with a 1.5-fold change in creatinine from 0.2 mg/dL to 0.3 mg/dL. Results: Using KDIGO, 90/185 (48.7%) children had AKI with 61/185 (33.0%) AKI cases present on admission, and 29/124 (23.4%) cases of incident AKI. Overall, 23 children with AKI had a 1.5-fold increase in creatinine from 0.2 mg/ dL to 0.3 m/dL. Using the sKDIGO-defnition, 67/185 (36.2%) children had AKI with 43/185 (23.2%) cases on admission, and 24/142 (16.9%) cases of incident AKI. The sKDIGO defnition, but not the original-KDIGO defnition, was associated with increased mortality (0.9% vs. 7.5%, p=0.024). Using logistic regression, AKI risk factors included age (aOR, 1.10, 95% CI 1.10, 1.20), hypovolemia (aOR, 2.98, 95% CI 1.08, 8.23), tender hepatomegaly (aOR, 2.46, 95% CI 1.05, 5.81), and infection (aOR, 2.63, 95% CI 1.19, 5.81) (p\u3c0.05). Conclusion: These results demonstrate that AKI is a common complication in children with SCA admitted with VOC. The sKDIGO defnition of AKI in children with SCA was a better predictor of clinical outcomes in children. There is need for promotion of targeted interventions to ensure early identifcation and treatment of AKI in children with SCA

Malaria-Associated Acute Kidney Injury in African Children: Prevalence, Pathophysiology, Impact, and Management Challenges

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 post-discharge 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

Evaluating kidney function using a point-of-care creatinine test in Ugandan children with severe malaria: a prospective cohort study

Background: Acute kidney injury (AKI) disproportionately affects individuals in low-and middle-income countries (LMIC). However, LMIC-particularly countries in sub-Saharan Africa- are under-represented in global AKI research. A critical barrier in diagnosing AKI is access to reliable serum creatinine results. We evaluated the utility of a point-of-care test to measure creatinine and diagnose AKI in Ugandan children with malaria. Methods: Paired admission creatinine was assessed in 539 Ugandan children 6 months to 4 years of age hospitalized with severe malaria based on blood smear or rapid diagnostic test. Creatinine levels were measured using isotope dilution mass spectrometry (IDMS)-traceable methods. The reference creatinine was measured using the modified Jaffe method by a certified laboratory and the point-of-care testing was conducted using an i-STAT blood analyzer (i-STAT1, with and without adjustment for the partial pressure of carbon dioxide). AKI was defined and staged using the Kidney Disease: Improving Global Outcomes criteria. Results: The mean age of children was 2.1 years, and 21.6% of children were stunted. Mortality was 7.6% in-hospital. Over the entire range of measured creatinine values (<0.20mg/dL-8.4mg/dL), the correlation between the reference creatinine and adjusted and unadjusted point-of-care creatinine was high with R2 values of 0.95 and 0.93 respectively; however, the correlation was significantly lower in children with creatinine values <1mg/dL (R2 of 0.44 between the reference and adjusted and unadjusted i-STAT creatinine). The prevalence of AKI was 45.5% using the reference creatinine, and 27.1 and 32.3% using the unadjusted and adjusted point-of-care creatinine values, respectively. There was a step-wise increase in mortality across AKI stages, and all methods were strongly associated with mortality (p<0.0001 for all). AKI defined using the reference creatinine measure was the most sensitive to predict mortality with a sensitivity of 85.4% compared to 70.7 and 63.4% with the adjusted and unadjusted point-of-care creatinine values, respectively. Conclusions: Point-of-care assessment of creatinine in lean Ugandan children <4 years of age underestimated creatinine and AKI compared to the clinical reference. Additional studies are needed to evaluate other biomarkers of AKI in LMIC to ensure equitable access to AKI diagnostics globally

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

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