sTREM-1: A Biomarker of Mortality in Severe Malaria Impacted by Acute Kidney Injury.

BACKGROUND: Malaria is an important cause of mortality in African children. Identification of biomarkers to identify children at risk of mortality has the potential to improve outcomes. METHODS: We evaluated 11 biomarkers of host response in 592 children with severe malaria. The primary outcome was biomarker performance for predicting mortality. Biomarkers were evaluated using receiver operating characteristic (ROC) curve analysis comparing the area under the ROC curve (AUROC). RESULTS: Mortality was 7.3% among children in the study with 72% of deaths occurring within 24 hours of admission. Among the candidate biomarkers, soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) had the highest AUROC (0.78 [95% confidence interval, .70-.86]), outperforming several other biomarkers including C-reactive protein and procalcitonin. sTREM-1 was the top-performing biomarker across prespecified subgroups (malaria definition, site, sex, nutritional status, age). Using established cutoffs, we evaluated mortality across sTREM-1 risk zones. Among children with acute kidney injury, 39.9% of children with a critical-risk sTREM-1 result had an indication for dialysis. When evaluated relative to a disease severity score, sTREM-1 improved mortality prediction (difference in AUROC, P = .016). CONCLUSIONS: sTREM-1 is a promising biomarker to guide rational allocation of clinical resources and should be integrated into clinical decision support algorithms, particularly when acute kidney injury is suspected.

Infections and Acute Kidney Injury: A Global Perspective.

Globally, there are an estimated 13.3 million cases of acute kidney injury (AKI) annually. Although infections are a common cause of AKI globally, most infection-associated AKI occurs in low- and lower-middle-income countries. There are marked differences in the etiology of infection-associated AKI across age groups, populations at risk, and geographic location. This article provides a global overview of different infections that are associated commonly with AKI, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human immunodeficiency virus, malaria, dengue, leptospirosis, tick-borne illnesses, and viral hemorrhagic fevers. Further discussion focuses on infectious conditions associated with AKI including sepsis, diarrheal diseases and pregnancy, peripartum and neonatal AKI. This article also discusses the future of infection-associated AKI in the framework of climate change. It explores how increased investment in achieving the sustainable development goals may contribute to the International Society of Nephrology's 0 by 25 objective to curtail avoidable AKI-related fatalities by 2025.

Nutritional status of young children born with low birthweight in a low resource setting: an observational study.

OBJECTIVE: Every year, an estimated 20 million babies are born with low birthweight and this number is increasing globally. Survivors are at risk of lifelong morbidities like undernutrition. We assessed the growth and nutritional status for children born with low birthweight at Mulago Hospital, Uganda. METHODS: We conducted a cross sectional study to describe the nutritional status of children aged between 22 and 38 months and born weighing ≤ 2000 g. Anthropometric measurements; weight for height, height for age and weight for age z-scores were generated based on the World Health Organization standards to define wasting, stunting and underweight respectively. Data was collected using a structured questionnaire and analysis was done using STATA version 14. RESULTS: Of the 251 children, 129 (51.4%) were male, mean age was 29.7 months SD 4.5) and maternal mean age was 29.9 (SD 5.3). A total of 101(40.2%) had normal nutritional status. The prevalence of wasting, underweight and stunting were: 8 (3.2%), 36 (14.4%) and 106 (42.2%) respectively. CONCLUSION: Six of ten children born with low birthweight were at risk of undernutrition in early childhood: underweight and stunting were higher than the national prevalence. Targeted interventions are needed for children with very low birth weight.

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 (neuron-specific enolase, tau), excitatory neurotransmission (kynurenine), as well as altered nitric oxide bioavailability and oxidative stress (p < 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-brain-barrier disruption (p = 0.0014), ischemic injury seen by indirect ophthalmoscopy (p < 0.05), altered osmolality (p = 0.0006) and through alterations in the amino acids transported into the brain. Conclusion: In children with cerebral malaria, there is evidence of kidney-brain injury with multiple potential pathways identified. These changes were specific to the kidney and not observed in the context of other clinical complications.

Prevalence and factors associated with Acute Kidney Injury among children aged 6month- 12years passing dark urine admitted at Soroti Regional Referral Hospital: A cross-sectional study.

Introduction: Acute Kidney Injury (AKI) is associated with a high mortality yet survivors are at risk for Hypertension, chronic kidney disease, long term neurocognitive and behavioural problems. Early recognition of patients with possible AKI is crucial for better treatment outcome, hence a need for evidence to guide targeted screening of patients with a risk factor for AKI. We sought to determine the prevalence and factors associated with AKI among children passing dark urine since haemoglobinuria, which presents as dark urine is a known risk factor for AKI. Methodology: This was a cross sectional study conducted at Soroti Regional Referral Hospital, among children aged 6month to 12years, who presented with dark urine. Urine colour was assessed using the Hammer Smith colour urine chart, only children with urine colour grade ≥ 5 were recruited. Serum creatinine analysis was done on the day of admission, within 48 hours and at day 7 or discharge. AKI was defined as a ≥ 1.5-fold increase in serum creatininefrom the baseline. Bivariate and multivariate analysis was used to determine factors associates with AKI with p values <0.05 level of significance. Results: Between January 2022 - July 2022, we enrolled a total of 255 participantswith median age of 4.0 (IQR, 2.0-6.58) years. About two thirds of the participants were males 157 (61.6%) and majority 111 (43.5%) presented with grade 8 of the urine colour. The prevalence of AKI was 38% (95% CI 32.3% - 44.2%). The factors found to be associated with AKI were grade of the urine colour ≥ 9 (aOR, 3.120 (95% CI 1.34-6.78) and reduced urine output (aOR, 3.226 (95% CI 1.10-9.81). Conclusion: The prevalence of AKI among children passing dark urine was high (38%). AKI was more likely to occur if the child was passing urine that is profoundly black and if there is history of reduced urine output. These findings reiterate the need for close monitoring of urine output of hospitalized children particularly those passing dark urine. Screening of those with profoundly black urine or reduced urine output should be done.

"My baby is fine, no need for more clinic visits." Facilitators and barriers for utilisation of follow-up services for children born preterm in low-resource setting: Parents' perceptions.

OBJECTIVES: We sought to understand the facilitators and barriers impacting utilisation of follow-up services for children born preterm as perceived by parents in a low-resource setting. METHODS: We conducted a qualitative study at Mulago Hospital, Uganda, with parents of children born preterm and aged 22-38 months at the time of the study. We collected data using five in-depth interviews and four focus group discussions. Data were analysed using thematic analysis informed by the social-ecological model. RESULTS: Ten subthemes emerged that could be grouped into three main themes: (1) Individual: parents' knowledge, parenting skills, perception of follow-up and infant's condition; (2) Relationship: support for the mother and information sharing; (3) Institution: facility setup, cost of care, available personnel and distance from the facility. Parents of preterm infants perceived receiving timely information, better understanding of prematurity and its complications, support from spouses, availability of free services and encouragement from health workers as facilitators for utilisation of follow-up services. Limited male involvement, parents' negative perception of follow-up, stable condition of infant, health facility challenges especially congestion at the hospital, distance and care costs were key barriers. CONCLUSION: An interplay of facilitators and barriers at individual, interpersonal and health system levels encourage or deter parents from taking their preterm children for follow-up services. Improving utilisation of services will require educating parents on the importance of follow-up even when children are not sick, eliciting maternal support from spouses and peers and addressing health system gaps that make follow-up unattractive and costly.

Prevalence and predictors of hypertension among adults in Mbarara City, Western Uganda.

OBJECTIVE: The study aim was to evaluate the prevalence and predictors of hypertension among an urban adult population in Mbarara city, Western Uganda. METHODS: We evaluated blood pressure measurements, social demographic and clinical parameters of adults living in Mbarara city, Uganda. These parameters were extracted from medical records of adults who participated in the Uganda World Kidney Day 2020 health screening activities. A total of 302 adults were evaluated for hypertension using the American College of Cardiology/American Heart Association 2017 (blood pressure threshold 130/80 mmHg) and International Society of Hypertension 2020 guidelines (threshold 140/90 mmHg). RESULTS: The mean age of the participants was 42.5 years (standard deviation: 15.1) and majority were male 195/302 (64.6%). Using American College of Cardiology/American Heart Association 2017 guidelines, 156/302 (51.7%) adults were newly diagnosed with hypertension compared to 68/302 (22.5%) newly diagnosed with hypertension using International Society of Hypertension 2020 guidelines. Only 23/302 (7.6%) were on treatment. Based on American College of Cardiology/American Heart Association 2017 guidelines, age ≥40 years and overweight/obesity were statistically significant predictors of hypertension (p < 0.05 for all) at multivariate analysis. Using the International Society of Hypertension 2020 guidelines, age ≥40 years predicted hypertension. DISCUSSION: The prevalence of hypertension is high among this urban adult population irrespective of the guidelines used, highlighting the need for hypertension prevention interventions.

Neutrophil gelatinase-associated lipocalin is elevated in children with acute kidney injury and sickle cell anemia, and predicts mortality.

Urine neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker of acute kidney injury that has been adapted to a urine dipstick test. However, there is limited data on its use in low-and-middle-income countries where diagnosis of acute kidney injury remains a challenge. To study this, we prospectively enrolled 250 children with sickle cell anemia aged two to 18 years encompassing 185 children hospitalized with a vaso-occlusive pain crisis and a reference group of 65 children attending the sickle cell clinic for routine care follow up. Kidney injury was defined using serial creatinine measures and a modified-Kidney Disease Improving Global Outcome definition for sickle cell anemia. Urine NGAL was measured using the NGAL dipstick and a laboratory reference. The mean age of children enrolled was 8.9 years and 42.8% were female. Among hospitalized children, 36.2% had kidney injury and 3.2% died. Measured urine NGAL levels by the dipstick were strongly correlated with the standard enzyme-linked immunosorbent assay for urine NGAL (hospitalized children, 0.71; routine care reference, 0.88). NGAL levels were elevated in kidney injury and significantly increased across injury stages. Hospitalized children with a high-risk dipstick test (300ng/mL and more) had a 2.47-fold relative risk of kidney injury (95% confidence interval 1.68 to 3.61) and 7.28 increased risk of death (95% confidence interval 1.10 to 26.81) adjusting for age and sex. Thus, urine NGAL levels were found to be significantly elevated in children with sickle cell anemia and acute kidney injury and may predict mortality.

Pathophysiology of Acute Kidney Injury in Malaria and Non-Malarial Febrile Illness: A Prospective Cohort Study.

Acute kidney injury (AKI) is a life-threatening complication. Malaria and sepsis are leading causes of AKI in low-and-middle-income countries, but its etiology and pathogenesis are poorly understood. A prospective observational cohort study was conducted to evaluate pathways of immune and endothelial activation in children hospitalized with an acute febrile illness in Uganda. The relationship between clinical outcome and AKI, defined using the Kidney Disease: Improving Global Outcomes criteria, was investigated. The study included 967 participants (mean age 1.67 years, 44.7% female) with 687 (71.0%) positive for malaria by rapid diagnostic test and 280 (29.1%) children had a non-malarial febrile illness (NMFI). The frequency of AKI was higher in children with NMFI compared to malaria (AKI, 55.0% vs. 46.7%, p = 0.02). However, the frequency of severe AKI (stage 2 or 3 AKI) was comparable (12.1% vs. 10.5%, p = 0.45). Circulating markers of both immune and endothelial activation were associated with severe AKI. Children who had malaria and AKI had increased mortality (no AKI, 0.8% vs. AKI, 4.1%, p = 0.005), while there was no difference in mortality among children with NMFI (no AKI, 4.0% vs. AKI, 4.6%, p = 0.81). AKI is a common complication in children hospitalized with acute infections. Immune and endothelial activation appear to play central roles in the pathogenesis of AKI.

Acute Kidney Injury Interacts With Coma, Acidosis, and Impaired Perfusion to Significantly Increase Risk of Death in Children With Severe Malaria.

BACKGROUND: Mortality in severe malaria remains high in children treated with intravenous artesunate. Acute kidney injury (AKI) is a common complication of severe malaria, but the interactions between AKI and other complications on the risk of mortality in severe malaria are not well characterized. METHODS: Between 2014 and 2017, 600 children aged 6-48 months to 4 years hospitalized with severe malaria were enrolled in a prospective clinical cohort study evaluating clinical predictors of mortality in children with severe malaria. RESULTS: The mean age of children in this cohort was 2.1 years (standard deviation, 0.9 years) and 338 children (56.3%) were male. Mortality was 7.3%, and 52.3% of deaths occurred within 12 hours of admission. Coma, acidosis, impaired perfusion, AKI, elevated blood urea nitrogen (BUN), and hyperkalemia were associated with increased mortality (all P < .001). AKI interacted with each risk factor to increase mortality (P < .001 for interaction). Children with clinical indications for dialysis (14.4% of all children) had an increased risk of death compared with those with no indications for dialysis (odds ratio, 6.56; 95% confidence interval, 3.41-12.59). CONCLUSIONS: AKI interacts with coma, acidosis, or impaired perfusion to significantly increase the risk of death in severe malaria. Among children with AKI, those who have hyperkalemia or elevated BUN have a higher risk of death. A better understanding of the causes of these complications of severe malaria, and development and implementation of measures to prevent and treat them, such as dialysis, are needed to reduce mortality in severe malaria.

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 modifications to the Kidney Disease: Improving Global Outcomes (KDIGO) definition would influence 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 defined using the original-KDIGO definition as ≥ 1.5-fold change in creatinine within seven days or an absolute change of ≥ 0.3 mg/dl within 48 h. The SCA modified-KDIGO (sKDIGO) definition 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-definition, 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 definition, but not the original-KDIGO definition, 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 < 0.05). CONCLUSION: These results demonstrate that AKI is a common complication in children with SCA admitted with VOC. The sKDIGO definition 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 identification and treatment of AKI in children with SCA.

Acute kidney injury, persistent kidney disease, and post-discharge morbidity and mortality in severe malaria in children: A prospective cohort study.

BACKGROUND: Globally, 85% of acute kidney injury (AKI) cases occur in low-and-middle-income countries. There is limited information on persistent kidney disease (acute kidney disease [AKD]) following severe malaria-associated AKI. METHODS: Between March 28, 2014, and April 18, 2017, 598 children with severe malaria and 118 community children were enrolled in a two-site prospective cohort study in Uganda and followed up for 12 months. The Kidney Disease: Improving Global Outcomes (KDIGO) criteria were used to define AKI (primary exposure) and AKD at 1-month follow-up (primary outcome). Plasma neutrophil gelatinase-associated lipocalin (NGAL) was assessed as a structural biomarker of AKI. FINDINGS: The prevalence of AKI was 45·3% with 21·5% of children having unresolved AKI at 24 h. AKI was more common in Eastern Uganda. In-hospital mortality increased across AKI stages from 1·8% in children without AKI to 26·5% with Stage 3 AKI (p < 0·0001). Children with a high-risk plasma NGAL test were more likely to have unresolved AKI (OR, 7·00 95% CI 4·16 to 11·76) and die in hospital (OR, 6·02 95% CI 2·83 to 12·81). AKD prevalence was 15·6% at 1-month follow-up with most AKD occurring in Eastern Uganda. Risk factors for AKD included severe/unresolved AKI, blackwater fever, and a high-risk NGAL test (adjusted p < 0·05). Paracetamol use during hospitalization was associated with reduced AKD (p < 0·0001). Survivors with AKD post-AKI had higher post-discharge mortality (17·5%) compared with children without AKD (3·7%). INTERPRETATION: Children with severe malaria-associated AKI are at risk of AKD and post-discharge mortality. FUNDING: This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke (R01NS055349 to CCJ) and the Fogarty International Center (D43 TW010928 to CCJ), and a Ralph W. and Grace M. Showalter Young Investigator Award to ALC.

Mineral bone disorders and kidney disease in hospitalized children with sickle cell anemia.

Background: Mineral bone disorders (MBD) are common in sickle cell anemia (SCA). Frequent vaso-occlusive crises (VOC) further impact MBD in children with SCA. We evaluated the prevalence of markers of SCA-related MBD (sMBD) in hospitalized children and assessed the relationship between sMBD and individual mineral abnormalities with kidney disease. Methods: We prospectively recruited 185 children with SCA hospitalized with a VOC. Serum measures of mineral bone metabolism (calcium, phosphate, parathyroid hormone, 25-hydroxy vitamin D, FGF23, osteopontin) were measured at enrollment. The primary outcome was markers of sMBD defined as a composite of hypocalcemia, hyperphosphatemia, hyperparathyroidism, or deficiency in 25-OH vitamin D. Secondary outcomes included individual abnormalities in mineral metabolism. The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines were used to define SCA-associated acute kidney injury (AKI). AKI was further assessed using urine NGAL as a marker of tubular injury. Acute kidney disease (AKD) was defined as a composite of AKI, an eGFR < 90 ml/min per 1.73 m2 using the Cystatin C GFR equation, or evidence of structural injury (positive biomarker test or albuminuria). Results: The mean age of children was 8.9 years and 41.6% were female. The prevalence of sMBD was 47.6%, with hypocalcemia the most frequent abnormality (29.9%, 55/184) followed by hyperphosphatemia (20.7%, 38/184), hyperparathyroidism (8.7%, 16/185), and vitamin D deficiency (5.4%, 10/185). There was no association between sMBD and sKDIGO-defined AKI using serial changes in creatinine or when incorporating biomarkers to define AKI. However, the presence of AKD was associated with a 2.01-fold increased odds of sMBD (95% CI 1.05 to 3.83) and was driven by a decrease in eGFR (OR, 2.90 95% CI: 1.59 to 5.29). When evaluating individual mineral abnormalities, hypocalcemia was associated with AKD and low eGFR while hyperparathyroidism was associated with low eGFR, AKI and structural injury. Vitamin D deficiency was associated with structural kidney injury. Vitamin D deficiency, hyperparathryoidism, and increases in FGF23 and osteopontin predicted mortality (p < 0.05 for all). Conclusion: MBD is common among children with SCA hospitalized with VOC. Biomarkers of kidney injury and bone health may help risk stratify children at risk of sMBD. Routine evaluation of sMBD in children with SCA may improve long-term bone health.

Screening for Kidney Disease in Low- and Middle-Income Countries.

Kidney disease is the 10th leading cause of death worldwide and disproportionately increases morbidity and mortality for people residing in low- and middle-income countries (LMICs). Considering the high burden of chronic kidney disease (CKD) on patients, society, and health care systems, strategies to improve screening for CKD need to be prioritized. With appropriate interventions, screening could prevent progression of early stages of CKD and, ultimately, reduce the need for kidney replacement therapy. Unfortunately, few data exist to inform screening strategies for early detection and management of CKD in LMICs, where risk factors for CKD may differ from those in high-income countries. We review here the epidemiology of kidney disease in LMICs, current practices for screening for kidney disease, and challenges and opportunities available to LMICs. We also recommend ways in which screening could be improved for early identification and care for patients with kidney disease in LMICs and highlight critical gaps in knowledge.

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.

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.

Prevalence and predictors of ocular complications among children undergoing nephrotic syndrome treatment in a resource-limited setting.

BACKGROUND: Nephrotic syndrome is the most common glomerulopathy among children aged 2-18 years and high dose corticosteroids are the backbone of its management. Potentially blinding ocular complications often result from nephrotic syndrome and/or its treatment. We conducted a study to determine the prevalence and predictors of ocular complications among children undergoing nephrotic syndrome treatment at Mulago National Referral Hospital. METHODS: This was a cross-sectional study conducted for three [3] months at the pediatric renal unit of Mulago National Referral Hospital (MNRH). Data from a consecutive sample of 100 children was collected using a semi-structured questionnaire, entered into Epi-data 4.4.2 and exported to STATA 14 for analysis at univariate, bivariate and multivariate levels. A robust Poisson regression model was used to identify predictors of ocular complications. RESULTS: Out of 100 patients examined, 80(80%) had ocular complications. The median age was 10 (IQR: 7-12) and 52 (52%) were girls. The most frequent complications were hypertrichosis and refractive errors in 71% (95%CI 61.1-79.6) and 56% (95%CI 45.7-65.9) of the patients respectively. Age above 10 years was the predictor for ocular complications with a RR = 1.37 (95%CI:1.14-1.64) p = 0.001. CONCLUSIONS: We found a high prevalence of ocular complications among children with nephrotic syndrome in this tertiary hospital. The predictor of ocular complications was age greater than 10 years. We recommend that all children with nephrotic syndrome undergo a baseline ocular examination prior to commencement of treatment and be reviewed periodically by an ophthalmologist.

Trends in the epidemiology of childhood nephrotic syndrome in Africa: A systematic review.

Background: Childhood nephrotic syndrome, if left untreated, leads to progressive kidney disease or death. We quantified the prevalence of steroid-sensitive nephrotic syndrome, steroid-resistant nephrotic syndrome, and histological types as the epidemiology of nephrotic syndrome in Africa remains unknown, yet impacts outcomes. Methods: We searched MEDLINE, Embase, African Journals Online, and WHO Global Health Library for articles in any language reporting on childhood nephrotic syndrome in Africa from January 1, 1946 to July 1, 2020. Primary outcomes included steroid response, biopsy defined minimal change disease, and focal segmental glomerulosclerosis (FSGS) by both pooled and individual proportions across regions and overall. Findings: There were 81 papers from 17 countries included. Majority of 8131 children were steroid-sensitive (64% [95% CI: 63-66%]) and the remaining were steroid-resistant (34% [95% CI: 33-35%]). Of children biopsied, pathological findings were 38% [95% CI: 36-40%] minimal change, 24% [95% CI: 22-25%] FSGS, and 38% [95% CI: 36-40%] secondary causes of nephrotic syndrome. Interpretation: Few African countries reported on the prevalence of childhood nephrotic syndrome. Steroid-sensitive disease is more common than steroid-resistant disease although prevalence of steroid-resistant nephrotic syndrome is higher than reported globally. Pathology findings suggest minimal change and secondary causes are common. Scarcity of data in Africa prevents appropriate healthcare resource allocation to diagnose and treat this treatable childhood kidney disease to prevent poor health outcomes. Funding: Funding was provided by the Canadian Institute for Health Research (CIHR) and the National Institute of Health (NIH) for the H3 Africa Kidney Disease Research Network. This research was undertaken, in part, from the Canada Research Chairs program.