Is mild dehydration a risk for progression of childhood chronic kidney disease?

Children with chronic kidney disease (CKD) can have an inherent vulnerability to dehydration. Younger children are unable to freely access water, and CKD aetiology and stage can associate with reduced kidney concentrating capacity, which can also impact risk. This article aims to review the risk factors and consequences of mild dehydration and underhydration in CKD, with a particular focus on evidence for risk of CKD progression. We discuss that assessment of dehydration in the CKD population is more challenging than in the healthy population, thus complicating the definition of adequate hydration and clinical research in this field. We review pathophysiologic studies that suggest mild dehydration and underhydration may cause hyperfiltration injury and impact renal function, with arginine vasopressin as a key mediator. Randomised controlled trials in adults have not shown an impact of improved hydration in CKD outcomes, but more vulnerable populations with baseline low fluid intake or poor kidney concentrating capacity need to be studied. There is little published data on the frequency of dehydration, and risk of complications, acute or chronic, in children with CKD. Despite conflicting evidence and the need for more research, we propose that paediatric CKD management should routinely include an assessment of individual dehydration risk along with a treatment plan, and we provide a framework that could be used in outpatient settings.

COVID-19-Associated Acute Kidney Injury and Longitudinal Kidney Outcomes.

Importance: COVID-19 infection is associated with a high incidence of acute kidney injury (AKI). Although rapid kidney function decline has been reported in the first few months after COVID-19-associated AKI (COVID-AKI), the longer-term association of COVID-AKI with kidney function remains unknown. Objective: To assess long-term kidney outcomes of patients who had COVID-19-associated AKI. Design, Setting, and Participants: This was a retrospective longitudinal multicenter cohort study conducted in a large hospital system using electronic health records data on adult hospitalized patients with AKI and COVID-19 or other illnesses. Included patients were hospitalized during the COVID-19 pandemic (March 2020-June 2022), were screened for SARS-CoV-2, had AKI, and survived to discharge, or had been hospitalized during the 5 years before the pandemic (October 2016-January 2020), had a positive influenza A or B test result, had AKI, and survived to discharge. Patients were followed up for a maximum of 2 years after hospital discharge. Data analyses were performed from December 2022 to November 2023. Exposure: COVID-19 and influenza. Main Outcomes and Measures: The primary outcome was major adverse kidney events (MAKE), defined as a composite of mortality and worsened kidney function (estimated glomerular filtration rate [eGFR] decline by ≥25% from discharge eGFR or kidney failure requiring dialysis). Multivariable time-to-event analyses were performed to compare MAKE between individuals with COVID-AKI and those who had AKI associated with other illnesses hospitalized during the same period. For further comparison, this outcome was assessed for a historic cohort of patients with influenza-associated AKI. Results: The study cohort included 9624 hospitalized patients (mean [SD] age, 69.0 [15.7] years; 4955 [51.5%] females) with AKI, including 987 patients with COVID-AKI, 276 with influenza-associated AKI, and 8361 with AKI associated with other illnesses (other-AKI). Compared with the other 2 groups, patients with COVID-19-associated AKI were slightly younger in age, had a higher baseline eGFR, worse baseline comorbidity scores, higher markers of illness severity, and longer hospital stay. Compared with the other-AKI group, the COVID-AKI group had lower MAKE (adjusted hazard ratio [aHR], 0.67; 95% CI, 0.59-0.75) due to lower all-cause mortality (aHR, 0.31; 95% CI, 0.24-0.39) and lower rates of worsened kidney function (aHR, 0.78; 95% CI, 0.69-0.88). Conclusions and Relevance: The findings of this multicenter cohort study indicate that survivors of hospitalization with COVID-AKI experience lower rates of MAKE, long-term kidney function decline, and mortality compared with patients with AKI associated with other illnesses.

Pediatric AKI in the real world: changing outcomes through education and advocacy-a report from the 26th Acute Disease Quality Initiative (ADQI) consensus conference.

BACKGROUND: Acute kidney injury (AKI) is independently associated with increased morbidity and mortality across the life course, yet care for AKI remains mostly supportive. Raising awareness of this life-threatening clinical syndrome through education and advocacy efforts is the key to improving patient outcomes. Here, we describe the unique roles education and advocacy play in the care of children with AKI, discuss the importance of customizing educational outreach efforts to individual groups and contexts, and highlight the opportunities created through innovations and partnerships to optimize lifelong health outcomes. METHODS: During the 26th Acute Disease Quality Initiative (ADQI) consensus conference, a multidisciplinary group of experts discussed the evidence and used a modified Delphi process to achieve consensus on recommendations on AKI research, education, practice, and advocacy in children. RESULTS: The consensus statements developed in response to three critical questions about the role of education and advocacy in pediatric AKI care are presented here along with a summary of available evidence and recommendations for both clinical care and research. CONCLUSIONS: These consensus statements emphasize that high-quality care for patients with AKI begins in the community with education and awareness campaigns to identify those at risk for AKI. Education is the key across all healthcare and non-healthcare settings to enhance early diagnosis and develop mitigation strategies, thereby improving outcomes for children with AKI. Strong advocacy efforts are essential for implementing these programs and building critical collaborations across all stakeholders and settings.

Current and Novel Biomarkers of Progression Risk in Children with Chronic Kidney Disease.

BACKGROUND: Due to the complexity of chronic kidney disease (CKD) pathophysiology, biomarkers representing different mechanistic pathways have been targeted for the study and development of novel biomarkers. The discovery of clinically useful CKD biomarkers would allow for the identification of those children at the highest risk of kidney function decline for timely interventions and enrollment in clinical trials. SUMMARY: Glomerular filtration rate and proteinuria are traditional biomarkers to classify and prognosticate CKD progression in clinical practice but have several limitations. Over the recent decades, novel biomarkers have been identified from blood or urine with metabolomic screening studies, proteomic screening studies, and an improved knowledge of CKD pathophysiology. This review highlights promising biomarkers associated with the progression of CKD that could potentially serve as future prognostic markers in children with CKD. KEY MESSAGES: Further studies are needed in children with CKD to validate putative biomarkers, particularly candidate proteins and metabolites, for improving clinical management.

A proposed framework for advancing acute kidney injury risk stratification and diagnosis in children: a report from the 26th Acute Disease Quality Initiative (ADQI) conference.

Acute kidney injury (AKI) in children is associated with increased morbidity, reduced health-related quality of life, greater resource utilization, and higher mortality. Improvements in the timeliness and precision of AKI diagnosis in children are needed. In this report, we highlight existing, novel, and on-the-horizon diagnostic and risk-stratification tools for pediatric AKI, and outline opportunities for integration into clinical practice. We also summarize pediatric-specific high-risk diagnoses and exposures for AKI, as well as the potential role of real-time risk stratification and clinical decision support to improve outcomes. Lastly, the key characteristics of important pediatric AKI phenotypes will be outlined. Throughout, we identify key knowledge gaps, which represent prioritized areas of focus for future research that will facilitate a comprehensive, timely and personalized approach to pediatric AKI diagnosis and management.

Recent ambient temperature and fine particulate matter (PM2.5) exposure is associated with urinary kidney injury biomarkers in children.

BACKGROUND: Limited research has examined associations between exposure to ambient temperature, air pollution, and kidney function or injury during the preadolescent period. We examined associations between exposure to ambient temperature and particulate matter with aerodynamic diameter ≤ 2.5 µm (PM2.5) with preadolescent estimated glomerular filtration rate (eGFR) and urinary kidney injury biomarkers. METHODS: Participants included 437 children without cardiovascular or kidney disease enrolled in the Programming Research in Obesity, Growth, Environment and Social Stressors birth cohort study in Mexico City. eGFR and urinary kidney injury biomarkers were assessed at 8-12 years. Validated satellite-based spatio-temporal models were used to estimate mean daily temperature and PM2.5 levels at each participant's residence 7- and 30-days prior to the date of visit. Linear regression and distributed lag nonlinear models (DLNM) were used to examine associations between daily mean temperature and PM2.5 exposure and kidney outcomes, adjusted for covariates. RESULTS: In single linear regressions, higher seven-day average PM2.5 was associated with higher urinary alpha-1-microglobulin and eGFR. In DLNM analyses, higher temperature exposure in the seven days prior to date of visit was associated with a decrease in urinary cystatin C of -0.56 ng/mL (95 % confidence interval (CI): -1.08, -0.04) and in osteopontin of -0.08 ng/mL (95 % CI: -0.15, -0.001). PM2.5 exposure over the seven days prior to date of visit was associated with an increase in eGFR of 1.77 mL/min/1.73m2 (95 % CI: 0.55, 2.99) and urinary cystatin C of 0.19 ng/mL (95 % CI: 0.03, 0.35). CONCLUSIONS: Recent exposure to ambient temperature and PM2.5 were associated with increased and decreased urinary kidney injury biomarkers that may reflect subclinical glomerular or tubular injury in children. Further research is required to assess environmental exposures and worsening subclinical kidney injury across development.

Effect Measure Modification by Birth Weight on the Association Between Overweight or Obesity and Hypertension in Children and Adolescents.

This cross-sectional study examines the prevalence of hypertension among children and adolescents with low, very low, normal, or high birth weight.

A randomized clinical trial assessing the effect of automated medication-targeted alerts on acute kidney injury outcomes.

Acute kidney injury is common among hospitalized individuals, particularly those exposed to certain medications, and is associated with substantial morbidity and mortality. In a pragmatic, open-label, National Institutes of Health-funded, parallel group randomized controlled trial (clinicaltrials.gov NCT02771977), we investigate whether an automated clinical decision support system affects discontinuation rates of potentially nephrotoxic medications and improves outcomes in patients with AKI. Participants included 5060 hospitalized adults with AKI and an active order for any of three classes of medications of interest: non-steroidal anti-inflammatory drugs, renin-angiotensin-aldosterone system inhibitors, or proton pump inhibitors. Within 24 hours of randomization, a medication of interest was discontinued in 61.1% of the alert group versus 55.9% of the usual care group (relative risk 1.08, 1.04 - 1.14, p = 0.0003). The primary outcome - a composite of progression of acute kidney injury, dialysis, or death within 14 days - occurred in 585 (23.1%) of individuals in the alert group and 639 (25.3%) of patients in the usual care group (RR 0.92, 0.83 - 1.01, p = 0.09). Trial Registration Clinicaltrials.gov NCT02771977.

Hypertension, Blood Pressure Variability, and Acute Kidney Injury in Hospitalized Children.

Background Although hypertensive blood pressure measurements are common in hospitalized children, the degree of inpatient hypertension and blood pressure variability (BPV) associated with end organ complications like acute kidney injury (AKI) is unknown. Methods and Results All analyses are based on a retrospective cohort of children aged 1 to 17 years with ≥2 creatinine measurements during admission from 2014 to 2018. We used time-updated Cox models to evaluate the association between BPV and hypertension with AKI. Time-varying BPV and hypertension were based on blood pressure in the preceding 72 hours. For the analysis of hypertension and AKI, we excluded patients on vasopressors to ensure comparison between hypertensive and normotensive patients. During 5425 pediatric encounters, 258 430 blood pressure measurements were recorded (median [interquartile range] 22 [11-47] readings per encounter). Among all measurements, 32.7% were ≥95th percentile and 18.9% were ≥99th percentile for age, sex, and height. AKI occurred in 389 (7.2%) encounters. We observed a U-shaped relationship between mean blood pressure and incident AKI. BPV was associated with AKI, with the largest effect sizes in the systolic and mean arterial pressure variability measures. Multiple hypertension thresholds were associated with AKI after controlling for confounders. In an additional multivariable model adjusted for BPV, the association between hypertension and AKI was attenuated but remained significant for hypertension defined as three stage 2 measurements in 1 day (hazard ratio, 1.43 [95% CI, 1.01-2.01]). Conclusions Hypertension and BPV are associated with AKI in hospitalized children. Future studies are needed to determine how pharmacologic and nonpharmacologic interventions modify AKI risk in pediatric inpatients with hypertension.

Association of Kidney Tubule Biomarkers With Cardiac Structure and Function in the Multiethnic Study of Atherosclerosis.

Markers of glomerular disease, estimated glomerular filtration rate (eGFR) and albuminuria, are associated with cardiac structural abnormalities and incident cardiovascular disease (CVD). We aimed to determine whether biomarkers of kidney tubule injury, function, and systemic inflammation are associated with cardiac structural abnormalities. Among 393 Multi-Ethnic Study of Atherosclerosis participants without diabetes, CVD, or chronic kidney disease, we assessed the association of 12 biomarkers of kidney tubule injury, function, and systemic inflammation with the left ventricular mass/volume ratio (LVmvr) and left ventricular ejection fraction (LVEF) on cardiac magnetic resonance imaging using linear regression. The average age was 60 ± 10 years; 48% were men; mean eGFR was 96±16 ml/min/1.73 m2; mean LVmvr was 0.93±0.18 g/ml, and mean LVEF was 62±6%. Each twofold greater concentration of plasma soluble urokinase plasminogen activator receptor was associated with a 0.04 g/ml (95% confidence interval [CI] 0.01 to 0.08 g/ml) higher LVmvr and 2.1% (95% CI 0.6 to 3.5%) lower LVEF, independent of risk factors for CVD, eGFR, and albuminuria. Each twofold greater plasma monocyte chemoattractant protein 1 was associated with higher LVmvr with a similar coefficient to that of plasma soluble urokinase plasminogen activator receptor. Each twofold greater concentration of plasma chitinase-3-like protein 1 and urine alpha-1-microglobulin was associated with a 1.1% (95% CI 0.4 to 1.7%) and 1.2% (95% CI 0.2 to 2.2%) lower LVEF, respectively. In conclusion, abnormal kidney tubule health may lead to cardiac dysfunction above and beyond eGFR and albuminuria.

Does This Child With High Blood Pressure Have Secondary Hypertension?: The Rational Clinical Examination Systematic Review.

Importance: Guidelines recommend that all children and adolescents with hypertension undergo evaluation for secondary causes. Identifying clinical factors associated with secondary hypertension may decrease unnecessary testing for those with primary hypertension. Objective: To determine the utility of the clinical history, physical examination, and 24-hour ambulatory blood pressure monitoring for differentiating primary hypertension from secondary hypertension in children and adolescents (aged ≤21 years). Data Sources and Study Selection: The databases of MEDLINE, PubMed Central, Embase, Web of Science, and Cochrane Library were searched from inception to January 2022 without language limits. Two authors identified studies describing clinical characteristics in children and adolescents with primary and secondary hypertension. Data Extraction and Synthesis: For each clinical finding in each study, a 2 × 2 table was created that included the number of patients with and without the finding who had primary vs secondary hypertension. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool. Main Outcomes and Measures: Random-effects modeling was used to calculate sensitivity, specificity, and likelihood ratios (LRs). Results: Of 3254 unique titles and abstracts screened, 30 studies met inclusion criteria for the meta-analysis and 23 (N = 4210 children and adolescents) were used for pooling in the meta-analysis. In the 3 studies conducted at primary care clinics or school-based screening clinics, the prevalence of secondary hypertension was 9.0% (95% CI, 4.5%-15.0%). In the 20 studies conducted at subspecialty clinics, the prevalence of secondary hypertension was 44% (95% CI, 36%-53%). The demographic findings most strongly associated with secondary hypertension were family history of secondary hypertension (sensitivity, 0.46; specificity, 0.90; LR, 4.7 [95% CI, 2.9-7.6]), weight in the 10th percentile or lower for age and sex (sensitivity, 0.27; specificity, 0.94; LR, 4.5 [95% CI, 1.2-18]), history of prematurity (sensitivity range, 0.17-0.33; specificity range, 0.86-0.94; LR range, 2.3-2.8), and age of 6 years or younger (sensitivity range, 0.25-0.36; specificity range, 0.86-0.88; LR range, 2.2-2.6). Laboratory studies most associated with secondary hypertension were microalbuminuria (sensitivity, 0.13; specificity, 0.99; LR, 13 [95% CI, 3.1-53]) and serum uric acid concentration of 5.5 mg/dL or lower (sensitivity range, 0.70-0.73; specificity range, 0.65-0.89; LR range, 2.1-6.3). Increased daytime diastolic blood pressure load combined with increased nocturnal systolic blood pressure load on 24-hour ambulatory blood pressure monitoring was associated with secondary hypertension (sensitivity, 0.40; specificity, 0.82; LR, 4.8 [95% CI, 1.2-20]). Findings associated with a decreased likelihood of secondary hypertension were asymptomatic presentation (LR range, 0.19-0.36), obesity (LR, 0.34 [95% CI, 0.13-0.90]), and family history of any hypertension (LR, 0.42 [95% CI, 0.30-0.57]). Hypertension stage, headache, and left ventricular hypertrophy did not distinguish secondary from primary hypertension. Conclusions and Relevance: Family history of secondary hypertension, younger age, lower body weight, and increased blood pressure load using 24-hour ambulatory blood pressure monitoring were associated with a higher likelihood of secondary hypertension. No individual sign or symptom definitively differentiates secondary hypertension from primary hypertension.

Association of clinical characteristics with urine uromodulin in children with chronic kidney disease.

BACKGROUND: Uromodulin is the most abundant protein in the urine of healthy adults, and higher urine concentrations mark better tubular health. Greater kidney size and function are predictors of higher uromodulin levels in adults. Urine uromodulin has not yet been studied in children with chronic kidney disease (CKD). Thus, we sought to determine the relationship between age and kidney function with urine uromodulin levels in children with CKD. METHODS: In the CKD in Children (CKiD) cohort, we utilized multivariable linear regression to evaluate the relationship of age and eGFR with urine uromodulin levels. The primary outcome was uromodulin indexed to urine creatinine (Umod/Cr, mg/g), which was log2-transformed given its skewed distribution. RESULTS: Among 677 CKiD participants, the median age was 11.8 years (8.2-15.3), the median eGFR was 49 ml/min/1.73 m2 (37-63), the etiology of CKD was glomerular disease in 31%, and the median Umod/Cr level was 0.114 mg/g (0.045-0.226). In the multivariable models, each one-year older age was associated with 0.18 (12%) lower log2(Umod/Cr) and 0.20 (13%) lower log2(Umod/Cr) among those with non-glomerular and glomerular disease, respectively (p < 0.001). However, we did not find a statistically significant association between eGFR and Umod/Cr in either participants with non-glomerular or glomerular disease (p = 0.13 and p = 0.58, respectively). CONCLUSIONS: Among children with CKD, older age is significantly associated with lower Umod/Cr, independent of eGFR. Further studies are needed to comprehensively evaluate age-specific reference ranges for urine uromodulin and to evaluate the longitudinal relationship of uromodulin with both age and eGFR in children with CKD. A higher resolution version of the Graphical abstract is available as Supplementary information.

Biomarkers of eGFR decline after cardiac surgery in children: findings from the ASSESS-AKI study.

BACKGROUND: Children who require surgery for congenital heart disease have increased risk for long-term chronic kidney disease (CKD). Clinical factors as well as urine biomarkers of tubular health and injury may help improve the prognostication of estimated glomerular filtration rate (eGFR) decline. METHODS: We enrolled children from 1 month to 18 years old undergoing cardiac surgery in the ASSESS-AKI cohort. We used mixed-effect models to assess the association between urinary biomarkers (log2-transformed uromodulin, NGAL, KIM-1, IL-18, L-FABP) measured 3 months after cardiac surgery and cyanotic heart disease with the rate of eGFR decline at annual in-person visits over 4 years. RESULTS: Of the 117 children enrolled, 30 (24%) had cyanotic heart disease. During 48 months of follow-up, the median eGFR in the subgroup of children with cyanotic heart disease was lower at all study visits as compared with children with acyanotic heart disease (p = 0.01). In the overall cohort, lower levels of both urine uromodulin and IL-18 after discharge were associated with eGFR decline. After adjustment for age, RACHS-1 surgical complexity score, proteinuria, and eGFR at the 3-month study visit, lower concentrations of urine uromodulin and IL-18 were associated with a monthly decline in eGFR (uromodulin ß = 0.04 (95% CI: 0.00-0.09; p = 0.07) IL-18 ß = 0.07 (95% CI: 0.01-0.13; p = 0.04), ml/min/1.73 m2 per month). CONCLUSIONS: At 3 months after cardiac surgery, children with lower urine uromodulin and IL-18 concentrations experienced a significantly faster decline in eGFR. Children with cyanotic heart disease had a lower median eGFR at all time points but did not experience faster eGFR decline. A higher-resolution version of the Graphical abstract is available as Supplementary information.

Biomarkers for acute kidney injury in children - where are we now?

PURPOSE OF REVIEW: Review the literature over the last 2 years on commonly evaluated biomarkers of acute kidney injury (AKI) and highlight the findings of these biomarkers. RECENT FINDINGS: Among several studied AKI biomarkers, urine neutrophil gelatinase-associated lipocalin (NGAL) and the combination of urine tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7) have been recently studied most frequently as diagnostic biomarkers of AKI and for AKI risk stratification. Urine NGAL has continued to show good discriminative value to predict and diagnose AKI in childhood. Urine TIMP-2∗IGFBP7 can provide modest improvement to clinical models of AKI. SUMMARY: Prior research supports that AKI biomarkers may identify AKI at an earlier time point and indicate clinically meaningful tubular injury. More effort should be made to understand if AKI biomarkers can guide treatments and improve outcomes.

Effect of intravenous antihypertensives on outcomes of severe hypertension in hospitalized patients without acute target organ damage.

BACKGROUND: Treatment of severe inpatient hypertension (HTN) that develops during hospitalization is not informed by guidelines. Intravenous (i.v.) antihypertensives are used to manage severe HTN even in the absence of acute target organ damage; however they may result in unpredictable blood pressure (BP) reduction and cardiovascular events. Our goal was to assess the association between i.v. antihypertensives and clinical outcomes in this population. METHODS: This is a multihospital retrospective study of adults admitted for reasons other than HTN who develop severe HTN during hospitalization without acute target end organ damage. We defined severe HTN as BP elevation of systolic >180 or diastolic >110 mmHg. Treatment was defined as receiving i.v. antihypertensives within 3 h of BP elevation. We used overlap propensity score weighted Cox models to study the association between treatment and clinical outcomes during index hospitalization. RESULTS: Of 224 265 unique, nonintensive care unit hospitalizations, 20 383 (9%) developed severe HTN, of which 5% received i.v. antihypertensives and 79% were untreated within 3 h of severe BP elevation. In the overlap propensity weighted population, patients who received i.v. antihypertensives were more likely to develop myocardial injury (5.9% in treated versus 3.6% in untreated; hazard ratio [HR]: 1.6 [1.13, 2.24]). Treatment was not associated with increased risk of stroke (HR: 0.7 [0.3, 1.62]), acute kidney injury (HR: 0.97 [0.81, 1.17]), or death (HR: 0.86 [0.49, 1.51]). CONCLUSIONS: Intravenous antihypertensives were associated with increased risk of myocardial injury in patients who develop severe HTN during hospitalization. These results suggest that i.v. antihypertensives should be used with caution in patients without acute target organ damage.