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.

Retrospective Validation of a Computerized Physiologic Equation to Predict Minute Ventilation Needs in Critically Ill Children.

OBJECTIVES: Mechanical ventilation (MV) is pervasive among critically ill children. We sought to validate a computerized physiologic equation to predict minute ventilation requirements in children and test its performance against clinician actions in an in silico trial. DESIGN: Retrospective, electronic medical record linkage, cohort study. SETTING: Quaternary PICU. PATIENTS: Patients undergoing invasive MV, serial arterial blood gas (ABG) analysis within 1-6 hours, and pharmacologic neuromuscular blockade (NMB). MEASUREMENTS AND MAIN RESULTS: ABG values were filtered to those occurring during periods of NMB. Simultaneous ABG and minute ventilation data were linked to predict serial Pa co2 and pH values using previously published physiologic equations. There were 15,121 included ABGs across 500 encounters among 484 patients, with a median (interquartile range [IQR]) of 20 (10-43) ABGs per encounter at a duration of 3.6 (2.1-4.2) hours. The median (IQR) Pa co2 prediction error was 0.00 (-3.07 to 3.00) mm Hg. In Bland-Altman analysis, the mean error was -0.10 mm Hg (95% CI, -0.21 to 0.01 mm Hg). A nested, in silico trial of ABGs meeting criteria for weaning (respiratory alkalosis) or escalation (respiratory acidosis), compared the performance of recommended ventilator changes versus clinician decisions. There were 1,499 of 15,121 ABGs (9.9%) among 278 of 644 (43.2%) encounters included in the trial. Calculated predictions were favorable to clinician actions in 1124 of 1499 ABGs (75.0%), equivalent to clinician choices in 26 of 1499 ABGs (1.7%), and worse than clinician decisions in 349 of 1499 ABGs (23.3%). Calculated recommendations were favorable to clinician decisions in sensitivity analyses limiting respiratory rate, analyzing only when clinicians made changes, excluding asthma, and excluding acute respiratory distress syndrome. CONCLUSIONS: A computerized equation to predict minute ventilation requirements outperformed clinicians' ventilator adjustments in 75% of ABGs from critically ill children in this retrospective analysis. Prospective validation studies are needed.

A Comparison of the Anticoagulation Efficacy and Safety of Epoprostenol to Heparin and Citrate in Children Receiving Continuous Renal Replacement Therapy.

INTRODUCTION: Anticoagulants are used in continuous renal replacement therapy (CRRT) to prolong filter life. There are no prior investigations directly comparing epoprostenol to more commonly used forms of anticoagulation in children. Therefore, the primary aim of this study was to assess the efficacy and safety of epoprostenol as compared to heparin and citrate anticoagulation in a pediatric cohort. METHODS: We performed a retrospective analysis of all patients <18 years of age admitted to an academic quaternary care children's hospital from 2017-2022 who received epoprostenol, heparin, or citrate exclusively for CRRT anticoagulation. Efficacy was evaluated by comparing the hours to the first unintended filter change and the ratio of filters used to CRRT days. Safety was assessed by evaluating changes in platelet count and vasoactive-ionotropic score (VIS). RESULTS: Of 101 patients, 44 received epoprostenol (43.6%), 38 received heparin (37.6%), and 19 received citrate (18.8%). The first filter change was more commonly planned in patients receiving anticoagulation with epoprostenol (43%) as compared to citrate (11%) or heparin (29%) (p = 0.034). Of those patients where the first filter change was unintended (n = 33), there were greater median hours until the filter was replaced in those receiving epoprostenol (29) when compared to citrate (21) (p = 0.002) or heparin (18) (p = 0.003). There was a smaller median ratio of filters used to days on therapy in the patients that received epoprostenol (0.53) when compared to citrate (1) (p = 0.003) or heparin (0.75) (p = 0.001). For those receiving epoprostenol, there was no significant decrease in platelet count when comparing values prior to CRRT initiation through 7 days of therapy. There was no significant difference in VIS when comparing values prior to CRRT initiation through the first 2 days of CRRT. CONCLUSIONS: Epoprostenol-based anticoagulation is effective when compared to other anticoagulation strategies used in pediatric CRRT with a favorable side effect profile.

Current practices in pediatric continuous kidney replacement therapy: a systematic review-guided multinational modified Delphi consensus study.

BACKGROUND: Continuous kidney replacement therapy (CKRT) has become an integral part of the care of critically ill children. However, uncertainty exists regarding the current state of how CKRT is prescribed and delivered in children. The main objective of this study was to identify the current practices for pediatric CKRT. METHODS: We conducted a systematic review of the literature from 2012 to 2022 to identify data regarding CKRT timing of initiation, dosing, anticoagulation, fluid removal, and quality monitoring. Using this data, we then performed a two-round modified Delphi process using a multinational internet-assisted survey of prescribers of CKRT. RESULTS: The survey was constructed using 172 articles that met inclusion criteria (12% of studies were pediatric focused). A total of 147 and 126 practitioners completed the survey in rounds 1 and 2, respectively. Participants represented Europe (9.5-11.6%) and North America including pediatric intensivists, nephrologists, and advance practice providers. Consensus (defined as a ≥ 75% participant response of "sometimes" or "always") was achieved for 26 statements. There was consensus in the practices of CKRT initiation, dosing, method of anticoagulation, and fluid removal. In contrast, there appears to be greater variability in the methods used for monitoring anticoagulation and the quality of the delivered treatment. CONCLUSIONS: Our study results suggest that the current state of pediatric CKRT practice is reflective of the literature over the last 10 years, which is largely based on the care of adult patients. This data provides a framework to study best practices to further improve outcomes for children receiving CKRT. A higher resolution version of the Graphical abstract is available as Supplementary information.

Effects of preoperative high-oral protein loading on short- and long-term renal outcomes following cardiac surgery: a cohort study.

BACKGROUND: Post-cardiac surgery acute kidney injury (AKI) is associated with increased mortality. A high-protein meal enhances the renal blood flow and glomerular filtration rate (GFR) and might protect the kidneys from acute ischemic insults. Hence, we assessed the effect of a preoperative high-oral protein load on post-cardiac surgery renal function and used experimental models to elucidate mechanisms by which protein might stimulate kidney-protective effects. METHODS: The prospective "Preoperative Renal Functional Reserve Predicts Risk of AKI after Cardiac Operation" study follow-up was extended to postoperative 12 months for 109 patients. A 1:2 ratio propensity score matching method was used to identify a control group (n = 214) to comparatively evaluate the effects of a preoperative protein load and standard care. The primary endpoints were AKI development and postoperative estimated GFR (eGFR) loss at 3 and 12 months. We also assessed the secretion of tissue inhibitor of metalloproteases-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7), biomarkers implicated in mediating kidney-protective mechanisms in human kidney tubular cells that we exposed to varying protein concentrations. RESULTS: The AKI rate did not differ between the protein loading and control groups (13.6 vs. 12.3%; p = 0.5). However, the mean eGFR loss was lower in the former after 3 months (0.1 [95% CI - 1.4, - 1.7] vs. - 3.3 [95% CI - 4.4, - 2.2] ml/min/1.73 m2) and 12 months (- 2.7 [95% CI - 4.2, - 1.2] vs - 10.2 [95% CI - 11.3, - 9.1] ml/min/1.73 m2; p < 0.001 for both). On stratification based on AKI development, the eGFR loss after 12 months was also found to be lower in the former (- 8.0 [95% CI - 14.1, - 1.9] vs. - 18.6 [95% CI - 23.3, - 14.0] ml/min/1.73 m2; p = 0.008). A dose-response analysis of the protein treatment of the primary human proximal and distal tubule epithelial cells in culture showed significantly increased IGFBP7 and TIMP-2 expression. CONCLUSIONS: A preoperative high-oral protein load did not reduce AKI development but was associated with greater renal function preservation in patients with and without AKI at 12 months post-cardiac surgery. The potential mechanisms of action by which protein loading may induce a kidney-protective response might include cell cycle inhibition of renal tubular epithelial cells. Clinical trial registration ClinicalTrials.gov: NCT03102541 (retrospectively registered on April 5, 2017) and ClinicalTrials.gov: NCT03092947 (retrospectively registered on March 28, 2017).

Acute kidney disease predicts chronic kidney disease in pediatric non-kidney solid organ transplant patients.

BACKGROUND: Acute kidney disease (AKD) is defined as impaired kidney function present for <90 days with or without an acute kidney injury (AKI) event. Adults with AKD have an increased risk for progression to chronic kidney disease (CKD) and mortality. There are no data on the epidemiology of AKD in children after transplant. The aim of this study was to evaluate the incidence and risk factors for AKI, AKD, and CKD in children after transplantation. METHODS: This is a retrospective cohort study of all children undergoing non-kidney solid organ transplant between 2011 and 2019 at UPMC Children's Hospital of Pittsburgh. AKI and AKD were defined using the Kidney Disease Improving Global Outcomes criteria. Patients with a new estimated glomerular filtration rate <60 ml/min/1.73m2 persisting for >3 months met criteria for new CKD. Variables associated with AKI, AKD, and CKD were analyzed. RESULTS: Among 338 patients, 37.9% met criteria for severe AKI, 13% for AKD, and 8% for a new diagnosis of CKD. Stage 3 AKI was independently associated with AKD (OR: 5.35; 95% CI: 2.23-12.86). Severe AKI was not associated with new-onset CKD, whereas AKD was associated with new-onset CKD (OR: 29.74; CI: 11.22-78.82). CONCLUSION: AKD may be superior to AKI in predicting risk of CKD in children after non-kidney solid organ transplantation.

Tandem Therapeutic Plasma Exchange Reduces Continuous Renal Replacement Therapy Downtime.

INTRODUCTION: Continuous renal replacement therapy (CRRT) has become a primary treatment of severe acute kidney injury in children admitted to the intensive care unit. CRRT "downtime" (when the circuit is not active) can represent a significant portion of the prescribed treatment time and adversely affects clearance. The objective of this study was to evaluate factors associated with CRRT "downtime" and to determine whether instituting a tandem therapeutic plasma exchange (TPE) protocol could significantly and robustly decrease circuit downtime in patients receiving both therapies. METHODS: This is a retrospective cohort study of 116 patients undergoing CRRT in the pediatric, neonatal, or cardiac ICU at UPMC Children's Hospital of Pittsburgh from January 2014 to July 2020. We performed multivariable logistic regression to determine factors associated with CRRT downtime. We instituted a tandem TPE protocol whereby TPE and CRRT could run in parallel without pausing CRRT in April 2018. We analyzed the effect of the protocol change by plotting downtime for patients undergoing CRRT and TPE on a run chart. The effect of initiating tandem TPE on downtime was assessed by special cause variation. RESULTS: For 108/139 (77.7%) sessions with downtime data available, the median (IQR) percentage of downtime was 6.2% (1.7-12.7%). Multivariable logistic regression showed that TPE was significantly associated with CRRT downtime (p = 0.003), and that age, sex, race, catheter size, and anticoagulation were not. For patients undergoing TPE, the median (IQR) percentage of downtime was 14.7% (10.5-26%) and 3.4% (1.3-4.9%) before and after initiation of tandem TPE, respectively (p < 0.001). The difference in downtime percentage met criteria for special cause variation. CONCLUSIONS: Interruptions for TPE increase CRRT downtime. Tandem TPE significantly reduces CRRT downtime in patients undergoing both procedures concomitantly.

Association of Acute Kidney Injury With Subsequent Sepsis in Critically Ill Children.

OBJECTIVES: Acute kidney injury is a major cause of morbidity and mortality in critically ill children. A growing body of evidence has shown that acute kidney injury affects immune function, yet little is known about the association between acute kidney injury and subsequent infection in pediatric patients. Our objective was to examine the association of non-septic acute kidney injury with the development of subsequent sepsis in critically ill children. DESIGN: A single-center retrospective cohort study. SETTING: The pediatric and cardiac ICUs at a tertiary pediatric care center. PATIENTS: All patients 0-18 years old without a history of chronic kidney disease, who did not have sepsis prior to or within the initial 48 hours of ICU admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed data for 5,538 children (median age, 5.3 yr; 58.2% male), and identified 255 (4.6%) with stage 2 or 3 acute kidney injury. Suspected sepsis occurred in 46 children (18%) with stage 2 or 3 acute kidney injury compared to 286 children (5.4%) with stage 1 or no acute kidney injury. On adjusted analysis, children with stage 2 or 3 acute kidney injury had 2.05 times greater odds of developing sepsis compared to those with stage 1 or no acute kidney injury (95% CI, 1.39-3.03; p < 0.001). Looking at acute kidney injury severity, children with stage 2 and 3 acute kidney injury had a 1.79-fold (95% CI, 1.15-2.79; p = 0.01) and 3.24-fold (95% CI, 1.55-6.80; p = 0.002) increased odds of developing suspected sepsis, respectively. CONCLUSIONS: Acute kidney injury is associated with an increased risk for subsequent infection in critically ill children. These results further support the concept of acute kidney injury as a clinically relevant immunocompromised state.

Outcomes of adults with congenital heart disease that experience acute kidney injury in the intensive care unit.

BACKGROUND: Young adults with congenital heart disease (CHD) are increasing in number with an increased risk for acute kidney injury. Little is known concerning the impact of non-recovery of kidney function for these patients. Therefore, we sought to explore the rates of acute kidney disease, persistent renal dysfunction, and their associations with adverse outcomes in young adults with CHD. METHODS: This is a single-centre retrospective study including all patients at the ages of 18-40 with CHD who were admitted to an intensive care unit between 2010 and 2014. Patients with a creatinine ≥ 1.5 times the baseline at the time of hospital discharge were deemed to have persistent renal dysfunction, while acute kidney disease was defined as a creatinine ≥ 1.5 times the baseline 7-28 days after a diagnosis of acute kidney injury. Outcomes of death at 5 years and length of hospital stay were examined using multivariable logistic regression and negative binomial regression, respectively. RESULTS: Of the (89/195) 45.6% of patients with acute kidney injury, 33.7% had persistent renal dysfunction and 23.6% met the criteria for acute kidney disease. Persistent renal dysfunction [odds ratio (OR), 3.27; 95% confidence interval (CI): 1.15-9.29] and acute kidney disease (OR: 11.79; 95% CI: 3.75-39.09) were independently associated with mortality at 5 years. Persistent renal dysfunction was associated with a longer duration of hospital stay (Incidence Rate Ratio: 1.96; 95% CI: 1.53-2.51). CONCLUSIONS: In young adults with CHD, acute kidney injury was common and persistent renal dysfunction, as well as acute kidney disease, were associated with increased mortality and length of hospitalisation.

The use of urinary biomarkers to predict acute kidney injury in children after liver transplant.

BACKGROUND: AKI after pediatric liver transplantation is associated with increased morbidity and mortality. The role of urinary biomarkers for the prediction of AKI in pediatric patients after liver transplantation has not been previously reported. The primary objective of this prospective pilot study was to determine the predictive capabilities of urinary KIM-1, NGAL, TIMP-2, and IGFBP7 for diagnosing AKI. METHODS: Sixteen children undergoing liver transplantation were enrolled in the study over a 19-month time period. The Kidney Disease Improving Outcomes criteria for urine output and serum creatinine were used to define AKI. Predictive ability was evaluated using the area under the curve obtained by ROC analysis. RESULTS: AKI occurred in 6 (37.5%) of the patients between 2 and 4 days after transplant. There were no differences in any of the biomarkers prior to transplant. When obtained within 6 hours after transplant, the area under the ROC curve for predicting AKI was 0.758 (95% CI: 0.458-1.00) for KIM-1, 0.900 (95% CI: 0.724-1.00) for NGAL, and 0.933 (95% CI: 0.812-1.00) for the product of TIMP-2 and IGFBP7 ([TIMP-2]·[IGFBP7]). CONCLUSIONS: Our results show that both NGAL and [TIMP-2]·[IGFBP7] provide significant discrimination for AKI risk following liver transplant in children. Larger studies are needed to determine the optimal time point for measuring these biomarkers and to validate our findings.

Piperacillin/Tazobactam and Antibiotic-Associated Acute Kidney Injury in Critically Ill Children.

BACKGROUND: There continues to be uncertainty about whether piperacillin/tazobactam (TZP) increases the risk of AKI in critically ill pediatric patients. We sought to compare rates of AKI among critically ill children treated with TZP or cefepime, an alternative frequently used in intensive care units, with and without vancomycin. METHODS: We conducted a retrospective cohort study assessing the risk of AKI in pediatric intensive care unit patients after exposure to vancomycin, TZP, and cefepime, alone or in combination, within 48 hours of admission. The primary outcome was development of stage 2 or 3 AKI or an increase in AKI stage from 2 to 3 within the 6 days after the 48-hour exposure window. Secondary outcomes included lengths of stay, need for RRT, and mortality. RESULTS: Of 5686 patients included, 494 (8.7%) developed stage 2 or 3 AKI. The adjusted odds of developing AKI after medication exposure were 1.56 for TZP (95% confidence interval [95% CI], 1.23 to 1.99), 1.13 for cefepime (95% CI, 0.79 to 1.64), and 0.86 for vancomycin (95% CI, 0.69 to 1.07). The adjusted odds of developing AKI for vancomycin plus TZP versus vancomycin plus cefepime was 1.38 (95% CI, 0.85 to 2.24). CONCLUSIONS: Observational data in critically ill children show that TZP use is associated with increased odds of AKI. A weaker, nonsignificant association between vancomycin plus TZP and AKI compared with vancomycin plus cefepime, creates some uncertainty about the nature of the association between TZP and AKI. However, cefepime is an alternative not associated with AKI.

eResearch in acute kidney injury: a primer for electronic health record research.

Acute kidney injury (AKI) has a significant impact on patient morbidity and mortality as well as overall health care costs. eResearch, which integrates information technology and information management to optimize research strategies, provides a perfect platform for necessary ongoing AKI research. With the recent adoption of a widely accepted definition of AKI and near-universal use of electronic health records, eResearch is becoming an important tool in AKI research. Conducting eResearch in AKI should ideally be based on a relatively uniform methodology. This article is the first of its kind to describe a methodology for pursuing eResearch specific to AKI and includes an illustrative database example for critically ill patients. We discuss strategies for using serum creatinine and urine output in large databases to identify and stage AKI and ways to interpolate missing values and validate data. Issues specific to the pediatric population include variation in serum creatinine with growth, varied severity of illness scoring systems and medication dosage based on weight. Many of these same strategies used to optimize AKI eResearch can be applicable to real-time AKI alerts with potential integration of additional clinical variables.

Drug-associated acute kidney injury: who's at risk?

The contribution of nephrotoxic medications to the development of acute kidney injury (AKI) is becoming better understood concomitant with the increased incidence of AKI in children. Treatment of AKI is not yet available, so prevention continues to be the most effective approach. There is an opportunity to mitigate severity and prevent the occurrence of AKI if children at increased risk are identified early and nephrotoxins are used judiciously. Early detection of AKI is limited by the dependence of nephrologists on serum creatinine as an indicator. Promising new biomarkers may offer early detection of AKI prior to the rise in serum creatinine. Early detection of evolving AKI is improving and offers opportunities for better management of nephrotoxins. However, the identification of patients at increased risk will remain an important first step, with a focus on the use of biomarker testing and interpretation of the results.

Renal Response to a Protein Load in Healthy Young Adults as Determined by Iohexol Infusion Clearance, Cimetidine-Inhibited Creatinine Clearance, and Cystatin C Estimated Glomerular Filtration Rate.

OBJECTIVE: Renal reserve (RR) measures the increase in glomerular filtration rate (GFR) in response to a protein load; lack of RR could indicate subclinical kidney disease but such a test is not routinely used in clinical practice. The purpose of this study was to compare a meat versus liquid protein load in a cystatin C-based (Cys-C) RR test using cimetidine-inhibited creatinine clearance (Cr Cl) and iohexol infusion clearance (Io Cl) for validation. The design was cross-sectional analysis and the setting was a Clinical Research Center. SUBJECTS: Participants (N = 16), mean (standard deviation [SD]) age 22 (2) years, had normal health and blood pressure without proteinuria. INTERVENTION: Participants 1 to 8 received a beef burger (1 g/kg protein) and participants 9 to 16 received a ProCel shake (1-1.5 g/kg protein). MAIN OUTCOME MEASURE: RR defined as the difference in stimulated versus baseline GFR. RESULTS: Baseline GFR (SD) in mL/minute/1.73 m2 averaged 103.0 (15.6) for Cr Cl, 94.8 (7.9) for Io Cl, and 117.0 (6.0) for Cys-C estimated GFR (eGFR). Mean RR (SD) for the burger group (N = 8, mL/minute/1.73 m2) was 16.6 (12.3) for Cr Cl (P = .006); 7.2 (3.7) for Io Cl (P < .001), and 4.9 (2.6) for Cys-C eGFR (P = .001). Mean RR for the shake group (N = 8) was 15.8 (5.8) for Cr Cl (P < .001), 10.1 (7.8) for Io Cl (P = .008), and 2.4 (2.9) for Cys-C eGFR (P = .05). CONCLUSION: Protein loading stimulates Io Cl and Cr Cl after a beef or milk-based protein load. The change in Cys-C eGFR is significant but smaller for the shake and burger group, which may be due to the dilutional effect of water loading or the length of Cys-C half-life in the blood.

Epidemiology and pathophysiology of cardiac surgery-associated acute kidney injury.

PURPOSE OF REVIEW: Acute kidney injury (AKI) remains a serious complication of cardiac surgery. An understanding of the epidemiology and pathophysiology of AKI in cardiac surgery patients is crucial to early recognition and proper management. RECENT FINDINGS: The article will review the current criteria used for defining AKI and the most recently published incidence rates of AKI in the cardiac surgery population. Variables associated with AKI will be reviewed. The cause of cardiac surgery-associated AKI is multifactorial involving genetic factors as well as insults because of nephrotoxins, ischemia and reperfusion, cardiac dysfunction, venous congestion, inflammation, and oxidative stress. SUMMARY: Investigators should aim to use consistent criteria for defining AKI in future studies. Efforts should be taken to use actual measurements rather than estimated values of baseline serum creatinine whenever possible. Further study of the more recently proposed pathophysiologic factors contributing to cardiac surgery-associated AKI, such as circulating damage-associated molecular patterns, venous congestion, and genetic predisposition, are warranted.

Remote Ischemic Preconditioning in the PICU: A Simple Concept With a Complex Past.

OBJECTIVE: In this study, we will review the most recently proposed mechanisms for remote ischemic preconditioning and summarize the past 10 years of clinical studies, as well as potential reasons for why, despite over 20 years of research on remote ischemic preconditioning, it is not routinely used in the pediatric critical care patient. In addition, future directions for remote ischemic preconditioning research will be discussed. DATA SOURCES: We searched the PubMed database for relevant literature. STUDY SELECTION AND DATA EXTRACTION: In PubMed, the search terms "ischemic preconditioning" and "remote preconditioning" were used. Randomized controlled trials published from 2006 until the present time that used a blood pressure cuff to induce remote ischemic preconditioning were included. We also reviewed the reference lists of the articles found in the PubMed search and included those thought to contribute to the objectives. All studies pertaining to remote ischemic preconditioning that included pediatric patients were reviewed. DATA SYNTHESIS AND CONCLUSIONS: Differences in study outcomes in the effect of remote ischemic preconditioning on organ protection have been reported and may have played a large role in limiting the translation of findings into routine clinical practice. Ongoing efforts to protocolize the remote ischemic preconditioning technique in large multicenter trials with clearly delineated patient risk groups, including the use of biomarkers for enrichment, may help to ultimately determine if this procedure can be safely and effectively used for critically ill children.