Faculty Bibliography

BACKGROUND:Access to pediatric dialysis is challenged in low-resource settings due to high costs, scarcity of equipment, and the lack of qualified personnel availability. We demonstrated the manual single lumen alternating micro-batch (mSLAMB) device can remove small solutes in vitro without the need for electricity, batteries, or pumps. We developed a new version (Kirpa Kit™) to address some of the technical limitations of mSLAMB. Here, we compare the in vitro clearance performance and ease of use of the Kirpa Kit™ with that of prior mSLAMB configurations. METHODS:A mixture of expired packed red blood cells, 0.9% NaCl, urea, and heparin was used to test the efficiency of two mSLAMB configurations and the Kirpa Kit™ in removing potassium and urea. Clearance was evaluated by measuring percent reduction after 25-min sessions with each device. A survey was used to evaluate the ease of use of each configuration. RESULTS:The Kirpa Kit™ achieved a median urea reduction of 82.4% and potassium reduction of 82.1%, which were higher than those achieved with the best-performing mSLAMB configuration (urea 71.9%, potassium 75.4%). The Kirpa Kit™ was easier to use with a shorter perceived time of use than the mSLAMB. CONCLUSIONS:The Kirpa Kit™, evolution of mSLAMB, is easy to use and may have improved efficacy, making it an optimal candidate for in vivo testing.

OBJECTIVES/OBJECTIVE:Pediatric sepsis-associated acute kidney injury (AKI) often requires continuous renal replacement therapy (CRRT), but limited data exist regarding patient characteristics and outcomes. We aimed to describe these features, including the impact of possible dialytrauma (i.e., vasoactive requirement, negative fluid balance) on outcomes, and contrast them to nonseptic patients in an international cohort of children and young adults receiving CRRT. DESIGN/METHODS:A secondary analysis of Worldwide Exploration of Renal Replacement Outcomes Collaborative in Kidney Disease (WE-ROCK), an international, multicenter, retrospective study. SETTING/METHODS:Neonatal, cardiac and PICUs at 34 centers in nine countries from January 1, 2015, to December 31, 2021. PATIENTS/METHODS:Patients 0-25 years old requiring CRRT for AKI and/or fluid overload. INTERVENTIONS/METHODS:None. MEASUREMENTS AND MAIN RESULTS/RESULTS:Among 1016 patients, 446 (44%) had sepsis at CRRT initiation and 650 (64%) experienced Major Adverse Kidney Events at 90 days (MAKE-90) (defined as a composite of death, renal replacement therapy [RRT] dependence, or > 25% decline in estimated glomerular filtration rate from baseline at 90 d from CRRT initiation). Septic patients were less likely to liberate from CRRT by 28 days (30% vs. 38%; p < 0.001) and had higher rates of MAKE-90 (70% vs. 61%; p = 0.002) and higher mortality (47% vs. 31%; p < 0.001) than nonseptic patients; however, septic survivors were less likely to be RRT dependent at 90 days (10% vs. 18%; p = 0.011). On multivariable regression, pre-CRRT vasoactive requirement, time to negative fluid balance, and median daily fluid balance over the first week of CRRT were not associated with MAKE-90; however, increasing duration of vasoactive requirement was independently associated with increased odds of MAKE-90 (adjusted OR [aOR], 1.16; 95% CI, 1.05-1.28) and mortality (aOR, 1.20; 95% CI, 1.1-1.32) for each additional day of support. CONCLUSIONS:Septic children requiring CRRT have different clinical characteristics and outcomes compared with those without sepsis, including higher rates of mortality and MAKE-90. Increasing duration of vasoactive support during the first week of CRRT, a surrogate of potential dialytrauma, appears to be associated with these outcomes.

RATIONALE & OBJECTIVE/OBJECTIVE:There are limited studies describing the epidemiology and outcomes of children and young adults receiving continuous kidney replacement therapy (CKRT). We aimed to describe associations between patient characteristics, CKRT prescription, and survival. STUDY DESIGN/METHODS:Retrospective multicenter cohort study. SETTING/METHODS:& Participants: 980 patients aged birth-25 years old who received CKRT between 2015 and 2021 at 1 of 32 centers in 7 countries participating in the Worldwide Exploration of Renal Replacement Outcomes Collaborative in Kidney Diseases (WE-ROCK). EXPOSURE/METHODS:CKRT for acute kidney injury or volume overload. OUTCOMES/RESULTS:Death before ICU discharge. ANALYTICAL APPROACH/METHODS:Descriptive statistics. RESULTS:Median age was 8.8 years (IQR 1.6, 15.0) with a median weight of 26.8 kg (IQR 11.6, 55.0). CKRT was initiated a median of 2 days (IQR 1, 6) after ICU admission and lasted a median of 6 days (IQR 3, 14). The most common CKRT modality was continuous veno-venous hemodiafiltration. Citrate anticoagulation was used in 62%, and the internal jugular vein was the most common catheter placement location (66%). 629 participants (64.1%) survived at least until ICU discharge. The CKRT dose, filter type, and anticoagulation were similar in those who did and did not survive to ICU discharge. There were apparent practice variations by institutional ICU size. LIMITATIONS/CONCLUSIONS:Retrospective design; limited representation from centers outside United States. CONCLUSIONS:In this study of children and young adults receiving CKRT approximately two-thirds survived at least until ICU discharge. While variations in dialysis mode, dose, catheter size and location, and anticoagulation were observed, survival was not detected to be associated with these parameters.

BACKGROUND:Metabolites represent a read-out of cellular processes underlying states of health and disease. METHODS:We evaluated cross-sectional and longitudinal associations between 1255 serum and 1398 urine known and unknown (denoted with "X" in name) metabolites (Metabolon HD4, 721 detected in both biofluids) and kidney function in 1612 participants of the Atherosclerosis Risk in Communities (ARIC) Study. All analyses were adjusted for clinical and demographic covariates, including for baseline eGFR and UACR in longitudinal analyses. RESULTS:At visit 5 of the ARIC study, the mean age of participants was 76 years (SD 6), 56% were women, mean eGFR was 62 ml/min/1.73m2 (SD 20), and median urine albumin-to-creatinine level (UACR) was 13 mg/g (IQR 25). In cross-sectional analysis, 675 serum and 542 urine metabolites were associated with eGFR (Bonferroni-corrected p < 4.0E-5 for serum analyses and p < 3.6E-5 for urine analyses), including 248 metabolites shared across biofluids. Fewer metabolites (75 serum and 91 urine metabolites, including 7 shared across biofluids) were cross-sectionally associated with albuminuria. Guanidinosuccinate, N2,N2-dimethylguanosine, hydroxy-N6,N6,N6-trimethyllysine, X-13844, and X-25422 were significantly associated with both eGFR and albuminuria. Over a mean follow-up of 6.6 years, serum mannose (HR 2.3 [1.6,3.2], p = 2.7E-5) and urine X-12117 (HR 1.7 [1.3,2.2], p = 1.9E-5) were risk factors for UACR doubling, whereas urine sebacate (HR 0.86 [0.80,0.92], p = 1.9E-5) was inversely associated. Compared to clinical characteristics alone, including the top 5 endogenous metabolites in serum and urine associated with longitudinal outcomes improved the outcome prediction (AUCs for eGFR decline: clinical model = 0.79, clinical + metabolites model = 0.87, p = 8.1E-6; for UACR doubling: clinical model = 0.66, clinical + metabolites model = 0.73, p = 2.9E-5). CONCLUSIONS:Metabolomic profiling in different biofluids provided distinct and potentially complementary insights into the biology and prognosis of kidney diseases.

PURPOSE/OBJECTIVE:Continuous renal replacement therapy (CRRT) is used for supportive management of acute kidney injury (AKI) and disorders of fluid balance (FB). Little is known about the predictors of successful liberation in children and young adults. We aimed to identify the factors associated with successful CRRT liberation. METHODS:The Worldwide Exploration of Renal Replacement Outcomes Collaborative in Kidney Disease study is an international multicenter retrospective study (32 centers, 7 nations) conducted from 2015 to 2021 in children and young adults (aged 0-25 years) treated with CRRT for AKI or FB disorders. Patients with previous dialysis dependence, tandem extracorporeal membrane oxygenation use, died within the first 72 h of CRRT initiation, and those who never had liberation attempted were excluded. Patients were categorized based on first liberation attempt: reinstituted (resumption of any dialysis within 72 h) vs. success (no receipt of dialysis for ≥ 72 h). Multivariable logistic regression was used to identify factors associated with successful CRRT liberation. RESULTS:A total of 622 patients were included: 287 (46%) had CRRT reinstituted and 335 (54%) were successfully liberated. After adjusting for sepsis at admission and illness severity parameters, several factors were associated with successful liberation, including higher VIS (vasoactive-inotropic score) at CRRT initiation (odds ratio [OR] 1.35 [1.12-1.63]), higher PELOD-2 (pediatric logistic organ dysfunction-2) score at CRRT initiation (OR 1.71 [1.24-2.35]), higher urine output prior to CRRT initiation (OR 1.15 [1.001-1.32]), and shorter CRRT duration (OR 0.19 [0.12-0.28]). CONCLUSIONS:Inability to liberate from CRRT was common in this multinational retrospective study. Modifiable and non-modifiable factors were associated with successful liberation. These results may inform the design of future clinical trials to optimize likelihood of CRRT liberation success.

OBJECTIVES/OBJECTIVE:Cardiac surgery-associated acute kidney injury (CS-AKI) is associated with adverse outcomes. Single-center studies suggest that the prevalence of CS-AKI is high after the Norwood procedure, or stage 1 palliation (S1P), but multicenter data are lacking. DESIGN/METHODS:A secondary analysis of the Neonatal and Pediatric Heart and Renal Outcomes Network (NEPHRON) multicenter cohort who underwent S1P. Using neonatal modification of Kidney Disease Improving Global Outcomes (KDIGO) criteria, perioperative associations between CS-AKI with morbidity and mortality were examined. Sensitivity analysis, with the exclusion of prophylactic peritoneal dialysis (PD) patients, was performed. SETTING/METHODS:Twenty-two hospitals participating in the Pediatric Cardiac Critical Care Consortium (PC 4 ) and contributing to NEPHRON. PATIENTS/METHODS:Three hundred forty-seven neonates (< 30 d old) with S1P managed between September 2015 and January 2018. INTERVENTIONS/METHODS:None. MEASUREMENTS AND MAIN RESULTS/RESULTS:Of 347 patients, CS-AKI occurred in 231 (67%). The maximum stages were as follows: stage 1, in 141 of 347 (41%); stage 2, in 51 of 347 (15%); and stage 3, in 39 of 347 (11%). Severe CS-AKI (stages 2 and 3) peaked on the first postoperative day. In multivariable analysis, preoperative feeding was associated with lower odds of CS-AKI (odds ratio [OR] 0.48; 95% CI, 0.27-0.86), whereas prophylactic PD was associated with greater odds of severe CS-AKI (OR 3.67 [95% CI, 1.88-7.19]). We failed to identify an association between prophylactic PD and increased creatinine (OR 1.85 [95% CI, 0.82-4.14]) but cannot exclude the possibility of a four-fold increase in odds. Hospital mortality was 5.5% ( n = 19). After adjusting for risk covariates and center effect, severe CS-AKI was associated with greater odds of hospital mortality (OR 3.67 [95% CI, 1.11-12.16]). We failed to find associations between severe CS-AKI and respiratory support or length of stay. The sensitivity analysis using PD failed to show associations between severe CS-AKI and outcome. CONCLUSIONS:KDIGO-defined CS-AKI occurred frequently and early postoperatively in this 2015-2018 multicenter PC 4 /NEPHRON cohort of neonates after S1P. We failed to identify associations between resource utilization and CS-AKI, but there was an association between severe CS-AKI and greater odds of mortality in this high-risk cohort. Improving the precision for defining clinically relevant neonatal CS-AKI remains a priority.

BACKGROUND:Cardiac surgery-associated acute kidney injury (CS-AKI) is common, but its impact on clinical outcomes is variable. Parsing AKI into sub-phenotype(s) and integrating pathologic positive cumulative fluid balance (CFB) may better inform prognosis. We sought to determine whether durational sub-phenotyping of CS-AKI with CFB strengthens association with outcomes among neonates undergoing the Norwood procedure. METHODS:Multicenter, retrospective cohort study from the Neonatal and Pediatric Heart and Renal Outcomes Network. Transient CS-AKI: present only on post-operative day (POD) 1 and/or 2; persistent CS-AKI: continued after POD 2. CFB was evaluated per day and peak CFB during the first 7 postoperative days. Primary and secondary outcomes were mortality, respiratory support-free and hospital-free days (at 28, 60 days, respectively). The primary predictor was persistent CS-AKI, defined by modified neonatal Kidney Disease: Improving Global Outcomes criteria. RESULTS:CS-AKI occurred in 59% (205/347) neonates: 36.6% (127/347) transient and 22.5% (78/347) persistent; CFB > 10% occurred in 18.7% (65/347). Patients with either persistent CS-AKI or peak CFB > 10% had higher mortality. Combined persistent CS-AKI with peak CFB > 10% (n = 21) associated with increased mortality (aOR: 7.8, 95% CI: 1.4, 45.5; p = 0.02), decreased respiratory support-free (predicted mean 12 vs. 19; p < 0.001) and hospital-free days (17 vs. 29; p = 0.048) compared to those with neither. CONCLUSIONS:The combination of persistent CS-AKI and peak CFB > 10% after the Norwood procedure is associated with mortality and hospital resource utilization. Prospective studies targeting intra- and postoperative CS-AKI risk factors and reducing CFB have the potential to improve outcomes. A higher resolution version of the Graphical abstract is available as Supplementary information.

BACKGROUND:The impact of disorders of fluid balance, including the pathologic state of fluid overload in sick children has become increasingly apparent. With this understanding, there has been a shift from application of absolute thresholds of fluid accumulation to an appreciation of the intricacies of fluid balance, including the impact of timing, trajectory, and disease pathophysiology. METHODS:The 26th Acute Disease Quality Initiative was the first to be exclusively dedicated to pediatric and neonatal acute kidney injury (pADQI). As part of the consensus panel, a multidisciplinary working group dedicated to fluid balance, fluid accumulation, and fluid overload was created. Through a search, review, and appraisal of the literature, summative consensus statements, along with identification of knowledge gaps and recommendations for clinical practice and research were developed. CONCLUSIONS:The 26th pADQI conference proposed harmonized terminology for fluid balance and for describing a pathologic state of fluid overload for clinical practice and research. Recommendations include that the terms daily fluid balance, cumulative fluid balance, and percent cumulative fluid balance be utilized to describe the fluid status of sick children. The term fluid overload is to be preserved for describing a pathologic state of positive fluid balance associated with adverse events. Several recommendations for research were proposed including focused validation of the definition of fluid balance, fluid overload, and proposed methodologic approaches and endpoints for clinical trials.

Pediatric acute kidney support therapy (paKST) programs aim to reliably provide safe, effective, and timely extracorporeal supportive care for acutely and critically ill pediatric patients with acute kidney injury (AKI), fluid and electrolyte derangements, and/or toxin accumulation with a goal of improving both hospital-based and lifelong outcomes. Little is known about optimal ways to configure paKST teams and programs, pediatric-specific aspects of delivering high-quality paKST, strategies for transitioning from acute continuous modes of paKST to facilitate rehabilitation, or providing effective short- and long-term follow-up. As part of the 26th Acute Disease Quality Initiative Conference, the first to focus on a pediatric population, we summarize here the current state of knowledge in paKST programs and technology, identify key knowledge gaps in the field, and propose a framework for current best practices and future research in paKST.

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.