Decreased Intraoperative Renal Tissue Oxygenation after Cardiopulmonary Bypass Predicts Cardiac Surgery-Associated Acute Kidney Injury in Neonates.

(1) Background: Near-infrared spectroscopy (NIRS) is a noninvasive tool frequently used during cardiac surgery and postoperatively in the cardiac intensive care unit to monitor regional tissue oxygen saturation. A relationship between trends of intraoperative renal oxygenation and the risk of developing cardiac surgery-associated acute kidney injury (AKI) post-operatively has not yet been established in the neonatal population. The objective of this study is to evaluate the relationship of cerebral and renal oxygenation during cardiopulmonary bypass with cardiac surgery-associated AKI in the first 72 h post-operation in neonates < 30 days of age. (2) Methods: A prospective cohort study at a tertiary care children's hospital was performed. Renal and cerebral oxygenation measured were collected intraoperatively from neonates < 30 days of age who underwent cardiopulmonary bypass for the correction of congenital heart disease. AKI was defined accordance with the Kidney Disease: Improving Global Outcomes criteria modified for neonates. Variables were compared between groups. (3) Results: 32 neonates with 35 cardiopulmonary bypass cases were included. AKI was diagnosed in 60% of cases. Intra-operative renal oxygenation, both on- and off-bypass, did not differ among the three AKI groups (p > 0.19). Renal oxygenation after coming off, but not during, cardiopulmonary bypass steadily decreased with increasing levels of AKI (Jonckheere's test, one-sided p = 0.024). (4) Conclusions: Renal oxygenation decreased in proportion to AKI severity after coming off, but not during, cardiopulmonary bypass.

Renal tissue oxygenation and development of AKI in preterm neonates born < 32 weeks' gestational age in the first week of age.

OBJECTIVE: To evaluate the relationship between regional renal saturation of oxygen (RrSO2) changes and serum creatinine (SCr) during the first eight days of age for preterm neonates born < 32 weeks' gestational age. DESIGN: Post-hoc analysis of multicenter prospectively measured neonatal RrSO2 values collected during the first 8 days of age in neonates born at < 32 weeks' gestation. Acute kidney injury (AKI) was defined by the neonatal modified Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Variables were compared between groups of neonates with and with AKI. RESULTS: One hundred nine neonates were included and 561 SCr values were obtained. Eight participants developed AKI by SCr criteria. A 10-percentage point increase in mean %RrSO2 was associated with a 40% decrease in risk of AKI (95%CI: 9.6-61%; p = 0.016). CONCLUSIONS: Increases in mean %RrSO2 in neonates born at < 32 weeks' GA were associated with a decreased risk of AKI. These findings support the design of further prospective trials utilizing RrSO2 monitoring to evaluate new therapies or clinical protocols to prevent and treat neonatal AKI.

Caffeine and kidney function at two years in former extremely low gestational age neonates.

BACKGROUND: Extremely low gestational age neonates (ELGANs) are at risk for chronic kidney disease. The long-term kidney effects of neonatal caffeine are unknown. We hypothesize that prolonged caffeine exposure will improve kidney function at 22-26 months. METHODS: Secondary analysis of the Preterm Erythropoietin Neuroprotection Trial of neonates <28 weeks' gestation. Participants included if any kidney outcomes were collected at 22-26 months corrected age. Exposure was post-menstrual age of caffeine discontinuation. PRIMARY OUTCOMES: 'reduced eGFR' <90 ml/min/1.73 m2, 'albuminuria' (>30 mg albumin/g creatinine), or 'elevated blood pressure' (BP) >95th %tile. A general estimating equation logistic regression model stratified by bronchopulmonary dysplasia (BPD) status was used. RESULTS: 598 participants had at least one kidney metric at follow up. Within the whole cohort, postmenstrual age of caffeine discontinuation was not associated with any abnormal measures of kidney function at 2 years. In the stratified analysis, for each additional week of caffeine, the no BPD group had a 21% decreased adjusted odds of eGFR <90 ml/min/1.73m2 (aOR 0.78; CI 0.62-0.99) and the BPD group had a 15% increased adjusted odds of elevated BP (aOR 1.15; CI: 1.05-1.25). CONCLUSIONS: Longer caffeine exposure during the neonatal period is associated with differential kidney outcomes at 22-26 months dependent on BPD status. IMPACT: In participants born <28 weeks' gestation, discontinuation of caffeine at a later post menstrual age was not associated with abnormal kidney outcomes at 22-26 months corrected age. When assessed at 2 years of age, later discontinuation of caffeine in children born <28 weeks' gestation was associated with a greater risk of reduced eGFR in those without a history of BPD and an increased odds of hypertension in those with a history of BPD. More work is necessary to understand the long-term impact of caffeine on the developing kidney.

Acute Kidney Injury Defined by Fluid-Corrected Creatinine in Premature Neonates: A Secondary Analysis of the PENUT Randomized Clinical Trial.

Importance: Acute kidney injury (AKI) and disordered fluid balance are common in premature neonates; a positive fluid balance dilutes serum creatinine, and a negative fluid balance concentrates serum creatinine, both of which complicate AKI diagnosis. Correcting serum creatinine for fluid balance may improve diagnosis and increase diagnostic accuracy for AKI. Objective: To determine whether correcting serum creatinine for fluid balance would identify additional neonates with AKI and alter the association of AKI with short-term and long-term outcomes. Design, Setting, and Participants: This study was a post hoc cohort analysis of the Preterm Erythropoietin Neuroprotection Trial (PENUT), a phase 3, randomized clinical trial of erythropoietin, conducted at 19 academic centers and 30 neonatal intensive care units in the US from December 2013 to September 2016. Participants included extremely premature neonates born at less than 28 weeks of gestation. Data analysis was conducted in December 2022. Exposure: Diagnosis of fluid-corrected AKI during the first 14 postnatal days, calculated using fluid-corrected serum creatinine (defined as serum creatinine multiplied by fluid balance [calculated as percentage change from birth weight] divided by total body water [estimated 80% of birth weight]). Main Outcomes and Measures: The primary outcome was invasive mechanical ventilation on postnatal day 14. Secondary outcomes included death, hospital length of stay, and severe bronchopulmonary dysplasia (BPD). Categorical variables were analyzed by proportional differences with the χ2 test or Fisher exact test. The t test and Wilcoxon rank sums test were used to compare continuous and ordinal variables, respectively. Odds ratios (ORs) and 95% CIs for the association of exposure with outcomes of interest were estimated using unconditional logistic regression models. Results: A total of 923 premature neonates (479 boys [51.9%]; median [IQR] birth weight, 801 [668-940] g) were included, of whom 215 (23.3%) received a diagnosis of AKI using uncorrected serum creatinine. After fluid balance correction, 13 neonates with AKI were reclassified as not having fluid-corrected AKI, and 111 neonates previously without AKI were reclassified as having fluid-corrected AKI (ie, unveiled AKI). Therefore, fluid-corrected AKI was diagnosed in 313 neonates (33.9%). Neonates with unveiled AKI were similar in clinical characteristics to those with AKI whose diagnoses were made with uncorrected serum creatinine. Compared with those without AKI, neonates with unveiled AKI were more likely to require ventilation (81 neonates [75.0%] vs 254 neonates [44.3%] and have longer hospital stays (median [IQR], 102 [84-124] days vs 90 [71-110] days). In multivariable analysis, a diagnosis of fluid-corrected AKI was associated with increased odds of adverse clinical outcomes, including ventilation (adjusted OR, 2.23; 95% CI, 1.56-3.18) and severe BPD (adjusted OR, 2.05; 95% CI, 1.15-3.64). Conclusions and Relevance: In this post hoc cohort study of premature neonates, fluid correction increased the number of premature neonates with a diagnosis of AKI and was associated with increased odds of adverse clinical outcomes, including ventilation and BPD. Failing to correct serum creatinine for fluid balance underestimates the prevalence and impact of AKI in premature neonates. Future studies should consider correcting AKI for fluid balance. Trial Registration: ClinicalTrials.gov Identifier: NCT01378273.

Correlation of Renal Tissue Oxygenation to Venous, Arterial, and Capillary Blood Gas Oxygen Saturation in Preterm Neonates.

OBJECTIVE: The aim of the study is to assess the correlation of renal regional tissue saturation of oxygen (RrSO2) measured by near-infrared spectroscopy (NIRS) in preterm neonates to venous oxygen saturation (SvO2) obtained from umbilical venous catheters (UVCs), arterial oxygen saturation (SaO2) obtained from umbilical artery catheters (UACs), and capillary oxygen saturation (ScO2) from capillary heel blood draws. STUDY DESIGN: A secondary analysis of a prospective RrSO2 monitoring study in preterm neonates born <32 weeks gestational age. Neonates with any blood gas obtained during RrSO2 monitoring were included. RrSO2 was compared with simultaneous O2 saturation using non-parametric Mann Whitney U-test and Spearman correlation coefficient. RESULTS: In 35 neonates, 25 UVC, 151 UAC, and 68 heel capillary specimens were obtained. RrSO2 was lower than the median SvO2 (58.8 vs. 78.9, p <0.01), SaO2 (51.0 vs. 93.2, p <0.01), and ScO2 (62.2 vs. 94.25, p <0.01). RrSO2 values correlated to both SaO2 and ScO2 (r = 0.32; p <0.01, r = 0.26; p = 0.03), but not SvO2 (r = 0.07; p = 0.74). CONCLUSION: In this secondary analysis, RrSO2 was consistently lower than blood gas O2 saturations and correlated with SaO2 and ScO2 but not SvO2. Lack of a correlation to SvO2 could be due to the small UVC sample size limiting statistical power. Future studies should prospectively evaluate if RrSO2 truly primarily reflects venous oxygenation in preterm neonates. KEY POINTS: · Renal oxygenation correlates with arterial and capillary oxygen saturation.. · Renal oxygenation did not correlate with venous oxygenation from umbilical venous catheters.. · Studies are needed to determine if renal oxygenation primarily reflects venous or arterial oxygen..

Survival of neonates born with kidney failure during the initial hospitalization.

BACKGROUND: Survival to hospital discharge in neonates born with kidney failure has not been previously described. METHODS: This was a retrospective, observational analysis of the Pediatric Health Information System (PHIS) database from 2005 to 2019. Primary outcome was survival at discharge; secondary outcomes were hospital and ICU length of stay (LOS). Univariate analysis was performed to describe the population by birth weight (BW) and characterize survival; multivariable generalized liner mixed modeling assuming a binomial distribution and logit link was performed to identify mortality risk factors. RESULTS: Of 213 neonates born with kidney failure (median BW 2714 g; GA 35 weeks; 68% male), 4 (1.9%) did not receive dialysis or peritoneal dialysis (PD) catheter placement, 152 (72.9%) received PD only, 49 (23.4%) received PD plus extracorporeal dialysis (ECD), and 8 (3.4%) were treated with an undocumented dialysis modality. Median age at dialysis initiation was 7 days; median hospital LOS and ICU LOS were 84 and 69 days, respectively. One-hundred and sixty-two patients (76%) survived to discharge. Non-survivors (n = 51) were more likely to have received ECD and mechanical ventilation, and had a longer duration of mechanical ventilation. Every day of mechanical ventilation increased the mortality odds by 2% (n = 189; adjusted OR 1.02; 1.01, 1.03); in addition, the odds of mortality were 2 times higher in those who received ECD vs. only PD (adjusted OR 2.25; 1.04, 4.86). CONCLUSIONS: Survival to initial hospital discharge occurs in the majority of neonates born with kidney failure. Predictors of increased mortality included longer duration of mechanical ventilation, as well as the requirement for ECD. A higher resolution version of the Graphical abstract is available as Supplementary information.

Documentation of acute kidney injury at discharge from the neonatal intensive care unit and role of nephrology consultation.

OBJECTIVE: To investigate whether NICU discharge summaries documented neonatal AKI and estimate if nephrology consultation mediated this association. STUDY DESIGN: Secondary analysis of AWAKEN multicenter retrospective cohort. EXPOSURES: AKI severity and diagnostic criteria. OUTCOME: AKI documentation on NICU discharge summaries using multivariable logistic regression to estimate associations and test for causal mediation. RESULTS: Among 605 neonates with AKI, 13% had documented AKI. Those with documented AKI were more likely to have severe AKI (70.5% vs. 51%, p < 0.001) and SCr-only AKI (76.9% vs. 50.1%, p = 0.04). Nephrology consultation mediated 78.0% (95% CL 46.5-109.4%) of the total effect of AKI severity and 82.8% (95% CL 70.3-95.3%) of the total effect of AKI diagnostic criteria on documentation. CONCLUSION: We report a low prevalence of AKI documentation at NICU discharge. AKI severity and SCr-only AKI increased odds of AKI documentation. Nephrology consultation mediated the associations of AKI severity and diagnostic criteria with documentation.

Renal oxygenation measured by near-infrared spectroscopy in preterm neonates in the first week.

OBJECTIVE: To describe renal regional saturation of oxygen (RrSO2) values during the first week of life for preterm neonates born at <32 weeks gestational age (GA). METHODS: RrSO2 values recorded over the first week of life using near-infrared spectroscopy were retrospectively analyzed in this two-center cohort study of preterm infants without known congenital anomalies of the kidney. RESULTS: A cohort of 109 neonates with a median GA of 26.9 weeks and a median of 120 (IQR: 87-141) hours of continuous RrSO2 monitoring were included. Separately fitted trends in RrSO2 did not differ (p = 0.52) between sites and demonstrated a consistent decrease in RrSO2 by 20 points (95% CI: 9.6-30.1) during the first 60 h of life, followed by a stabilization of RrSO2 thereafter. RrSO2 baseline trends increased by 2.1 (95% CI: 0.8-3.3) percentage points for each additional week GA between 24 and 32 weeks GA. CONCLUSIONS: Despite differences in adjusted RrSO2 values between sites, profiles over time are consistent, allowing for the determination of RrSO2 trajectories in preterm infants. This expected pattern of RrSO2 changes in the first week may help guide future investigations and interventions to identify and reduce kidney injury in the preterm neonate. IMPACT: Renal regional saturation of oxygen (RrSO2) slowly decreases during the first 60 h of age in <32-week preterm neonates. While site differences were identified with respect to absolute values, RrSO2 trends from two different centers were not different. Lower gestational age neonates have lower RrSO2 levels during the first week.

The effect of antenatal indomethacin on extremely preterm neonatal kidney function.

Introduction/Objective: Indomethacin is an effective tocolytic to prevent extremely preterm birth. Prior studies have associated antenatal indomethacin exposure with adverse preterm neonatal intestinal and neurological outcomes. Indomethacin is a nephrotoxic medication that may also affect preterm neonatal kidneys. We sought to evaluate the effect of antenatal indomethacin on extremely preterm neonatal kidney function and acute kidney injury (AKI) in the first week of age.Methods: A retrospective cohort study was conducted on neonates born < 29 weeks at a level III neonatal intensive care unit (NICU) from January 2018-April 2019. Serum creatinine (sCr) values and urine output (UOP) in the first seven days of age and the neonate's peak serum creatinine within the first 30 days were evaluated. Neonatal AKI was defined by the modified neonatal Kidney Disease Improving Global Outcomes (KDIGO) definition including urine output.Results: 17 of the 55 neonates meeting criteria for this study were exposed to indomethacin. The average gestational age at birth was similar between study groups. Maternal preeclampsia was more common among women who did not receive indomethacin (p = 0.021). Indomethacin exposed neonates received more gentamicin (p = 0.024). Overall, staging of the neonatal AKI did not differ significantly between the study groups, regardless of how it was quantified (sCr or UOP) or the duration of time in which the injury developed (7 days or 30 days). Separate analysis of sCr and UOP in the first seven days also failed to show any statistically significant differences between the two groups.Conclusion: In this small cohort study of extremely preterm neonates, those born to mothers treated with indomethacin did not have an increased incidence of AKI compared to neonates born to unexposed mothers. Although no statistically significant differences in UOP or sCr were found, they deserve further evaluation in adequately powered prospective clinical trials. Future prospective studies with long-term follow-up utilizing advanced biomarkers are needed to determine how antenatal indomethacin affects extremely preterm neonatal kidney function in the NICU, during childhood, and as adults.

Advances in Neonatal Acute Kidney Injury.

In this state-of-the-art review, we highlight the major advances over the last 5 years in neonatal acute kidney injury (AKI). Large multicenter studies reveal that neonatal AKI is common and independently associated with increased morbidity and mortality. The natural course of neonatal AKI, along with the risk factors, mitigation strategies, and the role of AKI on short- and long-term outcomes, is becoming clearer. Specific progress has been made in identifying potential preventive strategies for AKI, such as the use of caffeine in premature neonates, theophylline in neonates with hypoxic-ischemic encephalopathy, and nephrotoxic medication monitoring programs. New evidence highlights the importance of the kidney in "crosstalk" between other organs and how AKI likely plays a critical role in other organ development and injury, such as intraventricular hemorrhage and lung disease. New technology has resulted in advancement in prevention and improvements in the current management in neonates with severe AKI. With specific continuous renal replacement therapy machines designed for neonates, this therapy is now available and is being used with increasing frequency in NICUs. Moving forward, biomarkers, such as urinary neutrophil gelatinase-associated lipocalin, and other new technologies, such as monitoring of renal tissue oxygenation and nephron counting, will likely play an increased role in identification of AKI and those most vulnerable for chronic kidney disease. Future research needs to be focused on determining the optimal follow-up strategy for neonates with a history of AKI to detect chronic kidney disease.

Fluid management, electrolytes imbalance and renal management in neonates with neonatal encephalopathy treated with hypothermia.

Kidney dysfunction and acute kidney injury (AKI) frequently accompanies neonatal encephalopathy and contributes to neonatal morbidity and mortality. While there are currently no proven therapies for the treatment of AKI, understanding the pathophysiology along with early recognition and treatment of alterations in fluid, electrolyte and metabolic homeostasis that accompany AKI offer opportunity to reduce associated morbidity. Promising new tests and technologies, including urine and serum biomarkers and renal near-infrared spectroscopy offer opportunities to improve diagnosis and monitoring of neonates at risk for kidney injury. Furthermore, recent advances in neonatal kidney supportive therapies such as hemofiltration and hemodialysis may further improve outcomes in this population. This chapter provides an overview of disorders of fluid balance, electrolyte homeostasis and kidney function associated with neonatal encephalopathy and therapeutic hypothermia. Recommendations for fluid and electrolyte management based upon published literature and authors' opinions are provided.

Fluid Balance in the Critically Ill Child Section: "How Bad Is Fluid in Neonates?"

Fluid overload (FO) in neonates is understudied, and its management requires nuanced care and an understanding of the complexity of neonatal fluid dynamics. Recent studies suggest neonates are susceptible to developing FO, and neonatal fluid balance is impacted by multiple factors including functional renal immaturity in the newborn period, physiologic postnatal diuresis and weight loss, and pathologies that require fluid administration. FO also has a deleterious impact on other organ systems, particularly the lung, and appears to impact survival. However, assessing fluid balance in the postnatal period can be challenging, particularly in extremely low birth weight infants (ELBWs), given the confounding role of maternal serum creatinine (Scr), physiologic weight changes, insensible losses that can be difficult to quantify, and difficulty in obtaining accurate intake and output measurements given mixed diaper output. Although significant FO may be an indication for kidney replacement therapy (KRT) in older children and adults, KRT may not be technically feasible in the smallest infants and much remains to be learned about optimal KRT utilization in neonates. This article, though not a meta-analysis or systematic review, presents a comprehensive review of the current evidence describing the effects of FO on outcomes in neonates and highlights areas where additional research is needed.

Renal tissue oxygenation after caffeine administration in preterm neonates.

BACKGROUND: Caffeine has been associated with reduced rates of acute kidney injury (AKI) in preterm neonates. The effect of caffeine on preterm neonatal renal regional saturation of oxygen (RrSO2) is unknown. METHODS: RrSO2 was recorded continuously in neonates < 32 weeks' gestation until 7 days of age with INVOS™ neonatal near-infrared spectroscopy (NIRS) sensors. Baseline RrSO2 values were established by averaging the saturations in the 20 min prior to caffeine administration. Subgroup analysis was performed based on pre-caffeine RrSO2 averages. Change in RrSO2 was recorded at 0.5, 1, 2, 3, 4, 6, and 12 h after maintenance caffeine administration. RESULTS: Of 35 eligible neonates, 31 (median gestational age 28.4 weeks) received 156 caffeine doses (median 8 mg/kg). Analysis of combined doses showed no significant changes in RrSO2 after caffeine administration at any time. However, neonates with baseline 20-29.9% had significant increases from 1 to 12 h (range of increase 5.9-13.9%), and those with baseline 30-39.9 had significant increases at 1 h (8.06%, p < 0.05). CONCLUSIONS: Maintenance caffeine dosing increased RrSO2 in neonates with low RrSO2 in the first week. Further research is needed to determine the effect of loading doses of caffeine and if increases in RrSO2 correlate with improved clinical kidney outcomes. IMPACT: Caffeine administration is associated with increased renal tissue oxygenation in preterm neonates with low baseline values under 40%. The most significant renal tissue oxygenation changes occur in the first 3 h after IV caffeine administration. With recent studies suggesting low RrSO2 values in preterm neonates are associated with AKI, caffeine should be studied as a potential therapeutic for this common and complex morbidity in preterm neonates.