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.

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.

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..

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.

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.

Non-invasive continuous renal tissue oxygenation monitoring to identify preterm neonates at risk for acute kidney injury.

BACKGROUND: Near-infrared spectroscopy (NIRS) is an emerging tool to identify signs of inadequate tissue oxygenation in preterm neonates with acute kidney injury (AKI). Previous studies have shown a correlation between low renal tissue oxygenation (RrSO2) in the first 24 hours of age and the later development of AKI. In this prospective clinical trial, NIRS monitoring was used to identify changes in RrSO2 in comparison to traditional AKI markers, serum creatinine (SCr), and urine output (UOP). METHODS: We enrolled 35 preterm neonates born less than 32 weeks' gestation and applied neonatal NIRS sensors at less than 48 hours of age. Neonates underwent 7 days of continuous monitoring. Renal and demographic information were collected for the first 7 days of age. AKI was determined by the modified neonatal Kidney Disease: Improving Global Outcomes (KDIGO) definition including UOP. RESULTS: Three patients experienced AKI, all based on both SCr and UOP criteria. Each neonate with AKI had decreases in RrSO2 over 48 hours prior to changes in SCr and UOP. Patients with AKI had lower median RrSO2 values compared to patients without AKI over the first week of age, (32.4% vs. 60%, p < 0.001). CONCLUSION: RrSO2 monitoring identified preterm neonates at risk for AKI. NIRS detected a decline in RrSO2 prior to changes in SCr and UOP and was significantly lower in patients with AKI compared to those without AKI. Further studies are needed to evaluate the ability of RrSO2 monitoring to detect signs of kidney stress prior to the diagnosis of AKI. Graphical abstract.

Delayed Umbilical Cord Clamping is Not Associated with Acute Kidney Injury in Very Low Birth Weight Neonates.

OBJECTIVE: This study aimed to determine if delayed cord clamping (DCC) is associated with a reduction in neonatal acute kidney injury (AKI). STUDY DESIGN: A retrospective single-center cohort study of 278 very low birth weight (VLBW) neonates was performed to compare the incidence of AKI in the following groups: immediate cord clamping (ICC), DCC, and umbilical cord milking. AKI was diagnosed by the modified neonatal Kidney Diseases and Improving Global Outcomes (KDIGO) definition. RESULTS: The incidence of AKI in the first week was 20.1% with no difference between groups (p = 0.78). After adjustment for potential confounders, the odds of developing AKI, following DCC, compared with ICC was 0.93 (confidence interval [CI]: 0.46-1.86) with no reduction in the stage of AKI between groups. CONCLUSION: In this study, DCC was not associated with a reduced rate of AKI in VLBW neonates. However, the data suggest that DCC is also not harmful to the kidneys, further supporting the safety of DCC in VLBW neonates.

Immature megalin expression in the preterm neonatal kidney is associated with urinary loss of vitamin carrier proteins.

BACKGROUND: Vitamin A and D deficiencies are common in preterm infants. Megalin is an endocytic receptor in the proximal tubule, which reabsorbs retinol-binding protein (RBP) and vitamin D-binding protein (VDBP). Although the proximal tubule is immature in preterm infants, little is known about megalin expression during kidney development. In this study, we establish the abundance of megalin in the developing human kidney and its relationship to the urinary excretion of vitamin carriers in preterm infants. METHODS: We analyzed a postmortem group (20-40 weeks gestation), where we used morphometric means of measuring megalin and its ligands in kidney tissue and a living group of patients (28-40 weeks), where urinary RBP and VDBP were measured. RESULTS: The presence of megalin, RBP, and VDBP increased in the proximal tubule through gestation. At birth the urinary concentration of RBP and VDBP were higher in the 28-32 week group compared to the 38-40 week group and a significant inverse correlation of tissue megalin and urinary loss of RBP and VDBP existed. CONCLUSIONS: Preterm infants experience vitamin carrier protein losses, which are associated with decreased megalin expression. This developmental expression of megalin in the kidney has clinical implications in the prevention of vitamin deficiencies in preterm babies.

Neonatal hypertension: an educational review.

Hypertension is encountered in up to 3% of neonates and occurs more frequently in neonates requiring hospitalization in the neonatal intensive care unit (NICU) than in neonates in newborn nurseries or outpatient clinics. Former NICU neonates are at higher risk of hypertension secondary to invasive procedures and disease-related comorbidities. Accurate measurement of blood pressure (BP) remains challenging, but new standardized methods result in less measurement error. Multiple factors contribute to the rapidly changing BP of a neonate: gestational age, postmenstrual age (PMA), birth weight, and maternal factors are the most significant contributors. Given the natural evolution of BP as neonates mature, a percentile cutoff of 95% for PMA has been the most common definition used; however, this is not based on outcome data. Common causes of neonatal hypertension are congenital and acquired renal disease, history of umbilical arterial catheter placement, and bronchopulmonary dysplasia. The treatment of neonatal hypertension has mostly been off-label, but as evidence accumulates, the safety of medical management has increased. The prognosis of neonatal hypertension remains largely unknown and thankfully most often resolves unless secondary to renovascular disease, but further research is needed. This review discusses important factors related to neonatal hypertension including BP measurement, determinants of BP, and management of neonatal hypertension.

Follow-up of Acute kidney injury in Neonates during Childhood Years (FANCY): a prospective cohort study.

BACKGROUND: Very low birth weight (VLBW) neonates commonly experience acute kidney injury (AKI) in the neonatal intensive care unit (NICU). We hypothesize that VLBW neonates exposed to AKI in the NICU might be at a higher risk of renal dysfunction during childhood. METHODS: In this cohort study, VLBW children (aged 3-7 years) completed a kidney health evaluation and were stratified according to AKI status in the NICU. The primary outcome was renal dysfunction defined as any of the following: estimated glomerular filtration rate (eGFR) <90 mL/min/1.73 m2, urine protein/creatinine >0.2 or blood pressure ≥95th percentile. RESULTS: Thirty-four subjects completed the study. Twenty subjects had a history of neonatal AKI (stage 1, n = 8; stage 2, n = 9; and stage 3, n = 3). At a median age of 5 years, the AKI group had a higher risk of renal dysfunction compared with the group without AKI (65% vs 14%, relative risk 4.5 (1.2-17.1), p = 0.01). Overall, 26% of the total cohort had an eGFR <90 mL/min/1.73 m2 using serum cystatin C (35% of AKI subjects, 14% of no AKI subjects, p = 0.25). CONCLUSIONS: Evidence of renal dysfunction in neonates born VLBW can be found early in childhood. Further work is necessary to determine how to reduce renal disease in this vulnerable population.

Caffeine Exposure and Risk of Acute Kidney Injury in a Retrospective Cohort of Very Low Birth Weight Neonates.

OBJECTIVE: To evaluate the association between caffeine exposure and acute kidney injury (AKI) in very low birth weight (VLBW; ≤1500 g) neonates. STUDY DESIGN: We retrospectively reviewed a cohort of 140 VLBW neonates consecutively admitted to the University of Virginia's neonatal intensive care unit from March 2011 to June 2012, excluding only those admitted >2 days of age or who died at <2 days after birth. We separately analyzed a subgroup of 44 neonates who received prolonged invasive respiratory support (mechanical ventilation for first 7 days after birth). The exposure of interest was caffeine exposure in the first week after birth. The primary outcome was AKI within the first 10 days after birth according to the Kidney Disease: Improving Global Outcomes system, modified to include only serum creatinine. RESULTS: Caffeine exposure occurred in 72.1% of all patients and 54.5% of those who received prolonged invasive respiratory support. AKI occurred less frequently in neonates who received caffeine (all patients: 17.8% vs 43.6%; P = .002; prolonged invasive respiratory support: 29.2% vs 75.0%; P = .002). Caffeine exposure was associated with decreased odds for AKI in logistic regression models adjusted for sex, birth weight, gestational age, small for gestational age status, illness severity on admission, and receipt of indomethacin, invasive ventilation, dopamine, aminoglycosides, and vancomycin (all patients: OR 0.22; 95% CI 0.07-0.75, P = .02; prolonged invasive respiratory support subgroup: OR 0.06; 95% CI 0.01-0.57, P = .02). CONCLUSIONS: In a cohort of VLBW neonates, those exposed to caffeine were less likely to experience AKI.

A survey of certification for cardiopulmonary resuscitation in high school athletic coaches.

BACKGROUND: Cardiopulmonary resuscitation (CPR) can increase survival in instances of sudden cardiac arrest. Nationally, high school coaches are the first responders to sudden cardiac arrest in up to one-third of high school athlete collapses, but little is known about the status of their CPR certification. The primary goal of this study was to assess the proportion of Wisconsin high school coaches that are certified in CPR. METHODS: A prospective web-based survey was developed and distributed to high school athletic directors in Wisconsin. RESULTS: Seventy-eight percent of respondents reported that coaches are the primary responders to a collapse. The majority of high schools do not require CPR certification and only 50% of coaches are currently CPR certified. Athletic directors with greater than 12 years of experience were the most likely to have an emergency action plan in place (P= 0.004). CONCLUSION: In Wisconsin, the proportion of coaches who act as the primary responder to a collapse is greater than previously reported. Although the majority of coaches in Wisconsin serve as the primary responder to an episode of sudden cardiac arrest, only about 50% are CPR certified. Due to the severe consequences of sudden cardiac arrest, CPR certification among coaches should be required.

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.

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.