Continuous Kidney Replacement Therapy and Survival in Children and Young Adults: Findings From the Multinational WE-ROCK Collaborative.

RATIONALE & OBJECTIVE: There are limited studies describing the epidemiology and outcomes in children and young adults receiving continuous kidney replacement therapy (CKRT). We aimed to describe associations between patient characteristics, CKRT prescription, and survival. STUDY DESIGN: Retrospective multicenter cohort study. SETTING & PARTICIPANTS: 980 patients aged from birth to 25 years who received CKRT between 2015 and 2021 at 1 of 32 centers in 7 countries participating in WE-ROCK (Worldwide Exploration of Renal Replacement Outcomes Collaborative in Kidney Diseases). EXPOSURE: CKRT for acute kidney injury or volume overload. OUTCOMES: Death before intensive care unit (ICU) discharge. ANALYTICAL APPROACH: Descriptive statistics. RESULTS: Median age was 8.8 years (IQR, 1.6-15.0), and median weight was 26.8 (IQR, 11.6-55.0) kg. CKRT was initiated a median of 2 (IQR, 1-6) days after ICU admission and lasted a median of 6 (IQR, 3-14) days. The most common CKRT modality was continuous venovenous 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. 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: Retrospective design; limited representation from centers outside the United States. CONCLUSIONS: In this study of children and young adults receiving CKRT, approximately two thirds survived at least until ICU discharge. Although variations in dialysis mode and dose, catheter size and location, and anticoagulation were observed, survival was not detected to be associated with these parameters. PLAIN-LANGUAGE SUMMARY: In this large contemporary epidemiological study of children and young adults receiving continuous kidney replacement therapy in the intensive care unit, we observed that two thirds of patients survived at least until ICU discharge. However, patients with comorbidities appeared to have worse outcomes. Compared with previously published reports on continuous kidney replacement therapy practice, we observed greater use of continuous venovenous hemodiafiltration with regional citrate anticoagulation.

Deriving and validating a protocol to determine the need for prophylactic peritoneal dialysis in neonates after cardiopulmonary bypass surgery.

BACKGROUND: Prophylactic peritoneal dialysis (PD) in neonates undergoing cardiopulmonary bypass (CPB) is safe and improves outcomes. We sought to (1) derive the pre-operative characteristics of neonates who are most likely to benefit from PD after CPB and (2) validate a new prophylactic PD protocol based on our retrospective analysis. METHODS: First, we retrospectively evaluated neonates requiring cardiac surgery with CPB from October 2012 to June 2016. We categorized neonates as those who "needed PD" and those who "did not need PD" based on prior experience with neonates requiring kidney support therapy. Pre-operative serum creatinine ≥ 0.8 mg/dL, pre-operative weight ≤ 2.5 kg, or having an open chest post-operatively were independently associated with "needed PD." Next, beginning in March 2019, we implemented a new prophylactic PD protocol in which only those who met at least one of the three criteria derived in the retrospective analysis had a PD catheter placed in the OR. RESULTS: In Era 2, after the implementation of a new prophylactic PD protocol, 100% of neonates in the "needed PD" group had a PD catheter placed in the OR, which was more than in the prior era (Era 1 = 86.6%) (p = 0.05). Only 26.1% in the "did not need PD" group had a PD catheter placed in the OR which was less than in the prior era (Era 1 = 50.6%) (p < 0.01). CONCLUSIONS: We successfully developed and implemented an evidence-based prophylactic PD protocol that has improved our ability to provide prophylactic PD in neonates after CPB.

Peritoneal catheters in neonates undergoing complex cardiac surgery: a multi-centre descriptive study.

BACKGROUND: The use of peritoneal catheters for prophylactic dialysis or drainage to prevent fluid overload after neonatal cardiac surgery is common in some centres; however, the multi-centre variability and details of peritoneal catheter use are not well described. METHODS: Twenty-two-centre NEonatal and Pediatric Heart Renal Outcomes Network (NEPHRON) study to describe multi-centre peritoneal catheter use after STAT category 3-5 neonatal cardiac surgery using cardiopulmonary bypass. Patient characteristics and acute kidney injury/fluid outcomes for six post-operative days are described among three cohorts: peritoneal catheter with dialysis, peritoneal catheter with passive drainage, and no peritoneal catheter. RESULTS: Of 1490 neonates, 471 (32%) had an intraoperative peritoneal catheter placed; 177 (12%) received prophylactic dialysis and 294 (20%) received passive drainage. Sixteen (73%) centres used peritoneal catheter at some frequency, including six centres in >50% of neonates. Four centres utilised prophylactic peritoneal dialysis. Time to post-operative dialysis initiation was 3 hours [1, 5] with the duration of 56 hours [37, 90]; passive drainage cohort drained for 92 hours [64, 163]. Peritoneal catheter were more common among patients receiving pre-operative mechanical ventilation, single ventricle physiology, and higher complexity surgery. There was no association with adverse events. Serum creatinine and daily fluid balance were not clinically different on any post-operative day. Mortality was similar. CONCLUSIONS: In neonates undergoing complex cardiac surgery, peritoneal catheter use is not rare, with substantial variability among centres. Peritoneal catheters are used more commonly with higher surgical complexity. Adverse event rates, including mortality, are not different with peritoneal catheter use. Fluid overload and creatinine-based acute kidney injury rates are not different in peritoneal catheter cohorts.

Retrospective analysis comparing complication rates of centrifuge vs membrane-based therapeutic plasma exchange in the pediatric population.

BACKGROUND: There are two conventional modalities used to perform therapeutic plasma exchange (TPE): centrifuge TPE (cTPE) or membrane TPE (mTPE). There is limited data on complications with mTPE. OBJECTIVE: We sought to better understand the patient and machine complications of mTPE compared to cTPE. We hypothesize that our protocol for mTPE using heparin anticoagulation is well-tolerated. METHODS: In this retrospective cohort study of children <21 years of age, we evaluated differences in patient and machine characteristics and complications between cTPE (with citrate anticoagulation) vs mTPE (with heparin anticoagulation). RESULTS: Of the 105 patients who met inclusion/exclusion criteria, 63 received cTPE and 42 mTPE via Prismaflex. Those who used mTPE were younger (4.8 ± 2.8 years vs 15.2 ± 3.7 years, P = .0001) and weighed less (19.5 ± 10.6 vs 71.7 ± 28.5 kg, P = .0001). There were no significant differences in patient-related complications or indications for TPE between the two modalities. Of the 1031 therapies performed,1003 therapies were analyzed (646 using cTPE and 357 using mTPE) due to exclusion criteria. No significant difference in patient complications were detected between groups. Machine-related complications were infrequent in both approaches. More circuits clotted during mTPE than during cTPE (6.7% [24/357] vs 0% [0/646]; P < 0.001). CONCLUSION: Although we use mTPE in smaller children, we showed low rates of complications that were not statistically different from cTPE performed in older children. While the overall rate of circuit clotting using mTPE was low, it occurred more commonly than with cTPE.

Congenital heart surgery and acute kidney injury.

PURPOSE OF REVIEW: The incidence of cardiac surgery-associated acute kidney injury (CS-AKI) continues to increase and is associated with significant morbidity and mortality. Early diagnosis and identification of patients at risk are extremely important. Therefore, identifying associated risk factors, biomarkers for earlier detection, prevention and therapeutic options for CS-AKI warrant special attention. RECENT FINDINGS: The current diagnosis of acute kidney injury (AKI) largely depends upon the functional biomarkers serum creatinine and oliguria leading to delays in diagnosis and worsening outcomes. Novel biomarkers are now being investigated to aid in providing an earlier AKI diagnosis as well as predicting its severity. Combining functional and tubular biomarkers have proven to provide even better prediction of AKI development and severity. Due to the limited therapeutic options available for CS-AKI, it is imperative to identify those patients at risk early to help mitigate worsening or severe AKI; hence, combining biomarkers should be beneficial. SUMMARY: It is extremely important to identify those who are at increased risk for CS-AKI with the foremost goal being that of prevention to help decrease morbidity and mortality. Combining functional and tubular biomarkers can assist with early identification. Once identified, early interventions including avoidance of nephrotoxins, decreasing cardiopulmonary bypass time, avoiding fluid overload and early initiation of renal replacement therapy may lead to improved clinical outcomes.

Cell-specific regulation of L-WNK1 by dietary K.

Flow-induced K(+) secretion in the aldosterone-sensitive distal nephron is mediated by high-conductance Ca(2+)-activated K(+) (BK) channels. Familial hyperkalemic hypertension (pseudohypoaldosteronism type II) is an inherited form of hypertension with decreased K(+) secretion and increased Na(+) reabsorption. This disorder is linked to mutations in genes encoding with-no-lysine kinase 1 (WNK1), WNK4, and Kelch-like 3/Cullin 3, two components of an E3 ubiquitin ligase complex that degrades WNKs. We examined whether the full-length (or "long") form of WNK1 (L-WNK1) affected the expression of BK α-subunits in HEK cells. Overexpression of L-WNK1 promoted a significant increase in BK α-subunit whole cell abundance and functional channel expression. BK α-subunit abundance also increased with coexpression of a kinase dead L-WNK1 mutant (K233M) and with kidney-specific WNK1 (KS-WNK1), suggesting that the catalytic activity of L-WNK1 was not required to increase BK expression. We examined whether dietary K(+) intake affected L-WNK1 expression in the aldosterone-sensitive distal nephron. We found a paucity of L-WNK1 labeling in cortical collecting ducts (CCDs) from rabbits on a low-K(+) diet but observed robust staining for L-WNK1 primarily in intercalated cells when rabbits were fed a high-K(+) diet. Our results and previous findings suggest that L-WNK1 exerts different effects on renal K(+) secretory channels, inhibiting renal outer medullary K(+) channels and activating BK channels. A high-K(+) diet induced an increase in L-WNK1 expression selectively in intercalated cells and may contribute to enhanced BK channel expression and K(+) secretion in CCDs.

Therapy of acute hypertension in hospitalized children and adolescents.

Acute hypertension (HTN) in hospitalized children and adolescents occurs relatively frequently, and in some cases, if not recognized and treated promptly, it can lead to hypertensive crisis with potentially significant morbidity and mortality. In contrast to adults, where acute HTN is most likely due to uncontrolled primary HTN, children and adolescents with acute HTN are more likely to have secondary HTN. This review will briefly cover evaluation of acute HTN and various age-specific etiologies of secondary HTN and provide more in-depth discussion on treatment targets, potential risks of acute HTN therapy, and available pediatric data on intravenous and oral antihypertensive agents, and it proposes treatment schema including unique therapy of specific secondary HTN scenarios.

Atherosclerotic renal artery stenosis as a cause for hypertension in an adolescent patient.

BACKGROUND: Atherosclerosis causing renal artery stenosis (RAS) is one of the most common secondary causes of hypertension in adults, but is rare in children. CASE-DIAGNOSIS/TREATMENT: RAS associated with coronary artery stenosis was diagnosed in a teenage patient who presented with intermittent chest pain and elevated blood pressures for 6 years. The diagnosis of RAS was suspected after physical examination revealed an abdominal bruit. Renal ultrasound with Doppler revealed normal appearing kidneys with high velocity in the aorta and renal arteries. Computed tomography angiography (CTA) of the chest and abdomen demonstrated generalized calcified atherosclerotic narrowing of the arteries including the renal, celiac, superior mesenteric and coronary arteries in the setting of hyperlipidemia. The lipid panel revealed hypercholesterolemia with elevated serum plant sterol concentrations, suggesting the diagnosis of sitosterolemia. Cardiac catheterization demonstrated left anterior descending artery and left circumflex artery stenosis, which required bypass of the left anterior descending artery and stenting of the left circumflex artery. Aggressive lipid control was recommended and he was treated medically with a beta-blocker, low-dose angiotensin-converting enzyme inhibitor, aspirin, statin, and clopidogrel. CONCLUSION: Although very rare, generalized atherosclerosis caused by genetic disorders should be considered an underlying cause for severe hypertension in children with hyperlipidemia.

Urine Quantification Following Furosemide for Severe Acute Kidney Injury Prediction in Critically Ill Children.

A standardized, quantified assessment of furosemide responsiveness predicts acute kidney injury (AKI) in children after cardiac surgery and AKI progression in critically ill adults. The purpose of this study was to determine if response to furosemide is predictive of severe AKI in critically ill children outside of cardiac surgery. We performed a multicenter retrospective study of critically ill children. Quantification of furosemide response was based on urine flow rate (normalized for weight) measurement 0 to 6 hours after the dose. The primary outcome was presence of creatinine defined severe AKI (Kidney Disease Improving Global Outcomes stage 2 or greater) within 7 days of furosemide administration. Secondary outcomes included mortality, duration of mechanical ventilation and length of stay. A total of 110 patients were analyzed. Severe AKI occurred in 20% ( n = 22). Both 2- and 6-hour urine flow rate were significantly lower in those with severe AKI compared with no AKI ( p = 0.002 and p < 0.001). Cutoffs for 2- and 6-hour urine flow rate for prediction of severe AKI were <4 and <3 mL/kg/hour, respectively. The adjusted odds of developing severe AKI for 2-hour urine flow rate of <4 mL/kg/hour was 4.3 (95% confidence interval [CI]: 1.33-14.15; p = 0.02). The adjusted odds of developing severe AKI for 6-hour urine flow rate of <3 mL/kg/hour was 6.19 (95% CI: 1.85-20.70; p = 0.003). Urine flow rate in response to furosemide is predictive of severe AKI in critically ill children. A prospective assessment of urine flow rate in response to furosemide for predicting subsequent severe AKI is warranted.

Detection of Acute Kidney Injury in Neonates after Cardiopulmonary Bypass.

Cardiac surgery-associated acute kidney injury (CS-AKI) in neonates has been associated with poor outcomes. Early detection and intervention of acute kidney injury (AKI) are needed in order to mitigate some of these sequalae. Currently, serum creatinine (SCr) remains the gold standard for AKI diagnosis; however, changes are not seen until days after injury thus delaying the diagnosis. Serum creatinine in neonates varies based on multiple factors such as prematurity, the presence of maternal SCr and renal tubule immaturity. Acute kidney injury biomarkers, such as neutrophil gelatinase-associated lipocalin (NGAL), are useful for early AKI diagnosis. In addition to SCr and AKI biomarkers, a risk-based assessment of neonates at risk for CS-AKI could prove useful for early AKI diagnosis and intervention.

Prophylactic Peritoneal Dialysis After the Arterial Switch Operation: A Retrospective Cohort Study.

BACKGROUND: Fluid overload contributes to poor outcomes after neonatal cardiac surgery. The optimal strategy to mitigate fluid overload related morbidity is unknown. The utility of prophylactic peritoneal dialysis remains controversial. We aimed to assess the impact of prophylactic peritoneal dialysis on outcomes and hypothesized that prophylactic dialysis would be associated with less fluid overload and improved outcomes in neonates undergoing the arterial switch operation. METHODS: A single-center retrospective analysis of 41 consecutive neonates between June 2010 and March 2016 undergoing the arterial switch operation was performed. Fluid balance and other outcomes were compared between those who received peritoneal dialysis (n = 25) and those who did not (n = 16). RESULTS: Demographics were similar between groups, except cardiopulmonary bypass duration, which was significantly longer in the dialysis group (125 ± 20 minutes) compared with the no dialysis group (109 ± 15 minutes; P = .01). Median time to dialysis initiation was 9.1 hours (interquartile range, 7 to 9.8) and median time to termination from cardiac intensive care unit admission was 58.7 hours (interquartile range, 44 to 76.1). Cumulative fluid balance in the dialysis group was significantly more negative compared with the no dialysis group across all 7 postoperative days. In the multivariable analysis, use of dialysis was associated with a 42% reduction in hours of mechanical ventilation (relative risk 0.58; 95% confidence interval, 0.4 to 0.85; P < .01) and a 34% reduction in intensive care unit length of stay (relative risk 0.66; 95% confidence interval, 0.47 to 0.94; P = .02). Utilization of dialysis was associated with lower hospital costs (P < .01). CONCLUSIONS: Prophylactic peritoneal dialysis after the arterial switch operation is associated with improved postoperative outcomes without increased hospital costs (Graphical Abstract).

Furosemide response predicts acute kidney injury in children after cardiac surgery.

OBJECTIVE: A standardized assessment of response to furosemide is predictive of acute kidney injury progression in adults, but a paucity of data exists in pediatric patients. We evaluate furosemide responsiveness in a multicenter cohort of pediatric patients after cardiac surgery. METHODS: Children who underwent cardiac surgery with a Society of Thoracic Surgeons-European Association for Cardiothoracic Surgery score of 3 or greater were retrospectively identified. The first dose of furosemide after surgery was recorded, and hourly urine output for 6 hours was recorded after the index dose. Urine flow rate calculated as urine output per hour was used to predict development of acute kidney injury. RESULTS: A total of 166 patients from 4 institutions (median age, 6.3 months; interquartile range, 0.4-27.7) were included. Acute kidney injury occurred in 54 patients (33%). Compared with those without acute kidney injury, the 2- and 6-hour urine flow rates were significantly lower in patients in whom acute kidney injury developed: 2.9 (0.9-6.5) versus 5.0 (2.5-9.0) mL/kg/h for 2-hour urine flow rate, P = .004, and 2.4 (1.2-4.0) versus 4.0 (2.3-5.9) mL/kg/h for 6-hour flow rate, P = .001. In multivariable regression analysis, 2-hour (odds ratio, 1.2, P = .002) and 6-hour (odds ratio, 1.40, P < .001) urine flow rates were independently associated with acute kidney injury development. Lower urine flow rate at both 2 and 6 hours was also independently associated with longer hospital length of stay. CONCLUSIONS: Lower urine flow rate after furosemide administration, when evaluated in a heterogeneous cohort of children from multiple institutions after pediatric cardiac surgery, was independently associated with subsequent acute kidney injury and longer length of stay. Future prospective studies are needed to validate furosemide responsiveness as a predictor of acute kidney injury.

Cholecystokinin-8 increases Fos-like immunoreactivity in myenteric neurons of the duodenum and jejunum more after intraperitoneal than after intravenous injection.

The objective of this study was to measure the relative efficacy and potency of cholecystokinin-8 (CCK-8) given by intraperitoneal (i.p.) and intravenous (i.v.) injection to stimulate Fos-like immunoreactivity (Fos-LI) in neurons of the myenteric plexus in the duodenum and jejunum. The subjects for his experiment were 40 male Sprague-Dawley rats divided into eight treatment groups (n=5 rats per treatment). Four groups of rats were injected with 5, 10, and 40 microg/kg sulfated CCK-8 and saline (control) i.p., and the remaining groups with the same treatments i.v. We then detected Fos-LI, a marker for neuronal activation, in the myenteric plexus of the duodenum and jejunum, in response to the previous doses and routes. All of the CCK-8 doses administered by both routes increased Fos-LI in the myenteric plexus of the duodenum and jejunum significantly more than saline did. Although both routes were efficacious in increasing Fos-LI, CCK-8 i.p. was significantly more potent than CCK-8 i.v. These data provide immunohistochemical evidence that i.p. administration of CCK-8 is a more potent stimulant of Fos-LI in the neurons of the myenteric plexus of the duodenum and jejunum than i.v. injection.

Effects of cholecystokinin-receptor antagonists on Fos-like immunoreactivity stimulated by sulfated cholecystokinin-8 in neurons of the myenteric plexus and hindbrain of rats.

OBJECTIVE: To evaluate the role of cholecystokinin (CCK)-receptor antagonists in the activation of enteric and hindbrain neurons by sulfated CCK-8. ANIMALS: 81 male Sprague-Dawley rats. PROCEDURE: Rats were allocated to 10 groups (5 to 22 rats/group). Each rat received 2 IP injections (15 minutes between injections). The first injection consisted of a specific CCK2-receptor (CCK2R) antagonist (L365,260; 150, 500, or 1,000 microg/kg), a specific CCK1-receptor (CCK1R) antagonist (devazepide; 150 microg/kg), or 1% dimethyl sulfoxide (DMSO [ie, vehicle]), and the second injection consisted of sulfated CCK-8 (10 microg/kg) or saline (0.9% NaCl) solution. Rats were anesthetized and perfused with 500 mL of Krebs saline solution, and the myenteric plexuses of the duodenum and jejunum were collected. Rats were then perfused with 500 mL of phosphate-buffered 4% formaldehyde solution; rats were then euthanatized, and the hindbrain of each was harvested. Tissues were stained by use of a diaminobenzidine reaction enhanced with nickel to reveal Fos-like immunoreactivity (Fos-LI), a marker of neuronal activation, in the aforementioned neurons. RESULTS: Sulfated CCK-8 significantly increased Fos-LI in the myenteric and hindbrain neurons, compared with values for the DMSO injections. All dosages of L365,260 failed to attenuate this increase; however, injection of devazepide attenuated the increase in Fos-LI. CONCLUSIONS AND CLINICAL RELEVANCE: Analysis of the results of this study reveals that sulfated CCK-8 activates myenteric and hindbrain neurons of rats primarily through CCK1 R. It provides evidence that CCK2R are lacking or not functional in the gastrointestinal tract of rats.

Atypical Hemolytic Uremic Syndrome and Chronic Ulcerative Colitis Treated with Eculizumab.

BACKGROUND: Hemolytic-uremic syndrome (HUS) presents with hemolytic anemia, thrombocytopenia, and thrombotic microangiopathy of the kidney and usually results from Shiga-toxin induced activation of the alternative complement pathway. Gastroenteritis is a common feature of the Shiga-toxin producing Escherichia coli HUS, referred to as STEC-HUS. An inherited or acquired complement dysregulation may lead to HUS referred to as non-STEC or atypical (a)HUS. Although gastroenteritis is not a common presentation of aHUS, some patients develop ischemic colitis and may be misdiagnosed as acute appendicitis or acute ulcerative colitis (UC). CASE DIAGNOSIS ­TREATMENT: We present a patient with low circulating complement (C) 3 levels who developed aHUS in the course of chronic active UC. Resolution of renal and gastrointestinal manifestations in response to treatment with eculizumab, a humanized monoclonal antibody against terminal C5 protein suggests the role of alternative complement in the pathogenesis of both, aHUS and UC. CONCLUSION: This case illustrates that dysregulation of the alternative complement pathway may manifest in other organs besides the kidney and that the circulating C3 levels do not correlate with the disease activity or the clinical response to eculizumab.