Acute kidney injury during cisplatin therapy and associations with kidney outcomes 2 to 6 months post-cisplatin in children: a multi-centre, prospective observational study.

BACKGROUND: Few studies describe acute kidney injury (AKI) burden during paediatric cisplatin therapy and post-cisplatin kidney outcomes. We determined risk factors for and rate of (1) AKI during cisplatin therapy, (2) chronic kidney disease (CKD) and hypertension 2-6 months post-cisplatin, and (3) whether AKI is associated with 2-6-month outcomes. METHODS: This prospective cohort study enrolled children (aged < 18 years at cancer diagnosis) treated with cisplatin from twelve Canadian hospitals. AKI during cisplatin therapy (primary exposure) was defined based on Kidney Disease: Improving Global Outcomes (KDIGO) serum creatinine criteria (≥ stage one). Severe electrolyte abnormalities (secondary exposure) included ≥ grade three hypophosphatemia, hypokalemia, or hypomagnesemia (National Cancer Institute Common Terminology Criteria for Adverse Events v4.0). CKD was albuminuria or decreased kidney function for age (KDIGO guidelines). Hypertension was defined based on the 2017 American Academy of Pediatrics guidelines. RESULTS: Of 159 children (median [interquartile range [IQR]] age: 6 [2-12] years), 73/159 (46%) participants developed AKI and 55/159 (35%) experienced severe electrolyte abnormalities during cisplatin therapy. At median [IQR] 90 [76-110] days post-cisplatin, 53/119 (45%) had CKD and 18/128 (14%) developed hypertension. In multivariable analyses, AKI was not associated with 2-6-month CKD or hypertension. Severe electrolyte abnormalities during cisplatin were associated with having 2-6-month CKD or hypertension (adjusted odds ratio (AdjOR) [95% CI]: 2.65 [1.04-6.74]). Having both AKI and severe electrolyte abnormalities was associated with 2-6-month hypertension (AdjOR [95% CI]: 3.64 [1.05-12.62]). CONCLUSIONS: Severe electrolyte abnormalities were associated with kidney outcomes. Cisplatin dose optimization to reduce toxicity and clear post-cisplatin kidney follow-up guidelines are needed. A higher resolution version of the Graphical abstract is available as Supplementary information.

24-Hour ambulatory blood pressure monitoring 7 years after intensive care unit admission.

BACKGROUND: Children who develop acute kidney injury (AKI) in the pediatric intensive care unit (PICU) may be at higher risk of long-term chronic kidney disease and hypertension. The objectives of this study were to determine the prevalence of post-discharge hypertension and albuminuria using reference-standard measurements in children admitted to the PICU, and evaluate their association with AKI. METHODS: Single-center longitudinal cohort study of children admitted to the PICU from 2005 to 2010 with 7-8 years of follow-up (n = 207). Patients were excluded if they had pre-existing chronic kidney disease, were deceased, lived > 3.5-h drive away, were unwilling/unable to provide consent/assent, or had a clotting disorder. AKI was defined by the Kidney Disease: Improving Global Outcomes creatinine definition. Office blood pressure was evaluated using age, sex, and height-based percentiles. Hypertension was defined using 24-h ambulatory blood pressure monitoring (ABPM). Albuminuria was defined as first morning urine albumin:creatinine ratio ≥ 30 mg/g. Prevalence of blood pressure outcomes was calculated. The association between AKI and outcomes was evaluated using multivariable regression. RESULTS: Sixty of 207 (29%) children developed AKI during PICU admission. Overall, 6% had albuminuria and 21% had elevated office blood pressure or worse. One-hundred-and-seventy-seven (86%) patients had successful ABPM data. Of these, 10 (6%) had white coat, 18 (10%) had masked, and 5 (3%) had ambulatory hypertension. There was no statistically significant difference in outcomes across AKI stages. CONCLUSIONS: Blood pressure abnormalities are common in children 7 years after PICU admission. Future studies with longer follow-up are needed to further evaluate the association between AKI and hypertension. A higher-resolution version of the graphical abstract is available as Supplementary information.

24-hour ambulatory blood pressure monitoring 9 years after pediatric cardiac surgery: a pilot and feasibility study.

BACKGROUND: Children undergoing cardiac surgery are at risk of high blood pressure (BP), a risk factor for cardiovascular and kidney disease. Twenty-four-hour ambulatory BP monitoring (ABPM) is a reference standard hypertension (HTN) test. Little data exist on ABPM abnormalities in children several years post cardiac surgery. This study aimed to (a) determine ABPM feasibility; (b) describe and compare ABPM measures and abnormalities (percent load, masked HTN [MH]; non-dipping, mean systolic/diastolic BP > 95th percentile; pre-HTN (ABPM); white-coat HTN [WCH]) to casual BP; and (c) compare BP in patients with and without acute kidney injury (AKI). METHODS: Prospective, follow-up pilot study of children (0-18 years) who underwent cardiac surgery from 2007 to 2009 at Montreal Children's Hospital. We recorded if participants had post-operative AKI and assessed the following outcomes at 9-year follow-up: casual BP classified by three single-visit measures (normal; elevated BP [eBPSingleVisit]; HTNSingleVisit); ABPM. Bivariable analyses were used to compare characteristics between groups. RESULTS: Twenty-three patients (median [interquartile range], 8.6 [8.0, 9.0] years post cardiac surgery) were included; 16 (70%) male. Six participants (26%) had eBPSingleVisit or higher. On ABPM, 11 (48%) had ≥ 1 abnormality: 9 (39%) had non-dipping; 3 (13%) had pre-HTN; 3 (13%) had WCH; none had HTN or MH. There were no differences in ABPM according to AKI status. CONCLUSION: Our pilot study determined that ABPM was feasible in children years after cardiac surgery and frequently identified ABPM abnormalities. Future research in larger populations is needed to define specific risk factors for HTN in children after cardiac surgery.

Serum Creatinine Monitoring After Acute Kidney Injury in the PICU.

OBJECTIVES: It is unknown whether children with acute kidney injury during PICU admission have kidney function monitored after discharge. Objectives: 1) describe postdischarge serum creatinine monitoring after PICU acute kidney injury and 2) determine factors associated with postdischarge serum creatinine monitoring. DESIGN: Secondary analysis of longitudinal cohort study data. SETTING: Two PICUs in Montreal and Edmonton, Canada. PATIENTS: Children (0-18 yr old) surviving PICU admission greater than or equal to 2 days from 2005 to 2011. Exclusions: postcardiac surgery and prior kidney disease. Exposure: acute kidney injury by Kidney Disease: Improving Global Outcomes serum creatinine definition. INTERVENTIONS: None. MEASUREMENTS: Primary outcome: postdischarge serum creatinine measured by 90 days, 1 year, and 5-7 years. SECONDARY OUTCOMES: Healthcare events and nephrology follow-up. ANALYSIS: Proportions with outcomes; logistic regression to evaluate factors associated with the primary outcome. Kaplan-Meier analysis of time to serum creatinine measurement and healthcare events. MAIN RESULTS: Of n = 277, 69 (25%) had acute kidney injury; 29/69 (42%), 34/69 (49%), and 51/69 (74%) had serum creatinine measured by 90 days, 1 year, and 5-7 year postdischarge, respectively. Acute kidney injury survivors were more likely to have serum creatinine measured versus nonacute kidney injury survivors at all time points (p ≤ 0.01). Factors associated with 90-day serum creatinine measurement were inpatient nephrology consultation (unadjusted odds ratio [95% CI], 14.9 [1.7-127.0]), stage 2-3 acute kidney injury (adjusted odds ratio, 3.4 [1.1-10.2]), and oncologic admission diagnosis (adjusted odds ratio, 10.0 [1.1-93.5]). A higher proportion of acute kidney injury versus nonacute kidney injury survivors were readmitted by 90 days (25 [36%] vs 44 [21%]; p = 0.01) and 1 year (33 [38%] vs 70 [34%]; p = 0.04). Of 24 acute kidney injury survivors diagnosed with chronic kidney disease or hypertension at 5-7 year follow-up, 16 (67%) had serum creatinine measurement and three (13%) had nephrology follow-up postdischarge. CONCLUSIONS: Half of PICU acute kidney injury survivors have serum creatinine measured within 1-year postdischarge and follow-up is suboptimal for children developing long-term kidney sequelae. Knowledge translation strategies should emphasize the importance of serum creatinine monitoring after childhood acute kidney injury.

Kidney and blood pressure abnormalities 6 years after acute kidney injury in critically ill children: a prospective cohort study.

BACKGROUND: Acute kidney injury (AKI) in pediatric intensive care unit (PICU) children may be associated with long-term chronic kidney disease or hypertension. OBJECTIVES: To estimate (1) prevalence of kidney abnormalities (low estimated glomerular filtration rate (eGFR) or albuminuria) and blood pressure (BP) consistent with pre-hypertension or hypertension, 6 years after PICU admission; (2) if AKI is associated with these outcomes. METHODS: Longitudinal study of children admitted to two Canadian PICUs (January 2005-December 2011). Exposures (retrospective): AKI or stage 2/3 AKI (KDIGO creatinine-based definition) during PICU. Primary outcome (single visit 6 years after admission): presence of (a) low eGFR (<90 ml/min/1.73 m2) or albuminuria (albumin to creatinine ratio >30 mg/g) (termed "CKD signs") or (b) BP consistent with ≥pre-hypertension (≥90th percentile) or hypertension (≥95th percentile). RESULTS: Of 277 children, 25% had AKI. AKI and stage 2/3 AKI were associated with 2.2- and 6.6-fold higher adjusted odds, respectively, for the 6-year outcomes. Applying new hypertension guidelines attenuated associations; stage 2/3 AKI was associated with 4.5-fold higher adjusted odds for 6-year CKD signs or ≥elevated BP. CONCLUSIONS: Kidney and BP abnormalities are common 6 years after PICU admission and associated with AKI. Other risk factors must be elucidated to develop follow-up recommendations and reduce cardiovascular risk.

Follow-up after neonatal heart disease repair: watch out for chronic kidney disease and hypertension!

BACKGROUND: With advances in care, neonates undergoing cardiac repairs are surviving more frequently. Our objectives were to 1) estimate the prevalence of chronic kidney disease (CKD) and hypertension 6 years after neonatal congenital heart surgery and 2) determine if cardiac surgery-associated acute kidney injury (CS-AKI) is associated with these outcomes. METHODS: Two-center prospective, longitudinal single-visit cohort study including children with congenital heart disease surgery as neonates between January 2005 and December 2012. CKD (estimated glomerular filtration rate < 90 mL/min/1.73m2 or albumin/creatinine ≥3 mg/mmol) and hypertension (systolic or diastolic blood pressure ≥ 95th percentile for age, sex, and height) prevalence 6 years after surgery was estimated. The association of CS-AKI (Kidney Disease: Improving Global Outcomes definition) with CKD and hypertension was determined using multiple regression. RESULTS: Fifty-eight children with median follow-up of 6 years were evaluated. CS-AKI occurred in 58%. CKD and hypertension prevalence were 17% and 30%, respectively; an additional 15% were classified as having elevated blood pressure. CS-AKI was not associated with CKD or hypertension. Classification as cyanotic postoperatively was the only independent predictor of CKD. Postoperative days in hospital predicted hypertension at follow-up. CONCLUSIONS: The prevalence of CKD and hypertension is high in children having neonatal congenital heart surgery. This is important; early identification of CKD and hypertension can improve outcomes. These children should be systematically followed for the evolution of these negative outcomes. CS-AKI defined by current standards may not be a useful clinical tool to decide who needs follow-up and who does not.

Paucity of renal follow-up by school age after neonatal cardiac surgery.

INTRODUCTION: There are little data about renal follow-up of neonates after cardiovascular surgery and no guidelines for long-term renal follow-up. Our objectives were to assess renal function follow-up practice after neonatal cardiac surgery, evaluate factors that predict follow-up serum creatinine measurements including acute kidney injury following surgery, and evaluate the estimated glomerular filtration rate during follow-up using routinely collected laboratory values. METHODS: Two-centre retrospective cohort study of children 5-7 years of age with a history of neonatal cardiac surgery. Univariable and multivariable analyses were performed to determine factors associated with post-discharge creatinine measurements. Glomerular filtration rate was estimated for each creatinine using a height-independent equation. RESULTS: Seventeen of 55 children (30%) did not have any creatinine measured following discharge after surgery until the end of study follow-up, which occurred at a median time of 6 years after discharge. Of the 38 children who had the kidney function checked, 15 (40%) had all of their creatinine drawn only in the context of a hospitalisation or emergency department visit. Acute kidney injury following surgery did not predict the presence of follow-up creatinine measurements. CONCLUSIONS: A large proportion of neonates undergoing congenital heart repair did not have a follow-up creatinine measured in the first years following surgery. In those that did have a creatinine measured, there did not appear to be any identified pattern of follow-up. A follow-up system for children who are discharged from cardiac surgery is needed to identify children with or at risk of chronic kidney disease.

Urine biomarkers of acute kidney injury in noncritically ill, hospitalized children treated with chemotherapy.

BACKGROUND: Cisplatin (Cis), carboplatin (Carb), and ifosfamide (Ifos) are common nephrotoxic chemotherapies. Biomarkers of tubular injury may allow for early acute kidney injury (AKI) diagnosis. PROCEDURE: We performed a two-center (Canada, United States) pilot study to prospectively measure serum creatinine (SCr), urine neutrophil gelatinase-associated lipocalin (NGAL), and interleukin-18 (IL-18) in children receiving Cis/Carb (27 episodes), Ifos (30 episodes), and in 15 hospitalized, nonchemotherapy patients. We defined AKI using the Kidney Disease Improving Global Outcomes (KDIGO) definition. We compared postchemotherapy infusion NGAL and IL-18 concentrations (immediate postdose to 3 days later) to pre-infusion concentrations. We calculated area under the receiver operating characteristic curve (AUC) for postinfusion biomarkers to discriminate for AKI. RESULTS: Prechemotherapy infusion NGAL and IL-18 concentrations were not higher than nonchemotherapy control concentrations. Increasing chemotherapy dose was associated with increasing postinfusion (0-4 hr after infusion) NGAL (P < 0.05). Post-Ifos, immediate postdose, and daily postdose NGAL and IL-18 were significantly higher than pre-infusion biomarker concentrations (P < 0.05), during AKI episodes. NGAL and IL-18 did not rise significantly after Cis-Carb infusion, relative to predose concentrations (P > 0.05). NGAL and IL-18 measured immediately after Ifos infusion discriminated for AKI with AUCs is 0.80 (standard error = 0.13) and 0.73 (standard error = 0.16), respectively. NGAL and IL-18 were not diagnostic of Cis-Carb-associated AKI. When AUCs were adjusted for age, all biomarker AUCs (Cis-Carb and Ifos) improved. CONCLUSION: Urine NGAL and IL-18 show promise as early AKI diagnostic tests in children treated with ifosfamide and may have a potential role in drug toxicity monitoring.

Previous aminoglycoside use and acute kidney injury risk in non-critically ill children.

OBJECTIVES: Aminoglycosides (AG) are a group of bactericidal antibiotics with nephrotoxic effects that are commonly used in the treatment of hospitialized children. We have examined previous AG treatment as a risk factor for acute kidney injury (AKI) during current AG treatment. STUDY DESIGN: We performed a retrospective cohort study of children ranging in age from 1 month to 18 years who were treated with AG between October 2008 and April 2012 at Montreal's Children's Hospital. Children for whom no serum creatinine data (SCr) were available and those with baseline renal disease were excluded from the analysis. Main exposures were prior AG use (number and hours of prior treatments) and time since last AG treatment. The main outcome was AKI, defined on the basis of the Kidney Disease: Improving Global Outcomes guidelines. Logistic regression was used to examine exposure-outcome associations. RESULTS: AG treatments episodes with Stage 1, 2, and 3 AKI, respectively, were associated with a median of 98 [interquartile range (IQR) 339], 231 (IQR 688), and 111 (IQR 505) h of prior AG treatment, respectively, versus non-AKI (median 0, IQR 54 h) (p < 0.0001). AKI episodes were associated with a mean (± standard deviation) of 1.5 ± 1.8 AG treatments in the previous 6 months, versus 0.9 ± 1.6 AG treatments for non-AKI. The number of AG-treatment days during the preceding 6 months [adjusted odds ratio (adjOR) 1.04, 95 % confidence interval (CI) 1.03-1.06; p < 0.001], younger age (adjOR 0.96, 95 % CI 0.93-0.99; p = 0.009), admission to hematology-oncology department (adjOR 3.88, 95 % CI 2.17-6.96; p < 0.001), and tobramycin use (adjOR 1.77, 95 % CI 1.04-3.02; p = 0.04) were independently associated with AKI. Episodes with Stage 1 and 2 AKI were associated with fewer days since last treatment compared to non-AKI treatment (p < 0.02 and p < 0.005, respectively; Mann-Whitney test). CONCLUSIONS: Based on these results, prior AG treatment is a risk factor for AKI and should be considered when dosing and monitoring hospitalized children being treated with AG.

Biomarkers for Early Acute Kidney Injury Diagnosis and Severity Prediction: A Pilot Multicenter Canadian Study of Children Admitted to the ICU.

OBJECTIVE: Acute kidney injury occurs early in PICU admission and increases risks for poor outcomes. We evaluated the feasibility of a multicenter acute kidney injury biomarker urine collection protocol and measured diagnostic characteristics of urine neutrophil gelatinase-associated lipocalin, interleukin-18, and liver fatty acid binding protein to predict acute kidney injury and prolonged acute kidney injury. DESIGN: Prospective observational pilot cohort study. SETTING: Four Canadian tertiary healthcare PICUs. PATIENTS: Eighty-one children 1 month to 18 years old. Exclusion criteria were as follows: cardiac surgery, baseline severe kidney disease, and inadequate urine or serum for PICU days 1-3. INTERVENTIONS: PICUs performed standardized urine collection protocol to obtain early PICU admission urine samples, with deferred consent. MEASUREMENTS AND MAIN RESULTS: Study barriers and facilitators were recorded. Acute kidney injury was defined based on Kidney Disease: Improving Global Outcomes serum creatinine criteria (acute kidney injuryserum creatinine) and by serum creatinine and urine output criteria (acute kidney injuryserum creatinine+urine output) Prolonged acute kidney injury was defined as acute kidney injury duration of 48 hours or more. PICU days 1-3 neutrophil gelatinase-associated lipocalin, interleukin-18, and liver fatty acid binding protein were evaluated for acute kidney injury prediction (area under the curve). Biomarkers on the first day of acute kidney injury attainment (day 1 acute kidney injury) were evaluated for predicting prolonged acute kidney injury. Eighty-two to 95% of subjects had urine collected from PICU days 1-3. Acute kidney injuryserum creatinine developed in 16 subjects (20%); acute kidney injuryserum creatinine+urine output developed in 38 (47%). On PICU day 1, interleukin-18 predicted acute kidney injuryserum creatinine with area under the curve=0.82, but neutrophil gelatinase-associated lipocalin and liver fatty acid binding protein predicted acute kidney injuryserum creatinine with area under the curve of less than or equal to 0.69; on PICU day 2, area under the curve was higher (not shown). Interleukin-18 and liver fatty acid binding protein on day 1 acute kidney injury predicted prolonged acute kidney injuryserum creatinine (area under the curve=0.74 and 0.83, respectively). When acute kidney injuryserum creatinine+urine output was used to define acute kidney injury, biomarker area under the curves were globally lower. CONCLUSIONS: Protocol urine collection to procure early admission samples is feasible. Individual biomarker acute kidney injury prediction performance is highly variable and modest. Larger studies should evaluate utility and cost effectiveness of using early acute kidney injury biomarkers.

Cystatin C in acute kidney injury diagnosis: early biomarker or alternative to serum creatinine?

BACKGROUND: Early acute kidney injury (AKI) diagnosis is needed to pursue treatment trials. We evaluated cystatin C (CysC) as an early biomarker of serum creatinine (SCr)-AKI and an alternative to define AKI. METHODS: We studied 160 non-cardiac children in the intensive care unit (ICU). We measured daily CysC and SCr. AKI was staged by KDIGO (Kidney Disease: Improving Global Outcomes) guidelines using SCr and CysC (CysC-AKI). We calculated area under the curve (AUC) for (1) neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1) and urine CysC to diagnose SCr- and CysC-AKI; and (2) for CysC to diagnose SCr-AKI. We evaluated AKI associations with length of stay and ventilation duration. RESULTS: We found that 44 % of patients developed SCr-AKI; 32 % developed CysC-AKI. Early ICU NGAL was most diagnostic of CysC-AKI (AUC 0.69, 95% CI 0.54-0.84); IL-18 was most diagnostic for SCr-AKI (AUC 0.69 95% CI 0.55-0.82). Combining SCr and CysC-AKI definition led to higher biomarker diagnostic AUC's. CysC-AKI was not more strongly associated with clinical outcomes. Early ICU CysC predicted SCr-AKI development (AUC 0.70, 95 % CI 0.53-0.89). CONCLUSIONS: Our findings do not support replacing SCr by CysC to define AKI. Early ICU CysC predicts SCr-AKI development and combined SCr-CysC-AKI definition leads to stronger AKI biomarker associations.

Urine Neutrophil Gelatinase-Associated Lipocalin and Kidney Injury Molecule-1 to Detect Pediatric Cisplatin-Associated Acute Kidney Injury.

Background: Few studies have described associations between the AKI biomarkers urinary neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) with AKI in cisplatin-treated children. We aimed to describe excretion patterns of urine NGAL and KIM-1 and associations with AKI in children receiving cisplatin. Methods: Participants (n=159) were enrolled between 2013 and 2017 in a prospective cohort study conducted in 12 Canadian pediatric hospitals. Participants were evaluated at early cisplatin infusions (at first or second cisplatin cycle) and late cisplatin infusions (last or second-to-last cycle). Urine NGAL and KIM-1 were measured (1) pre-cisplatin infusion, (2) post-infusion (morning after), and (3) at hospital discharge at early and late cisplatin infusions. Primary outcome: AKI defined by serum creatinine rise within 10 days post-cisplatin, on the basis of Kidney Disease Improving Global Outcomes guidelines criteria (stage 1 or higher). Results: Of 159 children, 156 (median [interquartile range (IQR)] age: 5.8 [2.4-12.0] years; 78 [50%] female) had biomarker data available at early cisplatin infusions and 127 had data at late infusions. Forty six of the 156 (29%) and 22 of the 127 (17%) children developed AKI within 10 days of cisplatin administration after early and late infusions, respectively. Urine NGAL and KIM-1 concentrations were significantly higher in patients with versus without AKI (near hospital discharge of late cisplatin infusion, median [IQR] NGAL levels were 76.1 [10.0-232.7] versus 14.9 [5.4-29.7] ng/mg creatinine; KIM-1 levels were 4415 [2083-9077] versus 1049 [358-3326] pg/mg creatinine; P<0.01). These markers modestly discriminated for AKI (area under receiver operating characteristic curve [AUC-ROC] range: NGAL, 0.56-0.72; KIM-1, 0.48-0.75). Biomarker concentrations were higher and better discriminated for AKI at late cisplatin infusions (AUC-ROC range, 0.54-0.75) versus early infusions (AUC-ROC range, 0.48-0.65). Conclusions: Urine NGAL and KIM-1 were modest at discriminating for cisplatin-associated AKI. Further research is needed to determine clinical utility and applicability of these markers and associations with late kidney outcomes.

Biomarkers of acute kidney injury in children: discovery, evaluation, and clinical application.

Acute kidney injury (AKI) in children is associated with increased mortality and prolonged length of hospital stay and may also be associated with long-term chronic kidney disease development. Despite encouraging results on AKI treatment in animal studies, no specific treatment has yet been successful in humans. One of the important factors contributing to this problem is the lack of an early AKI diagnostic test. Serum creatinine, the current main diagnostic test for AKI, rises late in AKI pathophysiology and is an inaccurate marker of acute changes in glomerular filtration rate. Therefore, new biomarkers of AKI are needed. With great advancements in genomics, proteomics, and metabolomics, new AKI biomarkers, mainly consisting of urinary proteins that appear in response to renal tubular cell injury, have been, and continue to be, discovered. These new biomarkers offer promise for early AKI diagnosis and for the depiction of severity of renal injury occurring with AKI. This review provides a summary of what a biomarker is, why we need new biomarkers of AKI, and how biomarkers are discovered and should be evaluated. The review also provides a summary of selected AKI biomarkers that have been studied in children.

Incorporation of histone deacetylase inhibition into the structure of a nuclear receptor agonist.

1,25-dihydroxyvitamin D(3) (1,25D) regulates gene expression by signaling through the nuclear vitamin D receptor (VDR) transcription factor and exhibits calcium homeostatic, anticancer, and immunomodulatory properties. Histone deacetylase inhibitors (HDACis) alter nuclear and cytoplasmic protein acetylation, modify gene expression, and have potential for treatment of cancer and other indications. The function of nuclear receptor ligands, including 1,25D, can be enhanced in combination with HDACi. We designed triciferol, a hybrid molecule in which the 1,25D side chain was replaced with the dienyl hydroxamic acid of HDACi trichostatin A. Triciferol binds directly to the VDR, and functions as an agonist with 1,25D-like potency on several 1,25D target genes. Moreover, unlike 1,25D, triciferol induces marked tubulin hyperacetylation, and augments histone acetylation at concentrations that largely overlap those where VDR agonism is observed. Triciferol also exhibits more efficacious antiproliferative and cytotoxic activities than 1,25D in four cancer cell models in vitro. The bifunctionality of triciferol is notable because (i) the HDACi activity is generated by modifying the 1,25D side chain without resorting to linker technology and (ii) 1,25D and HDACi have sympathetic, but very distinct biochemical targets; the hydrophobic VDR ligand binding domain and the active sites of HDACs, which are zinc metalloenzymes. These studies demonstrate the feasibility of combining HDAC inhibition with nuclear receptor agonism to enhance their therapeutic potential.

Function of histone deacetylase 6 as a cofactor of nuclear receptor coregulator LCoR.

Ligand-dependent corepressor LCoR was identified as a protein that interacts with the estrogen receptor alpha (ERalpha) ligand binding domain in a hormone-dependent manner. LCoR also interacts directly with histone deacetylase 3 (HDAC3) and HDAC6. Notably, HDAC6 has emerged as a marker of breast cancer prognosis. However, although HDAC3 is nuclear, HDAC6 is cytoplasmic in many cells. We found that HDAC6 is partially nuclear in estrogen-responsive MCF7 cells, colocalizes with LCoR, represses transactivation of estrogen-inducible reporter genes, and augments corepression by LCoR. In contrast, no repression was observed upon HDAC6 expression in COS7 cells, where it is exclusively cytoplasmic. LCoR binds to HDAC6 in vitro via a central domain, and repression by LCoR mutants lacking this domain was attenuated. Kinetic chromatin immunoprecipitation assays revealed hormone-dependent recruitment of LCoR to promoters of ERalpha-induced target genes in synchrony with ERalpha. HDAC6 was also recruited to these promoters, and repeat chromatin immunoprecipitation experiments confirmed the corecruitment of LCoR with ERalpha and with HDAC6. Remarkably, however, although we find evidence for corecruitment of LCoR and ERalpha on genes repressed by the receptor, LCoR and HDAC6 failed to coimmunoprecipitate, suggesting that they are part of distinct complexes on these genes. Although small interfering RNA-mediated knockdown of LCoR or HDAC6 augmented expression of an estrogen-sensitive reporter gene in MCF7 cells, unexpectedly their ablation led to reduced expression of some endogenous estrogen target genes. Taken together, these data establish that HDAC6 can function as a cofactor of LCoR but suggest that they may act in enhance expressing some target genes.

Ligand-dependent corepressor LCoR is an attenuator of progesterone-regulated gene expression.

Ligand-dependent corepressor LCoR interacts with the progesterone receptor (PR) and estrogen receptor ERalpha in the presence of hormone. LCoR contains tandem N-terminal PXDLS motifs that recruit C-terminal-binding protein (CtBP) corepressors as well as a C-terminal helix-turn-helix (HTH) domain. Here, we analyzed the function of these domains in coregulation of PR- and ERalpha-regulated gene expression. LCoR and CtBP1 colocalize in nuclear bodies that also contain CtBP-interacting protein CtIP and polycomb group repressor complex marker BMI1. Coexpression of CtBP1 in MCF7 or T47D breast cancer cells augmented corepression by LCoR, whereas coexpression of CtIP did not, consistent with direct interaction of LCoR with CtBP1, but not CtIP. The N-terminal region containing the PXDLS motifs is necessary and sufficient for CTBP1 recruitment and essential for full corepression. However, LCoR function was also strongly dependent on the helix-turn-helix domain, as its deletion completely abolished corepression. LCoR, CtBP, and CtIP were recruited to endogenous PR- and ERalpha-stimulated genes in a hormone-dependent manner. Similarly, LCoR was recruited to estrogen-repressed genes, whereas hormone treatment reduced CtBP1 binding. Small interfering RNA-mediated knockdown of LCoR or CtBP1 augmented expression of progesterone- and estrogen-stimulated reporter genes as well as endogenous progesterone-stimulated target genes. In contrast, their ablation had gene-specific effects on ERalpha-regulated transcription that generally led to reduced gene expression. Taken together, these results show that multiple domains contribute to LCoR function. They also reveal a role for LCoR and CtBP1 as attenuators of progesterone-regulated transcription but suggest that LCoR and CtBP1 can act to enhance transcription of some genes.

The association of acute kidney injury with hospital readmission and death after pediatric cardiac surgery.

Background: Acute kidney injury (AKI) in children undergoing cardiac surgery (CS) is strongly associated with increased hospital mortality and length of stay. The association of AKI with postdischarge outcomes is unclear. We evaluated the association of AKI with all-cause readmissions and death within 30 days and 1 year of CS discharge. Methods: This was a prospective, 3-center cohort study of children after CS with cardiopulmonary bypass. The primary exposures were postoperative ≥stage 1 AKI and ≥stage 2 AKI defined by Kidney Disease: Improving Global Outcomes AKI definition. Two separate outcomes were hospital readmission and death within 30 days and 1 year of discharge. Association of AKI with time to outcomes was determined using multivariable Cox-proportional hazards analysis. Age, The Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery risk adjustment tool score ≥3, cardiopulmonary bypass >120 minutes, and cyanotic heart disease were evaluated as effect modifiers. Results: Of 402 participants included (median age 1.8 years [interquartile range 0.4, 5.2]), 32 (8.0%) and 109 (27.1%) were readmitted; 7 (1.7%) and 9 (2.2%) died within 30 days and 1 year of CS, respectively. AKI was not associated with readmission at 30 days or 1 year postdischarge. ≥Stage 2 AKI (adjusted hazard ratio, 11.68 [1.88, 72.61]) was associated with mortality 30 days post-CS. Conclusions: Postoperative AKI was not associated with readmission at 30 days and 1-year postdischarge. However, more severe AKI (≥stage 2) appears to be associated with increased morality risk at 30 days post-CS.

Epidemiologic Characteristics of Acute Kidney Injury During Cisplatin Infusions in Children Treated for Cancer.

Importance: Few multicenter pediatric studies have comprehensively described the epidemiologic characteristics of cisplatin-associated acute kidney injury using standardized definitions. Objective: To examine the rate of and risk factors associated with acute kidney injury among children receiving cisplatin infusions. Design, Setting, and Participants: This prospective cohort study examined children (aged <18 years) recruited from May 23, 2013, to March 31, 2017, at 12 Canadian pediatric academic health centers who were receiving 1 or more cisplatin infusion. Children whose estimated or measured glomerular filtration rate (GFR) was less than 30 mL/min/1.73 m2 or who had received a kidney transplant were excluded. Data analysis was performed from January 3, 2018, to September 20, 2019. Exposures: Cisplatin infusions. Main Outcomes and Measures: The primary outcome was acute kidney injury during cisplatin infusion, defined using a Kidney Disease: Improving Global Outcomes serum creatinine criteria-based definition (stage 1 or higher). The secondary outcome was acute kidney injury defined by electrolyte criteria from the National Cancer Institute Common Terminology Criteria for Adverse Events (grade 1 or higher). Assessments occurred at early (first or second cycle) and late (last or second to last cycle) cisplatin infusions. Results: A total of 159 children (mean [SD] age at early cisplatin infusion, 7.2 [5.3] years; 80 [50%] male) participated. The most common diagnoses were central nervous system tumors (58 [36%]), neuroblastoma (43 [27%]), and osteosarcoma (33 [21%]). Acute kidney injury (by serum creatinine level increase) occurred in 48 of 159 patients (30%) at early cisplatin infusions and 23 of 143 patients (16%) at late cisplatin infusions. Acute kidney injury (by electrolyte abnormalities) occurred in 106 of 159 patients (67%) at early cisplatin infusion and 100 of 143 patients (70%) at late cisplatin infusions. Neuroblastoma diagnosis and higher precisplatin GFR were independently associated with acute kidney injury (serum creatinine level increase) at early cisplatin infusions (adjusted odds ratio [aOR] for neuroblastoma vs other, 3.25; 95% CI, 1.18-8.95; aOR for GFR, 1.01; 95% CI, 1.00-1.03) and late cisplatin infusions (aOR for neuroblastoma vs other, 6.85; 95% CI, 1.23-38.0; aOR for GFR, 1.01; 95% CI, 1.00-1.03). Higher cisplatin infusion dose was also independently associated with acute kidney injury (serum creatinine level increase) at later cisplatin infusions (aOR, 1.05; 95% CI, 1.01-1.10). Conclusions and Relevance: The findings suggest that acute kidney injury is common among children receiving cisplatin infusions and that rate and risk factors differ at earlier vs later infusions. These results may help with risk stratification with a goal of risk reduction.

Healthcare Utilization after Acute Kidney Injury in the Pediatric Intensive Care Unit.

BACKGROUND AND OBJECTIVES: Little is known about the long-term burden of AKI in the pediatric intensive care unit. We aim to evaluate if pediatric AKI is associated with higher health service use post-hospital discharge. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This is a retrospective cohort study of children (≤18 years old) admitted to two tertiary centers in Montreal, Canada. Only the first admission per patient was included. AKI was defined in two ways: serum creatinine alone or serum creatinine and/or urine output. The outcomes were 30-day, 1-year, and 5-year hospitalizations, emergency room visits, and physician visits per person-time using provincial administrative data. Univariable and multivariable Poisson regression were used to evaluate AKI associations with outcomes. RESULTS: A total of 2041 children were included (56% male, mean admission age 6.5±5.8 years); 299 of 1575 (19%) developed AKI defined using serum creatinine alone, and when urine output was included in the AKI definition 355 of 1622 (22%) children developed AKI. AKI defined using serum creatinine alone and AKI defined using serum creatinine and urine output were both associated with higher 1- and 5-year hospitalization risk (AKI by serum creatinine alone adjusted relative risk, 1.42; 95% confidence interval, 1.12 to 1.82; and 1.80; 1.54 to 2.11, respectively [similar when urine output was included]) and higher 5-year physician visits (adjusted relative risk, 1.26; 95% confidence interval, 1.14 to 1.39). AKI was not associated with emergency room use after adjustments. CONCLUSIONS: AKI is independently associated with higher hospitalizations and physician visits postdischarge.