Publications by authors named "Ana Palijan"

20 Publications

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

Pediatr Nephrol 2021 Jan 7. Epub 2021 Jan 7.

Department of Pediatrics, Division of Nephrology, Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, 686 Bay Street, 11th floor, Room 11.9722, Toronto, ON, M5G 0A4, Canada.

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 [eBP]; HTN); 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 eBP 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.
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http://dx.doi.org/10.1007/s00467-020-04847-2DOI Listing
January 2021

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

Pediatr Nephrol 2020 11 4;35(11):2137-2145. Epub 2020 Jun 4.

Department of Pediatrics, Division of Nephrology, University of Alberta, Stollery Children's Hospital, Room 4-555, 11405-87 Avenue, Edmonton, AB, T6G 1C9, Canada.

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/1.73m 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.
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http://dx.doi.org/10.1007/s00467-020-04621-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515960PMC
November 2020

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

Cardiol Young 2020 Jun 19;30(6):822-828. Epub 2020 May 19.

Department of Pediatrics, Division of Nephrology, Stollery Children's Hospital, University of Alberta, Edmonton, AB, Canada.

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.
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http://dx.doi.org/10.1017/S1047951120001067DOI Listing
June 2020

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

JAMA Netw Open 2020 05 1;3(5):e203639. Epub 2020 May 1.

Peter Gilgan Centre For Research and Learning, Toronto, Ontario, Canada.

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.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.3639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210480PMC
May 2020

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

Pediatr Res 2020 08 2;88(2):271-278. Epub 2020 Jan 2.

Formerly, McGill University Health Centre Research Institute, McGill University Health Centre, Montreal, QC, Canada.

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 m) 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.
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http://dx.doi.org/10.1038/s41390-019-0737-5DOI Listing
August 2020

Long-term Mortality After Acute Kidney Injury in the Pediatric ICU.

Hosp Pediatr 2018 05;8(5):260-268

Division of Nephrology, Department of Pediatrics, Montreal Children's Hospital, McGill University Health Centre, Montreal, Canada;

Objectives: (1) To evaluate the association between acute kidney injury (AKI) in the PICU and long-term mortality and (2) to determine the extent to which adding the urine output (UO)-defined AKI alters the association.

Methods: A 2-center retrospective cohort study of children (≤18 years old) admitted to the PICU between 2003 and 2005 for noncardiac surgery, with follow-up until 2010. Patients with end stage renal disease, no provincial health insurance number, who died during hospitalization, or could not be linked to administrative data were excluded. One hospitalization per patient was included. AKI was defined by using serum creatinine criteria and/or UO criteria. Mortality was ascertained by using administrative data. Cox regression analysis was performed to evaluate the association between AKI and long-term mortality.

Results: The study population included 2041 patients (55.7% male, mean admission age 6.5 ± 5.8 years). Of 2041 hospital survivors, 9 (0.4%) died within 30 days, 51 (2.5%) died within 1 year, and 118 (5.8%) died within 5 to 7 years postdischarge. AKI was independently associated with 5- to 7-year mortality (adjusted hazard ratio [95% confidence interval]: 3.10 [1.46-6.57] and 3.38 [1.63-7.02], respectively). Including UO did not strengthen the association.

Conclusions: AKI is associated with 5- to 7-year mortality. Because this is an observational study we cannot determine if AKI is causative of mortality or of the pathophysiology. However, patients with AKI represent a high-risk group. It is reasonable that these patients be considered for targeted follow-up until future researchers better elucidate these relationships.
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http://dx.doi.org/10.1542/hpeds.2017-0215DOI Listing
May 2018

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

Clin J Am Soc Nephrol 2018 05 20;13(5):685-692. Epub 2018 Apr 20.

Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.

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.
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http://dx.doi.org/10.2215/CJN.09350817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5969475PMC
May 2018

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

Pediatr Crit Care Med 2017 Jun;18(6):e235-e244

1Divisions of Nephrology and Pediatric Critical Care Medicine, Department of Pediatrics, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada. 2Section of Nephrology, Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada 3Division of Nephrology, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada. 4Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH. 5Department of Pediatrics, University of Alberta, Women and Children's Health Research Institute, Edmonton, AL, Canada. 6Section of Pediatric Intensive Care, Department of Pediatrics and Child Health, University of Manitoba, Children's Hospital, Winnipeg, Manitoba, Canada. 7Division of Nephrology, Department of Pediatrics, University of Alberta, Edmonton, AL, Canada. 8Pediatric Intensive Care Unit, Children's Heart Centre, British Columbia Children's Hospital, Vancouver, BC, Canada.

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.
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http://dx.doi.org/10.1097/PCC.0000000000001183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6112234PMC
June 2017

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

Pediatr Blood Cancer 2017 Oct 18;64(10). Epub 2017 Apr 18.

Division of Nephrology, Department of Pediatrics, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada.

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.
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http://dx.doi.org/10.1002/pbc.26538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287509PMC
October 2017

Design and Methods of the Pan-Canadian Applying Biomarkers to Minimize Long-Term Effects of Childhood/Adolescent Cancer Treatment (ABLE) Nephrotoxicity Study: A Prospective Observational Cohort Study.

Can J Kidney Health Dis 2017 16;4:2054358117690338. Epub 2017 Feb 16.

Department of Pediatrics, Division of Pediatric Nephrology, Montreal Children's Hospital, McGill University Health Centre, Montreal, Canada.

Background: Childhood cancer survivors experience adverse drug events leading to lifelong health issues. The Applying Biomarkers to Minimize Long-Term Effects of Childhood/Adolescent Cancer Treatment (ABLE) team was established to validate and apply biomarkers of cancer treatment effects, with a goal of identifying children at high risk of developing cancer treatment complications associated with thrombosis, graft-versus-host disease, hearing loss, and kidney damage. Cisplatin is a chemotherapy well known to cause acute and chronic nephrotoxicity. Data on biomarkers of acute kidney injury (AKI) and late renal outcomes in children treated with cisplatin are limited.

Objective: To describe the design and methods of the pan-Canadian ABLE Nephrotoxicity study, which aims to evaluate urine biomarkers (neutrophil gelatinase-associated lipocalin [NGAL] and kidney injury molecule-1 [KIM-1]) for AKI diagnosis, and determine whether they predict risk of long-term renal outcomes (chronic kidney disease [CKD], hypertension).

Design: This is a 3-year observational prospective cohort study.

Setting: The study includes 12 Canadian pediatric oncology centers.

Patients: The target recruitment goal is 150 patients aged less than 18 years receiving cisplatin. : Patients with an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m or a pre-existing renal transplantation at baseline.

Measurements: Serum creatinine (SCr), urine NGAL, and KIM-1 are measured during cisplatin infusion episodes (pre-infusion, immediate post-infusion, discharge sampling). At follow-up visits, eGFR, microalbuminuria, and blood pressure are measured and outcomes are collected.

Methods: AKI is defined as per SCr criteria of the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. CKD is defined as eGFR <90 mL/min/1.73m2 or albumin-to-creatinine ratio≥3mg/mmol. Hypertension is defined as per guidelines. Patients are recruited before their first or second cisplatin cycle. Participants are evaluated during 2 cisplatin infusion episodes (AKI biomarker validation) and at 3, 12, and 36 months post-cisplatin treatment (late outcomes).

Limitations: The study has a relatively moderate sample size and short follow-up duration. There is potential for variability in data collection since multiple sites are involved.

Conclusions: ABLE will provide a national platform to study biomarkers of late cancer treatment complications. The Nephrotoxicity study is a novel study of AKI biomarkers in children treated with cisplatin that will greatly inform on late cisplatin renal outcomes and follow-up needs.
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http://dx.doi.org/10.1177/2054358117690338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5317038PMC
February 2017

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

Pediatr Nephrol 2017 01 7;32(1):173-179. Epub 2016 Oct 7.

Division of Nephrology, Department of Pediatrics, Montreal Children's Hospital, McGill University Health Centre, 2300 Tupper, Room E-213, Montreal, Quebec, Canada.

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.
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http://dx.doi.org/10.1007/s00467-016-3471-9DOI Listing
January 2017

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

Pediatr Nephrol 2015 Apr 5;30(4):665-76. Epub 2014 Dec 5.

Department of Pediatrics, McGill University Health Centre, Montreal, QC, Canada.

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.
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http://dx.doi.org/10.1007/s00467-014-2987-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4372053PMC
April 2015

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

Pediatr Nephrol 2011 Jan 10;26(1):29-40. Epub 2010 Jul 10.

Department of Pediatrics, Division of Nephrology, Montreal Children's Hospital, McGill University Health Centre, 2300 Tupper, Room E-213, Montreal, Quebec, H3H 1P3, Canada.

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.
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http://dx.doi.org/10.1007/s00467-010-1576-0DOI Listing
January 2011

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

J Biol Chem 2009 Oct 10;284(44):30275-87. Epub 2009 Sep 10.

Department of Physiology, McGill University, Montreal, Quebec H3G 1Y6, Canada.

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.
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http://dx.doi.org/10.1074/jbc.M109.051201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2781583PMC
October 2009

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

J Biol Chem 2009 Oct 10;284(44):30264-74. Epub 2009 Sep 10.

Department of Physiology, McGill University, Montreal, Quebec H3G 1Y6, Canada.

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.
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http://dx.doi.org/10.1074/jbc.M109.045526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2781582PMC
October 2009

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

Proc Natl Acad Sci U S A 2008 Jun 12;105(24):8250-5. Epub 2008 Jun 12.

Departments of Medicine and Physiology, McIntyre Building, McGill University, 3655 Drummond Street, Montreal, QC, Canada.

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.
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http://dx.doi.org/10.1073/pnas.0709279105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2426965PMC
June 2008

Dissecting quantitative trait loci into opposite blood pressure effects on Dahl rat chromosome 8 by congenic strains.

J Hypertens 2004 Aug;22(8):1495-502

Research Centre-CHUM, Hôtel Dieu, 3840 rue St Urbain, Montréal, Québec, H2W 1T8, Canada.

Objective: Our previous linkage analyses showed that there was likely a quantitative trait locus (QTL) for blood pressure (BP) on chromosome 8 (Chr 8) in the strain comparison between the Dahl salt-sensitive (S) and the Lewis (LEW) rats. The current work is to delineate the chromosome interval harboring this QTL by using congenic strains with different chromosome substitutions.

Methods: Two congenic strains were produced by replacing different segments of the S rats with the homologous segments of the LEW rats. A genome-wide marker screening was utilized to accelerate this process. The two strains generated are designated as C8S.L1 and C8S.L2, respectively. BPs of the rats were measured by telemetry.

Results: C8S.L1 showed a BP lower than that of S rats. In contrast, C8S.L2 did not have chromosome overlaps with C8S.L1, but unexpectedly, exhibited a BP-raising effect, higher than that of S rats.

Conclusion: There are at least two QTLs present in a section of Chr 8 that possess opposite BP effects. The current congenic work reveals not only the presence of QTLs, but the complexity of QTLs on BP. The novel congenic strain with hypertension more severe than S provides a new model for studies in elucidating physiological mechanisms controlling BP.
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http://dx.doi.org/10.1097/01.hjh.0000133720.94075.6fDOI Listing
August 2004

Combining congenic coverage with gene profiling in search of candidates for blood pressure quantitative trait loci in Dahl rats.

Hypertens Res 2004 Mar;27(3):203-12

Research Centre, Centre Hospitalier de l'Université de Montreal (CHUM), Quebec, Canada.

Chromosomes (Chr) 10 and 16 of the Dahl salt-sensitive (S) rat harbor quantitative trait loci (QTLs) for blood pressure (BP). To facilitate gene discovery of these QTLs, gene profiling based on microarrays was combined with fine QTL mapping to identify potential candidate genes that are differentially expressed. First, the region harboring the BP QTL on Chr 16 was narrowed by comparative congenic mapping. In this endeavor, a number of new chromosome markers were generated and used to physically define the chromosome interval in question. Second, in an effort to minimize the costs of gene profiling without sacrificing the chance of gene discovery, a combination congenic strain was produced by replacing one segment of Chr 10 along with one segment of Chr 16 of the hypertensive S rat by those of the normotensive Lewis (LEW) rat. Both of these regions are known to contain BP QTLs. Third, kidneys of this combination congenic strain and the S strain were employed for expression profiling studies. Finally, a comparison between the two strains yielded a number of potentially differentially expressed candidates. Six Established Sequence Tags (ESTs)/genes among them were located in Chr 10 regions and 1 was found in a Chr 16 region, and the genetic make-ups of all these regions were shown to be different between S and LEW. However, none of these ESTs/genes identified by gene profiling were located in an interval containing a QTL. Thus, the present study highlights the importance of correlating the results of gene expression profiling with fine congenic mapping.
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http://dx.doi.org/10.1291/hypres.27.203DOI Listing
March 2004

Quantitative trait loci with opposing blood pressure effects demonstrating epistasis on Dahl rat chromosome 3.

Physiol Genomics 2003 Sep 29;15(1):1-8. Epub 2003 Sep 29.

Research Centre-Centre Hospitalier de l'Université de Montreal CHUM, Hôtel Dieu, Montreal, Quebec H2W 1T8, Canada.

Our previous linkage studies indicated that there might be a blood pressure (BP) quantitative trait locus (QTL) on chromosome 3 (Chr 3) contrasting between the Dahl salt-sensitive (S) strain and the Lewis (LEW) strain. To prove and then to narrow down the segment containing this QTL, five congenic strains have been generated by replacing various segments of the S rats with the homologous segments of the LEW rats. They are designated as S.L1, S.L2, S.L3, S.L4, and S.L5, respectively. S.L2, S.L3, S.L4, and S.L5 are substrains of S.L1, i.e., they contain substitutions of smaller sections within the large fragment defined by S.L1. The construction of these congenic strains was facilitated by a genome-wide marker screening process. BPs of the rats were measured by telemetry. S.L2 and S.L3 shared a fragment of Chr 3 in common and both showed a BP-lowering effect, indicating the existence of "-BP" QTL alleles from LEW compared with S. In contrast, S.L4 involves a section with no overlap with either S.L2 or S.L3, and S.L4 showed a BP significantly higher than that of S rats, indicating the presence of "+BP" QTL alleles from LEW compared with S. Interestingly, the combined effect of the -BP QTL and +BP QTL alleles was "-" in S.L1, implying that the "-" QTL is epistatic to "+" QTL.
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http://dx.doi.org/10.1152/physiolgenomics.00084.2003DOI Listing
September 2003

Comprehensive congenic coverage revealing multiple blood pressure quantitative trait loci on Dahl rat chromosome 10.

Hypertension 2003 Oct 25;42(4):515-22. Epub 2003 Aug 25.

Research Centre-Centre Hospitalier de l'Université de Montréal, Hôtel Dieu, , Montreal, Quebec, Canada.

Chromosome mapping based on congenic strains can restrict quantitative trait loci (QTLs) for blood pressure (BP) into small intervals that are otherwise indistinguishable in linkage analysis. Also, congenic strains can be created to test a candidate gene to be a BP QTL. Taking full advantage of these features, we produced 10 congenic strains by replacing various segments of chromosome (Chr) 10 of the Dahl salt-sensitive (DSS) rat with those of the Lewis (LEW) rat. These strains were made to systematically cover an entire section of Chr 10. Three of the strains were designed to narrow the intervals that harbor previously mapped QTL1 and QTL2. Two of the strains were designed for the express purpose of testing the QTL candidacy of loci for inducible nitric oxide synthase (Nos2) and angiotensin-converting enzyme (Ace) genes. BPs of these strains were measured by telemetry and compared with those of the DSS rat. Consequently, QTL1 and QTL2 were narrowed to segments of 53.5 and 100.4 centiRays, respectively. A new QTL, QTL3, was found between QTL1 and QTL2. Both Nos2 and Ace have been disqualified as QTLs in the DSS and LEW comparison. Therefore, there are no obvious candidate genes in the segments that harbor these 3 QTLs, which represent genes previously not thought to be involved in BP regulation. These QTLs will likely have an influence on studies of human hypertension because of their homology with the human CHR 17 region in which QTLs for BP have been found.
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http://dx.doi.org/10.1161/01.HYP.0000090096.88509.15DOI Listing
October 2003