Background
Cisplatin is associated with acute kidney injury (AKI) and electrolyte abnormalities. Urine tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor-binding protein ...7 (IGFBP-7) may be early cisplatin-AKI biomarkers.
Methods
We conducted a 12-site prospective cohort study with pediatric patients treated with cisplatin (May 2013–December 2017). Blood and urine (measured for TIMP-2, IGFBP-7) were collected pre-cisplatin, 24-h post-cisplatin, and near hospital discharge during the first or second cisplatin cycle (early visit (EV)) and during second-to-last or last cisplatin cycle (late visit (LV)). Primary outcome: serum creatinine (SCr)-defined AKI (≥ stage 1).
Results
At EV (median (interquartile (IQR)) age: 6 (2–12) years; 78 (50%) female), 46/156 (29%) developed AKI; at LV, 22/127 (17%) experienced AKI. At EV, TIMP-2, IGFBP-7, and TIMP-2*IGFBP-7 pre-cisplatin infusion concentrations were significantly higher in participants with vs. those without AKI. At EV and LV, biomarker concentrations were significantly lower in participants with vs. those without AKI at post-infusion and near-hospital discharge. Biomarker values normalized to urine creatinine were higher in patients with AKI compared to without (LV post-infusion, median (IQR): TIMP-2*IGFBP-7: 0.28 (0.08–0.56) vs
.
0.04 (0.02–0.12) (ng/mg creatinine)
2
/1000;
P
< .001). At EV, pre-infusion biomarker concentrations had the highest area under the curves (AUC) (range: 0.61–0.62) for AKI diagnosis; at LV, biomarkers measured post-infusion and near discharge yielded the highest AUCs (range: 0.64–0.70).
Conclusions
TIMP-2*IGFBP-7 were poor to modest at detecting AKI post-cisplatin. Additional studies are needed to determine whether raw biomarker values or biomarker values normalized to urinary creatinine are more strongly associated with patient outcomes.
Graphical abstract
A higher resolution version of the Graphical abstract is available as
Supplementary information
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
SingleVisit
; HTN
SingleVisit
); 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
SingleVisit
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.
Cisplatin is a chemotherapeutic agent highly excreted in urine and known to cause acute kidney injury (AKI). As AKI diagnosis by serum creatinine (SCr) is usually delayed, endeavors for finding early ...AKI biomarkers continue. This study aims to determine if urine platinum (UP) concentration 24 hours after cisplatin infusion is associated with AKI, and to evaluate the association between urine platinum and tubular damage biomarkers: neutrophil gelatinase‐associated lipocalin (NGAL) and kidney injury molecule‐1 (KIM‐1). Children treated with cisplatin in 12 Canadian centers (April 2013 to December 2017) were included. Urine from the morning after the first cisplatin infusion of the first or second cisplatin cycle was measured for urine platinum, NGAL, and KIM‐1. SCr and serum electrolytes were used to detect AKI by either SCr elevation or urinary electrolyte wasting (potassium, magnesium, phosphate). The associations of urine platinum with AKI, NGAL, and KIM‐1 were assessed. A total of 115 participants (54% boys, median age, 8.5 years; interquartile range, 4.0‐13.4) were included, of which 29 (25%) and 105 (91%) developed AKI defined by SCr and electrolyte criteria, respectively. Higher urine platinum was associated with higher cisplatin dose (Spearman rho, 0.21) and with younger age (Spearman rho, –0.33). Urine platinum was not associated with postinfusion AKIor KIM‐1, but was weakly associated with NGAL, particularly in participants without SCr AKI (Pearson's r, 0.22). Urine platinum may be a marker of mild tubular injury but is not likely to be a useful biomarker of clinically evident AKI.
Urine kidney injury biomarkers measured during cisplatin therapy may identify patients at risk for adverse subsequent kidney outcomes. We examined relationships between tubular injury biomarkers ...collected early (early visit EV: first or second cisplatin cycle) and late (late visit LV: last or second-last cisplatin cycle) during cisplatin therapy, with 3-month post-cisplatin chronic kidney disease (CKD) and hypertension.
We analyzed data from the Applying Biomarkers to Minimize Long-Term Effects of Childhood/Adolescent Cancer Treatment Nephrotoxicity Study: twelve-center prospective cohort study of 159 children receiving cisplatin. We measured urine neutrophil gelatinase-associated lipocalin (NGAL)/creatinine, kidney injury molecule-1 (KIM-1)/creatinine, tissue inhibitor of metalloproteinase-2 (TIMP-2), and insulin-like growth factor-binding protein 7 (IGFBP-7) (TIMP-2 and IGFBP-7 expressed as their product, ng/ml^2/1000) at an EV and LV during cisplatin therapy with pre-infusion, post-infusion, and hospital discharge sampling. Area under the curve (AUC) was calculated for biomarkers to detect 3-month post-cisplatin CKD (KDIGO guidelines: low estimated glomerular filtration rate (eGFR) or elevated uACR for age) and hypertension (three blood pressures; per American Academy of Pediatrics guidelines).
At median follow-up of 90 days, 52/118 (44%) and 17/125 (14%) developed CKD and hypertension, respectively. Biomarker prediction for 3-month CKD was low to modest; NGAL combined with KIM-1 at EV discharge yielded the highest AUC (0.67, 95% CI 0.57-0.77). Biomarker prediction of 3-month hypertension was stronger, but modest; the highest AUC was from combining EV pre-infusion NGAL and TIMP-2*IGFBP-7 (0.71, 95% CI 0.62-0.80). When EV pre-infusion NGAL and TIMP-2*IGFBP-7 were added to the 3-month hypertension clinical predictive model, AUCs increased from 0.81 (0.72-0.91) to 0.89 (0.83-0.95) (p<0.05).
Tubular injury biomarkers we studied were individually not strong predictors of 3-month post-cisplatin kidney outcomes. Adding biomarkers to existing clinical prediction models may help predict post-therapy hypertension and identify higher kidney-risk patients.
Key Points Tubular injury biomarkers are not individually strong predictors of 3-month post-cisplatin CKD. When combined with clinical measures, tubular injury biomarkers can predict post-therapy ...hypertension and identify high-risk patients. Background Urine kidney injury biomarkers measured during cisplatin therapy may identify patients at risk of adverse subsequent kidney outcomes. We examined relationships between tubular injury biomarkers collected early (early visit EV: first or s econd cisplatin cycle) and late (late visit: last or second-last cisplatin cycle) during cisplatin therapy, with 3-month post-cisplatin CKD and hypertension (HTN). Methods We analyzed data from the Applying Biomarkers to Minimize Long-Term Effects of Childhood/Adolescent Cancer Treatment Nephrotoxicity study, a 12-center prospective cohort study of 159 children receiving cisplatin. We measured urine neutrophil gelatinase-associated lipocalin (NGAL)/creatinine, kidney injury molecule-1/creatinine, tissue inhibitor of metalloproteinase-2 (TIMP-2), and insulin-like growth factor-binding protein 7 (IGFBP-7) (TIMP-2 and IGFBP-7 expressed as their product, ng/ml 2 /1000) at an EV and late visit during cisplatin therapy with preinfusion, postinfusion, and hospital discharge sampling. Area under the curve (AUC) was calculated for biomarkers to detect 3-month post-cisplatin CKD (Kidney Disease Improving Global Outcomes guidelines: low eGFR or elevated urine albumin-to-creatinine ratio for age) and HTN (three BPs; per American Academy of Pediatrics guidelines). Results At median follow-up of 90 days, 52 of 118 patients (44%) and 17 of 125 patients (14%) developed CKD and HTN, respectively. Biomarker prediction for 3-month CKD was low to modest; NGAL combined with kidney injury molecule-1 at EV discharge yielded the highest AUC (0.67; 95% confidence interval, 0.57 to 0.77). Biomarker prediction of 3-month HTN was stronger, but modest; the highest AUC was from combining EV preinfusion NGAL and TIMP-2×IGFBP-7 (0.71; 95% confidence interval, 0.62 to 0.80). When EV preinfusion NGAL and TIMP-2×IGFBP-7 were added to the 3-month HTN clinical predictive model, AUCs increased from 0.81 (0.72 to 0.91) to 0.89 (0.83 to 0.95) ( P < 0.05). Conclusions Tubular injury biomarkers we studied were individually not strong predictors of 3-month post-cisplatin kidney outcomes. Adding biomarkers to existing clinical prediction models may help predict post-therapy HTN and identify higher kidney-risk patients.
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.
Participants (
=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 (
) pre-cisplatin infusion, (
) post-infusion (morning after), and (
) 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).
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;
<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).
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.
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