Association of Multiple Plasma Biomarker Concentrations with Progression of Prevalent Diabetic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Study.

2021

115-126

2021 01

1533-3450

<p><strong>BACKGROUND: </strong>Although diabetic kidney disease is the leading cause of ESKD in the United States, identifying those patients who progress to ESKD is difficult. Efforts are under way to determine if plasma biomarkers can help identify these high-risk individuals.</p>

<p><strong>METHODS: </strong>In our case-cohort study of 894 Chronic Renal Insufficiency Cohort Study participants with diabetes and an eGFR of &lt;60 ml/min per 1.73 m at baseline, participants were randomly selected for the subcohort; cases were those patients who developed progressive diabetic kidney disease (ESKD or 40% eGFR decline). Using a multiplex system, we assayed plasma biomarkers related to tubular injury, inflammation, and fibrosis (KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40). Weighted Cox regression models related biomarkers to progression of diabetic kidney disease, and mixed-effects models estimated biomarker relationships with rate of eGFR change.</p>

<p><strong>RESULTS: </strong>Median follow-up was 8.7 years. Higher concentrations of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were each associated with a greater risk of progression of diabetic kidney disease, even after adjustment for established clinical risk factors. After accounting for competing biomarkers, KIM-1, TNFR-2, and YKL-40 remained associated with progression of diabetic kidney disease; TNFR-2 had the highest risk (adjusted hazard ratio, 1.61; 95% CI, 1.15 to 2.26). KIM-1, TNFR-1, TNFR-2, and YKL-40 were associated with rate of eGFR decline.</p>

<p><strong>CONCLUSIONS: </strong>Higher plasma levels of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were associated with increased risk of progression of diabetic kidney disease; TNFR-2 had the highest risk after accounting for the other biomarkers. These findings validate previous literature on TNFR-1, TNFR-2, and KIM-1 in patients with prevalent CKD and provide new insights into the influence of suPAR and YKL-40 as plasma biomarkers that require validation.</p>

10.1681/ASN.2020040487

J Am Soc Nephrol

33122288

Association of early hypotension in pediatric sepsis with development of new or persistent acute kidney injury.

2020

2020 Jul 25

1432-198X

<p><strong>OBJECTIVE: </strong>To determine how hypotension in the first 48 h of sepsis management impacts acute kidney injury (AKI) development and persistence.</p>

<p><strong>STUDY DESIGN: </strong>Retrospective study of patients &gt; 1 month to &lt; 20 years old with sepsis in a pediatric ICU between November 2012 and January 2015 (n = 217). All systolic blood pressure (SBP) data documented within 48 h after sepsis recognition were collected and converted to percentiles for age, sex, and height. Time below SBP percentiles and below pediatric advanced life support (PALS) targets was calculated by summing elapsed time under SBP thresholds during the first 48 h. The primary outcome was new or persistent AKI, defined as stage 2 or 3 AKI present between sepsis day 3-7 using Kidney Disease: Improving Global Outcomes creatinine definitions. Secondary outcomes included AKI-free days (days alive and free of AKI) and time to kidney recovery.</p>

<p><strong>RESULTS: </strong>Fifty of 217 sepsis patients (23%) had new or persistent AKI. Patients with AKI spent a median of 35 min under the first SBP percentile, versus 4 min in those without AKI. After adjustment for potential confounders, the odds of AKI increased by 9% with each doubling of minutes spent under this threshold (p = 0.03). Time under the first SBP percentile was also associated with fewer AKI-free days (p = 0.02). Time spent under PALS targets was not associated with AKI.</p>

<p><strong>CONCLUSIONS: </strong>The duration of severe systolic hypotension in the first 48 h of pediatric sepsis management is associated with AKI incidence and duration when defined by age, sex, and height norms, but not by PALS definitions. Graphical abstract.</p>

10.1007/s00467-020-04704-2

Pediatr. Nephrol.

32710239

Variability of Two Metabolomic Platforms in CKD.

2018

2018 Dec 20

1555-905X

<p><strong>BACKGROUND AND OBJECTIVES: </strong>Nontargeted metabolomics can measure thousands of low-molecular-weight biochemicals, but important gaps limit its utility for biomarker discovery in CKD. These include the need to characterize technical and intraperson analyte variation, to pool data across platforms, and to outline analyte relationships with eGFR.</p>

<p><strong>DESIGN, SETTING, PARTICIPANTS, &amp; MEASUREMENTS: </strong>Plasma samples from 49 individuals with CKD (eGFR&lt;60 ml/min per 1.73 m and/or ≥1 g proteinuria) were examined from two study visits; 20 samples were repeated as blind replicates. To enable comparison across two nontargeted platforms, samples were profiled at Metabolon and the Broad Institute.</p>

<p><strong>RESULTS: </strong>The Metabolon platform reported 837 known metabolites and 483 unnamed compounds (selected from 44,953 unknown ion features). The Broad Institute platform reported 594 known metabolites and 26,106 unknown ion features. Median coefficients of variation (CVs) across blind replicates were 14.6% (Metabolon) and 6.3% (Broad Institute) for known metabolites, and 18.9% for (Metabolon) unnamed compounds and 24.5% for (Broad Institute) unknown ion features. Median CVs for day-to-day variability were 29.0% (Metabolon) and 24.9% (Broad Institute) for known metabolites, and 41.8% for (Metabolon) unnamed compounds and 40.9% for (Broad Institute) unknown ion features. A total of 381 known metabolites were shared across platforms (median correlation 0.89). Many metabolites were negatively correlated with eGFR at &lt;0.05, including 35.7% (Metabolon) and 18.9% (Broad Institute) of known metabolites.</p>

<p><strong>CONCLUSIONS: </strong>Nontargeted metabolomics quantifies &gt;1000 analytes with low technical CVs, and agreement for overlapping metabolites across two leading platforms is excellent. Many metabolites demonstrate substantial intraperson variation and correlation with eGFR.</p>

10.2215/CJN.07070618

Clin J Am Soc Nephrol

30573658

Risk factors and inpatient outcomes associated with acute kidney injury at pediatric severe sepsis presentation.

2018

2018 Jun 14

1432-198X

<p><strong>BACKGROUND: </strong>Little data exist on acute kidney injury (AKI) risk factors in pediatric sepsis. We identified risk factors and inpatient outcomes associated with AKI at sepsis recognition in children with severe sepsis.</p>

<p><strong>METHODS: </strong>Retrospective, cross-sectional study with inpatient outcome description of 315 patients &gt; 1&nbsp;month to &lt; 20&nbsp;years old with severe sepsis in a pediatric intensive care unit over 3&nbsp;years. Exposures included demographics, vitals, and laboratory data. The primary outcome was kidney disease: Improving Global Outcomes creatinine-defined AKI within 24&nbsp;h of sepsis recognition. Factors associated with AKI and AKI severity were identified using multivariable Poisson and multinomial logistic regression, respectively.</p>

<p><strong>RESULTS: </strong>AKI was present in 42% (133/315) of severe sepsis patients, and 26% (83/315) had severe (stage 2/3) AKI. In multivariable-adjusted analysis, hematologic/immunologic comorbidities, malignancies, chronic kidney disease (CKD), abdominal infection, admission illness severity, and minimum systolic blood pressure (SBP) ≤ 5th percentile for age and sex within 24&nbsp;h of sepsis recognition were associated with AKI. Factors associated with mild AKI were CKD and abdominal infection, while factors associated with severe AKI were younger age, hematologic/immunologic comorbidities, malignancy, abdominal infection, and minimum SBP ≤ 5th percentile. Patients with AKI had increased hospital mortality (17 vs. 8%, P = 0.02) and length of stay [median 20 (IQR 10-47) vs. 16&nbsp;days (IQR 7-37), P = 0.03].</p>

<p><strong>CONCLUSIONS: </strong>In pediatric severe sepsis, AKI is associated with age, comorbidities, infection characteristics, and hypotension. Future evaluation of risk factors for AKI progression during sepsis is warranted to minimize AKI progression in this high-risk population.</p>

10.1007/s00467-018-3981-8

Pediatr. Nephrol.

29948309