Urine Biomarkers of Kidney Tubule Health, Injury, and Inflammation are Associated with Progression of CKD in Children.

2021

2021 Sep 20

1533-3450

<p><strong>BACKGROUND: </strong>Novel urine biomarkers may improve identification of children at greater risk of rapid kidney function decline, and elucidate the pathophysiology of CKD progression.</p>

<p><strong>METHODS: </strong>We investigated the relationship between urine biomarkers of kidney tubular health (EGF and -1 microglobulin), tubular injury (kidney injury molecule-1; KIM-1), and inflammation (monocyte chemoattractant protein-1 [MCP-1] and YKL-40) and CKD progression. The prospective CKD in Children Study enrolled children aged 6 months to 16 years with an eGFR of 30-90ml/min per 1.73m. Urine biomarkers were assayed a median of 5 months [IQR: 4-7] after study enrollment. We indexed the biomarker to urine creatinine by dividing the urine biomarker concentration by the urine creatinine concentration to account for the concentration of the urine. The primary outcome was CKD progression (a composite of a 50% decline in eGFR or kidney failure) during the follow-up period.</p>

<p><strong>RESULTS: </strong>Overall, 252 of 665 children (38%) reached the composite outcome over a median follow-up of 6.5 years. After adjustment for covariates, children with urine EGF concentrations in the lowest quartile were at a seven-fold higher risk of CKD progression versus those with concentrations in the highest quartile (fully adjusted hazard ratio [aHR], 7.1; 95% confidence interval [95% CI], 3.9 to 20.0). Children with urine KIM-1, MCP-1, and -1 microglobulin concentrations in the highest quartile were also at significantly higher risk of CKD progression versus those with biomarker concentrations in the lowest quartile. Addition of the five biomarkers to a clinical model increased the discrimination and reclassification for CKD progression.</p>

<p><strong>CONCLUSIONS: </strong>After multivariable adjustment, a lower urine EGF concentration and higher urine KIM-1, MCP-1, and -1 microglobulin concentrations were each associated with CKD progression in children.</p>

10.1681/ASN.2021010094

J Am Soc Nephrol

34544821

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

Kidney Outcomes and Hypertension in Survivors of Wilms Tumor: A Prospective Cohort Study.

2020

2020 Dec 05

1097-6833

<p>Supported by a Pilot Grant from the Children's Hospital of Philadelphia Center for Pediatric Clinical Effectiveness (to D.C.). D.C. is also supported by the NIH/NIDDK (K23 DK125670). G.T. was supported by the NIH/NIDDK (K23 DK106428). Ja.G. was supported by NIH/NIDDK (K08 DK110536). M.D. was supported by the NIH/NIDDK (K23 DK093556). The NIH and NIDDK had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. The views expressed in this article are those of the authors and do not necessarily represent the official view of the NIDDK nor NIH. G.T. serves on the scientific advisory boards for Allena Pharmaceuticals, Novome Biotechnology, and Dicerna Pharmaceuticals and serves as a consultant for Alnylam Pharmaceuticals, all of which are unrelated to this work. M.D. receives research funding from Mallinckrodt unrelated to this work. The other authors declare no conflicts of interest. Portions of this study were presented at the Pediatric Academic Society annual meeting, May 5-8, 2020, Toronto, Canada.</p>

<p><strong>OBJECTIVE: </strong>To assess the prevalence of therapy-related kidney outcomes in survivors of Wilms tumor (WT).</p>

<p><strong>STUDY DESIGN: </strong>This prospective cohort study included survivors of WT who were ≥5 years old and ≥1 year from completing therapy, excluding those with pre-existing hypertension, prior dialysis or kidney transplant. Participants completed 24-hour ambulatory blood pressure monitoring (ABPM). Abnormal blood pressure (BP) was defined as ≥90 percentile. Masked hypertension was defined as having normal office BP and abnormal ABPM findings. Urine was analyzed for KIM-1, IL-18, EGF, albumin, and creatinine. Estimated glomerular filtration rate (eGFR) was calculated using the bedside CKiD equation. Recent kidney ultrasounds and echocardiograms were reviewed for contralateral kidney size and left ventricular hypertrophy (LVH), respectively. Clinical follow-up data was collected for approximately 2 years following study enrollment.</p>

<p><strong>RESULTS: </strong>Thirty-two participants (median age 13.6 [IQR: 10.5-16.3] years; 75% ≥Stage 3 WT) were evaluated at a median of 8.7 years (IQR: 6.5-10.8) post-therapy; 29 participants underwent unilateral radical nephrectomy, two bilateral partial nephrectomy, and one radical and contralateral partial nephrectomy. 72% received kidney radiotherapy and 75% received doxorubicin. Recent median eGFR was 95.6 ml/min/1.73m (IQR: 84.6-114.0; 11 (34%) had an eGFR &lt;90). Abnormal ABPM results were found in 22/29 participants (76%), masked hypertension in 10/29 (34%), and microalbuminuria in 2/32 (6%). 22/32 (69%) participants had abnormal EGF; few had abnormal KIM-1 or IL-18. Seven participants with previous unilateral nephrectomy lacked compensatory contralateral kidney hypertrophy. None had LVH.</p>

<p><strong>CONCLUSION: </strong>In survivors of WT, adverse kidney outcomes were common and should be closely monitored.</p>

10.1016/j.jpeds.2020.12.005

J Pediatr

33290810