Abstract
Introduction: Childhood-onset nephrotic syndrome has a variable clinical course. Improved predictive markers of long-term outcomes in children with nephrotic syndrome are needed. This study tests the association between baseline urinary epidermal growth factor (uEGF) excretion and longitudinal kidney function in children with nephrotic syndrome. Methods: The study evaluated 191 participants younger than 18 years enrolled in the Nephrotic Syndrome Study Network, including 118 with their first clinically indicated kidney biopsy (68 minimal change disease; 50 focal segmental glomerulosclerosis) and 73 with incident nephrotic syndrome without a biopsy. uEGF was measured at baseline for all participants and normalized by the urine creatinine (Cr) concentration. Renal epidermal growth factor (EGF) mRNA was measured in the tubular compartment microdissected from kidney biopsy cores from a subset of patients. Linear mixed models were used to test if baseline uEGF/Cr and EGF mRNA expression were associated with change in estimated glomerular filtration rate (eGFR) over time. Results: Higher uEGF/Cr at baseline was associated with slower eGFR decline during follow-up (median follow-up = 30 months). Halving of uEGF/Cr was associated with a decrease in eGFR slope of 2.0 ml/min per 1.73 m2 per year (P < 0.001) adjusted for age, race, diagnosis, baseline eGFR and proteinuria, and APOL1 genotype. In the biopsied subgroup, uEGF/Cr was correlated with EGF mRNA expression (r = 0.74; P < 0.001), but uEGF/Cr was retained over mRNA expression as the stronger predictor of eGFR slope after multivariable adjustment (decrease in eGFR slope of 1.7 ml/min per 1.73 m2 per year per log2 decrease in uEGF/Cr; P < 0.001). Conclusion: uEGF/Cr may be a useful noninvasive biomarker that can assist in predicting the long-term course of kidney function in children with incident nephrotic syndrome.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 414-425 |
| Number of pages | 12 |
| Journal | Kidney International Reports |
| Volume | 5 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 2020 |
Keywords
- disease progression
- epidermal growth factor
- focal segmental glomerulosclerosis
- nephrotic syndrome
- pediatrics
ASJC Scopus subject areas
- Nephrology
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Urinary Epidermal Growth Factor as a Marker of Disease Progression in Children With Nephrotic Syndrome. / Gipson, Debbie S.; Trachtman, Howard; Waldo, Anne et al.
In: Kidney International Reports, Vol. 5, No. 4, 04.2020, p. 414-425.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Urinary Epidermal Growth Factor as a Marker of Disease Progression in Children With Nephrotic Syndrome
AU - Gipson, Debbie S.
AU - Trachtman, Howard
AU - Waldo, Anne
AU - Gibson, Keisha L.
AU - Eddy, Sean
AU - Dell, Katherine M.
AU - Srivastava, Tarak
AU - Lemley, Kevin V.
AU - Greenbaum, Larry A.
AU - Hingorani, Sangeeta
AU - Meyers, Kevin E.
AU - Kaskel, Frederick J.
AU - Reidy, Kimberly J.
AU - Sethna, Christine B.
AU - Tran, Cheryl L.
AU - Wang, Chia shi
AU - Tuttle, Katherine R.
AU - Oh, Gia
AU - Neu, Alicia M.
AU - Brown, Elizabeth
AU - Lin, Jen Jar
AU - Yee, Jennifer Lai
AU - Roth, Therese M.
AU - Troost, Jonathan P.
AU - Gillespie, Brenda W.
AU - Sampson, Matthew G.
AU - Kretzler, Matthias
AU - Ju, Wenjun
N1 - Funding Information: NEPTUNE, U54-DK-083912, is a part of the National Institutes of Health (NIH) Rare Disease Clinical Research Network, supported through a collaboration between the Office of Rare Diseases Research , National Center for Advancing Translational Sciences , and the National Institute of Diabetes, Digestive, and Kidney Diseases . Additional funding and/or programmatic support for this project has also been provided by NIH funding to the Applied Systems Biology Core at the University of Michigan George M. O’Brien Kidney Translational Core Center (P30 DK081943), the University of Michigan, the NephCure Kidney International and the Halpin Foundation. Funding Information: JPT and DSG have research funding through the University of Michigan with Complexa Inc., Retrophin Inc., and Goldfinch Bio (DSG additionally has funding through the University of Michigan with Bristol-Meyers Squibb; JPT additional has fundingthrough the University of Michigan with Vertex Phamaceuticals and Pfizer Inc.). SE has research funding through the University of Michigan with AstraZeneca PLC, Eli Lilly and Company, Novo Nordisk A/S, Gilead Sciences, Inc., and Moderna, Inc., and owns shares of Gilead Sciences, Inc., Johnson & Johnson, ThermoFisher Scientific, Inc, and AbbVie, Inc. TS has received research support from Bristol-Myers Squibb, Mallinckrodt Pharmaceuticals, Goldfinch, and Retrophin, Inc. HT is a consultant to Otsuka (Chair, DMC) and Chemocentryx (DMC) and a consultant to Goldfinch and Retrophin (in contract through New York University). KJR is a site principal investigator for a Complexa study and Advicienne study unrelated to these data. MK receives research support through the University of Michigan with AstraZeneca PLC, Eli Lilly and Company, Novo Nordisk A/S, Gilead Sciences, Inc., Jansen, Angion, Certa, and Moderna, Inc. WJ and MK have a patent pending on biomarkers for chronic kidney disease (CKD) progression (encompassing urinary epidermal growth factor as a biomarker of CKD progression). All other disclosures are unrelated to these data. All the other authors declared no competing interests. Funding Information: We are indebted to the patients and families who generously participated in this research study. We also thank Michael P. Rose at the University of Michigan Department of Internal Medicine for his help with the visual abstract, and all members of the Nephrotic Syndrome Study Network Consortium (NEPTUNE) consortium listed as follows. Cleveland Clinic, Cleveland, Ohio, USA: J. Sedor, principal investigator; K. Dell, principal investigator; M. Schachere, study coordinator; and J. Negrey, study coordinator; Children's Hospital, Los Angeles, California, USA: K. Lemley, principal investigator; and E. Lim, study coordinator; Children's Mercy Hospital, Kansas City, Missouri, USA: T. Srivastava, principal investigator; and A. Garrett, study coordinator; Cohen Children's Hospital, New Hyde Park, New York, USA: C. Sethna, principal investigator; and K. Laurent, study coordinator; Columbia University, New York, New York, USA: G. Appel, principal investigator; and M. Toledo, study coordinator; Duke University, Durham, North Carolina, USA: L. Barisoni, principal investigator; Emory University, Atlanta, Georgia, USA: L. Greenbaum, principal investigator; C. Wang, co-investigator; and C. Kang, study coordinator; Harbor-University of California Los Angeles Medical Center, Torrance, California, USA: S. Adler, principal investigator; and J. LaPage, study coordinator; John H. Stroger Jr. Hospital of Cook County, Chicago, Illinois, USA: A. Athavale, principal investigator; and M. Itteera; Johns Hopkins Medicine, Baltimore, Maryland, USA: A. Neu, principal investigator; and S. Boynton, study coordinator; Mayo Clinic, Rochester, Minnesota, USA: F. Fervenza, principal investigator; M. Hogan, co-investigator; J. Lieske, principal investigator; and V. Chernitskiy, study coordinator; Montefiore Medical Center, Bronx, New York, USA: F. Kaskel, principal investigator; N. Kumar, principal investigator; and P. Flynn, study coordinator; National Institute of Diabetes and Digestive and Kidney Diseases Intramural, Bethesda, Maryland, USA: J. Kopp, principal investigator; and J. Blake, study coordinator; New York University Medical Center, New York, New York, USA: H. Trachtman, principal investigator; O. Zhdanova, co-investigator; F. Modersitzki, study coordinator; and S. Vento, study coordinator; Stanford University, Stanford, California, USA: R. Lafayette, principal investigator; and K. Mehta, study coordinator; Temple University, Philadelphia, Pennsylvania, USA: C. Gadegbeku, principal investigator; D. Johnstone, co-investigator; and S. Quinn-Boyle, study coordinator; University Health Network, Toronto, Ontario, Canada: D. Cattran, principal investigator; M.Hladunewich, co-investigator; H. Reich, co-investigator; P. Ling, study coordinator; and M. Romano, study coordinator; University of Miami, Miami, Florida, USA: A. Fornoni, principal investigator; and C. Bidot, study coordinator; University of Michigan, Ann Arbor, Michigan, USA: M. Kretzler, principal investigator; D. Gipson, principal investigator; A. Williams, study coordinator; and J. LaVigne, study coordinator; University of North Carolina, Chapel Hill, North Carolina, USA: V. Derebail, principal investigator; K. Gibson, principal investigator; A. Froment, study coordinator; and S. Grubbs, study coordinator; University of Pennsylvania, Philadelphia, Pennsylvania, USA: L. Holzman, principal investigator; K. Meyers, co-investigator; K. Kallem, study coordinator; and J. Lalli, study coordinator; University of Texas Southwestern, Dallas, Texas, USA: K. Sambandam, principal investigator; Z. Wang, study coordinator; and M. Rogers, study coordinator; University of Washington, Seattle, Washington, USA: A. Jefferson, principal investigator; S. Hingorani, co-investigator; K. Tuttle, co-investigator (also affiliated with University of Washington sub-site Providence Medical Research Center, Spokane, Washington, USA); M. Bray, study coordinator; M. Kelton, study coordinator; and A. Cooper, study coordinator, (also affiliated with University of Washington sub-site Providence Medical Research Center, Spokane, Washington, USA); Wake Forest University Baptist Health, Winston-Salem, North Carolina, USA: B. Freedman, principal investigator; and J.J. Lin, co-investigator. M. Kretzler, L. Barisoni, C. Gadegbeku, B. Gillespie, D. Gipson, L. Holzman, L. Mariani, M. Sampson, J. Troost, J. Zee, E. Herreshoff, S. Li, C. Lienczewski, J. Liu, T. Mainieri, M. Wladkowski, and A. Williams. Carmen Avila-Casado (UHN-Toronto), Serena Bagnasco (Johns Hopkins), Joseph Gaut (Washington University), Stephen Hewitt (National Cancer Institute), Jeff Hodgin (University of Michigan), Kevin Lemley (Children's Hospital LA), Laura Mariani (University of Michigan), Matthew Palmer (University of Pennsylvania), Avi Rosenberg (National Institute of Diabetes and Digestive and Kidney Diseases), Virginie Royal (Montreal), David Thomas (University of Miami), and Jarcy Zee (Arbor Research); Co-Chairs: Laura Barisoni (Duke University) and Cynthia Nast (Cedar Sinai). NEPTUNE, U54-DK-083912, is a part of the National Institutes of Health (NIH) Rare Disease Clinical Research Network, supported through a collaboration between the Office of Rare Diseases Research, National Center for Advancing Translational Sciences, and the National Institute of Diabetes, Digestive, and Kidney Diseases. Additional funding and/or programmatic support for this project has also been provided by NIH funding to the Applied Systems Biology Core at the University of Michigan George M. O'Brien Kidney Translational Core Center (P30 DK081943), the University of Michigan, the NephCure Kidney International and the Halpin Foundation. DSG, HT, KLG, KMD, TS, KVL, LAG, SH, KEM, FJK, KJR, CBS, CLT, C-sW, KRT, GO, AMN, EB, J-JL, and MK contributed substantially to the design and conduct of the study and enrollment of participants. SE, JLY, TMR, and MGS completed key laboratory measurements. DSG, HT, MK, and WJ conceived the overall research questions and approach for these analyses. All authors provided additional advice on content. AW and JPT led the statistical analyses. All authors contributed to drafting the manuscript and interpreting results. Publisher Copyright: © 2019 International Society of Nephrology
PY - 2020/4
Y1 - 2020/4
N2 - Introduction: Childhood-onset nephrotic syndrome has a variable clinical course. Improved predictive markers of long-term outcomes in children with nephrotic syndrome are needed. This study tests the association between baseline urinary epidermal growth factor (uEGF) excretion and longitudinal kidney function in children with nephrotic syndrome. Methods: The study evaluated 191 participants younger than 18 years enrolled in the Nephrotic Syndrome Study Network, including 118 with their first clinically indicated kidney biopsy (68 minimal change disease; 50 focal segmental glomerulosclerosis) and 73 with incident nephrotic syndrome without a biopsy. uEGF was measured at baseline for all participants and normalized by the urine creatinine (Cr) concentration. Renal epidermal growth factor (EGF) mRNA was measured in the tubular compartment microdissected from kidney biopsy cores from a subset of patients. Linear mixed models were used to test if baseline uEGF/Cr and EGF mRNA expression were associated with change in estimated glomerular filtration rate (eGFR) over time. Results: Higher uEGF/Cr at baseline was associated with slower eGFR decline during follow-up (median follow-up = 30 months). Halving of uEGF/Cr was associated with a decrease in eGFR slope of 2.0 ml/min per 1.73 m2 per year (P < 0.001) adjusted for age, race, diagnosis, baseline eGFR and proteinuria, and APOL1 genotype. In the biopsied subgroup, uEGF/Cr was correlated with EGF mRNA expression (r = 0.74; P < 0.001), but uEGF/Cr was retained over mRNA expression as the stronger predictor of eGFR slope after multivariable adjustment (decrease in eGFR slope of 1.7 ml/min per 1.73 m2 per year per log2 decrease in uEGF/Cr; P < 0.001). Conclusion: uEGF/Cr may be a useful noninvasive biomarker that can assist in predicting the long-term course of kidney function in children with incident nephrotic syndrome.
AB - Introduction: Childhood-onset nephrotic syndrome has a variable clinical course. Improved predictive markers of long-term outcomes in children with nephrotic syndrome are needed. This study tests the association between baseline urinary epidermal growth factor (uEGF) excretion and longitudinal kidney function in children with nephrotic syndrome. Methods: The study evaluated 191 participants younger than 18 years enrolled in the Nephrotic Syndrome Study Network, including 118 with their first clinically indicated kidney biopsy (68 minimal change disease; 50 focal segmental glomerulosclerosis) and 73 with incident nephrotic syndrome without a biopsy. uEGF was measured at baseline for all participants and normalized by the urine creatinine (Cr) concentration. Renal epidermal growth factor (EGF) mRNA was measured in the tubular compartment microdissected from kidney biopsy cores from a subset of patients. Linear mixed models were used to test if baseline uEGF/Cr and EGF mRNA expression were associated with change in estimated glomerular filtration rate (eGFR) over time. Results: Higher uEGF/Cr at baseline was associated with slower eGFR decline during follow-up (median follow-up = 30 months). Halving of uEGF/Cr was associated with a decrease in eGFR slope of 2.0 ml/min per 1.73 m2 per year (P < 0.001) adjusted for age, race, diagnosis, baseline eGFR and proteinuria, and APOL1 genotype. In the biopsied subgroup, uEGF/Cr was correlated with EGF mRNA expression (r = 0.74; P < 0.001), but uEGF/Cr was retained over mRNA expression as the stronger predictor of eGFR slope after multivariable adjustment (decrease in eGFR slope of 1.7 ml/min per 1.73 m2 per year per log2 decrease in uEGF/Cr; P < 0.001). Conclusion: uEGF/Cr may be a useful noninvasive biomarker that can assist in predicting the long-term course of kidney function in children with incident nephrotic syndrome.
KW - disease progression
KW - epidermal growth factor
KW - focal segmental glomerulosclerosis
KW - nephrotic syndrome
KW - pediatrics
UR - http://www.scopus.com/inward/record.url?scp=85078002747&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85078002747&partnerID=8YFLogxK
U2 - 10.1016/j.ekir.2019.11.018
DO - 10.1016/j.ekir.2019.11.018
M3 - Article
AN - SCOPUS:85078002747
SN - 2468-0249
VL - 5
SP - 414
EP - 425
JO - Kidney International Reports
JF - Kidney International Reports
IS - 4
ER -