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Urine biomarkers of chronic kidney damage and renal functional decline in childhood-onset systemic lupus erythematosus

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Abstract

Objectives

To delineate urine biomarkers that reflect kidney structural damage and predict renal functional decline in pediatric lupus nephritis (LN).

Methods

In this prospective study, we evaluated kidney biopsies and urine samples of 89 patients with pediatric LN. Urinary levels of 10 biomarkers [adiponectin, ceruloplasmin, kidney injury molecule-1, monocyte chemotactic protein-1, neutrophil gelatinase-associated lipocalin, osteopontin, transforming growth factor-ß (TGFß), vitamin-D binding protein, liver fatty acid binding protein (LFABP), and transferrin] were measured. Regression analysis was used to identify individual and combinations of biomarkers that determine LN damage status [NIH-chronicity index (NIH-CI) score ≤ 1 vs. ≥ 2] both individually and in combination, and biomarker levels were compared for patients with vs. without renal functional decline, i.e., a 20% reduction of the glomerular filtration rate (GFR) within 12 months of a kidney biopsy.

Results

Adiponectin, LFABP, and osteopontin levels differed significantly with select histological damage features considered in the NIH-CI. The GFR was associated with NIH-CI scores [Pearson correlation coefficient (r) = − 0.49; p < 0.0001] but not proteinuria (r = 0.20; p > 0.05). Similar to the GFR [area under the ROC curve (AUC) = 0.72; p < 0.01], combinations of osteopontin and adiponectin levels showed moderate accuracy [AUC = 0.75; p = 0.003] in discriminating patients by LN damage status. Renal functional decline occurred more commonly with continuously higher levels of the biomarkers, especially of TGFß, transferrin, and LFABP.

Conclusion

In combination, urinary levels of adiponectin and osteopontin predict chronic LN damage with similar accuracy as the GFR. Ongoing LN activity as reflected by high levels of LN activity biomarkers heralds renal functional decline.

Key messages

• Levels of osteopontin and adiponectin measured at the time of kidney biopsy are good predictors of histological damage with lupus nephritis.

• Only about 20% of children with substantial kidney damage from lupus nephritis will have an abnormally low urine creatinine clearance.

• Continuously high levels of biomarkers reflecting lupus nephritis activity are risk factors of declining renal function.

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Acknowledgements

We are indebted to Ms. Kasha Wiley for data management and Lukasz Itert for development of the electronic data entry platform. We acknowledge sample management support by Dr. Fahad Abu-Azzah, Mr. Allen Watts, Ms. Jamie Meyers-Eaton, Ms. Monica Tsoras, and Ms. Mackenzie Gauck at the Cincinnati Children’s Hospital Medical Center. A special thanks to Prof. Susan Thompson for the support of the Rheumatology Research Core Center (1 P30 AR070549). We thank Christopher Haffner and Qing Ma for the measurement of various urine biomarkers.

Funding

This study is supported by grants from the NIH (U01 AR059509 to HB, P50 DK096418 to PD and HB, P30 AR070549-01 to Susan Thompson) and the Innovation Fund from CCHMC; the CCTST at the University of Cincinnati is funded by the National Institutes of Health (NIH) Clinical and Translational Science Award (CTSA) program, grant 5UL1TR001425-03. The CTSA program is led by the NIH’s National Center for Advancing Translational Sciences (NCATS). The content of this website is solely the responsibility of the CCTST and does not necessarily represent the official views of the NIH.

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Authors and Affiliations

  1. Division of Rheumatology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Avenue, MC 4010, Cincinnati, OH, 45229, USA

    Hermine I. Brunner, Jessica Turnier, Pinar Ozge Avar Aydin, Michael R. Bennett & Prasad Devarajan

  2. Division of Allergy and Rheumatology, Department of Medicine, University of Cincinnati, Cincinnati, USA

    Gaurav Gulati

  3. Department of Pediatrics, Division of Rheumatology, Ann and Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, USA

    Marisa S. Klein-Gitelman

  4. Division of Rheumatology, Emory University School of Medicine, Children’s Healthcare of Atlanta, Atlanta, GA, USA

    Kelly A. Rouster-Stevens

  5. Division of Rheumatology, Department of Pediatrics, British Columbia Children’s Hospital, Vancouver, Canada

    Lori Tucker

  6. Division of Rheumatology, Department of Internal Medicine, Ohio State University Wexner Medical Center, Columbus, USA

    Stacey P. Ardoin

  7. Division of Pediatric Rheumatology, Hospital for Special Surgery, Weill Cornell Medicine, New York, NY, USA

    Karen B. Onel

  8. Division of Nephrology and Hypertension, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Rylie Mainville, Michael R. Bennett & Prasad Devarajan

  9. Division of Pathology, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, USA

    David Witte

  10. Division of Biostatistics and Epidemiology, Department of Pediatrics, Cincinnati Children’s Hospital and Medical Center, University of Cincinnati, Cincinnati, OH, USA

    Bin Huang

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  1. Hermine I. Brunner
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  2. Gaurav Gulati
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  3. Marisa S. Klein-Gitelman
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  4. Kelly A. Rouster-Stevens
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  8. Rylie Mainville
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  9. Jessica Turnier
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  10. Pinar Ozge Avar Aydin
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  11. David Witte
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  12. Bin Huang
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  13. Michael R. Bennett
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  14. Prasad Devarajan
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Corresponding author

Correspondence to Hermine I. Brunner.

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The study complied with the Declaration of Helsinki and was approved by the institutional review boards of all of the participating institutions.

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The authors declare no conflict of interest.

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Written informed consent was obtained from the parents of the children at each institution.

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Brunner, H.I., Gulati, G., Klein-Gitelman, M.S. et al. Urine biomarkers of chronic kidney damage and renal functional decline in childhood-onset systemic lupus erythematosus. Pediatr Nephrol 34, 117–128 (2019). https://doi.org/10.1007/s00467-018-4049-5

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