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LO-006 Change in urinary biomarkers at three months predicts 1-year treatment response of lupus nephritis better than proteinuria
  1. Andrea Fava1,
  2. Jill Buyon2,
  3. Laurence Magder3,
  4. Jeffrey Hodgin4,
  5. Avi Rosenberg5,
  6. Dawit Demeke4,
  7. Deepak Rao6,
  8. Arnon Arazi7,
  9. Alessandra Ida Celia1,8,
  10. Chaim Putterman9,10,
  11. Jennifer Anolik11,
  12. Jennifer Barnas11,
  13. Maria Dall’Era12,
  14. David Wofsy12,
  15. Richard Furie7,
  16. Diane Kamen13,
  17. Kenneth Kalunian14,
  18. Judith A James15,
  19. Joel Guthridge15,
  20. Mohamed G Atta16,
  21. Jose Monroy-Trujillo16,
  22. Derek Fine16,
  23. Robert Clancy2,
  24. H Michael Belmont2,
  25. Peter Izmirly2,
  26. William Apruzzese6,
  27. Daniel Goldman1,
  28. Celine Berthier4,
  29. Paul Hoover17,
  30. Nir Hacohen17,
  31. Soumya Raychaudhuri6,17,18,
  32. Anne Davidson7,
  33. Betty Diamond7,
  34. The Accelerating Medicines Partnership in ra/sle19 and
  35. Michelle Petri1
  1. 1Division of Rheumatology, Johns Hopkins University, USA
  2. 2Rheumatology, New York University, USA
  3. 3Epidemiology and Public Health, University of Maryland, USA
  4. 4Renal Pathology, University of Michigan, USA
  5. 5Renal Pathology, Johns Hopkins University, USA
  6. 6Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Harvard Medical School, USA
  7. 7Center for Autoimmune and Musculoskeletal Diseases, Feinstein Institutes for Medical Research, USA
  8. 8Reumatologia, Università La Sapienza, Italy
  9. 9Rheumatology, Albert Einstein College of Medicine, USA
  10. 10Rheumatology, Azrieli Faculty of Medicine of Bar-Ilan University, Israel
  11. 11Rheumatology, University of Rochester, USA
  12. 12Rheumatology, University of California San Francisco, USA
  13. 13Rheumatology, Medical University of South Carolina, USA
  14. 14Rheumatology, University of California San Diego, San Diego, USA
  15. 15Rheumatology, Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences, USA
  16. 16Nephrology, Johns Hopkins University, USA
  17. 17Broad Institute, Broad Institute, USA
  18. 18Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, University of Manchester, UK
  19. 19Multiple Institutions, Multiple Institutions, USA


Background A decline of urine protein-to-creatinine ratio (UPCR) to < 0.5 is associated with better long-term preservation of kidney function in lupus nephritis (LN). UPCR < 0.5 defines complete response in guidelines and clinical trials when achieved after 1 or 2 years. Biomarkers of early response are needed to guide early treatment changes. We studied longitudinal urine proteomic profiles in LN to identify early predictors of proteinuric response.

Methods We quantified 1200 biomarkers (Kiloplex, RayBiotech) in urine samples collected on the day of (73%) or within 3 weeks (27%) of kidney biopsy and week 12, 24, or 52 in LN patients (ISN class III, IV, V, or mixed) with proteinuria > 1 g/d. Response was defined at one year from renal biopsy: Complete = UPCR < 0.5, serum creatinine (sCr) < 125% of baseline, prednisone ≤ 10mg/d; Partial = UPCR < 50% from baseline but >0.5, sCr < 125% of baseline, but prednisone allowed to 15 mg/d; Non responder = not meeting previous definitions.

Results A total of 127 patients were included: 48 (38%) with pure proliferative LN (class III or IV), 41 (32%) with mixed LN (III or IV +/- V), and 38% (30%) with pure membranous LN. Response was complete in 34 (27%), partial in 29 (23%), and none in 64 (50%). There were no urinary biomarkers at baseline that predicted response. We then analyzed the changes in urinary proteins at 3 months compared to baseline. Patients who responded at 1 year showed an early decline in 51 urinary proteins led by CD163, IL-16, and CD206 (macrophage mannose receptor) (figure 1A) which matched the proteomic signature associated with histological activity (figure 1B). No changes were observed in nonresponders. The decline of several urinary biomarkers at 3 months outperformed a decline in UPCR (clinical standard) in predicting the 1 year response. In particular, a decline of CD163 predicted 1 year response in ROC analysis with an area under the curve (AUC) of 83% compared to an AUC of 75% for UPCR decline. In proliferative LN, urinary biomarkers displayed superior performance with an AUC of 91%, 86%, and 78% for the decline of CD206, CD163, and UPCR, respectively (figure 1C-D). Pathway enrichment analysis identified leukocyte activation, neutrophil degranulation, and matrix degradation as the main pathways reduced at 3 months in responders.

Conclusions An early decline in urinary biomarkers of histological activity is associated with proteinuric response at 1 year. These findings indicate that effective immunosuppression induces by three months an immunological response in the kidney that can be noninvasively monitored in the urine. Biomarkers of immunological response outperformed early decline of UPCR, the standard of care, in predicting 1-year proteinuric response, especially in proliferative LN. Because biomarkers of immunological response parallel intrarenal activity, they could detect early treatment response/failure and allow early treatment changes. They could serve as surrogate endpoints in clinical trials. Longitudinal studies are needed to confirm that this immunological response is a better predictor of long-term kidney function preservation than proteinuric responses.

Abstract LO-006 Figure 1

(A) Volcano plot of the changes of the urinary proteomic profile of treatment responders at 3 months after kidney biopsy compared to time of biopsy. (B) Correlation of urinary biomarkers at time of biopsy the NIH Activity Index. (C) Area under the curve (AUC) of the 1yr response prediction of the change of a biomarker at 3 months. (D) ROC curves comparing the performance of 3-months biomarker decline. FDR, false discovery rate. q, adjusted p value, UPCR, urine protein-to-creatinine ratio

  • lupus nephritis
  • biomarkers
  • -omics

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