Urinary Peptides as Potential Non-Invasive Biomarkers for Lupus Nephritis: Results of the Peptidu-LUP Study
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patients’ Characteristics
2.2. Kidney Biopsy Pathological Analysis
2.3. Sample Preparation
2.4. CE-MS Analysis and Data Processing
2.5. Biomarker Selection and Modelling
3. Results
3.1. Patients’ Characteristics
3.2. Absence of Urinary Peptides Predicting Proliferative LN
3.3. The Urinary Peptidome Does Not Predict Glomerulosclerosis
3.4. CKD273 Is Correlated to Tubulo-Interstitial Chronicity
3.5. LN 172 Is a Sensible Predictor for LN
3.6. The Urinary Peptidome Does Not Predict Early Remission
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Appendix A
Discovery Cohort | Validation Cohort | p | |
---|---|---|---|
Patients, n | 42 | 51 | |
Women—n (%) | 40 (95.2) | 46 (90.2) | 0.45 |
Mean age ± SD | 34 ± 7.7 | 36 ± 10 | 0.37 |
Ethnicity—n (%) | 0.66 | ||
European | 16 (38.1) | 24 (47.1) | 0.38 |
North African | 10 (23.8) | 13 (25.5) | 1 |
African | 11 (26.2) | 11 (21.6) | 0.78 |
Asian | 5 (11.9) | 3 (5.9) | 0.46 |
Characteristics at kidney biopsy | |||
Serum creatinine—μmol/L, mean ± SD | 99.4 ± 55 | 86.8 ± 32 | 0.82 |
eGFR—mL/min/1.73 m2, mean ± SD | 90.4 ± 32 | 92.3 ± 28.6 | 0.81 |
UPCR—g/g, mean ± SD | 2.12 ± 1.25 | 2.53 ± 1.7 | 0.74 |
SLE vintage | |||
First flare of SLE—n (%) | 10 (23.8) | 11 (21.6) | 0.99 |
Pre-existing SLE—n% | 32 (76.2) | 40 (78.4) | 0.99 |
Disease duration—years, mean ± SD | 9.8 ± 7 | 11.33 ± 9.6 | 0.78 |
First renal flare—n (%) | 22 (52.4) | 33 (64.7) | 0.32 |
LN duration—years, mean ± SD | 6.6 ± 5 | 10.5 ± 8.2 | 0.22 |
Kidney biopsies, n | |||
Class, n (%) | 0.15 | ||
I | 0 (0) | 1 (2.0) | 1 |
II | 4 (9.5) | 2 (3.9) | 0.40 |
III-A or -A/C ± V | 12 (28.6) | 10 (19.6) | 0.59 |
III-C ± V | 2 (4.8) | 3 (5.9) | 1 |
IV-A or -A/C ±V | 10 (23.8) | 23 (45.1) | 0.06 |
IV-C ± V | 1 (2.4) | 1 (2.0) | 0.45 |
Pure V | 12 (28.6) | 9 (17.6) | 0.32 |
VI | 1 (2.4) | 2 (3.9) | 1 |
IF/TA, n—(%) | 0.70 | ||
F0 | 20 (44.6) | 21 (41.2) | 0.68 |
F1 | 14 (33.3) | 19 (37.3) | 0.86 |
F2 | 4 (9.5) | 8 (15.7) | 0.54 |
F3 | 4 (9.5) | 3 (5.9) | 0.7 |
Group | |||
Active LN | 22(52.4) | 33 (64.7) | 0.36 |
Non-active LN | 20 (47.6) | 18 (35.3) | 0.36 |
Patients/center—n (%) | |||
Marseille | 7 (16.7) | 30 (58.8) | <0.001 |
Paris | 35 (83.3) | 18 (35.3) | <0.001 |
Toulouse | 0 (0) | 3 (5.9) | 0.25 |
Previous treatment for SLE—% | |||
Hydroxychloroquine | 78.6 | 82.4 | 0.84 |
Corticosteroids | 80.1 | 74.5 | 0.62 |
MMF/Mycophenolic acid | 30.9 | 21.6 | 0.31 |
Azathioprine | 16.7 | 21.6 | 0.74 |
Cyclophosphamide | 35.7 | 31.4 | 0.82 |
Rituximab | 4.8 | 11.8 | 0.29 |
Other | 14.3 | 13.7 | 1 |
Treatment for SLE at inclusion—% | |||
Hydroxychloroquine | 66.7 | 70.6 | 0.86 |
Corticosteroids | 76.2 | 66.7 | 0.44 |
MMF/Mycophenolic acid | 21.4 | 13.7 | 0.48 |
Azathioprine | 14.3 | 5.9 | 0.29 |
Cyclophosphamide | 2.4 | 0 | 0.45 |
Rituximab | 0 | 2 | 1 |
Methotrexate | 2.4 | 2 | 1 |
LN172+ | LN172− | p | |
---|---|---|---|
Patients, n (%) | 86 (92.5) | 7 (7.5) | |
Women—n (%) | 80 (93) | 6 (85.7) | 0.43 |
Mean age ± SD | 35 ± 11 | 36 ± 10 | 0.80 |
Ethnicity—n (%) | 0.07 | ||
European | 35 (40.7) | 5 (71.4) | 0.13 |
North African | 22 (25.6) | 1 (14.3) | 0.67 |
African | 21 (24.4) | 1 (14.3) | 1 |
Asian | 8 (9.3) | 0 (0) | 1 |
Characteristics of kidney biopsy | |||
Serum creatinine—μmol/L, mean ± SD | 80 ± 61 | 184.6 ± 114 | 0.003 |
eGFR—mL/min/1.73 m2, mean ± SD | 94.9 ± 38 | 46.2 ± 29 | 0.001 |
UPCR—g/g, mean ± SD | 2.29 ± 2.03 | 2.95 ± 2.48 | 0.79 |
CKD—n (%) | 6 (7.0) | 3 (42.9) | 0.01 |
Complement consumption (%) | 71.4 | 66.7 | 1 |
Anti-DNA antibodies (%) | 86.3 | 85.7 | 1 |
CKD273 score | 0.56 ± 0.35 | 0.86 ± 0.13 | 0.02 |
SLE vintage | |||
First flare of SLE—n (%) | 20 (23.3) | 1 (14.3) | 1 |
Pre-existing SLE—n% | 66 (76.7) | 6 (85.7) | 1 |
Disease duration—years, mean ± SD | 10.5 ± 8.6 | 11.7 ± 7.5 | 0.56 |
First renal flare—n (%) | 53 (61.6) | 2 (28.6) | 0.11 |
LN duration—years, mean ± SD | 8.0 ± 6.9 | 9.8 ± 7.8 | 0.58 |
Kidney biopsies, n | |||
Class, n (%) | 0.37 | ||
I | 1 (1.2) | 0 (0) | 1 |
II | 6 (7.0) | 0 (0) | 1 |
III-A or -A/C ± V | 19 (22.1) | 3 (42.9) | 0.36 |
III-C ± V | 5 (5.8) | 0 (0) | 1 |
IV-A or -A/C ±V | 30 (34.9) | 3 (42.9) | 0.70 |
IV-C ± V | 2 (1.2) | 0 (0) | 1 |
V | 21 (24.4) | 0 (0) | 0.34 |
VI | 2 (2.3) | 1 (1.2) | 0.21 |
IF/TA, n—(%) | 0.16 | ||
F0 | 40 (46.5) | 1 (14.3) | 0.13 |
F1 | 30 (34.9) | 3 (42.9) | 0.70 |
F2 | 10 (11.6) | 2 (28.6) | 0.22 |
F3 | 6 (7.0) | 1 (14.3) | 0.43 |
Group | |||
Active LN | 49 (57.0) | 6 (85.7) | 0.23 |
Non-active LN | 37 (43.0) | 1 (14.3) | 0.23 |
Patients/center—n (%) | 0.18 | ||
Marseille | 50 (58.1) | 3 (42.9) | 0.46 |
Paris | 34 (39.5) | 3 (42.9) | 1 |
Toulouse | 2 (2.3) | 1 (14.3) | 0.21 |
Previous treatment for SLE—% | |||
Hydroxychloroquine | 81.2 | 100 | 0.59 |
Corticosteroids | 78.8 | 83.3 | 1 |
MMF/Mycophenolic acid | 23.8 | 66.7 | 0.04 |
Azathioprine | 17.9 | 50 | 0.09 |
Cyclophosphamide | 32.1 | 66.7 | 0.18 |
Rituximab | 7.1 | 33.3 | 0.09 |
Other | 11.8 | 50 | 0.04 |
Treatment for SLE at inclusion—% | |||
Hydroxychloroquine | 69.4 | 83.3 | 0.67 |
Corticosteroids | 71.8 | 83.3 | 1 |
MMF/Mycophenolic acid | 16.7 | 33.3 | 0.29 |
Azathioprine | 9.5 | 16.7 | 0.48 |
Cyclophosphamide | 0 | 16.7 | 0.07 |
Rituximab | 1.2 | 0 | 1 |
Methotrexate | 2.4 | 0 | 1 |
Relapse of LN | |||
Total—n (%) | 19 (22.1) | 0 (0) | 0.33 |
Renal function at last follow-up | |||
Serum creatinine—μmol/L, mean ± SD | 70.7 ± 32.7 | 128.7 ± 109.8 | 0.064 |
eGFR—mL/min/1.73 m2, mean ± SD | 104.8 ± 29.9 | 67.5 ± 32 | 0.004 |
UPCR—g/g, mean ± SD | 0.42 ± 0.55 | 0.68 ± 1.52 | 0.17 |
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Characteristics | |
---|---|
Patients, n | 93 |
Women—n (%) | 86 (92.4) |
Age—years | 35 ± 11 |
Range—years | 19–58 |
Ethnicity—n (%) | |
European | 40 (43) |
North African | 23 (24.7) |
African | 23 (23.7) |
Asian | 8 (8.6) |
Characteristics at kidney biopsy | |
Serum creatinine—μmol/L | 92.1 ± 68.5 |
eGFR—mL/min/1.73 m2 | 91.4 ± 39.2 |
UPCR—g/g | 2.34 ± 2.23 |
SLE vintage | |
First flare of SLE—n (%) | 21 (22.6) |
Pre-existing SLE—n% | 72 (77.4) |
Disease duration—years | 10.6 ± 8.5 |
First renal flare—n (%) | 55 (59.1) |
LN duration—years | 8.2 ± 6.9 |
Kidney biopsies—n (%) | 93 |
Class ISN/RPS 2003 | |
I | 1 (1.1) |
II | 6 (6.5) |
III-A or -A/C ± V | 22 (23.7) |
III-C ±V | 5 (5.4) |
IV-A or -A/C ± V | 33 (35.5) |
IV-C ±V | 2 (2.2) |
Pure V | 21 (22.6) |
VI | 3 (3.2) |
Group | |
Active LN | 55 (59.1) |
Non-active LN | 38 (40.9) |
IF/TA | |
F0 | 41 (44.1) |
F1 | 33 (35.5) |
F2 | 12 (12.9) |
F3 | 7 (7.5) |
Previous treatment for SLE (%) | |
Hydroxychloroquine | 80.6 |
Corticosteroids | 77.4 |
MMF/Mycophenolic acid | 25.8 |
Azathioprine | 19.4 |
Cyclophosphamide | 33.3 |
Rituximab | 8.6 |
Other | 14 |
Treatment for SLE at inclusion (%) | |
Hydroxychloroquine | 68.8 |
Corticosteroids | 70.1 |
MMF/Mycophenolic acid | 17.2 |
Azathioprine | 9.7 |
Cyclophosphamide | 1.1 |
Rituximab | 1.1 |
Other | 2.2 |
Patients/center—n (%) | |
Marseille | 37 (39.8) |
Paris | 53 (57) |
Toulouse | 3 (3.2) |
Discovery Cohort | Validation Cohort | p | |
---|---|---|---|
Follow-up—months, median [IQR] | 63.5 (51–69) | 32 (24–39) | <0.001 |
Renal function at M24 | |||
Serum creatinine—μmol/L, mean ± SD | 64.8 ± 12.5 | 75.3 ± 19.9 | 0.12 |
eGFR—mL/min/1.73 m2, mean ± SD | 109 ± 22.1 | 96.6 ± 23.8 | 0.12 |
UPCR—g/g, mean ± SD | 0.55 ± 0.57 | 0.42 ± 0.36 | 0.73 |
Renal function at last follow-up | |||
Serum creatinine—μmol/L, mean ± SD | 73.5 ± 23.1 | 76.2 ± 20.8 | 0.31 |
eGFR—mL/min/1.73 m2, mean ± SD | 106.8 ± 26 | 96.1 ± 19.6 | 0.22 |
UPCR—g/g, mean ± SD | 0.56 ± 0.55 | 0.37 ± 0.35 | 0.44 |
Relapse of LN | |||
Total—n (%) | 11 (26.2) | 8 (15.7) | 0.21 |
Early relapse <M24—n (%) | 5 (11.9) | 8 (15.7) | 1 |
Time until relapse—months, mean ± SD | 29.3 ± 19.6 | 12.3 ± 3.6 | 0.016 |
CKD (eGFR < 60 mL/min/1.73 m2) | |||
Total, n (%) | 6 (14.3) | 6 (11.8) | 0.56 |
New onset CKD at last follow-up | 2 (4.8) | 1 (2) | 0.58 |
New onset CKD at M24 | 0 | 0 | NS |
Time until CKD—months, mean ± SD | 27.5 ± 1.5 | 35 | NS |
ESKD | |||
At M24—n (%) | 2 (4.8) | 0 | NS |
At the end of follow up—n (%) | 3 (7.1) | 2 (3.9) | NS |
Time until ESKD—months, mean± SD | 17.3 ± 8.4 | 23 ± 11 | 0.55 |
Death—n (%) | 3 (7) | 1 (2) | |
Time until death—months mean± SD | 26.3 ± 13.1 | 39 | NS |
Active LN | Non-Active LN | p | Sensitivity | Specificity | PPV | NPV | |
---|---|---|---|---|---|---|---|
Peptidomic | No profile | NA | NA | NA | NA | ||
Complement consumption (%) | 84 | 46.1 | 0.001 | 0.84 | 0.54 | 0.78 | 0.64 |
Anti-DNA antibodies (%) | 95.8 | 71.9 | 0.007 | 0.96 | 0.28 | 0.67 | 0.82 |
Hematuria (%) | 53.1 | 40.0 | 0.37 | 0.53 | 0.60 | 0.68 | 0.44 |
Pyuria (%) | 64.3 | 33.3 | 0.03 | 0.64 | 0.67 | 0.77 | 0.52 |
Mean eGFR (mL/min/1.73 m2) | 82.7 ± 31 | 104.4 ± 47 | 0.01 | NA | NA | NA | NA |
Mean UPCR (g/g) | 2.63 ± 2.3 | 1.97 ± 1.7 | 0.09 | NA | NA | NA | NA |
Mean serum creatinine (μmol/L) | 96.7 ± 71 | 87.1 ± 71 | 0.01 | NA | NA | NA | NA |
Parameter | r | p |
---|---|---|
Peptidomic | No profile | |
CKD273 | 0.314 | 0.0015 |
SLE duration | 0.408 | <0.0001 |
LN duration | 0.450 | <0.0001 |
Age | 0.231 | 0.026 |
Serum creatinine | 0.274 | 0.008 |
eGFR (MDRD) | −0.290 | 0.005 |
UPCR | 0.164 | 0.121 |
Hematuria | −0.031 | 0.783 |
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Tailliar, M.; Schanstra, J.P.; Dierckx, T.; Breuil, B.; Hanouna, G.; Charles, N.; Bascands, J.-L.; Dussol, B.; Vazi, A.; Chiche, L.; et al. Urinary Peptides as Potential Non-Invasive Biomarkers for Lupus Nephritis: Results of the Peptidu-LUP Study. J. Clin. Med. 2021, 10, 1690. https://doi.org/10.3390/jcm10081690
Tailliar M, Schanstra JP, Dierckx T, Breuil B, Hanouna G, Charles N, Bascands J-L, Dussol B, Vazi A, Chiche L, et al. Urinary Peptides as Potential Non-Invasive Biomarkers for Lupus Nephritis: Results of the Peptidu-LUP Study. Journal of Clinical Medicine. 2021; 10(8):1690. https://doi.org/10.3390/jcm10081690
Chicago/Turabian StyleTailliar, Maxence, Joost P. Schanstra, Tim Dierckx, Benjamin Breuil, Guillaume Hanouna, Nicolas Charles, Jean-Loup Bascands, Bertrand Dussol, Alain Vazi, Laurent Chiche, and et al. 2021. "Urinary Peptides as Potential Non-Invasive Biomarkers for Lupus Nephritis: Results of the Peptidu-LUP Study" Journal of Clinical Medicine 10, no. 8: 1690. https://doi.org/10.3390/jcm10081690
APA StyleTailliar, M., Schanstra, J. P., Dierckx, T., Breuil, B., Hanouna, G., Charles, N., Bascands, J. -L., Dussol, B., Vazi, A., Chiche, L., Siwy, J., Faguer, S., Daniel, L., Daugas, E., Jourde-Chiche, N., & on behalf of the Groupe Coopératif sur le Lupus Rénal (GCLR). (2021). Urinary Peptides as Potential Non-Invasive Biomarkers for Lupus Nephritis: Results of the Peptidu-LUP Study. Journal of Clinical Medicine, 10(8), 1690. https://doi.org/10.3390/jcm10081690