Monocyte/macrophage related biomarkers in assessment of lupus nephritis activity
Ranjan Gupta, Akhilesh Yadav, Amita AggarwalDepartment of Clinical Immunology, SGPGIMS, Lucknow
Disclosures: Funding by DBT to AA
Introduction
• Lupus nephritis (LN) affects almost 70% patients
• Limitations of conventional markers of LN:Proteinuria: damage vs activityActive sediment: reproducibilityRenal biopsy: invasive nature and associated risks
Quest to find new urinary biomarkers
Urinary Monocytes/Macrophages in LN
• Monocytes/MΦs: Most abundant urinary cells in LN
• MCP-1: Macrophage chemoattractantuMCP-1 surrogate marker for MΦs infiltration
Kopetschke et al. Arthritis Research & Therapy, 2015
Monocytes/Macrophages in renal biopsy
Olmes et al. Arthritis Research & Therapy, 2016
sCD163 in ANCA associated vasculitis
• sCD163:Glycosylated protein on monocytes/MΦsScavenger of Hb-Haptoglobin complexes
O’Reilly et al. J Am Soc Nephrol, 2016
Objectives
To evaluate MCP-1 and sCD163 as biomarkers of LN disease activity in a cross-sectional as well as longitudinal study
MethodsSLE patients: ACR 1997 criteriaExclusions: Pregnancy and infections
Baseline evaluation: SLEDAIUrine: active sediment, 24 hr. proteinuria, Spot U Pr/Cr ratioSerum and cell-free urine samples stored at -80oC
Active Non-Renal (ANR) Active Renal (AR) Inactive Disease (ID)
Treated as per ACR, 2012 guidelines
3 monthly follow-up visits for 1 year: SLEDAIUrine: active sediment, Spot U Pr/Cr ratioSerum and cell-free urine samples stored at -80oC
± renal biopsy
Controls: 20 healthy subjects and 20 rheumatoid arthritis patients
Results: Patients
Total patients: 117 (F:M – 109:8)
AR n=57
ANRn=23
ID n=37 Class III
n=16
Class IIN=5
Class Vn=7
Class VIn=1
Biopsy not donen=10
Class IVn=16
Baseline characteristics
Active Nephritis (AR)
Active Non-Renal (ANR)
Inactive Disease (ID)
Number 57 23 37
F:M 55:2 18:5 36:1
Median age (yrs) 27 (13 – 50) 29 (15 – 50) 28 (14 – 48)
rSLEDAI 8 (4 – 16) 0 (0) 0 (0)
SLEDAI 18 (6 – 28) 10 (5 – 20) 2 (0 – 4)
Low C3 45 10 2
Low C4 45 12 6
Anti-ds DNA (IU/ml) 200 (24 – >300) 185 (<6.25 – >300) 53.6 (<6.25 – >300)
UPr/UCr ratio 3.37 (0.3 – 20.25) 0.37 (0.04 – 1.46) 0.11 (0 – 10.69)
Serum Creatinine (mg/dl) 0.9 (0.4 – 3.87) 0.81 (0.6 – 1.25) 0.77 (0.4 – 1.3)
Urinary levels: Cross sectional analysisMCP-1 sCD163
Relationship with disease activity
MCP-1 sCD163
Serum levels: Cross sectional analysis
MCP-1 sCD163
Serum and urinary levels: correlation
Poor correlation between serum and urinary biomarker levels
MCP-1 sCD163
ROC analysis: AR vs ANR
AUCuMCP-1 – 0.75sMCP-1 – 0.31Anti-ds DNA – 0.6C3 – 0.65C4 – 0.61
AUCUrinary sCD163 – 0.72Serum sCD163 – 0.46Anti-ds DNA – 0.6C3 – 0.65C4 – 0.61
MCP-1 sCD163
Results: Longitudinal analysis
Baseline 3 months 6 months 9 months 12 months
Number 57 51 51 46 46
rSLEDAI 8 (4 – 16) 0 (0 – 12) 0 (0 – 4) 0 (0 – 8) 0 (0 – 8)
SLEDAI 18 (6 – 28) 2 (0 – 14) 2 (0 – 6) 2 (0 – 10) 2 (0 – 15)
Low C3 45 3 5 6 2
Low C4 45 15 14 9 7
Anti-ds DNA (IU) 200 (24 – >300)
87.9 (8.4 – >300)
53.75 (<6.25 – >300)
61.5 (<6.5 – 300)
63.8 (8 – 216.66)
UPr/UCr ratio 3.7 (0.3 – 20.25)
0.35 (0 – 13.55)
0.62 (0 – 3.98)
0.22 (0 – 6.98)
0.24 (0 – 6.25)
Serum Creatinine (mg/dl)
0.9 (0.4 – 3.87)
0.77 (0 – 4.12)
0.8 (0.56 – 1.7)
0.79 (0.4 – 1.3)
0.81 (0.4 – 1.3)
Urinary levels: Longitudinal analysisMCP-1 sCD163
Serum levels: Longitudinal analysisMCP-1 sCD163
Relapse & poor renal response
↓
↓
↓
↓
MCP-1 sCD163
↓ = Relapse of Nephritis
Discussion & Conclusion• Urinary MCP-1 & sCD163 levels:
Higher in renal disease compared to ANR & IDCorrelate with rSLEDAI and SLEDAINo association with serum MCP-1 & sCD163 levels
MCP-1 & sCD163 are produced locally in kidneys in LN• ROC analysis: perform better than conventional markers
• Renal inflammation M0 MΦs M2c MΦs1
Source: Urinary MCP-1 : Infiltrating Monocytes/MΦs & tubular
cells Urinary sCD163 : Infiltrating M2c MΦs
IL-6, IL-10M-CSF
MCP-1
1Endo N et al. Nephrol Dial Transplant, 2016
Discussion & Conclusion• With immunosuppression ↓Inflammation, cytokines and renal injury ↓Disease activity ↓uMCP-1 & sCD163 levels paralleling traditional
markers
• MCP-1/sCD163: ‘different elements of same process’
• uMCP-1 & sCD163 are potential biomarkers of LN Help differentiate LN from ANR diseaseLevels parallel renal activityMay predict relapse of LN
Acknowledgement: Support of our Lupus patients
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