Article Figures & Data
Figures
- Figure 1.
Study cohort of membranous lupus nephritis. Membranous lupus nephritis is categorized into EXT1/EXT2-positive and EXT1/EXT-2 negative cohorts, which are further subcategorized with and without proliferative features.
- Figure 2.
Light microscopy and immunohistochemistry (IHC) of EXT1/EXT2-positive LMN. (A–C) Top panel showing pure class 5 LMN, and (D–F) bottom panel showing class 5 LMN with class 3 proliferative LN. (B and E) IHC for EXT1 (×40 magnification). (C and F) IHC for EXT2 (×40 magnification).
- Figure 3.
Light microscopy and immunohistochemistry (IHC) of EXT1/EXT2-negative LMN. (A–C) Top panel showing pure class 5 LMN, (D–F) and bottom panel showing class 5 LMN with class 3 proliferative LN. (B and E) IHC for EXT1 (×40 magnification). (C and F) IHC for EXT2 (×40 magnification).
- Figure 4.
Cumulative incidence of ESKD in patients with LMN. Kaplan-Meier plots of the cumulative incidence of ESKD over 10 years. (A) EXT1/EXT2-positive and EXT1/EXT2-negative LMN (with or without class 3/4 LN): 64 EXT1/EXT2-positive versus 96 EXT1/EXT2-negative LMN; two versus 18 events; P=0.007. (B) EXT1/EXT2-positive and EXT1/EXT2-negative pure class 5 LMN (with no class 3/4 LN): 48 EXT1/EXT2-positive versus 65 EXT1/EXT2-negative LMN; two versus 11 events; P=0.08. (C) EXT1/EXT2-positive and EXT1/EXT2-negative class 5 LMN with class 3/4 LN: 16 EXT1/EXT2-positive versus 31 EXT1/EXT2-negative LMN; zero versus seven events; P=0.03.
- Figure 5.
Schematic of EXT1/EXT2-positive and EXT1/EXT2-negative LMN. (A) EXT1/EXT2-negative LMN. There is no increased secretion of EXT1/EXT2 into the glomerular basement membrane (GBM). (B and C) EXT1/EXT2-positive LMN. (B) In EXT1/EXT2-positive LMN, there is increased secretion of the catalytic domain of exostosin into the GBM that is part of the immune complexes. (C) EXT1/EXT2 generate more heparan sulfates in the GBM and those coating the immune complexes. Red circle indicates exostosin, blue lines indicate increased expression of heparan sulfates in the GBM and around the deposits, green indicates immune complexes, and dashed lines indicate GBMs. C, catalytic domain of exostosin; P, podocyte; S, stalk.
Tables
Variable EXT1/EXT2-Positive, n=122 EXT1/EXT2-Negative, n=252 P Valuea Age, yr Median: 32 Median: 35 0.01 IQR: 25–41 IQR: 27–45 Sex Male: 16 (13.1%) Male: 47 (18.7%) 0.18 Female: 106 (86.9%) Female: 205 (81.3%) SCr at presentation, mg/dl Median: 0.8 Median: 0.9 0.02 IQR: 0.6–1.2; n=112 IQR: 0.7–1.4; n=227 Proteinuria at presentation, g/24 h Median: 3.5 Median: 3 0.08 IQR: 2–6.6; n=95 IQR: 1.8–4.8; n=199 Proteinuria ≥3.5 g/d at presentation 57 (60%); n=95 87 (43.7%); n=199 0.009 Hematuria 41 (33.6%) 87 (34.5%) 0.86 Other autoimmune disease 32 (26.2%) 47 (18.7%) 0.09 Sclerosed glomeruli, % Median: 3.8 Median: 9.1 0.001 IQR: 0–12.1 IQR: 0–24.8 IFTA, % Median: 0 Median: 10 <0.001 IQR: 0–10 IQR: 5–20 Proliferative features on light microscopy 30 (24. 6%) 81 (32.1%) 0.13 Immunofluorescence (glomerular staining) Total cases with immunofluorescence (n=118) Total cases with immunofluorescence (n=244) — IgG: 2–3+ (n=118, 100%) IgG (n=244, 100%): IgA (n=89, 75.4%); trace (n=3); trace (n=17); 1+ (n=8); 1+ (n=22); 2–3+ (233) 2–3+ (50) IgA (n=186, 76.2%): IgM (n=103, 87.3%): trace (n=35); trace (n=23); 1+ (n=53); 1+ (n=32); 2–3+ (98) 2–3+ (48) IgM (n=220, 90.2%): C1q (n=107, 90.7%): trace (n=27); trace (n=18); 1+ (n=75); 1+ (n=20); 2–3+ (118) 2–3+ (69) C1q (n=216, 88.5%): C3 (n=117, 99.2%): trace (n=38); trace (n=2); 1+ (n=39); 1+ (n=6); 2–3+ (139) 2–3+ (109) C3 (n=238, 97.5%): κ light chain (n=118, 100%): trace (n=11); trace (n=3); 1+ (n=29); 1+ (n=8); 2–3+ (198) 2–3+ (107) κ light chain (n=241, 98.8%): λ light chain (n=118, 100%): trace (n=12); trace (n=1); 1+ (n=31); 1+ (n=1); 2–3+ (198) 2–3+ (116) λ light chain (n=241, 98.8%): trace (n=10); 1+ (n=22); 2–3+ (209) Electron microscopy Subepithelial deposits: 122 (100%), of which 62 (50.8%) also had intramembranous deposits Subepithelial deposits: 250 (99.2%), of which 153 (61.2%) also had intramembranous deposits — Mesangial/paramesangial deposits: 116 (95.1%) Intramembranous deposits only: 2 (0.8%) Subendothelial deposits: 71 (58.2%) Mesangial/paramesangial deposits: 239 (94.8%) Tubuloreticular inclusions: 107 (87.7%) Subendothelial deposits: 146 (57.9%) Tubuloreticular inclusions: 199 (79.0%) ↵a P<0.05 is considered significant.
- Table 2.
Electron microscopy class on the basis of the Ehrenreich and Churg classification
Ehrenreich and Churg Classification EXT1/EXT2-Negative, n=252 (67.4%) EXT1/EXT2-Positive, n=122 (32.6%) P Valuea 1 9 (3.6%) 8 (6.6%) 0.19 2 72 (28.6%) 58 (47.5%) <0.001 3 167 (66.3%) 56 (45.9%) <0.001 4 3 (1.2%) 0 (0.0%) 0.23 ↵a P<0.05 is considered significant.
Case Glomeruli/Sclerosed IFTA, % Follow-Up, yr Rebiopsy: Glomeruli/Sclerosed Rebiopsy: IFTA, % 1 17/1 (5.9%) 0 2 17/2 (11.8%) 0 2 10/0 (0%) 0 2 26/0 (0%) 0 3 3/0 (0%) 0 10 42/2 (4.8%) 0 4 7/0 (0%) 0 7 42/19 (45.2%) 25 Cases 1–3 are EXT1/EXT2-positive LMN and case 4 is EXT1/EXT2-negative LMN.
- Table 4.
Clinical characteristics, follow-up, and outcomes of EXT1/EXT2-positive and EXT1/EXT2-negative LMN, with and without LN (combined class 5 LMN with or without class 3/4 LN)
Variable EXT1/EXT2-Positive LMN, n=64/122 (52.5%) EXT1/EXT2-Negative LMN, n=96/252 (38.1%) P Valuea Age at presentation, median (IQR), yr 33 (25–42) 38 (28–47) 0.10 Female, n (%) 57 (89.1) 75 (78.1) 0.07 SCr at presentation, median (IQR), mg/dl 0.80 (0.60–1.00), n=61 0.90 (0.70–1.40), n=89 0.004 Proteinuria at presentation, median (IQR), g/24 h 3.9 (1.6–6.7) n=53 3.0 (1.5–4.9), n=76 0.3 Proteinuria at presentation ≥3.5/d, n (%) 32 (60.4), n=53 33 (43.4), n=76 0.06 Hematuria, n (%) 19 (29.7) 35 (36.5) 0.38 Proliferative features, n (%) 16 (25.0) 31 (32.3) 0.32 Other autoimmune diseases, n (%) 19 (29.7) 22 (22.9) 0.34 Sclerosed glomeruli, median (IQR), % 0.0 (0.0–10.2) 13.2 (1.82–25.0) <0.001 IFTA, median (IQR), % 0.0 (0.0–0.0) 10.0 (5.0–20.0) <0.001 SCr at end of follow-up, median (IQR), mg/dl 0.90 (0.70–1.20), n=51 1.10 (0.70–1.60), n=71 0.05 Proteinuria at end of follow-up, median (IQR), g/24 h 0.85 (0.20–2.00), n=36 0.90 (0.25–2.35), n=57 0.89 Proteinuria at end of follow-up ≥3.5/d, n (%) 3 (8.3), n=36 9 (15.8), n=57 0.3 ESKD, n (%) 2 (3.1) 18 (18.8) 0.003 Death, n (%) 2 (3.1) 8 (8.3) 0.18 Time of follow-up, median (IQR), mo 48.6 (33.1–76.5) 50.6 (32.7–86.8) 0.85 ↵a P<0.05 is considered significant.
- Table 5.
Clinical characteristics, follow-up, and outcomes of EXT1/EXT2-positive and EXT1/EXT2-negative LMN without proliferative features (pure class 5)
Variable EXT1/EXT2-Positive LMN, n=48/64 (75.0%) EXT1/EXT2-Negative LMN, n=65/96 (67.7%) P Valuea Age at presentation, median (IQR), yr 33 (25–42) 40 (28–47) 0.12 Female, n (%) 42 (87.5) 53 (81.5) 0.39 SCr at presentation, median (IQR), mg/dl 0.70 (0.60–0.90), n=46 0.80 (0.60–1.30), n=58 0.01 Proteinuria at presentation, median (IQR), g/24 h 3.5 (1.5–5.9), n=40 2.8 (1.40–4.3), n=51 0.23 Proteinuria at presentation ≥3.5/d, n (%) 23 (57.5), n=40 18 (35.3), n=51 0.04 Hematuria, n (%) 15 (31.3) 22 (33.8) 0.77 Other autoimmune diseases, n (%) 14 (29.2) 15 (23.1) 0.46 Sclerosed glomeruli, median (IQR), % 0.0 (0.0–8.5) 9.5 (0.0–24.4) <0.001 IFTA, median (IQR), % 0.0 (0.0–0.0) 10.0 (5.0–25.0) <0.001 SCr at end of follow-up, median (IQR), mg/dl 0.85 (0.70–1.13), n=38 1.00 (0.70–1.57), n=51 0.09 Proteinuria at end of follow-up, median (IQR), g/24 h 0.95 (0.20–2.55), n=26 0.90 (0.20–1.93), n=42 0.46 Proteinuria at end of follow-up ≥3.5/d, n (%) 3 (11.5), n=26 6 (14.3), n=42 0.75 ESKD, n (%) 2 (4.2) 11 (16.9) 0.04 Death, n (%) 2 (4.2) 2 (3.1) 0.76 Time of follow-up, median (IQR), mo 52.5 (31.6–81.2) 53.6 (34.2–97.1) 0.61 ↵a P<0.05 is considered significant.
- Table 6.
Clinical characteristics, follow-up, and outcomes of all EXT1/EXT2-positive and EXT1/EXT2-negative LMN with proliferative features (class 5 with class 3/4 LN)
Variable EXT1/EXT2-Positive LMN, n=16/64 (25.0%) EXT1/EXT2-Negative LMN, n=31/96 (32.3%) P Valuea Age at presentation, median (IQR), yr 32 (25–43) 33 (28–47) 0.39 Female, n (%) 15 (93.8) 22 (71.0) 0.07 SCr at presentation, median (IQR), mg/dl 1.0 (0.8–2.0), n=15 1.20 (0.8–2.3), n=31 0.35 Proteinuria at presentation, median (IQR), g/24 h 6.6 (1.5–7.9), n=13 3.7 (1.7–6.5), n=25 0.48 Proteinuria at presentation ≥3.5/d, n (%) 9 (69.2), n=13 15 (60), n=25 0.58 Hematuria, n (%) 4 (25.0) 13 (41.9) 0.25 Other autoimmune diseases, n (%) 5 (31.3) 7 (22.6) 0.52 Sclerosed glomeruli, median (IQR), % 4.6 (0.0–12.5) 20.0 (3.22–27.8) 0.01 IFTA, median (IQR), % 0.0 (0.0–8.75) 10.0 (5.0–20.0) 0.003 SCr at end of follow-up, median (IQR), mg/dl 0.90 (0.8–1.5), n=13 1.30 (0.70–1.9), n=20 0.32 Proteinuria at end of follow-up, median (IQR), g/24 h 0.60 (0.20–1.25), n=10 1.5 (0.30–3.40), n=15 0.12 Proteinuria at end of follow-up ≥3.5/d, n (%) 0 (0.0), n=10 3 (20.0), n=15 0.13 ESKD, n (%) 0 (0.0) 7 (22.6) 0.04 Death, n (%) 0 (0.0) 6 (19.4) 0.06 Time of follow-up, median (IQR), mo 48.6 (43.0–76.3) 43.4 (27.1–77.9) 0.27 ↵a P<0.05 is considered significant.
Factors Univariable Cox Regression Multivariable Cox Regression HR (95% CI) P Valuea HR (95% CI) P Valuea Combined class 5 LMN with or without class 3/4 LN Age 0.97 (0.94 to 1.01) 0.21 Male 2.82 (1.12 to 7.08) 0.03 2.92 (1.16 to 7.34) 0.02 EXT1/EXT2-negative 5.85 (1.36 to 25.24) 0.02 SCr at presentation 1.36 (1.10 to 1.69) 0.004 Proteinuria at presentation 0.96 (0.83 to 1.11) 0.58 Hematuria 1.15 (0.66 to 1.98) 0.63 Other autoimmune diseases 1.08 (0.39 to 2.97) 0.88 ≥25% glomerulosclerosis 3.93 (1.63 to 9.47) 0.002 4.03 (1.67 to 19.71) 0.002 ≥25% IFTA 4.23 (1.74 to 10.28) 0.001 Only class 5 LMN (without class 3/4 LN) Age 0.99 (0.95 to 1.04) 0.67 Male 2.35 (0.72 to 7.70) 0.16 EXT1/EXT2-negative 3.56 (0.79 to 16.08) 0.1 SCr at presentation 1.27 (0.9 to 1.81) 0.18 Proteinuria at presentation 1.02 (0.91 to 1.15) 0.77 Hematuria 1.40 (0.66 to 2.99) 0.38 Other autoimmune diseases 1.29 (0.4 to 4.18) 0.68 ≥25% glomerulosclerosis 4.31 (1.44 to 12.88) 0.009 ≥25% IFTA 3.91 (1.31 to 11.73) 0.02 Class 5 LMN with class 3/4 LN Age 0.93 (0.84 to 1.04) 0.20 Male 6.33 (1.03 to 38.8) 0.05 8.35 (1.11 to 62.60) 0.04 EXT1/EXT2-negative — — — — SCr at presentation 1.40 (1.02 to 1.92) 0.04 1.53 (1.04 to 2.25) 0.03 Proteinuria at presentation 0.21 (0.02 to 3.04) 0.25 Hematuria 0.73 (0.30 to 1.75) 0.48 Other autoimmune diseases 0.85 (0.1 to 7.50) 0.88 ≥25% glomerulosclerosis 2.52 (0.55 to 11.50) 2.52 ≥25% IFTA 6.36 (1.27 to 31.80) 0.02 ↵a P<0.05 is considered significant.
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