Table 2.
Performances of selected biomarkers of clinical disease activity in LN.
| Biomarker | Sample | Comparator | Disease activity | Metrics | References |
|---|---|---|---|---|---|
| Autoantibodies | |||||
| Anti-C1q (+) | Serum/ Plasma |
N/A | SLEDAI; ECLAM | r = 0.47 (SLEDAI); r = 0.28 (ECLAM) |
Bock et al., 2015 [104] |
| Inactive LN | proteinuria; SLEDAI | AUC = 0.76; sens.: 72%; spec.: 55%; r = 0.28 (proteinuria); r = 0.28 (SLEDAI) |
Gómez-Puerta et al., 2018 [41] | ||
| Inactive LN | proteinuria; active urinary sediment | AUC = 0.73; sens.: 63%; spec.: 75%; PPV: 69%; NPV: 67%; OR = 5.1 | Kianmehr et al., 2021 [105] | ||
| Inactive LN | proteinuria; active urinary sediment | OR = 8.4 | Sjöwall et al., 2018 [50] | ||
| SLE with no renal flares | renal flares | sens.: 70%; spec.: 44% | Birmingham et al., 2016 [51] | ||
| SLE with no renal flare | renal flares | sens.: 75%; spec.: 69%; PPV: 35%; NPV: 93%; HRadj = 1.1 | Fatemi et al., 2016 [106] | ||
| Anti-dsDNA (+) | Serum/ Plasma |
Inactive LN | proteinuria; SLEDAI |
AUC = 0.88; sens.: 71%; spec.: 88% | Jakiela et al., 2018 [61] |
| Inactive LN | proteinuria; active urinary sediment; SLEDAI | AUC = 0.70; sens.: 71%; spec.: 63%; PPV: 63%; NPV: 71%; OR = 4.2 r = 0.23 (SLEDAI) |
Kianmehr et al., 2021 [105] | ||
| Inactive LN | proteinuria; active urinary sediment | OR = 4.8 | Sjöwall et al., 2018 [50] | ||
| SLE with no renal flares | renal flares | AUC = 0.85; sens.: 88%; spec.: 83%; PPV: 43%; NPV: 97%; HR = 21.7 | Fasano et al., 2020 [107] | ||
| PTEC-binding IgG (+) | Serum/Plasma | Inactive LN | renal flares | AUC = 0.63; sens.: 46%; spec.: 80%; PPV: 44%; NPV: 81% | Yap et al., 2016 [108] |
| Complements | |||||
| C3 (low) | Serum/ Plasma |
Inactive LN | proteinuria; SLEDAI | AUC = 0.88; sens.: 100%; spec.: 65% | Jakiela et al., 2018 [61] |
| N/A | SLEDAI | r = −0.99 (SLEDAI) | Selvaraja et al., 2019 [109] | ||
| Active non-renal SLE | renal flares | sens.: 70%; spec.: 59%; OR = 2.5 | Ruchakorn et al., 2019 [110] | ||
| SLE with no renal flares | renal flares | AUC = 0.76; sens.: 100%; spec.: 51%; PPV: 23%; NPV: 100%; HR = 6.0 | Fasano et al., 2020 [107] | ||
| C4 (low) | Serum/ Plasma |
N/A | SLEDAI | r = −0.83 (SLEDAI) | Selvaraja et al., 2019 [109] |
| Inactive LN | proteinuria; SLEDAI | AUC = 0.88; sens.: 81%; spec.: 88% | Jakiela et al., 2018 [61] | ||
| SLE with no renal flares | renal flares | AUC = 0.82; sens.: 100%; spec.: 62%; PPV: 28%; NPV: 100%; HR = 5.5 | Fasano et al., 2020 [107] | ||
| SLE with no renal flares | renal flares | ORadj = 5.6 | Buyon et al., 2017 [111] | ||
| Kidney disease-related markers | |||||
| Proteinuria (↑) (>500 mg/24 h) | Urine | Inactive LN | proteinuria; active urinary sediment | AUC = 0.94 | Dolff et al., 2013 [112] |
| Inactive LN | proteinuria; SLEDAI | AUC = 0.99; sens.: 88%; spec.: 100% | Jakiela et al., 2018 [61] | ||
| SLE with no renal flares | renal flares | PPV: 43%; NPV: 85%; HRadj = 1.1 | Fatemi et al., 2016 [106] | ||
| WBC (↑) | Urine | Inactive LN | proteinuria; SLEDAI | AUC = 0.75; sens.: 71%; spec.: 73% | Jakiela et al., 2018 [61] |
| RBC (↑) | Urine | Inactive LN | proteinuria; SLEDAI | AUC = 0.92; sens.: 77%; spec.: 100% | Jakiela et al., 2018 [61] |
| Granular casts (+) | Urine | Inactive LN | proteinuria; SLEDAI | AUC = 0.91; sens.: 82%; spec.: 91% | Jakiela et al., 2018 [61] |
| Cytokines/chemokines | |||||
| IL-10 (↑) | Serum/ Plasma |
Inactive LN | proteinuria; SLEDAI | AUC = 0.87; sens.: 71%; spec.: 85% | Jakiela et al., 2018 [61] |
| N/A | SLEDAI | r = 0.98 (SLEDAI) | Selvaraja et al., 2019 [109] | ||
| IL-17 (↑) | Serum/ Plasma |
Inactive LN | SLEDAI | AUC = 0.91; r = 0.63 (SLEDAI) |
Dedong et al., 2019 [77] |
| Inactive LN | BILAG renal score | AUC = 0.81; r = 0.26 (BILAG renal score) | Nordin et al., 2019 [113] | ||
| IL-7 (↑) | Urine | Inactive SLE | rSLEDAI | AUC = 0.92; sens.: 84%; spec.: 95%; PPV: 95%; NPV: 84%; r = 0.70 (rSLEDAI) |
Stanley et al., 2019 [78] |
| IL-12 p40 (↑) | AUC = 0.93; sens.: 87%; spec.: 100%; PPV: 100%; NPV: 88%; r = 0.67 (rSLEDAI) |
||||
| IL-15 (↑) | AUC = 0.91; sens.: 93%; spec.: 100%; PPV: 100%; NPV: 92%; r = 0.67 (rSLEDAI) |
||||
| MCP-1 (↑) | Urine | Inactive LN; Non-renal SLE | rSLEDAI | AUC = 0.70; r = 0.35 (rSLEDAI) |
Liu et al., 2020 [87] |
| Inactive LN | SLEDAI | AUC = 0.76; sens.: 81%; spec.: 85% | Bona et al., 2020 [86] | ||
| Inactive SLE | rSLEDAI | AUC = 0.79; sens.: 93%; spec.: 68%; PPV: 93%; NPV: 68% | Stanley et al., 2020 [11] | ||
| Inactive LN | proteinuria; rSLEDAI | AUC = 1.00; sens.: 100%; spec.: 100%; PPV: 100%; NPV:100%; r = 0.84 (proteinuria); r = 0.92 (rSLEDAI) |
Elsaid et al., 2021 [30] | ||
| Inactive LN | SLEDAI-2K | AUC = 0.81; sens.: 50%; spec.: 90%; r = 0.39 (SLEDAI-2K) |
Rosa et al., 2012 [84] | ||
| Inactive LN | proteinuria; SLEDAI | AUC = 0.71; sens.: 70%; spec.: 58%; r = 0.47 (proteinuria); r = 0.33 (SLEDAI) |
Gómez-Puerta et al., 2018 [41] | ||
| Inactive LN | N/A | AUC = 0.90; sens.: 89%; spec.: 63%; OR = 19.4 | Xia et al., 2020 [91] | ||
| IP-10/CXCL10 (↑) | Urine | Inactive SLE | rSLEDAI | AUC = 0.94; sens.: 87–88%; spec.: 81–100%; PPV: 100%; NPV: 88%; r = 0.67–0.74 (rSLEDAI) | Stanley et al., 2019 [78] |
| Inactive LN | proteinuria; SLEDAI | AUC = 0.93; sens.: 88%; spec.: 81% | Jakiela et al., 2018 [61] | ||
| Healthy controls | N/A | AUC = 0.92 | Zhang et al., 2020 [12] | ||
| PF-4 (↑) | Urine | Inactive SLE | rSLEDAI | AUC = 0.71–0.88; sens.: 54–93%; spec.: 79–96%; PPV: 82–94%; NPV: 77–88% | Stanley et al., 2020 [11] |
| TARC (↑) | Urine | Inactive SLE | rSLEDAI | AUC = 0.91; sens.: 78%; spec.: 92%, PPV: 91%; NPV: 80%; r = 0.70 (rSLEDAI) |
Stanley et al., 2019 [78] |
| TGFβ1 (↑) | Urine | Active non-renal SLE | proteinuria | r = 0.51 (proteinuria) | Fava et al., 2022 [79] |
| Active non-renal SLE | rSLEDAI | AUC = 0.78; r = 0.37 (rSLEDAI) |
Vanarsa et al., 2020 [80] | ||
| TWEAK (↑) | Urine | N/A | proteinuria | r = 0.61 (proteinuria) | Reyes-Martínez et al., 2018 [27] |
| Inactive LN | proteinuria; rSLEDAI | AUC = 1.00; sens.: 100%; spec.: 100%; PPV: 100%; NPV: 100%; r = 0.84 (proteinuria); r = 0.89 (rSLEDAI) |
Elsaid et al., 2021 [30] | ||
| Angiogenesis-related molecules | |||||
| Angptl4 (↑) | Urine | Active non-renal SLE | rSLEDAI | AUC = 0.96; r = 0.66 | Vanarsa et al., 2020 [80] |
| Healthy controls | N/A | AUC = 0.92 | Zhang et al., 2020 [12] | ||
| Angiostatin (↑) | Serum/ Plasma |
Inactive LN | SLEDAI | AUC = 0.83 | Wu et al., 2016 [13] |
| Urine | Inactive LN | rSLEDAI | AUC = 0.99; sens.: 83%; spec.: 100%; r = 0.33 (rSLEDAI) |
Soliman et al., 2017 [95] | |
| Healthy controls | N/A | AUC = 0.97 | Zhang et al., 2020 [12] | ||
| Inactive SLE | rSLEDAI; SLEDAI; SLICC-RAS | AUC = 0.83 r = 0.52 (rSLEDAI); r = 0.36 (SLEDAI); r = 0.68 (SLICC-RAS) |
Wu et al., 2013 [69] | ||
| Haemostasis-related molecules | |||||
| Plasmin (↑) | Urine | Inactive LN | rSLEDAI; SLICC-RAS |
AUC = 0.86; sens.: 100%; spec.: 70%; PPV: 96%; NPV: 50%; r = 0.50 (rSLEDAI); r = 0.58 (SLICC-RAS) |
Qin et al., 2019 [97] |
| Tissue Factor (↑) | AUC = 0.74; sens.: 61%; spec.: 85%; PPV: 90%; NPV: 35%; r = 0.33 (rSLEDAI); r = 0.38 (SLICC-RAS) |
||||
| TFPI (↑) | AUC = 0.77; sens.: 86%; spec.: 58%; PPV: 92%; NPV: 36%; r = 0.40 (rSLEDAI); r = 0.31 (SLICC-RAS) |
||||
| Inactive SLE | rSLEDAI | AUC = 0.71–0.88; sens.: 57–80%; spec.: 84–89%; PPV: 73–89%; NPV: 73–82% | Stanley et al., 2020 [11] | ||
| Cell adhesion molecules | |||||
| ALCAM (↑) | Urine | N/A | rSLEDAI | r = 0.35–0.41 (rSLEDAI) | Chalmers et al., 2022 [67] |
| Inactive SLE | rSLEDAI | AUC = 0.84% sens.: 79–94%; spec.: 70–95%; PPV: 86–91%; NPV: 90–92% | Stanley et al., 2020 [11] | ||
| N/A | rSLEDAI; SLICC-RAS | r = 0.55 (rSLEDAI); r = 0.58 (SLICC-RAS) |
Ding et al., 2020 [68] | ||
| ICAM-1 (↑) | Urine | Inactive LN | proteinuria; active urinary sediment | AUC = 0.97; sens.: 93–98%; spec.: 81–86% | Wang et al., 2018 [114] |
| SLE with no renal flares | renal flares | AUC = 0.75; sens.: 88%; spec.: 59%; PPV: 25%; NPV: 97%; HR = 8.5 | Fasano et al., 2020 [107] | ||
| NCAM-1 (↑) | Urine | Inactive LN | proteinuria; active urinary sediment | AUC = 0.88; sens.: 82%; spec.: 87% | Wang et al., 2018 [114] |
| Healthy controls | N/A | AUC = 0.75 | Zhang et al., 2020 [12] | ||
| VCAM-1 (↑) | Serum/ Plasma |
Inactive LN | rSLEDAI-2K; SLEDAI-2K | AUC = 0.86; sens.: 69%; spec.: 90%; r = 0.61 (rSLEDAI-2K); r = 0.62 (SLEDAI-2K) |
Yu et al., 2021 [115] |
| Urine | N/A | rSLAM-R | r = 0.26 (rSLAM-R) | Howe et al., 2012 [100] | |
| Inactive SLE | rSLEDAI | AUC = 0.84–0.87; sens.:92–96%; spec.: 65–74%; PPV: 93–95%; NPV: 60–72% | Stanley et al., 2020 [11] | ||
| N/A | rSLEDAI | r = 0.55 (rSLEDAI) | Liu et al., 2020 [87] | ||
| SLE with no renal flares | renal flares | AUC = 0.76; sens.: 75%; spec.: 75%; PPV: 32%; NPV: 95%; HR = 7.5 | Fasano et al., 2020 [107] | ||
| Inactive LN | rSLEDAI; SLEDAI |
AUC = 0.98; sens.: 100%; spec.: 90%; r = 0.32 (rSLEDAI); r = 0.32 (SLEDAI) |
Soliman et al., 2017 [95] | ||
| Other proteins | |||||
| Axl (↑) | Serum/ Plasma |
Inactive LN | SLEDAI | AUC = 0.87 | Wu et al., 2016 [13] |
| Calpastatin (↑) | Urine | Inactive SLE | rSLEDAI | AUC = 0.72–0.75; sens.: 50–66%; spec.: 78–100%; PPV: 75–82%; NPV: 70–100% | Stanley et al., 2020 [11] |
| CD163 (↑) | Urine | Inactive LN | N/A | AUC = 0.98–0.99; sens.: 97%; spec.: 94% | Mejia-Vilet et al., 2020 [101] |
| Active non-renal SLE | rSLEDAI | AUC = 0.87–0.94; r = 0.45–0.75 (rSLEDAI) |
Zhang et al., 2020 [103] | ||
| N/A | proteinuria | r = 0.40 (proteinuria) | Fava et al., 2022 [79] | ||
| Ferritin (↑) | Serum/ Plasma |
Inactive LN | SLEDAI | AUC = 0.84 | Wu et al., 2016 [13] |
| FOLR2 (↑) |
Urine |
Active non-renal SLE | rSLEDAI | AUC = 0.73; r = 0.62 (rSLEDAI) |
Vanarsa et al., 2020 [80] |
| Hemopexin (↑) | Urine | Inactive SLE | rSLEDAI | AUC = 0.73–0.80; sens.: 85–100%; spec.: 56–99%; PPV: 79–100%; NPV: 57–70% | Stanley et al., 2020 [11] |
| IGFBP-2 (↑) | Serum/ Plasma |
N/A | rSLEDAI | r = 0.41 (rSLEDAI) | Ding et al., 2016 [71] |
| L-selectin (↑) | Urine | Active non-renal SLE | rSLEDAI | AUC = 0.86; r = 0.73 (rSLEDAI) |
Vanarsa et al., 2020 [80] |
| NGAL (↑) | Urine | Inactive LN | rSLEDAI-2K | AUC = 0.83; sens.: 89%; spec.: 67% | Alharazy et al., 2013 [116] |
| Inactive LN | proteinuria; SLEDAI | AUC = 0.67; sens.: 70%; spec.: 62%; r = 0.40 (proteinuria); r = 0.30 (SLEDAI) |
Gómez-Puerta et al., 2018 [41] | ||
| N/A | rSLEDAI | r = 0.42 (rSLEDAI) | Liu et al., 2020 [87] | ||
| PDGFRβ (↑) | Urine | Active non-renal SLE | rSLEDAI | AUC = 0.67 | Vanarsa et al., 2020 [80] |
| Peroxiredoxin 6 (↑) | Urine | Inactive SLE | rSLEDAI | AUC = 0.64–0.75; sens.: 50–56%; spec.: 79–91%; PPV: 68–87%; NPV: 64–68% | Stanley et al., 2020 [11] |
| Progranulin (↑) | Serum/ Plasma |
Stable LN |
rSLEDAI; SLEDAI |
AUC = 0.88; sens.: 53%; spec.: 89%; PPV: 82%; NPV: 66% | Wu et al., 2016 [117] |
| Non-LN renal disorder | AUC = 0.67; sens.: 60%; spec.: 100%; PPV: 100%; NPV: 73%; r = 0.57 (rSLEDAI); r = 0.62 (SLEDAI) |
||||
| Urine | Inactive LN | AUC = 0.90; sens.: 65%; spec.: 99%; PPV: 98%; NPV: 74%; r = 0.59 (rSLEDAI); r = 0.58 (SLEDAI) |
|||
| Properdin (↑) | Urine | Inactive SLE | rSLEDAI | AUC = 0.71–0.85; sens.: 62–86%; spec.: 84–90%; PPV: 79–90%; NPV: 68–86% | Stanley et al., 2020 [11] |
| RBP4 (↑) | Urine | SLE with no proteinuric flare | proteinuric flares | AUC = 0.67; sens.: 93%; spec.: 67%; HR = 9.5 | Go et al., 2018 [118] |
| N/A | rSLEDAI; SLEDAI; uPCR | r = 0.31 (rSLEDAI); r = 0.31 (SLEDAI); r = 0.39 (uPCR) |
Aggarwal et al., 2017 [119] | ||
| SDC-1 (↑) | Serum/ Plasma |
Inactive LN | proteinuria; rSLEDAI-2K; SLEDAI-2K | AUC = 0.91; sens.: 85%; spec.: 86%; r = 0.57 (proteinuria); r = 0.68 (rSLEDAI-2K); r = 0.54 (SLEDAI-2K) |
Yu et al., 2021 [120] |
| N/A | SLEDAI; uPCR | r = 0.60 (SLEDAI); r = 0.45 (uPCR) |
Kim et al., 2015 [121] | ||
| sTNFRII (↑) | Serum/ Plasma |
Non-renal SLE | rSLEDAI; rLAI | AUC = 0.77; r = 0.30 (rSLEDAI); r = 0.39 (rLAI) |
Smith et al., 2019 [122] |
| Inactive LN | N/A | AUC = 0.81 | Wu et al., 2016 [13] | ||
| TSP1 (↑) | Urine | Active non-renal SLE | rSLEDAI | AUC = 0.72 | Vanarsa et al., 2020 [80] |
| TTP1 (↑) | Urine | Active non-renal SLE | rSLEDAI | AUC = 0.84 | Vanarsa et al., 2020 [80] |
| Microparticles | |||||
| MP-HMGB1+ (↑) | Urine | Inactive LN | N/A | AUC = 0.83; sens.: 55%; spec.: 93% | Burbano et al., 2019 [48] |
Biomarkers are structured into subgroups (highlighted in bold) based on clinical/functional affinities. ALCAM: activated leukocyte cell adhesion molecule; Angptl4: angiopoietin-like protein 4; Anti-dsDNA: anti-double-stranded DNA; AUC: area under the curve; BILAG: British Isles Lupus Assessment Group; CCL: C-C motif chemokine ligand; Cr: creatinine; CXCL: C-X-C motif chemokine ligand; C3: complement component 3; C4: complement component 4; ECLAM: European Consensus Lupus Activity Measurement; FOLR2: folate receptor beta; HMGB1: high mobility group box 1; HR: hazard ratio; HRadj: adjusted hazard ratio; ICAM-1: intercellular cell adhesion molecule 1; IGFBP-2: insulin-like growth factor binding protein 2; IP-10/CXCL10: interferon gamma inducible protein-10/C-X-C motif chemokine ligand 10; LN: lupus nephritis; MCP-1: monocyte chemoattractant protein 1; MP: microparticle; N/A: not applicable; NCAM-1: neural cell adhesion molecule 1; NGAL: neutrophil gelatinase associated lipocalin; NPV: negative predictive value; OR: odds ratio; PDGFRβ: platelet-derived growth factor receptor beta; PF-4: platelet factor 4; PPV: positive predictive value; PTEC-binding IgG: proximal renal tubular epithelial cell-binding immunoglobulin G; r: correlation coefficient; RBC: red blood cells; RBP4: retinol binding protein 4; rLAI: renal Lupus Activity Index; rSLEDAI: renal SLEDAI; rSLEDAI-2K: renal SLEDAI 2000; SDC-1: syndecan 1; sens.: sensitivity; sIL-7R: soluble interleukin 7 receptor; SLAM-R: Systemic Lupus Activity Measure Revised; SLE: systemic lupus erythematosus; SLEDAI: Systemic Lupus Erythematosus Disease Activity Index; SLICC: Systemic Lupus International Collaborating Clinics; SLICC-RAS: Systemic Lupus International Collaborating Clinics Renal Activity Score; spec.: specificity; sTNFRII: soluble tumour necrosis factor alpha receptor II; TARC: thymus- and activation-regulated chemokine; TFPI: tissue factor pathway inhibitor; TGFβ1: transforming growth factor β1; TSP1: thrombospondin 1; TTP1: tripeptidyl-peptidase 1; TWEAK: TNF-like weak inducer of apoptosis; uPCR: urine protein to creatinine ratio; VCAM-1: vascular cell adhesion molecule 1; WBC: white blood cells; (+): positivity; ↑: elevated.