Nephritis-Associated Plasmin Receptor (NAPlr): An Essential Inducer of C3-Dominant Glomerular Injury and a Potential Key Diagnostic Biomarker of Infection-Related Glomerulonephritis (IRGN)
Abstract
1. Introduction
2. Isolation and Characterization of NAPlr
3. Clinical and Histological Characteristics of PSAGN in Relation to Complements, ICs, and NAPlr
4. Proposed Mechanism for PSAGN
- (1)
- Complement profile in PSAGN
- (2)
- Complement activation by NAPlr
- (3)
- C3-dominant glomerular injury
IC-Dominant GI | C3-Dominant GI | ||
---|---|---|---|
Major difference | C3 with IgG | C3 without IgG | |
NAPlr deposition | +~++ | +~++ | |
Plasmin activation | +~++ | +~++ | |
Complement activation | |||
Alternative pathway | + | ++ | |
Classical pathway | + | + | |
Serum complement | |||
CH50 | ↓ | ↓ | |
C3 | ↓ | ↓ | |
C4 | → | → | |
Underlying complement dysregulation | unknown | unknown | |
C3 Nephritic factor | + ? | + ? | [68] |
Anti-factor B antibody | ++ ? | ++ ? | [67] |
Pathology | |||
LM | |||
Endocapillary GN | ++ | ++ | |
Exudative change | ++ | ++ | |
IF | |||
C3 | ++~+++ | ++~+++ | |
IgG | +~++ | − | |
C4 | +~− | − | |
EM | |||
Hump | ++ | ++ | |
Circulating IC | ++ | ++ | [63] |
Circulating NAPlr antibody | ++ | ++ | [2] |
5. NAPlr as a Key Diagnostic Biomarker of IRGN
5.1. Glomerular NAPlr Deposition and Related Plasmin Activity in Streptococcal Infection-Related Nephritis
5.2. Positive Staining for NAPlr/Plasmin Activity in Non-Streptococcal IRGN
5.3. Plasmin-Binding Capacity of GAPDH in Non-Streptococcal Bacteria
5.4. NAPlr as a General Diagnostic Biomarker of IRGN
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Time from Onset to Biopsy | n | NAPlr | Plasminogen | Fibrinogen | C3 | IgG | IgA | IgM |
---|---|---|---|---|---|---|---|---|
1–14 d | 25 | 25/25 (100%) | 10/25 (40) | 15/25 (60) | 25/25 (100) | 16/25 (64) | 11/25 (44) | 10/25 (40) |
15–30 d | 18 | 11/18 (61) | 5/18 (28) | 11/18 (61) | 18/18 (100) | 11/18 (61) | 8/18 (44) | 9/18 (50) |
31–90 d | 7 | 0/7 (0) | 0/7 (0) | 4/7 (57) | 6/7 (86) | 3/7 (43) | 3/7 (43) | 3/7 (43) |
Total | 50 | 36/50 (72) | 15/50 (30) | 30/50 (60) | 49/50 (98) | 30/50 (60) | 22/50 (44) | 22/50 (44) |
Time from Onset to Biopsy | n | P | C1q | C4 | C5 | C9 | S | MAC |
1–14 d | 25 | 23/25 (92%) | 7/25 (28) | 8/25 (32) | 25/25 (100) | 24/25 (96) | 24/25 (96) | 25/25 (100) |
15–30 d | 18 | 16/18 (89) | 6/18 (33) | 3/18 (17) | 18/18 (100) | 17/18 (94) | 17/18 (94) | 18/18 (100) |
31–90 d | 7 | 5/7 (71) | 2/7 (29) | 1/7 (14) | 6/7 (86) | 5/7 (71) | 5/7 (71) | 6/7 (86) |
Total | 50 | 44/50 (88) | 15/50 (30) | 12/50 (24) | 49/50 (98) | 46/50 (92) | 46/50 (92) | 49/50 (98) |
Biopsy Specimens | Onset to Biopsy | Glomerular NAPlr (+) | |
---|---|---|---|
PSAGN | 1–14 days | 25/25 | (100%) |
15–30 days | 11/18 | (61%) | |
31–90 days | 0/7 | (0%) | |
Total | 36/50 | (72%) | |
Non-PSAGN | 4/100 | (4%) | |
Normal kidneys | 0/10 | (0%) |
Age in Years Range | Anti-NAPlr Antibody (+) | Anti-NAPlr Antibody Titers | |
---|---|---|---|
PSAGN | (5–72 y, mean 29.3) | 46/50 (92%) | 566 ± 106.1 |
Streptococcal infection | (8–64 y, mean 29.0) | 30/50 (60%) | 227.1 ± 51.2 |
Pediatric I | (0.2–10 y, mean 7.2) | 13/50 (26%) | 138.9 ± 23.4 |
Pediatric II | (11–20 y, mean 14.1) | 18/50 (36%) | 166.0 ± 25.7 |
Normal adults I | (25–35 y, mean 30.0) | 24/50 (48%) | 100.1 ± 18.0 |
Normal adults II | (52–59 y, mean 53.0) | 36/50 (72%) | 186.0 ± 17.3 |
Case | Age/ Gender | Diagnosis | Onset | UP | U-RBC (/hpf) | SCr (mg/dL) | CH50 (U/mL) | C3 (mg/dL) | C4 (mg/dL) | CH50 (U/mL) | EP | IF | NAPlr | Ref. |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | 14/F | DDD | AGN | +++ | +++ | 0.48 | <10 | 8 | - | 1090 | +++ | C3 cap | +++ | [71] |
2 | 12/M | DDD | AKI on CGN | +++ | 30–49 | 0.44 | 31.1 | 48 | 27 | 333 | +++ | C3 cap | +++ | [70] |
3 | 6/F | DDD | Asymptomatic | ± | 20–29 | 0.36 | 23.5 | 36 | 19 | 290 | ++ | C3 cap | + | our case |
4 | 62/F | MPGN I | AKI on CGN | +++ | 20–29 | 3.6 | 21.7 | - | - | 170 | ++ | IgG, IgM, C3 cap | ++ | [73] |
5 | 6/F | HSPN | Abd pain, purpura | +++ | many | 0.35 | 67.1 | 89 | 32 | 154 | ++ | IgA, C3 mes-cap | ++ | our case |
6 | 25/M | HSPN | Abd pain, purpura | + | 30–49 | 1.3 | 28 | 50 | 22 | 743 | +++ | IgA, C3 mes-cap | +++ | [76] |
7 | 71/M | SVV | Pain and swelling of the rt. ankle | +++ | 50–99 | 3.28 | - | 42 | 27 | 512 | +++ | C3 mes-cap | +++ | [75] |
8 | 17/M | GPA | AGN | ++ | 100< | 7.53 | - | 10 | 26 | 301 | − | C3 mes | + | [74] |
Case | Age/ Gender | Infection Focus | Pathogen | Complement C3/C4/CH50 | NAPlr /PA | Light Microscopy | IF | EM (Dense Deposits) | Ref. |
---|---|---|---|---|---|---|---|---|---|
1 | 12/F | respiratory infection | Streptococcus pneumoniae | 10/33/- | +/+ | cellular crescent formation, endocapillary proliferative GN | C3 | GBM hump (−) | [77] |
2 | 64/M | endocarditis | Aggregatibacter actinomycetemcomitans | 86/16/- | +/− | proliferative GN with inflammatory cell infiltration | IgG IgM C3 C1q IgA | Subend Mes hump (−) | [78] |
3 | 7/F | respiratory infection | Mycoplasma pneumoniae | WNL | +/+ | endocapillary proliferation and cellular crescents | IgA IgM C3 | Mes Parames Subendo hump (−) | [79] |
4 | 70/M | cellulitis | Staphylococcus aureus (MSSA) | 118/43.9/75.3 | +/+ | endocapillary proliferative GN | IgG IgA IgM C3 C1q | GBM Parames hump (−) | Our case |
Pathogen | Amino Acid Sequence of GAPDH | |||
---|---|---|---|---|
Total Amino Acid | Identity Similarity (%) | C Terminal Amino Acid | ||
Streptococcal pyogenes | 336 | - | - | T L E Y F A K I A K |
Streptococcus pneumoniae | 359 | 92 | 99 | T L E Y F A K I A K |
Aggregatibacter actinomycetemcomitans | 334 | 50 | 85 | L V A H V Y N Y K D |
Mycoplasma pneumoniae | 337 | 54 | 87 | V R V V N Y C A K L |
Staphylococcus aureus (MSSA) | 336 | 67 | 92 | T L A Y L A E L S K |
Case | Age/ Gender | Infection Focus | Underlying Disease | Pathogen | Complement C3/C4/CH50 | NAPlr/ PA | Light Microscopy | IF | EM (Dense Deposits) | Ref. |
---|---|---|---|---|---|---|---|---|---|---|
5 | 68/M | sinusitis | - | unknown | 25.1/20.8/<12 | +/+ | proliferative and exudative GN, MPGN type I | IgG C3 | Parames hump (−) | [89] |
6 | 17/F | unknown | C3G | unknown | 6/15/<12 | +/+ | lobulation of the glomerular capillary tufts, proliferation of glomerular mesangial cells, increased mesangial matrix, MPGN type III | C3 | Subendo Subepi | [85] |
7 | 55/M | unknown | CFH mutation | unknown | 108/43/61.6 | +/+ | cellular crescents and diffuse endocapillary and mesangial proliferation with double contour formation along the capillary walls | C3 IgG | Subepi Subendo hump (−) | [83] |
8 | 70/M | respiratory infection | - | unknown | 80/11.8/15.8 | +/+ | endocapillary proliferative GN | IgG C3 | Subepi hump (+) | [84] |
9 | 75/M | unknown | ANCA negative SVV | unknown | 105/26/52.7 | +/+ | cellular crescents/segmental endocapillary proliferation with neutrophils and tuft necrosis | C3 | Mes, GBM, Subepi, hump (+) | [86] |
10 | 82/M | unknown | - | unknown | 64/25/- | +/+ | subendothelial deposits including wire loop lesions, endocapillary proliferation, cellular crescents | IgA C3 IgG/IgM C1q/C4 | Subendo, Mes hump (−) | [88] |
11 | 27/M | unknown | IgA nephropathy | unknown | 18/23/- | +/+ | mesangial cell proliferation, increased mesangial matrix increasing, endocapillary proliferation | IgA C3 | Mes hump (−) | [87] |
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Yoshizawa, N.; Yamada, M.; Fujino, M.; Oda, T. Nephritis-Associated Plasmin Receptor (NAPlr): An Essential Inducer of C3-Dominant Glomerular Injury and a Potential Key Diagnostic Biomarker of Infection-Related Glomerulonephritis (IRGN). Int. J. Mol. Sci. 2022, 23, 9974. https://doi.org/10.3390/ijms23179974
Yoshizawa N, Yamada M, Fujino M, Oda T. Nephritis-Associated Plasmin Receptor (NAPlr): An Essential Inducer of C3-Dominant Glomerular Injury and a Potential Key Diagnostic Biomarker of Infection-Related Glomerulonephritis (IRGN). International Journal of Molecular Sciences. 2022; 23(17):9974. https://doi.org/10.3390/ijms23179974
Chicago/Turabian StyleYoshizawa, Nobuyuki, Muneharu Yamada, Masayuki Fujino, and Takashi Oda. 2022. "Nephritis-Associated Plasmin Receptor (NAPlr): An Essential Inducer of C3-Dominant Glomerular Injury and a Potential Key Diagnostic Biomarker of Infection-Related Glomerulonephritis (IRGN)" International Journal of Molecular Sciences 23, no. 17: 9974. https://doi.org/10.3390/ijms23179974
APA StyleYoshizawa, N., Yamada, M., Fujino, M., & Oda, T. (2022). Nephritis-Associated Plasmin Receptor (NAPlr): An Essential Inducer of C3-Dominant Glomerular Injury and a Potential Key Diagnostic Biomarker of Infection-Related Glomerulonephritis (IRGN). International Journal of Molecular Sciences, 23(17), 9974. https://doi.org/10.3390/ijms23179974