Multiplex Bead Array Assay of a Panel of Circulating Cytokines and Growth Factors in Patients with Albuminuric and Non-Albuminuric Diabetic Kidney Disease
Abstract
:1. Introduction
2. Materials and Methods
2.1. Design
2.2. Ethical Principals
2.3. Participants
2.4. Methods
2.5. Statistical Analysis
3. Results
3.1. Clinical Characteristics of T2D Patients
3.2. IL-2, IL-4, IL-7, IL-9, IL-13, IL-15
3.3. IL-5, GM-CSF, G-CSF, IL-6, and IL-12
3.4. IL-10 and IFN-γ
3.5. IL-1β, IL-1Ra, TNF-α, and IL-17A
3.6. MCP-1, MIP-1α, MIP-1β, RANTES, Eotaxin, IP-10, and IL-8
3.7. bFGF, VEGF, and PGDF-BB
3.8. Correlation Analysis and Logistic Regression Models
4. Discussion
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
Appendix A
Parameter | Discovery Cohort | Validation Cohort |
---|---|---|
N | 86 | 44 |
Sex, M/F, n (%) | 29/57 (33.7%/66.3%) | 16/28 (36.4%/63.4%) |
Age, years | 65 (58; 69) | 65.5 (58.5; 70) |
Smokers, n (%) | 10 (11.6%) | 5 (11.4%) |
BMI, kg/m2 | 33.4 (29.4; 37.4) | 33.2 (29.8; 38.9) |
Diabetes duration, years | 13.5 (11; 17) | 14 (11; 18) |
CKD−/NA-CKD/A-CKD−/A-CKD+, n | 22/22/21/21 | 11/11/11/11 |
Appendix B
Family | Protein |
---|---|
Archetypical cytokines signaling through classical-cytokine receptors Type I helical Cytokine families signaling through Class I cytokine receptors (CRF1 family or Hematopoietin family) | |
IL-2 Family, or Common Gamma Chain Receptor Family | IL-2, IL-4 subfamily(IL-4, IL-13), IL-9, IL-15, and IL-7 subfamily(IL-7) |
Common Beta Chain Receptor Cytokine Family | IL-5, Colony Stimulating Factor 2/Granulocyte Monocyte-Stimulating Factor (CSF2/GM-CSF) |
Prolactin family | Colony Stimulating Factor 3/Granulocyte-Stimulating Factor (CSF3/G-CSF) |
IL-6 Family | IL-6 |
IL-12 Family | IL-12 (p70) |
Type II Cytokine families signaling through Class II cytokine receptors (CRF2 family or IL-10/IFN superfamily) | |
IL-10 Family | IL-10 |
Type II IFN | IFNγ |
Cytokine families signaling through immunoglobulin (Ig) superfamily cytokine receptors non-Receptor tyrosine-kinase (RTK) | |
IL-1 Family | IL-1β, IL-1Ra |
Cytokine TNF family signaling through TNF receptor family | |
Family A | TNFα (TNFSF2) |
Chemokine superfamily signaling through chemokine receptors (seven-transmembrane heptahelical(serpentine) receptors associated with G-protein trimeric system) | |
Chemokine CC Motif Ligand Family (CCL) | MCP1 (CCL2), MIP-1α (CCL3), MIP-1β (CCL4), RANTES (CCL5) and eotaxin(CCL11) |
Chemokine CXC Motif Ligand Family (CXCL) | IP-10 (CXCL10), IL-8 (CXCL8) |
Orphan and other cytokine family members | |
IL-17 Family | IL-17A |
Growth factors and signaling proteins | |
Platelet-Derived Growth Factor Family | PDGF-BB (Platelet-Derived Growth Factor subunit B) |
Vascular Endothelial Growth Factor Family | VEGF (Vascular Endothelial Growth Factor)/Vascular Permeability Factor (VPF) |
Fibroblast Growth Factor Family | bFGF(FGF2/FGF-β) |
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Parameter | CKD− | NA-CKD | A-CKD− | A-CKD+ |
---|---|---|---|---|
N | 33 | 33 | 32 | 32 |
Sex, M/F, n | 12/21 | 12/21 | 12/20 | 12/20 |
Age, years | 64 (58; 69) | 65 (58; 67) | 63 (57; 67) | 65 (58; 69.5) |
Smokers, n (%) | 3 (9.1%) | 5 (15.1%) | 4 (12.5%) | 3 (9.4%) |
BMI, kg/m2 | 34.4 (28.1; 36.9) | 34.7 (30.1; 38.9) | 33.8 (31.2; 40.0) | 32.9 (30.3; 36.7) |
WHR | 0.97 (0.93; 1.1) | 1.02 (0.9; 1.1) | 1.00 (0.93; 1.1) | 1.00 (0.91; 1.07) |
Diabetes duration, years | 13 (11; 16) | 14 (12; 19) | 13.5 (11; 17) | 13.5 (11; 17.5) |
Diabetic complications and associated diseases | ||||
Obesity, n (%) | 21 (63.6%) | 24 (72.7%) | 25 (78.2%) | 26 (81.3%) |
Diabetic retinopathy, n (%) | 17 (51.5%) | 17 (51.5%) | 20 (62.5%) | 21 (65.6%) |
Arterial hypertension, n (%) | 31 (93.9%) | 33 (100%) | 31 (96.9%) | 32 (100%) |
Coronary artery disease, n (%) | 13 (39.4%) | 16 (48.5%) | 16 (50.0%) | 18 (56.2%) |
Myocardial infarction in anamnesis, n (%) | 4 (12.1) | 7 (21.2%) | 5 (15.6%) | 10 (31.3%) |
Cerebrovascular event in anamnesis, n (%) | 1 (3.0%) | 6 (18.2%) | 3 (9.4%) | 2 (6.3%) |
Peripheral artery disease, n (%) | 17 (51.5%) | 22 (66.7%) | 20 (62.5%) | 23 (71.9%) |
Treatment | ||||
Metformin, n (%) | 26 (78.8%) | 20 (60.6%) | 23 (71.9%) | 20 (62.5%) |
Sulfonylurea, n (%) | 8 (24.2%) | 15 (45.5%) | 12 (37.5%) | 9 (28.1%) |
Insulin, n (%) | 21 (63.6%) | 22 (66.7%) | 21 (65.6%) | 26 (81.3%) |
RAS blockers, n (%) | 33 (100%) | 27 (81.8%) | 26 (81.3%) | 27 (84.4%) |
Diuretics, n (%) | 12 (36.4%) | 17 (51.5%) | 16 (50.0%) | 17 (53.1%) |
Calcium channel blockers, n (%) | 8 (24.2%) | 16 (48.5%) | 10 (31.3%) | 14 (43.8%) |
Antiplatelet agents, n (%) | 21 (63.6%) | 27 (81.8%) | 19 (59.4%) | 24 (75.0%) |
Statins, n (%) | 13 (39.4%) | 23 (69.7%) | 7 (21.9%) ### | 17 (53.1%) |
Parameter | CKD− | NA-CKD | A-CKD− | A-CKD+ | |
---|---|---|---|---|---|
N | 33 | 33 | 32 | 32 | |
Renal tests | |||||
Serum creatinine, μmol/L | 76 (68; 87) | 111 (102; 124) *** | 87 (79; 97) §§§ ### | 117 (98; 144) *** | |
eGFR, mL/min/1.73 m2 | 84 (73; 94) | 51 (45; 55) *** | 71 (65; 77) §§§ ### | 51 (43; 55) *** | |
UACR, mg/mmol | 0.6 (0.3; 0.9) | 0.6 (0.3; 0.9) | 13.5 (6.4; 38.4) *** ### | 14.1 (7.2; 82.5) *** ### | |
Urinary nephrin excretion, ng/mmol | 12.1 (4.7; 21.1) | 7.8 (4.1; 16.3) | 22.6 (16.6; 36.2) *** ### | 22.2 (17.1; 32.9) *** ### | |
Urinary podocin excretion, ng/mmol | 133 (86; 222) | 105 (65.4; 193.9) | 250 (144; 421) *** ### | 268 (134; 411) *** ### | |
Urinary excretion of WFDC2, ng/mmol | M | 442 (310; 941) +++ | 723 (406; 811) +++ | N/D | 628 (410; 1277) +++ |
F | 5.6 (0; 81) | 129 (0; 330) ** | N/D | 231 (110; 619) ** | |
Other biochemical parameters | |||||
HbA1C | % | 8.48 (7.5; 9.8) | 9.06 (7.9; 10.26) | 9.36 (8.25; 11.58) | 8.81 (7.64; 10.1) |
mmol/mol | 69 (58; 84) | 76 (63; 89) | 79 (67; 103) | 73 (60; 87) | |
Total cholesterol, mmol/L | 4.92 (4.32; 5.51) | 5.14 (4.11; 6.07) | 4.89 (4.06; 5.89) | 5.5 (4.19; 6.25) | |
LDL-cholesterol, mmol/L | 3.02 (2.7; 3.59) | 3.21 (2.51; 3.92) | 3.19 (2.6; 3.95) | 3.26 (2.54; 4.18) | |
HDL-cholesterol, mmol/L | 1.13 (1; 1.31) | 1.22 (1.09; 1.41) | 1.07 (0.93; 1.25) # | 1.12 (1; 1.41) | |
Triglycerides, mmol/L | 1.76 (1.15; 2.47) | 1.9 (1.5; 2.6) | 2.2 (1.64; 3.3) | 1.93 (1.54; 3.08) | |
Uric acid, μmol/L | 298 (243; 352) | 341 (315; 392) | 322 (281; 383) | 366 (272; 418) | |
Serum hs-CRP, mg/L | 4.1 (2.3; 8.2) | 6.2 (2.3; 8.4) | 4.4 (1.4; 7.3) | 6.7 (2.2; 13.1) | |
Hematology and coagulation tests | |||||
Hemoglobin, g/L | 139 (131; 148) | 141 (128; 151) | 141 (127; 152) | 141 (126; 153) | |
RBC, × 1012/L | 4.79 (4.5; 4.9) | 4.72 (4.44; 5.06) | 4.85 (4.6; 5.13) | 4.7 (4.26; 4.87) | |
WBC, × 109/L | 6.18 (5.93; 7.65) | 7.44 (5.61; 8.34) | 7.52 (6.03; 8.85) | 7.31 (5.53; 8.15) | |
Platelets, × 109/L | 244 (218; 269) | 253 (207; 282) | 247 (212; 278) | 206 (181; 275) | |
ESR, mm/h | 15 (9; 22) | 19 (12; 26.5) | 22.5 (15.5; 29) | 23.5 (18; 30) ** | |
Fibrinogen, g/L | 4.15 (3.3; 5.3) | 3.9 (3.2; 4.45) | 4.4 (3.7; 5.5) | 4.6 (4; 5.3) | |
SFMCs, mg/dL | 4 (3.5; 13.5) | 14 (3.5; 21) | 10.5 (6; 21.5) | 12 (8; 19) | |
D-dimer, ng/mL | 255 (215; 309) | 251 (231; 385) | 268 (231; 297) | 277 (238; 327) |
Parameter | Crude OR (95% CI), p-Value | Adjusted OR (95% CI), p-Value |
---|---|---|
eGFR <60 mL/min × 1.73 m21 | ||
IL-17A, pg/mL | 1.04(1.01–1.09), p = 0.004 | 1.03(1.01–1.09), p = 0.01 |
MIP-1α, pg/mL | 1.30(1.06–1.49), p = 0.02 | 1.15(1.02–1.50), p = 0.03 |
Serum hs-CRP, mg/L | 1.01(0.96–1.05), p = 0.10 | 1.20(1.02–1.30), p = 0.02 |
Age, years | 1.06 (0.98–1.15), p = 0.16 | 1.04(0.99–1.14), p = 0.08 |
UACR ≥3.0 mg/mmol2 | ||
Eotaxin, 10 pg/mL | 0.98(0.94–1.00), p = 0.09 | 0.95(0.90–1.00), p = 0.03 |
IL-15, 10 pg/mL | 1.03(0.98–1.06), p = 0.20 | 1.04(0.98–1.07), p = 0.09 |
Parameter | Crude OR (95% CI), p-Value | Adjusted OR (95% CI), p-Value |
---|---|---|
NA-CKD1 | ||
IL-17A, pg/mL | 1.08 (1.04–1.18), p = 0.001 | 1.06 (1.02–1.12), p = 0.004 |
MIP-1α, pg/mL | 1.70 (1.20–2.30), p = 0.008 | 1.45 (1.02–2.06), p = 0.03 |
A-CKD−2 | ||
IL-13, pg/mL | 1.20 (0.96–1.50), p = 0.09 | 1.24 (1.01–1.54), p = 0.04 |
HbA1C, % | 1.15 (0.94–1.52), p = 0.12 | 1.30 (0.98–1.62), p = 0.06 |
A-CKD+3 | ||
IL-6, pg/mL | 1.27 (1.02–1.64), p = 0.02 | 1.37 (1.08–1.69), p = 0.009 |
Serum hs-CRP, mg/L | 1.06 (0.92–1.32), p = 0.21 | 1.18 (1.01–1.36), p = 0.04 |
Age, years | 1.03 (0.90; 1.12), p = 0.26 | 1.09 (0.98–1.20), p = 0.10 |
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Klimontov, V.V.; Korbut, A.I.; Orlov, N.B.; Dashkin, M.V.; Konenkov, V.I. Multiplex Bead Array Assay of a Panel of Circulating Cytokines and Growth Factors in Patients with Albuminuric and Non-Albuminuric Diabetic Kidney Disease. J. Clin. Med. 2020, 9, 3006. https://doi.org/10.3390/jcm9093006
Klimontov VV, Korbut AI, Orlov NB, Dashkin MV, Konenkov VI. Multiplex Bead Array Assay of a Panel of Circulating Cytokines and Growth Factors in Patients with Albuminuric and Non-Albuminuric Diabetic Kidney Disease. Journal of Clinical Medicine. 2020; 9(9):3006. https://doi.org/10.3390/jcm9093006
Chicago/Turabian StyleKlimontov, Vadim V., Anton I. Korbut, Nikolai B. Orlov, Maksim V. Dashkin, and Vladimir I. Konenkov. 2020. "Multiplex Bead Array Assay of a Panel of Circulating Cytokines and Growth Factors in Patients with Albuminuric and Non-Albuminuric Diabetic Kidney Disease" Journal of Clinical Medicine 9, no. 9: 3006. https://doi.org/10.3390/jcm9093006