Longitudinal Analysis of Urinary Cytokines and Biomarkers in COVID-19 Patients with Subclinical Acute Kidney Injury
Abstract
:1. Introduction
2. Results
2.1. Characteristics of Study Participants
2.2. Performance of Biomarkers and Cytokines as Predictors of AKI
2.3. Higher Levels of Urinary EGF Were Protective for AKI
2.4. Correlation of Urinary EGF with Kidney Stress Biomarkers
2.5. Imputation of Cytokine and Chemokine Missing Values
2.6. Principal Component Analysis of Cytokines
3. Discussion
4. Materials and Methods
4.1. Study Population
4.2. Definition of Acute Kidney Injury
4.3. Biomarker Determinations
4.4. Cytokine Determinations
4.5. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent statement
Data Availability Statement
Conflicts of Interest
References
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Variable | Overall (n = 51) | AKI ** (n = 28) | Non-AKI (n = 23) | p |
---|---|---|---|---|
Age, years * | 53 (40–61) | 56 (40.5–61.5) | 51 (40–55) | 0.12 |
Male (n (%)) | 30 (58.8) | 19 (68) | 11 (47) | 0.14 |
BMI, kg/m2 * | 29.3 (25.9–31.6) | 16 (57) | 14 (46.7) | 0.71 |
Comorbidities | ||||
Obesity (n (%)) | 21 (41.2) | 12 (43) | 9 (39) | 0.78 |
Diabetes (n (%)) | 16 (31.4) | 8 (28) | 8 (35) | 0.63 |
Hypertension (n (%)) | 14 (27.5) | 12 (42) | 2 (8.7) | 0.01 |
2 ≥ comorbidities (n (%)) | 21 (41.2) | 14 (50) | 7 (30.4) | 0.15 |
Critical care variables | ||||
IMV (n (%)) | 32 (62.7) | 20 (71.4) | 12 (52.2) | 0.15 |
PaO2/FiO2 ratio, mmHg * | 141 (108–187) | 139 (101–162) | 167 (132–220) | 0.06 |
PEEP, cm H2O * | 10 (9.5–14) | 10 (10–14) | 10 (10–12) | 0.79 |
pH * | 7.41 (7.33–7.44) | 7.39 (7.34–7.44) | 7.41 (7.33–7.46) | 0.53 |
pCO2, mmHg * | 38.0 (32.3–51.9) | 42.1 (35–52.5) | 37.5 (25–47) | 0.15 |
SOFA score, points * | 4 (2–6) | 4 (3–7) | 3 (2–6) | 0.01 |
Treatments | ||||
Vasoactive drugs (n (%)) | 16 (31.4) | 10 (62.5) | 6 (26) | 0.46 |
Inotropic drug (n (%)) | 2 (3.9) | 1 (50) | 1 (4.3) | 0.88 |
Systemic steroids (n (%)) | 25 (49) | 13 (52) | 12 (52) | 0.68 |
Hydroxychloroquine (n (%)) | 7 (13.7) | 5 (71.4) | 2 (8.69) | 0.34 |
Lopinavir/Ritonavir (n (%)) | 12 (23.5) | 4 (33.3) | 8 (34.7) | 0.08 |
Nephrotoxic drugs (n (%)) | 1 (2) | 0 (0.0) | 1 (4.34) | 0.26 |
Renal function indicators | ||||
Serum creatinine, mg/dL, Day 1 * | 0.60 (0.50–0.72) | 0.61 (0.51–0.76) | 0.60 (0.49–0.70) | 0.58 |
eGFR, mL/min/1.73m2, Day 1 * | 112.38 (98.45–121.40) | 113 (96–118) | 111 (106–124) | 0.73 |
Serum creatinine, mg/dL, Day 5 * | 0.69 (0.54–0.88) | 0.79 (0.67–1.13) | 0.60 (0.51–0.75) | 0.01 |
eGFR, mL/min/1.73m2, Day 5 * | 104 (90–117.50) | 99 (69.5–109.5) | 110 (103–121) | 0.01 |
Final serum creatinine, mL/min * | 0.67 (0.55–0.97) | 0.74 (0.61–1.09) | 0.61 (0.52–0.76) | 0.13 |
Final eGFR, mL/min/1.73m2 * | 104 (90–118-50) | 102 (88.5–113) | 107 (102–121) | 0.07 |
Laboratories at Day 1 | ||||
Hemoglobin, g/dL * | 13.3 (12.6–14.9) | 13.4 (12.5–15) | 13.3 (12.7–14.4) | 0.99 |
Leucocytes, 10 ×3 mm3 * | 8.9 (6.3–13.4) | 9.3 (7.8–12.1) | 7.8 (5.1–13.5) | 0.22 |
Lymphocytes, 10 ×3 mm3 * | 0.8 (0.6–1.0) | 0.8 (0.45–1) | 0.8 (0.65–1) | 0.37 |
Platelets, 10 ×3 mm3 * | 272 (219–329) | 272 (216–362) | 272 (219–314) | 0.75 |
Lactate dehydrogenase, U/mL * | 387 (299–557) | 386 (314–544) | 397 (265–572) | 0.37 |
Total bilirubin, mg/dL * | 0.47 (0.37–0.63) | 0.56 (0.40–0.88) | 0.43 (0.34–0.54) | 0.07 |
Creatine phosphokinase, U/L * | 140 (39–443) | 224.5 (79.5–739.5) | 60 (35.5–291) | 0.02 |
D-dimer, µg/mL * | 0.91 (0.42–2.50) | 1.08 (0.55–4.27) | 0.49 (0.34–1.29) | 0.04 |
C-reactive protein, mg/dL * | 16.5 (10–27.6) | 18 (13–31.9) | 13.2 (10–22.4) | 0.05 |
Fibrinogen, mg/dL * | 734 (580–821) | 742 (604–805) | 685 (565–786) | 0.41 |
Procalcitonin, ng/mL * | 0.39 (0.11–0.92) | 0.62 (0.35–1.26) | 0.14 (0.08–0.34) | 0.01 |
Troponin, pg/mL * | 5.6 (3.3–37) | 11.8 (3.8–37) | 3.9 (1.5–9) | 0.04 |
Ferritin, ng/mL * | 745 (358–1883) | 710 (304–2491) | 756 (457–953) | 0.83 |
Urinary kidney biomarkers | ||||
TIMP-2, ng/mL, Day 1 * | 5.64 (3.03–9.02) | 6.16 (3.49–9.66) | 5.07 (3.01–7.24) | 0.26 |
TIMP-2, ng/mL, Day 5 * | 5.21 (3.31–7.81) | 4.16 (3.18–7.36) | 5.26 (3.65–12.03) | 0.11 |
IGFBP7, ng/mL/1000, Day 1 * | 13.83 (8.60–24.65) | 17.43 (9.35–30.20) | 12.50 (7.04–19.92) | 0.12 |
IGFBP7, ng/mL/1000, Day 5 * | 22.75 (12.63–46.20) | 28.44 (13.05–77.78) | 16.53 (11.93–32.35) | 0.22 |
[TIMP2] × [IGFBP7], (ng/mL)2/1000, Day 1 * | 0.085 (0.05–0.24) | 0.16 (0.05–0.32) | 0.07 (0.04–0.11 | 0.04 |
[TIMP2] × [IGFBP7], (ng/mL)2/1000, Day 5 * | 0.14 (0.05–0.28) | 0.13 (0.05–0.32) | 0.14 (0.06–0.19) | 0.99 |
NGAL, ng/mL, Day 1 * | 39.3 (19.2–98.5) | 54.70 (36.40–117.40) | 32.40 (14–40.05) | 0.00 |
NGAL, ng/mL, Day 5 * | 33 (14–106.2) | 35.20 (17.55–118.95) | 20.50 (11.45–52.50) | 0.07 |
Outcomes | ||||
Day in hospital | 16 (12–27) | 20.5 (14.5–28) | 13 (10.5–22.5) | 0.03 |
Days on IMV | 13 (10–22.2) | 13 (12–22) | 10.5 (8–26) | 0.43 |
Mortality (n (%)) | 10 (19.6) | 7 (25) | 3 (13) | 0.28 |
Cytokine/ Chemokine (pg/mL) | Overall (n = 51) | AKI (n = 25) | No-AKI (n = 26) | p a | q b |
---|---|---|---|---|---|
FGF * Day 1 | 3.21 (1.78–9.14) | 2.61 (1.74–7.31) | 4.52 (1.97–11.81) | 0.30 | 0.89 |
FGF * Day 5 | 2.86 (1.44–6.64) | 2.43 (1.42–6.64) | 3.75 (1.74–6.09) | 0.76 | 0.97 |
IL-1β * Day 1 | 10.17 (5.54–20.11) | 9.77 (4.92–15.94) | 17.21 (7.71–25.31) | 0.16 | 0.84 |
IL-1β * Day 5 | 7.38 (3.78–12.41) | 6.48 (3.60–12.29) | 9.07 (5.92–12.73) | 0.22 | 0.97 |
G-CSF * Day 1 | 173.98 (123.48–197.43) | 171.05 (119.76–224.19) | 176.49 (166.81–188.64) | 0.51 | 0.89 |
G-CSF * Day 5 | 159.05 (93.93–199.12) | 181.37 (109.50–211.79) | 157.53 (94.46–191.30) | 0.56 | 0.97 |
IL-10 * Day 1 | 1.94 (1.70–4.48) | 1.84 (1.70–3.16) | 4.48 (1.88–13.35) | 0.09 | 0.60 |
IL-10 * Day 5 | 3.52 (2.13–5.03) | 3.52 (2.47–4.72) | 2.59 (2.14–4) | 0.73 | 0.97 |
IL-13 * Day 1 | 6.30 (3.01–9.28) | 5.56 (2.67–7.87) | 7.12 (4.03–9.93) | 0.51 | 0.89 |
IL-13 * Day 5 | 5.68 (2.93–7.83) | 5.33 (2.64–7.65) | 6.05 (3.07–8.05) | 0.65 | 0.97 |
IL-6 * Day 1 | 7.46 (3.57–15.43) | 6.15 (3.71–14) | 10.37 (3.39–19.61) | 0.27 | 0.89 |
IL-6 * Day 5 | 6.16 (2.22–12.98) | 5.92 (2.54–13.14) | 6.97 (2.11–10.22) | 0.90 | 0.99 |
IL-12 * Day 1 | 2.22 (1.73–3.40) | 2.19 (1.75–3.26) | 2.38 (1.73–3.27) | 0.80 | 0.89 |
IL-12 * Day 5 | 2.26 (1.51–4.41) | 1.83 (1.33–2.37) | 2.80 (1.74–5.65) | 0.01 | 0.41 |
RANTES * Day 1 | 13.83 (9.38–22.67) | 17.40 (13.2–25.4) | 10.7 (7.9–12.8) | 0.01 | 0.14 |
RANTES * Day 5 | 15.98 (12.93–25.14) | 15.62 (11.14–28.60) | 16.11 (12.94–22.84) | 0.82 | 0.99 |
Eotaxin * Day 1 | 2.20 (1.12–4.24) | 2.52 (1.17–4.24) | 1.87 (1.13–4.62) | 0.82 | 0.89 |
Eotaxin * Day 5 | 3.50 (1.24–6.29) | 3.26 (1.84–6.18) | 4.10 (0.68–6.24) | 0.64 | 0.97 |
IL-17A * Day 1 | 3.05 (2.34–5.23) | 3.19 (2.21–8.20) | 2.90 (2.53–3.19) | 0.37 | 0.89 |
IL-17A * Day 5 | 3.04 (2.50–3.21) | 3.08 (2.60–3.63) | 2.99 (2.44–3.20) | 0.60 | 0.97 |
MIP-1α * Day 1 | 21.35 (10.97–35.89) | 21.35 (9.61–30.61) | 20.85 (11.79–35.89) | 0.69 | 0.89 |
MIP-1α * Day 5 | 11.79 (6.04–29.27) | 9.08 (4.90–29.27) | 11.79 (9.61–20.85) | 0.52 | 0.97 |
GM-CSF * Day 1 | 0.65 (0.38–1.27) | 0.75 (0.43–1.27) | 0.59 (0.34–1.22) | 0.46 | 0.89 |
GM-CSF * Day 5 | 0.68 (0.43–1.32) | 0.53 (0.38–1.38) | 0.74 (0.53.1.26) | 0.44 | 0.97 |
MIP-1β * Day 1 | 3.27 (1.84–8.16) | 3.27 (1.84–6.64) | 3.25 (1.84–8.17) | 0.79 | 0.89 |
MIP-1β * Day 5 | 4.32 (1.66–6.62) | 2.87 (1.37–6.64) | 4.37 (2.13–6.03) | 0.65 | 0.97 |
MCP-1 * Day 1 | 137.22 (50.57–311) | 148.43 (61.49–323.19) | 121.02 (49.56–237.50) | 0.62 | 0.89 |
MCP-1 * Day 5 | 124.6 (50.77–242.04) | 116.29 (91.46–254.88) | 143.23 (45.57–219.43) | 0.88 | 0.99 |
IL-15 * Day 1 | 127.72 (82.62–196.61) | 108.47 (79.62–240.22) | 130.74 (93.11–193.87) | 0.73 | 0.89 |
IL-15 * Day 5 | 140.19 (97.14–176.12) | 145.27 (128.26–190.80) | 103.37 (56.60–142.85) | 0.12 | 0.97 |
EGF * Day 1 | 4083.27 (1218.24–5768.37) | 2044 (719–4083) | 5568 (5056–5974) | 0.01 | 0.14 |
EGF * Day 5 | 4127.73 (1722.80–5494.66) | 3934.24 (1552.42–5254.31) | 4614.17 (3537.42–5424.23) | 0.55 | 0.97 |
IL-5 * Day 1 | 0.77 (0.23–2.38) | 0.91 (0.23–4.73) | 0.67 (0.29–1.25) | 0.34 | 0.89 |
IL-5 * Day 5 | 2.38 (0.46–5.85) | 2.38 (0.35–6.40) | 2.38 (1.44–2.71) | 0.75 | 0.97 |
HGF * Day 1 | 41.18 (21.27–80.86) | 40.12 (21.27–80.22) | 41.18 (21.99–81.51) | 0.80 | 0.89 |
HGF * Day 5 | 53.12 (28.68–79.97) | 54.82 (28.84–70.20) | 52.50 (32.45–79.97) | 0.86 | 0.99 |
VEGF * Day 1 | 2.59 (0.82–4.41) | 2.26 (0.82–3.79) | 3 (0.70–4.74) | 0.77 | 0.89 |
VEGF * Day 5 | 2.74 (0.77–4.41) | 2.88 (0.95–3.76) | 1.36 (0.77–4.60) | 0.60 | 0.97 |
IFN-α * Day 1 | 10.90 (1.89–17.50) | 10.90 (1.55–16.77) | 13.64 (2.52–17.50) | 0.27 | 0.89 |
IFN-α * Day 5 | 12.09 (1.92–17.21) | 10.90 (1.92–14.39) | 13.45 (2.08–18.82) | 0.41 | 0.97 |
IL-1RA * Day 1 | 2829.72 (1209.25–5344.40) | 2689.10 (1238.42–5813.46) | 3421.78 (1263.64–4084.19) | 0.90 | 0.93 |
IL-1RA * Day 5 | 1879.33 (1000.58–4591.50) | 1675.03 (1071.18–3571.60) | 2088.81 (830.36–4601.67) | 0.72 | 0.97 |
IL-2 * Day 1 | 1.57 (1.27–2.51) | 1.58 (1.45–2.27) | 1.53 (1.12–2.23) | 0.45 | 0.89 |
IL-2 * Day 5 | 1.83 (1.26–2.52) | 1.79 (1.34–3) | 1.88 (1.26–2.27) | 0.98 | 1 |
IL-7 * Day 1 | 14.31 (4.35–29.41) | 15.69 (4.65–30.05) | 12.93 (4.54–27.03) | 0.66 | 0.89 |
IL-7 * Day 5 | 10.41 (3.71–30.71) | 12.59 (3.95–43.47) | 6.78 (4.06–16.37) | 0.42 | 0.97 |
IP-10 * Day 1 | 2.38 (2.04–6.06) | 2.52 (2.02–7.33) | 2.24 (2.19–3.63) | 0.64 | 0.89 |
IP-10 * Day 5 | 2.93 (1.44–5.02) | 3.06 (1.81–6.77) | 2.78 (1.75–3.75) | 0.49 | 0.97 |
IL-2R * Day 1 | 653 (197.59–1633.81) | 649.43 (203.20–1429.30) | 786.61 (193.19–1686.19) | 0.84 | 0.89 |
IL-2R * Day 5 | 296.03 (116.97–990.57) | 304.80 (121.13–1103) | 296.03 (107.33–818.01) | 0.89 | 1 |
MIG * Day 1 | 43.28 (21.73–52.93 | 39.96 (15.74–56.63) | 46.12 (25.48–51.75) | 0.67 | 0.89 |
MIG * Day 5 | 39.97 (21.73–61.45) | 34.17 (21.73–60.93) | 49.22 (22.28–61.45) | 0.53 | 0.97 |
IL-4 * Day 1 | 70.19 (3.15) | 6.36 (6.36–6.36) | 6.36 (6.36–6.36) | ||
IL-4 * Day 5 | 10.29 (6.18) | 34.98 (6.18–63.78) | 1 | 1 | |
IL-8 * Day 1 | 8.52 (2.66–28.19) | 9.04 (2.63–28.60) | 7.83 (3.47–26.93) | 1 | 0.89 |
IL-8 * Day 5 | 15.09 (5.14–76.49) | 10.81 (5.22–73.64) | 16.42 (3.18–135.60) | 0.61 | 0.97 |
Biomarker | AUC | 95% CI | p | Cutoff | Sensitivity (%) | Specificity (%) | PPV (%) | NPV (%) | Accuracy (%) |
---|---|---|---|---|---|---|---|---|---|
Prediction of AKI on day 1 | |||||||||
EGF (pg/mL) | 0.788 | 0.597–0.979 | 0.014 | 4600 | 80.00 | 81.82 | 74.58 | 85.99 | 81.09 |
[TIMP2] × [IGFBP7] (ng/mL)2/1000 | 0.672 | 0.521–0.823 | 0.036 | 0.2 | 42.86 | 95.65 | 86.79 | 71.52 | 74.53 |
NGAL (ng/mL) | 0.797 | 0.668–0.927 | 0.014 | 40.0 | 68.00 | 73.91 | 63.47 | 77.60 | 71.55 |
Variables | Unadjusted OR (CI 95%) | p | Adjusted OR (CI 95%) | p |
---|---|---|---|---|
Age > 60 years | 2.29 (0.44–11.91) | 0.324 | 0.84 (0.06–11.22) | 0.901 |
Men | 2.25 (0.34–14.61) | 0.396 | 2.75 (0.28–26.68) | 0.381 |
Hypertension | 11.42 (1.15–113) | 0.037 | 5.75 (0.32–103) | 0.235 |
D-Dimer μg/ml | 1.35 (0.18–10.0) | 0.769 | - | - |
NGAL > 40 ng/ml | 2.66 (0.46–15.25) | 0.270 | - | - |
EGF > 4600 pg/mL * | 0.05 (0.008–0.40) | 0.004 | 0.095 (0.01–0.81) | 0.031 |
Principal Component | Unadjusted OR (95% CI) | p | Adjusted OR (95% CI) * | p |
---|---|---|---|---|
Day 1 | ||||
PC-1: IFN-α; EGF | 0.5 (0.23–1.11) | 0.08 | 0.24 (0.07–0.78) | 0.01 |
PC-2: IL-1R; G-CSF; IP-10; IL-5 | 7.14 (0.58–87.78) | 0.12 | 15.95 (0.31–817) | 0.16 |
PC-3: IL-10 | 0.45 (0.13–1.51) | 0.19 | - | - |
PC-4: IL-12; MIP-1β | 7.38 (0.95–57.18) | 0.05 | 51.09 (2.12–1233) | 0.01 |
PC-5: HGF; MCP-1; IL-6 | 0.39 (0.12–1.22) | 0.10 | - | - |
Day 5 | ||||
PC-1: IFN-α; EGF | 0.37 (0.14–0.97) | 0.04 | 0.09 (0.01–0.74) | 0.02 |
PC-2: IL-1R; G-CSF; IP-10; IL-5 | 1.81 (0.64–5.13) | 0.26 | 7.7 (1.06–55.74) | 0.04 |
PC-3: IL-10 | 6.46 (0.72–58.29) | 0.09 | - | - |
PC-4: IL-12; MIP-1β | 0.42 (0.11–1.57) | 0.19 | 0.2 (0.02–1.73) | 0.14 |
PC-5: HGF; MCP-1; IL-6 | 1.13 (0.41–3.12) | 0.81 | 9.37 (0.97–90.1) | 0.05 |
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Casas-Aparicio, G.; Alvarado-de la Barrera, C.; Escamilla-Illescas, D.; León-Rodríguez, I.; Del Río-Estrada, P.M.; González-Navarro, M.; Calderón-Dávila, N.; Olmedo-Ocampo, R.; Castillejos-López, M.; Figueroa-Hernández, L.; et al. Longitudinal Analysis of Urinary Cytokines and Biomarkers in COVID-19 Patients with Subclinical Acute Kidney Injury. Int. J. Mol. Sci. 2022, 23, 15419. https://doi.org/10.3390/ijms232315419
Casas-Aparicio G, Alvarado-de la Barrera C, Escamilla-Illescas D, León-Rodríguez I, Del Río-Estrada PM, González-Navarro M, Calderón-Dávila N, Olmedo-Ocampo R, Castillejos-López M, Figueroa-Hernández L, et al. Longitudinal Analysis of Urinary Cytokines and Biomarkers in COVID-19 Patients with Subclinical Acute Kidney Injury. International Journal of Molecular Sciences. 2022; 23(23):15419. https://doi.org/10.3390/ijms232315419
Chicago/Turabian StyleCasas-Aparicio, Gustavo, Claudia Alvarado-de la Barrera, David Escamilla-Illescas, Isabel León-Rodríguez, Perla Mariana Del Río-Estrada, Mauricio González-Navarro, Natalia Calderón-Dávila, Rossana Olmedo-Ocampo, Manuel Castillejos-López, Liliana Figueroa-Hernández, and et al. 2022. "Longitudinal Analysis of Urinary Cytokines and Biomarkers in COVID-19 Patients with Subclinical Acute Kidney Injury" International Journal of Molecular Sciences 23, no. 23: 15419. https://doi.org/10.3390/ijms232315419