Increased Heparanase Levels in Urine during Acute Puumala Orthohantavirus Infection Are Associated with Disease Severity
Abstract
:1. Introduction
2. Materials and Methods
2.1. Ethics Statement and Clinical Samples
2.2. HPSE Measurement Assay
2.3. ELISAs
2.4. Virus Isolates
2.5. Podocyte Cultures
2.6. Immunofluorescence
2.7. HPSE mRNA Expression
2.8. Statistical Analysis
3. Results
3.1. HPSE and Syndecan–1 Levels Are Increased in Urine of Acute PUUV–HFRS Patients
3.2. Urinary HPSE Levels Correlate with Albuminuria and Other Disease Severity Markers
3.3. Urinary HPSE Levels Possess Predictive Power over Disease Severity, Albuminuria and Hypotension
3.4. Upregulation of HPSE in Orthohantavirus–Infected Podocytes
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Variable (Unit) | Mean (SE; Range) |
---|---|
Number of patients | 56 |
Hospital length of stay (days) | 5.81 (0.46; 2–25) |
Age (years) | 41 (1.65; 22–73) |
Male: Female ratio | 2.3:1 |
Min eGFR (mL/min/1.73m2) | 63 (5.75; 5–141) |
Max plasma creatinine (μmol/L) | 266.22 (35.61; 45–1071) |
Urine albumin: creatinine ratio (mg/g) | 1012.12 (190.67; 2.9–5530.8) |
Max urine HPSE: creatinine ratio (mg/g) | 0.22 (0.04; 0–1.17) |
Min plasma albumin (g/dL) | 2.41 (0.08; 2.3–3.5) |
Max plasma HPSE (ng/mL) | 4.54 (0.70; 0–20.23) |
Max urine syndecan–1: creatinine ratio | 36.3 (9.5; 0–411.62) |
Urine IL–6: creatinine ratio (pg/μg) | 0.21 (0.05; 0.005–1.30) |
Plasma IL–6 (pg/mL) | 128.58 (39.9; 10–785.8) |
Urine IL–8: creatinine ratio (pg/μg) | 0.45 (0.18; 0.003–5.80) |
Plasma IL–8 (pg/mL) | 41.26 (8.72; 10–234.86) |
Urine IP–10: creatinine ratio (pg/μg) | 4.47 (0.70; 0.22–16.92) |
Plasma IP–10 (pg/mL) | 4734.39 (764.17; 739.8–18224) |
Urine MCP–1: creatinine ratio (pg/μg) | 7.64 (1.97; 0.01–63.64) |
Plasma MCP–1 (pg/mL) | 373.97 (120.78; 23.5–3636.78) |
MPO (ng/mL) | 150.85 (9.5; 46–332.17) |
Severity score | 4.04 (0.24; 0–7) |
Min mean arterial pressure (mmHg) | 84.11 (1.42; 51.33–103.33) |
Max CRP (mg/L) | 67.32 (5.11; 9.7–155.2) |
Min thrombocytes (109/L) | 85.56 (5.66; 36–266) |
Max leukocytes (109/L) | 10.62 (0.58; 4.1–25.5) |
Dependent Variables | Type of Regression | Independent Variables | Estimate | Std. Error | 95% CI | t Value | p–Value of Variable | R2 | F– Statistic | p–Value of Model |
---|---|---|---|---|---|---|---|---|---|---|
Minimum mean arterial pressure | Simple | Plasma albumin | 15.594 | 4.715 | [5.488–24.7] | 3.440 | 0.0031 ** | 0.2425 | 10.25 | 0.0031 ** |
Multiple | Plasma albumin | 15.4735 | 4.8731 | [5.507–25.44] | 3.175 | 0.0035 ** | 0.3417 | 5.017 | 0.0064 ** | |
Urinary albumin: creatinine ratio | −0.1508 | 0.1774 | [−0.5136–0.2121] | −0.85 | 0.0724 | |||||
Urinary HPSE: creatinine ratio | 0.3703 | 0.1854 | [−0.0088–0.7495] | 1.998 | 0.0502 | |||||
Severity score | Simple | Urinary albumin: creatinine ratio | 3.254 | 1.014 | [1.210–5.299] | 3.211 | 0.0025 ** | 0.1934 | 10.31 | 0.0025 ** |
Simple | Urinary HPSE: creatinine ratio | 2.799 | 1.082 | [0.6167–4.982] | 2.586 | 0.0132 * | 0.1346 | 6.690 | 0.0132 * | |
Urinary albumin: creatinine ratio | Simple | Urinary HPSE: creatinine ratio | 0.7355 | 0.1027 | [0.5257–0.9376] | 0.1027 | <0.0001 *** | 0.5276 | 51.26 | <0.0001 *** |
Multiple | Urinary HPSE: creatinine ratio | 0.6587 | 0.0941 | [0.4687–0.8486] | 6.998 | <0.0001 *** | 0.621 | 37.02 | <0.0001 *** | |
eGFR | −0.0848 | 0.0308 | [−0.1469–−0.0227] | −2.756 | 0.0086 ** |
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Cabrera, L.E.; Schmotz, C.; Saleem, M.A.; Lehtonen, S.; Vapalahti, O.; Vaheri, A.; Mäkelä, S.; Mustonen, J.; Strandin, T. Increased Heparanase Levels in Urine during Acute Puumala Orthohantavirus Infection Are Associated with Disease Severity. Viruses 2022, 14, 450. https://doi.org/10.3390/v14030450
Cabrera LE, Schmotz C, Saleem MA, Lehtonen S, Vapalahti O, Vaheri A, Mäkelä S, Mustonen J, Strandin T. Increased Heparanase Levels in Urine during Acute Puumala Orthohantavirus Infection Are Associated with Disease Severity. Viruses. 2022; 14(3):450. https://doi.org/10.3390/v14030450
Chicago/Turabian StyleCabrera, Luz E., Constanze Schmotz, Moin A. Saleem, Sanna Lehtonen, Olli Vapalahti, Antti Vaheri, Satu Mäkelä, Jukka Mustonen, and Tomas Strandin. 2022. "Increased Heparanase Levels in Urine during Acute Puumala Orthohantavirus Infection Are Associated with Disease Severity" Viruses 14, no. 3: 450. https://doi.org/10.3390/v14030450