Validation of Candidate Phospholipid Biomarkers of Chronic Kidney Disease in Hyperglycemic Individuals and Their Organ-Specific Exploration in Leptin Receptor-Deficient db/db Mouse
Abstract
:1. Introduction
2. Results
2.1. Associations of the Two Metabolites with eGFR and CKD in Hyperglycemic Individuals
2.1.1. Characteristics of the KORA FF4 Study Participants
2.1.2. Inverse Associations of the Two Metabolites with eGFR in Hyperglycemic Individuals
2.1.3. Associations of the Two Metabolites with CKD Are Specific for Hyperglycemia
2.2. Organ-Specific Trends of the Candidate Biomarkers in Diabetic Mice
2.2.1. Characteristics of the Mouse Model
2.2.2. Analysis of Creatinine in Eight Murine Tissues
2.2.3. Organ-Specific Trends of the Two Metabolites
3. Discussion
4. Materials and Methods
4.1. Study Participants, Outcome Definition
4.2. Mouse Study
4.3. Metabolite Quantification and Normalization
4.4. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Clinical Variables | Hyperglycemic Participants | NGT Participants | ||||
---|---|---|---|---|---|---|
CKD n = 83 | Non-CKD n = 427 | p-Value | CKD n = 85 | Non-CKD n = 1312 | p-Value | |
Age, years | 74.36 ± 7.66 | 64.32 ± 10.53 | 1.003 × 10−12 | 72.05 ± 8.23 | 55.47 ± 10.53 | 3.255 × 10−27 |
Sex, male, % | 49.4 | 57.61 | 1.686 × 10−1 | 48.24 | 43.9 | 4.361 × 10−1 |
BMI, kg/m2 | 29.25 ± 4.3 | 30.16 ± 5.02 | 1.228 × 10−1 | 28.11 ± 4.94 | 26.52 ± 4.37 | 1.415 × 10−3 |
HbA1C (%) | 5.74 ± 0.42 | 5.73 ± 0.54 | 7.552 × 10−1 | 5.56 ± 0.32 | 5.3 ± 0.32 | 7.958 × 10−12 |
Fasting glucose, mg/dl | 112.55 ± 20.44 | 111.3 ± 16.37 b | 6.440 × 10−1 | 96.79 ± 7.68 | 94.02 ± 7.3 | 1.130 × 10−3 |
2-h glucose, mg/dl | 164.43 ± 38.98 b | 160.63 ± 46.66 b | 3.724 × 10−1 | 103.16 ± 21.18 | 95.89 ± 19.9 | 3.232 × 10−3 |
Systolic BP, mmHg | 120.31 ± 22.27 | 124.78 ± 18.03 | 4.847 × 10−2 | 116.65 ± 18.23 | 115.85 ± 16.06 | 6.617 × 10−1 |
Diastolic BP, mmHg | 68.27 ± 11.15 | 74.93 ± 10.55 | 5.054 × 10−7 | 69.41 ± 10.14 | 73.06 ± 8.95 | 3.048 × 10−4 |
Triglyceride, mg/dl a | 121.11 (93.44–157.4) | 128 (92.98–178.27) | 9.711 × 10−1 | 109 (78–143.79) | 93 (70–127.46) | 1.492 × 10−2 |
Total cholesterol, mg/dl | 208.58 ± 41.45 | 220.93 ± 42.16 | 1.533 × 10−2 | 211.48 ± 43.58 | 218.59 ± 37.7 | 9.597 × 10−2 |
HDL cholesterol, mg/dl | 61.12 ± 18.42 | 59.78 ± 17.54 | 5.303 × 10−1 | 65.63 ± 18.42 | 68.57 ± 18.75 | 1.612 × 10−1 |
LDL cholesterol, mg/dl | 126.3 ± 35.49 | 140.65 ± 37.2 | 1.456 × 10−3 | 130.94 ± 37.34 | 135.83 ± 34.05 | 2.025 × 10−1 |
Creatinine, mg/dl | 1.24 ± 0.21 | 0.89 ± 0.15 | 3.916 × 10−21 | 1.25 ± 0.28 | 0.86 ± 0.16 | 6.345 × 10−31 |
eGFR, mL/min/1.73 m² | 50.5 ± 7.87 | 81.33 ± 11.9 | 3.645 × 10−47 c | 50.97 ± 8.01 | 86.92 ± 12.69 | 5.563 × 10−54 c |
UACR, mg/g a | 9.76 (5.73–26.07) | 5.43 (3.39–9.86) | 1.180 × 10−7 | 7.33 (4.44–15.38) | 4.26 (2.94–7.07) | 1.604 × 10−8 |
Smoking, % | 7.394 × 10−3 | 8.080 × 10−5 | ||||
Nonsmoker | 55.42 | 43.79 | Ref. | 40 | 41.54 | Ref. |
Former smoker | 40.96 | 42.39 | 2.789 × 10−1 | 56.47 | 40.4 | 1.086 × 10−1 |
Current smoker | 3.61 | 13.82 | 1.028 × 10−2 | 3.53 | 18.06 | 8.628 × 10−3 |
Medication usage, % | ||||||
Lipid-lowering | 34.94 | 22.48 | 1.684 × 10−2 | 32.94 | 7.7 | 2.377 × 10−12 |
Antihypertensive | 84.34 | 47.07 | 1.367 × 10−8 | 69.41 | 19.97 | 2.272 × 10−19 |
Models | SM C18:1 | PC aa C38:0 | ||
---|---|---|---|---|
Effect Estimate (95% CI) | p-Value | Effect Estimate (95% CI) | p-Value | |
Adjusted imbalanced covariates | −1.51 (−2.92 to −0.1) a | 3.624 × 10−2 | −1.82 (−3.04 to −0.59) b | 3.757 × 10−3 |
Basic model | −1.83 (−2.98 to −0.68) | 1.879 × 10−3 | −1.91 (−3.11 to −0.72) | 1.784 × 10−3 |
Full model | −1.76 (−2.9 to −0.62) | 2.499 × 10−3 | −1.81 (−2.99 to −0.63) | 2.607 × 10−3 |
Metabolites | Models | NGT Participants | Hyperglycemic Participants | ||
---|---|---|---|---|---|
OR (95% CI) | p-Value | OR (95% CI) | p-Value | ||
SM C18:1 | Adjusted imbalance covariates | 0.96 (0.77–1.21) a | 7.233 × 10−1 | 1.46 (1.09–1.97) b | 1.169 × 10−2 |
Basic model | 1.05 (0.82–1.35) | 6.986 × 10−1 | 1.93 (1.38–2.78) | 2.251 × 10−4 | |
Full model | 1.14 (0.86–1.51) | 3.733 × 10−1 | 1.99 (1.37–2.96) | 4.482 × 10−4 | |
PC aa C38:0 | Adjusted imbalance covariates | 0.98 (0.78–1.23) c | 8.438 × 10−1 | 1.61 (1.2–2.17) d | 1.487 × 10−3 |
Basic model | 1.12 (0.87–1.46) | 3.752 × 10−1 | 1.68 (1.24–2.29) | 8.723 × 10−4 | |
Full model | 1.19 (0.91–1.58) | 2.142 × 10−1 | 1.71 (1.23–2.41) | 1.578 × 10−3 |
Clinical Variables | db/db Mice n = 10 | Wild Type Mice n = 10 | p-Value |
---|---|---|---|
Body weight, g | 47.87 ± 2.37 | 21.97 ± 0.58 | 1.796 × 10−4 |
Kidney weight, g | 0.20 ± 0.02 | 0.16 ± 0.02 | 2.057 × 10−4 |
Liver weight, g | 2.56 ± 0.3 | 1.02 ± 0.09 | 1.083 × 10−5 |
Heart weight, g | 0.14 ± 0.01 | 0.12 ± 0.01 | 4.871 × 10−4 |
Blood glucose, mg/dL | 421.60 ± 41.24 | 106.7 ± 16.88 | 1.806 × 10−4 |
Plasma insulin, µg/L | 7.76 ± 2.33 | 1.03 ± 0.4 | 1.083 × 10−5 |
Triglyceride, mg/dL | 224.78 ± 106.51 | 122.24 ± 24.52 | 5.869 × 10−2 |
Total cholesterol, mg/dL | 153.24 ± 16.14 | 100.58 ± 12.16 | 1.817 × 10−4 |
HDL cholesterol, mg/dL | 125.28 ± 13.12 | 84.28 ± 8.65 | 1.083 × 10−5 |
LDL cholesterol, mg/dL | 18.76 ± 3.67 | 14.5 ± 2.08 | 8.127 × 10−3 |
C-reactive protein, mg/L | 13.12 ± 3.27 | 5.36 ± 1.12 | 1.786 × 10−4 |
Plasma creatinine a, mg/dL | 0.05 ± 0.01 | 0.08 ± 0.01 | 2.076 × 10−4 |
Plasma albumin, g/dL | 3.10 ± 0.34 | 2.56 ± 0.13 | 5.509 × 10−4 |
Tissue | Creatinine | SM C18:1 | PC aa C38:0 | |||
---|---|---|---|---|---|---|
t Statistic | p-Value | t Statistic | p-Value | t Statistic | p-Value | |
Plasma | −5.68 | 2.284 × 10−5 | 4.71 | 3.160 × 10−4 | 0.35 | 7.327 × 10−1 |
Urine a | −9.20 | 9.396 × 10−8 | −2.39 | 4.193 × 10−2 | −4.56 | 4.516 × 10−4 |
Liver | −9.21 | 5.298 × 10−8 | 6.00 | 1.288 × 10−5 | 0.19 | 8.499 × 10−1 |
Lung | −3.54 | 2.531 × 10−3 | 2.46 | 2.440 × 10−2 | 3.60 | 2.173 × 10−3 |
Adrenal glands b | 1.33 | 2.098 × 10−1 | 0.16 | 8.745 × 10−1 | 4.11 | 9.695 × 10−4 |
Adipose tissue c | −0.49 | 6.308 × 10−1 | −3.70 | 1.763 × 10 −3 | −2.36 | 3.856 × 10−2 |
Cerebellum | −0.37 | 7.164 × 10−1 | 1.18 | 2.543 ×10−1 | 1.46 | 1.605 × 10−1 |
Testis | 2.05 | 5.560 × 10−2 | −0.52 | 6.069 × 10−1 | −0.28 | 7.849 × 10−1 |
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Huang, J.; Covic, M.; Huth, C.; Rommel, M.; Adam, J.; Zukunft, S.; Prehn, C.; Wang, L.; Nano, J.; Scheerer, M.F.; et al. Validation of Candidate Phospholipid Biomarkers of Chronic Kidney Disease in Hyperglycemic Individuals and Their Organ-Specific Exploration in Leptin Receptor-Deficient db/db Mouse. Metabolites 2021, 11, 89. https://doi.org/10.3390/metabo11020089
Huang J, Covic M, Huth C, Rommel M, Adam J, Zukunft S, Prehn C, Wang L, Nano J, Scheerer MF, et al. Validation of Candidate Phospholipid Biomarkers of Chronic Kidney Disease in Hyperglycemic Individuals and Their Organ-Specific Exploration in Leptin Receptor-Deficient db/db Mouse. Metabolites. 2021; 11(2):89. https://doi.org/10.3390/metabo11020089
Chicago/Turabian StyleHuang, Jialing, Marcela Covic, Cornelia Huth, Martina Rommel, Jonathan Adam, Sven Zukunft, Cornelia Prehn, Li Wang, Jana Nano, Markus F. Scheerer, and et al. 2021. "Validation of Candidate Phospholipid Biomarkers of Chronic Kidney Disease in Hyperglycemic Individuals and Their Organ-Specific Exploration in Leptin Receptor-Deficient db/db Mouse" Metabolites 11, no. 2: 89. https://doi.org/10.3390/metabo11020089