The Effects of Indoxyl Sulfate and Oxidative Stress on the Severity of Peripheral Nerve Dysfunction in Patients with Chronic Kidney Diseases
Abstract
:1. Introduction
2. Patients and Methods
2.1. Peripheral Nerve Function Assessment
2.2. Measurements of Biomarkers for Oxidative Stress, Endothelial Dysfunction, and Protein-Binding Uremic Toxins
2.3. Statistical Analysis
3. Results
3.1. Baseline Characteristics of the Patients
3.2. Clinical Score, NCS, and ESC in CKD
3.3. Effect of Protein-Bound Uremic Toxin and Cardiometabolic Risk Factors on Composite Amplitude Scores in Patients with CKD
3.4. Clinical Factors Are Significantly Associated with Composite Amplitude Scores in Patients with CKD
3.5. Mediation Analysis for Uremic Toxin (IS), the Severity of Peripheral Nerve Dysfunction (CAS), and Endothelial Dysfunction (sVCAM-1 Level)
4. Discussion
4.1. Major Findings of Our Study
4.2. The Pathophysiology of Protein-Binding Uremic Toxins
4.3. The Potential Pathogenesis of Protein-Binding Uremic Toxins in Peripheral Nerve Function
4.4. Electrophysiological Parameters and Clinical Scores in Patients with CKD
4.5. Study Limitations
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Diabetic CKD (n = 27) | Non-Diabetic CKD (n = 27) | p-Value | |
---|---|---|---|
Baseline characteristics | |||
Age (year) | 69.7 ± 12.4 | 67.0 ± 10.2 | 0.22 |
Sex (male/female) | 16/11 | 18/9 | 0.57 |
Diabetes duration (year) | 16.2 ± 11.1 | - | |
Height (cm) | 163.3 ± 8.0 | 161.5 ± 8.3 | 0.42 |
Body mass index | 26.5 ± 5.4 | 26.5 ± 5.4 | 0.11 |
Waist circumstance (cm) | 96.8 ± 14.8 | 90.0 ± 10.3 | 0.10 |
Systolic blood pressure (mmHg) | 140.5 ± 23.2 | 151.9 ± 25.6 | 0.09 |
Diastolic blood pressure (mmHg) | 75.3 ± 14.9 | 81.9 ± 16.5 | 0.13 |
ACE inhibitor or angiotensin II receptor blocker | 20 | 22 | 0.51 |
Beta-blocker | 13 | 13 | 1.0 |
Calcium channel blocker | 18 | 14 | 0.27 |
Diuretics | 8 | 1 | 0.02 |
Alpha-blocker | 4 | 3 | 1.0 |
Antiplatelet medications | 13 | 9 | 0.27 |
Lipid-lowering medications | 22 | 15 | 0.04 |
Diabetic CKD (n = 27) | Non-Diabetic CKD (n = 27) | p-Value | |
---|---|---|---|
Peripheral blood studies | |||
WBC counts (×103/mL) | 7.5 ± 2.5 | 6.0 ± 1.6 | 0.02 |
RBC counts (×106/mL) | 4.0 ± 0.6 | 4.0 ± 1.0 | 0.93 |
Hemoglobin, g/dL | 12.0 ± 1.7 | 12.0 ± 2.1 | 0.96 |
Hematocrit | 36.0 ± 4.8 | 36.0 ± 6.8 | 0.98 |
Platelet counts (×103/mL) | 236.2 ± 55.1 | 195.7 ± 55.5 | 0.02 |
UACR (mg/g) | 258.9 (78.3, 1052.5) | 276.6 (18.0, 758.6) | 0.43 |
eGFR (mL/min/1.73 m2) | 31.2 ± 9.8 | 30.6 ± 11.4 | 0.08 |
Creatinine (mmol/L) | 2.0 ± 0.8 | 2.3 ± 0.7 | 0.1 |
Albumin (mg/dL) | 4.5 ± 0.3 | 4.6 ± 0.3 | 0.49 |
Total cholesterol l(mmol/L) | 160.9 ± 38.5 | 183.3 ± 57.8 | 0.11 |
Triglyceride (mmol/L) | 117.5 ± 65.3 | 118.2 ± 53.7 | 0.97 |
HDL-C (mmol/L) | 45.5 ± 11.0 | 47.5 ± 13.4 | 0.56 |
LDL-C (mmol/L) | 88.3 ± 30.6 | 111.2 ± 44.8 | 0.03 |
Glycohemoglobin (%) | 6.9 ± 1.1 | 5.5 ± 0.3 | <0.0001 * |
Uric acid (mg/dL) | 6.6 ± 1.9 | 6.9 ± 1.5 | 0.57 |
Calcium (mmol/L) | 9.3 ± 0.4 | 9.4 ± 0.4 | 0.48 |
hs-CRP, mg/L | 2.2 ± 1.4 | 1.7 ± 1.0 | 0.47 |
Potassium (mmol/L) | 4.5 ± 0.8 | 4.5 ± 0.7 | 0.91 |
Sodium (mmol/L) | 139.7 ± 4.3 | 139.4 ± 3.5 | 0.78 |
Phosphate (mmol/L) | 3.7 ± 0.8 | 3.6 ± 0.6 | 0.65 |
CO2 | 29.2 ± 22.7 | 31.7 ± 24.6 | 0.74 |
iPTH (pg/mL) | 125.5 ± 87.8 | 156.3 ± 94.0 | 0.6 |
Biomarkers for endothelial dysfunction | |||
sICAM-1 (ng/mL) | 242.2 ± 69.1 | 245.1 ± 29.6 | 0.93 |
sVCAM-1 (ng/mL) | 1083.0 ± 259.5 | 971.1 ± 94.0 | 0.36 |
Biomarkers for oxidative stress | |||
TBARS, μmol/L | 13.4 ± 7.9 | 9.9 ± 2.6 | 0.09 |
Thiols, μmol/L | 1.0 ± 0.5 | 1.1 ± 0.4 | 0.57 |
Protein-bound uremic toxin | |||
Free-form Indoxyl sulfate (μg/mL) | 0.24 ± 0.17 | 0.21 ± 0.15 | 0.54 |
Free-form p-Cresol sulfate (μg/mL) | 0.50 ± 0.49 | 0.45 ± 0.41 | 0.73 |
Total-form Indoxyl sulfate (μg/mL) | 4.0 ± 3.3 | 3.9 ± 2.3 | 0.88 |
Total-form p-Cresol sulfate (μg/mL) | 11.6 ± 10.4 | 10.4 ± 9.8 | 0.65 |
Diabetic CKD (n = 27) | Non-Diabetic CKD (n = 27) | p-Value | |
---|---|---|---|
Toronto Clinical Neuropathy Score | 5.7 ± 4.1 | 3.4 ± 3.0 | 0.02 * |
Composite amplitude score | 5.3 ± 3.2 | 3.2 ± 2.8 | 0.008 * |
Median nerve, motor | |||
DML | 4.4 ± 0.6 | 4.1 ± 0.7 | 0.12 |
CMAP | 8.5 ± 2.1 | 9.6 ± 2.9 | 0.12 |
MNCV | 51.1 ± 4.3 | 52.9 ± 4.2 | 0.12 |
Ulnar nerve, motor | |||
DML | 3.1 ± 0.4 | 3.0 ± 0.4 | 0.17 |
CMAP | 7.9 ± 2.3 | 9.8 ± 2.6 | 0.004 * |
MNCV | 51.3 ± 5.5 | 54.6 ± 4.9 | 0.02 * |
Peroneal nerve, | |||
DML | 4.1 ± 0.6 | 3.8 ± 0.6 | 0.03 * |
CMAP | 2.4 ± 1.8 | 4.2 ± 2.7 | 0.004 * |
MNCV | 41.4 ± 4.3 | 46.0 ± 5.1 | 0.001 * |
Tibial nerve | |||
DML | 4.2 ± 0.6 | 4.0 ± 0.5 | 0.06 |
CMAP | 7.4 ± 5.3 | 8.7 ± 4.3 | 0.29 |
MNCV | 41.3 ± 5.3 | 44.5 ± 3.3 | 0.01 * |
Median nerve, sensory | |||
Latency | 3.3 ± 0.4 | 3.1 ± 0.5 | 0.04 * |
SNAP | 23.2 ± 13.2 | 30.4 ± 15.6 | 0.06 |
SNCV | 42.6 ± 5.8 | 46.2 ± 7.8 | 0.04 * |
Ulnar nerve, sensory | |||
Latency | 2.6 ± 0.4 | 2.4 ± 0.3 | 0.04 * |
SNAP | 17.8 ± 12.2 | 27.7 ± 13.5 | 0.004 * |
SNCV | 46.8 ± 6.4 | 49.8 ± 5.3 | 0.07 |
Sural nerve | |||
Latency | 3.1 ± 0.4 | 2.9 ± 0.3 | 0.07 |
SNAP | 4.0 ± 2.7 | 9.9 ± 7.0 | 0.001 * |
SNCV | 44.8 ± 4.8 | 48.3 ± 5.3 | 0.04 * |
Sudoscan | |||
Hand ESC, µS | 40.6 ± 19.7 | 45.7 ± 18.5 | 0.30 |
Feet ESC, µS | 44.4 ± 18.2 | 48.4 ± 23.6 | 0.54 |
Variables | Composite Amplitude Scores | |
---|---|---|
r | p-Value | |
Age (year) | 0.27 | 0.04 * |
Height (cm) | 0.18 | 0.23 |
Body mass index | 0.12 | 0.43 |
Waist circumstance (cm) | 0.14 | 0.39 |
eGFR (mL/min/1.73 m2) | −0.008 | 0.96 |
UACR (mg/g) | 0.29 | 0.046 * |
Free-form Indoxyl sulfate (μg/mL) | 0.39 | 0.009 * |
Free-form p-Cresol sulfate (μg/mL) | 0.26 | 0.10 |
Total-form Indoxyl sulfate (μg/mL) | 0.28 | 0.07 |
Total-form p-Cresol sulfate (μg/mL) | 0.31 | 0.05 |
sICAM-1 (ng/mL) | 0.31 | 0.02 * |
sVCAM-1 (ng/mL) | 0.44 | <0.0001 * |
TBARS, μmol/L | 0.35 | 0.002 * |
Thiols, μmol/L | −0.28 | 0.045 * |
Total cholesterol(mmol/L) | −0.19 | 0.22 |
Triglyceride(mmol/L) | −0.20 | 0.18 |
HDL-C (mmol/L) | −0.16 | 0.28 |
LDL-C (mmol/L) | −0.08 | 0.6 |
Uric acid (mmol/L) | −0.04 | 0.8 |
hs-CRP (mmol/L) | 0.18 | 0.3 |
HbA1c (%) | 0.04 | 0.82 |
Model | |||
---|---|---|---|
Regression Coefficient | Standard Error | p-Value | |
Constant | 0.56 | 0.94 | 0.56 |
TBARS, μmol/L | 0.17 | 0.06 | 0.007 |
Indoxyl sulfate (μg/mL) | 5.04 | 2.65 | 0.035 |
Path Coefficient | Standard Error | p-Value | |
---|---|---|---|
Total effects (total relationship, path c) Ω | |||
The relationship between the IS (independent variable) and CAS (dependent variable) | 7.87 | 2.50 | 0.003 |
Direct effects, path c′ | |||
The relationship between the IS (independent variable) and CAS (dependent variables) by including the sVCAM-1 (mediator) into the model | 5.06 | 2.56 | 0.45 |
Indirect effect, path a | |||
The effect of the IS (independent variable) on the sVCAM-1 (mediator) | 704.08 | 235.26 | 0.004 |
Indirect effect, path b | |||
The effect of the sVCAM-1 (mediator) on the CAS (dependent variable by controlling the effect for the IS (independent variable) | 0.004 | 0.001 | 0.01 |
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Lai, Y.-R.; Cheng, B.-C.; Lin, C.-N.; Chiu, W.-C.; Lin, T.-Y.; Chiang, H.-C.; Kuo, C.-E.A.; Huang, C.-C.; Lu, C.-H. The Effects of Indoxyl Sulfate and Oxidative Stress on the Severity of Peripheral Nerve Dysfunction in Patients with Chronic Kidney Diseases. Antioxidants 2022, 11, 2350. https://doi.org/10.3390/antiox11122350
Lai Y-R, Cheng B-C, Lin C-N, Chiu W-C, Lin T-Y, Chiang H-C, Kuo C-EA, Huang C-C, Lu C-H. The Effects of Indoxyl Sulfate and Oxidative Stress on the Severity of Peripheral Nerve Dysfunction in Patients with Chronic Kidney Diseases. Antioxidants. 2022; 11(12):2350. https://doi.org/10.3390/antiox11122350
Chicago/Turabian StyleLai, Yun-Ru, Ben-Chung Cheng, Chia-Ni Lin, Wen-Chan Chiu, Ting-Yin Lin, Hui-Ching Chiang, Chun-En Aurea Kuo, Chih-Cheng Huang, and Cheng-Hsien Lu. 2022. "The Effects of Indoxyl Sulfate and Oxidative Stress on the Severity of Peripheral Nerve Dysfunction in Patients with Chronic Kidney Diseases" Antioxidants 11, no. 12: 2350. https://doi.org/10.3390/antiox11122350
APA StyleLai, Y.-R., Cheng, B.-C., Lin, C.-N., Chiu, W.-C., Lin, T.-Y., Chiang, H.-C., Kuo, C.-E. A., Huang, C.-C., & Lu, C.-H. (2022). The Effects of Indoxyl Sulfate and Oxidative Stress on the Severity of Peripheral Nerve Dysfunction in Patients with Chronic Kidney Diseases. Antioxidants, 11(12), 2350. https://doi.org/10.3390/antiox11122350