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Author Spotlight: Advancing the Analysis of Plasma Extracellular Vesicle Proteome for Cardiovascular Biomarker Studies
Published on: January 31, 2025
Urinary proteomics reveals association between pediatric nephrolithiasis and cardiovascular disease
Larisa Kovacevic1, Hong Lu2, Joseph A Caruso3
1Department of Pediatric Urology, Children's Hospital of Michigan, 3901 Beaubien Blvd, Detroit, MI, 48201, USA. lkovacev@dmc.org.
Insights
Children with kidney stones and abnormal urine composition show altered urinary proteins linked to cardiovascular disease. This suggests shared risk factors like inflammation and endothelial dysfunction may connect these conditions.
Area of Science:
- Pediatric Nephrology
- Proteomics
- Cardiovascular Disease Research
Background:
- Kidney stones in children, particularly with hypercalciuria and hypocitraturia, represent a significant health concern.
- Understanding the molecular underpinnings of pediatric kidney stones is crucial for identifying associated health risks.
- Cardiovascular disease (CVD) risk factors in childhood are increasingly recognized, necessitating research into early-onset conditions.
Purpose of the Study:
- To compare urinary protein profiles between children with kidney stones (RS) and healthy controls (HC).
- To investigate the association of identified urinary proteins with various diseases, focusing on cardiovascular implications.
- To determine if specific urinary protein alterations are linked to hypercalciuria and hypocitraturia in pediatric kidney stone patients.
Main Methods:
- Quantitative proteomic analysis of pooled urine samples from pediatric kidney stone patients and age/gender-matched healthy controls.
- Mass spectrometry was employed to identify and quantify urinary proteins.
- Proteins were selected based on significant differential abundance (≥2-fold change, p≤0.05) and spectral counts (≥5).
Main Results:
- 229 out of 1813 identified proteins met the selection criteria, with 162 up-regulated in the kidney stone group.
- The most prominent protein group (30/229) was associated with cardiovascular disease, including coagulation, inflammation, lipid transport, and oxidative stress markers.
- These protein alterations were predominantly observed in children with hypercalciuria and hypocitraturia, not in those with normal metabolic work-ups.
Conclusions:
- A significant association exists between pediatric kidney stones (nephrolithiasis) with hypercalciuria/hypocitraturia and cardiovascular disease.
- Shared risk factors, including endothelial dysfunction and atherosclerosis driven by abnormal coagulation, adhesion, lipid metabolism, oxidative stress, and inflammation, likely link these conditions.
- Further research into the pathophysiological connections is vital for developing novel therapeutic strategies for both nephrolithiasis and associated CVD in children.
Purpose:
To study (1) the differences in the relative abundance of urinary proteins between children with kidney stones (RS) and hypercalciuria, hypocitraturia, normal metabolic work-up, and healthy controls (HC); (2) the association of these proteins with various diseases.
Methods:
Quantitative proteomic comparison of pooled urine from RS (N = 30, 24 females, mean age 12.95 ± 4.03 years) versus age- and gender-matched HC, using mass spectrometry. Relative protein abundance was estimated using spectral counting. Proteins of interest were selected using the following criteria: (1) ≥ 5 spectral counts; (2) ≥ twofold difference in spectral counts; and (3) ≤ 0.05 p value for the Fisher's Exact Test.
Results:
Of the 1813 proteins identified, 229 met the above criteria, with 162 proteins up-regulated in the RS group and 67 up-regulated in HC. The largest group of proteins (30 out of 229) was found to be associated with cardiovascular disease (CVD). Of those, 16 were involved in coagulation, fibrinolysis, and adhesion, 10 in inflammation, 5 in lipid transport and metabolism, and 4 in oxidative stress. All except two were exclusively found in children with hypercalciuria and hypocitraturia, and were not seen in children with normal metabolic work-up.
Conclusion:
Using a proteomic approach, we found a significant association between hypercalciuric and hypocitraturic nephrolithiasis and CVD in children. The shared risk factors among both diseases are endothelial dysfunction and atherosclerosis caused by abnormal coagulation, adhesion, disturbance of lipid transport and metabolism, oxidative stress and inflammation. Further understanding of the pathophysiological link between nephrolithiasis and CVD is necessary for developing new therapeutic targets.
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