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A Modified Two Kidney One Clip Mouse Model of Renin Regulation in Renal Artery Stenosis
Published on: October 26, 2020
Effect of renal impairment on atherosclerosis: only partially mediated by homocysteine
J David Spence1, Bradley L Urquhart2, Heejung Bang3
1Stroke Prevention and Atherosclerosis Research Centre, Robarts Research Institute, Western University, London, ON, Canada.
Insights
Elevated total homocysteine (tHcy) partially explains how reduced kidney function (eGFR) increases atherosclerosis risk. This finding suggests potential therapeutic targets beyond traditional risk factors for cardiovascular disease in renal failure patients.
Area of Science:
- Nephrology
- Cardiology
- Vascular Biology
Background:
- Cardiovascular disease (CVD) risk is elevated in renal failure patients.
- Plasma total homocysteine (tHcy) levels are also high in this population.
- High tHcy may significantly contribute to increased CVD risk.
Purpose of the Study:
- To assess the mediating role of tHcy in the association between estimated glomerular filtration rate (eGFR) and atherosclerosis.
- To investigate the relationship between eGFR, tHcy, carotid total plaque area (TPA), and carotid stenosis.
Main Methods:
- Carotid TPA and stenosis measured via ultrasound in 1967 patients.
- Multiple linear regression used to analyze associations.
- Adjustments made for age, sex, blood pressure, smoking, lipids, and weight.
Main Results:
- Reduced eGFR and elevated tHcy were independently associated with increased TPA.
- tHcy significantly mediated the relationship between eGFR and TPA.
- Mediation by tHcy was not significant for carotid stenosis.
Conclusions:
- tHcy accounts for a significant portion of the link between renal impairment and atherosclerosis.
- Residual effects may be due to other uremic toxins, possibly from the gut microbiome.
- This suggests novel therapeutic strategies for renal failure patients.
Background:
Cardiovascular risk and plasma total homocysteine (tHcy) are high in patients with renal failure. High tHcy may account for a substantial part of the increased risk. We assessed mediation by tHcy of the association of estimated glomerular filtration rate (eGFR CKD/EPI) with carotid total plaque area (TPA) and carotid stenosis.
Methods:
TPA and carotid stenosis were measured by ultrasound. Multiple linear regression was used to assess the effects of eGFR and/or tHcy after adjustment for age, sex, systolic blood pressure (SBP), smoking, LDL, HDL and weight.
Results:
Complete data were available for 1967 patients. eGFR decreased, and TPA and total stenosis increased linearly with age. After adjustment [age, sex, SBP, smoking (in pack years), low-density lipoprotein (LDL), high-density lipoprotein (HDL) and weight], eGFR and tHcy were independently associated with TPA (P < 0.01), but when both were added to the model, their significance was attenuated (P = 0.06 for eGFR, 0.03 for tHcy). Mediation analysis showed that tHcy seems to contribute to a significant mediation of the association of eGFR with TPA but not stenosis; after adjustment for the set of risk factors listed above, tHcy still demonstrated significant mediation on TPA (P = 0.03), but not on stenosis (P = 0.16).
Conclusions:
tHcy accounts for a significant part, but not all of the effect of renal impairment on atherosclerosis. Other uremic toxins including metabolic products of the intestinal microbiome may explain residual effects of renal failure on atherosclerosis. Therapeutic approaches arising from that hypothesis are discussed.
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