Effect of renal impairment on atherosclerosis: only partially mediated by homocysteine

Nephrol Dial Transplant. 2016 Jun;31(6):937-44. doi: 10.1093/ndt/gfv380. Epub 2015 Nov 14.


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.

Keywords: ADMA; TMAO; cardiovascular risk; indoles; intestinal microbiome.

Publication types

  • Multicenter Study

MeSH terms

  • Atherosclerosis / complications*
  • Atherosclerosis / diagnosis
  • Atherosclerosis / metabolism
  • Biomarkers / blood
  • Carotid Stenosis / blood
  • Carotid Stenosis / diagnosis
  • Carotid Stenosis / etiology*
  • Disease Progression
  • Female
  • Glomerular Filtration Rate / physiology
  • Homocysteine / metabolism*
  • Humans
  • Male
  • Middle Aged
  • Prognosis
  • Renal Insufficiency, Chronic / complications*
  • Renal Insufficiency, Chronic / metabolism
  • Renal Insufficiency, Chronic / physiopathology
  • Risk Factors


  • Biomarkers
  • Homocysteine