Small Dense Low-Density Lipoprotein Cholesterol and Renal Function: A Missing Link in Cardiovascular Risk Assessment for Chronic Kidney Disease Patients　― Reply ―

We sincerely appreciate the interest and constructive comments from Drs. Ito and Mori about our study.¹ We completely agree with their insight that small dense low-density lipoprotein cholesterol (sdLDL-C) might be one of the essential mediators linking renal dysfunction and cardiovascular events. In our study, subjects with high levels of sdLDL-C had lower levels of estimated glomerular filtration rate,¹ and a post-hoc cross-sectional study¹ using 21,586 subjects divided by chronic kidney disease (CKD) staging (Figure A) also showed that subjects with a higher CKD stage had a higher level of sdLDL-C (Figure B), indicating an association between sdLDL-C level and renal dysfunction in a Japanese general population.

Figure.

Levels of sdLDL-C based on the classification of CKD staging. (A) Selection of study participants in a post-hoc cross-sectional study. (B) Levels of sdLDL-C in subjects with CKD stages. *P<0.05 vs. stage 1; ^†P<0.05 vs. stage 2. CKD, chronic kidney disease; sdLDL-C; small dense low-density lipoprotein cholesterol.

Although sdLDL-C is a potent risk factor for cardiovascular events, its clinical application had been limited due to the complexity of measurement.² However, direct measurement techniques and reliable estimation methods using conventional lipid parameters of sdLDL-C have been recently developed.² We previously showed that high levels of sdLDL-C calculated by the Sampson equation³ were associated with new onset of ischemic heart disease⁴ and hypertension,⁵ suggesting that targeting sdLDL-C is a promising strategy for the management and prevention of cardiovascular events and possibly CKD.

Regarding the lipid nephrotoxicity hypothesis,⁶ we have also showed that metabolic dysfunction-associated fatty liver disease (MAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD) was independently associated with an increased risk for the development of CKD.^7,8 A close link between sdLDL-C and MAFLD has been reported by other group.⁹ Furthermore, as a possible factor within the framework of lipid nephrotoxicity, we demonstrated that fatty acid-binding protein 4 (FABP4), a bioactive molecule secreted from adipocytes, macrophages and injured glomerular endothelial cells, is one of the key mediators linking cardiovascular disease, MASLD/MAFLD and renal dysfunction.^10–13

We previously showed that increased levels of low-density lipoprotein cholesterol were associated with deterioration of renal function in males,¹⁴ but the association of sdLDL-C levels with the time course of renal function has not been investigated yet. Future research focusing on the effect of sdLDL-C on the development of CKD and elucidation of the complex pathophysiological roles of sdLDL-C in renal injury might contribute to the development of novel therapeutic strategies for lipid nephrotoxicity.

• Marenao Tanaka, MD, PhD
• Tatsuya Sato, MD, PhD
• Wataru Kawaharata, MD
• Hiroki Aida, MD
• Masato Furuhashi, MD, PhD
• Department of Cardiovascular, Renal and Metabolic Medicine (M.T., T.S., W.K., H.A., M.F.), Department of Cellular Physiology and Signal Transduction (T.S.), Sapporo Medical University School of Medicine, Sapporo, Japan

References

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