Remnant Cholesterol Directly Associated With Higher Risk of Chronic Kidney Disease Development

Remnant cholesterol (RC) is directly associated with a higher risk of developing chronic kidney disease (CKD) and progression to end-stage renal disease (ESRD) in patients with type 2 diabetes (T2D)-related kidney disease, according to results from a meta-analysis published in Diabetes, Obesity and Metabolism.¹

High levels of remnant cholesterol contribute to cardiovascular risk and, in turn, chronic kidney disease. | Image Credit: © Withun - stock.adobe.com

Remnant Cholesterol’s Role in CKD Pathogenesis

CKD constitutes a vast global burden, with estimates of approximately 850 million individuals across the world suffering from the disease. T2D and hypertension remain the main drivers of incident CKD, though dyslipidemia has been more recently evaluated as a critical driver of pathogenesis and progression of CKD. Particularly, RC has emerged as a novel lipoprotein marker that is linked to elevated triglyceride levels.^1,2

As with other forms of cholesterol, numerous studies have demonstrated RC as a significant factor for T2D, cardiovascular disease, and all-cause mortality. Thus, RC could offer prognostic value beyond that of standard lipid parameters and possibly serve as an additional tool for risk stratification and CKD management. The current systematic review and meta-analysis sought to evaluate the link between RC and CKD.^1,3

Systematic Review Confirms Heightened Risk of CKD With High RC Levels

Eligible studies included randomized controlled trials or observational studies that examined adult populations. The primary end point for the meta-analysis was the association between RC levels and CKD risk, which is defined by an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m². Key secondary end points included associations between RC and eGFR and the risk of progression to ESRD.¹

A total of 12 studies were included in the analysis, encompassing 4,139,674 individuals. The median follow-up period across the studies was 5.1 years, with mean RC levels ranging from 0.37 to 0.79 mmol/L. Nine studies from the selected 12 directly assessed the association between RC and CKD.¹

For these 9 studies, individuals with RC values in the highest quantile had meaningfully higher odds of CKD compared with those in the lowest quantile (odds ratio [OR]: 1.46 [95% CI, 1.26–1.68); P < .001). Furthermore, individuals with T2D and RC in the higher quantile demonstrated heightened odds of CKD compared with those in the lowest quantile (OR: 1.46 [95% CI, 1.20–1.78; P < .0001). Importantly, the association remained strong when RC was investigated as a continuous variable, with a 49% increase in CKD risk for each 1 mmol/L increase in RC (OR: 1.49 [95% CI, 1.23–1.82]; P < .001), according to the authors.¹

Investigators next investigated the association between RC and progression to ESRD. They observed that patients with T2D-related CKD had a 24% significantly increased risk of progression to ESRD for each 1 standard deviation increase in RC (hazard ratio [HR]: 1.24 [95% CI, 1.04–1.47]; P = .015).¹

RC Could Serve as New Therapeutic Target for CKD

Even with adequate control of low-density lipoprotein levels (LDL-C), RC has been recognized as a major factor contributing to cardiovascular disease risk, with literature indicating the ability of RC to influence vascular disease and move beyond its role in lipid metabolism. Given this potential relationship, the investigators called for further research to better elucidate the relationship between microvascular dysfunction and RC in the setting of CKD.¹

“Considering the relatively limited treatment options currently available for preventing and effectively managing CKD, RC potentially emerges as a novel therapeutic target for this patient population,” the study authors concluded. “However, the debate on the optimal RC levels and the potential additive benefit for patients who have already achieved the recommended LDL-C goals remains to be definitively addressed in future large-scale, rigorously designed RCTs.”¹

REFERENCES

1. Karakasis P, Patoulias D, Rizzo M, Fragakis N, Mantzoros CS, et al. Association between remnant cholesterol and chronic kidney disease: Systematic review and meta-analysis. Diabetes, Obesity, and Metabolism. 2025. doi:10.1111/dom.16258

2. Yen C, Fan P, Lee C, et al. Association of low-density lipoprotein cholesterol levels during statin treatment with cardiovascular and renal outcomes in patients with moderate chronic kidney disease. J Amer Heart Assoc. 2022;11(19). doi:10.1161/JAHA.122.027516

3. Ginsberg HN, Packard CJ, Chapman MJ, et al. Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies—a consensus statement from the European Atherosclerosis Society. Euro Heart Journ. 2021;42(47):4791-4806. doi:10.1093/eurheart/ehab551