Introduction

In recent years, the incidence of diabetes mellitus has considerably increased, reaching approximately 536.6 million cases worldwide, and is projected to increase to 783.2 million by 20451. Diabetic kidney disease (DKD) is one of the most common complications of diabetes, affecting approximately 20–40% of individuals2,3. In China, DKD has been identified as the leading cause of chronic kidney disease in adults, accounting for 26.7% of all renal disease cases4. Furthermore, DKD is widely recognized as a major contributor to end-stage renal disease and imposes a substantial health burden worldwide5,6. Despite efforts to achieve the recommended blood glucose and blood pressure targets, the residual risk of DKD remains high7, indicating an ongoing challenge in managing and preventing DKD progression. Therefore, given the profound impact of DKD, many researchers have increasingly focused on identifying clinical risk factors and biomarkers for the early detection, prevention, and intervention of DKD in recent decades8,9,10.

High-density lipoprotein cholesterol (HDL-C) is primarily synthesized in the liver, facilitating the cholesterol transportation from the extracellular tissues to the liver for metabolic processes. HDL-C has been considered a protective factor against cardiovascular events11,12,15,16,27. However, other studies showed significant differences in HDL-C levels between the two groups, with the DKD group having significantly lower HDL-C levels than the non-DKD group9,28. The reasons for the discrepancy in these research results might include differences in the study populations and variations in the methods used to measure HDL-C levels. When HDL-C was categorized into four quartiles, our findings indicated that, compared with the lowest quartile of HDL-C, the second, third, and fourth quartiles had a lower risk of DKD, with the lowest risk observed in the third quartile. As a result, the hypothesis of a nonlinear U-shaped relationship between HDL-C levels and DKD risk was proposed, which was subsequently confirmed by the RCS and stratified analyses in this study.

A previous investigation7 based on Italian diabetes centers analyzed the relationship between plasma HDL-C levels and the prevalence of DKD in patients with T2D. They found that low HDL-C level was an independent risk factor for the prevalence of DKD, as evidenced by associations with low eGFR, eGFR reduction, and albuminuria. This relationship remained statistically significant when analyzing HDL-C concentration as a continuous variable (each 10 mg/dL increase) and exhibited only attenuation following adjustment for numerous confounding factors in the multivariate analysis (P < 0.05)7. The discrepancy between the data and ours might be explained by the different study populations and the differential lipid metabolism profiles within the two study populations (1.35 ± 0.39 vs. 1.16 ± 0.35 mmol/L for the average HDL-C levels). Regardless of the case, the U-shaped relationship between HDL-C levels and the prevalence of DKD in patients with T2D provided a reasonable explanation for low levels of HDL-C being an important risk factor for DKD; however, extremely high levels of HDL-C showed diminished protective effects against DKD.

The U-shaped association between HDL-C levels and DKD risk indicates that low and high HDL-C levels can increase DKD risk. First, low HDL-C levels are associated with increased oxidative stress and inflammation, both of which play crucial roles in the pathogenesis of renal damage in patients with diabetes29. Specifically, low HDL-C levels may impair the reverse cholesterol transport mechanism, leading to lipid accumulation in renal cells and thereby exacerbating kidney injury29. Additionally, low HDL-C levels may reflect an overall dyslipidemic condition, including elevated triglyceride and LDL-C levels, which increase vascular damage risk and promote the progression of microvascular complications in diabetes30. Conversely, very high HDL-C levels may not provide cardiovascular protection and even pose risks31. This apparent contradiction may be because of functional impairments of HDL-C at high concentrations. This can include reduced efficacy of reverse cholesterol transport and anti-inflammatory activities, potentially increasing the risk of cardiovascular and renal complications31,32. Genetic and environmental factors may play significant roles in this complex relationship33,34. For instance, genetic variations affecting HDL-C metabolism and the impact of chronic conditions such as diabetes can alter the protective effects of HDL-C. Further research is required to elucidate the underlying mechanisms.

Intriguingly, the increased DKD risk associated with high HDL-C levels (> 1.54 mmol/L) was not confirmed in the male or over 60 years of age subgroups. A study on the relationship between high HDL-C levels and the risk of cardiovascular events yielded similar results, showing that high HDL-C levels have different effects on the risk of cardiovascular events in men and women31. These findings might be explained by sex-based differences in cholesterol. For instance, well-documented evidence shows that women typically exhibit higher HDL-C levels than men31,35, and estrogen can elevate HDL-C36. The reasons for the differential impact of high HDL-C (> 1.54 mmol/L) on DKD risk in the two age subgroups remain unclear; it may be associated with alterations in lipid metabolism among individuals over 60 years of age.

This study has several limitations. First, the number of participants at the higher end of the HDL-C concentration spectrum was relatively small. Second, not all the factors influencing HDL levels were considered comprehensively. Specifically, variables such as obesity, dietary habits, sedentary lifestyle, alcohol consumption, and genetic diseases were not thoroughly controlled for and analyzed, potentially introducing bias into our results. This study did not systematically evaluate the impact of drugs known to affect HDL-C levels. Beta-blockers, thiazide diuretics, androgens, and anabolic steroids, known to potentially decrease HDL-C levels, were not included in our analysis. Conversely, drugs, such as niacin and PCSK9 inhibitors, known to increase HDL-C levels, were not systematically assessed. This variability in drug effects could have significantly affected HDL-C levels, thereby affecting the DKD risk assessment. Additionally, the potential effects of fluctuating estrogen levels during menopause and thyroid dysfunction on HDL-C levels were not addressed. In particular, hypothyroidism may cause abnormal lipid metabolism and lower HDL-C levels. This might have also contributed to bias in our findings. Finally, as this was a cross-sectional observational study, the findings could not robustly demonstrate nonlinear associations between HDL-C levels and DKD risk in patients with T2D. This study also did not conclusively prove a causal relationship between elevated HDL-C levels and an increased DKD risk. This preliminary study provided evidence of a U-shaped association between HDL-C levels and DKD risk, highlighting the importance and necessity of planning and conducting a prospective confirmatory study with a sufficiently large, randomly selected sample.

Conclusion

Although HDL-C is generally considered a cardiovascular protective factor, at very high levels, this protective effect does not seem to hold true and may be associated with an increased DKD risk. Our findings suggest that a low HDL-C level increases the DKD risk, and HDL-C levels greater than 1.54 mmol/L are significantly associated with an increased DKD risk, especially in women. These findings may provide guidance for managing blood lipids to prevent and treat DKD in patients with T2D.

Ethics approval and consent to participate

The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Affiliated **hua Hospital, Zhejiang University School of Medicine (approval code: (Res) 2020-Ethical Review-200). Written informed consent was obtained from all participants.