This MR study provides suggestive evidence regarding the relationship between HMGCR expression, HMGCR-mediated LDL cholesterol levels, and the risk of rapid kidney function decline outcomes. Firstly, in the IVW-MR analysis, a negative correlation was observed between LDL-C levels mediated by HMGCR and the risk of both CKDi25 (OR1 = 0.74, 95% CI1=[0.60–0.90]) and Rapid3 (OR2 = 0.85, 95% CI2=[0.74–0.98]) outcomes, suggesting that HMGCR inhibitors might increase the risk of rapid kidney function decline. Secondly, in the SMR analysis, an increase in PCSK9 gene expression in the blood was positively associated with the risk of the Rapid3 outcome (OR = 1.11, 95% CI= [1.00–1.23]), but no significant association was found with the CKDi25 outcome (p > 0.05). This indicates that PCSK9 inhibitors might reduce the risk of rapid kidney function decline defined in absolute values but not in ratio-defined terms. However, in the cis MR, heterogeneity was observed between PCSK9 and the Rapid3 outcome when using LDL cholesterol GWAS as an instrument, but this correlation was nullified after MR-PRESSO correction. Lastly, no association was found between NPC1L1 gene expression and the outcome of rapid kidney function decline. These study results suggest that different lipid-lowering drugs may have varying effects on rapid kidney function decline. Further validation of this phenomenon is warranted to determine its clinical significance.
Compared to conventional observational studies, Mendelian randomization offers a method to evaluate the causal relationship between exposure and outcomes. There is genetic evidence from studies indicating a potential adverse correlation between HMGCR inhibition and kidney function28. The decline in kidney function among patients with chronic kidney disease is often non-linear. Retrospective analyses of end-stage renal disease patients demonstrate that the decline in estimated glomerular filtration rate (eGFR) is typically more pronounced in the year leading up to end-stage disease7. Therefore, studying rapid kidney function decline holds significance for preventing patients from progressing to end-stage disease, reducing the need for hemodialysis or peritoneal dialysis, and lowering mortality rates. In the KDIGO 2013 Lipid Management Guidelines for Adults with CKD, it is recommended that adults over 50 years of age with CKD (excluding chronic dialysis patients) receive statin therapy29. Moreover, in the later stages of CKD (stages 3–5, eGFR < 60 mL/min/1.73 m²), a combination of statins and ezetimibe is recommended. The overall benefit of statin therapy in CKD patients likely stems from a reduction in coronary heart disease risk 30. According to a statement by the American Heart Association, maximum doses of statins might lead to transient microscopic hematuria and proteinuria, with uncertain significance for kidney function 31. An SHARP trial also indicated that the effect of LDL reduction on kidney function remains unclear32. A recent Mendelian randomization study utilizing genetic variants in the HMGCR gene reported an association between genetically predicted HMGCR inhibition and lower eGFR, while genetically predicted PCSK9 inhibition was associated with higher eGFR. However, this study does not rule out the use of HMGCR inhibitors for cardiac protection, even for those at risk of renal impairment or diagnosed with CKD. Additionally, clinicians should carefully tailor statin drug regimens for such individuals and consider potential side effects that might affect kidney function31. Regarding the impact of PCSK9 inhibition on the kidneys, there have been case reports suggesting a potential therapeutic role of PCSK9 inhibitors in acute kidney injury33. However, the FOURIER trial showed no significant difference in eGFR decline between the PCSK9 inhibitor group and the placebo group, and the alirocumab trial also indicated no significant effect on kidney function32,34,35. A meta-analysis suggested that PCSK9 inhibitors significantly reduce cardiovascular event risk in CKD patients, but the effect on kidney function decline remains unclear36.
Limitations of Study
This study has several limitations. First, it utilized aggregated data instead of individual-level data, precluding subgroup analyses. Second, Bonferroni correction for multiple tests indicates that we cannot rule out the possibility of false positives in finding the potentially negative effect of statins on kidney function decline and the protective effect of PCSK9 on kidney function decline. Third, with the emergence of a range of new lipid targets and novel lipid-lowering drugs, further validation is needed to establish the impact of lipids on rapid kidney function decline. Fourth, the eQTL and GWAS data used in this study primarily originated from European populations, so caution should be exercised in generalizing these findings to other populations.