High Lp(a) causally associated with increased CKD risk

EAS 2024 - In a Danish, population-based Mendelian randomization study, higher Lp(a) levels were both observationally and genetically associated with increased risk of CKD.

This summary is based on the presentation of Anne Langsted, MD, PhD (Copenhagen and Herlev, Denmark) at the EAS Congress 2024 - High lipoprotein(s) as a cause of chronic kidney disease: a population-based Mendelian randomization study.

Introduction and methods

CKD has been linked to high plasma Lp(a) levels, but it is not clear whether there is a causal relationship between the two. In a population-based Mendelian randomization study, Danish researchers examined whether high Lp(a) levels are genetically, causally associated with increased risk of CKD.

To this end, they utilized data on eGFR, plasma Lp(a) levels, and LPA genotype collected from 108,439 participants of the Copenhagen General Population Study from 2003 through 2015. CKD was defined as eGFR <60 mL/min/1.73 m², chronic kidney insufficiency, need for dialysis due to CKD, or need for hemodialysis due to CKD.

Main results

• In observational analysis, lower eGFR appeared to be associated with higher plasma Lp(a) levels, whereas genetic analysis showed eGFR decreased with lower LPA KIV-2 copy number. Of note, there is an inverse relation between the KIV-2 copy number and plasma Lp(a) concentrations.
• The risk of CKD increased with increasing plasma Lp(a) levels. For example, the OR was 1.74 (95%CI: 1.55–1.96) for individuals with Lp(a) in the 96th–100th percentiles (>95 mg/dL; >203 nmol/L) compared with those with Lp(a) in the 1st–50th percentiles (<10 mg/dL; <18 nmol/L) (P for trend=3 x 10¯²²).
• A lower KIV-2 copy number was also associated with a higher CKD risk (OR for <23 vs. >35 repeats: 1.40; 95%CI: 1.27–1.55; P for trend=1 x 10¯¹⁹).
• Carriers of the LPA single-nucleotide polymorphism rs10455872 had 1.2-fold increased CKD risk compared with non-carriers (OR: 1.18; 95%CI: 1.11–1.26).
• Instrumental variable analysis combining the KIV-2 copy number and rs10455872 genotype indicated an association between genetically predicted higher Lp(a) levels and CKD risk (genetic, causal risk ratio per 50 mg/dL (105 nmol/L) increase in Lp(a): 1.30; 95%CI: 1.12–1.51).
• This was consistent with the observational increased odds of CKD with higher plasma Lp(a) levels (OR: 1.25; 95%CI: 1.20–1.30).

Conclusion

In this Danish, population-based Mendelian randomization study, higher Lp(a) levels were both observationally and genetically associated with increased risk of CKD. These findings indicate that, given the effective Lp(a)-lowering drugs that are currently under investigation in large CV outcome trials, therapeutic strategies to prevent CKD are underway.

- Our reporting is based on the information provided at the EAS Congress 2024 -