Circulating sphingomyelin: A causal risk-factor of chronic kidney disease?

Background and aims: Abnormal levels of circulating sphingomyelin (SM) have been shown to associate with albuminuria and kidney function in type 1 diabetes. However, the sign of association has varied from cohort to another, suggesting potential influence of confounding factors. In one of these efforts, we previously demonstrated in a cohort at Steno Diabetes Center Copenhagen that three individual SM species measured at baseline were inversely associated with albuminuria at baseline as well as with all-cause mortality during a four-year follow-up in. In this study, we attempt to validate this finding in external cohorts and to probe for causal links between SM levels and chronic kidney disease (CKD).

Materials and methods: We computed an estimate for the causal effect of circulating SM level on the risk of CKD via bidirectional two-stage Mendelian randomization (MR) using the MR-Egger method on genome-wide association studies acquired from the MR Base. First, we acquired the genetic instruments to SM from a multinational European pan-cohort of 13,307 individuals. Second, we acquired the association between the genetic instruments and chronic kidney disease from 117,465 individuals from 48 European cohorts.

Results: The MR estimate for the causal effect of SM on CKD was -1.217 (SE=0.3483; p=0.07303). Alternative methods yielded weaker effect estimates but were consistent with the sign of the effect. In the reverse analysis, the effect of CKD on SM was -0.03059 (SE=0.1651; p=0.8701).

Conclusion: We found a statistically weak causal effect, where a decrease of one standard deviation in the level of circulating SM means a 70 % higher risk of CKD in the general population. Although not statistically significant in the general population, the causal effect was in clear agreement with our previous findings from a more focused longitudinal cohort of 700 persons type 1 diabetes. Furthermore, we confirm that abnormal SM levels are more likely to cause CKD rather than the reverse. Based on these combined results, we suggest that the sphingolipid pathway could serve as an effective preventive target of kidney disease in high-risk groups, such as persons with long-standing type 1 diabetes.

Disclosure: T. Suvitaival: None.