Cardiovascular disease (CVD) accounts for half of all deaths in end-stage renal failure and the burden of CVD in chronic kidney disease (CKD) is not fully explained by traditional risk factors.1 This suggests that alternative pathways may be implicated in the disproportionately high CVD risk in patients with declining renal function.2 CKD is recognised as a low-grade but persistent inflammatory state, with raised levels of inflammatory biomarkers such as interleukin-1β (IL-1β) interleukin-6 (IL-6), tumour necrosis factor α (TNF-α) and C-reactive protein (CRP).3 Inflammation plays a critical role in atherosclerosis and it is possible that the inflammatory milieu of CKD contributes to the excessive risk of CVD in CKD.4,5Inflammatory markers such as high-sensitive CRP and IL-6 are predictive of cardiovascular events and IL-6 levels are independent predictors of CVD and mortality in patients with CKD.6,7 Inhibition of IL-1β and IL-6 have shown promising results in lowering cardiovascular events.8,9 There are now plans to trial the IL-6 signalling inhibitor, ziltivekimab for reduction of CVD in patients with CKD.10 However, it has not been established whether direct IL-6 signalling inhibition has an impact on renal function.
Mendelian randomization (MR) employs genetic polymorphisms as instrumental variables to study the effect of an exposure on an outcome.11 MR is less susceptible to confounding due to the balancing of environmental factors at conception with the independent assortment and random allocation of genetic variants. For a valid MR study, the following assumptions must hold: the genetic proxy must be associated with the exposure, the genetic variant only affects the outcome through the exposure of interest with no horizontal pleiotropic effect, the genetic variant is not associated with any known confounder affecting the exposure and the outcome.11In principle, a valid MR study represents an endogenous randomised controlled trial based on the randomisation of genetic variants at conception. Applied to drug development, MR provides an in-silicoplatform to predict adverse drug consequences and explore drug repurposing, minimising confounding and reducing potential for reverse causality.12 Pre-clinical MR studies could also reduce the exposure of trial participants to potentially harmful compounds and enable us to determine whether new drug targets are suitable to be trialled among vulnerable populations, such as patients with CKD.12 Considering the growing interest of IL-6 inhibition in patients with CKD, the aim of the present study was to investigate the effect of inhibition of IL-6 signalling on renal function by MR methods.