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.