Discussion
This MR study did not provide evidence to suggest that genetically
proxied inhibition of IL-6 signalling has an effect on renal function.
IL-6 inhibitors such as tocilizumab are currently licenced for use in
rheumatoid arthritis, juvenile arthritis and more recently were under
investigation for treatment of excessive inflammation in patients with
severe acute respiratory syndrome coronavirus 2
infection.16 Atherosclerotic cardiovascular disease is
an inflammatory disorder and both MR studies and randomised
controlled-trials suggest that inhibition of IL-6 signalling reduces
risk of cardiovascular outcomes (coronary artery disease, atrial
fibrillation) and thromboembolic events.8,9 Given the
disproportionate burden of cardiovascular disease in patients with CKD
and the inflammatory nature of both these conditions, there is growing
interest in repurposing IL-6 inhibitors to treat CVD in
CKD.10 Our current findings support that
pharmacological IL-6 inhibition would be unlikely to have a direct
adverse effect on renal function.
The findings of this MR study are in line with an earlier study of renal
function in patients with rheumatoid arthritis and renal insufficiency
receiving tocilizumab therapy.17 However, this
observational study is small (120 participants), had large numbers of
patient stopping or switching therapy (60% switching biological
therapy) and may be susceptible to confounding factors (patients
receiving IL-6 inhibition were older and had rheumatoid arthritis for
longer).17 The present MR study adds support to the
initial pharmacovigilance surveys, and further is less prone to
confounding and reverse causality. Furthermore, manufacturer notes for
the tocilizumab (tradename: Actemra) suggest that no dose adjustment is
required for patients with mild renal impairment, however, cautions that
the drug has not been studied in patients with moderate to severe
dysfunction.18 This highlights a potential limitation
of available clinical trial data - despite over 10% of patients in the
developed world having renal impairment, patients with CKD are excluded
from up to 75% of all randomised-controlled trials.19MR may help in evaluating the safety of drugs in-silico prior to
trials in vulnerable patients. For example, MR drug safety studies have
in the past substantiated the causal relationship between statin therapy
and the increased risk of diabetes.20 Furthermore, MR
can provide more immediate drug safety information compared to usual
pharmacovigilance strategies such as the Medicines and Healthcare
Products Regulatory Agency yellow card system.
Our study has a number of strengths. To ensure the strength of the
genetic-variant mimicked the strength of pharmacological inhibition of
IL-6, the variant-exposure association was scaled to a reduction in CRP
levels.8 In an attempt to minimise the bias related to
pleiotropic effects of variants, instrumental variables were selected
based on their proximity to the IL6R gene and relation to
biomarkers of IL-6 signalling. In addition, the MR-Egger method did not
provide evidence to suggest biasing pleiotropy. Furthermore, the
consistency of our results across different MR methods and different
measurements of renal dysfunction further substantiates the null
findings. Our study also has limitations. It is important to interpret
our findings within the context of an MR study, which considers
genetically proxied inhibition of IL-6 signalling, rather than the
effect of a discrete clinical intervention. Our approach looks at IL-6
signalling in isolation, and it is possible that pharmacological IL-6
inhibitors could have off-target effects (aside from IL-6R signalling)
on other renal or extra-renal pathways which may ameliorate or
exacerbate renal function indirectly. There are also the possibility of
drug-drug interactions that cannot be accounted for in the present MR
analysis.
In conclusion, this study is consistent with the hypothesis that
inhibition of IL-6 signalling does not adversely affect renal function,
supporting this approach as a therapeutic opportunity for reducing the
risk of CVD in patients with CKD.