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.