The leading electromagnetic (e.m.) and strong isospin-breaking corrections to the $pi^+ to mu^+ u[gamma]$ and $K^+ to mu^+ u[gamma]$ leptonic decay rates are evaluated for the first time on the lattice. The results are obtained using gauge ensembles produced by the European Twisted Mass Collaboration with $N_f = 2 + 1 + 1$ dynamical quarks. The relative leading-order e.m.~and strong isospin-breaking corrections to the decay rates are 1.53(19)% for $pi_{mu 2}$ decays and 0.24(10)% for $K_{mu 2}$ decays. Using the experimental values of the $pi_{mu 2}$ and $K_{mu 2}$ decay rates and updated lattice QCD results for the pion and kaon decay constants in isosymmetric QCD, we find that the Cabibbo-Kobayashi-Maskawa matrix element $ | V_{us}| = 0.22538(46)$, reducing by a factor of about $1.8$ the corresponding uncertainty in the Particle Data Group review. Our calculation of $|V_{us}|$ allows also an accurate determination of the first-row CKM unitarity relation $| V_{ud}|^2 + | V_{us}|^2 + | V_{ub}|^2 = 0.99988(46)$. Theoretical developments in this paper include a detailed discussion of how QCD can be defined in the full QCD+QED theory and an improved renormalisation procedure in which the bare lattice operators are renormalised non-perturbatively into the (modified) Regularization Independent Momentum subtraction scheme and subsequently matched perturbatively at $O(alpha_{em}alpha_s(M_W))$ into the W-regularisation scheme appropriate for these calculations.
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