Although the association of angiotensin I-converting enzyme inhibitors (ACEis) with a negatively charged membrane is thought to be responsible for hypersensitivity reactions (HSRs) during hemodialysis, we hypothesize that these complications are due to changes in plasma aminopeptidase P (APP) activity and genotype. To test this hypothesis, we measured plasma APP activity in 14 patients who suffered HSR (HSR+) while dialyzed with an AN69 membrane and simultaneously treated with an ACEi. APP activity was also studied in a control group (n=39) dialyzed under the same conditions, but who did not suffer any side effect (HSR-). We found significantly decreased plasma APP activity (P=0.013) in HSR+ subjects as well as altered degradation of endogenous des-Arginine(9)-bradykinin, with a significantly lower beta value (P<0.001). The same analytical approach was taken in 171 relatives of HSR+ patients. Variance component analysis suggested that genetic differences may explain 61% of the phenotypic variability of plasma APP activity (P<0.001) and the kinetic parameters that characterized kinin degradation. We also showed that the C-2399A single-nucleotide polymorphism at the XPNPEP2 locus was a significant predictor of APP activity in the 39 HSR- controls (P=0.029). Furthermore, a recessive genetic model for the A allele disclosed a significant difference in mean APP activity by genotype (P<0.001). Finally, our study defined the nonspecific inhibition of recombinant APP by some ACEis. In conclusion, this paper highlights the complexity of HSR in hemodialysis, suggesting, as with angioedema, that these rare, but life-threatening adverse events are governed by several metabolic and genetic factors.