*Purpose: Alemtuzumab is an effective drug for the treatment of severe or glucocorticoid-resistant acute kidney allograft rejection (AR), but can also cause severe adverse events. There is a clinical need for superior treatment stratification to assess which patients will respond to alemtuzumab treatment. This study aimed to find clinical variables and gene expression profiles related to alemtuzumab treatment response in AR.

*Methods: One hundred and thirteen patients from the Erasmus MC, that were treated with alemtuzumab for severe or glucocorticoid-resistant AR in January 2012 until January 2018 were included in this retrospective study. Clinical characteristics were retrieved from electronic health records. mRNA was isolated from formalin-fixed paraffin-embedded tissues of diagnostic kidney transplant biopsies and used for targeted gene expression profiling using the Banff-Human Organ Transplant panel of NanoString®. Response to alemtuzumab treatment was defined as allograft survival plus an estimated glomerular filtration rate (eGFR) above 30 mL/min/1.73 m² at 1 year after alemtuzumab therapy. The advanced analysis module of nSolver software and SPSS statistics were used to analyze the data.

*Results: For clinical variable analysis, data of 101 patients (50 responders and 51 non-responders) was available and for gene expression analysis mRNA samples of 58 patients (29 responders and 29 non-responders) were available. Multivariate analysis identified three clinical factors that were associated with a good response to treatment: early timing of AR (<3 months after transplantation: 64% of responders and 41% of non-responders, p=0.002), a low delta eGFR between baseline eGFR and eGFR at the moment of AR (<25%/25-50%/>50%: responders:18/15/4 and non-responders: 11/11/15, p=0.01), and glucocorticoid maintenance therapy at the time of AR (90% of responders and 65% of non-responders, p=0.002). In addition, gene expression analysis revealed that genes involved in the B-cell receptor signaling pathway were related to inferior response to therapy.

*Conclusions: Alemtuzumab treatment appears to be most effective in patients with severe or refractory AR in whom the diagnosis is made less than three months after transplantation, kidney function loss is limited and those who are on glucocorticoid maintenance therapy. Moreover, patients with high expression of B-cell receptor signaling genes are less likely to respond to alemtuzumab therapy. These findings can add to the development of superior stratification of patients who will benefit from alemtuzumab treatment.

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