Resolution of IgA vasculitis nephritis in patient with activated PI3Kdelta syndrome after treatment with leniolisib

Activated PI3K-delta syndrome is a combined immunodeficiency disease with a heterogenous immune phenotype. Common clinical manifestations include recurrent respiratory infections, persistent herpesvirus infections, lymphoproliferative disease, and autoimmunity. We describe the case of a patient with APDS who developed IgA vasculitis nephritis that responded to steroids, plasmapheresis, rituximab, and initiation of a new selective PI3Kdelta inhibitor, leniolisib. 19-year-old male with APDS (pathogenic variant in PI3KCD, p.E81K) complicated by recurrent ear and sinus infections, marginal zone B-cell hyperplasia, and EBV lymphadenitis who presented to the hospital with hematuria and fatigue. Initial work-up revealed acute kidney injury (Cr 1.72 mg/dL) with gross hematuria and nephrotic range proteinuria. A renal biopsy was performed which demonstrated IgA dominant immune complex glomerulonephritis (10% focal cellular crescents). The patient was started on empiric high-dose steroids. However, due to worsening renal injury (Cr peak to 4.1 mg/dL) and proteinuria, plasmapheresis and rituximab were administered. Additionally, leniolisib, a new oral PI3Kdelta inhibitor, was initiated at 70 mg twice daily. The patient’s renal function began to stabilize after administration of these therapies, and he was discharged on daily prednisone and leniolisib. On outpatient follow-up over the course of six months, he demonstrated normalization of his creatinine and improvement of his proteinuria. Glomerulonephritis has been reported as an autoimmune renal manifestation in APDS. This case highlights the first reported instance of treatment response to leniolisib and immunomodulatory agents in an APDS patient with IgA vasculitis nephritis. While leniolisib is an unapproved selective PI3K-delta inhibitor, its use should be considered in the management of APDS patients with significant autoimmune complications.