Idiopathic nephrotic syndrome (NS) is characterized by severe proteinuria, hypoalbuminemia, and/or edema and affects about 1 to 3 per 100,000 children and young adults.1 Corticosteroids represent the first line therapy for primary NS, leading to disease remission in 70% to 80% of cases.2 However, 70% to 80% may relapse after steroid withdrawal, and approximately 10% to 30% of patients have steroid-resistant NS. Treatment of steroid-resistant NS includes calcineurin inhibitors, mycophenolate mofetil, and anti-CD20 monoclonal antibodies (rituximab or obinutuzumab) used alone or in combination.3 With these approaches, remission can be achieved in about 40% to 60% of steroid-resistant cases; however, relapses may occur despite chronic immunosuppressive therapies (multidrug-dependent NS).4 The remaining patients are defined as multidrug-resistant NS and the lack of effective treatment response often leads to end-stage kidney disease.5 The main histopathological entities in steroid-resistant NS cases are focal segmental glomerulosclerosis, minimal change disease, and diffuse mesangial sclerosis. The glomerular deposition of IgM and C3 represents a negative prognostic factor.6 Considering that mechanistic studies suggest that autoreactive IgM play a pathogenic role through complement activation,7 we tested the hypothesis that combined B cell and plasma cell depletion (both cells are responsible for IgM production) safely promotes remission in subjects affected by multidrug dependent or steroid resistant NS. Treatment with rituximab or cyclophosphamide in the 6 months before enrolment represented an exclusion criterion. Rituximab and daratumumab were administered as single doses at 375 mg/m2 and 16 mg/kg, respectively. After combined treatment, oral immunosuppressive drugs were progressively tapered and withdrawn in all subjects over 4 to 6 weeks. In multidrug-resistant NS, the primary end point was the achievement of partial or complete remission of proteinuria, defined according to KDIGO guidelines.S1 In multidrug-dependent NS, the end point was the time on remission without immunosuppressive drugs. Full methods are provided in the supplemental file
Angeletti, A., Bin, S., Kajana, X., Spinelli, S., Bigatti, C., Caridi, G., et al. (2024). Combined Rituximab and Daratumumab Treatment in Difficult-to-Treat Nephrotic Syndrome Cases. KIDNEY INTERNATIONAL REPORTS, 9(6), 1892-1896 [10.1016/j.ekir.2024.04.006].
Combined Rituximab and Daratumumab Treatment in Difficult-to-Treat Nephrotic Syndrome Cases
Bin, Sofia;Magnasco, Alberto;
2024
Abstract
Idiopathic nephrotic syndrome (NS) is characterized by severe proteinuria, hypoalbuminemia, and/or edema and affects about 1 to 3 per 100,000 children and young adults.1 Corticosteroids represent the first line therapy for primary NS, leading to disease remission in 70% to 80% of cases.2 However, 70% to 80% may relapse after steroid withdrawal, and approximately 10% to 30% of patients have steroid-resistant NS. Treatment of steroid-resistant NS includes calcineurin inhibitors, mycophenolate mofetil, and anti-CD20 monoclonal antibodies (rituximab or obinutuzumab) used alone or in combination.3 With these approaches, remission can be achieved in about 40% to 60% of steroid-resistant cases; however, relapses may occur despite chronic immunosuppressive therapies (multidrug-dependent NS).4 The remaining patients are defined as multidrug-resistant NS and the lack of effective treatment response often leads to end-stage kidney disease.5 The main histopathological entities in steroid-resistant NS cases are focal segmental glomerulosclerosis, minimal change disease, and diffuse mesangial sclerosis. The glomerular deposition of IgM and C3 represents a negative prognostic factor.6 Considering that mechanistic studies suggest that autoreactive IgM play a pathogenic role through complement activation,7 we tested the hypothesis that combined B cell and plasma cell depletion (both cells are responsible for IgM production) safely promotes remission in subjects affected by multidrug dependent or steroid resistant NS. Treatment with rituximab or cyclophosphamide in the 6 months before enrolment represented an exclusion criterion. Rituximab and daratumumab were administered as single doses at 375 mg/m2 and 16 mg/kg, respectively. After combined treatment, oral immunosuppressive drugs were progressively tapered and withdrawn in all subjects over 4 to 6 weeks. In multidrug-resistant NS, the primary end point was the achievement of partial or complete remission of proteinuria, defined according to KDIGO guidelines.S1 In multidrug-dependent NS, the end point was the time on remission without immunosuppressive drugs. Full methods are provided in the supplemental fileI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
