Refractory lupus nephritis: national multicenter study

Refractory lupus nephritis (LN) remains a major therapeutic challenge and a leading cause of progression to end-stage kidney disease (ESKD) in systemic lupus erythematosus (SLE). To characterize a large multicenter cohort of refractory LN, evaluate therapeutic strategies used after non-response, and determine long-term renal outcomes. Multicenter longitudinal cohort including 68 patients with refractory LN from several Spanish centers. Refractoriness was defined according to the GLOSEN consensus as failure to reduce proteinuria by  > 25% or worsening of proteinuria and/or renal function after ≥3 months of triple immunosuppressive therapy. Demographic, clinical, histological, therapeutic and outcome data were collected. The cohort included 68 patients (61 women), mean age 34.5 [27-45] years. Renal biopsy showed predominantly proliferative classes (III-IV and mixed forms). Extrarenal involvement was frequent, mainly articular (82.3%), hematological (70.6%) and cutaneous (60.3%). Before non-response, most patients had received corticosteroids (98.5%), mycophenolate mofetil (82.3%), antimalarials (91.2%) and cyclophosphamide (36.8%). Non-response occurred after 16.1  ±  9.5 months and was due to persistent proteinuria (61.8%), worsening renal function (25%) or both (13.2%). Over 12 months, creatinine remained stable, from 0.96 to 1.02 mg/dL (p = 0.726), C3 increased from 56.3 to 85.55 mg/dL (p < 0.001), C4 rose from 0.82 to 1.02 mg/dL (p < 0.001), while proteinuria decreased from 1.9 ± 0.5 to 0.57 ± 0.24 g/24 h (p < 0.001). After treatment modification or intensification-including tacrolimus (39.7%), rituximab (27.9%) and belimumab (27.9%), 41 patients (60.3%) achieved LN remission during a mean follow-up of 59.7 ± 46 months. Ten patients progressed to ESKD (6 requiring hemodialysis and 4 undergoing kidney transplantation). Infections were the most frequent complication (30.9%). Therapeutic escalation allowed LN remission in a substantial proportion patients with refractory LN; however. the risk of progression to ESKD remained high. These findings highlight the need for earlier recognition of non-response and more effective treatment strategies to prevent irreversible renal damage.