Fibrosis can be defined as a pathological process in which deposition of connective tissue replaces normal parenchyma. The kidney, like any organ or tissue, can be impacted by this maladaptive reaction, resulting in persistent inflammation or long-lasting injury. While glomerular injury has traditionally been regarded as the primary focus for classification and prognosis of lupus nephritis (LN), increasing attention has been placed on interstitial fibrosis and tubular atrophy as markers of injury severity, predictors of therapeutic response, and prognostic factors of renal outcome in recent years. This review will discuss the fibrogenesis in LN and known mechanisms of renal fibrosis. The importance of the chronicity index, which was recently added to the histological categorization of LN, and its role in predicting treatment response and renal prognosis for patients with LN, will be explored. A better understanding of cellular and molecular pathways involved in fibrosis in LN could enable the identification of individuals at higher risk of progression to chronic kidney disease and end-stage renal disease, and the development of new therapeutic strategies for lupus patients.

Refractory lupus nephritis (RLN) is a clinical condition with high risk of a poor outcome and often life-threatening. Six patients (one male and 5 females), aged 41.3 years (range 20 to 61 years) were treated with Daratumumab monotherapy, a monoclonal antibody targeting CD38 which is highly expressed on the surface of many immune cells, especially plasma cells. The treatment protocol consisted of 16 mg/kg daratumumab administered intravenously weekly for 8 weeks, then every two weeks 8 more times, and lastly monthly (maximum 8 infusions). All patients failed previous treatments with the Standard of Care (SOC) including mycophenolate mofetil (MMF), cyclophosphamide (CYC), azathioprine and rescue therapies including Rituximab (RTX), Ocrelizumab, Belimumab, and iv IgG. One out of six patients did not show clinical response after 6 months of therapy, and Daratumumab was discontinued. Five patients showing a clinical response over the same period continued to be treated and reached a 12-month observation. Renal biopsy performed before daratumumab administration revealed a class IV LN in 1 patient, class V LN in 1 patient, class III + V LN in 1 patient and class IV + V LN in the other 2. Three patients achieved a complete renal response and the other two a partial renal response. A significant decrease in proteinuria from 5.6 gr/24 hours to 0.8 g/24 hours (p = 0.001) was achieved at 12 months. The mean value of serum Creatinine (sCr) decreased from 2.3 to 1.5 mg/dl. Improvement of clinical symptoms was paralleled by seroconversion of anti-double-stranded DNA antibodies (p = 0.03), significant decrease in interferon-gamma values (p = 0.0006), BMCA-B-cell maturation antigen (p = 0.0005) and soluble CD163 levels (p = 0.045), and increase in C4 (p = 0.018) and IL 10 levels (p = 0.0006). Clinical remission was substantiated by improvement of SLEDAI-2K score (p = 0.03). Daratumumab was generally well tolerated. These data suggest that Daratumumab administered alone (i.e., without any other immunosuppressant or agents targeting B-cell activating factor) is highly effective in RLN.