Treatment of fibrillary glomerulonephritis with rituximab: a 12-month pilot study

Abstract

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Fibrillary glomerulonephritis (FGN) is a rare type of glomerulonephritis with poor prognosis, with no known effective therapies available for treatment. The objective of the study was to evaluate the efficacy and safety of rituximab in treatment of patients with FGN and to investigate the effect of rituximab on DNAJB9 levels.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>This was a pilot prospective clinical trial in which patients with idiopathic FGN were treated with two courses of rituximab (1 g each) 2 weeks apart at the beginning and then again at 6 months. Primary outcome was defined as preservation of kidney function at 12 months with stable or increased creatinine clearance. Secondary outcome was defined as achieving complete remission (CR) defined as proteinuria &amp;lt;300 mg/24 h or partial remission (PR) with proteinuria &amp;lt;3 g/24 h and at least 50% reduction in the proteinuria. DNAJB9 levels were also measured in the serum at baseline, 6 and 12 months.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>The creatinine clearance did not change significantly during this time, from 47.7 mL/min/1.73 m2 at baseline to 43.7 mL/min/1.73 m2 during follow-up (P = 0.15). Proteinuria declined from 4.43 (1.6–5.53) g/24 h at baseline to 1.9 (0.46–5.26) g/24 h at 12 months but did not reach significance (P = 0.06). None of the patients reached CR, and 3 of the 11 achieved PR. There was no change in the DNAJB9 levels following treatment with rituximab. The most common adverse event was nasal congestion, fatigue and muscle cramps.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Treatment of patients with two courses of rituximab over a span of 6 months was associated with stabilization of renal function but did not result in a significant change in proteinuria and with no change in the DNAJB9 levels.</jats:p> </jats:sec>

Fibrillary Glomerulonephritis, DNAJB9, and the Unfolded Protein Response

“…At 1 year, there was an overall ∼50% reduction in proteinuria (which did not meet statistical significance), and 3 patients experienced a partial response [54]. Neither treatment nor disease remission status affected DNAJB9 serum levels [54].…”

“…In the first prospective clinical trial of rituximab in 11 patients with FGN, investigators observed no significant change in the eGFR at 12 months [54]. At 1 year, there was an overall ∼50% reduction in proteinuria (which did not meet statistical significance), and 3 patients experienced a partial response [54].…”

“…Supporting this possibility is DNAJB9's known cellular roles, particularly its propensity to bind aggregation prone peptide regions [74,79], as discussed above. Additionally, serum levels of DNAJB9 are elevated in FGN patients, possibly due to increased protein production [80], although they do not appear to correlate with the disease state or response to therapy [54] and have an inverse correlation with the eGFR [80,81], suggesting that some of the elevation could potentially be due to decreased filtration in the setting of chronic kidney disease. However, if DNAJB9 were present simply in response to a misfolded protein, a similar abundance may be expected in amyloidosis.…”

Monoclonal Gammopathy of Renal Significance: A Molecular Middle Earth between Oncology, Nephrology, and Pathology

“…Currently, the best therapeutic strategy for these cases is still debated and the relatively poor effects of numerous immunosuppressive treatments and proteasome inhibitors are stressing the need for alternative approaches. Recent research has focused on the role of rituximab in FGN, showing a subset of patients who might benefit from it, with current efforts aimed at identifying that group [ 32 ]. However, the current lack of a circulating responsible antibody that would help in following up the depletion of pathogenetic B cell is still representing a limitation for monitoring treatment in FGN.…”

Fibrillary Glomerulonephritis and Monoclonal Gammopathy: Potential Diagnostic Challenges

“…Given the unclear pathogenesis, the role of DNAJB9 in disease activity and treatment response is not fully understood. In the recent pilot study of using rituximab to treat FGN, there was no significant change in serum DNAJB9 levels before and after treatment ( 30 ).…”