Bortezomib for Reduction of Proteinuria in IgA Nephropathy

Abstract

IntroductionIgA nephropathy is the most common glomerulonephritis in the world. We conducted a pilot trial (NCT01103778) to test the effect of bortezomib in patients with IgA nephropathy and significant proteinuria.MethodsWe treated 8 consecutive subjects from July 2011 until March 2016 with 4 doses of bortezomib. All subjects had biopsy-proven IgA nephropathy and proteinuria of greater than 1 g per day. They were given 4 doses of bortezomib i.v. at 1.3 mg/m2 of body surface area per dose. Changes in proteinuria and renal function were followed for 1 year after enrollment. The primary endpoint was full remission defined as proteinuria of less than 300 mg per day.ResultsAll 8 subjects received and tolerated 4 doses of bortezomib over a 2-week period during enrollment. The median baseline daily proteinuria was 2.46 g (interquartile range: 2.29–3.16 g). At 1-year follow-up, 3 subjects (38%) had achieved the primary endpoint. The 3 subjects who had complete remission had Oxford classification T scores of 0 before enrollment. Of the remaining 5 subjects, 1 was lost to follow-up within 1 month of enrollment and 4 (50%) did not have any response or had progression of disease.ConclusionProteasome inhibition by bortezomib may reduce significant proteinuria in select cases of IgA nephropathy. Subjects who responded to bortezomib had Oxford classification T score of 0 and normal renal function.

Weighted Gene Co-expression Network Analysis Reveals Different Immunity but Shared Renal Pathology Between IgA Nephropathy and Lupus Nephritis

“…Previous GWAS has identified PSMB8 and PSMB9 as the susceptibility genes of IgAN, and PSMB9 was found to upregulate in the epidermis of SLE patients (Kiryluk et al, 2012;Nakamura et al, 2016). The proteasome inhibitor bortezomib was effective for the remission of LN and reducing the proteinuria in patients with IgAN (Alexander et al, 2015;Hartono et al, 2018), supporting our results that blue module is involved in the common pathogenesis of IgAN and LN via immunity pathways. In addition, the tubule-specific pink module was broadly downregulated in both diseases and enriched for death pathway.…”

Immunoproteasome in IgA Nephropathy: State-of-Art and Future Perspectives

“…Different to rituximab in other autoimmune disease, B-cell depletion in IgA nephropathy, which has been suggested to be an autoimmune disease, did not show expected efficacy [14]. In comparison, after a 1-year follow-up in the trial, of all 8 subjects, 3 subjects (38%) had complete remission with proteinuria less than 300 mg per day [15]. The evidence suggests that the (immuno) proteasome may play an important role in IgAN.…”

“…Notably, several interesting trials testing the effect of proteasome inhibitor in patients with IgAN and significant proteinuria have been performed [15,59]. The outcomes of a single-center open-label pilot trial showed the potential of therapy targeted at (immuno) proteasome in IgAN treatment.…”

“…The outcomes of a single-center open-label pilot trial showed the potential of therapy targeted at (immuno) proteasome in IgAN treatment. After 1-year follow-up, of all 8 subjects who received and tolerated 4 doses of bortezomib over a 2-week period during enrollment, 3 subjects (38%) had complete remission defined as proteinuria of less than 300 mg per day [15]. However, the trial has several significant limitations, including small sample size, no control group and nonrandomization.…”

Perspectives on how mucosal immune responses, infections and gut microbiome shape IgA nephropathy and future therapies

“…Bortezomib is a proteasome inhibitor known to target plasma cells. Short term use of bortezomib in select cases of IgAN has demonstrated promising ramifications in reducing proteinuria 154 . A similar unexpected efficiency of rituximab could also be observed in patients with lupus nephritis 155 .…”