Tubular Lesions Predict Renal Outcome in Antineutrophil Cytoplasmic Antibody–Associated Glomerulonephritis after Rituximab Therapy

Abstract

Histopathological features in renal biopsies of patients with antineutrophil cytoplasmic antibody-associated vasculitis have predictive value for renal outcome in patients who receive standard treatment with cyclophosphamide and corticosteroids; however, whether the same holds true for rituximab-treated patients is unknown. We describe associations between renal histopathology and outcomes among patients treated with a rituximab-based regimen in the Randomized Trial of Rituximab versus Cyclophosphamide in ANCAAssociated Vasculitis trial. Two pathologists, blinded to clinical data, reviewed biopsies from 30 patients according to a standardized protocol that included assessment of T cell, B cell, and plasma cell infiltration, as well as scoring for tubulitis, interstitial inflammation, and glomerulitis. We did not observe associations between immunohistology scores and age, sex, estimated GFR at entry, or requirement for dialysis. However, tubulointerstitial inflammation was more severe among patients who had a positive test for the myeloperoxidase antineutrophil cytoplasmic antibody. In a multiple linear regression model, both CD3 + T cell tubulitis and tubular atrophy independently associated with estimated GFR at 12 months. Tubular atrophy remained an independent predictor at 24 months (P,0.01). These results suggest that in addition to anti-B cell therapy, therapy directed at T cells may improve renal outcomes in antineutrophil cytoplasmic antibody-associated vasculitis. Established treatment regimens for systemic antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and GN, consisting of cyclophosphamide and high-dose glucocorticoids, target both T and B cells. Standard treatment is associated with serious adverse events and the accumulation of therapy-related adverse events is an important cause of early mortality. 1,2 Therefore, ongoing studies involve the search for treatments that improve rates of sustained remission while minimizing adverse events. Several small studies of off-label treatment with rituximab, an anti-CD20 mAb, suggest that it induces remission in patients with systemic AAV refractory to standard therapy. 3-11 A multicenter study of 65 patients with refractory AAV demonstrated peripheral B cell depletion in all patients after a first course of rituximab, and complete remission was achieved in 75% (n=49) of patients. 12 Of the 49 patients who experienced initial complete

Predictors of Treatment Outcomes in ANCA-Associated Vasculitis with Severe Kidney Failure

“…These findings suggest that the tubulointerstitial compartment lesions have a significant effect on the renal outcome of patients with ANCA-associated nephritis (6,26). The difference between our results and those of the EUVAS schema with respect to the prognostic value of histopathologic classification is probably related to the selection of patients with severe renal failure in our patient population, leading to a narrower spectrum of histopathologic findings, and possibly an increased prominence of scarring of both the glomerular and tubulointerstitial compartments.…”

“…The renal biopsy specimens of 153 patients were reviewed. The median number of glomeruli examined per biopsy specimen was 16 (IQR, [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26]. The pattern of glomerular injury according to the EUVAS schema was categorized as sclerotic in 32% of cases, focal in 6%, crescentic in 43%, and mixed class in 6%.…”

The New Histopathologic Classification of ANCA-Associated GN and Its Association with Renal Outcomes in Childhood

“…Our study also lacked power to ascertain other factors from within the crescentic/mixed group apart from need for dialysis and degree of proteinuria, which may provide further prognostic information. Perhaps other pathologic factors, such as tubular atrophy and interstitial fibrosis or the degree of CD3+ tubulitis, may help in this regard in future studies (9,(23)(24)(25).…”

Letter to AJT editor re: Nankivell et al

“…[4][5][6][7] In renal transplants, this will be associated with progression when compared to controls that have atrophy scarring, with no inflammation because inflammation in areas of atrophy scarring indicates a more active or recent injury process than atrophy fibrosis with no inflammation, reflecting recent or ongoing stress. In some cases, this will follow severe treated TCMR, often due to nonadherence, but this does not justify the conclusion that the cognate TCMR process is still active.…”