Association between glomerular mTORC1 activation and crescents formation in lupus nephritis patients.

OBJECTIVE: This study aims to explore the association between glomerular mammalian target of rapamycin complex 1 (mTORC1) pathway activation and crescents' degree in lupus nephritis (LN) patients. METHODS: A total of 159 biopsy-proven LN patients were enrolled in this retrospective study. The clinical and pathological data of them were collected at the time of renal biopsy. mTORC1 pathway activation was measured by immunohistochemistry, expressed by the mean optical density (MOD) of p-RPS6 (ser235/236), and multiplexed immunofluorescence. The association of mTORC1 pathway activation with clinico-pathological features especially renal crescentic lesions, and the composite outcomes in LN patients was further analyzed. RESULTS: mTORC1 pathway activation could be detected in the crescentic lesions and was positively correlated with the percentage of crescents (r = 0.479, P < 0.001) in LN patients. Subgroup analysis showed mTORC1 pathway was more activated in patients with cellular or fibrocellular crescentic lesions (P < 0.001), but not fibrous crescentic lesions (P = 0.270). The optimal cutoff value of the MOD of p-RPS6 (ser235/236) was 0.0111299 for predicting the presence of cellular-fibrocellular crescents in >7.39% of the glomeruli by the receiver operating characteristic curve. Cox regression survival analysis showed that mTORC1 pathway activation was an independent risk factor for the worse outcome (defined by composite endpoints of death, end-stage renal disease and a decrease of >30% in eGFR from baseline). CONCLUSION: Activation of mTORC1 pathway was closely associated with the cellular-fibrocellular crescentic lesions and could be a prognostic marker in LN patients.

Renal NLRP3 Inflammasome activation is associated with disease activity in lupus nephritis.

The current study was initiated to comprehensively evaluate renal NLRP3 inflammasome pathway activation in lupus nephritis (LN) patients and their clinicopathological significances based on a Chinese LN cohort. We found that the expressions of NLRP3, ASC, caspase-1, IL-1ß and IL-18 were all significantly higher in the kidneys of LN patients and were predominantly expressed in glomerular mesangial cells, podocytes, renal tubular epithelial cells and macrophages. The expressions of NLRP3, ASC, caspase-1 and IL-1ß were positively correlated to SLEDAI scores and several renal pathological activity indices, while the expression of NLRP3 was negatively associated with chronicity scores. Moreover, the foot process width was positively correlated with glomerular caspase-1 levels, and several podocyte injury markers were decreased significantly in LN patients with higher caspase-1 expression compared with those with lower expression. Our findings indicated that renal NLRP3 inflammasome was activated in LN patients and correlated with disease activity, which needs further explorations.