Clinical impact of urinary CD11b and CD163 on the renal outcomes of anti-neutrophil cytoplasmic antibody-associated glomerulonephritis.

BACKGROUND: The detection of leukocyte-derived CD11b (α subunit of integrin Mac-1) and CD163 (scavenger receptor) in urine may reflect renal inflammation in antineutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-GN). The objective of this study was to evaluate the clinical significance of urinary CD11b (U-CD11b) and CD163 (U-CD163) in ANCA-GN. METHODS: U-CD11b and U-CD163 were examined using enzyme-linked immunosorbent assay in ANCA-GN urine samples from our institutional cohort (n = 88) and a nationwide cohort (n = 138), and their association with renal histology was subsequently analyzed. Logistic regression analyses were performed on a nationwide ANCA cohort to determine the associations of the two urinary molecules with renal remission failure at 6 months or with yearly estimated glomerular filtration rate (eGFR) slope over a 24-month observation period. RESULTS: U-CD11b and U-CD163 were significantly associated with cellular crescent formation and leukocyte accumulation in glomerular crescents. With regard to interstitial inflammation, both levels of U-CD11b and U-CD163 at diagnosis remarkably increased in ANCA-GN compared with the levels observed in nonglomerular kidney disorders including nephrosclerosis, immunoglobulin G4-related disease and tubulointerstitial nephritis; however, the presence of U-CD11b alone was significantly correlated with tubulointerstitial leukocyte infiltrates. Although neither U-CD11b nor U-CD163 at diagnosis was associated with remission failure at 6 months, multivariate analysis demonstrated that the baseline U-CD11b levels were significantly associated with the increase in eGFR following immunosuppressive therapy. CONCLUSIONS: Although both U-CD11b and U-CD163 reflect renal leukocyte accumulation, U-CD11b at diagnosis provides additional clinical value by predicting the recovery rate after the treatment of ANCA-GN.

PsbQ-Like Protein 3 Functions as an Assembly Factor for the Chloroplast NADH Dehydrogenase-Like Complex in Arabidopsis.

Angiosperms have three PsbQ-like (PQL) proteins in addition to the PsbQ subunit of the oxygen-evolving complex of photosystem II. Previous studies have shown that two PQL proteins, PnsL2 and PnsL3, are subunits of the chloroplast NADH dehydrogenase-like (NDH) complex involved in the photosystem I (PSI) cyclic electron flow. In addition, another PsbQ homolog, PQL3, is required for the NDH activity; however, the molecular function of PQL3 has not been elucidated. Here, we show that PQL3 is an assembly factor, particularly for the accumulation of subcomplex B (SubB) of the chloroplast NDH. In the pql3 mutant of Arabidopsis thaliana, the amounts of NDH subunits in SubB, PnsB1 and PsnB4, were decreased, causing a severe reduction in the NDH-PSI supercomplex. Analysis using blue native polyacrylamide gel electrophoresis suggested that the incorporation of PnsL3 into SubB was affected in the pql3 mutant. Unlike other PsbQ homologs, PQL3 was weakly associated with thylakoid membranes and was only partially protected from thermolysin digestion. Consistent with the function as an assembly factor, PQL3 accumulated independently in other NDH mutants, such as pnsl1-3. Furthermore, PQL3 accumulated in young leaves in a manner similar to the accumulation of CRR3, an assembly factor for SubB. These results suggest that PQL3 has developed a distinct function as an assembly factor for the NDH complex during evolution of the PsbQ protein family in angiosperms.

Urinary levels of the leukocyte surface molecule CD11b associate with glomerular inflammation in lupus nephritis.

Noninvasive biomarkers of disease activity are needed to monitor response to therapy and predict disease recurrence in patients with glomerulonephritis. The leukocyte surface markers integrin Mac-1 and CD16b have been implicated in the pathogenesis of lupus nephritis (LN). Mac-1 comprises a unique α subunit (CD11b) complexed with a common ß2 subunit, which are released along with CD16b from specific leukocyte subsets under inflammatory conditions including glomerulonephritis. We investigated the association of urinary CD11b and CD16b with histopathological activity in 272 patients with biopsy-proven glomerular diseases, including 118 with LN. Urine CD11b and CD16b were measured via enzyme-linked immunosorbent assay. Urinary levels of both markers were increased in LN, but only urinary CD11b was correlated with the number of glomerular leukocytes and with overall histopathological activity. In a subset of patients with samples available from the time of biopsy and subsequent clinical remission of LN, urinary levels of CD11b decreased with successful glucocorticoid treatment. Receiver-operating characteristic curve analysis demonstrated that urinary CD11b was superior to CD16b, the scavenger receptor CD163, and monocyte chemotactic protein-1 for the prediction of proliferative LN. In anti-mouse nephrotoxic serum glomerulonephritis, urinary CD11b correlated with histologic damage and decreased with corticosteroid treatment. In vitro, CD11b levels were decreased on activated mouse neutrophils displaying Fcγ receptor clustering and transendothelial migration, suggesting that leukocyte activation and transmigration are required for CD11b shedding in urine. Together, our results suggest that urinary CD11b may be a useful biomarker to estimate histopathological activity, particularly glomerular leukocyte accumulation, in LN.

Vascular endothelial growth factor (VEGF)-A and VEGF-A165b are associated with time to remission of granulomatosis with polyangiitis in a nationwide Japanese prospective cohort study.

BACKGROUND: Effective prognostic markers are needed for antineutrophil cytoplasmic antibody-associated vasculitis (AAV). This study evaluated the clinical associations of serum vascular endothelial growth factor-A (sVEGF-A) and sVEGF-A165b (an antiangiogenic isoform of VEGF-A) concentrations with time to remission of AAV in a nationwide Japanese prospective follow-up cohort. METHODS: We collected samples from patients with AAV who were enrolled in the nationwide Japanese cohort study (RemIT-JAV-RPGN). We measured sVEGF-A and sVEGF-A165b concentrations using enzyme-linked immunosorbent assays in 57 serum samples collected 6 months before and after initiation of AAV treatment. Patients were classified based on AAV disease subtypes: microscopic polyangiitis, granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis (EGPA). RESULTS: Results revealed significant reductions in sVEGF-A and sVEGF-A165b concentrations in patients with microscopic polyangiitis and EGPA, respectively. However, despite the comparable concentrations of sVEGF-A and sVEGF-A165b during the 6 months of treatment in granulomatosis with polyangiitis patients, correlation analysis revealed that the differences in log2-transformed concentrations of sVEGF-A and sVEGF-A165b were inversely correlated with time to remission in granulomatosis with polyangiitis patients. CONCLUSION: These results suggest that sVEGF-A and -A165b can serve as potential markers of time to remission in patients with granulomatosis with polyangiitis.