A relapsing case of pulmonary-renal syndrome after a sequential rise in MPO-ANCA and anti-GBM antibodies.

A 69-year-old woman who presented with severe renal dysfunction and diffuse alveolar hemorrhage was diagnosed with pulmonary-renal syndrome (PRS) based on the coexistence of serum myeloperoxidase (MPO)-antineutrophil cytoplasmic antibodies (ANCA) and anti-glomerular basement membrane (GBM) antibodies (Ab). Hemodialysis was started; plasma exchange and intravenous methylprednisolone pulse therapy were administered followed by oral prednisolone administration. Pulmonary hemorrhage decreased; however, renal dysfunction persisted. On maintenance hemodialysis and prednisolone therapy, MPO-ANCA and anti-GBM Ab became negative at 4 and 10 months, respectively; thereafter, they became positive again at 18 and 35 months, respectively. At 36 months, there was relapse of pulmonary hemorrhage. Plasma exchange and intravenous methylprednisolone pulse therapy were administered; pulmonary hemorrhage ceased, and both antibodies became negative. It is known that PRS cases that are double positive for ANCA and anti-GBM Ab occasionally relapse after remission, and, even though they are double positive at initial diagnosis, most relapses occur with reappearance or re-elevation of ANCA but with absence of anti-GBM-Ab. Therefore, this was a rare relapsing case that presented with double-positive serology. Further, our observation that the reappearance of ANCA preceded that of anti-GBM-Ab suggests that ANCA contribute to the reproduction of anti-GBM Ab.

Involvement of infiltrating macrophage-derived activin A in the progression of renal damage in MRL-lpr mice.

Lupus nephritis is a life-threatening complication of systemic lupus erythematosus (SLE). Various growth factors, cytokines, and chemokines are implicated in the development of SLE. However, the pathophysiological processes involved in the development of lupus nephritis still remain unclear. In this study, we examined the involvement of activin A, a member of the transforming growth factor ß (TGF-ß) superfamily, in the progression of renal damage in lupus-prone MRL-lpr mice. Activin A was not expressed in the kidneys of control MRL-MpJ mice but was detectable in perivascular infiltrating cluster of differentiation 68 (CD68)-positive cells in the kidneys of MRL-lpr mice. Urinary activin A, which was also absent in MRL-MpJ mice, was detectable in MRL-lpr mice from 16 wk onward. Urinary activin A levels were significantly correlated with the number of perivascular inflammatory cell layers, the number of crescentic glomeruli, and the percentage of Elastica van Gieson (EVG)-positive fibrotic areas, but not with urinary protein levels or serum activin A. When activin action was blocked in vivo by the intraperitoneal administration of an activin antagonist, follistatin, the number of crescentic glomeruli, percentage of EVG-positive fibrotic areas, CD68-positive cell infiltration, and proteinuria were significantly reduced in a dose-dependent manner. These data suggest that infiltrating macrophage-derived activin A is involved in the progression of renal damage in MRL-lpr mice.

Clinical and histological features of lupus nephritis in Japan: A cross-sectional analysis of the Japan Renal Biopsy Registry (J-RBR).

AIM: The clinical and histological features of lupus nephritis (LN) are highly variable, depending on race and ethnicity. The Japan Renal Biopsy Registry (J-RBR) is a nationwide registry of renal biopsies. Here, we report a cross-sectional analysis of Japanese LN using the J-RBR database. METHODS: Out of 18 463 patients registered in the J-RBR, 331 LN patients, who received renal biopsy for the first time, were extracted and their clinical features were analyzed according to the ISN/RPS 2003 classification. RESULTS: The median age of the 331 LN patients was 37 years (women, 81.3%). The frequencies of each of the ISN/RPS Classes were as follows: I, 1.2%; II, 7.9%; III (±V), 25.1%; IV-S (±V), 13.0%; IV-G (±V), 31.1%; V, 20.8%; and VI, 0.9%. The level of proteinuria and the prevalence of nephrotic syndrome were highest for Class IV-G (±V). When Classes I, II, and VI were excluded from the analysis, Class IV-G (±V) was significantly associated with a lower eGFR and severer haematuria than the other classes. CONCLUSION: This nationwide study revealed that Class IV-G (±V) was the most prevalent form of LN in Japan and was associated with a severe clinical renal presentation.

Renal outcomes in mixed proliferative and membranous lupus nephritis (Class III/IV + V): A long-term observational study.

OBJECTIVES: In this study, we aimed to assess the effect of combination of proliferative and membranous lesions (Class III + V or IV + V) on renal outcomes as an independent category distinct from Class III and IV. METHODS: We retrospectively analyzed 103 Japanese patients (14 male and 89 female) with Class III/IV LN, with or without Class V, who underwent renal biopsy and were treated at our institution. Renal endpoint was defined as doubling of serum creatinine or end-stage renal disease (ESRD). RESULTS: The number of patients in each group was as follows: pure Class III/IV, 81 patients and mixed Class III/IV + V, 22 patients. During a median follow-up period of 125.0 months, 10 patients developed renal endpoint: five had Class III/IV LN and five had a combination of Class III/IV + V. Kaplan-Meier analyses demonstrated that patients with mixed Class III/IV + V LN had significantly poorer renal outcomes than patients with Class III/IV LN. Multivariate Cox regression analyses identified serum creatinine, active and chronic lesions (A/C), and mixed Class III/IV + V) as independent risk factors for poor renal outcomes. CONCLUSIONS: This study demonstrated a combination of proliferative and membranous LN (ISN/RPS Class III/IV + V) predicts poor renal outcomes.

Successful treatment of severe crescentic lupus nephritis by multi-target therapy using tacrolimus and mycophenolate mofetil.

Treatment of severe lupus nephritis (LN) has been controversial, and according to recent guidelines and recommendations, cyclophosphamide still remains a first-line therapy. Herein, we present the case of a 37-year-old female patient who developed rapidly progressive glomerulonephritis, which was histologically diagnosed as class IV + V LN, with a large number of cellular to fibrocellular crescents (62 % of glomeruli). Although the patient was considered to have the most severe form of LN, complete remission was achieved within 6 months by multi-target therapy using tacrolimus and mycophenolate mofetil combined with methylprednisolone pulse therapy. Our experience suggests that multi-target therapy could be a potential treatment option for patients with severe crescentic LN.

Interleukin-6 promotes destabilized angiogenesis by modulating angiopoietin expression in rheumatoid arthritis.

OBJECTIVE: To examine whether IL-6 promotes angiogenesis by modulating angiopoietin (Ang) expression in RA. METHODS: Synovial fibroblasts derived from RA patients (RASFs) and human umbilical vein endothelial cells (HUVECs) were co-cultured for 6 days with or without recombinant IL-6, VEGF or Ang-1. HUVECs were stained with anti-CD31 antibody and their growth was determined by quantifying the CD31-positive area. SFs were collected from RA (n = 25) and OA (n = 7) patients. RESULTS: In the co-culture system, IL-6 and VEGF significantly enhanced HUVEC growth to a similar extent. However, the morphology of proliferating cells was distinct between IL-6- and VEGF-stimulated HUVEC. HUVEC stimulated with IL-6 exhibited small, loose clusters surrounded by dispersed single cells, suggesting destabilized angiogenesis by IL-6. In the supernatants, IL-6 up-regulated VEGF compared with controls and Ang-2, while it down-regulated Ang-1. In contrast, down-regulation of Ang-1 was not observed with VEGF stimulation. Consistent with the destabilized morphology, stimulation with IL-6 decreased cell surface expression of vascular endothelial cadherin (VE-cadherin) on HUVEC, presumably by inducing internalization. Interestingly, adding recombinant Ang-1 partially inhibited IL-6-induced morphological changes in HUVEC including a destabilized morphology with small, loose clusters and internalization of VE-cadherin. In SFs from RA patients, VEGF was negatively correlated with Ang-1 (r = -0.559, P=0.004). CONCLUSION: IL-6 not only enhances VEGF expression but also inhibits Ang-1 signalling by directly down-regulating Ang-1 expression and up-regulating Ang-2, an antagonist of Ang-1. These synergistic effects may play a critical role in destabilized angiogenesis in RA.

Interleukin-1ß measurement in stimulated whole blood cultures is useful to predict response to anti-TNF therapies in rheumatoid arthritis.

OBJECTIVE: In RA, response to TNF blockers may be associated with a profile of cytokine production unique to each patient. This study sought to predict the response to biologic agents by examining pro-inflammatory cytokine synthesis in stimulated whole blood cultures (WBCs). METHODS: We measured the concentration of TNF-α, IL-1ß and IL-6 in supernatants of lipopolysaccharide (LPS)-stimulated WBCs obtained from RA patients (n = 41) before anti-TNF therapy (infliximab, 13; etanercept, 26; and adalimumab, 2) and from healthy controls (n = 12). At 24 weeks after biologics, whole bloods were again drawn from 14 of 41 patients. Response was defined by the European League Against Rheumatism response criteria after 24 weeks of therapy. RESULTS: Among 41 patients, 32 were responders (good 14/moderate 18), while 9 were non-responders. All cytokines measured were significantly lower in RA patients than in controls. In RA, IL-1ß production was lower in non-responders than in responders [median (interquartile range): 3.5 (1.5-9.4) vs 10.0 (5.1-93.1) pg/ml, P = 0.048]. The area under the curve from a receiver operating characteristic curve analysis for the prediction of response using IL-1ß was 0.717 (95% CI 0.520, 0.914). The sensitivity and specificity of IL-1ß (cut-off value 4.84 pg/ml) was 78.1 and 77.8%, respectively. All cytokines were significantly higher 6 months later compared with their respective baseline. CONCLUSION: IL-1ß measurement in LPS-stimulated WBC is useful to predict responsiveness to anti-TNF agents. Cytokine production capacities in LPS-stimulated WBCs are up-regulated by biologics.

Insulin-like growth factor binding protein-related protein 1 is expressed in rheumatoid synovium and regulates synovial fibroblast proliferation.

Insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) is a secretory protein that shares a structural similarity with IGFBP. Studies have shown that IGFBP-rP1 synergistically increases fibroblast growth with insulin and stimulates angiogenesis in tumor tissues. In this report, we examined the expression and function of IGFBP-rP1 in rheumatoid arthritis (RA). IGFBP-rP1 expression in synovial tissues was examined by reverse transcription-polymerase chain reaction (RT-PCR), real-time PCR, and immunohistochemical analysis. In vitro, IGFBP-rP1 expression was examined in synovial fibroblasts established from rheumatoid synovium (RASFs) by RT-PCR, Western blot, and immunostaining. The effect of IGFBP-rP1 small interfering RNA (siRNA) on RASF proliferation was assessed by alamarBlue assay. IGFBP-rP1 mRNA was detected by RT-PCR in all synovial tissues from RA and OA patients. In immunohistochemical analysis, IGFBP-rP1 was mainly expressed in synovial cells in the lining layers and endothelial cells in the sublining layers of RA synovium. In vitro, constitutive expression of IGFBP-rP1 in RASFs was detected by RT-PCR, Western blot, and immunostaining. Treatment with IGFBP-rP1 siRNA induced a 26% decrease in RASF growth compared to control siRNA. A similar extent of growth-suppressive effect by IGFBP-rP1 siRNA was also observed when RASF proliferation was induced by TNF-α. Collectively, these data suggest that IGFBP-rP1 may regulate synovial fibroblast proliferation in RA.

Successful treatment of lipoprotein glomerulopathy in a daughter and a mother using niceritrol.

We report two patients, a daughter and a mother, with lipoprotein glomerulopathy (LPG) who were successfully treated with niceritrol. Both patients carried a mutation in the apolipoprotein E (apoE) gene known as ApoE Tokyo/Maebashi. The daughter was found to have proteinuria at the age of 4 years. Four years later, she was diagnosed as having LPG based on a renal biopsy. She was treated with several medications including pravastatin, ethyl icosapentate, enalapril, warfarin and cyclophosphamide, all of which failed to reduce her proteinuria. At the age of 17 years, she exhibited an increase in proteinuria and a decline in renal function, despite ongoing treatment with pravastatin and enalapril. After switching from pravastatin to niceritrol, a marked reduction in the proteinuria and an improvement in renal function were observed. Her mother was found to have proteinuria at the age of 57 years and was diagnosed as having LPG based on a renal biopsy. She was also treated with niceritrol, resulting in an improvement in her proteinuria and renal function. These cases suggest that niceritrol might be a useful therapeutic option for LPG.