Novel 3D analysis using optical tissue clearing documents the evolution of murine rapidly progressive glomerulonephritis.

Recent developments in optical tissue clearing have been difficult to apply for the morphometric analysis of organs with high cellular content and small functional structures, such as the kidney. Here, we establish combinations of genetic and immuno-labelling for single cell identification, tissue clearing and subsequent de-clarification for histoimmunopathology and transmission electron microscopy. Using advanced light microscopy and computational analyses, we investigated a murine model of crescentic nephritis, an inflammatory kidney disease typified by immune-mediated damage to glomeruli leading to the formation of hypercellular lesions and the rapid loss of kidney function induced by nephrotoxic serum. Results show a graded susceptibility of the glomeruli, significant podocyte loss and capillary injury. These effects are associated with activation of parietal epithelial cells and formation of glomerular lesions that may evolve and obstruct the kidney tubule, thereby explaining the loss of kidney function. Thus, our work provides new high-throughput endpoints for the analysis of complex tissues with single-cell resolution.

Gp130-dependent signaling in the podocyte.

Renal inflammation, in particular glomerular, is often characterized by increased IL-6 levels. The in vivo relevance of IL-6 signaling in glomerular podocytes, which play central roles in most glomerular diseases, is unknown. Here, we show that in normal mice, podocytes express gp130, the common signal-transducing receptor subunit of the IL-6 family of cytokines. Following systemic IL-6 or LPS injection in mice, podocyte IL-6 signaling was evidenced by downstream STAT3 phosphorylation. Next, we generated mice deficient for gp130 in podocytes. Expectedly, these mice exhibited abrogated IL-6 downstream signaling in podocytes. At the age of 40 wk, they did not show spontaneous renal pathology or abnormal renal function. The mice were then challenged using two LPS injury models as well as nephrotoxic serum to induce crescentic nephritis. Under all conditions, circulating IL-6 levels increased markedly and the mice developed the pathological hallmarks of the corresponding injury models such as proteinuria and development of glomerular crescents, respectively. However, despite the capacity of normal podocytes to transduce IL-6 family signals downstream, there were no significant differences between mice bearing the podocyte-specific gp130 deletion and their control littermates in any of these models. In conclusion, under the different conditions tested, gp130 signaling was not a critical component of the (patho-)biology of the podocyte in vivo.

A case of unusual renal manifestation in a patient with neuronal intranuclear inclusion disease treated with steroids.

Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disorder characterized by intranuclear inclusions. Kidney injury involvement and successful treatment for NIID have rarely been reported. A NIID patient developed crescentic IgA nephropathy. Steroid therapy resolved digestive symptoms and recovered renal function. Steroids are considered for concomitant symptoms of NIID.

Clinicopathological Patterns and Predictors of the Functional Restoration of Immunoglobulin G4-Related Kidney Disease: A Chinese Single-Center Cohort Study.

Background: Immunoglobulin G4-related disease (IgG4-RD) is a systemic immunoreactivity-based fibro-inflammatory disease. Immunoglobulin G4-related kidney disease (IgG4-RKD) is a frequently overlooked diagnosis. This study aimed to describe IgG4-RKD and examine the factors relevant to the renal outcomes of IgG4-RD. Methods: We studied a prospective IgG4-RKD cohort between January 2012 and December 2020 with close follow-up. Clinicopathologic data at kidney biopsy were collected and analyzed. We aimed to explore independent risk factors for long-term renal outcome and disease relapse. Patients with an eGFR<45 ml/min per 1.73m2 at 12 months were defined as having poor outcomes. Results: The included 42 patients with IgG4-RKD had a mean age of 58.5 ± 8.7 years (male-to-female ratio = 5:1). The IgG4-RD responder index (RI) was 12.2 ± 3.3. A total of 66.7% of the patients presented with acute on kidney disease or acute on chronic kidney disease. Eight patients (19.0%) showed nephrotic-range proteinuria, and nine (21.4%) had high-titer IgG4-autoantibodies, including antineutrophil cytoplasmic antibody and anti-phospholipase A2 receptor. A kidney biopsy was conducted in 40 patients. Thirty-seven (90.0%) patients were diagnosed with IgG4-related tubulointerstitial nephritis, and 19 (47.5%) of them had concurrent glomerular diseases (membranous nephropathy [MN], n = 3; crescentic glomerulonephritis [CrGN], n = 11; diabetic kidney disease, n = 3; and both MN and CrGN, n = 2). IgG4-RD RI had a close relationship with serum C3 (R = -0.509, P = 0.001), C4 (R = -0.314, P = 0.049) levels, and peripheral blood eosinophil count (PBEC; R = 0.377, P = 0.024), factors that were not included in RI scores. Correlation analysis disclosed that IgG4-RD RI (R = 0.422, P = 0.007), organs involved (R = 0.452, P = 0.003), and C3 (R = -0.487, R = 0.002) were correlated with the percentage decrease of serum creatinine at 1 month. However, multivariate regression analysis failed to identify any clinicopathological parameters that could predict short-term renal restoration and IgG4-RKD relapse. Ten out of 29 variables, of most importance, were identified by the least absolute shrinkage and selection operator (LASSO) regression analysis. By multivariate logistic regression a higher serum IgG4 (OR = 0.671, P = 0.010), IgG1 (OR = 1.396, P = 0.049), IgG3 (OR = 19.154, P = 0.039), and erythrocyte sedimentation rate (ESR; OR = 1.042, P = 0.032) were found to be independent factors for poor long-term outcome. Conventional immunosuppressive medications and/or rituximab were prescribed, and in 83.3% of the patients, the kidney function improved. Repeat kidney biopsies confirmed the remission of interstitial inflammation in two patients under immunosuppressive therapy. However, the disease relapse rate was as high as 31.0%. Conclusions: We strongly recommend a kidney biopsy in active IgG4-RD, especially when there is proteinuria and renal dysfunction, because concurrent glomerular involvement and active interstitial inflammation should be assessed. A higher serum IgG1, IgG3, and ESR were independent factors for the poor long-term renal outcome; however, elevated IgG4 predicted a good renal prognosis, and appropriate and timely immunosuppressive therapy can help achieve a better prognosis.

Effects of mycophenolate mofetil on patients with pauci-immune crescentic glomerulonephritis / 中国实用内科杂志

Objective To compare the effect,relapse rate and outcomes between mycophenolate mofetil(MMF)and pulse intravenous cyclophosphamide(CTX)in the induction therapy of pauci-immune crescentic glomerulonephritis(PICGN)in Chinese.Methods A total of 44 patients who had PICGN[16 male,28 female,age(46.8?13.7)y],of whom 25 patients were ANCA positive,were enrolled in this study.All patients had renal involvement with ≥50% crescent formation prior to the study and received either MMF treatment(MMF group,n=22)or intermittent CTX pulse therapy(CTX group,n=22).The patients in both groups also received methylprednisolone(MP)pulse therapy followed by oral prednisone.General conditions,clinicopathological findings,remission rate,relapse rate,and outcomes were compared.All the patients were followed up until June 2005,with an average follow-up of 8～60(Med 27)months in the MMF group,and 6～72(Med 29)months in the CTX group.Results No significant difference was found between MMF group and CTX group in general conditions,base parameters of clinical and pathological findings.The remission rate at the 12th month in MMF and CTX group was 90.9% and 72.7% respectively.The complete remission rate in MMF group(59.1%)was significantly higher than that of the CTX group(27.3%)(P