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Activin A, a member of the transforming growth factor-beta superfamily, is a critical modulator of inflammation and plays a key role in controlling the cytokine cascade that drives the inflammatory response. However, the role of activin A in inflammatory kidney diseases remains unknown. To address this issue, we examined here whether activin A can be detected in the kidney and/or urine from patients with antineutrophil cytoplasmic antibody (ANCA) -associated vasculitis (AAV). Fifty-one patients who had been diagnosed with AAV and were treated in our department between November 2011 to March 2018 were included in this study. Forty-one patients had renal complications (renal AAV). Serum and urinary activin A levels were measured by enzyme-linked immunosorbent assay. Correlation of urinary activin A concentration with clinical parameters was analyzed. Urinary activin A was undetectable in healthy volunteers. In contrast, urinary activin A concentration was significantly increased in patients with renal AAV but not in those with non-renal AAV. Urinary activin A concentration decreased rapidly after immunosuppressive treatment. There was a significant correlation of urinary activin A level with urinary protein, L-FABP, and NAG. Histologic evaluation revealed that urinary activin A levels were significantly higher in patients with cellular crescentic glomeruli than in those lacking this damage. In situ hybridization demonstrated that the mRNA encoding the activin A βA subunit was undetectable in normal kidneys but accumulated in the proximal tubules and crescentic glomeruli of the kidneys of patients with renal AAV. Immunostaining showed that activin A protein also was present in the proximal tubules, crescentic glomeruli, and macrophages infiltrating into the interstitium in the kidneys of patients with renal AAV. These data suggested that urinary activin A concentration reflects renal inflammation and tubular damage in AAV and may be a useful biomarker for monitoring renal AAV. [ABSTRACT FROM AUTHOR]

The N-type Ca2+ channel (Cav2.2) is distributed in sympathetic nerves that innervate the tubules, the vessels, and the juxtaglomerular granular cells of the kidney. However, the role of N-type Ca2+ channels in renal disease remains unknown. To address this issue, Cav2.2 knockout mice were utilized. Immunoreactive Cav2.2 was undetectable in normal kidneys of C57BL/6N mice, but it became positive in the interstitial S100-positive nerve fibers after unilateral ureteral obstruction (UUO). There were no significant differences in mean blood pressure, heart rate, and renal function between wild-type littermates and Cav2.2-knockout mice at baseline, as well as after UUO. Cav2.2 deficiency significantly reduced the EVG-positive fibrotic area, alpha-SMA expression, the production of type I collagen, and the hypoxic area in the obstructed kidneys. The expression of tyrosine hydroxylase, a marker for sympathetic neurons, was significantly increased in the obstructed kidneys of wild-type mice, but not in Cav2.2-knockout mice. These data suggest that increased Cav2.2 is implicated in renal nerve activation leading to the progression of renal fibrosis. Blockade of Cav2.2 might be a novel therapeutic approach for preventing renal fibrosis. [ABSTRACT FROM AUTHOR]

Tubulogenesis, the organization of epithelial cells into tubular structures, is an essential step during renal organogenesis as well as during the regeneration process of renal tubules after injury. In the present study, endothelial cell-derived factors that modulate tubule formation were examined using an in vitro human tubulogenesis system. When human renal proximal tubular epithelial cells (RPTECs) were cultured in gels, tubular structures with lumens were induced in the presence of hepatocyte growth factor (HGF). Aquaporin 1 was localized in the apical membrane of these tubular structures, suggesting that these structures are morphologically equivalent to renal tubules in vivo. HGF-induced tubule formation was significantly enhanced when co-cultured with human umbilical vein endothelial cells (HUVECs) or in the presence of HUVEC-conditioned medium (HUVEC-CM). Co-culture with HUVECs did not induce tubular structures in the absence of HGF. A phospho-receptor tyrosine kinase array revealed that HUVEC-CM markedly enhanced phosphorylation of Ret, glial cell-derived neurotrophic factor (GDNF) receptor, in HGF-induced tubular structures compared to those without HUVEC-CM. HUVECs produced GDNF, and RPTECs expressed both Ret and GDNF family receptor alpha1 (co-receptor). HGF-induced tubule formation was significantly enhanced by addition of GDNF. Interestingly, not only HGF but also GDNF significantly induced phosphorylation of the HGF receptor, Met. These data indicate that endothelial cell-derived GDNF potentiates the tubulogenic properties of HGF and may play a critical role in the epithelial-endothelial crosstalk during renal tubulogenesis as well as tubular regeneration after injury. [ABSTRACT FROM AUTHOR]

Hepatitis E is an acute self-limiting disease caused by hepatitis E virus (HEV). Recent reports show that HEV can induce chronic hepatitis or be reactivated in immunocompromised hosts. We report a 63-year-old woman with rheumatoid arthritis (RA) who developed hepatitis E during treatment with tocilizumab. Analysis of serially stocked serum samples confirmed that hepatitis was caused by primary infection with HEV and not by viral reactivation. Her liver function improved after discontinuing tocilizumab and remained within the normal range without reactivation of HEV for >5 years after restarting tocilizumab. We also reviewed the published cases of hepatitis E that developed during RA treatment. [ABSTRACT FROM AUTHOR]

Transforming growth factor (TGF)-β1 contributes to podocyte injury in various glomerular diseases, including diabetic kidney disease, probably at least in part by attenuating the expression of Wilms' tumor 1 (WT1). However, the precise mechanisms remain to be defined. We performed miRNA microarray analysis in a human podocyte cell line cultured with TGF-β1 to examine the roles of miRNAs in podocyte damage. The microarray analysis identified miR-143-3p as the miRNA with the greatest increase following exposure to TGF-β1. Quantitative RT-PCR confirmed a significant increase in the miR-143-3p/145-5p cluster in TGF-β1-supplemented cultured podocytes and demonstrated upregulation of miR-143-3p in the glomeruli of mice with type 2 diabetes. Ectopic expression of miR-143-3p and miR-145-5p suppressed WT1 expression in cultured podocytes. Furthermore, inhibition of Smad or mammalian target of rapamycin signaling each partially reversed the TGF-β1-induced increase in miR-143-3p/145-5p and decrease in WT1. In conclusion, TGF-β1 induces expression of miR-143-3p/145-5p in part through Smad and mammalian target of rapamycin pathways, and miR-143-3p/145-5p reduces expression of WT1 in cultured human podocytes. miR-143-3p/145-5p may contribute to TGF-β1-induced podocyte injury. NEW & NOTEWORTHY This study by miRNA microarray analysis demonstrated that miR-143-3p expression was upregulated in cultured human podocytes following exposure to transforming growth factor (TGF)-β1. Furthermore, we report that the miR-143/145 cluster contributes to decreased expression of Wilms' tumor 1, which represents a possible mechanism for podocyte injury induced by TGF-β1. This study is important because it presents a novel mechanism for TGF-β-associated glomerular diseases, including diabetic kidney disease (DKD), and suggests potential therapeutic strategies targeting miR-143-3p/145-5p.

Objectives: Otitis media with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV) is a new category of otitis media in which cases of otitis media due to ANCA-associated vasculitis (AAV) are classified, regardless of ANCA variant or ANCA serotype. We aimed to describe the clinical features and course of patients with OMAAV and identify factors associated with hearing outcomes., Methods: We retrospectively analysed 30 patients with OMAAV, classified based on the criteria proposed by the Japan Otological Society in 2016., Results: Single-positive myeloperoxidase-ANCA, single-positive proteinase 3-ANCA, double-positive ANCA, and double-negative ANCA were identified in 47%, 33%, 7%, and 13% of the patients, respectively. All patients subjected to audiometry showed hearing impairments, and 85% were affected bilaterally. Mixed- and sensorineural-type hearing impairments were identified in 80% and 20% of impaired ears, respectively. Hypertrophic pachymeningitis (HPM) was identified in 37% of the patients. Immunosuppressive therapy was administered to 93% of patients, and the median air conduction hearing levels at pre- and post-treatment were 66.1 dB and 43.4 dB, respectively, indicating significant hearing improvements. HPM and a long interval between disease onset and treatment initiation were significantly correlated with poor hearing prognosis., Conclusions: OMAAV develops under any type of ANCA-serology and typically causes mixed or sensorineural bilateral hearing loss. The early initiation of immunosuppressive therapy and the absence of HPM were associated with good hearing outcomes., (© Japan College of Rheumatology 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Anti-melanoma differentiation-associated gene 5 (MDA5) autoantibody-positive and age at onset ≥60 years are poor prognosis factors in polymyositis (PM) and dermatomyositis (DM) associated with interstitial lung disease (ILD) among Japanese patients. However, the influence of age on the clinical features of anti-MDA5 autoantibody-positive patients with DM remains unclear., Methods: We retrospectively examined 40 patients with DM and anti-MDA5 autoantibodies according to age. We compared patients aged <60 and ≥60 years with respect to clinical features including laboratory test findings, high-resolution lung computed tomography data, treatment content, and complications such as infections and prognosis. We also examined clinical features between surviving and deceased patients in the older patient group., Results: Of 40 enrolled patients, 13 were classified as old and 27 as young. Older patients had significantly fewer clinical symptoms including arthralgia/arthritis ( p  < .01), skin ulceration ( p  = .02), and higher mortality than younger patients ( p  = .02) complicated with rapidly progressive ILD (RP-ILD), combination immunosuppressive therapy, and strictly controlled infections., Conclusion: Clinical features and mortality of anti-MDA5 autoantibody-positive DM patients were influenced by age. Patients aged ≥60 years had a worse prognosis, and combination immunosuppressive therapy was often ineffective for RP-ILD in older patients.

Nivolumab is an anti-programmed cell death-1 (PD-1) antibody that is utilized as an immune checkpoint inhibitor (ICI) for cancer therapy. We herein present the case of a 57-year-old man who developed acute kidney injury during treatment with nivolumab for lung cancer. A renal biopsy revealed acute tubulointerstitial nephritis. Immunohistochemical staining demonstrated marked infiltration of macrophages and T cells together with mild B cell infiltration. Of note, strong CD163 + M2 macrophage infiltration was observed. The cessation of nivolumab and high-dose prednisolone therapy improved the renal function of the patient. Further, we review the pertinent literature on renal-infiltrating cells in ICI-induced tubulointerstitial nephritis.

Acute kidney injury (AKI) is a common but complex condition that is associated with increased morbidity and mortality. In the present study, we examined whether urinary activin A, a member of the TGF-beta superfamily, is present in mice with ischemia-reperfusion injury and in humans with AKI, as well as its potential as a biomarker for AKI. Expression of activin A was markedly increased in ischemic mouse kidneys. In situ hybridization demonstrated that activin mRNA was expressed in tubular cells of ischemic kidneys but not of normal kidneys. Immunoreactive activin A, which was absent in normal kidneys, was detected in the cytoplasm of proximal tubular cells in ischemic kidneys. Activin A was undetectable in the urine of normal mice. In contrast, activin A was significantly increased in the urine of ischemic mice at 3 h after reperfusion. Urinary activin A levels increased according to the period of ischemia. In humans, urinary activin A was almost undetectable in healthy volunteers and in patients with pre-renal AKI, but was significantly increased in patients with renal AKI. There was no significant correlation between urinary activin A and serum activin A. Collectively, urinary activin A might be a useful biomarker reflecting the severity of AKI.

Background: The process of epithelial-mesenchymal transition (EMT), which is generally defined by phenotypic changes of injured tubules such as loss of epithelial markers or acquisition of mesenchymal markers, implies various activating steps, including proliferation, migration, and ability to produce extracellular matrix proteins. We established here a novel approach for the detection of tubular cell migration into the interstitium during renal fibrosis in vivo., Results: Using an osmotic pump, bromodeoxyuridine (BrdU) was continuously given to 7-week-old Wistar rats for 4 weeks, and BrdU-positive cells were detected by immunostaining. BrdU-positive cells were present in aquaporin-1-positive proximal tubules, but not in the interstitium of BrdU-treated rat kidneys. After unilateral ureteral obstruction (UUO), some BrdU-positive tubular cells protruded from the basement membrane and migrated into the interstitium. Interstitial BrdU-positive cells were co-localized with alpha-smooth muscle actin, fibroblast specific protein-1, vimentin, and type I collagen, but not with CD68 or CD3. No BrdU-positive cells were observed in the interstitium of sham-operated kidneys. The number of BrdU-positive cells migrating into the interstitium significantly increased and peaked at 8 days after UUO., Conclusions: Long-term BrdU labeling marked some of the proximal tubular cells and enabled us to detect tubular cell migration into the interstitium after UUO. This simple method might be useful to detect EMT in vivo.