Hiroko Hamatani

Effects of proteasome inhibitors on rat renal fibrosis in vitro and in vivo

Aim:  Transforming growth factor‐β (TGF‐β) is involved in renal tubulointerstitial fibrosis. Recently, the ubiquitin proteasome system was shown to participate in the TGF‐β signalling pathway. The aim of this study was to examine the effects of proteasome inhibitors on TGF‐β‐induced transformation of renal fibroblasts and tubular epithelial cells in vitro and on unilateral ureteral obstruction (UUO) in vivo.

Nephrotic Syndrome Caused by Immune-Mediated Acquired LCAT Deficiency

Lecithin-cholesterol acyltransferase (LCAT) is an enzyme involved in maintaining cholesterol homeostasis. In familial LCAT deficiency (FLD), abnormal lipid deposition causes renal injury and nephrotic syndrome, frequently progressing to ESRD. Here, we describe a 63-year-old Japanese woman with no family history of renal disease who presented with nephrotic syndrome. The laboratory data revealed an extremely low level of serum HDL and undetectable serum LCAT activity. Renal biopsy showed glomerular lipid deposition with prominent accumulation of foam cells, similar to the histologic findings of FLD. In addition, she had subepithelial electron-dense deposits compatible with membranous nephropathy, which are not typical of FLD. A mixing test and coimmunoprecipitation study demonstrated the presence of an inhibitory anti-LCAT antibody in the patients serum. Immunohistochemistry and immunofluorescence detected LCAT along parts of the glomerular capillary walls, suggesting that LCAT was an antigen responsible for the membranous nephropathy. Treatment with steroids resulted in complete remission of the nephrotic syndrome, normalization of serum LCAT activity and HDL level, and disappearance of foam cell accumulation in renal tissue. In summary, inhibitory anti-LCAT antibody can lead to glomerular lesions similar to those observed in FLD.

Diaphragmatic Hernia with Ischemic Bowel Obstruction in Pregnancy : Report of a Case

Diaphragmatic hernia complicating pregnancy is rare and is associated with high morbidity and mortality, particularly if surgical intervention is delayed. We report a case of diaphragmatic hernia in a pregnant 25-year-old woman. The patient was referred to our hospital in respiratory distress in the 28th week of her pregnancy. Chest radiograph and computed tomography showed air-filled bowel loops in the left side of the chest, with a marked mediastinal shift. Immediately after an emergency caesarean section, the herniated abdominal viscera were reduced through the opening in the diaphragm. We resected the ischemic segment of ileum and repaired the diaphragmatic defect with interrupted sutures and a Gore-Tex sheet. She had an uneventful postoperative course and her baby boy also recovered well. We report this case to alert surgeons to the possibility of this rare surgical emergency during pregnancy.

Expression of a novel stress-inducible protein, sestrin 2, in rat glomerular parietal epithelial cells

Sestrin 2, initially identified as a p53 target protein, accumulates in cells exposed to stress and inhibits mammalian target of rapamycin (mTOR) signaling. In normal rat kidneys, sestrin 2 was selectively expressed in parietal epithelial cells (PECs), identified by the marker protein gene product 9.5. In adriamycin nephropathy, sestrin 2 expression decreased in PECs on day 14, together with increased expression of phosphorylated S6 ribosomal protein (P-S6RP), a downstream target of mTOR. Sestrin 2 expression was markedly decreased on day 42, coinciding with glomerulosclerosis and severe periglomerular fibrosis. In puromycin aminonucleoside nephropathy, decreased sestrin 2 expression, increased P-S6RP expression, and periglomerular fibrosis were observed on day 9, when massive proteinuria developed. These changes were transient and nearly normalized by day 28. In crescentic glomerulonephritis, sestrin 2 expression was not detected in cellular crescents, whereas P-S6RP increased. In conditionally immortalized cultured PECs, the forced downregulation of sestrin 2 by short hairpin RNA resulted in increased expression of P-S6RP and increased apoptosis. These data suggest that sestrin 2 is involved in PEC homeostasis by regulating the activity of mTOR. In addition, sestrin 2 could be a novel marker of PECs, and decreased expression of sestrin 2 might be a marker of PEC injury.

Hydronephrosis caused by a relapse of granulomatosis with polyangiitis (Wegener’s)

We describe a case of relapsed granulomatosis with polyangiitis (Wegener’s) (GPA) that presented with abdominal pain. 18F-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET)/computed tomography (CT) clearly depicted an inflammation of the left peri-iliac arterial soft tissue, which was thought to be the cause of the ureteral obstruction and hydronephrosis. Our case shows that peri-iliac arterial inflammation occurs in GPA and causes hydronephrosis. In addition, FDG-PET/CT is a useful tool for management of this systemic inflammatory disease.

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

Abstract 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.

SIRPα signaling regulates podocyte structure and function

Signal-regulatory protein-α (SIRPα) is a transmembrane protein that contains tyrosine phosphorylation sites in its cytoplasmic region; two tyrosine phosphatases, SHP-1 and SHP-2, bind to these sites in a phosphorylation-dependent manner and transduce multiple intracellular signals. Recently, SIRPα was identified as one of the major tyrosine-phosphorylated proteins in the glomeruli and found to be expressed in podocytes. In the present study, we examined the role of SIRPα expression in podocytes using knockin mice (C57BL/6 background) expressing mutant SIRPα that lacks a cytoplasmic region (SIRPα-mutant mice). Light microscopic examination revealed no apparent morphological abnormalities in the kidneys of the SIRPα-mutant mice. On the other hand, electron microscopic examination revealed abnormal podocytes with irregular major processes and wider and flattened foot processes in the SIRPα-mutant mice compared with their wild-type counterparts. Significantly impaired renal functions and slight albuminuria were demonstrated in the SIRPα-mutant mice. In addition, adriamycin injection induced massive albuminuria together with focal glomerulosclerosis in the SIRPα-mutant mice, while their wild-type counterparts were resistant to adriamycin-induced nephropathy. These data demonstrate that SIRPα is involved in the regulation of podocyte structure and function as a filtration barrier under both physiological and pathological conditions.

TGF-β1 Alters DNA Methylation Levels in Promoter and Enhancer Regions of the WT1 Gene in Human Podocytes: TGF-β1 Modulates DNA Methylation of WT1

Wilms’ tumour 1 (WT1) is essential for normal podocyte function. Previous reports have demonstrated that the WT1 promoter is often methylated in cancers, leading to transcriptional silencing. Transforming growth factor‐β1 (TGF‐β1) is reported to down‐regulate WT1 expression in podocytes. Based on the hypothesis that epigenetic modification plays a role in this process, we examined whether TGF‐β1 affects the methylation status of WT1 regulatory regions.

SAT0337 Hypertrophic Pachymeningitis Associated with ANCA Vasculitis; A Case Series of 16 Patients

Background Recent reports indicate that hypertrophic pachymeningitis (HPM) develops in association with myeloperoxidase (MPO) anti-neutrophil cytoplasmic antibody (ANCA)-positive vasculitis1,2). However, little is known about clinical features and outcomes of the disease. Objectives We aimed to describe clinical, laboratory and radiological features and treatment course of HPM occurred in patients with ANCA-associated vasculitis (AAV). Methods We retrospectively analyzed 16 Japanese adult patients (11 males and 5 females), who had been treated at our hospital in a study period from January 2006 through December 2015. Diagnosis of HPM was made with MRI T1 sequence with gadolinium by detecting thickening and enhancing of brain and/or spinal dura mater in patients manifesting neurological symptoms. Diagnosis and classification of AAV was performed according to a report by Watts, et.al.3). Results The mean age at HPM onset was 60.1 years (range, 35–78 years). Out of 16 patients, HPM was detected at the onset of AAV in 9 (56.3%), at the relapsing AAV under treatment in 6 (37.5%), and before the diagnosis of AAV as idiopathic HPM in 1 (6.3%). Headache and cranial nerve palsy due to HPM were observed in 13 (81.3%) and 11 (68.8%) patients, respectively. Otitis media and sinusitis were found as complications of AAV in 7 (43.8%) and 6 (37.5%) patients. Twelve patients (75%) were classified as granulomatosis with polyangiitis (GPA). Microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis and unclassifiable vasculitis were applied to 2 (12.5%), 1 (6.3%) and 1 (6.3%) patients, respectively. Serum myeloperoxidase (MPO)-ANCA and proteinase 3 (PR3)-ANCA were positive in 9 (56.3%) and 5 (31.3%), respectively, and 2 (12.5%) patients had neither of them. The mean serum C-reactive protein levels were 4.87 mg/dL (range, 0.26–17.11 mg/dL). Spinal fluids were analyzed in 6 patients, and a mild increase in spinal cell counts and protein levels were identified in 3 patients each. With MRI, thickening of dura mater in cranial fossa and tentorium cerebelli were found in 11 (68.8%) and 9 (56.3%) patients, respectively. All patients were treated with corticosteroids and 10 (62.5%) patients were concomitantly administered with other agents including cyclophosphamide, methotrexate, azathioprine and mizoribine for remission induction. All patients achieved remission of the neurological symptoms and improvement of dura mater thickening. In a mean follow-up period of 41.8 months (range, 5–89 months) after diagnosis, 4 (25%) patients experienced a relapse of HPM and received re-induction therapy. Conclusions Our results indicate that occurrence of HPM is mostly associated with GPA having either type of ANCA serology. Dura mater in cranial fossa and tentorium cerebelli was commonly involved, which could lead to cranial nerve impairment. Immunosuppressive therapy is effective, but a relapse of HPM occasionally occurs. References Yokoseki A, et al. Brain. 2014 Feb;137(Pt2):520–36. Nagashima T, et al. Neuropathology. 2000 Mar;20(1):23–30. Watts R, et al. Ann Rheum Dis. 2007 Feb;66(2):222–7. Disclosure of Interest None declared