Renal protective roles of macrophage matrix metalloproteinase-12 in mice with obstructed kidneys.

Matrix metalloproteinase (MMP)-12 has been reported to have diverse functions, including regulation of immune reactions and anti-inflammatory effects, but the potential roles of MMP-12 in kidney injury have not been fully elucidated. This study aimed to determine whether MMP-12 contributes to tubulointerstitial injury in a unilateral ureteric obstruction (UUO) model. MMP-12-deficient (MMP-12-/-) mice and C57BL/6J mice as controls (MMP-12+/+) were subjected to UUO and analysed 7 days after UUO. To analyse the functions of MMP-12 on monocytes/macrophages, we generated MMP-12-deficient, irradiated, chimeric mice (BM-MMP-12-/-) and performed UUO. Bone marrow-derived macrophages (BMDMs) were isolated from both groups of mice and used for investigations. MMP-12-/- mice showed exacerbation of macrophage accumulation and interstitial fibrosis in the UUO-kidney compared with control mice. BM-MMP-12-/- mice also showed exacerbation of kidney injury. UUO induced accumulation of Ly6C+ macrophages in MMP-12-/- mice compared with control mice. Increases in inflammatory cytokine (tumour necrosis factor α, interleukin [IL]-1ß, IL-6) levels from BMDMs after lipopolysaccharide stimulation were higher in MMP-12-/- mice than in MMP-12+/+ mice. MMP-12 may play protective roles against kidney injury by UUO in mice, decreasing inflammatory cytokines from BMDMs and macrophage accumulation.

Development of a Kidney Prognostic Score in a Japanese Cohort of Patients With Antineutrophil Cytoplasmic Autoantibody Vasculitis.

Introduction: Glomerulonephritis is frequent in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and crucial to disease outcomes. We conducted a detailed assessment of renal pathology in Japanese patients with AAV, and developed a new score that would predict renal outcome. Methods: Two hundred twenty-one patients who were diagnosed with AAV and underwent a kidney biopsy were enrolled. Data on glomerular, tubular, interstitial, and vascular lesions from kidney biopsies were analyzed; the 3 established classification and prognostic scoring systems (Berden Classification, Mayo Clinic/RPS Chronicity Score [MCCS], and ANCA Renal Risk Score [ARRS]) were validated. Further, we developed a new prognostic score by including variables relevant for Japanese patients with ANCA-glomerulonephritis. Results: Median follow-up was 60 months (interquartile range: 6-60). End-stage kidney disease (ESKD) risk prediction by the MCCS and the ARRS was confirmed. Moreover, our analysis identified 4 items with significant ESKD risk prediction capacity, namely percentage of cellular, fibrocellular, and fibrous crescents; and sclerotic glomeruli. Based on our findings, we created a score evaluating the percentage of these lesions to total glomeruli, the Percentage of ANCA Crescentic Score (PACS). The area under the receiver operating characteristic (ROC) curve evaluating PACS was 0.783. The PACS had a comparable performance as the ARRS in predicting ESKD. The optimal PACS cut-off for ESKD risk over 60 months was 43%. In addition, the percentage of cellular crescents and presence of interstitial inflammation were independent predictors of kidney function recovery. Conclusion: We developed a new score predicting renal prognosis using histopathological data of Japanese patients with ANCA-glomerulonephritis. Studies are needed to validate our results in international cohorts.

Moon-like Facies by Glucocorticoid Is Associated With the Development of Diabetes and Body Image Disturbance.

Context: Moon-like facies (MLF) are a typical side effect of glucocorticoid (GC) therapy; however, its predisposing factors, relationship with GC-induced complications, and effects on body image are not well understood. Objective: This study aimed to determine the predisposing factors for MLF during GC therapy; its association with GC-induced diabetes, hypertension, and dyslipidemia; and its effects on body image. Methods: This prospective observational study spanned 24 weeks and targeted patients who received GC therapy at the University of Yamanashi Hospital from June 2020 to August 2022. The MLF was defined based on the following 3 factors: (1) an increase in facial measurement lengths, (2) subjective facial changes by patients' self-assessment using a visual analog scale; (3) objective and qualitative facial changes assessed by physicians. We examined the predisposing factors for MLF and the association of MLF with GC-induced diabetes, hypertension, dyslipidemia, and body image. Results: The cumulative incidence rate of MLF at 24 weeks was 37.6%. Predisposing factors for MLF were an initial oral prednisolone dosage of ≥ 30 mg/day [odds ratio (OR) 63.91, 95% confidence interval (CI) 5.82-701.81] and female (OR 6.66, 95% CI 1.35-32.79). MLF showed a significant association with the onset of GC-induced diabetes (OR 6.58, 95% CI 1.25-34.74). MLF was also an independent factor contributing to body image disturbance (ß = -18.94, P = .01). Conclusion: MLF contributes to body image disturbance and is associated with the development of GC-induced diabetes; therefore, it is clinically important as a physical manifestation of GC therapy.

Antidiabetic effects of hydroxychloroquine in two Japanese patients with systemic lupus erythematosus.

Hydroxychloroquine (HCQ), an antimalarial drug, is recommended for all patients with systemic lupus erythematosus (SLE), and is widely used around the world. HCQ has various beneficial effects, including antidiabetic effects but was unavailable in Japan until gaining approval for SLE treatment in 2015. We present herein the cases of two Japanese women with SLE and diabetes mellitus (DM) who were treated using HCQ and achieved reductions in glycosylated hemoglobin (HbA1c). A 48 year-old Japanese woman with SLE and DM (patient 1) received oral HCQ at 200 mg/day for the treatment of lupus nephritis. HbA1c levels decreased from 7.2-6.2% after 14 months of HCQ without any loss of body weight or alterations in doses of glucocorticoid or hypoglycemic agents. A 64 year-old Japanese woman with SLE and DM (patient 2) received oral HCQ at 200 mg and 400 mg on alternate days for the treatment of erythema. She also received intensive insulin therapy. HCQ drastically reduced both HbA1c levels, from 10.3 to 7.5%, and the insulin doses required without altering the doses of glucocorticoid or hypoglycemic agents, although body weight increased slightly. No episodes of hypoglycemia were seen in either patient. HCQ can achieve antidiabetic effects in Japanese SLE patients.

Hyperthyroidism exacerbates ischemic reperfusion injury in the kidney.

Thyroid hormones are critical regulators of vertebrate development and metabolism. Under hyperthyroid conditions, excess thyroid hormones induce expression of several enzymes and activities via activation of ligand-bound thyroid hormone receptors (TRs). Arginase (ARG) is downstream of a ligand-bound TR and overexpression of ARG2 induces the production of reactive oxygen species and subsequent exacerbation of kidney ischemia/reperfusion (I/R) injury. To clarify the association between I/R-induced kidney injury and hyperthyroidism, mice were pretreated with L-thyroxine (LT4) or vehicle alone, then subjected to I/R. Proximal tubular cell-specific conditional knockout of thyroid hormone receptor ß (TRßcKO) mice was generated and the effects of I/R were analyzed. Hyperthyroidism enhanced tubular damage and fibrosis in the kidneys of mice after I/R. Hyperthyroidism induced tubular cell necroptosis following inflammatory cell accumulation in the kidney after I/R. ARG2 expressions and reactive oxygen species accumulated in the kidneys of hyperthyroid mice after I/R, but these changes were ameliorated in the kidneys of TRßcKO mice. Hyperthyroidism-enhanced kidney injury was ameliorated in the kidney of TRßcKO mice after I/R. These results suggest that excess thyroid hormones are disadvantageous for the kidney under ischemic stress. Overt hypothyroidism represents a severe thyroid hormone deficiency disease that requires LT4 treatment, while overreplacement or iatrogenic thyrotoxicosis might cause kidney injury.

Ultrasound of shoulder and knee improves the accuracy of the 2012 EULAR/ACR provisional classification criteria for polymyalgia rheumatica.

OBJECTIVE: Recent studies suggest that the knee is frequently involved in PMR. In this study, we aimed to determine whether the US assessment of the shoulder and knee discriminates between PMR and other differential diagnoses and improves the accuracy of the 2012 EULAR/ACR provisional classification criteria for PMR. METHODS: We consecutively enrolled 81 untreated patients who received a diagnosis of PMR. These patients were divided into two groups based on the final diagnosis made at 1-year follow-up: PMR-definite group (n = 60) and PMR-mimic group (n = 21). We also enrolled age/sex-matched untreated RA patients with shoulder pain from an independent cohort (RA group, n = 60). All patients underwent comprehensive US assessment of the shoulder and knee for synovitis, bursitis, tenosynovitis, tendinitis and ligament inflammation at baseline. RESULTS: US scores for tenosynovitis, tendinitis and ligament inflammation better discriminated the PMR-definite group from the PMR-mimic and RA groups than do those for synovitis or bursitis. Among logistic regression models to identify US variables that were associated with the PMR-definite group, the best fitted model included two US variables: the bilateral involvement of the shoulder (long head of biceps, supraspinatus or subscapularis tendon) and the bilateral involvement of the knee (popliteus tendon or medial or lateral collateral ligament). Incorporating these two items into the 2012 EULAR/ACR provisional classification criteria numerically increased the accuracy to classify the PMR-definite group. CONCLUSION: US assessment of the tendon/ligament-related lesions in the shoulder and knee may improve the accuracy of the 2012 EULAR/ACR provisional classification criteria for PMR.

Hypoxia-induced thyroid hormone receptor expression regulates cell-cycle progression in renal tubule epithelial cells.

Hypoxia occurs in the kidneys of chronic kidney disease (CKD) patients, inducing interstitial fibrosis and tubule cell death. Renal tubule cell death is an important determinant of mortality in CKD. We focused on the regulation of cell-cycle-mediated protein expression to prevent cell death under chronic hypoxia in the kidneys of CKD patients. Paraffin-embedded kidney sections from patients with CKD (diabetes nephropathy, nephrosclerosis, or IgA nephropathy) were analyzed for the expression of hypoxia-inducible factor (HIF), thyroid hormone receptor (TR) ß, or p21 and levels of interstitial fibrosis. Human renal proximal tubule cells were exposed to hypoxia and analyzed for the expression of HIF, TRß, or p21 and the cell-cycle stage. TRß expression was enhanced early on when fibrosis was not fully developed in the tubule cells of CKD patients. HIF1α bound to the TRß promoter and directly induced its transcription. Further, HIF1α expression induced the expression of TRß and inhibited cell-cycle progression. In the early stage of kidney injury, TRß might act as a guardian to prepare and organize cell-cycle proliferation and prevent cell death. While the molecular mechanism that regulates the expression of cell-cycle regulators in renal tubule cells remains controversial, TRß has strong potential as a new therapeutic target.

Membranous Nephropathy with Proteinase 3-ANCA-associated Vasculitis Successfully Treated with Rituximab.

Membranous nephropathy (MN) with anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (ANCA-GN) is seen infrequently. Previous reports of patients with ANCA-GN with MN showed that the most frequent ANCA subtype was myeloperoxidase-ANCA. We herein present a 73-year-old woman with scleritis, hematuria, proteinuria, and positive serum proteinase 3 (PR3)-ANCA. She underwent a renal biopsy and was diagnosed with MN and ANCA-GN. Immunofluorescence staining for PR3 colocalized with IgG along the glomerular basement membrane were observed. Oral prednisolone and intravenous rituximab therapy immediately improved her symptoms and urinalysis abnormalities. PR3-ANCA may be involved in the pathogenesis of MN via the formation of immune complexes.