Yukiko Nozawa

Effects of connexin-mimetic peptides on perfusion pressure in response to phenylephrine in isolated, perfused rat kidneys

BackgroundGap junction intercellular communication plays a fundamental role in various tissues and organs. Gap junctions transfer ions and molecules between adjacent cells and are formed by connexins (Cx). It is supposed that vascular conducted responses, which most likely spread through gap junctions in vascular beds, regulate microcirculatory blood flow and maintain vascular resistance. This study provides functional evidence supporting the critical role of gap junctions in a physiological setting and in phenylephrine (PE)-induced vasoconstriction using an ex vivo kidney perfusion technique.MethodsUsing the isolated, perfused kidney model, infusion of gap junction inhibitors and PE, we examined the local effect of gap junction communication. Additionally, gap junction proteins Cx37, Cx40 and Cx43 were detected by immunofluorescence.ResultsFirst, changes in the perfusion pressure were analyzed by infusing the nonselective gap junction uncoupler, 18α-glycyrrhetinic acid (18α-GA), and specific connexin-mimetic peptide inhibitors, 37,43Gap27, 40Gap27 and 43Gap26. Administration of 18α-GA and 43Gap26 significantly elevated perfusion pressure while infusion of 40Gap27 and 37,43Gap27 had no effect. Second, we examined the effect of infusing gap junction inhibitors on PE-induced vasoconstriction. Infusion of 18α-GA and 40Gap27 significantly suppressed the increase in perfusion pressure induced by PE, while 43Gap26 and 37,43Gap27 had no effect. Third, we confirmed by immunofluorescence that Cx37, Cx40 and Cx43 were found in the endothelial cells of interstitial microvessels and that Cx40 was localized in glomerular mesangial cells as well as in smooth muscle cells of the juxtaglomerular area.ConclusionsThis study showed that Cx43 plays a pivotal role in regulating renal vascular resistance and that Cx40 attenuates PE-induced vasoconstriction. These results provide new evidence that gap junctions may control renal circulation and vascular responses.

Adult-onset Chronic Recurrent Multifocal Osteomyelitis with High Intensity of Muscles Detected by Magnetic Resonance Imaging, Successfully Controlled with Tocilizumab

Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disorder that generally occurs in children and predominantly affects the long bones with marginal sclerosis. We herein report two cases of adult-onset CRMO involving the tibial diaphysis bilaterally, accompanied by polyarthritis. Magnetic resonance imaging (MRI) showed both tibial osteomyelitis and high intensity of the extensive lower leg muscles. Anti-interleukin-6 therapy with tocilizumab (TCZ) effectively controlled symptoms and inflammatory markers in both patients. High intensity of the lower leg muscles detected by MRI also improved. These cases demonstrate that CRMO should be included in the differential diagnosis of adult patients with bone pain, inflammation, and high intensity of the muscles detected by MRI. TCZ may therefore be an effective therapy for muscle inflammation of CRMO.

Significant association between renal function and area of amyloid deposition in kidney biopsy specimens in both AA amyloidosis associated with rheumatoid arthritis and AL amyloidosis

Abstract The kidney is a major target organ for systemic amyloidosis, which results in proteinuria and an elevated serum creatinine level. The clinical manifestations and precursor proteins of amyloid A (AA) and light-chain (AL) amyloidosis are different, and the renal damage due to amyloid deposition also seems to differ. The purpose of this study was to clarify haw the difference in clinical features between AA and AL amyloidosis are explained by the difference in the amount and distribution of amyloid deposition in the renal tissues. A total of 119 patients participated: 58 patients with an established diagnosis of AA amyloidosis (AA group) and 61 with AL amyloidosis (AL group). We retrospectively investigated the correlation between clinical data, pathological manifestations, and the area occupied by amyloid in renal biopsy specimens. In most of the renal specimens the percentage area occupied by amyloid was less than 10%. For statistical analyses, the percentage area of amyloid deposition was transformed to a common logarithmic value (Log10%amyloid). The results of sex-, age-, and Log10%amyloid-adjusted analyses showed that systolic blood pressure (SBP) was higher in the AA group. In terms of renal function parameters, serum creatinine, creatinine clearance (Ccr) and estimated glomerular filtration rate (eGFR) indicated significant renal impairment in the AA group, whereas urinary protein indicated significant renal impairment in the AL group. Pathological examinations revealed amyloid was predominantly deposited at glomerular basement membrane (GBM) and easily transferred to the mesangial area in the AA group, and it was predominantly deposited at in the AL group. The degree of amyloid deposition in the glomerular capillary was significantly more severe in AL group. The frequency of amyloid deposits in extraglomerular mesangium was not significantly different between the two groups, but in AA group, the degree amyloid deposition was significantly more severe, and the deposition pattern in the glomerulus was nodular. Nodular deposition in extraglomerular mesangium leads to renal impairment in AA group. There are significant differences between AA and AL amyloidosis with regard to the renal function, especially in terms of Ccr, eGFR and urinary protein, even after Log10%amyloid was adjusted; showing that these inter-group differences in renal function would not be depend on the amount of renal amyloid deposits. These differences could be explained by the difference in distribution and morphological pattern of amyloid deposition in the renal tissue.

Characterization of patients with systemic lupus erythematosus who meet the diagnostic criteria for TAFRO syndrome

Purpose TAFRO syndrome is a novel disorder manifesting as fever, anasarca, thrombocytopenia, renal insufficiency and organomegaly, and its etiology has not been clarified. The aim of this study was to elucidate similarities and differences between systemic lupus erythematosus (SLE) and TAFRO syndrome. Methods We examined 46 consecutive patients diagnosed with SLE and determined whether they meet the proposed diagnostic criteria for TAFRO syndrome (2015 version). Results Of the 46 patients with SLE, four (8.7%) also met the TAFRO syndrome criteria (TAFRO-like group). All patients in the TAFRO-like group were males, and their mean age was significantly higher than that of the non-TAFRO group (67.5 ± 8.7 vs. 39.3 ± 18.1 years, p = 0.004). C-reactive protein and γ-glutamyl transpeptidase levels were significantly higher, and frequencies of anti-dsDNA and anti-Sm antibodies were significantly lower in the TAFRO-like than non-TAFRO group. Elder cases (onset age ≥ 50 years) met significantly more categories of the diagnostic criteria for TAFRO syndrome than did those with younger cases. Conclusions Several patients with SLE, especially elder cases, showed features similar to those of TAFRO syndrome. Although exclusion of SLE is needed in the diagnostic criteria for TAFRO syndrome, TAFRO syndrome-like SLE should be considered.

Utility of estimated glomerular filtration rate using cystatin C and its interpretation in patients with rheumatoid arthritis under glucocorticoid therapy

BACKGROUND Patients with rheumatoid arthritis (RA) often have reduced muscle mass. Estimated glomerular filtration ratio using the serum cystatin C concentration (eGFRcys) is more accurate than eGFR using the serum creatinine (eGFRcreat) because cystatin C is not influenced by muscle mass, but glucocorticoid therapy may affect serum cystatin C concentration. METHODS Fifty patients with RA were included in this study. Renal inulin clearance (Cin) was measured and compared with eGFRcreat, eGFRcys, or the mean of eGFRcreat and eGFRcys (eGFRavg). RESULTS The mean creatine kinase (CK) concentration was low (36.8 ± 24.4 U/l).The eGFRcreat and eGFRcys regression lines were significantly different from y = x. The mean eGFRcreat value was significantly higher than Cin and that of eGFRcys was lower than Cin. The difference between eGFRcys and Cin was negatively correlated with daily PSL dose. The mean eGFRcys value of patients taking <10 mg PSL was not different from Cin and the eGFRcys regression line was not different from y = x. CONCLUSION eGFRcys of patients taking a daily PSL dose ≥10 mg was inaccurate, while eGFRcys was underestimated. eGFRcys was more accurate than eGFRcreat or eGFRavg for patients taking a daily PSL dose of <10 mg.

AB0406 Significant association between renal function and area of amyloid deposition in kidney biopsy specimens in both aa amyloidosis associated with rheumatoid arthritis and al amyloidosis

Background The kidney is a major target organ for systemic amyloidosis, which results in proteinuria and an elevated serum creatinine level. The clinical manifestations and precursor proteins of amyloid A (AA) and light-chain (AL) amyloidosis are different, and the renal damage due to amyloid deposition also seems to differ. Objectives The purpose of this study was to clarify haw the difference in clinical features between AA and AL amyloidosis are explained by the difference in the amount and distribution of amyloid deposition in the renal tissues. Methods A total of 119 patients participated: 58 patients with an established diagnosis of AA amyloidosis (AA group) and 61 with AL amyloidosis (AL group). We retrospectively investigated the correlation between clinical data, pathological manifestations, and the area occupied by amyloid in renal biopsy specimens. In most of the renal specimens the percentage area occupied by amyloid was less than 10%. For statistical analyses, the percentage area of amyloid deposition was transformed to a common logarithmic value (Log10%amyloid). Results The results of sex-, age-, and Log10%amyloid-adjusted analyses showed that systolic blood pressure (SBP) was higher in the AA group. In terms of renal function parameters, serum creatinine, creatinine clearance (Ccr) and estimated glomerular filtration rate (eGFR) indicated significant renal impairment in the AA group, whereas urinary protein indicated significant renal impairment in the AL group. Pathological examinations revealed amyloid was predominantly deposited at glomerular basement membrane (GBM) and easily transferred to the mesangial area in the AA group, and it was predominantly deposited at in the AL group. The degree of amyloid deposition in the glomerular capillary was significantly more severe in AL group. The frequency of amyloid deposits in extraglomerular mesangium was not significantly different between the two groups, but in AA group, the degree amyloid deposition was significantly more severe, and the deposition pattern in the glomerulus was nodular. Nodular deposition in extraglomerular mesangium leads to renal impairment in AA group. There are significant differences between AA and AL amyloidosis with regard to the renal function, especially in terms of Ccr, eGFR and urinary protein, even after Log10%amyloid was adjusted; showing that these inter-group differences in renal function would not be depend on the amount of renal amyloid deposits. Conclusions These differences could be explained by the difference in distribution and morphological pattern of amyloid deposition in the renal tissue. References [1] Kuroda T, et al. Significant association between renal function and area of amyloid deposition in kidney biopsy specimens in reactive amyloidosis associated with rheumatoid arthritis. Rheumatol Int. 2012;32:3155–3162. [2] Kuroda T, et al. Significant association between renal function and area of amyloid deposition in kidney biopsy specimens in both AA amyloidosis associated with rheumatoid arthritis and AL amyloidosis. Amyloid2017:14:1–8. Acknowledgements This work was supported by JSPS KAKENHI Grant Number 17 K09973. Disclosure of Interest None declared

Significant association between renal function and area of amyloid deposition evident in kidney biopsy specimens in both AA and AL amyloidosis

We previously described the relationship between clinical manifestations and amount of amyloid deposition in the renal biopsy specimens of amyloid A (AA) and light-chain (AL) amyloidosis. The amount of amyloid deposition was significantly correlated with renal damage [1,2]. However, renal damage and clinical manifestations were different. The purpose of this study was to clarify the correlation between amount of amyloid deposition, amyloid distribution, and clinical parameters in both amyloidosis.

THU0198 Serum angiopoietin-2 level strongly reflects the disease activity and renal function in ANCA-associated vasculitis

Background Angiopoietin-2 (Ang-2) has emerged as a key mediator of endothelial cell activation. Ang-1 and Ang-2 are antagonistic ligands which bind with similar affinity to the extracellular domain of the tyrosine kinase with Ig-like and epidermal growth factor-like domains 2 (Tie-2) receptor, which is almost exclusively expressed by endothelial cells. Ang-1/Tie-2 signalling maintains vessel integrity, inhibits vascular leakage, suppresses inflammatory gene expression and prevents recruitment and transmigration of leukocytes. In contrast, binding of Ang-2 disrupts protective Ang-1/Tie-2 signalling and facilitates endothelial inflammation. Recently, serum Ang-2 levels have been reported to be elevated in autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosus, and ANCA-associated vasculitis (AAV). Objectives To examine the serum Ang-2 levels in patients with AAV, and investigate the relationship with the clinical and laboratory findings. Methods Fifty-nine patients with AAV (microscopic polyangitis (n=27), polyangitis with granulomatosis (n=15), Churg-Strauss syndrome (n=14), others (n=3)), who had been referred to Niigata University Medical and Dental Hospital between 2000 and 2011, were participated in this study. Written informed consent was obtained from each participant.The patients were divided into 2 groups according to their disease activities using Birminghamvasculitis activity score (BVAS) (active disease group (AD group, n=45) and remission disease group (RD group, n=14)). Serum Ang-2 levels and laboratory findings were examined in each subject. The data from all subjects were also analyzed using Spearman’s rank correlation coefficient to determine the relationship with serum Ang-2 levels. Results The serum Ang-2 level, C-reactive protein (CRP), white blood cell count, and urinary protein excretion were significantly higher in patients with AD group compared with those with RD group. In Spearman’s rank correlation coefficient analysis using data from all subjects, the serum Ang-2 level was positively correlated with BVAS (r=0.62, p<0.0001), CRP (r=0.47, p=0.0003), serum creatinine (r=0.38, p=0.005), and urinary protein excretion (r=0.55, p<0.0001), and negatively correlated with estimated glomerular filtration rate (r=-0.37, p=0.005). Conclusions Serum Ang-2 level was strongly correlated with the disease activity and renal function in AAV. These results indicated the possible role of Ang-2 in the development of AAV through endothelial injuries. References P Kümpers, et al. Ann Rheum Dis 2009; 68: 1638-43. P Kümpers, et al. Nephrol Dial Transplant 2009; 24: 1845-50. J Westra, et al. Rheumatology 2011; 50: 665-73. Disclosure of Interest None Declared