Ritsuya Noda

Suppression of Experimental Membranous Glomerulonephritis in Rats by an Anti-MHC Class II Antibody

Background: We previously reported that idiopathic membranous nephropathy (IMN) strongly correlated with HLA-DRB1*1501-DRB5*0101-DQAI*0102-DQB1* 0602, a specific haplotype of human major histocompatibility complex (MHC), in Japanese patients. To investigate the role of MHC in the development of rat Heymann nephritis (HN), an animal model of membranous nephropathy, a monoclonal antibody (mAb) specific to rat MHC class II antigen (RT1B) was administered, and its effectiveness in inhibiting HN was assessed. Methods: Active HN was induced in HN-sensitive Lewis rats by administering brush border proteins of rat proximal uriniferous tubules (FX1A). Rats were divided into four groups: rats treated with 1,000 µg anti-rat MHC class II mAb, rats treated with 100 µg anti-rat MHC class II mAb, rats treated with murine myeloma IgG, and rats that did not receive either FX1A or any other mAb. We examined the differences in 24-hour urinary protein excretion and serum alloantibody titers against FX1A between groups at different time intervals, and the histologic features of kidneys at the end of the study. Results: HN was induced in Lewis rats by inoculation with FX1A antigen. Administration of anti-MHC class II mAb successfully lowered urinary proteins, production of anti-FX1A alloantibodies, and the development of glomerular lesions in a dose-dependent manner. Conclusion: The present results demonstrated that the MHC class II molecule itself is directly involved in the pathogenesis of HN, and suggest that this therapy would be any better (or less toxic) than nonselective immunosuppressants in the treatment of IMN.

Association between HLA-DRB1*15 and Japanese patients with rheumatoid arthritis complicated by renal involvement.

We performed serological phenotyping of HLA antigens in 175 patients with rheumatoid arthritis (RA) with (n = 41) and without (n = 134) renal involvement (RI), and DNA typing of HLA class II alleles in 75 patients. Among the patients with RA, the frequency of serologically determined HLA-DR4 was found to be significantly increased (odds ratio: 1.8, confidence interval: 1.3–2.5, p = 2.4×10–4). In the patients without RI, the frequency of serological DR4 significantly increased (odds ratio: 2.2, confidence interval: 1.6–3.3, p = 2.6×10–5). On the other hand, among the patients with RI, a serological determinant, DR15, did significantly increase (odds ratio: 2.7, confidence interval: 0.9–8.4, p = 1.2×10–3) in comparison to the controls. At the DNA level, we found that the association of Japanese RA patients with serological HLA-DR4 was based on that with a genotype of HLA-DRB1*0405 (odds ratio: 2.4, confidence interval: 1.5–4.0, p = 4.4×10–4) and also found an association of HLA-DRB1*1501 (odds ratio: 2.8, confidence interval: 1.2–6.6, p = 0.017) with RA patients having RI. Our results confirmed the association of HLA-DRB1*04 with RA over the ethnic barrier at the DNA level. Our results also suggested a distinct genetic effect of HLA-DRB1*1501 in the aspect of the susceptibility of RI in RA.

Olmesartan is More Effective Than Other Angiotensin Receptor Antagonists in Reducing Proteinuria in Patients With Chronic Kidney Disease Other Than Diabetic Nephropathy

Background Angiotensin II receptor antagonists (ARBs) have a protective effect in patients with chronic kidney disease (CKD) by suppressing progression, possibly by controlling hypertension. One marker of progression in such patients is the degree of proteinuria. Objective We aimed to retrospectively examine the protective effect of ARBs (olmesartan, losartan, candesartan, and valsartan) on CKD patients without a history of diabetic nephropathy. Methods Data were retrieved from medical records of patients with a diagnosis of CKD (serum creatinine [Cre] <3.0 mg/dL [265.2 μmol/L] and urinary protein of 0.3–3.5 g/g Cre) who were treated with ARBs and those with diabetic nephropathy were excluded. Blood pressure, serum Cre, urinary protein, urinary Cre, and estimated glomerular filtration rate were measured before the research began and at 1, 3, 6, 12, and 24 months after the ARB treatment was started. Results Forty-four patients completed the research protocol. Of these, 10 took olmesartan, 13 took losartan, 9 took candesartan, 9 took valsartan, and 3 took telmisartan. Systolic blood pressure was decreased in all cases. The extent of this decrease 1 month after starting ARB treatment was greater for olmesartan than for candesartan (P < 0.05), and after 2 years, it was greater than for losartan (P < 0.05). Diastolic blood pressure decreased in all patients; this decrease was significantly greater with olmesartan 1 month after treatment started than with candesartan (P < 0.05). Olmesartan significantly decreased daily urinary protein compared with that with the other ARBs during follow-up. This decrease 1 month after starting ARB treatment was greater for olmesartan than losartan, valsartan, and candesartan (P < 0.01, P < 0.01, and P < 0.05, respectively), and after 2 years, this effect was still significant (P < 0.05, P < 0.01, and P < 0.01, respectively). Conclusions Olmesartan is more effective in reducing urinary protein than other ARBs, suggesting that the renal protective effects of olmesartan may be better than those of other ARBs.

Relationship between Fluctuation Pattern of Blood Pressure during Hemodialysis Treatment and Cardiovascular Morphology: An Autopsy Study of 53 Cases

Background: Cardiovascular morphological changes are often conspicuous in autopsy examination of chronic hemodialysis (HD) patients. On the other hand, the fluctuation pattern in blood pressure (BP) during HD treatment varies from one patient to another. Cardiovascular changes may correlate with clinical findings including BP fluctuation patterns during HD, although no autopsy studies have previously examined this issue. Methods: In this study, 53 autopsies of patients who had been on chronic HD were reviewed. We determined the relationship between BP fluctuation during HD treatment along with stable and cardiovascular morphology, including heart weight, ventricular wall thickness, circumferences of the valves and the severity of aortic arteriosclerosis and coronary stenosis. Patients were divided into 4 groups according to the pattern of BP fluctuation during HD treatment at about 6 months before death: group 1 (n = 13), symptomatic hypotension and/or decline pattern during HD; group 2 (n = 11), continuously high BP during HD treatment; group 3 (n = 17), continuous normal BP during HD treatment, and group 4 (n = 12), continuously low BP without symptomatic hypotension during HD treatment. Results: Heart weight and ventricular wall thickness were greatest in group 2. The scores for aortic arteriosclerosis in groups 1 and 2 were higher than in groups 3 and 4. The coronary stenosis index was significantly higher in group 1 than in the other groups, and that in group 2 was higher than in group 4. Multiple regression analysis showed that age, HD duration and pulse pressure were independent variables for the score of arteriosclerosis, and the decline pattern of BP fluctuation during HD and pulse pressure were independent variables for coronary stenosis index. Conclusions: Our results suggest that certain clinical parameters including BP during HD may reflect cardiovascular morphological changes in stable HD patients, although further examination, such as 24-hour blood pressure measurement is recommended to elucidate the pathophysiology of cardiovascular diseases in HD patients.

IL-1β promotes tubulointerstitial injury in MPO-ANCA-associated glomerulonephritis .

BACKGROUND It is widely accepted that tubulointerstitial injury (TII) is caused by glomerular injury (GI) in glomerular diseases. Glomerular endocapillary inflammation may result in crescent formation and exuded protein leakage, which may induce TII in antineutrophil cytoplasmic antibody-associated glomerulonephritis (ANCAGN). However, some reports have indicated a glomerulonephritis-independent mechanism of TII in ANCAGN. The aim of this study was to determine the principle cytokines correlated with TII severity and to elucidate a characteristic mechanism for TII in ANCAGN. METHODS 28 myeloperoxidase-ANCA-positive ANCAGN patients were enrolled, and their kidney biopsy specimens were histologically evaluated with regard to GI and TII. The mRNA expression of various cytokines was examined in 28 specimens. RESULTS Interleukin (IL)-1β was significantly correlated with the severity of TII. The mRNA expression of Toll-like receptor 4 (TLR4) and Nod-like receptor family pyrin domain-containing-3 (NLRP3) also correlated with TII severity. Immunohistochemical analysis demonstrated that TLR4 protein was positively stained in the tubulointerstitial infiltrating cells. NRLP3 protein was detected in macrophages in the severe infiltrating area but was absent or only very faintly expressed in the glomeruli. These results indicated that NLRP3 inflammasome-dependent processing in macrophages releases the mature active form of IL-1β, which may lead to the development and deterioration of TII. CONCLUSIONS Sterile inflammation leads to the formation of ANCA-mediated neutrophil extracellular traps (NETs), which may stimulate macrophages and dendritic cells via TLR4 and induce NF-κB-dependent mRNA expression and translation of pro-IL-1β. Simultaneously, damage-associated molecular pattern signals resulting from NETs promote NLRP3 inflammasome-dependent processing and release mature active IL-1β. Sterile inflammation utilizing the NLRP3 inflammasome might be a characteristic reaction limited to the tubulointerstitium. Thus, neutralizing IL-1β may be a promising strategy to suspend the progress of TII and improve the prognosis of chronic kidney disease resulting from ANCAGN.
.

Relationship of predialytic intact parathyroid hormone on secondary hyperparathyroidism in chronic maintenance haemodialysis patients.

Methods and Results:  In order to clarify the predialytic factors influencing the onset of secondary hyperparathyroidism (SHPT) in patients on chronic maintenance haemodialysis, the time‐course changes of serum levels of intact‐PTH (i‐PTH) during haemodialysis for 5 years were investigated. The subjects were 69 non‐diabetic patients who had a serum aluminium level of less than 1.85 nmol/L at the end of observation. Patients were divided into two groups based on i‐PTH levels obtained at the start of dialysis; the high group (H group) consisted of patients whose i‐PTH levels were more than 22.00 pmol/L, the low group (L group) had levels less than 22.00 pmol/L. In the H group, i‐PTH was 41.46 ± 2.87 pmol/L at the start of dialysis (vs L group, P < 0.0001) and 15.82 ± 2.85 pmol/L after haemodialysis initiation. In the L group, i‐PTH levels did not significantly change and was 11.69 ± 2.50 pmol/L 12 months after the start of dialysis (at the 12th month). However, at the 60th month, the i‐PTH level was 33.24 ± 5.30 pmol/L in the H group, and 9.85 ± 2.13 pmol/L in the L group (P < 0.005).

HLA genotypes and serum levels of hepatitis C virus RNA in Japanese patients on maintenance hemodialysis

AbstractBackground. The prevalence of anti-hepatitis type C virus (HCV) antibodies in patients on maintenance hemodialy-sis (HD) is high, ranging from 5% to more than 50%. Although blood transfusion and/or impaired cellular immunity may contribute to HCV infection, the exact mechanisms remain undetermined. Here, we assess the role of HLA genotypes in chronic HCV infection in Japanese HD patients. Methods. Genotyping for HLA-A, B, and DRB1 was performed in 113 patients. All patients had anti-HCV antibodies in serum, and endstage renal disease treated by HD. Patients were divided into two groups – those with a low amount of HCV-RNA in their sera (group L; HCV-RNA <50 KIU/ml; n = 50) and those with a high amount (group H; HCV-RNA ≧50 KIU/ml; n = 63). Another group, of 264 Japanese patients on maintenance HD without HBV or HCV infection, served as disease controls. Results. The proportions of group L patients with HLA-B*07, B*46, and DRB1*01 alleles and that of group H patients with HLA-B*52 were significantly higher than those in the controls. On the other hand, the proportion of group H patients with HLA-DRB1*04 was significantly lower than that in the controls. Conclusions. Our data suggest that HLA-B*07, B*46, and DRB1*01 may be associated with the immunological elimination of HCV in Japanese patients on HD.