Nobuo Akiyama

Haplotype study on C4 polymorphism in Japanese. Associations with MIHC Alleles, complotypes, and HLA-complement haplotypes

Genetic polymorphism of the fourth component of human complement (C4) was investigated in 83 Japanese families which have been typed for HLA-A, -B, -C, -DR, C2, and BF. Four common C4A alleles and four common C4B alleles were observed. The allele frequencies estimated from unrelated parents were as follows: C4A3, 0.686; A4, 0.132; A2, 0.106; AQ0, 0.067; ARares, 0.009; C4B1, 0.587; B2, 0.167; B5, 0.088; and BQ0, 0.158. Eight different C4 haplotypes were observed with frequencies of more than 0.01. The estimated haplotype frequencies were as follows: C4A3-B1, 0.513; A4-B2, 0.114; A2-BQ0, 0.106; A3-B5, 0.088; AQ0-B1, 0.059; A3-BQ0, 0.047; A3-B2,0.038; A4-B1, 0.015; and Rares, 0.021. Strong positive gametic associations were found in the following C4-HLA haplotypes: C4A2BQ0-A24, C4A2BQ0-Bw52, C4A3B5-Bw54, C4A3B5-Bw59, C4A4B2-Bw46, C4A3B5-Cw1, C4A2BQ0-DR2, and C4A3B5-DR4. Eleven complotypes were observed with frequencies of more than 0.01. C4A2BQ0 and C4A3B5 were exclusively associated with BFS-C2C. BFF was associated with C4A3B1, C2AT, C2B, and C2BH were associated with C4A3B1, A4B2, and C4A3B1, respectively. Eight different HLA-complement haplotypes were found to be characteristic of Japanese. These combinations are considerably different from those reported in Caucasoid populations.

Clinical effect of recombinant human erythropoietin on anemia associated with chronic renal failure. A multi-institutional study in Japan.

Clinical effect and safety of recombinant human erythropoietin (r-HuEPO) were evaluated in 66 hemodialysis patients with intractable anemia. Initially, 50U/kg dry weight (DW) of r-HuEPO was administered intravenously at the end of every hemodialysis procedure for 4 weeks, then the dosage was increased to 100 and 200U/kg DW for poor responders. The patients’ hematocrits rose from 19.8 ± 2.3% (pretreatment) to 30.2 ± 4.9% after 12 weeks. From 206 U of blood transfusion requirement in the 3-month period before the study, only 34 U were needed after treatment. Serum iron and ferritin levels fell significantly during the study, and iron storage was considered to be one of the decisive factors in the response to r-HuEPO. Blood pressure rose in the course of r-HuEPO administration, but uncontrollable hypertension was rarely observed. There was no significant adverse effect of r-HuEPO except for this mild hypertension. These results indicate that r-HuEPO is an excellent therapeutic aid for the anemia associated with chronic renal failure.

Two subtypes of HLA-B51 differing by substitution at position 171 of the α2 helix

Newly defined antigens of the B5, B35 cross-reacting group have been found in Japanese and North American Indians. Nucleotide sequencing of the alleles encoding the Japanese B5.35 antigen and the variant B5 antigen from the Piman Indians show them to be identical. This new allele, B*5102, differs from B*5101 by a single nucleotide substitution that changes residue 171 from histidine to tyrosine. Residue 171, which is part of the α2 helix, is believed to contribute directly to peptide interaction in the A pocket of the binding groove and is either histidine or tyrosine in all HLA-A, B, C heavy chains. Tyrosine 171 is shared by B*5102, B*3501, B*3502, and B*5301 and must be responsible for the serological cross-reactivities of these molecules not shared with B*5101. Stimulation of lymphocytes from a B*5101 positive donor with B*5102 positive cells failed to generate cytotoxic T cells with specificity for the difference between these molecules. However, one out of five clones of cytotoxic T cells raised against B*5101 failed to lyse targets expressing B*5102. Substitution of histidine for tyrosine at residue 171 affected recognition of HLA-B35-restricted human minor histocompatibility antigen-specific T cell clones.

No evidence for linkage between the loci for coagulation factor XIII-A and HLA

SummaryThe linkage analysis between the locus for coagulation factor XIII-A (F13A) and HLA region genes (HLA-A,-C,-B) was performed. In males, the maximum of lod scores between F13A and HLA was 0.33 at θ=0.30, and in females lod scores were negative at all values of θ. The results provided no evidence for close linkage between F13A and HLA genes.

Does H2-receptor antagonist alter the renal function of cyclosporine-treated kidney grafts?

Histamine-type 2 antagonists (H2-blockers) as represented by cimentidine have been shown to adversely affect renal allograft function, particularly when coadministered with cyclosporine, currently a major immunosuppressant. To determine whether or not a newer and more powerful H2-blocker, famotidine, would produce similar adverse effects, we assessed seven cyclosporine-treated renal allograft recipients with regard to changes in their renal function on or off the H2-blocker over a one-week period. Neither the administration nor withdrawal of famotidine (20–40 mg/day) resulted in any significant changes in serum creatine, BUN, urine output or cyclosporine trough levels, suggesting that famotidine can be safely administered as an H2-blocker to cyclosporine-treated renal allograft recipients.

Cross-reactive antibodies against human cultured B cells and bovine erythrocytes in human renal transplantation sera.

Sera of 58 recipients of renal allografts were studied for the presence of antibodies against cell cultures of human B lymphoid cell lines (B-LCL) and bovine erythrocytes (BRBC). Cytotoxic anti-B-LCL antibodies were found in 13% of the sera from recipients with the grafts and in 67% of the sera obtained after removal of the rejected grafts. Most of these sera also contained BRBC lysins of high titers. Absorption studies showed that the anti-B-LCL antibodies are directed against antigens shared by BRBC and that they can be absorbed with corresponding graft tissues. The specificity of BRBC lysins found in some of the transplantation sera was shown to be similar to that of Hanutziu-Deicher antibodies.

IDENTIFICATION OF INFLAMMATORY CELLS INFILTRATING RENAL ALLOGRAFTS

Eight nephrectomies and 13 biopsies of renal allografts (living 15, cadaveric 6) were investigated on the origin of inflammatory cells in the graft tissues by the use of an immunohistologic method (ABC method). Various monoclonal antibodies and heterosera were used to identify different leukocyte subsets. In all specimens the most predominant inflammatory cells were T cells. Other cells decreased in the following order; B cells, neutrophils and monocytes, and natural killer cells. In T cell subsets Leu 2a‐positive cells (suppressor/ cytotoxic T cells) predominated over Leu 3a‐positive cells (helper/inducer T cells) in 4 nephrectomies (living 1, cadaveric 3) and 12 biopsies (living 11, cadaveric 1). Among these 16 cases, 7 were undergoing acute rejection in various degrees, and 9 were without clinical rejection. In the former 7 cases only one was suffering from another disease. In contrast, Leu 3a‐positive cells predominated over Leu 2a‐positive cells in 1 biopsy (living) and 4 nephrectomies (living 2, cadaveric 2). Four of these 5 cases concurrently had other diseases in addition to acute rejection. Two cases underwent acute tubular necrosis (cadaveric graft nephrectomies) and 2 underwent chronic rejection and crescentic glomerulonephritis (living graft nephrectomies). The one remaining case was without clinical rejection.

Renal Allografts With Glomerulonephritic Change and Proteinuria

Eight cases of renal allografts with glomerulonephritic change and proteinuria were classified into three groups according to the morphological features of the glomerular lesions. Group I (3 cases): By light microscope, remarkable reduplication of glomerular basement membrane (GBM), widening of mesangial region, and slight increase in mesangial cells, were observed. Electron microscopy revealed thickening of subendothelial space by deposition of electron‐lucent material, mesangial interposition, and dense deposits in various regions (mainly in the subendothelial space). Group II (3 cases): By light microscope, crescent formation and reduplication of GBM were observed, while by electron microscope, changes of GBM similar to group I, but less remarkable, were seen. Group III (2 cases): Light microscope revealed spike formation in one case, but not in the other. With an electron microscope, subepithelial dense deposits were observed in both cases. Thickening of subendothelial space by deposition of electron‐lucent material was noted in one case, while thickening of lamina densa was observed in the other case. Morphological change caused by rejection was observed in all eight cases, with six cases showing massive proteinuria and the other two showing slight proteinuria.

REPORT ON THE PATIENTS ON DIALYSIS FOR MORE THAN 10 YEARS

日本透析療法学会の調べでは, 1985年末現在10年以上透析を受けている患者は7050名に達しているが, 今回アンケート調査を行い92施設から2065名の患者につき解答を得たのでその結果を報告する.原疾患は慢性糸球体腎炎が79.5%ともっとも多く, 発病後5年で腎不全におちいり, その1年後に透析が開始されている. 現在入院中の患者が5.0%いるが, 50.8%は昼間外来透析を受け, 43.1%が夜間透析を受けている. 血液透析が97.6%で週3回計13時間の透析を受けており, CAPDは1.1%と少ない.最近1年間に輸血をされた患者は14.5%で平均輸血量は1428mlである. 透析開始後10年までの期間に重大な合併症を経験した患者は32.4%で, 23.2%が現在も持続する合併症を有する. 合併症の主要なものは骨およびCa代謝の障害で, 血管壁ならびに軟部組織の石灰化が15.0%, 骨折が6.0%にみられ, 骨痛ないし関節痛を有するものは36.0%に達する. すでに上皮小体摘除術を受けた患者は7.3%にある. 最近注目されている手根管症候群は13.1%にみられた.主婦を含む71.2%が週5日以上就業しており, 透析ライフの満足度を良とするものが60%を超え, 種々の合併症はあっても社会復帰状況は10年を超えても, 1-5年, 5-10年に比較して低下していない.現在の検査成績は血圧129-74mmHg, Ht 26.8%, 透析前BUN 81.6mg/dl, Cr 13.2mg/dlと透析患者の目標値を維持している.