40 200230 IgA 2003 31 2006 34 HLA 1 haplotype identical 0h Cr 1 29mg dl 4 2009Cr 1 7 2 0 dl 0 25g g Cr 3 ARB 120 130 70 80mmHg HbA1c 5 8% 2012 7 Cr3 2mg dl 5 0g g Cr 2006 12 2007 9 Cr (mg/dl) (g/g Cr) PSL ( ) CyA ( ) MZ ( ) C A (ng/ml) 1.2-1.4 0.1 10 200 100 130-150 7.5 2009 1.7-2.0 0.25 175 130 2010 0.6-1.0 70-90 2011 2.0-2.3 1.0-2.3 170 100-120 2012 2.5-3.2 3.5-5.0 70-80 7 5 1 M 170 2 9 21 100 2 M A 25 1 M 5 1 A10 1 A 25 1 M 3T1 M 200 4C 2 1 2 Key WordIgA AMR de 3 novo 104
第 59 回神奈川腎炎研究会 入院時身体所見 血算 WBC RBC Hb Ht Plt 6200 290 104 9.8 29.1 21.6 104 Cl Ca IP AST ALT LDH ALP CRP Glu TG Tchol LDL-C /μl /μl g/dl % /μｌ 血液ガス 静脈 ph 7.336 PCO2 29.4 mmhg BE -9.2 mmol/l HCO315.3 meq/l 生化学 TP Alb BUN Cr UA Na K 尿検査 ph 比重 尿蛋白 潜血 尿糖 ケトン WBC 5.8 g/dl 3.1 g/dl 40 mg/dl 3.17 mg/dl 6.0 mg/dl 133 meq/l 4.1 meq/ll (2002 101 meq/l 8.5 mg/dl 3.9 mg/dl 16 U/l 16 U/l 296 U/l 201 U/l <0.09 mg/dl 125 mg/dl 298 mg/dl 278 mg/dl 119 mg/dl 6.0 1.005 3+ 1+ - - - 尿沈渣 赤血球 白血球 硝子円柱 赤血球形態 24時間蓄尿 蛋白 1-4 /HPF 1-4 /HPF 1+ 糸球体性 3.59 感染症 HBs Ag HCVAb 梅毒TPAb - - - 凝固 APTT PT% INR 27 138 0.81 g sec % ) 1 IgA IgG 図2 IgA 図3 105
腎炎症例研究 30 巻 2014 年 (2006, 0h) 2 ; Slight interstitial edema of the kidney 図4 (2012 3 図7 6 ) Paramesangial deposit Mesangiolysis 2 図5 76 22 4 (28.9%), (5.3%), 図8 4 (5.3%) 図6 図9 106
第 59 回神奈川腎炎研究会 PTC C4 [ ] [ ] PTC PTC C3 図 10 図 13 IgG IgA IgA 図 11 図 14 [ 図 12 図 15 107 ]
腎炎症例研究 30 巻 2014 年 De novo membranous nephropathy 2%(de novo ) Ivanyi B. Nat Clin Pract, Nephrol 4(8); 446-457, 2008 El Kossi M, et al. Clin Transplant 22; 124-127, 2008 Alport IgA PTC Ponticelli C and Glassock RJ. Transpl Int 25; 1205-1210, 2012 MN 7 PLA2R Debiec H, et al. AJT 11; 2144-2152, 2011 図 16 図 18 腎生検所見のまとめ ① IgA 腎症再発 H-Grade Ⅱ A/C ②慢性活動性抗体関連型拒絶反応 ③ CNI 慢性毒性による細動脈硬化症 ④ de novo 膜性腎症 stage2 Banff 09 score:i2, t1, g1, v0, ci2, ct2, cg0, cv0, 1988 ptc2, ptcbm2, mm1, ah3, aah3, 17 (DSA) C4d3 考 2006 de novo MN ( 12 5 DSA ) 図 19 察 再発腎炎について 2 de novo 膜性腎症について 1 De novo MN Control MN De novo MN T De novo MN AMR Ivanyi B. Nat Clin Pract, Nephrol 4(8); 446-457, 2008 IgA HLA IgA 6 Cr 1g/ 図 20 図 17 108 17
第 59 回神奈川腎炎研究会 Graft loss Table 2. Pt no. Age/se x ( ABO HLA mismach DSA Titer By PRA Class / (%) scr at Bx Urine protein g/day at Bx Tx DSA Follow -up O O 3 9.9/37.9 2.00 4.0 MP CNI +PE MMF/ARB Not done ) 1 37/M 12 2 21/M 15 A A 3 68.2/28.7 1.76 1+ MP CNI Not done 3 33/M 50 O O 2 3.9/24.6 1.74 0.36 MP CNI +MMF Positive 4 42/M 58 O B 2 Not done 3.80 5.0 MP CNI + PE DSG Pulse Not done 5 47/F 166 A A 2 4.8/81.5 1.00 - MP CNI +DSG Negative de novo MN AMR 図 21 図 22 まとめ 臨床経過および病理所見から 移植後早期よ り 慢性活動性 AMR および CNI 毒性が出現 De novo MN IgG4 subclass し その後細胞性半月体を伴う 比較的活動 性の高い再発 IgA 腎症を合併したと考える de novo 膜性腎症は 上記が基礎となり発症 し ネフローゼレベルの蛋白尿はこれに伴 い出現した可能性もある 血清 Cr の上昇や尿蛋白が増加がみられた段 階で腎生検を施行し 治療内容を変更する必 図 23 要があったと考える 結 語 再発 IgA 腎症と慢性抗体型関連拒絶反応に de novo 膜性腎症を合併した 移植腎の一例を経験した De novo MN (n=17) Control (n=17) P-value Age 37.7±3.14yr 37.9±3.13yr ns Male/Female 10/7 10/7 ns Period between Tx and Bx 102±16.6 months 104.3±16.9 months ns Urine protein excretion>(+) 15/17(88%) 11/17(64.7%) ns 2.00±0.20 ns ABO compatibility Number of 1.94±0.28 mismatch in HLA 図 24 109
30 2002 IgA 2003 2006 HLA 1haplotype identical 0h 1 29 4 2009 1 7 2 0 0 25 3 ARB 120 130 70 80 HbA1c 5 8 2012 7 3 2 5g gcr 1 2 1 4 2009 1 7 2 2011 2 2012 2 53 0 1 2009 0 25 2011 1g 2g 2012 nephrotic 3 10mg 7 5 200mg 170 100mg 7 5170 10ARB 152 4cm49kg110 63 62009 8 110
total protein5 8 ALB3 1 BUN Cr 40 3 17 CRP 0 09 LDL 119 3 + 1 + 24 3 59g 1 2002 IgA mesangium IgA patchy IgA IgG lineal 2 0h edema 6 76 22 28 9 4 1 3 mesangium mesangiolysis paramesangium deposit IgA deposit PAM spike PTC Elastica Masson calcineurin inhibitor 111
C4d PTC C3 IgA mesangium IgA IgG IgA IgA mesangium deposit PTC PTC IgA Histological Grade acute and chronic A C calcineurin inhibitorde novo Nature review table IgA 730 FSGS MPGN HLA IgA de novo 2 de novo de novo 2008 Clinical Transplantation Alport IgA 7 phospholipase A2 receptor de novo 9 Clinical Transplantation2011 1988 2006 de novo 17 donor specific antibody 5 5 12 112
de novo control 17 de novo tubulitis interstitial cell infiltration glomerulonephritis transplant glomerulopathy PTC PTC AMR de novo donor specific antibody 5 30 40 ABO minor mismatch HLA mismatch 2 graft loss 1 4g 2 graft loss 2 1 1 76graft loss DSA Titer 3 plasma exchange de novo de novo 5 DSA graft loss AMR AMR calcineurin IgA de novo AMR nephrotic range IgA de novo AMR IgA 113
de novo 01 65 segmental lesion 14 global sclerosis 31 segmental lesion IgA 02 global sclerosis cellular glomerulus 03 segmental cellular lesion sclerosis capsule segmental 04 peritubular capillaritis tubulitis 05 ischemic mesangium 06 pseudo tubular formation 07segmental sclerosis 08 09IgA mesangium dense deposit ballooning mesangiolytic IgA deposition 10 IgA deposition 11 segmental deposition IgA IgA deposition IgA IgA 12 C4d 114
peritubular capillaritis 13 C4d 14 peritubular capillaritis grading peritubular capillaritis 15 calcineurin foamy 16 foam cell foam cell foam cell foam cell accelerate 17 foam cell foam cell 18 19 20 PAM 21 mesangium IgA deposit 22 23 24 mesangium cell interposition subepithelial deposit De novo IgA 115
de novo 5 10 IgA de novo carnitine inhibitor IgA IgA native 12 tubular interstitial creatinine 3 creatinine 3 interstitial fibrosis tubular atrophy 25 creatinine 13 14IgA crescentic mesangium crescentic hyalinosis 15global crescentic mesangium aneurisma 16 adenomatoid crescent IgA mesangium 17 nephron mass nephron 18 mesangium transplant glomerulitis collapse perfusion 19 116
hyalinosis aneurisma atrosclerotic vascular rejection atrosclerotic 20 peritubular capillary C4d capillary 21 elastica carnitine inhibitor mucoid intimal thickening 22 mucoid intimal thickening chronic TMA 23 24crescentic 25 aneurisma mesangium 26 peritubular capillaritis 5PTCitis 2 1 2 27 mesangial IgA deposit 28 29 IgG de novo PAM spike IF deposit 30peritubular capillary 31 deposit transplant glomerulopathy mesangial inter position transplant glomerulopathy macrophage mesangial deposit IgA 32epithelial deposit 117
33 chronic thrombotic microangiopathy alternative arteriolar hyalinosis mucoid intimal thickening of inter 02 11 49 AMR chronicle transplant glomerulopathy glomerulitis peritubular capillaropacy PTCBA 1 moderate capillaritis recurrent IgA de novo membranous DSA DSA DSA PTC early chronic early PTC C4d creatinine 3 5 2009 creatinine chronicle AMR chronicle active creatinine IgA calcineurin inhibitor TMA IgA chronic active de novo 2 118
119
65 Glomeruli Segmental lesions 14 Global sclerosis 21 120
C4d 121
C4d 122
123
124
125
IgA IgA IgG 126
C4d 1. Chronic thrombotic microangiopathy, most-likely a. Alternative arteriolar hyalinosis, severe b. Mucoid intimal thickening of interlobular arteries 2. Chronic antibody-mediated rejection, most-likely a. Transplant glomerulopathy with mild glomerulitis, mild b. Peritubular capillaropathy with moderate capillaritis, mild 3. Recurrent IgA nephritis with crescents 4. De novo membranous glomerulonephritis (Banff:IF/TA;III, i1, t1, g1, v0, ci3, ct3, cg1, cv0, ptc2, ptcbm1, ah3, aah3) cortex/medulla=9/1, global sclerosis/collapse/glomeruli= 22/12/76 spikes TMA Peritubular capillaritis C4d(+: ptc)iga(+: mesangial), IgG(+: peripheral) GBM GBMGBM 127
腎炎症例研究 30 巻 2014 年 山口先生 _25 山口先生 _28 山口先生 _26 山口先生 _29,, de novo,,.,. GVHD.. 山口先生 _27 山口先生 _29 128
第 59 回神奈川腎炎研究会 山口先生 _30 129