2012/3/22. WBC 7400 /µl RBC /µl Hb 10.9 g/dl Plt /µl

Transcription

1 Case 3 A case of MPGN type 3, second form Post-meeting material onset and course He has been treated with medication against hypertension, hyperlipidemia, and hyperuricemia in clinics from 1994 (40 yrs old) 2003: proteinuria (-), 2004: proteinuria (+/-), 2005 : proteinuria(+), proteinuria (+) 2009 April: proteinuria(3+), August : Hypoalbuminemia Blood pressure /90mmhg, scr mg/dl 2010 January: leg edema, October: Hypertension >200mmHg. Kensuke Joh, MD, PhD 1), Yasuhiro Nakamura, MD 2) 1) Division of Pathology, Sendai-Shaho Hospital Sendai-city, Japan, 2) Department of Pathology, Tohoku University Hospital, Sendai, Japan He was introduced to our hospital for further investigation and treatment. Body weight 79.5kg edema(+) Diuretic drug : Lasix (20) in December against edema Renal Pathology Specialty Conference, March 18 Convention Centre st Annual Meeting of USCAP, Vancouver, 2012 At admission Height:165.5cm Body weight :84.2kg(+6kg) BMI :30.7 Blood pressure:154/79mmhg (after medication) Pulse rate:78/min Body temperature:36.4c f.h Father:hypertension, angina pectoris, Mother: hypertension smoking np alcohol drinking np occupation car mechanic WBC 7400 /µl RBC /µl Hb 10.9 g/dl Plt /µl gravity PH 6.0 uob (2+) upro (3+) 3.9g/day urbc 5-9 /HPF uwbc 1-4 /HPF HC 10-29/HPF Oval fat body (+) una 83 meq/l ucr 168 meq/l FENa 0.51 % uβ 2 MG 215 µg/l unag 36.7 U/L Clinical finding1 BUN 23 mg/dl scr 1.5 mg/dl CCr 49 ml/min egfr 39 ml/min/1.73m 2 UA 5.3 mg/dl Na 144 meq/l K 4.3 meq/l Cl 113 meq/l Ca 9.3 mg/dl P 3.6 mg/dl AST 18 IU/L ALT 12 IU/L T.bil 0.5 mg/dl LDH 255 IU/L Tcho 223 mg/dl TG 146 mg/dl TP 5.5 g/dl Alb 3.0 g/dl α1 6.0 α β1 6.5 β2 6.3 γ 11.6 IgG 646 mg/dl IgA 193 mg/dl IgM 35 mg/dl CRP ESR <0.1 mg/dl 42 mm HbA1c 5.5 % 75gOGTT IGT pattern PTINR 0.91 APTT 26.6 sec Fib 451mg/dL FDP 3.0 µg/ml C mg/dl C mg/dl CH U/mL ASLO 32 IU/mL Parvo B19 Ab IgM 0.2 Abdominal Echo:Normal Kidney Heart Ech0 :mild LVH ECG :sinus rhythm LVH Chest Xp :CTR 58% Clinical findings 2 ANA < x80 RF (-) MPOANCA (-) PR3ANCA (-) Anti SSA/B Ab (-) Anti Scl-70 Ab (-) Anti centromea Ab(-) Stool occult blood(-) Eye Fundus :Scheie H1S1, Diabetic retinopathy(-) Endoscope:erosive gastritis, Reflux esophagitis PRA 0.8 ng/ml/hr aldosteron 4.1 ng/dl PAC/PRA 5.1 ACTH 23.4 pg/ml Cortisol 8.9 µg/dl Upro(g/gCr) SCr(mg/dl) Course after admission 9 Bx mpsl500mg 8 7 PSL /1 2/2 2/15 2/21 3/1 BP(mmHg) / / / /70-80 uob (1+) (1+) (2+) (2+) (+/-) (+/-) (-) BW(kg) PSL 20

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3 Light microscopic diagnosis was MPGN with hypertensive nephrosclerosis Lightmicroscopic findings Glomeruli Global sclerosis 4/14(29%), Mesangial hypercellularity 4/10 (40(%), Endocapillary hypercellularity 0 (0%), Crescent 0 (0%), Segmental sclerosis and hyalinosis 4(40%), Adhesion 2 (20%) GBM: thickening (double contour), No spike, No bubbling No glomerular enlargement 200µm Tubule/Interstitium Tubular atrophy/ Interstitial fibrosis with edema (30%) Inflammation (10%) : lymphocytes and foam cells Vascular change: Interlobular artery : severe intimal fibroelastosis Afferent artery: severe intimal hyalinosis As basic findings a. mild mesangial cell proliferation with mesangial matrix widening b. Thickening of GBM double contour No spike and No bubbling As adjacent findings a. No endocapillary hypercellularity b. No crescentic formation c. Segmental sclerosis and hyalinosis with adhesion PAM-EM 14 G M A C3c C3d C1q Immunohistochemistry using alcohol fixed paraffin embedded sections ()

4 Immunohistochemistry: C3c dominant with other immunoglobulin and complements Granular diffuse peripheral pattern IgG-, IgM +, IgA +, C3c ++, C3d +, C1q + Differential diagnosis of Primary membranoproliferative glomerulonephritis (MPGN) (No sign and symptome of collagen disease, infectious disease and paraproteinemia) Electron microscopy: EM(U/Pb) Massive intramembranous continuous dense deposits mesangial interposition EM-PAM Lamina densa was disrupted, whereas lamina rara externa was well preserved 20 Primary MPGN Type III First form (Burkholder) Type 1 Type II (DDD) and Type III Second form (Strife&Anders) 21 Classification of primary MPGN Type I (subendothelial deposits with intact GBM) Type II (DDD) (intramembranous continuous dense deposit) (C3 but no immunoglobulin) Type III first form (Burkholder type) epimembranous deposits second form (Strife and Anders type) intramembranous continuous dense deposits contains C3 and immunoglobulin?) 22 Primary MPGN type 1 C MPGN type 1 24

5 MPGN type1 C Primary MPGN type 1 C3 (C ) 25 Case 1 6y.o. female MPGN type 2 : Dense deposit disease DDD MPGN type 2 Ribbon like thickening C3 B , Case 3 B , Case 3 linked sausage appearance yrs later

6 Case 3b MPGN type 3, first form (Burkholder type) MPGN type3-1st form Cp , EL7047 MPGN type 3, second form (Strife and Anders type) MPGN type III-1 st form Burkholder type Cp EL MPGN type III-2nd form Strife & Anders type Case 1 P yrs old male Other 2 examples (Case 1 and Case 2) 36

7 IgA IgG MPGN type III-2nd form Strife & Anders type Case 1 P C1q C3 κ λ 37 Case 1, P MPGN III, 2 nd form Case 2 41 yrs Female NS+ HTN+ Hypo C3 MPGN type III-2nd form Strife & Anders type P EM-PAM MPGN type III-2nd 39 IgM MPGN III, 2 nd form Case 2, 41 yrs Female NS+ HTN+ Hypo C3 MPGN type III-2nd form Strife & Anders type Case 1 P

8 G M A MPGN type III 1. MPGN type III first form Burkholder type (mixed membranous and mesangial proliferative GN (Lab Invest 23, 1970) C1q C4 C3 2. MPGN type III second form (Strife CF et al, Clin Nephrol 7,1977, Anders D et al. Virchows Archiv 376, 1977) Differential diagnosis of MPGN III second form a. In LM, MPGN III second form is similar to MPGN I. b. In EM, MPGN III second form is similar to MPGN II (DDD) MPGN III, 2 nd form Case 2, 41 yrs Female NS+ HTN+ Hypo C3 Immunostain and silver impregnation (EM-PAM) are important information 44 Differential diagnosis of primary MPGN MPGN I MPGN II (DDD) MPGN III 1 st form (Burkholder) MPGN III 2 nd form (Streife& Anders) Double contour Ribbon-like (PAS) Spike& bubbling Double contour (PAM) LM (GBM) (PAM) or double contour (PAM) IF C3 dominant C3 isolated Igs and C3 C3 and Igs(?) EM (U/Pb) Subendothelial Intramembranous Epimembranous Intramembranous or subendothelial EM-PAM GBM intact Enhancement of GBM No GBM disruption Spike GBM disruption MPGN II, EM ur/pb Basement Membrane Changes in MPGN II and MPGN III second form Silver Impregnation of Ultra Thin Sections MPGN II, EM-PAM MPGN III 2 nd form, EM MPGN III 2 nd form, EM-PAM D. Anders, B. and W. Thoenes et al. Virchows Arch. A Path. Anat. and Histol, 376, l - 19 (1977) The final diagnosis of the present patient? EM(U/Pb) shows no epimembranous deposit. MPGN type 3 first form was denied EM-PAM shows disruption of GBM MPGN type 1 and MPGN type 2 were denied. EM-PAM MPGN III 1 st form I prefer to diagnose this case as MPGN type 3, second form. Epimembranous deposits

9 Forms of C3 Glomerulopathy Problem to be solved Does MPGN III 2 nd form belong to C3 nephropathy? 1. Dense deposit disease (Galle & Mahieu Am J Med 1975) 2. Idiopathic C3 glomerulonephritis (Levy et al. Clin Immunol Immunopathol 1978) 3. Familial MPGN type III? Neary J, et al. ( 2002). J. Am. Soc. Nephrol. 13 Neary J, et al. (2002) Am. J. Kidney Dis CFHR5 nephropathy (familial C3 glomerulonephritis a/w heterozygous mutation in CFHR5) (Fakouri et al. Nat. Rev. Nephrol 2010) Investigations for C3 glomerulopathy Literatures 1.Anders D et al. Basement membrane changes in membranoproliferative glomerulonephritis. II. Characterization of a third type by silver impregnation of ultra thin sections. Virchows Arch A Path Anat Hist 376:1-19, Streife CF, et al. Membranoproliferative glomerulonephritis with disruption of the glomerular basement membrane. Clin Nephrol 7:65-72, Streife CF, et al.: Type III membranoproliferative glomerulonephritis: long-term clinical and morphological evaluation. Clin Nephrol 21: , Burkholder PM et al. Mixed membranous and proliferative glomerulonephritis. Lab Invest 23: , Sibley KS, et al. Dense intramembranous dense deposit disease: New pathologic features. Kidney Int 25: , Joh K et al. Morphologic variations of dense deposit disease. Light and electron microscopic, immunohistochemical, and clinical findings in 10 patients. Acta Pathol Jpn , Walker PD, et al. Dense deposit disease is not a membranoproliferative glomerulonephritis. Modern Pathol 20: , 2007