1. Case Presentation 洪小妹 7-year-old female Date of first visit: 97/10-GU clinic 義大醫院 吳展耀醫師

2. Chief Complaint:  Referred from local clinic due to proteinuria and hematuria

3. Past History&Family History  Denied systemic disease and hospitalization history  Denied family history of renal disease  Vaccine history: as schedule

4. Physical Examination  General appearance: easy-looking  Body weight: 28.7kg  Vital signs: BP: 91/66mmHg,  HEENT: not anemic conjunctiva, no puffy eyelid  Chest: clear B.S no retraction  Heart: RHB, no murmur  Abdomen: soft, no hepatomegaly  Ext: no pitting edema  Skin: no rash, no mottled skin  Joint: no swelling, no limitation of motion

5. Lab. Exams(98-01-03)  Urinalysis: RBC 50-100/HPF, Pro 3+, ob 4+  WBC: 8480, Hgb: 14.1, MCV 84.8, Plt: 355k  Cr: 0.7, GOT/GPT: 57/39, Alb:3.5, Na/k:136/4.3, Ca:9.2 TG/Chol: 69/173, Glu 92  C3 99.2 (90-180), C4 19.6 (10-40), IgA 68.2  ANA: homogenous (40x)  Anti-ds DNA: negative 24 hours urine CCR: 64.4 ml/min 24 hours urine daily protein: 1234.2 mg/day  Enalapril (5mg) ½ #qd

6. 98.1.30  Urinalysis: RBC 10-25/HPF, OB 2+, Pro+  Daily urine protein 300mg/day 98.2.23  Urinalysis RBC 10-25/HPF, Pro 2+ 98.3.5  Urinalysis RBC 25-50/HPF, Pro –  Cr 0.6 mg/dl  24hrs urine protein 175.5mg/day

7. kidney biopsy (98.3.6) Light microscopy: I.Glomerulus number: 3 Diffuse global glomerular capillary wall thickening, moderate, with subepithelial deposits and spike and focal chain-like formation of glomerular basement membrane. Focal segmental sclerosis in one glomerulus is also present. II.Tubulointerstitium: Unremarkable III.Blood vessel: Unremarkable

8. Diffuse global glomerular capillary wall thickening

10. spike and focal chain-like formation of glomerular basement membrane

11. Immunofluorescence microscopy Glomerular number: 4 IgG+++, IgM+, C1q+, C3+/-, polyclonal kappa++ and lambda++ deposit along glomerular capillary wall, diffuse global, granular pattern Negative for IgA

12. C1q IgG IgM

13. Electron microscopy  No glomerulus in this part of specimen  Tubulointerstitium is unremarkable

14. Final Diagnosis  Diffuse membranous glomerulopathy, stage 2-3

15. Causes and classification Primary/idiopathic  85% of MGN cases are classified as primary membranous glomerulonephritis. Secondary  autoimmune conditions (e.g., systemic lupus erythematosus)  infections (e.g., syphilis, malaria, hepatitis B)  drugs (e.g., captopril, NSAIDs, gold, mercury, penicillamine, nonsteroidal anti- inflammatory agents, probenecid).  tumors (in particular, chronic lymphocytic leukemia, carcinoma of the lung and colon, and melanoma)

16. Pathology Stage I  By light microscopy glomeruli appear normal, although the capillary lumen is mildly dilated and a stiffness of the capillary wall can be detected.  Finely granular or pseudo-linear IgG deposits are present all along the glomerular capillary wall.  By electron microscopy, small electron-dense subepithelial deposits with segmental distribution can be observed. Focal foot process effacement is a constant feature.

17. Stage II  This stage is characterized by glomerular enlargement and diffuse thickening of the capillary wall. Mesangial expansion and proliferation are usually absent.  The typical feature of membranous glomerulonephritis is best highlighted by silver staining: argyrophilic extensions of the glomerular basement membrane (spikes) look black,  Some cases of Stage II MGN show focal and segmental sclerotic lesions, indistinguishable from idiopathic focal segmental glomerulosclerosis. According to some authors, the cases with these superimposed lesions present a worse outcome compared to those with pure membranous GN.

18. Stage III  Diffuse immune deposits and a more severe thickening of the basement membrane are detectable by light microscopy.  Huge and diffuse granular deposits are present all along the glomerular basement membrane. Stage IV  A further thickening of the glomerular basement membrane together with segmental or global glomerulosclerosis are detectable by light microscopy

19. Treatment  Treatment of secondary membranous nephropathy is guided by the treatment of the original disease. For treatment of idiopathic membranous nephropathy Immunosuppressive therapy  Corticosteroids: They have been tried with mixed results, with one study showing prevention of progression to renal failure without improvement in proteinuria.  Chlorambucil  Cyclosporine  Tacrolimus  Cyclophosphamide  Mycophenolate mofetil

20. a six-month course of methylprednisolone and chlorambucil can bring about sustained remission of the nephrotic syndrome and help to preserve renal function in patients with idiopathic membranous nephropathy.

21. a six-month therapy with methylprednisolone and chlorambucil increases the probability of remission of proteinuria and protects from renal function deterioration even in the long-term. This treatment may avoid dialysis or death within 10 years to about one third of nephrotic patients with membranous nephropathy.

22. Methylprednisolone /Chlorambucil 1. treated /untreated patients, renal survival rate 92%/60% 2. MTP/Chlorambucil V.S. MTP alone, remission of NS 64% V.S. 38% 3. equivalent results between MTP/C and MTP/cyclophosphamide 4. cyclosporine in reducing proteinuria, relapse when cyclosporine stopped

28. -Remission was complete in 75% of the patients and partial in 17%. -One patient (8%) with chronic kidney disease (stage 2) -Complete remission was significantly associated with the absence of chronic histological changes (p = 0.03). -Children with NS and/or NRP associated with MGN appear to have a good prognosis when treated with a combination of corticosteroids and cyclophosphamide.