1. Intern Seminar : IgA Nephropathy Teacher : 邱元佑醫師 Presentation : 陳沛吟

2. Brief history ： 17-year-old, Boy 民國 85/4 (10 y/o) ： proteinuria was found incidentally in school health examination  Persistent proteinuria  86/11 ： renal biopsy ： IgA nephropathy Lab ： IgG:576↓, IgA:142, IgE:<28.3 C3:111, C4:27.8 BUN:13, Crea:0.6, albumin:3.9 DPL:1911 mg/day

3. Brief history Proteinuria 85/4 (10 y/o) 86/11 Biopsy ： IgAN 2 nd Biopsy ： FSGS & TIN 92/192/10 CAPD OPD F/U H/D 92/9 (17 y/o) 1. Captopril→Losartan 2. 89/4 ~ 92/1 Predinisolone + Solumedrol Proteinuria ： 150~500 mg/dL Persistent proteinuria Heavy proteinuria + echo ： parenchymal dz. BUN/Cr: 134/15.4

4. BUN / Creatinine ： BP ： 100/70 118/84 138/94 142/98 136 18.8 16 1.2

5. Discussion: IgA Nephropathy

6. Definition: Only by biopsy ： IgA immunocomplex deposits in the glomerular mesangium

8. Mesangial electron dense deposits with ↑mesangial matrix & cellularity in IgAN

9. Incidence ： Japan, France, Australia ： 18~40% of all primary glomerular diseases United States, Canada ： only 2~10% male > female Occur at all ages predominate ： older children and young adults, 20+~30+ y/o ： ↑

10. Causes: IgAN ： Primary (idiopathic) or secondary Cause of primary IgAN ： unknown

12. Genetic factors ： Familial clustering ： familial predisposition is a very common finding (9.6% of IgAN pt’s siblings have GN) ACE gene polymorphism (DD genotype) ： correlated to the pathological severity and course of IgAN. HLA genes ： class Ⅱ products – DP, DQ, and DR ： susceptibility to IgAN.

13. Genetic factors ： Platelet-activating factor (PAF) acetylhydrolase gene mutation ： degree of proteinuria and the extent of mesangial cell proliferation. IgA immune system ： IgA1 synthesis Complement factors ： homozygous null C4 phenotype↑, C3FF homozygous phenotype↑ (Pediatric Nephrology 2001, 16:446-457)

14. Causes of Secondary IgAN Infection ： HIV, leprosy Neoplasia ： ca. of the lung, pancreas Liver diseases ： Hepatitis B, cirrhosis, Skin diseases ： Psoriasis Lung diseases ： sarcoidosis Systemic immunological disorders ： SLE, RA, AS, Reiter’s syndrome……

15. Five Clinical syndromes 1. Gross hematuria (U.S.) 2. Asymptomatic microscopic hematuria with/without proteinuria----62% (Japan, Asia) 3. Acute nephritis with hypertension and/or renal insufficiency 4. Nephrotic syndrome 5. A mixed nephritic-nephrotic syndrome

16. IgAN In Children ： > 80% children have experience of gross hematuria (in U.S.) Recurrent gross hematuria is traditionally regarded as the hallmark of childhood IgAN. Gross hematuria as initial feature: ¼ (asymptomatic child found in school screening) Gross hematuria is fewer in adults

17. IgAN In Children ： Gross hematuria often in association with URI. Proteinuria ： often, but severity < nephrotic Hypertension ： mild to moderate Serum IgA level ： 8~16%↑in children (30~50%↑ in adults) ※ no diagnostic value

18. Differential Diagnosis ： Henoch-Schönlein purpura (HSP) HSP ： clinical syndrome Same ： histopathological alterations Difference ： HSP has systemic symptoms ： purpuric rash, arthralgias, abdominal pain, acute onset, self-limited. Variants of the same pathophysiologic process

19. Outcome ： Used to be thought ： benign Highly variable range of prognosis ： ~ spontaneous remission ~ impaired renal function ~ ESRD 20~30%, 15~20 years  ESRD

20. Pool prognostic Factors ： Clinical presentation ： 1. Persistent hypertension 2. ↑Serum cr., ↓renal function when onset 3. Prolonged or heavy proteinuria (>1g/day) Pathological expression ： 1. Diffuse mesangial proliferation 2. Extensive glomerular crescents 3. Glomerulosclerosis and tubulointerstitial change

21. Treatment

22. Treatment: Goal: prevent progression of disease and protect renal function ACE Inhibitors Corticosteroids Immunosuppressants Fish-oil supplement Tonsillectomy

23. Corticosteroid ： Corticosteroid ： antiinflammatory & immunosuppressive Floege et al ： for proteinuria <1.5g/day and normal GFR ： can↓proteinuria High risk or renal function worsen ： steroid + cyclophosphamide/cytotoxic No effect on renal function was observed On-going ： corticoteroid + azathioprine

24. Angiotensinogen Endothelium Renin-Angiotensin System Angiotensin Ⅰ Angiotensin II Bradykinin Inactive peptides ATI Receptor Renin ACE Angiotensin Ⅱ O2-O2- O2-O2- A Ⅱ Receptor

25. ACEI & Angiotensin Ⅱ Receptor Blocker ： Angiotensin is a central factor in the progression of glomerular sclerosis. hypothesis ： ↓BP has protective renal effects in cases of mild insufficiency with hypertension in IgAN. ACEI for preserve renal function ： ? But,↓BP,↓proteinuria ： proven

26. ACE inhibitor ： Probability of renal survival (<50% increase of baseline serum creatinine) in enalapril-treated group and control group. (Roland et al) P < 0.05

27. Fish Oil Supplements ： n-3 polyunsaturated fatty acids (DHA, EPA) Depress eicosanoid and cytokine production  may ↓renal inflammation and glomerulosclerosis  may prevent renal injury Review ： ＊ 2 studies ： benefits on renal function ＊ 2 studies ： no difference

28. Fish Oil Supplements ： Danadio et al ： in persistent proteinuria (>1g/day) & SCr <3 mg/dL ： ↓82% risk in SCr↑ and ↓67% risk of death or ESRD. High-dose: 3.76g EPA+2.94g DHA (8#) v.s. Low-dose: 1.88g EPA+1.47g DHA (4#) ： no difference

29. Fish Oil Supplements ：

30. Tonsillectomy ： IgA ： mucosa defense Popular in Japan and France. Indication ： chronic infections (dental abscess, sinusitis) In pediatric ： tonsillectomy ： ↓ gross hematuria episodes. No evidence for affect the progression to CRI or ESRD. Recommended ： controversial

31. Renal Transplantation ： When ESRD: It is best to transplantation In U.S. ： IgAN -- 10% of primary GN with renal transplantation Survival ： excellent Recurrence ： 20~60% in 5 years Equal rates over cadaveric, living, or related donor.

32. Conclusion ： In low risk (proteinuria < 1.5g/day)  1. Steroid for ↓proteinuria (grade B) 2. ACEI (grade C) In higher risk ： immunosuppressive therapy (grade A)  proteinuria 1~3.5g/day steroid x 6 months  progressive renal failure ： steroid + cytotoxic treatment

33. About This Case ： No gross hematuria Serum IgA level ： normal Poor predictors ： persistent heavy proteinuria, hypertension Onset~ESRD ： only 7 years Poor drug compliance? Unknown herbs? Hypertension?

34. Summary ： Primary IgAN ： the most common primary GN Diagnosis ： biopsy ： IgA deposition Prognosis ： variable, 20~30%  ESRD Treatment ： Immunosuppressive therapy (steroid/ cyclophophamide/ AZT) ACEI Fish-oil Tonsillectomy Renal transplantation

35. References: JV Donadio, IgA Nephropathy. N Engl J Med 2003;347(10):738-48. Yoshikawa N. Tanaka R. Iijima K. Pathophysiology and treatment of IgA nephropathy in children. Pediatr Nephrol 2001;16(5):446-57. Wyatt RJ. Hogg RJ. Evidence-based assessment of treatment options for children with IgA nephropathies. Pediatr Nephrol 2001;16(2):156-67. D'Amico G. Natural history of idiopathic IgA nephropathy: role of clinical and histological prognostic factors. Am J Kidney Dis 2000;36(2):227- 37.

36. References: Donadio JV Jr. Use of fish oil to treat patients with immunoglobulin A nephropathy. Am J Clin Nutr 2000;71(1 Suppl):373S-5S. Julian BA. Treatment of IgA nephropathy. Semin Nephrol 2000;20(3):277-85. Jurgen Floege. Evidence-based recommendations for immunosuppression in IgA nephropathy: handle with caution. Nephrol Dial Transplantation 2003;18:241-5. Testbook of Pediatrics, Nelson 17 th Edition