1. Case Report What’s hiding behind IgA nephropathy? Case Report Bauerova L., Honsova E. Department of Pathology, the The First faculty of Medicine and General Teaching Hospital, Charles University Prague Nephropathology training: Department of Clinical and Transplantant Pathology, IKEM

2. Clinical history: Clinical history: 31– year – old woman Proteinuria, fatigue, edema of the hands Tinnitus and sudden hearing loss of the left ear Arterial hypertension Nephrotic proteinuria (5g/day) and microscopic hematuria Serum creatinine level of 73μmol/l (0,79mg/dl) Audiometry → hearing abnormalities Immunology was negative (ELISA testing – IgA, IgM, IgG, C3 and C4 complement, extractable nuclear antigen (ENA), anti- nuclear antibodies (ANA), ds-DNA antibodies, ANCA, rheuma factor).

3. IgA

7. Diagnosis: IgA nephropathy + suspicious Fabry´s disease ↓ Genetic testing was recommended ↓ (Low -galactosidase A activity in plasma and leucocytes) + Heterozygous mutation of α-Gal A gene

8. IgG-IgA1, IgA1-IgA1 complexes Complement components Aberrantly glycosylated IgA1 Production of antiglycan antibodies Proliferation of mesangial cells Expansion of ECM Cytokines and growth factors production Local complement activation Podocytes and tubular cells damage Fibronectin Type IV collagen IgA nephropathy

9. Fabry´s disease X-linked recessive lysosomal storage disorder Deficient activity of α-galactosidase A Clinical manifestations are variable Skin lesions, corneal dystrophy, paresthesias and proteinuria During adulthood: heart disease, premature cerebrovascular accidents, and progressive renal disease

10. Fabry´s disease The link between the metabolic abnormality in Fabry´s disease and kidney tissue injury is still unclear In females, there are highly variable levels of enzyme activity and broader range of clinical symptoms Most females are affected; in various studies, 12% of Fabry´s patients on dialysis are women

11. In a kidney biopsy sample Swollen, finely vacuolated podocytes in LM Dark blue bodies in semi-thin sections embedded in epoxy resin Osmiophilic, lamellar bodies mainly in podocytes (myelin figures, “zebra” bodies) in ELMI All renal cells can be affected Difficulties in cases with more advanced stages of FD

12. A case for second opinion

13. Differential diagnosis Myelin-like inclusions are not entirely specific for Fabry´s disease Long-term treatment with cationic amphiphilic drugs (chloroquine and amiodarone) Chloroquine-induced lipidosis in the kidney is not so rare curvilinear inclusions Specific curvilinear inclusions in podocytes are not present in FD (Prof. Ferluga in his lecture, 23 rd ECP, Helsinki 2011) Dusan Ferluga: Electron microscopy of Fabry nephropathy and drug-induced phospholipidosis. 23 rd ECP, Helsinki 2011

14. The coexistence of IgA nephropathy and Fabry´s disease: The coexistence of FD and immune disorders such as SLE, rheumatoid arthritis and pauci- immune and immune complex-mediated necrotizing crescentic glomerulonephritis has been described in the literature The combination of FD and IgAN is rare

15. Patient´s follow up: Human α-galactosidase A replacement therapy Antihypertensive drugs with diuretics Cardiac function and blood pressure in the normal range S-Cr: S-Cr: 65 μmol/l (0.71 mg/dl) Proteinuria decreased (1g/day) Peripheral edema disappeared Still suffering from Still suffering from: fatigue, paresthesia, tinnitus, and hearing loss

16. Thank You