Fibrillary and Immunotactoid Glomerulopathy: Core Curriculum Part 5

1. Fibrillary and Immunotactoid Glomerulopathy: Core Curriculum Part 5 Neda Poommipanit September 17, 2008

2. Overview • First described in 1977 by Rosenmann and Eliakim • > 200 cases reported in past 25 years • Considerable debate about relationship of fibrillary to immunotactoid glomerulonephritis. One entity or two?

3. Synonyms for fibrillary – immunotactoid glomerulopathy • Fibrillary glomerulopathy • Fibrillary nephritis • Fibrillary glomerulonephritis • Immunotactoid glomerulopathy • Amyloid-like glomerulopathy • Non-amyloidotic fibrillary glomerulopathy • Congo-red negative amyloidosis-like glomerulopathy • Amyloid-stain negative microfibrillary glomerulopathy

4. Unifying characteristic Characterized by extracellular deposition of nonbranching microfibrils or microtubules within the mesangium and capillary walls of glomeruli

5. Epidemiology • Accounts for < 4% of renal biopsies for nephrotic syndrome • Ages 10-81 years old with average age 44 years at presentation • Caucasian predominance • Slight female predominance with fibrillary and male predominance with immunotactoid

6. Clinical Features • Proteinuria presenting feature in all patients • 60-70% cases with nephrotic syndrome • Hypertension and microscopic hematuria common (> 65%) • Renal insufficiency at time of diagnosis > 45% • Clinical features do not differ between fibrillary and immunotactoid

7. Demographics and presenting clinical features of 186 patients

8. Laboratory Studies • Serological evaluation for cryoglobulins and paraproteins negative • Serum complements normal • ANA, ANCA, antiGBM and RF negative • 19% have ANA positivity but no clinical features of SLE or systemic disease

9. Classification of organized glomerular electron dense deposits

10. Pathology • Confined exclusively to glomeruli • Light microscopy: diverse and not diagnostic • 95% have mesangial expansion with hypercellularity • 95% have glomerular capillary wall thickening • Crescents are common with fibrillary variant (25%) • Rosenstock et al. evaluated 61 patients with FGN and 6 patients with ITG • MPGN pattern most common with FGN • MPGN and DPGN equal with ITG

11. Light Microscopy MPGN: mesangial proliferation and double contours of GBM MES: Mesangial pattern with expansion with normal GBM thickness

12. Light Microscopy MGN: global thickening of glomerular capillary walls containing spike like projections DPGN: global endocapillary proliferation with infiltrating leukocytes along with fibrinoid necrosis. Early cellular crescent at top.

13. Light Microscopy IT: Contains mixed MPGN and MGN with lobular appearance DS: diffuse and global solidification with PAS positive material and loss of cellular elements

14. Electron microscopy: Fibrillary • Microfibrils 15-25 nm in diameter (larger than amyloid 6-10 nm) • Within individuals, fibrils tend to be uniform size • Randomly arranged • Typically found in mesangium but also in subendothelial and subepithelial spaces

15. Electron Microscopy: Immunotactoid • Larger fibrils (> 30 nm in diameter) • Visible lumen (microtubules) • Arranged in parallel bundles

16. Comparison of EM • Amyloid. Fibrils are randomly arranged and nonbranching • Fibrillary. Fibrils are thicker than amyloid and randomly arranged. • Immunotactoid. Microtubules with visible lumen.

17. Immunofluorescence • IgG, C3, kappa and lambda light chains in distribution that correspond to deposits of microfibrils and microtubules • IgG4 is the predominant class in fibrillary

18. Pathogenesis • Unknown mechanism of fibrillogenesis • Many hypotheses: • Fibrils contain immunoglobulin (both heavy and light chains) and complement as well as amyloid P component • Amyloid P raises possibility that fibrillogenesis similar to amyloidosis without beta pleated sheets. • Intact normal immunoglobulins do not crystallize. Abnormal production of immunoglobulins with unusual structure produced in such small quantities to escape detection but, as a consequence of ultrafiltration, have increased concentration and deposition exclusively in glomeruli.

19. Pathogenesis • Hypotheses continued: • Structural alterations along filtration surface of glomerulus predispose to fibril formation • Absence of CD2 associate protein in mice • CD2 associated protein – Protein that binds to nephrin, a component of the podocyte slit diaphragm. Also plays role in T lymphocytes and APC. • Knockout mice have nephrotic syndrome, immunodeficiency, and die of renal failure at 6-7 weeks • Glomeruli show mesangial and subendothelial deposits of parallel arrays of microtubules similar to ITG • Deposits secondary to acquired defects in critical podocyte cellular functions involved in clearance of immunoglobulins

20. Extrarenal involvement • Extremely rare. Disease usually limited to kidneys • Case reports involving the following: • Lung (1) • Liver (1) • Bone (1) • Cardiac (1) • Malignancy association?

21. One or two entities • Proponents of two entities • Statistically significant differences with respect to incidence of associated monoclonal gammopathy and hematologic malignancy

22. Association with malignancy When including patients with serum or urinary paraprotein as evidence of malignancy, the incidence of malignancy was higher in immunotactoid (33%) variant compared to fibrillary (7%). When patients with a paraprotein were excluded, incidence of malignancy was similar (3-7%).

23. One or two entities • Proponents of one entity • The higher incidence of malignancy with immunotactoid occurs only if paraproteins included • Similar clinical features • Insufficient data on pathogenesis to classify by mechanism • No clinical significance of distinguishing between two entities • Overlap between fibril size and arrangement

24. Treatment • Response to immunosuppressive treatment poor. • Therapeutic trials with steroids alone, steroids with cytotoxic agents, and steroids with plasmapheresis reported in 33 patients resulted in remission of proteinuria < 10%.

25. Prognosis • Because usually no systemic involvement, patient survival high independent of renal survival • Overall renal course is progressive with 50% ESRD at 5 years

26. Prognosis • Histological patterns correlate with clinical outcomes • Those with DS, DPGN, and MPGN progressed to ESRD with mean average 7, 20, and 44 months respectively • Those with MES and MGN had lower risk of progression and slower rate with mean 80 and 87 months

27. Renal Transplantation • Pronovost et al. noted rate of deterioration of GFR was slower in allografts than native kidneys in recurrence • Carles et al. report case of successful treatment of recurrence with plasmapheresis, steroids, and cytotoxics.

28. Conclusions • Rare. • Presents with proteinuria, often nephrotic range, renal insufficiency, hypertension, and microscopic hematuria • Extracellular deposition of nonbranching microfibrils (< 30 nm) or microtubules (> 30 nm) within the mesangium and capillary walls of glomeruli • No known pathogenesis • No effective treatment • Patient survival is high but renal prognosis is progressive with 50% ESRD at 5 years depending on histological subtype • Renal transplantation showed slower renal deterioration of disease recurrent • Distinction between FGN and ITG depends on inclusion of patients with evidence of paraproteins

29. References • Rosenstock et al. Fibrillary and immunotactoid glomerulonephritis: Distinct entities with different clinical and pathological features. KI, 63 (2003): 1450-1461 • Pronovost et al. Clinical features, predictors of disease progression and results of renal transplantation in fibrillary/immunotactoid glomerulopathy. NDT (1996) 11: 837-842 • Schwartz et al. Immunotactoid glomerulopathy. JASN 13: 1390-1397, 2002 • Iskandar et al. Clinical and pathologic features of fibrillar glomerulonephritis. KI, 42 (1992): 1401-1407. • Alpers et al. Fibrillary glomerulonephritis and immunotactoid glomerulopathy. JASN 19: 34-37, 2008 • Brady, HR. Fibrillary glomerulopathy. KI, 53 (1998): 1421-1429. • Korbet et al. Immunotactoid glomerulopathy (fibrillary glomerulonephritis). CJASN 1 (2006): 1351-1356. • Shih et al. Congenital nephrotic syndrome in mice lacking CD2- associated protein. Science 286: 312-315, 1999 • Kim et al. CD2 associated protein haploinsufficiency linked to glomerular disease susceptibility. Science 300: 1298-1300, 2003 • Masson et al. Pulmonary hemorrhage in a patient with fibrillary glomerulonephritis. NEJM 326: 36-39, 1992 • Ozama et al. Case report of amyloid-like glomerulopathy with hepatic involvement. Nephron 58: 347-350, 1991 • Wallner et al. Immunotactoid glomerulopathy with extrarenal bone deposits and cholestatic liver disease. NDT 11(8): 1619-24, 1996 • Sabatine et al. Images in cardiovascular medicine. Fibrillary/immunotactoid glomerulopathy with cardiac involvement. Circ 2002: 105(15) • Carles et al. Successful treatment of recurrence of immunotactoid glomerulopathy in a kidney allograft recipient. Nephrol Dial Transplant (2000) 15: 897-900 • Brenner et al. The Kidney.