FIBRILLARY GLOMERULONEPHRITIS DIAGNOSTIC CRITERIA, PITFALLS, AND DIFFERENTIAL DIAGNOSIS

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1 FIBRILLARY GLOMERULONEPHRITIS DIAGNOSTIC CRITERIA, PITFALLS, AND DIFFERENTIAL DIAGNOSIS Guillermo A. Herrera MD Louisiana State University, Shreveport

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3 Fibrils in bundles nm d Diabetic fibrillosis

4 SILVER METHENAMINE STAIN

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6 SEEN IN A CHILD 10 Y/O PROTEINURIA IS OFTEN SEVERE / 70% WITH HYPERTENSION ROUGHLY HALF OF THE PATIENTS TO ESRD WITHIN 2 YEARS AFTER DIAGNOSIS

7 CLINICAL INFORMATION Mean age at diagnosis= 53 years Majority 95% caucasian patients Female to male ratio 1.2:1 PRESENTATION: PROTEINURIA- 100% (maybe massive), NEPHROTIC SYNDROME- 38%, RENAL INSUFFICIENCY- 66%, HEMATURIA- 52%, AND HYPERTENSION- 71% / few cases rapidly progressive renal disease Underlying diseases- malignancies- MOST COMMON CARCINOMA 23%, dysproteinemia- 17% and autoimmune diseases 15% of all patients in series Nasr, et al: Fibrillary glomerulonephritis: A report of 66 cases from a single institution. Clin J Am Soc Nephrol 6: , 2011

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9 Light microscopy, IF, AND EM Varied morphologic patterns by LM MOST COMMON- Mesangial proliferative / sclerosing features followed by membranoproliferative in some cases mimics amyloidosis OR MEMBRANOUS NEPHROPATHY- CRESCENTS IN SOME CASES FINAL DIAGNOSIS MADE ULTRASTRUCTURALLY BUT IF PATTERN CAN BE DIAGNOSTIC (or highly suggestive)

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17 FIBRILLARY GN LIGHT MICROSCOPIC FINDINGS Can be confused with membranous GN, mesangial proliferative and membrano proliferative GN, focal proliferative, and amyloidosis Crescents are seen in 25-33% of fibrillary GN cases, and; therefore, it can also be confused with crescentic GN.

18 A IgG B

19 IMMUNOFLUORESCENCE Smudgy staining for IgG, C3, kappa and lambda light chains in most cases along peripheral capillary walls and / or in mesangium / IgA-IgM rare & small amounts C1q also rarely seen- but may be found in a few cases IgG 4 is the dominant IgG in the great majority of the cases (IgG1 in some cases) AMYLOID P COMPONENT (SAP) PRESENT- may play a role in fibrillogenesis APO-E PRESENT AS IN AMYLOID

20 IF FOR IgG

21 A B

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23 ELECTRON MICROSCOPY Characteristic fibrils which are randomly disposed, non-branching, and typically measure nm in diameter FIBRILS IN MESANGIUM AND IN MOST CASES ALSO ALONG PERIPHERAL CAPILLARY WALLS SIMILAR APPEARANCE TO AMYLOID BUT SIGNIFICANTLY THICKER

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28 AMYLOID FIBRILLARY GN

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30 FIBRILLARY GN PATHOGENESIS Most likely a result of polymerization of immune complexes and, possibly monoclonal light chains in some cases Role that amyloid-p component plays still unclear but may be significant The fact that a particular IgG (IgG4) is dominant in many (?all- some IgG1) of the cases probably represents an important pathogenetic consideration HIGHLY STRUCTURED IMMUNE COMPLEXES

31 FIBRILLARY GN TREATMENT RENIN ANGIOTENSIN SYSTEM BLOCKADE (ACE inhibitors) STEROIDS ADDITIONAL IMMUNOSUPPRESANTS SUCH AS CYTOXAN / MMF S/T combined RITUXIMAB IN COMBINATION WITH STEROIDS OR ALONE IMMUNOMODULATION

32 FIBRILLARY GN OTHER IMPORTANT FACTS Mostly a renal limited disorder Thioflavin T may be very rarely positive and be confused with amyloidosis / However these cases are Congo red negative Diverse glomerular morphology Membranous variant can also be confusingoften kappa restricted (r/o underlying lymphoproliferative disorder) Diabetic fibrillosis may be an important differential diagnosis in patients with diabetic nephropathy

33 FIBRILLARY GN PROGNOSIS Average follow-up months of 61 patients 13% complete or partial remission 43% persistent renal dysfunction 44% progressed to ESRD recurrence in 36% of 14 patients with renal transplants PREDICTORS OF ESRD- Older age, higher serum creatinine and proteinuria at the time of biopsy Nasr et al: Clin J Am Soc Nephrol. 6: , 2011

34 FIBRILLARY GN AND RENAL TRANSPLANTATION 15 TRANSPLANTED KIDNEYS IN 12 PATIENTS Group 1-5 patients WITH FIB GN alone Group 2-7 patients WITH FIB GN AND MONOCLONAL GAMMOPATHY RECURRENCE DID NOT OCCUR IN GROUP 1 BUT DEVELOPED IN 5 kidneys OF patients from GROUP 2 7 allografts failed- 1 in Group 1 (graft thromboembolism) and 6 in Group 2. Czarnecki et al: Long-term outcome of kidney transplantation in patients with fibrillary glomerulonephritis or mononclonal gammopathy with fibrillary deposits. Kid Int 75: , 2009

35 DIFFERENTIAL DIAGNOSIS

36 FIBRILLARY GN DIFFERENTIAL DIAGNOSIS Membranous GN- when only IF available Amyloidosis Immunotactoid glomerulopathy Diabetic fibrillosis Fibrillary collagen

37 AMYLOIDOSIS Systemic disorder Involvement of all 3 renal compartments Congo red / Thioflavin T positive More than 30 amyloid precursor proteins IF- addresses light and heavy chains / fibrinogen IH- AA amyloidosis, β2 microglobulin, calcitonin, LEC-2 and so forth Stains for serum amyloid protein and Apo E Can be confused with hyalinosis (especially vascular)

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40 A B

41 A B THIOFLAVIN T

42 Thioflavin T

43 AMYLOID VIEWED UNDER TEXAS RED FLUORESCENCE GATE

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45 DIAGNOSIS OF AMYLOIDOSIS IS MADE THEN WHAT?? DETERMINING TYPE OF AMYLOID look for light and heavy chain monoclonality- IF evaluate fibrinogen IF stain perform pertinent immunohistochemical stains ie. AA protein, B-2 microglobulin, calcitonin, transthyretin, lactoferrin, lysozyme and so forth* PROBLEMS: DIFFICULTY IDENTIFYING HEREDITARY AMYLOIDOSES AND SOME ABNORMAL LIGHT CHAINS DEPOSITED IN TISSUES *TYPE OF AMYLOID IDENTIFIED IN 92% OF THE CASES (formalin fixed and paraffin embedded) IN SURGICAL PATHOLOGY SPECIMENS. Kebbel and Rocken Am J Surg Pathol 2006; 30:

46 AMYLOID-A PROTEIN IH

47 Heavy chain amyloidosis AH-amyloidosis Only a handful of cases reported (one with ultrastructural labeling) Most gamma HC-associated Similar light and EM features as other amyloidoses Pathogenesis unclear

48 LIGHT AND HEAVY CHAIN AMYLOIDOSIS (AL/AH) 16 patients with AL/AH amyloidosis Typing using laser microdissection and mass spectroscopy (LMD/MS) (12) and by IF (4) Median age at biopsy- 63 All caucasian WHEN COMPARED WITH AL-AMYLOIDOSIS Less cardiac involvement Higher incidence of hematuria Better survival 42% of patients could have been diagnosed with IF Nasr, SH et al: The diagnosis and characteristics of renal heavy chain/light chain amyloidosis and comparison with renal light-chain amyloidosis. Kidney Int 2013; 83:

49 LIGHT / HEAVY CHAIN AMYLOIDOSIS (AL/AH) MORPHOLOGICAL DIFFERENCES WITH AL-AMYLOIDOSIS More hypercellularity in mesangial areas with amyloid deposition Strong PAS staining associated with amyloid deposits Silver staining in areas with amyloid deposition

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52 EVEN C1q in selected cases MAY VARY FROM NM FREQUENTLY PARALLEL TO EACH OTHER

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54 IF- IgG

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59 IMMUNOTACTOID GN MICROTUBULAR STRUCTURES CAN BE LONG AND GENERALLY ORGANIZED IN PARALLEL BUNDLES ORGANIZED MICROTUBULAR STRUCTURES WHICH MEASURE NM IN WIDTH NEGATIVE FOR CONGO RED AND THIOFLAVIN T MAIN DIFFERENTIAL DX IS CRYOS

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61 IMMUNOTACTOID GN EXTRARENAL DEPOSITS ARE EXTREMELY RARE SIMILAR ENTITY IN THE EYE- relationship to renal disease unclear Can be confused with cryoglobulinemic nephropathy as the deposits are microtubular not FIBRILLARY

62 DIABETIC FIBRILLOSIS Appearance of fibrils ultrastructurally identical to FIBRILLARY GN BUT FIBRILS ONLY IN MESANGIUM IF IS NEGATIVE FOR IgG / kappa / lambda (LINEAR IgG and albumin seen in DN) AND OCCURS IN THE SETTING OF NODULAR GLOMERULOSCLEROSIS

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