fibrillary glomerulonephritis

FIBRILLARY
GLOMERULONEPHRITIS
DIAGNOSTIC CRITERIA,
PITFALLS,
AND DIFFERENTIAL DIAGNOSIS
Guillermo A. Herrera MD
Louisiana State University, Shreveport
Fibrils in
bundles
10-20 nm d
Diabetic
fibrillosis
SILVER METHENAMINE
STAIN
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
CLINICAL INFORMATION
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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: 775784, 2011
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)
A
B
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.
IgG
A
B
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
IF FOR IgG
A
B
ELECTRON MICROSCOPY
 Characteristic fibrils which are randomly
disposed, non-branching, and typically
measure 10-25 nm in diameter
 FIBRILS IN MESANGIUM AND IN MOST
CASES ALSO ALONG PERIPHERAL
CAPILLARY WALLS
 SIMILAR APPEARANCE TO AMYLOID
BUT SIGNIFICANTLY THICKER
AMYLOID
FIBRILLARY GN
A
B
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
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
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
FIBRILLARY GN
PROGNOSIS
 Average follow-up- 52.3 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: 775-784, 2011
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: 420-427, 2009
DIFFERENTIAL
DIAGNOSIS
FIBRILLARY GN
DIFFERENTIAL DIAGNOSIS
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Membranous GN- when only IF available
Amyloidosis
Immunotactoid glomerulopathy
Diabetic fibrillosis
Fibrillary collagen
AMYLOIDOSIS
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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)
A
B
THIOFLAVIN T
A
B
Thioflavin T
AMYLOID VIEWED UNDER
TEXAS RED FLUORESCENCE GATE
A
B
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; 30:673-683.
AMYLOID-A PROTEIN IH
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
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:
463-470
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
EVEN C1q in selected cases
MAY VARY FROM
10-90 NM
FREQUENTLY PARALLEL TO EACH OTHER
IF- IgG
IMMUNOTACTOID GN
 MICROTUBULAR STRUCTURES CAN BE
LONG AND GENERALLY ORGANIZED IN
PARALLEL BUNDLES
 ORGANIZED MICROTUBULAR
STRUCTURES WHICH MEASURE 30-50
NM IN WIDTH
 NEGATIVE FOR CONGO RED AND
THIOFLAVIN T
 MAIN DIFFERENTIAL DX IS CRYOS
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
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
DIABETIC FIBRILLOSIS