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•Alpers CE: Glomerulopathies of dysproteinemias,
abnormal immunoglobulin deposition, and lymphoproliferative
disorders. Curr Opin Nephrol Hypertens 1994 May;3(3):349-55.
Department of Pathology, University of Washington Medical
Center, Seattle 98195.
The glomerulopathies associated with dysproteinemias and
lymphoproliferative disorders exhibit diversity in their
morphologic appearance and underlying pathophysiology. Some
entities, such as amyloidosis, light-chain nephropathy, and
monoclonal immunoglobulin deposition disease, are now
well-recognized clinical entities. The disease processes of
fibrillary glomerulonephritis and immunotactoid
glomerulopathy, which may be associated with these
disorders, are becoming increasingly recognized and
established entities as reports on significant series of
patients continue to be published. Most new information
about the pathogenesis of these entities comes from
structural, biochemical, and synthetic studies of individual
pathogenic paraproteins. The ability to use individual
pathogenic human paraproteins to recreate disease in
experimental animals is a development that may allow better
understanding of disease pathophysiology. The determination
of effective therapeutic strategies for the management of
these disorders continues to be elusive.
•Bellotti V, Mangione P, Merlini G: Review:
immunoglobulin light chain amyloidosis-The archetype of
structural and pathogenic variability. J Struct Biol 2000
Jun;130(2-3):280-9. Department of Biochemistry, University
of Pavia, Pavia, Italy.
AL amyloidosis is caused by deposition in target tissue of
amyloid fibrils constituted by monoclonal immunoglobulin
light chains. The amyloidogenic plasma cells derive from a
transformed memory B cell that can be identified by
anti-idiotype monoclonal antibodies. Comparison of the
primary structures of amyloidogenic and nonamyloidogenic
light chains does not show any common structural motif in
the amyloidogenic variants but reveals peculiar replacements
which can destabilize the folding state. Reduced folding
stability now appears to be a unifying property of
amyloidogenic light chains. The tendency of these proteins
to populate a partially unfolded intermediate state is a key
event in the self-association that progresses to the
formation of oligomers and fibrils. The mechanism of organ
damage caused by AL amyloid deposition is not known, but
clinical findings suggest that the process of amyloid fibril
formation itself exerts tissue toxic effects independently
of the amount of amyloid deposited. Since the disease is
caused by the neoplastic expansion of the plasma cell
population synthesizing the amyloidogenic light chains, the
clone represents the prime therapeutic target of
conventional chemotherapy and experimental immunotherapy. In
common with other types of amyloidosis the therapeutic
strategy can take advantage of drugs able to improve the
reabsorption of the amyloid deposits or able to bind and
stabilize the light chain in the native-like folded state.
•Buxbaum J, Gallo G:
Nonamyloidotic monoclonal immunoglobulin deposition disease.
Light-chain, heavy-chain, and light- and heavy-chain
deposition diseases. Hematol Oncol Clin North Am 1999
Dec;13(6):1235-48. Department of Medicine, New York
University School of Medicine, New York, USA.
Buxbaum@New-York.va.gov
In 1990 and 1992, in previous reviews of the literature and
in reports of their experience with both amyloid and
non-amyloid monoclonal immunoglobulin deposition diseases,
the authors proposed a classification scheme encompassing
all the forms of non-antibody-mediated monoclonal
immunoglobulin deposition. The premise underlying the
proposal was that the mode of pathogenesis of each of the
various disorders is similar. Monoclonal expansion of a
B-cell and plasma-cell population producing an excess
immunoglobulin polypeptide with structural characteristics
predisposing to tissue deposition in either the fibrillar or
nonfibrillar state would be associated with
organ-compromising deposits in tissue. At that time it
appeared that LCDD and LHCDD were more likely to occur in
the course of myeloma in which the other features of the
neoplastic cells (i.e., marrow suppression, lytic lesions,
recurrent infections) were also clearly evident. At this
time, the authors' additional experience suggests that this
judgment may have been premature, based in part on too small
an initial sample and in part on the use of diagnostic
criteria for multiple myeloma that may have not been
sufficiently precise. The authors now believe that the
nodular glomerulopathic form of NAMIDD is similar in both
course and prognosis to AL amyloidosis occurring in the
absence of multiple myeloma (primary amyloidosis). The
primarily tubular basement-membrane form of the disease
usually seen with concurrent myeloma kidney with BJCN, is
associated with more aggressively proliferative plasma-cell
neoplasms. The authors believe that these associations
relate to the size of the malignant clone which, in turn,
determines the amount of depositionogenic protein available
and the rate of its presentation to the target organ
(primarily the kidney). The distinction is not trivial, for
if the authors are correct, their data suggest that not all
forms of renal disease occurring in the course of
plasma-cell dyscrasias have the same bleak prognosis. The
outlook for nodular glomerular disease, as an indirect
marker of clone size, may be intrinsically better than that
of a renal biopsy showing cast nephropathy and tubular
basement membrane LCDD deposits and clinical renal failure.
Since 1992, it has also become less certain that there are
general structural differences between light chains forming
amyloid and those producing non-Congophilic tissue deposits.
The current data suggest that light-chain proteins with the
capacity to form pathogenic tissue deposits may exist in a
spectrum, with one end represented by those only capable of
forming amylord, the other by those depositing in a more
amorphous, nonfibrillar manner, and a group in the center
capable of either or both, depending on circumstances that
are presently not understood. An alternative view suggests
that all or most proteins depositing as fibrils pass through
a non-Congophilic, nonfibrillar phase, of a length varying
according to their primary structure, which is not detected
in vivo because of the vagaries imposed by clinical
sampling. More structural analyses of material extracted
from deposits in tissue may resolve this issue.
Cazeneuve C, Ajrapetyan H, Papin S, Roudot-Thoraval F,
Genevieve D, Mndjoyan E, Papazian M, Sarkisian A, Babloyan
A, Boissier B, Duquesnoy P, Kouyoumdjian JC,
Girodon-Boulandet E, Grateau G, Sarkisian T, Amselem S:
Identification of MEFV-independent modifying genetic factors
for familial mediterranean fever. Am J Hum Genet 2000
Nov;67(5):1136-43. Service de Biochimie et de Genetique
Moleculaire and Institut National de la Sante et de la
Recherche Medicale (Unite 468), H opital Henri-Mondor, 94010
Creteil, France.
Familial Mediterranean fever (FMF) is a recessively
inherited disorder predisposing to renal amyloidosis and
associated with mutations in MEFV, a gene encoding a protein
of unknown function. Differences in clinical expression have
been attributed to MEFV-allelic heterogeneity, with the
M694V/M694V genotype associated with a high prevalence of
renal amyloidosis. However, the variable risk for patients
with identical MEFV mutations to develop this severe
complication, prevented by lifelong administration of
colchicine, strongly suggests a role for other genetic
and/or environmental factors. To overcome the well-known
difficulties in the identification of modifying genetic
factors, we investigated a relatively homogeneous population
sample consisting of 137 Armenian patients with FMF from 127
independent families living in Armenia. We selected the
SAA1, SAA2, and APOE genes-encoding serum amyloid proteins
and apolipoprotein E, respectively-as well as the patients'
sex, as candidate modifiers for renal amyloidosis. A
stepwise logistic-regression analysis showed that the
SAA1alpha/alpha genotype was associated with a sevenfold
increased risk for renal amyloidosis, compared with other
SAA1 genotypes (odds ratio [OR] 6. 9; 95% confidence
interval [CI] 2.5-19.0). This association, which was
present whatever the MEFV genotype, was extremely marked in
patients homozygous for M694V (11/11). The risk for male
patients of developing renal amyloidosis was fourfold higher
than that for female patients (OR=4.0; 95% CI=1.5-10.8).
This association, particularly marked in patients who were
not homozygous for M694V (34.0% vs. 11.6%), was independent
of SAA1-allelic variations. Polymorphisms in the SAA2 or
APOE gene did not appear to influence susceptibility to
renal amyloidosis. Overall, these data, which provide new
insights into the pathophysiology of FMF, demonstrate that
susceptibility to renal amyloidosis in this Mendelian
disorder is influenced by at least two MEFV-independent
factors of genetic origin-SAA1 and sex-that act
independently of each other.
Devaney K, Sabnis SG, Antonovych TT: Nonamyloidotic
fibrillary glomerulopathy, immunotactoid glomerulopathy, and
the differential diagnosis of filamentous glomerulopathies.
Mod Pathol 1991 Jan;4(1):36-45. Department of Genitourinary
Pathology, Armed Forces Institute of Pathology, Washington,
DC.
Kidney biopsies from 12 patients between the ages of 10 and
63 yr were diagnosed as nonamyloidotic fibrillary
glomerulopathy (NAFG) or immunotactoid glomerulopathy (IG)
on the basis of the electron microscopic finding of
filamentous or tubular material within the glomerular
capillaries and mesangium. Six patients were male and six
were female. Eleven presented with nephrotic syndrome and
one with acute renal failure. Eight were hypertensive, and
four of these patients had gross or microscopic hematuria as
well. Biopsies from 11 patients were Congo red negative; one
was weakly positive. By light microscopy, the predominant
glomerular change was thickening of the capillary basement
membrane with or without widening of the mesangium; these
changes were suggestive of membranous glomerulonephritis.
Immunofluorescent studies performed in four of the cases
were positive for immunoglobulin G (IgG). Immunoperoxidase
staining for beta 2-microglobulin was negative in four
patients. Ultrastructurally, filaments or tubules were
identified in the glomerular capillary basement membrane
and/or mesangium in each patient. The filaments in NAFG, IG,
amyloidosis, and other paraprotein deposits can be
differentiated by size, arrangement, and location of
filamentous material.
Fogo A, Qureshi N, Horn RG: Morphologic and clinical
features of fibrillary glomerulonephritis versus
immunotactoid glomerulopathy. Am J Kidney Dis. 1993
Sep;22(3):367-77. Department of Pathology, Vanderbilt
University Medical Center, Nashville, TN 37232.
Renal diseases characterized by Congo red-negative
extracellular fibrillary deposits, either organized arrays
of larger, microtubular fibrils (immunotactoid
glomerulopathy [IT]) or smaller, randomly organized
fibrils (fibrillary glomerulonephritis), have been
recognized recently. The clinical significance, if any, of
the distinction of these patterns has not been determined.
On review of all renal biopsy specimens evaluated in a
private referral renal pathology laboratory over the last 11
years, 26 cases with fibrillary glomerulonephritis pattern
were identified and compared with our six most recent cases
with the IT pattern. The fibrillary glomerulonephritis
patients, 17 women and nine men, had an average age of 50
+/- 2 years and contributed 1% of the renal biopsy specimens
examined. All patients had marked proteinuria and 16 had
microscopic hematuria. Follow-up at 23 +/- 5 months in 25 of
these patients revealed end-stage renal disease in 11
patients (44%) and one death due to renal failure. End-stage
renal disease developed an average of 10 +/- 5 months after
biopsy. One patient developed multiple myeloma. Twenty-four
renal biopsy specimens showed proliferation, with crescents
in seven. Immunofluorescence showed moderate to intense
staining for immunoglobulin G and weaker staining for C3, in
a predominantly mesangial pattern, with weaker glomerular
basement membrane (GBM) staining, corresponding to electron
microscopic deposit localization. In four cases, linear GBM
staining by immunofluorescence corresponded to extensive
subendothelial or transmembranous deposits. The average
fibril diameter was 14.0 +/- 0.5 nm (range, 10.4 to 18.4
nm). Immunotactoid glomerulopathy patients (three women and
three men) were significantly older, 62 +/- 2 years (P <
0.025). All had marked proteinuria, with microscopic
hematuria in two patients. Associated hematopoietic diseases
were present in four patients, with monoclonal proteins
and/or abnormal plasma cell proliferation in three. One
patient died of nonrenal causes. The remaining five patients
have stable renal function at 20 +/- 5 months. Biopsy
specimens showed proliferative (n = 3) or membranous-like (n
= 3) patterns. Immunofluorescence showed immunoglobulin G
and weaker C3 staining in a granular GBM pattern, with
lesser mesangial staining. The microtubular fibril diameter
was on average 43.2 +/- 10.3 nm (range, 16.8 to 90.0 nm).
Thus, fibrillary glomerulonephritis and IT can be separated
based on ultrastructurally distinct features. Patients with
fibrillary glomerulonephritis are less likely than those
with IT to have associated hematopoietic disease and also
have poorer renal survival. We propose that classification
based on these morphologic differences appears to have
clinical significance.
•Grove P, Neale PH, Peck M, Schiller B, Haas M:
Monoclonal immunoglobulin G1-kappa fibrillary
glomerulonephritis. Mod Pathol 1998 Jan;11(1):103-9.
Department of Pathology, The University of Chicago, Illinois
60637, USA.
We report here a case of fibrillary glomerulonephritis
arising in a 43-year-old man with a polyclonal gammopathy,
who presented with progressive renal insufficiency,
microscopic hematuria, and mild proteinuria (0.7 g/d).
Ultrastructural studies showed deposits of randomly oriented
fibrils in the glomerular mesangium and adjacent portions of
some glomerular basement membranes, with a mean fibril
thickness of 14.3 nm, highly consistent with fibrillary
glomerulonephritis. The Congo red stain was negative on
histologic sections. Immunofluorescence studies revealed
strong mesangial and focal glomerular capillary staining for
immunoglobulin (Ig) G, complement (C) 3, and kappa light
chains, with minimal staining for IgA, IgM, C1q, or lambda
light chains. The IgG present was entirely of the IgG1
subclass. This case is quite unusual for fibrillary
glomerulonephritis, which typically presents with polyclonal
IgG deposits and IgG4 as the dominant IgG subclass present.
Monoclonal deposits are more frequently associated with
immunotactoid glomerulopathy, characterized
ultrastructurally by microtubule-like structures 30 to 50
nmn thick, often in parallel arrays. The present case
illustrates that although fibrillary glomerulonephritis and
immunotactoid glomerulopathy might be distinguishable on
ultrastructural grounds, there is overlap between these two
entities with respect to the potential composition of the
glomerular deposits present.
Iskandar SS, Falk RJ, Jennette JC: Clinical and
pathologic features of fibrillary glomerulonephritis. Kidney
Int 1992 Dec;42(6):1401-7. Department of Pathology, Bowman
Gray School of Medicine, Wake Forest University, Winston
Salem, North Carolina. A diagnosis of fibrillary
glomerulonephritis was made in 31 renal biopsies from 28
patients on the basis of the electron microscopic
identification of glomerular deposits of randomly arranged
fibrils that resembled amyloidosis but were larger. This
accounted for approximately 1% of all nontransplant renal
biopsy diagnoses. Renal biopsy specimens with parallel
arrays of 30 nm to 50 nm microtubules (that is,
immunotactoid glomerulopathy) were not included in the
study. The patients had a mean age of 49 years with a range
of 21 to 75. The male to female ratio was 1:1.8 and the
ratio of Whites to Blacks was 8.3:1, which differs from the
3:1 ratio in our overall biopsy population. All patients had
proteinuria (mean 6.0 g/day), and most had hematuria and
renal insufficiency. After a mean follow-up of 24 months,
there was 48% renal survival. The light microscopic
appearance of the fibrillary glomerulonephritis was quite
varied. Capillary wall thickening and matrix expansion were
the most frequent alterations. Nineteen percent of specimens
had crescents. Morphometric ultrastructural analysis
demonstrated a mean fibril diameter of 22.4 +/- 7.4 nm.
Immunofluorescence microscopy revealed that IgG was the
dominant and often the only immunoglobulin class in immune
deposits, and subclass analysis revealed that IgG4 was the
dominant or exclusive subclass in all specimens tested. We
hypothesize that the relatively homogeneous nature of the
immunoglobulin in the immune deposits is the basis for the
fibril formation.
•Korbet SM, Schwartz MM,
Lewis EJ. The fibrillary glomerulopathies. Am J Kidney Dis
1994 May;23(5):751-65.
Department of Medicine, Rush Presbyterian St Lukes
Medical Center, Chicago, IL.
Fibrillary glomerulopathy is a category of glomerular
disease that is defined by the ultrastructural feature of
organized deposits of extracellular, nonbranching,
microfibrils. The best-known disease in this category is
amyloidosis, but cryoglobulinemia, light chain deposition
disease, systemic lupus erythematosus, immunotactoid
glomerulopathy, and diabetic fibrillosis may have similar
ultrastructural findings and comprise the differential
diagnosis of the fibrillary glomerulopathies. Because they
have disease-specific therapeutic and prognostic
implications, differentiating among these entities is
important for nephrologists and nephropathologists. To aid
the physician, we will review the fibrillary
glomerulopathies using an algorithm based on morphology,
clinical features, and serologic assessment. We believe this
approach will prove to be practical and useful to the
practicing nephrologist.
Kronz JD, Neu AM, Nadasdy T: When noncongophilic
glomerular fibrils do not represent fibrillary
glomerulonephritis: nonspecific mesangial fibrils in
sclerosing glomeruli. Clin Nephrol 1998
Oct;50(4):218-23. Department of Pathology, The Johns
Hopkins University, Baltimore, MD 21205, USA.
In addition to fibrillary glomerulonephritis (FGN), Congo
red negative mesangial fibrils may commonly be seen in
sclerosing glomerular diseases. Rarely, these nonspecific
mesangial fibrils (NMF) may mimic fibrils in FGN and cause a
differential diagnostic pitfall. Following an interesting
case of sclerosing crescentic glomerulonephritis with
abundant NMF (which is presented in some detail) we have
reviewed our renal biopsy files for a period of two and a
half years and found additional 16 cases where the presence
of NMF warranted studies to exclude FGN and other diseases
with fibrillary deposits. The immunofluorescence pattern
characteristically seen in FGN was not present in any of
these cases. Our data confirm that mesangial fibrillary
material seen ultrastructurally in sclerosing glomeruli with
negative or nonspecific immunofluorescence (IF) represents a
nonspecific reaction of the mesangial matrix to chronic
glomerular injury. The presence of NMF should not lead to
the erroneous diagnosis of FGN. Negative or nonspecific
immunofluoresence, localization to the mesangium in a
usually segmental fashion, and the more bundle-like than
random arrangement of fibrils are helpful diagnostic hints
in differentiating NMF from fibrils in FGN.
•Looi LM: Fibrillary deposits: amyloids and
tactoids. Malays J Pathol 1995 Jun;17(1):1-10. Department of
Pathology, Faculty of Medicine, University of Malaya,
Malaysia.
Two forms of abnormal fibrillary protein deposition are
considered: amyloidosis and fibrillary (immunotactoid)
glomerulonephritis. Amyloid is characterised by an
antiparallel, beta-pleated configuration which imparts to it
a unique apple-green birefringence after Congo red staining.
Inspite of its fairly constant physical properties, the
chemical composition of amyloid fibrils is amazingly
diverse, encomposing AA protein, light chain fragments,
transthyretin, procalcitonin, islet amyloid polypeptide,
atrial natriuretic peptides, beta-amyloid protein,
beta-2-microglobulin, cystatin C, gelsolin, apolipoprotein
A1, lyzozyme and their mutant variants. Amyloid P component
and heparan sulphate proteoglycan are ubiquitous
non-fibrillary amyloid components which have significant
roles in the amyloidogenetic process, as do also precursor
fibril proteins. Different amyloid fibril proteins relate to
different amyloidosis syndromes and different histological
patterns, and provide the basis for new diagnostic
approaches to this disorder. Glomerular deposits in
fibrillary glomerulonephritis (FGN), although often mistaken
for amyloid, differ from it in its negative Congophilia,
wider fibril width and highly organised,
microtubular-tactoidal appearance ultrastructurally. FGN is
essentially a primary glomerulopathy resulting in
progressive renal failure. Despite certain differences,
intriguing similarities between both entities of fibrillary
deposition pose a challenge to researchers as to the
mechanisms of abnormal protein crystallization and fibril
formation in tissues.
•Palanichamy V, Saffarian N, Jones B, Nakhleh RE,
Oh HK, Provenzano R, Tayeb JS: Fibrillary glomerulonephritis
in a renal allograft. Am J Kidney Dis 1998 Nov;32(5):E4.
Department of Internal Medicine, St John Hospital and
Medical Center, Detroit, MI 48236, USA.
Fibrillary glomerulonephritis is an uncommon disease seen in
approximately 1% of all native kidney biopsy specimens. We
present here a case of a 40-year-old white woman with the
rapid loss of graft function secondary to fibrillary
glomerulonephritis within 7 days of receiving a
living-related renal allograft. This case emphasizes the
values of combining urinalysis with prompt allograft kidney
biopsy in recipients with an elevated serum creatinine
posttransplantation. When one encounters rapidly progressing
glomerulonephritis or a pulmonary-renal syndrome in the
immediate posttransplantation period, fibrillary
glomerulonephritis must be considered in the differential
diagnosis. Because of a high recurrence rate and no
available treatment to modify a potentially malignant course
of this disease, we recommend caution when considering these
patients for transplantation.
•Pronovost PH, Brady HR, Gunning ME, Espinoza O,
Rennke HG: Clinical features, predictors of disease
progression and results of renal transplantation in
fibrillary/immunotactoid glomerulopathy. Nephrol Dial
Transplant 1996 May;11(5):837-42. Department of Medicine,
Brigham and Women's Hospital, Harvard Medical School,
Boston, USA.
BACKGROUND. The clinical manifestations of
fibrillary-immunotactoid glomerulopathy are still being
appreciated. It is unclear whether fibrillary-immunotactoid
glomerulopathy actually represents two distinct
clinicopathological entities, fibrillary glomerulopathy (FG)
and immunotactoid glomerulopathy (ITG), or a single disease
with different ultrastructural variants. METHODS. To address
these issues, we analysed the clinical features of 186
patients with fibrillary-immunotactoid glomerulopathy
referred to our institutions (25 patients) or reported in
the literature (161 patients). In separate analyses,
patients were subclassified as having either fibrillary
glomerulopathy (FG) or immunotactoid glomerulopathy (ITG)
according to fibril diameter (FG<=30nm, ITG>30 nm) or
arrangement (FG, random; ITG, focally organized). RESULTS.
Proteinuria (FG approximately 100%, ITG approximately 100%),
nephrotic syndrome (FG approximately 71%, ITG approximately
82%), haematuria (FG approximately 71%, ITG approximately
64%), hypertension (FG approximately 67%, ITG approximately
45%), and renal insufficiency (FG approximately 54%, ITG
approximately 42%) were frequent clinical correlates of both
FG and ITG, irrespective of the ultrastructural criteria for
diagnosis. Twenty-five patients presenting to our
institutions (24 FG, 1 ITG) were divided into three groups
based on rate of decline of GFR (mean slope of 1/serum
creatinine versus time: group 1 -0. 103+/-0.238; group 2
0.121+/-0.040; group 3 0.466+/-0.318) in an attempt to
identify clinical predictors of progression at presentation.
Rapid progressors (Group 3) had an increased incidence of
nephrotic syndrome and tended to have higher blood pressure
than patients with milder disease, but did not differ from
other groups in age, prevalence of haematuria or degree of
renal insufficiency. The number of patients requiring
dialysis was 0/10 in group 1, 2/6 in group 2, and 2/4 in
group 3 over a follw-up period 47+/-46, 55+/-32, and 19+/-19
months respectively; two predialysis deaths being recorded
in group 3. Four patients received five renal allografts
(one patient being transplanted twice) and were followed for
4-11 years. Whereas recurrence of FG was documented in three
allografts undergoing post-transplant biopsy, the rate of
deterioration of GFR was invariably slower in allografts
than native kidneys (mean slope of 1/Cr versus time:
0.036+/-0.01 versus 0. 0301+/-0.18 respectively). The
strength of association between FG-ITG and
lymphoproliferative malignancy varied depending on whether
patients with monoclonal-gammopathy-associated fibrillary
deposits were included or excluded from the analysis.
CONCLUSIONS. We contend that patients presenting with
Congo-red-negative fibrillary deposits on renal biopsy
should be evaluated carefully for monoclonal-gammopathy and
cryoglobulins, but there is insufficient published data, as
yet, to justify subclassification of FG and ITG as distinct
clinical entities. Indeed, we argue that it remains to be
determined if FG-ITG represents a unique condition or a
forme fruste of cryoglobulin- or gammopathy-associated renal
disease. Although the optimal treatment for FG-ITG has not
been determined, renal transplantation appears an attractive
option in patients with end-stage renal failure.
Serpell LC, Sunde M, Benson MD, Tennent GA, Pepys MB,
Fraser PE: The protofilament substructure of amyloid
fibrils. J Mol Biol 2000 Jul 28;300(5):1033-9. Neurobiology
Division, Medical Research Council Centre, Laboratory of
Molecular Biology, Hills Road, Cambridge, CB2 2QH, UK.
serpell@mrc-lmb.cam.ac.uk
Tissue deposition of normally soluble proteins, or their
fragments, as insoluble amyloid fibrils causes the usually
fatal, acquired and hereditary systemic amyloidoses and is
associated with the pathology of Alzheimer's disease, type 2
diabetes and the transmissible spongiform encephalopathies.
Although each type of amyloidosis is characterised by a
specific amyloid fibril protein, the deposits share
pathognomonic histochemical properties and the structural
morphology of all amyloid fibrils is very similar. We have
previously demonstrated that transthyretin amyloid fibrils
contain four constituent protofilaments packed in a square
array. Here, we have used cross-correlation techniques to
average electron microscopy images of multiple
cross-sections in order to reconstruct the sub-structure of
ex vivo amyloid fibrils composed of amyloid A protein,
monoclonal immunoglobulin lambda light chain, Leu60Arg
variant apolipoprotein AI, and Asp67His variant lysozyme, as
well as synthetic fibrils derived from a ten-residue peptide
corresponding to the A-strand of transthyretin. All the
fibrils had an electron-lucent core but the packing
arrangement comprised five or six protofilaments rather than
four. The structural similarity that defines amyloid fibres
thus exists principally at the level of beta-sheet folding
of the polypeptides within the protofilament, while the
different types vary in the supramolecular assembly of their
protofilaments.
Sezer O, Eucker J, Jakob C, Possinger K: Diagnosis and
treatment of AL amyloidosis. Clin Nephrol 2000
Jun;53(6):417-23. Universitatsklinikum Charite,
Campus Mitte, Medizinische Klinik, Humboldt Universitat,
Berlin, Germany.
AL (amyloid light-chain) amyloidosis is a plasma cell
disorder in which depositions of amyloid light-chain protein
cause progressive organ failure. Virtually all patients with
AL amyloidosis have a monoclonal protein in the serum or
urine or a monoclonal population of plasma cells in the bone
marrow. The most common target organ is the kidney and renal
amyloidosis manifests as proteinuria or nephrotic syndrome
in 3/4 of the patients. The median survival is one to two
years. It is important to recognize that the amyloidosis is
a dynamic process, and chemotherapy induced reduction of the
activity of the plasma cell clone reduces the supply of the
amyloid precursor protein and can result in a major
regression of the deposits. Amyloid-related nephrotic
syndrome and renal failure are potentially reversible.
Conventional-dose melphalan as standard treatment can
prolong the median duration of survival about 10 months, but
the clinical response rates with improvement of impaired
organ function are low with a slow response. Upfront
high-dose chemotherapy with autologous peripheral blood stem
cell transplantation is much more effective and can result
in a major improvement of the patient's clinical condition,
but the treatment-related toxicity can be relevant due to
impaired organ function. The initial use of a
conventional-dose chemotherapy consisting of vincristine,
doxorubicin and dexamethasone (VAD) to achieve a remission
and subsequent high-dose chemotherapy is the concept of a
German trial. The improvement of the condition of the
patient by this approach may increase the tolerability of
high-dose chemotherapy and reduce transplantation-related
problems.
•Solomon A, Weiss DT, Murphy C. Primary
amyloidosis associated with a novel heavy-chain fragment (AH
amyloidosis). Am J Hematol 1994
Feb;45(2):171-6. Department of
Medicine, University of Tennessee Medical Center/Graduate
School of Medicine, Knoxville 37920.
Primary or AL amyloidosis occurs in patients with monoclonal
plasma cell-related disorders and is typically associated
with the systemic deposition as amyloid fibrils of the
light-chain portion of the immunoglobulin molecule.
Recently, the discovery that heavy chains could be involved
in amyloid formation led to the designation of this type of
disease process as AH amyloidosis. We have now identified a
second example of heavy chain-associated amyloidosis in a
patient (MAD) who had a serum IgG monoclonal gammopathy and
Bence Jones proteinuria. In this case, the renal and splenic
amyloid deposits consisted solely of the VH-D-encoded
portion of the heavy polypeptide chain, in contrast to the
first case, where the amyloid contained an immunoglobulin
component composed of the entire heavy-chain variable and
third constant domains. In this respect, the chemical
composition of the amyloid protein MAD differed not only
from that of the first reported case of AH amyloidosis but
from all other structurally abnormal components found in
patients with heavy chain-associated disease. The discovery
that certain forms of heavy chains, as well as light chains,
can form amyloid provides further information on the
chemical basis of amyloidogenicity and the diverse nature of
this disease.
•Strom EH, Hurwitz N, Mayr AC, Krause PH,
Mihatsch MJ. Immunotactoid-like glomerulopathy with massive
fibrillary deposits in liver and bone marrow in monoclonal
gammopathy. Am J Nephrol 1996;16(6):523-8. Institute for
Pathology, University of Basel, Switzerland.
At autopsy, massive nonamyloid fibrillar deposits,
immunoreactive to IgG and kappa light chain, were found in
glomeruli, liver, and bone marrow of a 72-year-old woman.
The patient suffered from severe nephrotic syndrome,
hepatomegaly and cholestasis, normochromic anemia, and IgG
kappa monoclonal gammopathy. Fibrillary glomerulopathies,
most often denoted as fibrillary glomerulonephritis or
immunotactoid glomerulopathy, are generally considered to
have deposits restricted to the glomeruli. However, this
study indicates that fibrillary deposits may be a systemic
manifestation of fibrillary glomerulonephritis or
immunotactoid glomerulopathy, at least when the patient is
suffering from a monoclonal gammopathy.
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