J Am Soc Nephrol 12: 1558 –1565, 2001
DISEASE OF THE MONTH
Eberhard Ritz, Feature Editor
Light Chain Deposition Disease: A Model of
Glomerulosclerosis Defined at the Molecular Level
PIERRE M. RONCO,* MARIE-ALEXANDRA ALYANAKIAN,†
BÉATRICE MOUGENOT,* and PIERRE AUCOUTURIER†
*Renal Division, INSERM Unit 489 and University Pierre et Marie Curie (Paris 6), Hôpital Tenon
(Assistance Publique–Hôpitaux de Paris), and †INSERM Unit 25 and University René Descartes (Paris 5),
Hôpital Necker, Paris, France.
Because the renal plasma flow represents 20% of the total
plasma flow and the glomerulus is the renal filtering unit
continuously exposed to plasma proteins, the glomerulus is a
prominent target for deposition of abnormal proteins or pro-
teins with a peculiar affinity for constituents of the capillary
wall. Among these proteins, monoclonal Ig or their heavy-
chain (HC) or light-chain (LC) subunits are responsible for a
wide spectrum of glomerular diseases that can be classified
into two categories by electron microscopy (Table 1). The first
category is those with organized deposits and includes diseases
with fibril formation, mainly amyloidosis, and diseases with
microtubule formation, including cryoglobulinemic kidney and
immunotactoid glomerulonephritis. Only amyloid deposits
stain for Congo red, a tinctorial property related to the
␤-pleated sheet organization of amyloid fibrils common to all
forms of amyloid. The second category of diseases is charac-
terized by nonorganized electron-dense granular deposits.
They are localized in basement membranes in most tissues,
especially the kidney, and define a disease now called mono-
clonal Ig deposition disease (MIDD) (1,2), a term that by
convention excludes Ig-derived amyloidosis. MIDD differs
from amyloidosis by the lack of affinity for Congo red. The
distinction between amyloid light-chain (AL) amyloidosis and
MIDD also is justified by the different pathophysiology of
amyloid that implicates one-dimensional elongation of a
pseudocrystalline structure and MIDD that involves nonorga-
nized amorphous precipitation of Ig chains (see Pathogenesis
section).
History
It was known from the late 1950s that nonamyloidotic forms
of glomerular disease resembling diabetic glomerulosclerosis
could occur in multiple myeloma (3,4). The presence of mono-
clonal LC in these lesions was recognized in 1973 by An-
Correspondence to Dr. Pierre Ronco, INSERM U 489, Hôpital Tenon, 4 rue de
la Chine, 75020 Paris, France. Phone: 33-1-56-01-66-39; Fax: 33-1-56-01-69-
99; E-mail: pierre.ronco@tnn.ap-hop-paris.fr
1046-6673/1207-1558
Journal of the American Society of Nephrology
Copyright © 2001 by the American Society of Nephrology
tonovych et al. (5) and confirmed by Randall et al. (6), who
published in 1976 the first description of LC deposition disease
(LCDD). Although the deposits in AL amyloidosis contain
monoclonal LC or LC fragments, the term light-chain deposi-
tion disease is used only for the disease that features nonamy-
loid electron-dense granular deposits as described by Randall
et al. (6). Monoclonal HC were found together with LC in the
tissue deposits from certain patients (6,7), and the term light-
and heavy-chain deposition disease (LHCDD) (1) was pro-
posed. More recently, deposits containing monoclonal HC in
the absence of detectable LC were observed in patients who
were affected by otherwise typical Randall’s disease (heavy-
chain deposition disease [HCDD]) (8), and the first series of
four patients was reported in 1999 (9).
Pathogenesis
At variance with amyloidosis, lesions in MIDD are related
clearly to accumulation of extracellular matrices (ECM). The
Ig chains that are responsible for this effect display peculiar
structural properties and proneness to precipitate in certain
extracellular areas where they most likely stimulate ECM
production.
Ig Chain Structure
Ig are made up of two pairs of subunits: two HC and two LC,
each of which includes a variable domain implicated in antigen
recognition, and a constant region that itself includes one or
several domains and that activates a variety of effector sys-
tems. Binding to antigen and activating effector cells or com-
plement (i.e., antibody function) is made possible by the asso-
ciation of two HC and two LC. LC may be of ␬ or ␭ type, with
one constant and one variable domain (termed CL and VL). HC
may be of nine isotypes (␮, ␥1, ␥2, ␥3, ␥4, ␣1, ␣2, ␦, and ␧)
that define Ig classes and subclasses: IgM, IgG (including IgG1
to IgG4), IgA (including IgA1 and IgA2), IgD, and IgE. HC
include from the ⫺NH2 to the ⫺COOH terminus one variable
domain (VH) from a common repertoire for all isotypes and
three (for IgG, IgA, and IgD) or four (for IgM and IgE)
constant domains, termed CH1 to CH4 (see Figure 1).
Normal Ig display a striking structural heterogeneity that is
borne essentially by the variable domains and is related to the
J Am Soc Nephrol 12: 1558 –1565, 2001
Table 1. Glomerular diseases with monoclonal immunoglobulin deposition
Immunoglobulin Deposits
Organized
fibrillar
microtubular
Nonorganized, granular
diversity of the antigenic determinants that they are supposed
to recognize. These regions of the Ig chains are encoded by
numerous gene segments, the rearrangement of which occurs
during B-cell differentiation and is mandatory for Ig produc-
tion. Comparison of VH and VL sequences allowed definition
of variability subgroups on the basis of their homologies: HC
express six VH subgroups, ␬ chains express four V␬ subgroups,
and ␭ chains express six V␭ subgroups. The variability of VH
and VL is even higher in three small peptidic portions called
complementarity determining regions (CDR1, CDR2, and
CDR3) that form three loops at one end of the domain that
constitutes the antibody binding site.
At variance with normal polyclonal Ig, monoclonal Ig are
secreted by a single clone of differentiated B cells that expands
excessively, either in a tumoral context (myeloma, Walden-
ström’s disease, etc.) or without patent hematologic malig-
nancy (monoclonal gammopathy of undetermined signifi-
cance). A monoclonal Ig may be secreted as free LC (or rarely,
HC) that displays structural anomalies causing tissue
deposition.
Abnormal Structures of LC Variable Domains
In LCDD, isotype restriction is significant; ␬ chains occur in
approximately 80% of cases. This contrasts with the increased
Figure 1. Domain structure of an IgG. The light- (LC) and heavy-
chain domains are shown in gray and white, respectively. VL, light-
chain (LC) variable domain; CL, LC constant domain; VH, heavy-
chain (HC) variable domain; CH, HC constant domain.
Light Chain Deposition Disease 1559
Glomerular Disease
Amyloidosis
Cryoglobulinemia, immunotactoid glomerulonephritis
Monoclonal immunoglobulin deposition disease:
light chain, heavy chain, and light plus heavy
chain deposition disease
␭ to ␬ ratio seen in amyloidosis. Data on N-terminal sequences
of the LC from six consecutive patients with LCDD suggested
an overrepresentation of the rare V␬IV variability subgroup
(10). This subgroup features a longer CDR1 loop that contains
some hydrophobic residues. The role of LC variable region
(VL) in LC deposition is suggested by the fact that amino acid
changes in VL were sufficient to promote tissue deposition in
mice that expressed a human LCDD V␬IV chain (11).
The primary structures of a few additional LCDD precursors
were analyzed at the cDNA (12,13) and protein levels (14). As
in AL amyloidosis, no common structural motif emerged from
these studies. The most remarkable observations were unusual
hydrophobic residues at positions where they either could be
exposed to the solvent or strongly modify the conformation,
especially in the CDR (13,14). In particular, molecular mod-
eling experiments performed on V␬I and V␬IV LC underline
the presence of leucine, isoleucine, or tyrosine at positions 27
and/or 31 in all known cases of LCDD. Other nonpolar groups
may be exposed on CDR regions, which suggests that hydro-
phobic interactions are important either in the amorphous pre-
cipitation of LC or in the mechanisms that lead to overproduc-
tion of ECM components (15). Of note, in contrast to LCDD
LC, those involved in AL amyloidosis often present particular
acidic residues in CDR and might form fibrils through elec-
trostatic interactions.
When pathogenic LC could not be detected in the serum and
urine, which occurred in 15 to 30% of patients, they seemed to
be N-glycosylated in all tested cases (10,16). In vitro biosyn-
thetic labeling experiments on short-term cultures showed that
LC that were absent in the urine actually were secreted by the
bone marrow plasma cells (1,17,18). Thus, together with the
presence of hydrophobic residues, glycosylation might in-
crease the LC propensity to precipitate in tissues and displace
the equilibrium from soluble toward deposited amorphous
forms.
Truncated HC
Twenty-two cases of HCDD have been reported (19 and
reviewed in reference 20). In all patients, a monotypic HC
without LC was detected in the deposits. A deletion of the CH1
domain was found in the deposited or circulating HC in the 10
patients with ␥ HCDD where it was searched for. It also was
suggested in a patient with ␣ HCDD (21). Deletions of the
CH1, hinge, and CH2 domains were found in one case (8).
The loss of the CH1 domain suggests that secretion of the
free, abnormal HC is required for tissue deposition. Normal
1560 Journal of the American Society of Nephrology
HC associate posttranslationally with Ig binding protein (BIP)
in the endoplasmic reticulum. The LC later assemble with HC,
and the complex is transferred to the Golgi apparatus for
further processing and secretion. Because the binding site of
BIP is located in the CH1 domain, when a mutant HC lacks the
CH1 domain, it fails to associate with BIP and thus may be
secreted as a free subunit in the circulation. However, CH1
deletion seems necessary but not sufficient for deposition, and
it is likely that the VH also contributes to tissue deposition,
ultrastructural aspects of the deposits, and ECM accumulation.
Indeed, in HC disease, a lymphoproliferative disorder with free
HC secretion without corresponding tissue deposition, the vari-
able regions are found to be deleted partially or entirely,
together with the CH1 domain. In HCDD, the variable regions
are present without major structural alteration, although in the
two cases in which they were sequenced (8,22), they contained
unusual amino acid substitutions that might change the phys-
icochemical properties (e.g., charge, hydrophobicity). In addi-
tion, the structure of an HCDD HC (8) was strikingly similar to
that reported in a case of amyloid HC amyloidosis (23), from
which it differed essentially at the V domain level. It is worth
noting that in most cases of HCDD, the circulating HC is
associated with a ␭-type LC. This bias may reflect a preferen-
tial association of the VH with ␭ VL domains.
Deposition Does Not Mean Pathogenicity
The finding by Solomon et al. (24) of unexpectedly frequent
(14 of 40) deposition of human monoclonal LC along basement
membranes in a mouse experimental model raises the question
of the relationship between tissue precipitation and pathogenic
effects. Human LC that were found deposited along basement
membranes in mice were predominantly of the ␭ type (9 of 14),
contrasting with the striking predominance of ␬ chains in
MIDD (24). In addition, LC deposition similar in aspect to
LCDD by immunofluorescence but with no or only scanty
granular electron-dense deposits in the tubular basement mem-
brane may occur in the absence of glomerular lesions and
Figure 2. Light microscopy of an LC nephropathy with predominant tubulointerstitial lesions. (A) Thickening of tubular basement membranes
and diffuse interstitial fibrosis. (B) Strongly periodic acid-Schiff (PAS)-positive deposits delineating the spaces between myocytes in an
interlobular artery. Magnifications: ⫻125 in A (PAS); ⫻312 in B (PAS).
J Am Soc Nephrol 12: 1558 –1565, 2001
tubular basement membrane thickening (19,25). One patient
(Aucouturier P, Droz D, personal data) had an important LC
secretion and typical basement membrane deposits by immu-
nofluorescence in the kidney, without histologic alteration, and
with normal renal functions 2 yr after kidney biopsy. Thus, the
propensity of a given LC to form deposits does not necessarily
mean that it is pathogenic, and immunofluorescence staining
should not be considered a sufficient criterion for pathologic
diagnosis of MIDD. As shown by characteristic pathologic
changes and experimental evidence, MIDD lesions are associ-
ated with local fibrosis.
LC-Induced Mesangial Fibrosis
Results of an in vitro study (26) suggest that pathogenic Ig
chains may stimulate mesangial cells to secrete ECM compo-
nents through growth factors, in particular transforming growth
factor-␤ (TGF-␤). LC-induced overproduction of collagen IV,
laminin, fibronectin, and tenascin was shown to be maximal at
72 h of incubation with mesangial cells (27). Accumulation
may be increased by a concomitant inhibition of collagenase
IV, which also is mediated by TGF-␤. None of these effects
was found with amyloid LC (27). One way to prevent the
LC-induced fibrosis is to study the detailed mechanism of
putative ligand-receptor interactions that may govern the abil-
ity of a given LC to stimulate the ECM synthesis. Other
possibilities are to prevent the secretion of TGF-␤ or to inter-
fere with the TGF-␤ signaling pathway.
Renal Pathology
Light Microscopy
Despite clinical manifestations that feature impairment of
glomerular function in most cases, MIDD should not be con-
sidered a purely glomerular disease. In fact, tubular lesions
may be more conspicuous than the glomerular damage. Tubu-
lar lesions are characterized by the deposition of a refractile,
eosinophilic, periodic acid-Schiff (PAS)-positive, ribbon-like
material along the tubular basement membrane (Figure 2A).
J Am Soc Nephrol 12: 1558 –1565, 2001
The deposits predominate around the distal tubules, the loops
of Henle, and, in some instances, the collecting ducts whose
epithelium is flattened and atrophied. Typical myeloma casts
are only occasionally seen in pure forms of MIDD (see below
for association with myeloma cast nephropathy). In advanced
stages, a marked interstitial fibrosis including refractile depos-
its frequently is associated with tubular lesions.
Glomerular lesions are much more heterogeneous (28,29).
Nodular glomerulosclerosis (NGS) is the most characteristic; it
is found in 60 (30) to 100% (19) of patients with LCDD.
Expansion of the mesangial ECM was observed in all cases of
HCDD, with NGS in almost all of them. Mesangial nodules are
composed of PAS-positive membrane-like material and often
are accompanied by mild mesangial hypercellularity. The cap-
illary loops stretch at the periphery of florid nodules and may
undergo aneurysmal dilation. Bowman’s capsule may contain a
material that is identical to that present in the center of the
nodules. These lesions resemble nodular diabetic glomerulo-
sclerosis, but some characteristics are distinctive: the distribu-
tion of the nodules is fairly regular in a given glomerulus, the
nodules are poorly argyrophilic, and exudative lesions as “fi-
brin caps” and extensive hyalinosis of the efferent arterioles are
not observed. In occasional cases with prominent endocapillary
cellularity and mesangial interposition, the glomerular features
mimic lobular glomerulonephritis. Milder forms of LCDD
simply show an increase in mesangial matrix and sometimes in
mesangial cells and a modest thickening of the basement
membranes that are abnormally bright and rigid. Glomerular
lesions may not even be detected by light microscopy but
require ultrastructural examination. These lesions may repre-
sent early stages of glomerular disease or be induced by LC
with a weak pathogenic potential. Their diagnosis would be
unrecognized without the immunostaining results. Arteries,
arterioles, and peritubular capillaries all may contain PAS-
positive deposits in close contact with their basement mem-
branes (Figure 2B). Deposits do not show the staining charac-
teristics of amyloid, but they may be associated with Congo
red–positive amyloid deposits in approximately 10% of pa-
tients (19).
Immunofluorescence Microscopy
A key step in the diagnosis of the various forms of MIDD is
immunofluorescence examination of the kidney. All biopsy
specimens show evidence of monotypic LC (mostly ␬) and/or
HC fixation along tubular basement membranes. This criterion
is requested for the diagnosis of MIDD.
The tubular deposits stain strongly and predominate along
the loops of Henle and the distal tubules, but they also often are
detected along the proximal tubules. In contrast, the pattern of
glomerular immunofluorescence displays marked heterogene-
ity. In patients with NGS, deposits of monotypic Ig chains
usually are found along the peripheral glomerular basement
membranes and, to a lesser extent, in the nodules themselves.
The staining in glomeruli typically is weaker than that ob-
served along the tubular basement membranes. This may not
be a function of the actual amount of deposited material,
because several cases in which glomerular immunofluores-
Light Chain Deposition Disease 1561
cence was negative despite the presence of large amounts of
granular glomerular deposits by electron microscopy have been
reported (31). Local modifications of deposited LC thus might
change their antigenicity (18). In patients without nodular
lesion (Figure 3A), glomerular staining occurs mainly along
the basement membrane, but it may involve the mesangium in
some cases. A linear staining usually decorates Bowman’s
capsule. Deposits frequently are found in vascular walls and
interstitium.
In patients with HCDD, immunofluorescence with anti-LC
polyclonal and monoclonal antibodies is negative despite typ-
ical NGS. Monotypic deposits of ␥, ␣, or ␮ HC may be
identified. All ␥ subclasses may be observed. Analysis of the
kidney biopsy with monoclonal antibodies specific for the
constant domains of the ␥ HC allowed identification of a
deletion of the CH1 domain in all tested cases. In most cases of
HCDD, except those with deposits of ␥ 4 that does not activate
complement, complement components could be demonstrated
in a granular or pseudolinear pattern.
The accessory proteins (serum amyloid P component, apo-
lipoprotein E, and ubiquitin) that are associated with AL amy-
loidosis and other amyloidoses are not present in LCDD
deposits.
The composition of glomerular matrix proteins has been
examined comparatively in NGS associated with LCDD and
diabetes mellitus (32). Nodules are made of normal ECM
constituents (collagen type IV, laminin, fibronectin) that are
produced in excess and stain weakly for the small proteogly-
cans, decorin and biglycan (33). In a series of 36 patients with
LC-related renal diseases including AL amyloidosis, cast ne-
phropathy, fibrillary glomerulopathy, and LCDD, TGF-␤ was
detected only in glomeruli of the 3 patients with LCDD and
nodular glomerular lesions (34). In the control series, it was
found essentially in nodular diabetic glomerulosclerosis, which
may suggest that distinct initial insults to the glomerular mes-
angium may trigger similar fibrogenetic pathways.
Electron Microscopy
The most characteristic ultrastructural feature is the presence
of finely to coarsely granular electron-dense deposits along the
outer (interstitial) aspect of the tubular basement membranes.
In the glomerulus, they predominate in a subendothelial posi-
tion along the glomerular basement membrane and are located
mainly along and in the lamina rara interna. They also can be
found in mesangial nodules, Bowman’s capsule, and the wall
of small arteries between the myocytes. Nonamyloid fibrils
have been reported in a few patients with LCDD or HCDD.
Association with Myeloma Cast Nephropathy
The association of monoclonal LC deposits, mostly along
renal tubule membranes, with typical myeloma cast nephrop-
athy is more frequent than reported initially (see Figure 3, B
and C). It was found in 23 of 72 (32%) patients with nonamy-
loid monoclonal LC deposits in a French series (30) and in 11
of 34 (32%) patients with MIDD in a recent North American
study (19). NGS is, however, infrequent (⬍10%), and some
ribbon-like tubular basement membranes are seen in fewer than
1562 Journal of the American Society of Nephrology J Am Soc Nephrol 12: 1558 –1565, 2001

half of the patients (30). In addition, one third of the patients do
not have granular-dense deposits by electron microscopy. The
lack of ECM accumulation in most of these patients who
present with acute renal failure in the setting of a true myeloma
may be due to insufficient time for the development of fibrosis
or to a weaker sclerogenic effect of the LC, if any. As dis-
cussed previously, the presence of LC deposits along the
tubular basement membrane is not sufficient to make a diag-
nosis of MIDD.
Clinical Features of LCDD
The main clinical features of MIDD are renal and cardiac
manifestations, as in AL amyloidosis. Data collected from the
largest series as yet published (1,19,29,35–37) show an unex-
pectedly wide range of affected ages (35 to 80 yr) with a male
gender preponderance. Mean age tends to be higher in patients
with LCDD and myeloma cast nephropathy (67 yr) (19) than in
those with pure MIDD (51 to 58 yr).
Renal Disease
Renal involvement is a constant feature of MIDD, and
proteinuria (composed mostly of albumin) and renal failure
often dominate the clinical presentation. In 23 to 53% of the
patients, albuminuria is associated with nephrotic syndrome.
However, in approximately 25% of them, it is less than 1 g/d,
and these patients exhibit mainly a tubulointerstitial syndrome
(Figure 2A). Albuminuria is not correlated with the existence
of NGS, at least initially, and may occur in the absence of
significant glomerular lesions by light microscopy. Hematuria
is more frequent (29 to 67%) than one would expect for a
nephropathy in which cell proliferation usually is modest, with
a few exceptions. The prevalence of hypertension is variable
but must be interpreted according to medical history.
The high prevalence (⬎90%), early appearance, and severity
of renal failure are other salient features of MIDD. In most
cases, renal function declines rapidly, which is a main reason
for referral.

Figure 3. (A) Immunofluorescence of renal biopsy specimen from a ␬ LC nephropathy without nodular glomerulosclerosis. Bright staining is
shown along tubular basement membranes, and heavy deposits are shown in an arteriolar wall. Glomerular staining involves Bowman’s capsule
and capillary basement membranes as well as mildly increased mesangium. (B) In a patient who presented with overt myeloma and acute renal
failure, direct immunofluorescence of renal biopsy specimen with the use of anti-␬ antibody showed numerous myeloma casts and staining of
most of the tubular basement membranes. (C) In the same patient, examination of a post mortem liver biopsy revealed ␬ deposits along
sinusoids. (D) Renal biopsy from a patient with HC deposition disease. Direct immunofluorescence with fluorescein-conjugated anti-␥ antibody
shows bright staining of mesangial nodular areas and peripheral capillary walls but, in this case, no staining along basement membranes of the
surrounding tubules. Magnification, ⫻312.
J Am Soc Nephrol 12: 1558 –1565, 2001
Renal features of the 22 patients with HCDD basically are
similar to those seen in LCDD and LHCDD (see below).
Extrarenal Manifestations
MIDD is a systemic disease, but visceral LC deposits may
be totally asymptomatic and found only at autopsy. Liver and
cardiac involvements are the most common (29).
Liver deposits were constant in patients whose liver was ex-
amined (38) (Figure 3C). They are discrete, confined to sinusoids
and basement membranes of biliary ductules without associated
parenchymal lesions, or massive with marked dilation and multi-
ple ruptures of sinusoids resembling peliosis. Hepatomegaly with
mild alterations of liver function tests are the most usual symp-
toms, but several patients develop hepatic insufficiency and portal
hypertension, and some of them die of hepatic failure (29).
Cardiac manifestations have been noted in as many as 80%
of the reported cases of LCDD, but they must be interpreted
with caution because of other age-dependent potential causes
of heart disease. Arrhythmias, conduction disturbances, and
congestive heart failure are seen. Echocardiography and cath-
eterization may reveal diastolic dysfunction and a reduction in
myocardial compliance similar to that seen in cardiac amyloid.
As in the kidney and the liver, immunofluorescence showed
monotypic LC deposits in the vascular walls and perivascular
areas of the heart in all autopsy cases (16).
Deposits also may occur along the nerve fibers and in the
choroid plexus, as well as in the lymph nodes, bone marrow,
spleen, pancreas, thyroid gland, submandibular glands, adrenal
glands, gastrointestinal tract, abdominal vessels, lungs, and
skin. They may be responsible for peripheral neuropathy (20%
of the reported cases), gastrointestinal disturbances, pulmonary
nodules, amyloid-like arthropathy, and sicca syndrome.
Hematologic Disease
The most common underlying disease in MIDD is myeloma,
which accounts for 40 to 50% of pure MIDD (1,19,29,35–37) and
⬎90% of LC deposits associated with myeloma cast nephropathy.
MIDD and AL amyloidosis are found at postmortem examination
in 5 and 10% of myeloma patients, respectively (39). MIDD, like
AL amyloidosis, often is the presenting disease that leads to the
discovery of myeloma at an early stage. In some patients who first
presented with “common” myeloma and with normal-sized
monoclonal Ig without kidney disease, LCDD occurred when the
disease relapsed after chemotherapy, together with Ig structural
abnormalities (7,16). Because melphalan was shown to induce Ig
gene mutations, the disease in these patients might result from the
emergence of a variant clone induced by the alkylating agent.
Apart from myeloma, MIDD may complicate Waldenström’s
macroglobulinemia and chronic lymphocytic leukemia in rare
cases (17). It often occurs in the absence of a detectable malignant
process, even after prolonged (⬎10 yr) follow-up. In such “pri-
mary” forms, a monoclonal bone marrow plasma cell population
can be documented easily by immunofluorescence examination.
Diagnostic Investigation
The diagnosis of MIDD must be suspected in any patient
who has nephrotic syndrome or rapidly progressive tubuloin-
Light Chain Deposition Disease 1563
terstitial nephritis or who has echocardiographic findings that
indicate diastolic dysfunction and a monoclonal Ig component
in the serum and/or the urine. The same combination also is
seen in AL amyloidosis, but the latter more often is associated
with the ␭ LC isotype. Because sensitive techniques, including
immunofixation, fail to identify a monoclonal Ig component in
15 to 30% of patients, renal biopsy plays an essential role in the
diagnosis of MIDD and of the associated dysproteinemia.
The definitive diagnosis is made by the immunohistologic
analysis of tissue from an affected organ, in most cases the
kidney, with the use of a panel of Ig chain–specific antibodies,
including anti-␬ and anti-␭ LC antibodies to stain the noncon-
gophilic deposits. When the biopsy stains for a single HC
isotype and does not stain for LC isotypes, the diagnosis of
HCDD should be suspected (see below).
The diagnosis of plasma cell dyscrasia relies on bone mar-
row aspiration and bone marrow biopsy with cell morphologic
evaluation and, if necessary, immunophenotyping with anti-␬
and anti-␭ antisera to demonstrate monoclonality. Diagnostic
criteria for a multiple myeloma are present in no more than
50% of the patients with LCDD.
Variants of LCDD: LHCDD and HCDD
A monotypic HC is associated with the monotypic LC in
approximately 10% of patients with LCDD. Whether HC and
LC precipitate as independent subunits or as a whole Ig mol-
ecule remains to be established. In one case, we found different
patterns of kidney deposition of the HC and LC (Rose C,
unpublished observation). Anomalies of the HC structure sug-
gesting deletion were demonstrated in LHCDD (7). Clinical
presentation and pathologic data in patients with LHCDD are
similar to those in LCDD.
The first patients with HCDD were reported in 1993 (8).
Twenty-two cases have been described so far (19 and reviewed
in reference 20). The clinical and pathologic features of HCDD
basically are the same as in LCDD, although several differ-
ences can be noted. First, lesions of NGS are constant in
patients with HCDD, whereas only a faint staining of tubular
basement membranes was seen in some patients (Figure 3D).
Second, extrarenal deposits are less frequent in these patients
than in those with LCDD. They have been reported in heart, in
synovial tissue, in skin, in striated muscles, in pancreas, around
thyroid follicles, and in Disse spaces of the liver (8 and
reviewed in reference 20). Third, signs of complement activa-
tion with renal complement deposition are present in most
patients with ␥1 or ␥3 HCDD (19).
In some patients with HCDD, a monoclonal component
cannot be detected in serum and urine (8). In other patients, a
monoclonal IgG1␭ can be found in serum, but no deletion is
found in the HC (9). Identification of the nephritogenic deleted
HC that circulates in low amounts then requires serum frac-
tionation followed by Western blotting (9) (Figure 4). This
finding suggests that serum fractionation also should be per-
formed in patients with LCDD in whom usual immunochemi-
cal methods have failed to detect a circulating monoclonal
component.
1564 Journal of the American Society of Nephrology
Figure 4. Immunoblotting study after agarose nondenaturing electro-
phoresis of a 5S Sephadex-G200 fraction from the serum of patients
A and B. Blots were revealed with monoclonal antibodies of Ig
domain specificities as indicated. Note that both fractions contained a
monoclonal IgG1␭ exhibiting normal reactivity with anti-␥ constant
domain antibodies (including the two anti-␥CH1 tested) and an iso-
lated ␥ chain of IgG1 subclass (reactivity with NL16) lacking CH1
domain epitopes (arrow). The fraction from the serum of patient A
also included a free ␭ LC (from Moulin et al., J Am Soc Nephrol 10:
526, 1999; reprinted with permission of the publisher).
Outcome and Treatment
The outcome of MIDD remains uncertain, mainly because
extrarenal deposits of LC can be totally asymptomatic or cause
severe organ damage that leads to death. Survival from onset of
symptoms varies from 1 mo to 10 yr, whereas by comparison,
the prognosis of a related disease, AL amyloidosis, is much
more homogeneous with a median survival time of 18 mo
under chemotherapy (40). Although renal prognosis is poor,
patient survival can be considerable with 70 and 37% 5-yr
patient survival and renal survival, respectively (36). The only
predictor of renal patient survival seems to be the initial serum
creatinine at the time of biopsy, whereas the presence of
multiple myeloma does not seem to influence renal or patient
survival (19). Outcomes in terms of renal and patient survival
are significantly better in patients with pure MIDD, compared
with those who present with myeloma cast nephropathy (19).
As in AL amyloidosis, treatment should be aimed at reduc-
ing Ig production. Chemotherapy is logical in patients with MIDD
and myeloma. It is controversial in the absence of overt malig-
nancy given the uncertain outcome of LCDD and the absence of
reliable follow-up criteria, especially in patients without detect-
able M component. However, it has become general practice to
J Am Soc Nephrol 12: 1558 –1565, 2001
treat patients with steroids plus melphalan or a cytotoxic agent,
irrespective of the accompanying hematologic disease.
Whether appropriate treatment can result in sustained remission
has long remained unclear. Clearance of the LC deposits has been
demonstrated unequivocally in some patients after intensive che-
motherapy with syngeneic bone marrow transplantation or blood
stem cell autografting (41,42). Disappearance of nodular mesan-
gial lesions and LC deposits also was reported after long-term
chemotherapy (43). These observations are of paramount impor-
tance: they demonstrate that fibrotic nodular glomerular lesions
are reversible, and they argue for intensive chemotherapy in
patients with severe visceral involvement.
Kidney transplantation has been performed in a few patients
with MIDD and end-stage renal failure. Recurrence of the
disease usually is observed. Therefore, intensive chemotherapy
should be performed before kidney transplantation.
In conclusion, MIDD is a rare systemic disease that is
characterized by severe renal failure as a result of the deposi-
tion of a monotypic LC and/or HC of Ig. Glomerular lesions
are so similar to diabetic nephropathy that MIDD may serve as
a model for the understanding of this plague of the third
millennium. MIDD indeed is the only sclerotic glomerular
disease in which the offending molecule is defined perfectly.
As in AL amyloidosis, controlled trials are required to define
the best chemotherapy combination according to clinical pre-
sentation and severity of renal failure.
Acknowledgments
We thank Catherine Bazaud for excellent secretarial assistance.
This work was supported by a grant from the Programme Hospitalier
de Recherche Clinique (AOM 96058).
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