Onco-Nephrology: Glomerular Diseases with Cancer

Jean-François Cambier* and Pierre Ronco*†‡

Summary
Glomerular diseases occurring in the course of malignancies remain rare. Diverse glomerular lesions can be
observed in a variety of neoplasms and involve different pathophysiologic links between the glomerulopathy and
the cancer. The pathophysiology of solid tumor–associated glomerulopathies remains obscure, whereas in
hematologic malignancy–induced paraneoplastic glomerulopathies, a molecular link can usually be demon-
strated. The aim of this review is to provide an update on glomerular diseases associated with carcinoma and *Nephrology and
Dialysis Department,
hematologic malignancies, covering epidemiology, pathophysiology, clinical presentation, and therapy. Special Assistance Publique-
emphasis will be placed on the potential usefulness of novel biomarkers, such as antiphospholipase A2 receptor Hôpitaux de Paris,
antibodies, for the diagnosis of membranous nephropathy, and on new associations and recent entities, including Tenon Hospital, Paris,
(proliferative) GN with nonorganized monoclonal immunoglobulin deposits and myeloproliferative neoplasm– France †Institut
National de la Santé et
related glomerulopathy.
de la Recherche
Clin J Am Soc Nephrol 7: 1701–1712, 2012. doi: 10.2215/CJN.03770412 Médicale, Unité Mixte
de Recherche
Scientifique 702,
Paris, France; and
‡
Introduction albuminuria and cancer, with an increased risk for Université Pierre et
Marie Curie, Paris,
The term paraneoplastic syndrome refers to clinical bladder and lung cancers (8.3- and 5.4-fold, respec- France
manifestations that are not directly related to tumor tively) in patients with an albumin-to-creatinine ratio
burden, invasion, or metastasis but are caused by the in the highest quintile (5). Nevertheless, the relationship Correspondence:
secretion of tumor cell products, such as hormones, between glomerular disease and cancer can at times Dr. Pierre Ronco,
growth factors, cytokines, and tumor antigens. The be misleading because of potential detection bias (e.g., Néphrologie et
concept of paraneoplastic glomerulopathy was intro- in the case of membranous nephropathy, in which pa- Dialyses, Hôpital
Tenon, 4 rue de la
duced by Galloway in 1922. Since then, the spectrum tients are likely to be more aggressively screened for Chine, 75020 Paris.
of paraneoplastic glomerulopathies has markedly ex- cancer); the demographic characteristics of the popula- Email: pierreronco@
panded with the description of glomerular complica- tion (e.g., membranous nephropathy and cancer tend yahoo.fr
tions of hematologic malignancies. The relationship to occur more often in the elderly); and the use of alky-
between malignancy and glomerular disease is better lating agents to treat glomerular disease, which can
understood, allowing a more precise diagnostic ap- itself lead to subsequent malignancies.
proach and the description of new entities.

Epidemiology
The prevalence of renal involvement in patients with
cancer has been analyzed in autopsy and clinical series.
Data from autopsy series are conflicting because of
technical limits to postmortem study. In clinical series,
the prevalence (range, 7%–34%) is overestimated be-
cause the threshold of proteinuria was low and hema-
turia was detected by qualitative dipstick tests only
(1,2).
The prevalence of cancer in patients with glomer-
ulopathy is easier to establish. The first study, pub-
lished by Lee et al., found that 11% of patients with
the nephrotic syndrome had carcinoma (3). Analysis
of the Danish Kidney Biopsy Registry, which in-
cluded all biopsies performed in Denmark since
1985, showed that the risk for cancer at 1 year and
1–4 years after the diagnosis of glomerulopathy was
increased by 2.4- and 3.5-fold, respectively, compared
with risk in the general population (4). However, this
result was not confirmed at 5 years or thereafter. The
Tromso study described an association between
Carcinoma-Associated Paraneoplastic
Glomerulopathies
Membranous Nephropathy
Membranous nephropathy (MN) is a rare disease,
whereas cancer is common. A secondary cause, such
as systemic lupus erythematosus, hepatitis B, or other
chronic infections, and various drugs can be found in
approximately 20% of cases; the remaining cases are
considered idiopathic or primary MN (6). The associ-
ation between MN and cancer was first reported in
1966 (3). Since then, several case series suggested a
strong link and emphasized the importance of an ex-
tensive screening for malignancy in patients diag-
nosed with MN without evident secondary cause
(7,8). However, other authors believe that this associ-
ation has been overemphasized (9). It is indeed in-
triguing that subepithelial deposits were not found,
or were noted very infrequently, in autopsy series of
patients with cancer (10).
The prevalence of cancer in patients with MN is es-
timated at 6%–22% (11). Malignancy is usually found
within 12 months of the diagnosis of MN, and most

www.cjasn.org Vol 7 October, 2012 Copyright © 2012 by the American Society of Nephrology 1701
1702 Clinical Journal of the American Society of Nephrology

(80%) cases are discovered before or at the time of the renal
diagnosis (7,12). Compared with age- and sex-adjusted gen-
eral population, the standardized incidence ratio of cancer in
patients with MN is 2.25; the annual incidence continues to
increase for more than 5 years after the histologic diagnosis
of nephropathy (13). The malignancies most frequently
associated with MN are solid tumors, including lung, gas-
trointestinal, and prostate carcinomas (8,10,11,13). Not
surprisingly, age and heavy smoking increase the likeli-
hood of malignancy in MN patients. Patients with MN
plus malignancy have a poorer prognosis than those with-
out cancer (13).
The diagnosis of paraneoplastic glomerulopathy should
rely on three strong criteria (11). First, a remission occurs
after complete removal of the tumor by surgery, chemother-
apy, or other treatments. Second, a renal relapse accompa-
nies recurrence of the neoplasia. Third, a pathophysiologic
link is established between cancer and MN, including the
detection of tumor antigens (such as carcinoembryonic anti-
gen and prostate-specific antigen) and antitumor antibodies
within subepithelial immune deposits (9,11). However, their
presence does not mean that they are causative because they
can be passively deposited as a result of increased glomer-
ular permeability to proteins. Four mechanisms recently
reviewed by Beck (14) can be involved in malignancy-
associated MN; however, they are not yet elucidated, in
part because of the lack of a reliable experimental model
(Figure 1).
Several advances have recently been made in MN path-
ophysiology, allowing a more precise distinction between
idiopathic and malignancy-associated MN. In 2009, the
transmembrane glycoprotein M-type phospholipase A2 re-
ceptor (PLA2R1) was identified as the major target podocyte
antigen involved in the majority of adult idiopathic MN
cases (15). The sensitivity and specificity of detection of anti-
PLA2R1 antibody by immunoblot or immunofluorescence
assay in idiopathic MN are about 70% and 90%, respectively,
whereas a very low prevalence of these antibodies is ob-
served in “secondary MN,” for which coincidental occurrence
of idiopathic MN with the “associated” disease cannot be
excluded (14–19). For instance, Qin et al. described few pa-
tients (3 of 10) having positivity for anti-PLA2R1 antibodies
and MN associated with solid tumors, but all three patients
showed persistence or relapse of proteinuria despite resec-
tion of the tumor; this finding suggests that the two disea-
ses were not causally related (19). In idiopathic MN, IgG4 is
the predominant subclass of anti-PLA2R1 antibodies show-
ing co-localization with the PLA2R1 antigen within the
subepithelial immune deposits (15), whereas in malig-
nancy-associated MN, IgG1 and IgG2 are the prevailing
subclasses (20). The absence of glomerular IgG4 deposition
at an early stage could thus be an independent predictor for
cancer occurrence (21). Sensitivity and specificity of the ab-
sence of IgG4 are 88% and 86%, respectively (21). More-
over, the presence of more than eight inflammatory cells
infiltrating the glomeruli seems to strongly increase the
likelihood of malignancy in patients with MN (sensitivity
of 92% and specificity of 75%; Figure 2) (8).
These new findings will have a strong effect on the care
of patients with a diagnosis of MN, who should benefit from
the detection of circulating anti-PLA2R1 antibody and the
study of IgG subclasses and inflammatory cells (Figure 3).

Figure 1. | Mechanisms by which solid tumors and membranous nephropathy (MN) may be linked. MN is defined by subepithelial deposits
that form in the glomerular basement membrane (GBM) beneath the foot processes of the glomerular visceral epithelial cell, or podocyte.
Antibodies may be generated against an antigen identical to, or bearing an epitope similar to, an endogenous podocyte antigen, thereby leading
to in situ immune complex formation (A). Alternatively, shed tumor antigens may form circulating immune complexes that become trapped in
the capillary wall (B). Complexes may initially form in a subendothelial location, dissociate, and reform in a subepithelial position. Tumor
antigens also may, on the basis of size and charge, become planted in a subepithelial location, where they react with circulating antibodies at
a later stage (C). Finally, extrinsic processes, such as infection with an oncogenic virus or altered immune function (D), potentially could cause
both malignancy and MN. From reference 14, with permission.
Clin J Am Soc Nephrol 7: 1701–1712, October, 2012 Glomerular Diseases with Cancer, Cambier and Ronco 1703

Figure 2. | Glomerular diseases occurring during several malignancies and showing membranous nephropathy histologic patterns. Light
microscopy findings in a patient who developed membranous nephropathy in the setting of bronchogenic carcinoma, showing inflammatory
cells infiltrating the glomeruli (A) (Masson trichrome stain) and, by immunofluorescence, typical subepithelial deposits (B) (immunofluores-
cence with anti-g antibody). A second patient followed for chronic lymphocytic leukemia (CLL) developed proliferative GN with nonorganized
monoclonal immunoglobulin deposits defined by immune deposits on the external aspect of the glomerular basement membrane with frequent
mesangial hypertrophy on light microscopy (C) (Masson trichrome stain); the deposits have irregular size (inset of C), have a parietal granular
distribution by immunofluorescence (D) (immunofluorescence with anti-g antibody), and are nonorganized in the subepithelial space on
ultrastructural study (E). The kidney biopsy specimen of another patient with CLL shows atypical membranous nephropathy: note segmental
mesangial and cellular proliferation (F) (Masson trichrome stain). Diffuse granular deposits were found along the capillary walls with pre-
dominant subepithelial location, staining exclusively for IgG and k light chain by immunofluorescence (H) (immunofluorescence with anti-k
antibody on the left panel; in the right, note the absence of deposits with anti-l antibody) and showing microtubular substructure on
ultrastructural studies, as described previously in immunotactoid glomerulopathy (G). Parts C–E from reference 53, with permission. Original
magnifications: A, 31000; B, C, D, and F, 3400; E and G, 320,000; G inset, 350,000; H, 3200.

Search for malignancy is warranted in older patients with
newly diagnosed MN once other secondary causes have
been excluded, especially if there is no anti-PLA2R1 anti-
body and a majority of IgG1 and IgG2 deposits. In addition
to a search for personal and hereditary cancer risk factors,
physical examination, and standard biologic tests, an initial
workup adapted to sex and age should include low-dose
chest computed tomography in heavy smokers, colonos-
copy, prostate-specific antigen testing, and mammography.
If malignancy is not detected on initial screening, these
1704 Clinical Journal of the American Society of Nephrology

Figure 3. | Management of newly diagnosed membranous nephropathy. In patients with anti-PLA2R1 antibody AND predominant IgG4
deposits AND with few or no inflammatory cells in the glomerulus, a diagnosis of cancer related to MN is unlikely. Further investigations could
be stopped except in the presence of cancer risk factors. In patients without anti-PLA2R1 antibody, in those with prevailing IgG1/IgG2 deposits,
or in the presence of more than 8 inflammatory cells per glomeruli, a search for cancer should be performed. PLA2R1, phospholipase A2
receptor 1; MN, membranous nephropathy.

patients should be closely followed because of the long-term
risk for cancer occurrence.
Other Carcinoma-Associated Glomerulopathies
In 1984, Mustonen et al. reported that malignancy was
not uncommon among older patients with IgA nephropa-
thy. Of 26 patients aged 60 or older, 6 (23%) had cancer
compared with none of the 158 patients younger than age
60 (22). Any IgA nephropathy in a patient older than 60
years should prompt a search for a solid tumor, especially
in the respiratory tract, the buccal cavity, and the naso-
pharynx (22). However, this association can be fortuitous
or be strengthened by alcoholism, which is a risk factor for
both hepatopathy-induced IgA nephropathy and cancers
of the upper respiratory tract.
An association between IgA nephropathy and renal cell
carcinoma has also been described. IgA nephropathy was
present in 11 of the 60 kidneys removed by surgery for renal
cell carcinoma; 6 of them showed regression of proteinuria
and hematuria within 2–3 months after surgery (23).
Paraneoplastic Henoch-Schönlein purpura (HSP) should
be suspected when IgA nephropathy is associated with
necrotic skin lesions in the absence of cryoglobulin. Com-
pared with age-matched controls, patients with HSP have
an increased relative risk (5.25) for malignancy (24). Per-
tuiset et al. reviewed 19 cases of suspected malignancy-
associated HSP; 37% of them had a hematologic malignancy
and 63% a solid tumor. In most cases, however, no conclu-
sive evidence showed that HSP was a paraneoplastic syn-
drome (25). In a retrospective review of 250 patients,
Pillebout et al. showed a mortality rate of 26% during a
15-year period of follow-up; cancer was the primary cause,
accounting for 27% of deaths, and there was no correlation
with immunosuppressive treatment. Cancers preferentially
involved the lung (14%) and upper respiratory and diges-
tive tracts (8%) (26).
Several reports suggest an association between rapidly
progressive GN and malignancies, with a prevalence of cancer
between 7% and 9% (27,28). A variety of tumors have been
described (10). Renal cell carcinomas were more common in a
retrospective comparison of 477 patients with granulomatosis
with polyangiitis and 479 patients with rheumatoid arthritis
(odds ratio, 8.73), but the link between renal neoplasia and
granulomatosis with polyangiitis remains unclear (29). The
increased risk for malignancy has been confirmed in a recent
retrospective review of 200 patients with ANCA-associ-
ated vasculitis, demonstrating a significantly increased rela-
tive risk (6.02) compared with age-matched controls (24).
However, tumors occurred up to 512 months after the di-
agnosis of ANCA-associated vasculitis, and thus the para-
neoplastic nature remains uncertain (because cancer could
be a side effect of the cytotoxic treatment).
AA-type amyloidosis is found in approximately 3% of
renal cell carcinomas (30). Of all carcinomas associated with
Clin J Am Soc Nephrol 7: 1701–1712, October, 2012
amyloidosis, 25%–33% are renal cell carcinomas, although
this tumor accounts for only 2%–3% of all carcinomas. The
pathophysiology could involve an excessive production of
IL-6 by renal tumor cells responsible for chronic inflamma-
tion. Remission of the nephrotic syndrome can be achieved
by nephrectomy.
Membranoproliferative GN (MPGN) and minimal-change
disease also occur in patients with carcinoma, although these
lesions are more typical of lymphoproliferative disorders
(10,31). The number of observations is too small to allow us
to conclude that a causal relationship exists between carci-
noma and the renal disease, except for minimal-change dis-
ease and thymoma (32). Two thirds of the patients presented
with minimal-change disease, sometimes occurring later
after curative treatment of thymoma (range, 8–180 months)
and remaining steroid sensitive in most cases.
Hematologic Malignancy-Induced Paraneoplastic
Glomerulopathies
Hodgkin Disease
The prevalence of glomerulopathy in Hodgkin lymphoma
has been studied in two large series comprising 1700 patients,
which showed minimal-change disease in 0.4% and AA
amyloidosis in 0.1% (33,34). Amyloidosis occurred in late,
inflammatory stages of the disease in the absence of an M-
component (35). Its markedly reduced incidence is most
likely attributable to the rapid remission of the hematologic
malignancy induced by modern treatment protocols.
At present, minimal-change disease is the most frequent
paraneoplastic manifestation of classic Hodgkin lymphoma.
The nephrotic syndrome usually appears early, revealing
the lymphoma in about 40% of cases, and displaying a high
frequency of steroid resistance (50%) and cyclosporine re-
sistance (36). Effective treatment of classic Hodgkin lym-
phoma generally induces simultaneous remission of
nephrotic syndrome whatever the therapeutic strategy,
even without corticosteroids. Nephrotic syndrome usually
relapses simultaneously with the hematologic malignancy,
remaining highly responsive to specific treatment for the
cancer. Minimal-change disease can occur at the time of re-
lapse even if it was initially absent, emphasizing the need
to evaluate proteinuria during the follow-up of classic
Hodgkin lymphoma. Between-disease interval can be as
long as 156 months (36). No particular subgroup of patients
with classic Hodgkin lymphoma seems to be at higher risk
for minimal-change disease with respect to age, sex, or dis-
ease stage (except for systemic symptoms and inflammatory
syndrome, which occur more frequently). Minimal-change
disease seems to be more frequent in classic Hodgkin lym-
phoma that exhibits a mixed cellularity and is of the nodular
sclerosing subtype (36,37). The pathogenesis of minimal-
change disease seems to involve a putative circulating factor
secreted by T lymphocytes, leading to cytoskeleton disorga-
nization and heavy proteinuria (38). A new gene named for
c-maf–inducing protein (c-mip) has recently been isolated
(39). During primary nephrotic syndrome, c-mip increases
in the podocytes and turns off podocyte signaling by
preventing the interaction of nephrin with the tyrosine
kinase Fyn, thereby decreasing nephrin phosphorylation.
Moreover, c-mip inhibits interactions between Fyn and
neural Wiskott Aldrich syndrome protein and between
Glomerular Diseases with Cancer, Cambier and Ronco 1705
Nck and nephrin, potentially accounting for cytoskeletal
disorganization and the effacement of foot processes (40).
Audard et al. demonstrated that c-mip was selectively
induced both in podocytes and in Hodgkin and Reed-
Sternberg cells in patients with classic Hodgkin lymphoma–
associated minimal-change disease but not in patients
with isolated classic Hodgkin lymphoma, suggesting its
potential involvement in the pathogenesis of this associa-
tion (Figure 4) (41).
Other glomerulopathies have been associated with clas-
sic Hodgkin lymphoma but remain anecdotal (11,42).
Chronic Lymphocytic Leukemia, Related B Cell
Lymphomas, and Waldenström Macroglobulinemia
B cell hematologic malignancies can be responsible for the
production of small amounts of a monoclonal immunoglob-
ulin whose detection in serum or urine is greatly facilitated by
sensitive techniques, such as immunofixation and immuno-
electrophoresis. However, these tests fail to detect an M-
component in some patients. The newer nephelometric free
light chain immunoassay, which can detect free light chains at
very low concentrations (43), suggests monoclonality through
an increase or decrease in the k-to-l ratio (44) and is useful
for monitoring the activity and response to treatment. An-
other diagnostic approach to monoclonality is the careful
analysis of the biopsy specimen with anti–light chain isotype
antibodies and anti-g heavy-chain subclass antibodies.
The finding of monotypic deposits should lead investiga-
tors to analyze their organization by electron microscopy.
The coexistence of chronic lymphocytic leukemia (CLL)
and nephrotic syndrome was first described by Scott in
1957 (45). The prevalence of nephrotic syndrome in pa-
tients with CLL is 1%–2% (46). The CLL-associated glo-
merulopathies generally fulfill the three criteria of a
paraneoplastic syndrome. First, they often reveal CLL
with a simultaneous diagnosis of both diseases in about
50% of patients. Second, improvement of GN is mainly
due to control of hematologic disease, as shown by the
first series of 13 cases demonstrating remission of the ne-
phrotic syndrome with chlorambucil alone, a drug ordi-
narily not effective in idiopathic MPGN and MN (47).
Third, the link between CLL and GN is the dysproteinemia
produced by the B cell clone, either a cryoglobulin or a
noncryoprecipitating M-component, detected in about half
of patients. Such a high percentage contrasts with its low
incidence in CLL without renal involvement (5%–10%).
The most common lesions are MPGN and MN (11,47).
Several mechanisms may be involved (Table 1). First, MPGN
can be caused by cryoglobulinemia, predominantly a mixed
type II cryoglobulin involving a monoclonal IgM with rheu-
matoid factor activity and polyclonal IgG (49), although type
I cryoglobulin composed of a single monoclonal immuno-
globulin can also be implicated.
Second, monotypic immunoglobulin deposits can occur in
the absence of cryoglobulinemia and complement activation.
Some patients present with features typical of monoclonal
immunoglobulin deposition disease (MIDD; see following
section on plasma cell dyscrasias) first described by Randall
and associates (50), whereas others show an atypical form
of MN or MPGN corresponding to an immunotactoid glo-
merulopathy (Table 1 and Figure 2).
1706 Clinical Journal of the American Society of Nephrology

Figure 4. | Malignancy-induced minimal-change disease: the case of Hodgkin lymphoma. (A) Normal podocyte. The tyrosine kinase Fyn
phosphorylates nephrin and Wiskott Aldrich syndrome protein (WASP), which is required for interactions between Nck and these proteins,
thereby accounting for cytoskeletal organization. Moreover, the phosphorylated nephrin interacts with several kinases, such as Akt, that are
implicated in podocyte survival. (B) Classic Hodgkin lymphoma–associated minimal-change disease. C-mip increases in Hodgkin and Reed-
Sternberg cells and in the podocytes and turns off podocyte signaling by preventing the interaction of nephrin with Fyn, thereby decreasing
nephrin and WASP phosphorylation. Moreover, c-mip inhibits interactions between Fyn and WASP and between Nck and nephrin, potentially
accounting for cytoskeletal disorganization and the effacement of foot processes. uPAR, urokinase-type plasminogen activator receptor.

Table 1. Clinical and pathologic differences among proliferative GN with nonorganized monoclonal immunoglobulin deposits, type I
cryoglobulinemic GN, and immunotactoid glomerulopathy

PGNMID Type I Cryoglobulinemic Immunotactoid

Variable
(%) GN (%) Glomerulopathy (%)

Hypocomplementemia 27 58 33
Serum or urine monoclonal protein 30 76 67
Underlying myeloma Very rare Very rare Very rare
Lymphoma/leukemia Very rare 33 17
Renal insufficiency at presentation 60 76 83
Nephrotic syndrome 53 38 50
Intracapillary monocyte infiltration 1 111 1
Intracapillary protein thrombi No Yes No
Most common IgG subclass IgG3 IgG3 IgG1
Texture of deposits on EM Granular Focal annular-tubular Microtubular with a diameter of
or fibrillar 30–50 nm and hollow centers in
parallel stacks

From reference 48, with permission. 1 and 111 refer to the intensity of monocyte infiltration.

At variance with MIDD, in which the deposits display a with microtubule formation can be found in leukemic lym-
nonorganized granular pattern, deposits in immunotactoid phocytes and glomeruli, as demonstrated by Bridoux et al.
glomerulopathy are organized with a microtubular aspect and (51). These authors proposed the term glomerulonephritis with
are restricted to the glomerulus. Similar organized deposits organized microtubular monoclonal immunoglobulin deposition.
Clin J Am Soc Nephrol 7: 1701–1712, October, 2012
Rare patients have a noncryoglobulinemic proliferative
GN with nonorganized monoclonal immunoglobulin
deposits, a new entity recently described by Nasr et al.
with the acronym PGNMID (Table 1) (48,52). At variance
with MIDD, in which deposits predominate along tubular
basement membranes and cell proliferation is usually mild
or absent, PGNMID is a proliferative GN in which deposits
are confined to the mesangium and the glomerular base-
ment membrane (Figure 2); hence, the term non–Randall-
type proliferative GN is also used for this entity. Although
no case of CLL and related B cell lymphoma was reported
in the first series (48,52), 9 of 26 patients with noncryoglo-
bulinemic GN and monoclonal immunoglobulin deposits
recently reported by Guiard et al. featured an overt hema-
tologic malignancy (53). Among them, one patient had
CLL, two had myeloma, and two had non-Hodgkin lym-
phoma with nonorganized electron-dense deposits fulfill-
ing the definition of PGNMID. Histologic studies
showed a striking correspondence between the localiza-
tion of IgG deposits, defining MPGN or MN histologic
patterns, and the subclass of the monoclonal IgG found
in the deposits, with a predominance of IgG3 in MPGN
and IgG1 in MN. In PGNMID with MPGN pattern, a
monoclonal IgM can also be found (54). Among the 28
patients with monoclonal gammopathy and MPGN re-
ported by Sethi et al. (54), 2 patients showed CLL, 1
showed lymphoplasmacytic lymphoma/Waldenström
macroglobulinemia (WM), 3 showed low-grade B cell
lymphoma, and 6 showed myeloma. The remaining 16
cases featured the characteristics of monoclonal gamm-
opathy of undetermined significance, which, in this con-
text, should instead be called monoclonal gammopathy
with related MPGN (54).
In a third group of patients presenting with various
glomerular lesions and neither cryoglobulin nor mono-
typic glomerular deposits, a clear-cut pathophysiologic link
between CLL and the glomerulopathy could not be estab-
lished (47).
WM-related glomerulonephritides include characteristic
intracapillary deposits of IgM (with or without cryoglobu-
linemia) and AL-amyloidosis (55). Subsequent case reports
described immunotactoid glomerulopathy and nonamyloid
fibrillary glomerulopathy (56,57), cryoglobulinemia-related
GN (58), crescentic GN (59,60), light-chain deposition disease
(LCDD) (61), and MPGN without cryoglobulinemia (62).
The incidence of renal complications of malignant IgM-
secreting proliferation has decreased, mostly because of
Table 2. Pathologic classification of diseases with tissue deposition or precipitation of monoclonal immunoglobulin-related material
Organized
Crystals Fibrillar Microtubular
Myeloma cast AL amyloidosis Cryoglobulinemia
nephropathy kidney
Fanconi syndrome Fibrillary GN Immunotactoid
GN
Other (extrarenal)
Glomerular Diseases with Cancer, Cambier and Ronco 1707
improved treatment of WM, the major cause of those ne-
phropathies. Audard et al. (62), who recently revisited the
disease spectrum, showed that GN with intracapillary
thrombi of IgM, originally described by Morel-Maroger
et al. as Waldenström macroglobulinemic glomerulonephritis
(55), was not specific for WM and suggested that the term
intracapillary monoclonal deposits disease may be more appro-
priate in this context.
Plasma Cell Dyscrasias
Since the first description of immunoglobulin amyloid-
osis by Glenner et al. in 1971 (63), the spectrum of glomer-
ular diseases occurring in patients with plasma cell
dyscrasias has expanded dramatically. On the basis
of the distribution of the deposits, these diseases can be
classified into two categories by electron microscopy
(Table 2).
The most frequent glomerulopathy in plasma cell dys-
crasias is AL-amyloidosis, found in about 5%–11% of pa-
tients with myeloma at autopsy, whereas the prevalence of
LCDD is 3%–5% (64,65). MIDD differs from amyloidosis in
that the granular deposits lack affinity for Congo red and
do not have a fibrillar organization (66).
Myeloma is found in approximately 50% of patients with
LCDD or light- and heavy-chain deposition disease and
in approximately 25% of those with heavy-chain deposition
disease (HCDD). In some patients who presented with
“common” myeloma and normal-sized monoclonal immu-
noglobulin without kidney involvement, LCDD occurred
when the disease relapsed after chemotherapy, together
with immunoglobulin structural abnormalities (67). Because
melphalan may induce immunoglobulin gene mutations, the
disease in these patients might result from the emergence
of a variant clone caused by the alkylating agent. MIDD
occasionally may complicate WM, CLL, and nodal marginal-
zone lymphoma (68). Like AL-amyloidosis, MIDD can
also occur in the absence of a detectable malignant process,
even after prolonged follow-up (.10 years), illustrating that
“paraneoplastic-like glomerulopathies” can occur with be-
nign proliferation. A monoclonal bone marrow plasma cell
population then is easily detectable by immunofluorescence
examination.
The pathogenesis of MIDD involves the kidney deposi-
tion of monoclonal immunoglobulin subunits; however,
in contrast to amyloidosis, deposition induces a dramatic
accumulation of extracellular matrix that is responsible for
glomerular and tubular basement membrane thickening,
Nonorganized (Granular)
Monoclonal immunoglobulin Other
deposition disease
(Randall-type)
Light-chain deposition Non–Randall-type
disease proliferative GN
Light- and heavy- chain Non–Randall-type
deposition disease nonproliferative GN
Heavy-chain deposition IgM capillary thrombi
disease
1708 Clinical Journal of the American Society of Nephrology

Table 3. Light-chain peculiarities associated with amyloidosis and light-chain deposition disease

Variable AL-Amyloidosis Light-Chain Deposition Disease

Predominant isotype l k
Variability subgroup VlVIa VkIVa
Size abnormalities Fragments in urine Short or large light chains
(glysosylation) b
Amino acid residues Acidic Hydrophobic
exposed to solvent
Interaction with Extracellular matrix componentsc —

From reference 11, with permission.

a
All VlVI light chains are amyloidogenic. Not all VkIV light chains induce light-chain deposition disease.
b
Glycosylation correlates with the lack of circulating and urinary light chains by sensitive detection techniques, as observed in about
20% of patients with light-chain deposition disease.
c
Reactivity with extracellular matrix components may be explained by high dimerization constant and antibody-like behavior of the V-domain.

Figure 5. | Interactions between mesangial cells and glomerulopathic light chains and mesangial matrix alterations. Light chain deposition
disease–light chains (LCDD-LCs) interact with surface receptors on cells and are metabolized in the early endosomes. AL-amyloidosis–light
chains (AL-Am-LCs) are endocytosed avidly and processed in the mature lysosomes, resulting in opposing TGFb, extracellular matrix (ECM),
and matrix metalloproteinase (MMP) alterations. MMP secretion and expression are increased by human mesangial cells (HMCs) in AL-
amyloidosis and are decreased in LCDD HMCs. HMCs incubated with LCDD–light chains acquire a well developed rough endoplasmic
reticular system and transform into myofibroblasts, whereas HMCs incubated with amyloidogenic light chains transform into a macrophage
phenotype, acquiring numerous lysosomes and losing their normal smooth muscle features. From reference 70, with permission.

nodular glomerulosclerosis, and interstitial fibrosis. Un- common caveolae-associated receptor and to induce
usual properties of light chains are involved in LCDD and divergent phenotypic transformation of mesangial cells
amyloidosis (Table 3) (66). In LCDD and AL-amyloidosis, in relation to distinct cellular trafficking of LCDD and
light chains are supposed to bind to an as-yet unidentified AL-amyloid light chains, as shown in Figure 5 (69,70). In
Clin J Am Soc Nephrol 7: 1701–1712, October, 2012
Table 4. Comparison of clinical manifestations, renal lesions, and hematologic features in patients with monoclonal immunoglobulin
deposition disease
Characteristic
Male-to-female ratio
Age (range) (yr)
Hypertension (%)
Renal failure (serum creatinine $ 130 mmol/L) (%)
Nephrotic syndromec (%)
Hematuria (%)
Nodular glomerulosclerosis (%)
Multiple myeloma (%)
M-component (blood or urine) (%)
LCDD, light-chain deposition disease; LHCDD, light- and heavy-chain deposition disease; HCDD, heavy-chain deposition disease.
a
Patients are from the series described in references 72–78.
b
Cases are from references 66,76,78–92.
c
Proteinuria $3 g/d.
d
Including two cases with only free k chain.
HCDD, deletion of the first constant domain CH1 is re-
quired for secretion of free heavy chains, which are rapidly
cleared from the circulation by organ deposition (71).
Clinical manifestations of MIDD are summarized in Table
4. In HCDD, the higher prevalence of hypertension, ne-
phrotic syndrome, and hematuria might be explained by
the greater severity of renal lesions. Liver and cardiac in-
volvement occur in approximately 25% of patients with
LCDD and LHCDD, thereby increasing the risk for death
(72). Extrarenal deposits are less common in patients with
HCDD (66).
Treatment is aimed at reducing immunoglobulin produc-
tion (93). The outcome of patients with MIDD has improved,
as recently reported by Nasr et al. (78). This improvement
results from earlier diagnosis and more potent chemothera-
peutic regimens, including stem cell transplantation; stem
cell transplants are now challenged by new drugs, such as
bortezomib (93). Survival from onset of symptoms varies
from 1 month to 10 years. As in other paraneoplastic syn-
dromes, glomerular lesions can regress in patients who un-
dergo complete remission of their hematologic malignancy
(93,94).
AL-amyloidosis has been extensively reviewed in recent
publications (94,95).
Myeloproliferative Neoplasms
Glomerulopathies have occasionally been reported in
patients with myeloproliferative neoplasm (MPN). A first
small series in 1999 showed FSGS and mesangial sclerosis
(96). Said et al. recently reported on a series of 11 patients
with MPN who developed proteinuria and renal insuffi-
ciency (97). Kidney biopsy revealed a peculiar form of
glomerulopathy called MPN-related glomerulopathy, char-
acterized by a combination of mesangial sclerosis and hy-
percellularity, segmental sclerosis, features of chronic
thrombotic microangiopathy, and intracapillary hematopoi-
etic cell infiltration. Most patients (73%) had primary
myelofibrosis, a disease that is less common than polycythe-
mia vera, essential thrombocythemia, and chronic myeloge-
nous leukemia, suggesting that patients with primary
Glomerular Diseases with Cancer, Cambier and Ronco 1709
LCDD/LHCDDa HCDDb
1.6 0.7
57 (22–94) 55 (26–79)
66 91
98 88
32 51
53 85
31–100 94
55 24
85 69d
myelofibrosis are more at risk of developing MPN-related
glomerulopathy. This entity is, however, not considered a
pure paraneoplastic disease because of the presence of he-
matopoietic cell infiltration.
Conclusion
Recent advances have occurred in the understanding of
the pathophysiology of paraneoplastic glomerulopathies.
Although the link with hematologic malignancies is most
often established, the molecular mechanisms of carcinoma-
associated glomerulopathies remain poorly understood.
When the causative disease can be induced in complete
remission owing to the development of more potent chemo-
therapies, the glomerulopathy can usually be cured. That, in
turn, opens up new therapeutic avenues for the so-called
idiopathic glomerular diseases. Paraneoplastic glomerulopa-
thies can thus be considered as models for more common
glomerulopathies, elucidating their mechanisms and facili-
tating improvements in therapy.
Acknowledgments
We thank Patrice Callard, Department of Pathology, Tenon Hos-
pital, for the gift of pathology pictures.
Disclosures
None.
References
1. Puolijoki H, Mustonen J, Pettersson E, Pasternack A, Lahdensuo
A: Proteinuria and haematuria are frequently present in patients
with lung cancer. Nephrol Dial Transplant 4: 947–950, 1989
2. Sawyer N, Wadsworth J, Wijnen M, Gabriel R: Prevalence, con-
centration, and prognostic importance of proteinuria in patients
with malignancies. Br Med J (Clin Res Ed) 296: 1295–1298, 1988
3. Lee JC, Yamauchi H, Hopper J Jr: The association of cancer and
the nephrotic syndrome. Ann Intern Med 64: 41–51, 1966
4. Birkeland SA, Storm HH: Glomerulonephritis and malignancy:
A population-based analysis. Kidney Int 63: 716–721, 2003
5. Jørgensen L, Heuch I, Jenssen T, Jacobsen BK: Association of al-
buminuria and cancer incidence. J Am Soc Nephrol 19:
992–998, 2008
1710 Clinical Journal of the American Society of Nephrology
6. Glassock RJ: The pathogenesis of idiopathic membranous ne-
phropathy: A 50-year odyssey. Am J Kidney Dis 56: 157–167,
2010
7. Burstein DM, Korbet SM, Schwartz MM: Membranous glomer-
ulonephritis and malignancy. Am J Kidney Dis 22: 5–10, 1993
8. Lefaucheur C, Stengel B, Nochy D, Martel P, Hill GS, Jacquot C,
Rossert J; GN-PROGRESS Study Group: Membranous nephrop-
athy and cancer: Epidemiologic evidence and determinants of
high-risk cancer association. Kidney Int 70: 1510–1517, 2006
9. Alpers CE, Cotran RS: Neoplasia and glomerular injury. Kidney
Int 30: 465–473, 1986
10. Bacchetta J, Juillard L, Cochat P, Droz JP: Paraneoplastic
glomerular diseases and malignancies. Crit Rev Oncol Hematol
70: 39–58, 2009
11. Ronco PM: Paraneoplastic glomerulopathies: New insights into
an old entity. Kidney Int 56: 355–377, 1999
12. Eagen JW: Glomerulopathies of neoplasia. Kidney Int 11: 297–
303, 1977
13. Bjørneklett R, Vikse BE, Svarstad E, Aasarød K, Bostad L,
Langmark F, Iversen BM: Long-term risk of cancer in membra-
nous nephropathy patients. Am J Kidney Dis 50: 396–403, 2007
14. Beck LH Jr: Membranous nephropathy and malignancy. Semin
Nephrol 30: 635–644, 2010
15. Beck LH Jr, Bonegio RG, Lambeau G, Beck DM, Powell DW,
Cummins TD, Klein JB, Salant DJ: M-type phospholipase A2 re-
ceptor as target antigen in idiopathic membranous nephropathy.
N Engl J Med 361: 11–21, 2009
16. Hoxha E, Harendza S, Zahner G, Panzer U, Steinmetz O, Fechner
K, Helmchen U, Stahl RA: An immunofluorescence test for
phospholipase-A₂-receptor antibodies and its clinical usefulness
in patients with membranous glomerulonephritis. Nephrol Dial
Transplant 26: 2526–2532, 2011
17. Ronco P, Debiec H: Pathogenesis of membranous nephropathy:
Recent advances and future challenges. Nat Rev Nephrol 8:
203–213, 2012
18. Debiec H, Ronco P: Nephrotic syndrome: A new specific test for
idiopathic membranous nephropathy. Nat Rev Nephrol 7:
496–498, 2011
19. Qin W, Beck LH Jr, Zeng C, Chen Z, Li S, Zuo K, Salant DJ, Liu Z:
Anti-phospholipase A2 receptor antibody in membranous
nephropathy. J Am Soc Nephrol 22: 1137–1143, 2011
20. Ohtani H, Wakui H, Komatsuda A, Okuyama S, Masai R, Maki N,
Kigawa A, Sawada K, Imai H: Distribution of glomerular IgG
subclass deposits in malignancy-associated membranous ne-
phropathy. Nephrol Dial Transplant 19: 574–579, 2004
21. Qu Z, Liu G, Li J, Wu LH, Tan Y, Zheng X, Ao J, Zhao MH: Ab-
sence of glomerular IgG4 deposition in patients with membra-
nous nephropathy may indicate malignancy. Nephrol Dial
Transplant 27: 1931–1937, 2012
22. Mustonen J, Pasternack A, Helin H: IgA mesangial nephropathy
in neoplastic diseases. Contrib Nephrol 40: 283–291, 1984
23. Magyarlaki T, Kiss B, Buzogány I, Fazekas A, Sükösd F, Nagy J:
Renal cell carcinoma and paraneoplastic IgA nephropathy.
Nephron 82: 127–130, 1999
24. Pankhurst T, Savage CO, Gordon C, Harper L: Malignancy is in-
creased in ANCA-associated vasculitis. Rheumatology (Oxford)
43: 1532–1535, 2004
25. Pertuiset E, Lioté F, Launay-Russ E, Kemiche F, Cerf-Payrastre I,
Chesneau AM: Adult Henoch-Schönlein purpura associated with
malignancy. Semin Arthritis Rheum 29: 360–367, 2000
26. Pillebout E, Thervet E, Hill G, Alberti C, Vanhille P, Nochy D:
Henoch-Schönlein Purpura in adults: Outcome and prognostic
factors. J Am Soc Nephrol 13: 1271–1278, 2002
27. Whitworth JA, Morel-Maroger L, Mignon F, Richet G: The sig-
nificance of extracapillary proliferation. Clinicopathological re-
view of 60 patients. Nephron 16: 1–19, 1976
28. Biava CG, Gonwa TA, Naughton JL, Hopper J Jr: Crescentic
glomerulonephritis associated with nonrenal malignancies. Am J
Nephrol 4: 208–214, 1984
29. Tatsis E, Reinhold-Keller E, Steindorf K, Feller AC, Gross WL:
Wegener’s granulomatosis associated with renal cell carcinoma.
Arthritis Rheum 42: 751–756, 1999
30. Vanatta PR, Silva FG, Taylor WE, Costa JC: Renal cell carcinoma
and systemic amyloidosis: demonstration of AA protein and re-
view of the literature. Hum Pathol 14: 195–201, 1983
31. Glassock RJ: Secondary minimal change disease. Nephrol Dial
Transplant 18[Suppl 6]: vi52–vi58, 2003
32. Karras A, de Montpreville V, Fakhouri F, Grünfeld JP, Lesavre P;
Groupe d’Etudes des Néphropathies Associées aux Thymomes:
Renal and thymic pathology in thymoma-associated nephropa-
thy: report of 21 cases and review of the literature. Nephrol Dial
Transplant 20: 1075–1082, 2005
33. Plager J, Stutzman L: Acute nephrotic syndrome as a manifesta-
tion of active Hodgkin’s Disease. Report of four cases and review
of the literature. Am J Med 50: 56–66, 1971
34. Kramer P, Sizoo W, Twiss EE: Nephrotic syndrome in Hodgkin’s
disease. Report of five cases and review of the literature. Neth J
Med 24: 114–119, 1981
35. Franklin EC, Pras M, Levin M, Frangione B: The partial amino acid
sequence of the major low molecular weight component of two
human amyloid fibrils. FEBS Lett 22: 121–123, 1972
36. Audard V, Larousserie F, Grimbert P, Abtahi M, Sotto JJ, Delmer A,
Boue F, Nochy D, Brousse N, Delarue R, Remy P, Ronco P, Sahali
D, Lang P, Hermine O: Minimal change nephrotic syndrome and
classical Hodgkin’s lymphoma: Report of 21 cases and review
of the literature. Kidney Int 69: 2251–2260, 2006
37. Moorthy AV, Zimmerman SW, Burkholder PM: Nephrotic syn-
drome in Hodgkin’s disease. Evidence for pathogenesis alternative
to immune complex deposition. Am J Med 61: 471–477, 1976
38. Shalhoub RJ: Pathogenesis of lipoid nephrosis: A disorder of
T-cell function. Lancet 2: 556–560, 1974
39. Grimbert P, Valanciute A, Audard V, Pawlak A, Le gouvelo S, Lang
P, Niaudet P, Bensman A, Guellaën G, Sahali D: Truncation of C-
mip (Tc-mip), a new proximal signaling protein, induces c-maf
Th2 transcription factor and cytoskeleton reorganization.
J Exp Med 198: 797–807, 2003
40. Zhang SY, Kamal M, Dahan K, Pawlak A, Ory V, Desvaux D,
Audard V, Candelier M, BenMohamed F, Matignon M, Christov
C, Decrouy X, Bernard V, Mangiapan G, Lang P, Guellaën G,
Ronco P, Sahali D: c-mip impairs podocyte proximal signaling
and induces heavy proteinuria. Sci Signal 3: ra39, 2010
41. Audard V, Zhang SY, Copie-Bergman C, Rucker-Martin C, Ory V,
Candelier M, Baia M, Lang P, Pawlak A, Sahali D: Occurrence of
minimal change nephrotic syndrome in classical Hodgkin lym-
phoma is closely related to the induction of c-mip in Hodgkin-Reed
Sternberg cells and podocytes. Blood 115: 3756–3762, 2010
42. Bergmann J, Buchheidt D, Waldherr R, Maywald O, van der
Woude FJ, Hehlmann R, Braun C: IgA nephropathy and Hodg-
kin’s disease: A rare coincidence. Case report and literature re-
view. Am J Kidney Dis 45: e16–e19, 2005
43. Bradwell AR, Carr-Smith HD, Mead GP, Tang LX, Showell PJ,
Drayson MT, Drew R: Highly sensitive, automated immunoassay
for immunoglobulin free light chains in serum and urine. Clin
Chem 47: 673–680, 2001
44. Katzmann JA, Clark RJ, Abraham RS, Bryant S, Lymp JF, Bradwell
AR, Kyle RA: Serum reference intervals and diagnostic ranges for
free kappa and free lambda immunoglobulin light chains: Rela-
tive sensitivity for detection of monoclonal light chains. Clin
Chem 48: 1437–1444, 2002
45. Scott RB: Leukaemia. Lancet 272: 1162–1167, 1957
46. Seney FD Jr, Federgreen WR, Stein H, Kashgarian M: A review of
nephrotic syndrome associated with chronic lymphocytic leu-
kemia. Arch Intern Med 146: 137–141, 1986
47. Moulin B, Ronco PM, Mougenot B, François A, Fillastre JP,
Mignon F: Glomerulonephritis in chronic lymphocytic leukemia
and related B-cell lymphomas. Kidney Int 42: 127–135, 1992
48. Nasr SH, Satoskar A, Markowitz GS, Valeri AM, Appel GB, Stokes
MB, Nadasdy T, D’Agati VD: Proliferative glomerulonephritis with
monoclonal IgG deposits. J Am Soc Nephrol 20: 2055–2064, 2009
49. Brouet JC, Clauvel JP, Danon F, Klein M, Seligmann M: Biologic
and clinical significance of cryoglobulins. A report of 86 cases.
Am J Med 57: 775–788, 1974
50. Randall RE, Williamson WC Jr, Mullinax F, Tung MY, Still WJ:
Manifestations of systemic light chain deposition. Am J Med
60: 293–299, 1976
51. Bridoux F, Hugue V, Coldefy O, Goujon JM, Bauwens M, Sechet
A, Preud’Homme JL, Touchard G: Fibrillary glomerulonephritis
and immunotactoid (microtubular) glomerulopathy are associ-
ated with distinct immunologic features. Kidney Int 62: 1764–
1775, 2002
Clin J Am Soc Nephrol 7: 1701–1712, October, 2012
52. Nasr SH, Markowitz GS, Stokes MB, Seshan SV, Valderrama E,
Appel GB, Aucouturier P, D’Agati VD: Proliferative glomerulone-
phritis with monoclonal IgG deposits: A distinct entity mimicking
immune-complex glomerulonephritis. Kidney Int 65: 85–96, 2004
53. Guiard E, Karras A, Plaisier E, Duong Van Huyen JP, Fakhouri F,
Rougier JP, Noel LH, Callard P, Delahousse M, Ronco P: Patterns
of noncryoglobulinemic glomerulonephritis with monoclonal Ig
deposits: Correlation with IgG subclass and response to ritux-
imab. Clin J Am Soc Nephrol 6: 1609–1616, 2011
54. Sethi S, Zand L, Leung N, Smith RJH, Jevremonic D, Herrmann
SS, Fervenza FC: Membranoproliferative glomerulonephritis
secondary to monoclonal gammopathy. Clin J Am Soc Nephrol
5: 770–782, 2010
55. Morel-Maroger L, Basch A, Danon F, Verroust P, Richet G: Pa-
thology of the kidney in Waldenström’s macroglobulinemia.
Study of sixteen cases. N Engl J Med 283: 123–129, 1970
56. Da’as N, Kleinman Y, Polliack A, Amir G, Ne’eman Z, Kopolovic
J, Bits H, Darmon D: Immunotactoid glomerulopathy with mas-
sive bone marrow deposits in a patient with IgM kappa mono-
clonal gammopathy and hypocomplementemia. Am J Kidney Dis
38: 395–399, 2001
57. Dussol B, Kaplanski G, Daniel L, Brunet P, Pellissier JF, Berland Y:
Simultaneous occurrence of fibrillary glomerulopathy and AL
amyloid. Nephrol Dial Transplant 13: 2630–2632, 1998
58. Tomiyoshi Y, Sakemi T, Yoshikawa Y, Shimokama T, Watanabe T:
Fibrillar crystal structure in essential monoclonal IgM kappa
cryoglobulinemia. Clin Nephrol 49: 325–327, 1998
59. Meyrier A, Simon P, Mignon F, Striker L, Ramée MP: Rapidly
progressive (‘crescentic’) glomerulonephritis and monoclonal
gammapathies. Nephron 38: 156–162, 1984
60. Garcia-Pacheco I, Khan A, Venkat KK: Rapidly progressive glo-
merulonephritis in a patient with Waldenström’s macroglobuli-
nemia. Clin Nephrol 64: 396–399, 2005
61. Nakamoto Y, Imai H, Hamanaka S, Yoshida K, Akihama T, Miura
AB: IgM monoclonal gammopathy accompanied by nodular
glomerulosclerosis, urine-concentrating defect, and hypo-
reninemic hypoaldosteronism. Am J Nephrol 5: 53–58, 1985
62. Audard V, Georges B, Vanhille P, Toly C, Deroure B, Fakhouri F,
Cuvelier R, Belenfant X, Surin B, Aucouturier P, Mougenot B,
Ronco P: Renal lesions associated with IgM-secreting mono-
clonal proliferations: Revisiting the disease spectrum. Clin J Am
Soc Nephrol 3: 1339–1349, 2008
63. Glenner GG, Terry W, Harada M, Isersky C, Page D: Amyloid
fibril proteins: proof of homology with immunoglobulin light
chains by sequence analyses. Science 172: 1150–1151, 1971
64. Iványi B: Frequency of light chain deposition nephropathy rela-
tive to renal amyloidosis and Bence Jones cast nephropathy in a
necropsy study of patients with myeloma. Arch Pathol Lab Med
114: 986–987, 1990
65. Herrera GA, Joseph L, Gu X, Hough A, Barlogie B: Renal path-
ologic spectrum in an autopsy series of patients with plasma cell
dyscrasia. Arch Pathol Lab Med 128: 875–879, 2004
66. Ronco P, Plaisier E, Mougenot B, Aucouturier P: Immunoglobulin
light (heavy)-chain deposition disease: From molecular medicine
to pathophysiology-driven therapy. Clin J Am Soc Nephrol 1:
1342–1350, 2006
67. Ganeval D, Noël LH, Preud’homme JL, Droz D, Grünfeld JP:
Light-chain deposition disease: Its relation with AL-type
amyloidosis. Kidney Int 26: 1–9, 1984
68. Went P, Ascani S, Strøm E, Brorson SH, Musso M, Zinzani PL,
Falini B, Dirnhofer S, Pileri S: Nodal marginal-zone lymphoma
associated with monoclonal light-chain and heavy-chain de-
position disease. Lancet Oncol 5: 381–383, 2004
69. Teng J, Russell WJ, Gu X, Cardelli J, Jones ML, Herrera GA: Dif-
ferent types of glomerulopathic light chains interact with me-
sangial cells using a common receptor but exhibit different
intracellular trafficking patterns. Lab Invest 84: 440–451, 2004
70. Keeling J, Herrera GA: Matrix metalloproteinases and mesangial
remodeling in light chain-related glomerular damage. Kidney Int
68: 1590–1603, 2005
71. Ronco PM, Alyanakian MA, Mougenot B, Aucouturier P: Light
chain deposition disease: A model of glomerulosclerosis defined
at the molecular level. J Am Soc Nephrol 12: 1558–1565, 2001
Glomerular Diseases with Cancer, Cambier and Ronco 1711
72. Droz D, Noel LH, Carnot F, Degos F, Ganeval D, Grunfeld JP:
Liver involvement in nonamyloid light chain deposits disease.
Lab Invest 50: 683–689, 1984
73. Buxbaum JN, Chuba JV, Hellman GC, Solomon A, Gallo GR:
Monoclonal immunoglobulin deposition disease: light chain and
light and heavy chain deposition diseases and their relation to
light chain amyloidosis. Clinical features, immunopathology,
and molecular analysis. Ann Intern Med 112: 455–464, 1990
74. Heilman RL, Velosa JA, Holley KE, Offord KP, Kyle RA: Long-term
follow-up and response to chemotherapy in patients with light-
chain deposition disease. Am J Kidney Dis 20: 34–41, 1992
75. Kambham N, Markowitz GS, Appel GB, Kleiner MJ, Aucouturier
P, D’agati VD: Heavy chain deposition disease: The disease
spectrum. Am J Kidney Dis 33: 954–962, 1999
76. Lin J, Markowitz GS, Valeri AM, Kambham N, Sherman WH,
Appel GB, D’Agati VD: Renal monoclonal immunoglobulin
deposition disease: The disease spectrum. J Am Soc Nephrol
12: 1482–1492, 2001
77. Masai R, Wakui H, Togashi M, Maki N, Ohtani H, Komatsuda A,
Sawada K: Clinicopathological features and prognosis in im-
munoglobulin light and heavy chain deposition disease. Clin
Nephrol 71: 9–20, 2009
78. Nasr SH, Valeri AM, Cornell LD, Fidler ME, Sethi S, D’Agati VD,
Leung N: Renal monoclonal immunoglobulin deposition dis-
ease: A report of 64 patients from a single institution. Clin J Am
Soc Nephrol 7: 231–239, 2012
79. Aucouturier P, Khamlichi AA, Touchard G, Justrabo E, Cogne M,
Chauffert B, Martin F, Preud’homme JL: Brief report: Heavy-chain
deposition disease. N Engl J Med 329: 1389–1393, 1993
80. Katz A, Zent R, Bargman JM: IgG heavy-chain deposition disease.
Mod Pathol 7: 874–878, 1994
81. Yasuda T, Fujita K, Imai H, Morita K, Nakamoto Y, Miura AB:
Gamma-heavy chain deposition disease showing nodular glo-
merulosclerosis. Clin Nephrol 44: 394–399, 1995
82. Herzenberg AM, Lien J, Magil AB: Monoclonal heavy chain
(immunoglobulin G3) deposition disease: Report of a case. Am J
Kidney Dis 28: 128–131, 1996
83. Cheng IK, Ho SK, Chan DT, Ng WK, Chan KW: Crescentic nod-
ular glomerulosclerosis secondary to truncated immunoglobulin
alpha heavy chain deposition. Am J Kidney Dis 28: 283–288,
1996
84. Husby G, Blichfeldt P, Brinch L, Brandtzaeg P, Mellbye OJ,
Sletten K, Stenstad T: Chronic arthritis and g heavy chain disease:
Coincidence or pathogenic link? Scand J Rheumatol 27: 257–
264, 1998
85. Rott T, Vizjak A, Lindic J, Hvala A, Perkovic T, Cernelc P: IgG
heavy-chain deposition disease affecting kidney, skin, and skel-
etal muscle. Nephrol Dial Transplant 13: 1825–1828, 1998
86. Polski JM, Galvin N, Salinas-Madrigal L: Non-amyloid fibrils in
heavy chain deposition disease. Kidney Int 56: 1601–1602, 1999
87. Moulin B, Deret S, Mariette X, Kourilsky O, Imai H, Dupouet L,
Marcellin L, Kolb I, Aucouturier P, Brouet JC, Ronco PM,
Mougenot B: Nodular glomerulosclerosis with deposition of
monoclonal immunoglobulin heavy chains lacking C(H)1. J Am
Soc Nephrol 10: 519–528, 1999
88. Liapis H, Papadakis I, Nakopoulou L: Nodular glomerulo-
sclerosis secondary to m heavy chain deposits. Hum Pathol 31:
122–125, 2000
89. Vedder AC, Weening JJ, Krediet RT: Intracapillary proliferative
glomerulonephritis due to heavy chain deposition disease.
Nephrol Dial Transplant 19: 1302–1304, 2004
90. Soma J, Sato K, Sakuma T, Saito H, Sato H, Sato T, Abbas A,
Aucouturier P: Immunoglobulin gamma3-heavy-chain de-
position disease: Report of a case and relationship with hypo-
complementemia. Am J Kidney Dis 43: E10–E16, 2004
91. Soma J, Tsuchiya Y, Sakuma T, Sato H: Clinical remission and
histopathological resolution of nodular lesions in a patient with
gamma3 heavy-chain deposition disease. Clin Nephrol 69: 383–
386, 2008
92. Oe Y, Nakaya I, Yahata M, Sakuma T, Sato H, Soma J: A case of
g1-heavy chain deposition disease successfully treated with
melphalan and prednisolone therapy. Intern Med 49: 1411–
1415, 2010
1712 Clinical Journal of the American Society of Nephrology

93. lymphoplasmacytic disorders: An update. Semin Nephrol 30:

557–569, 2010
94. Ronco P, Bridoux F, Aucouturier P: Monoclonal gammopathies:
Multiple myeloma, amyloidosis, and related disorders. In: Dis-
eases of the Kidney, edited by Neilson EG, Molitoris B, Coffman T,
Falk R, and Schrier RW, 9th Ed., Philadelphia, Lippincott Williams
& Wilkins, 2012, in press
95. Sanchorawala V: Light-chain (AL) amyloidosis: Diagnosis and
treatment. Clin J Am Soc Nephrol 1: 1331–1341, 2006
96. Au WY, Chan KW, Lui SL, Lam CC, Kwong YL: Focal segmental
glomerulosclerosis and mesangial sclerosis associated with my-
eloproliferative disorders. Am J Kidney Dis 34: 889–893, 1999
97. Said SM, Leung N, Sethi S, Cornell LD, Fidler ME, Grande JP,
Herrmann S, Tefferi A, D’Agati VD, Nasr SH: Myeloproliferative
neoplasms cause glomerulopathy. Kidney Int 80: 753–759, 2011

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