REVIEW

CURRENT
OPINION Spectrum of manifestations of monoclonal
gammopathy-associated renal lesions
Sanjeev Sethi a, Fernando C. Fervenza b, and S. Vincent Rajkumar c

Purpose of review
Monoclonal gammopathies result from an overt malignant process, such as multiple myeloma, or a
premalignant process, such as monoclonal gammopathy of undetermined significance. The kidney is often
affected in the setting of a monoclonal gammopathy. The term ‘monoclonal gammopathy of renal significance
(MGRS)’ was recently introduced to draw attention to renal diseases related to the monoclonal gammopathy.
In this review, we define the pathology of these monoclonal gammopathy-associated kidney diseases.
Recent findings
Renal disease can be caused by deposition of the monoclonal immunoglobulin (direct mechanism) or by
activation of the alternative pathway of complement by the monoclonal immunoglobulin (indirect
mechanism). The deposition of monoclonal immunoglobulin can affect the glomeruli, tubules, and the
interstitium and vessels. The glomerular diseases include proliferative glomerulonephritis with monoclonal
immunoglobulin deposits, immunotactoid glomerulopathy, and, less commonly, fibrillary glomerulonephritis.
Tubular lesions associated with monoclonal immunoglobulin include cast nephropathy and light-chain
proximal tubulopathy. Lesions involving the glomeruli, tubules, interstitium or vessels include amyloidosis
and monoclonal immunoglobulin deposition diseases. Rarely, monoclonal immunoglobulin may also cause
C3 glomerulopathy or atypical hemolytic uremic syndrome by interfering with the regulation of the
alternative pathway of complement.
Summary
Monoclonal gammopathy are associated with a variety of kidney diseases. The monoclonal gammopathy-
associated renal diseases are distinct in their pathogenesis, kidney biopsy findings, clinical presentation,
progression, prognosis, and treatment. The term monoclonal gammopathy of renal significance helps
highlight patients who have renal disease secondary to monoclonal immunoglobulin secreted by a
premalignant or malignant clone, but is not a disease or diagnosis in itself.
Keywords
C3 glomerulonephritis, dense deposit disease, glomerulonephritis, monoclonal gammopathy of renal
significance, monoclonal gammopathy of undetermined significance

INTRODUCTION as multiple myeloma and Waldenström macro-

Monoclonal gammopathies consist of a hetero-
geneous group of disorders characterized by clonal
proliferation of immunoglobulin producing
B-lymphocytes or plasma cell clone [1,2]. In most
patients, the proliferating cells continue to secrete
immunoglobulin, which can be detected in the
blood or the urine as a monoclonal immunoglobu-
lin [monoclonal (M) protein]. The M protein may
consist of a heavy (commonly g, less commonly m,
and rarely a, e, or d chain) and light chain (either k or
l), light chain only, or less commonly, heavy chain
only [3,4].
There is a wide spectrum of monoclonal gammo-
pathies, extending from the premalignant process
called monoclonal gammopathy of undetermined
significance (MGUS) to overt malignancy such
globulinemia. Patients with monoclonal gammo-
pathies may develop symptoms not just because
of malignant transformation, but also because of
idiosyncratic properties of the secreted M protein.
Thus, disorders such as AL amyloidosis (amyloid
a
Division of Anatomic Pathology, Department of Laboratory Medicine and
Pathology, bDivision of Hypertension and Nephrology, Department of
Internal Medicine and cDivision of Hematology, Department of Internal
Medicine, Mayo Clinic, Rochester, Minnesota, USA
Correspondence to Sanjeev Sethi, MD, PhD, Division of Anatomic
Pathology, Department of Laboratory Medicine and Pathology, Mayo
Clinic 200 1st Street SW, Rochester, MN 55905, USA. Tel: +1 507 538
1414; fax: +1 507 284 1875; e-mail: sethi.sanjeev@mayo.edu
Curr Opin Nephrol Hypertens 2016, 25:127–137
DOI:10.1097/MNH.0000000000000201

1062-4821 Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved. www.co-nephrolhypertens.com

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Clinical nephrology
KEY POINTS
 MIg can cause of a number of renal diseases from
direct deposition of the MIg involving the glomeruli,
tubules, interstitium or vessels (direct mechanism).
 Deposition of MIg in the glomeruli can cause a
proliferative glomerulonephritis and immunotactoid
glomerulopathy. Accumulation of the MIg in proximal
tubular epithelial cells can cause light chain proximal
tubulopathy, while accumulation in distal tubules can
result in myeloma cast nephropathy. MIg-amyloidosis
can involve the glomeruli, tubules, interstitium or vessels,
and MIDD involves both the glomeruli and tubules.
 Rarely, MIg may also cause C3 glomerulopathy or
atypical hemolytic uremic syndrome by interfering with
the regulation of the alternative pathway of complement
(indirect mechanism).
 The monoclonal gammopathy-associated renal diseases
are distinct in their pathogenesis, kidney biopsy findings,
clinical presentation, progression, prognosis and
treatment.
 The term MGRS highlights patients who have renal
disease secondary to monoclonal Ig secreted by a
premalignant or malignant clone, but is not a disease or
diagnosis in itself.
light-chain amyloidosis), cryoglobulinemia, and
cold-agglutinin disease may occur without the need
for malignant transformation, primarily because of
the unique disease-producing properties of the indi-
vidual M protein. However, some patients may have
both: malignancy and paraprotein-related manifes-
tation. For example, approximately 10% of patients
have both AL amyloidosis and multiple myeloma.
Similarly, cryoglobulinemia can occur in patients
with immunoglobulin M (IgM) type of MGUS (pre-
malignancy) or in patients with overt Waldenström
macroglobulinemia (malignancy).
The kidney may be affected by a variety of
lesions in the setting of a monoclonal gammopathy.
Different examples of monoclonal gammopathy-
associated renal lesions include: AL or heavy-chain
amyloidosis, proliferative glomerulonephritis with
monoclonal immunoglobulin deposits, immuno-
tactoid glomerulopathy, light-chain proximal
tubulopathy, crystal storing histiocytosis, etc. In
most cases, the renal injury is secondary to the M
protein secreted in the premalignant MGUS stage
(rather than the malignant stages of multiple myel-
oma or Waldenström macroglobulinemia). The
term ‘monoclonal gammopathy of renal sig-
nificance (MGRS)’ has been introduced to indicate
that although the patient has MGUS (and not
malignancy) the renal lesion is nevertheless a
128 www.co-nephrolhypertens.com
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
consequence of the M protein, and thus has major
implications for management and prognosis [5–7].
The term MGRS helps highlight patients who have
renal disease secondary to M protein secreted by a
premalignant clone, but is not a disease or diagnosis
in itself. Monoclonal gammopathy-associated renal
diseases encompassed by the term MGRS are quite
distinct in their pathogenesis, kidney biopsy find-
ings, clinical presentation, progression, prognosis,
and treatment.
In this review, we discuss the pathology and
management of specific monoclonal immuno-
globulin (MIg) associated-renal lesions. Most of
these disorders are characterized by deposition
of the MIg (direct mechanism), whereas in a few
cases the renal lesion is caused by the MIg dys-
regulating the complement pathway (indirect
mechanism) (Fig. 1). In general, the treatment of
monoclonal gammopathy-associated renal lesions is
directed at eliminating the underlying clonal
plasma cell population to decrease or stop the pro-
duction of the offending M protein. This is done
most effectively by using chemotherapy regimens
that have been developed for the treatment of
multiple myeloma and AL amyloidosis.
MONOCLONAL GAMMOPATHY-
ASSOCIATED RENAL LESIONS (DIRECT
MECHANISM)
This group of renal lesions is characterized by the
finding of MIg in the renal lesion. The physiochem-
ical properties and size of MIg is likely responsible
for the type of renal lesion. Thus, deposition of MIg
can result in diseases involving the glomeruli
or tubules, or both. Larger molecular weight MIg
molecules consisting of a heavy and light chain are
unlikely to pass the glomerular capillary wall barrier
resulting in glomerular deposition of the MIg with
ensuing glomerular inflammation (MIg-associated
glomerulonephritis, immunotactoid glomerulop-
athy). On the other hand, low molecular weight
MIg consisting of only light chains are more likely
to pass the glomerular capillary wall barrier resulting
in primarily tubular disease such as cast nephro-
pathy and light-chain-associated proximal tubulo-
pathy. Finally, MIg consisting of light or heavy
chains but linked with other proteins are likely to
cause both glomerular and tubular lesions such as
MIg-amyloidosis (AL and heavy-chain amyloidosis)
and MIg deposition diseases (MIDDs).
MONOCLONAL IMMUNOGLOBULIN-
ASSOCIATED GLOMERULAR LESIONS
Glomerular deposition of MIg results in a prolifer-
ative lesion (i.e., glomerulonephritis). Typically, the
lesions involve deposition of MIg that consists of a
Volume 25  Number 2  March 2016
 Monoclonal gammopathy-associated renal lesions Sethi et al.

(a)
Monoclonal Ig-associated renal lesions
direct mechanism

Glomerular lesions Tubular lesions Glomerular, Others

-Proliferative GN with MIg deposits -Cast nephropathy tubular, vascular - Crystal storing
-Immunotactoid glomerulopathy -Light chain proximal lesions histiocytosis
-Fibrillary glomerulonephritis tubulopathy -Amyloidosis
-Monoclonal Ig
deposition disease

(b)
Indirect mechanism

Glomerular lesions Vascular lesions

-C3 glomerulopathy: dense -Atypical HUS
deposit disease and C3
glomerulonephritis

FIGURE 1. Schematic diagram of monoclonal gammopathy-associated renal lesions. GN, glomerulonephritis; HUS, hemolytic
uremic syndrome; Ig, immunoglobulin.

monoclonal heavy and light chain, for example,
IgM k, immunoglobulin G (IgG) l, etc. The lesions
include proliferative glomerulonephritis with MIg
deposits with or without cryoglobulins, and a pro-
liferative glomerulonephritis where the deposits
have an organized substructure, such as immuno-
tactoid glomerulopathy or fibrillary glomerulo-
nephritis. As the lesion is that of a proliferative
glomerulonephritis, the patients typically present
with hematuria and proteinuria. Hypertension
and impaired kidney function may also be present.
Monoclonal immunoglobulin-associated
proliferative glomerulonephritis, with or
without cryoglobulins
The kidney biopsy shows a membranoproliferative
pattern of injury in most cases (Fig. 2). Less com-
monly, other patterns of proliferative glomerulo-
nephritis can be seen, including mesangial
proliferative, diffuse proliferative, crescentic and
necrotizing, and sclerosing glomerulonephritis
[7,8]. Immunofluorescence studies are crucial to
the diagnosis and show mesangial and capillary
wall MIg deposits. The MIg most often contains
heavy-chain IgG, less commonly IgM, or rarely
IgA, with k or l light-chain restriction. Less com-
monly, only heavy or light chains may be present.
Electron microscopy shows mesangial and subendo-
thelial electron dense deposits, and rarely subepi-
thelial and intramembranous deposits. Glomerular
capillary wall remodeling with double contour
formation is often present. Features that suggest
glomerulonephritis because of MIg-associated cryo-
globulins (type 1 cryoglobulins) include intralumi-
nal periodic acid–Schiff (PAS) positive (hyaline-like)
deposits on light microscopy, intraluminal MIg on
immunofluorescence microscopy, and substruc-
tures (microtubules, fibrillary, and finger prints)
on electron microscopy.
In cases where the heavy chain consists of IgG,
subtyping of the IgG is useful in confirming the
diagnosis. The IgG3 subclass is the most common
subclass. Interestingly, this class of deposits is most
likely to have undetectable circulating MIg by rou-
tine serum and urine electrophoresis studies [9].
In a recent study of MIg-associated membrano-
proliferative glomerulonephritis, 26 of 28 patients
had a positive M-spike on serum electrophoresis,
and 27 of the 28 patients had monoclonal or
biclonal band on serum immunofixation studies.
Furthermore, bone marrow studies revealed a MGUS
in 16 patients, of which two converted to multiple
myeloma, two cases showed chronic lymphocytic
leukemia (CLL), one showed lymphoplasmacytic
lymphoma (LPL)/Waldenström’s macroglobuline-
mia, three showed low-grade B-cell lymphoma not
further classifiable, and six patients showed multiple
myeloma [7].
Clinical presentation: nearly all patients pre-
sented with significant proteinuria, variable degrees
of hematuria, hypertension, and renal insufficiency.
A low serum C3 level was present in 40–50% of
the cases. On the other hand, cryoglobulinemic
glomerulonephritis usually presents as part of a

1062-4821 Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved. www.co-nephrolhypertens.com 129

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Clinical nephrology

(a) (b) (c)

(d) (e) (f)

FIGURE 2. MIg-associated proliferative glomerulonephritis. (a) Light microscopy showing a membranoproliferative pattern of
injury with mesangial and endocapillary hypercellularity, double contours along the capillary walls and lobular accentuation
of glomerular capillary tufts. (b–e) Immunofluorescence studies showing bright granular capillary wall staining for (b) IgG,
(c) k light chains and (e) C3, with negative staining for (d) l light chains. Electron microscopy showing numerous subendothelial
electron dense deposits and double contours along the capillary walls, arrows point to the deposits (a–e, 40; f, 4800).

systemic inflammatory syndrome with arthralgias
or arthritis, palpable purpura, and peripheral neuro-
pathy. Glomerular involvement is usually mani-
fested by active urinary sediment, proteinuria,
nephrotic syndrome, or renal impairment. Hyper-
tension is common and may be severe. Serum levels
of C3 and C4 are typically low because of the acti-
vation of complement by the classic pathway.
Management: there is no standard treatment
for MIg-associated proliferative glomerulonephritis.
In many patients, the condition shows an indolent
course, with mild proteinuria and stable renal
function on conservative treatment. In patients
with progressive proteinuria or deteriorating renal
function, immunosuppressive therapy with the
use of corticosteroids (alone or in combination
with alkylating agents), thalidomide, bortezomib,
mycophenolate mofetil, cyclosporine, and rituxi-
mab have been used in a small number of patients
with variable outcomes. At the present time, treat-
ment decisions are made purely based on clinical
experience. In our practice, if the offending mono-
clonal immunoglobulin detected on renal biopsy is
also detected in serum or urine, or both, we prefer
treatment with bortezomib, cyclophosphamide,
and dexamethasone (VCD) for IgG or IgA M
proteins, and rituximab (anti-CD20 monoclonal
antibody) alone or in combination with cyclophos-
phamide and dexamethasone for IgM monoclonal
proteins. In patients who do not have evidence of a
monoclonal protein on serum and urine studies,
multiple myeloma/Waldenström macroglobuline-
mia type of treatments described above may be
reasonable to consider if after at least 3 months of
therapy with steroids or steroids plus cyclophospha-
mide there is no renal response. In patients with
cryoglobulinemic glomerulonephritis, rituximab,
with or without corticosteroids, is a reasonable
option for initial therapy.
Fibrillary glomerulonephritis
Fibrillary glomerulonephritis is characterized by
proliferative glomerulonephritis on light micro-
scopy, IgG deposits on immunofluorescence micro-
scopy, and mesangial and capillary wall fibrillary
deposits on electron microscopy [10,11]. Light
microscopy typically shows a mesangial prolifera-
tive or membranoproliferative pattern of injury. On
immunofluorescence studies, the fibrils stain for
IgG. In most cases the IgG deposits are polyclonal,
and a recent study showed that only 11% of biopsies
of fibrillary glomerulonephritis stained showed k or
l light-chain restriction on immunofluorescence
studies [12]. Electron microscopy shows randomly
oriented fibrillary deposits in the mesangium and
along the capillary walls; both intramembranous
and subendothelial fibrillary deposits may be
present. The fibrils measure 10–30 nm in diameter

130 www.co-nephrolhypertens.com Volume 25  Number 2  March 2016

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.


and are Congo red negative. Tubular and interstitial
deposits are extremely rare in fibrillary glomerulo-
nephritis [13].
It is important to recognize that a majority of
patients of fibrillary glomerulonephritis do not have
a monoclonal gammopathy. In a recent study of 66
cases of fibrillary glomerulonephritis, monoclonal
IgG deposits with light-chain restriction was noted
in only seven patients, of which six had a corre-
sponding monoclonal gammopathy in circulation.
For comparison, an M spike was detected by serum
electrophoresis/immunofixation studies in 16%
patients with fibrillary glomerulonephritis, com-
pared with 63% in immunotactoid glomerulopathy
[12,14].
Clinical presentation: renal involvement is
typically manifested by proteinuria, mostly neph-
rotic, hematuria, hypertension, and various degrees
of renal insufficiency. Cases presenting as rapidly
progressive glomerulonephritis have also been
described.
Management: Patients with normal kidney
function and low-degree proteinuria should be man-
aged conservatively with angiotensin II blockade,
aiming for blood pressure control and reduction in
proteinuria. Immunosuppressive therapy with glu-
cocorticoids, with or without other agents (e.g.,
cyclophosphamide, mycophenolate mofetil, cyclo-
sporine, melphalan, azathioprine, and rituximab),
has been reported in uncontrolled studies with lim-
ited and inconsistent results. In patients where a
monoclonal immunoglobulin is present treatment
with VCD could be considered.
Immunotactoid glomerulopathy
Immunotactoid glomerulopathy is characterized
by proliferative glomerulonephritis on light micro-
scopy, IgG deposits on immunofluorescence
microscopy, and capillary wall deposits with a
microtubular substructure on electron microscopy
(a) (b)
FIGURE 3. Immunotactoid glomerulopathy. Electron microscopy showing the characteristic findings of electron dense deposits
with a microtubular substructure, the microtubules measure 40.8 nm in diameter, arrows point to the deposits (a, 4200;
b, 24500; c, 46000).
1062-4821 Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
Monoclonal gammopathy-associated renal lesions Sethi et al.
[15,16]. Light microscopy typically shows a mem-
branoproliferative pattern of injury. In most cases,
the IgG deposits are monoclonal with either k or l
light-chain restriction. The characteristic electron
microscopy finding is the microtubular substructure
of the deposits that range from 30–60 nm in
diameter (Fig. 3).
Patients are generally older and often have an
underlying lymphoproliferative disorder. Although
most series have excluded patients with systemic
lupus or cryoglobulinemia, in some series a transient
positive test for serum cryoglobulin has been
reported [11,16,17]. In a recent study of 16 patients,
an M spike was detected in 63% of the patients, and a
hematologic malignancy was present in 38% of cases,
which included CLL, LPL, and rarely myeloma [14].
Clinical presentation: renal manifestations are
similar to patients with fibrillary glomerulonephri-
tis with the exception that presentation as rapidly
progressive glomerular nephritis is uncommon.
Management: the management strategy should
aim at the treatment of the underlying hematologi-
cal process if one is recognized.
Crystal storing histiocytosis/glomerulopathy
Crystal storing histiocytosis is a rare disorder, in
which numerous histiocytes/foam cells containing
MIg are noted in the glomeruli or interstitium. On
light microscopy, the glomeruli show prominent
infiltration by histiocytes that contain eosinophilic
granular cytoplasmic inclusions. The glomeruli may
sometimes also show a membranoproliferative pat-
tern of injury with endocapillary proliferation and
double contour formation; this is related to the
presence of MIg deposits along the capillary walls
(in addition to the MIg in the histiocytes). A CD68
stain is helpful in identifying the histiocytes. Immu-
nofluorescence microscopy shows the MIg within
the glomeruli; MIg with k light-chain restriction
is most common. Electron microscopy shows
(c)
www.co-nephrolhypertens.com 131
Clinical nephrology

histiocytes within in the capillary loops that are
filled with crystals. The reason for the persistence
of crystals of MIg within the histiocytes is not clear.
It is suggested that larger crystal aggregates form
within the histiocytes following ingestion of
smaller-sized light chains that resist proteolysis.
It has been typically described in the setting of
multiple myeloma and lymphoproliferative dis-
orders, and only very rarely in the setting of MGRS
[18–22]. Crystal storing histiocytosis is different
from the crystals noted in light-chain proximal
tubulopathy/Fanconi syndrome in that the crystals
are present within histiocytes and not in the epi-
thelial cells of proximal tubules.
Clinical presentation: renal involvement is
manifested by proteinuria, ranging from nonneph-
rotic to full nephrotic syndrome, accompanied by
renal insufficiency in the majority of cases.
Management: the management strategy should
be aimed at the treatment of the underlying
hematological process.
MONOCLONAL IMMUNOGLOBULIN-
ASSOCIATED TUBULAR LESIONS
Cast nephropathy
Myeloma cast nephropathy is characterized by tub-
ular injury and the presence of casts that are brightly
eosinophilic with hematoxylin and eosin but nega-
tive with PAS stain. The casts are typically present in
the distal tubules and often have ‘fractured’,
‘brittle’, or other geometric shapes, and are sur-
rounded by an inflammatory reaction with mono-
nuclear cells, neutrophils, and sometimes giant
cells [23,24]. Immunofluorescence studies are very
helpful and show that the casts stain intensely for
one of the light chains (k or l light chains) (Fig. 4)
[25].
Myeloma cast nephropathy is the most common
renal lesion associated with multiple myeloma, and
more than 90% of the patients with cast nephrop-
athy have multiple myeloma. Cast nephropathy is
considered a myeloma-defining event, and hence is
incompatible with a diagnosis of MGUS [26].
Clinical presentation: renal involvement may
manifest acutely or as chronic progressive disease,
but hypertension is uncommon. The presence of
monoclonal light chains in the blood or urine is
found in virtually all patients with cast nephrop-
athy. The diagnosis of myeloma should be con-
sidered in any patient with unexplained renal
failure, normal size kidneys, and bland urinary sedi-
ment. Urine dipstick testing may be negative since it
identifies albumin, not light chains. Patients with
suspected cast nephropathy need a renal biopsy for
confirmation of diagnosis. However, if the serum-
free light-chain levels are more than 500 mg/l in a

(a) (b)

(c) (d)

FIGURE 4. Cast nephropathy. (a and b) Light microscopy showing periodic acid–Schiff negative casts with a fractured and
fragmented appearance. The casts are surrounded by an inflammatory reaction. (c and d) Immunofluorescence microscopy
showing that (c) stain brightly for l light chains and (d) are negative for k light chains (a and b, 40; a and d, 20).

132 www.co-nephrolhypertens.com Volume 25  Number 2  March 2016

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

 Monoclonal gammopathy-associated renal lesions Sethi et al.

(a) (b) (c)

(d) (e) (f)

FIGURE 5. Light-chain proximal tubulopathy. (a–c) Immunofluorescence studies showing (a and b) bright staining for k light
chains in proximal tubules and (c) negative staining for l light chains. (d–f) Electron microscopy showing crystals with
geometrical shapes in the proximal tubules, arrows point to crystals (a, 10; b, 40; c, 10; d, 2900; e, 4800;
f, 49000).

patient in whom multiple myeloma/cast nephrop-
athy is suspected, a renal biopsy can be deferred [26].
Management: in addition to the usual renal
supportive measures, including fluids, diuresis, cor-
rection of hypercalcemia, and removal of nephro-
toxic drugs, the mainstay of therapy is the initiation
of effective multiple myeloma therapy as soon as
possible. A bortezomib-based triplet, such as VCD or
bortezomib, thalidomide, dexamethasone (VTD), is
recommended. We also recommend the use of a
high cut-off hemodialysis filter or plasmapheresis
aiming to reduce serum free light chains to less than
500 mg/l [27].
Light-chain proximal tubulopathy
Light-chain proximal tubulopathy (LCPT) is charac-
terized by cytoplasmic inclusions within proximal
tubular cells that stain for k or l light chains [28,29].
The inclusions may be crystalline or noncrystal-
line. The entity of noncrystalline LCPT is still poorly
defined in that the inclusions may signify reabsorp-
tion granules, and may not represent a true patho-
logical entity. Tubules also show degenerative
changes with distention and flattening of the epi-
thelial cells. The glomeruli are essentially normal,
and there are varying degrees of associated tubular
atrophy and interstitial fibrosis present. Immuno-
fluorescence studies show k light-chain restriction
in almost all the LCPT with crystals (Fig. 5), whereas
one-third of the LCPT without crystals shows l
light-chain restriction. In some cases, LCPT may
require antigen retrieval to demonstrate MIg by
immunofluorescence studies [28]. Electron micro-
scopy confirms the presence of crystals that appear
as needle shaped, rectangular to rhomboidal in
shape (Fig. 5). The crystals may be free or maybe
within lysosomes that appear membrane bound.
The noncrystalline cytoplasmic inclusions appear
as cytoplasmic droplets, granules, or vacuoles.
In a recent large series of 46 patients, LCPT was
associated with a MGRS in 46% (of which 4% con-
verted to multiple myeloma), multiple myeloma in
33%, smoldering multiple myeloma in 15%, non-
Hodgkin’s lymphoma in 4% and CLL in 2% of the
patients [28].
Clinical presentation: proteinuria is present in
more than 95% of the patients but full nephrotic
syndrome is unusual, and a majority of patients also
exhibit some degree of renal insufficiency. In many
cases, a Fanconi syndrome, characterized by normo-
glycemic glycosuria, aminoaciduria, and phospha-
turia is the classical presentation. Metabolic acidosis
(proximal renal tubular acidosis), hypophosphate-
mia, and hypouricemia may also be present.
Management: the optimal treatment of patients
with LCPT is unknown. In patients with an under-
lying malignancy, such as myeloma, lymphoma, or
CLL, therapy should be directed to controlling the
malignancy and the monoclonal protein levels. In
patients without an underlying malignancy but

1062-4821 Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved. www.co-nephrolhypertens.com 133

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Clinical nephrology

(a) (b) (c)

(d) (e) (f)

FIGURE 6. Amyloid light-chain (l light chain) amyloidosis. (a) Light microscopy showing acellular mesangial expansion
periodic acid–Schiff negative material. (b) The deposits are Congo red positive and show apple green birefringence under
polarized light. (c and d) Immunofluorescence studies show that the deposits are (c) brightly positive of l light chains and
(d) negative for k light chains. (e and f) Electron microscopy showing amyloid fibrils (e) along the capillary walls forming
spicules and (f) in the mesangium (a, 20; b, 20; c, 40; d, 40; e, 6400; f, 46000).

just MGUS, a decision must first be made if the
underlying LCPT is of a severity adequate to justify
chemotherapy similar to the one outlined for MIg-
associated proliferative glomerulonephritis. More
recently, stem cell transplantation has been tried
in patients with LCPT resulting in stabilization or
improvement in kidney function, indicating the
benefit of aggressive therapy in selected cases.
MONOCLONAL IMMUNOGLOBULIN-
ASSOCIATED GLOMERULAR AND
TUBULAR LESIONS
Amyloid light-chain/amyloid heavy-chain
amyloidosis
Amyloidosis is caused by extracellular deposition of
proteins in an insoluble b-pleated physical confor-
mation. Amyloid deposits are typically character-
ized by finding acellular PAS and silver negative
deposits in the glomeruli, interstitium, or vessel
walls (Fig. 6). The amyloid deposits are identified
based on their apple-green birefringence under a
polarized light microscope on Congo red stains
and the presence of rigid, nonbranching fibrils
7.5–10 nm in diameter on electron microscopy
[30,31]. The most common forms of systemic amy-
loidosis are immunoglobulin AL amyloidosis and
reactive secondary amyloidosis because of chronic
inflammatory diseases (e.g., rheumatoid arthritis
and chronic infections). AL amyloidosis is charac-
terized by the finding of either k or l light chains in
the glomeruli, interstitium, or vessels. Less com-
monly, heavy-chain amyloidosis results from the
deposition of MIg heavy chains, most commonly
g chains, with no staining for other heavy or light
chains. Rarely, both AL plus heavy-chain amyloido-
sis, most commonly IgGl, may be present [32].
Other forms of amyloidoses increasingly diagnosed
include the amyloid derived from leukocyte cell-
derived chemotaxin-2, fibrinogen a-chain, trans-
thyretin, lysozyme, and apolipoproteins [33,34].
Laser microdissection and mass spectrometry has
become a crucial tool in the diagnosis and confir-
mation of many forms of amyloidosis [35,36,37].
Over 95–98% of patients with systemic AL or
heavy-chain amyloidosis will have a detectable M
protein on serum or urine protein immunofixation,
or an abnormal serum free light-chain ratio. In the
small percentage of patients in whom evidence of
a monoclonal process is not apparent on these
studies, a bone marrow biopsy will show evidence
of clonal plasma cells.
Clinical presentation: renal manifestations
include proteinuria and nephrotic syndrome, but
hematuria is uncommon. Renal insufficiency is
common but hypertension is unusual. Typically,
the kidneys appear large on renal ultrasound.

134 www.co-nephrolhypertens.com Volume 25  Number 2  March 2016

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

 Monoclonal gammopathy-associated renal lesions Sethi et al.

Management: AL or heavy-chain amyloidosis is cases, but a membranoproliferative and mesangial

treated with a triplet regiment such as VCD with a
goal of reducing serum free light chains to less than
40 mg/l. Patients who are candidates for autologous
stem cell transplantation can be considered for the
procedure in centers with adequate expertise.
Recently, treatments that prevent deposition of
the offending FLC’s in organs are also being studied
[38].
Monoclonal immunoglobulin deposition
disease
MIDD is characterized by the deposition of MIg
along the glomerular and tubular basement mem-
branes. MIDD is classified into light-chain depo-
sition disease (LCDD) when the deposits are
composed of light chains only, heavy-chain depo-
sition disease (HCDD) when the deposits are com-
posed of heavy chains only and light and HCDD
when the deposits are composed of both light and
heavy chains. LCDD is the most common; the
deposits are most commonly composed of k light
chains. On the other hand, the deposits of HCDD
are typically composed of g chain, and rarely a and m
chains, and often lack the C (H)1 domain [39–44].
Recently, HCDD was described based on laser micro-
dissection and mass spectrometry [45]. Light micro-
scopy shows a nodular sclerosing lesion in many
proliferative pattern of injury is also common, and
rarely crescents may be present. Importantly, the
glomerular and tubular basement membranes are
thickened. Immunofluorescence microscopy is
characteristic and shows diffuse linear staining of
the heavy or light chain, or both, depending on the
type of MIDD. Electron microscopy is characteristic
and shows punctate granular deposits in mesan-
gium and along the glomerular and tubular base-
ment membranes (Fig. 7).
A recent study of 64 patients with MIDD showed
that 97% of the patients had an underlying mono-
clonal gammopathy, and 59% of the patients had
multiple myeloma, whereas one patient had a LPL
[41]. In another study of 34 patients of MIDD, 39%
of the patients had multiple myeloma and 39%
were diagnosed with MGUS [42]. In approximately
10% of the patients no hematological abnormality
is detected.
Clinical presentation: renal involvement in
LCDD most commonly presents as proteinuria,
nephrotic syndrome, and renal insufficiency. The
presence of hematuria and hypertension is variable.
Monoclonal free light chains and albumin are the
main proteins found in the urine but the amount of
excreted light chains is usually lower than in
patients with cast nephropathy, and MIg deposits

(a) (b)

(c) (d)

FIGURE 7. Light-chain (k) deposition disease. (a) Light microscopy showing mesangial expansion periodic acid–Schiff positive
material forming mesangial nodules. (b and c) Immunofluorescence studies showing (b) bright staining for k light chains and
(c) negative for l light chains along the tubular basement membranes. (d) Electron microscopy showing fine granular electron
dense deposits along the tubular basement membranes (a, 40; b, 10; c, 20; d, 7400).

1062-4821 Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved. www.co-nephrolhypertens.com 135

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Clinical nephrology
in other organs may result in a myriad of associated
clinical symptoms.
Management: in patients with MIDD and end-
stage renal disease, no specific therapy is needed if
evidence of concomitant disorder such as multiple
myeloma or AL or heavy-chain amyloidosis is
not present. However, if patients present with neph-
rotic syndrome or progressive renal dysfunction,
then therapy similar to that used to treat multiple
myeloma should be considered. This includes a
bortezomib-based triplet such as VCD, as well as
consideration for autologous stem cell transplant
in eligible patients.
MONOCLONAL GAMMOPATHY-
ASSOCIATED RENAL LESIONS
(INDIRECT MECHANISM)
Monoclonal gammopathy-associated C3
glomerulopathy
C3 glomerulopathy is a rare disease that results from
dysregulation of the alternative pathway of comp-
lement, and is characterized by glomerular depo-
sition of C3 and other complement proteins. C3
glomerulopathy includes C3 glomerulonephritis
(C3GN) and dense deposit disease (DDD). C3GN
is characterized by mesangial and subendothelial,
and occasionally intramembranous and subepithe-
lial electron dense deposits, whereas DDD is charac-
terized by dense mesangial and intramembranous
deposits on electron microscopy [46–49]. Dysregu-
lation of the alternative pathway of complement
may be ‘de novo’, that is, resulting from mutations in
complement regulating proteins, or may be secon-
dary (acquired), that is resulting from insults that
cause over activation of the alternative pathway of
complement [50].
Monoclonal proteins may inhibit regulation of
the alternative pathway of complement by interfer-
ing with the function of complement regulating
proteins such as factor H (functional inhibition),
acting as mini autoantibody to the complement
factor H (direct inhibition), or as an autoantibody
to complement factor B that is component of C3
convertase (C3 nephritic factory-C3NeF), thereby
increasing the half-life of the C3 convertase, all of
which may result in the over activation of the
alternative pathway of complement [51–53], result-
ing in DDD or C3GN, or rarely atypical hemolytic
uremic syndrome [54].
In a recent study, of 14 patients with DDD
49 years and older, 10 (71.4%) had a concomitant
diagnosis of MGUS [55,56]. Similarly, in a study of
32 cases of C3GN, 10 patients (31.3%) had evidence
of a MIg in the serum [56,57].
136 www.co-nephrolhypertens.com
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
Clinical presentation: hematuria and proteinu-
ria with or without renal impairment. In some
patients proteinuria can be severe resulting in a full
nephrotic syndrome. Serum C3 complement (rarely
C4) levels can be low.
Management: as in for patients with MIg-associ-
ated proliferative glomerulonephritis, there is no
standard treatment. In many cases the condition
remains indolent with mild proteinuria and stable
renal function on conservative therapy. In cases
with progressive proteinuria or deteriorating renal
function immunosuppressive therapy, we prefer
treatment with VCD in patients who have IgG or
IgA monoclonal protein, and rituximab (anti-CD20
monoclonal antibody) alone or in combination
with cyclophosphamide and dexamethasone for
IgM monoclonal proteins. Data are limited on the
treatment of these patients with the multiple myel-
oma/Waldenström macroglobulinemia type of
treatments described above. Thus, it may be reason-
able to consider them if after at least 3 months of
therapy with steroids or steroids plus cyclophos-
phamide there is a failure to produce a renal
response.
CONCLUSION
To summarize, MIg can cause a variety of renal
diseases resulting from the direct renal deposition
of the MIg, and rarely from an indirect mechanism
via dysregulation of the alternative pathway of
complement. The monoclonal gammopathy-associ-
ated renal diseases are distinct in their pathogenesis,
kidney biopsy findings, clinical presentation, pro-
gression, prognosis, and treatment. A thorough and
complete evaluation of the MIg-associated renal
disease needs to be performed to appropriately man-
age these patients.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
REFERENCES
1. Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis in
monoclonal gammopathy of undetermined significance. N Engl J Med 2002;
346:564–569.
2. Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and
response assessment of multiple myeloma. Leukemia 2008; 23:3–9.
3. Rajkumar SV, Kyle RA, Therneau TM, et al. Serum free light chain ratio is
an independent risk factor for progression in monoclonal gammopathy of
undetermined significance. Blood 2005; 106:812–817.
Volume 25  Number 2  March 2016

4. Dispenzieri A, Katzmann JA, Kyle RA, et al. Prevalence and risk of progression
of light-chain monoclonal gammopathy of undetermined significance: a retro-
spective population-based cohort study. Lancet 2010; 375:1721–1728.
5. Fermand J-P, Bridoux F, Kyle RA, et al. How I treat monoclonal gammopathy of
renal significance (MGRS). Blood 2013; 122:3583–3590.
6. Bridoux F, Leung N, Hutchison CA, et al. Diagnosis of monoclonal gammo-
pathy of renal significance. Kidney Int 2015; 87:698–711.
7. Sethi S, Zand L, Leung N, et al. Membranoproliferative glomerulonephritis
secondary to monoclonal gammopathy. Clin J Am Soc Nephrol 2010; 5:770–
782.
8. Nasr SH, Satoskar A, Markowitz GS, et al. Proliferative glomerulonephritis
with monoclonal IgG deposits. J Am Soc Nephrol 2009; 20:2055–2064.
9. Bhutani G, Nasr SH, Said SM, et al. Hematologic characteristics of prolif-
erative glomerulonephritides with nonorganized monoclonal immunoglobulin
deposits. Mayo Clin Proc 2015; 90:587–596.
10. Alpers CE, Kowalewska J. Fibrillary glomerulonephritis and immunotactoid
glomerulopathy. J Am Soc Nephrol 2008; 19:34–37.
11. Fogo A, Qureshi N, Horn R. Morphologic and clinical features of fibrillary
glomerulonephritis versus immunotactoid glomerulopathy. Am J Kidney Dis
1993; 22:367–377.
12. Nasr SH, Valeri AM, Cornell LD, et al. Fibrillary glomerulonephritis: a report
of 66 cases from a single institution. Clin J Am Soc Nephrol 2011; 6:775–
784.
13. Adeyi OA, Sethi S, Rennke HG. Fibrillary glomerulonephritis: a report of
2 cases with extensive glomerular and tubular deposits. Human Pathol 2001;
32:660–663.
14. Nasr SH, Fidler ME, Cornell LD, et al. Immunotactoid glomerulopathy:
clinicopathologic and proteomic study. Nephrology Dial Transplant 2012;
27:4137–4146.
15. Schwartz MM, Korbet SM, Lewis EJ. Immunotactoid Glomerulopathy. J Am
Soc Nephrol 2002; 13:1390–1397.
16. Rosenstock JL, Markowitz GS, Valeri AM, et al. Fibrillary and immunotactoid
glomerulonephritis: distinct entities with different clinical and pathologic
features. Kidney Int 2003; 63:1450–1461.
17. Bridoux F, Hugue V, Coldefy O, et al. Fibrillary glomerulonephritis and
immunotactoid (microtubular) glomerulopathy are associated with distinct
immunologic features. Kidney Int 2002; 62:1764–1775.
18. Jones D, Bhatia VK, Krausz T, et al. Crystal storing histiocytosis: a disorder
occurring in plasmacytic tumors expressing immunoglobulin kappa light
chain. Human Pathol 1999; 30:1441–1448.
19. Sethi S, Cuiffo B, Pinkus G, et al. Crystal-storing histiocytosis involving the
kidney in a low-grade B-cell lymphoproliferative disorder. Am J Kidney Dis
2002; 39:183–188.
20. Yamamoto T, Hishida A, Honda N, et al. Crystal-storing histiocytes and
crystalline tissue deposition in multiple myeloma. Arch Pathol Lab Med
1991; 115:351–354.
21. Stokes MB, Aronoff B, Siegel D, et al. Dysproteinemia-related nephropathy
associated with crystal-storing histiocytosis. Kidney Int 2006; 70:597–602.
22. Vankalakunti M, Bonu R, Shetty S, et al. Crystalloid glomerulopathy in
monoclonal gammopathy of renal significance (MGRS). Clin Kidney J
2014; 7:296–298.
23. Cohen A. The kidney in plasma cell dyscrasias: Bence-Jones cast nephro-
pathy and light chain deposit disease. Am J Kidney Dis 1998; 32:529–
532.
24. Nasr SH, Valeri AM, Sethi S, et al. Clinicopathologic correlations in multiple
myeloma: a case series of 190 patients with kidney biopsies. Am J Kidney Dis
2012; 59:786–794.
25. Markowitz GS. Dysproteinemia and the Kidney. Adv Anat Pathol 2004;
11:49–63.
26. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma
Working Group updated criteria for the diagnosis of multiple myeloma. Lancet
Oncol 2014; 15:e538–e548.
27. Rajkumar SV. Multiple myeloma: 2013 update on diagnosis, risk-stratification,
and management. Am J Hematol 2013; 88:225–235.
28. Stokes MB, Valeri AM, Herlitz L, et al. Light chain proximal tubulopathy: clinical
and pathologic characteristics in the modern treatment era. J Am Soc Nephrol
2015; doi: 10.1681/ASN.2015020185. [Epub ahead of print]
29. Larsen CP, Bell JM, Harris AA, et al. The morphologic spectrum and clinical
significance of light chain proximal tubulopathy with and without crystal
formation. Mod Pathol 2011; 24:1462–1469.
30. Dember LM. Amyloidosis-associated kidney disease. J Am Soc Nephrol
2006; 17:3458–3471.
1062-4821 Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
Monoclonal gammopathy-associated renal lesions Sethi et al.
31. Merlini G, Bellotti V. Molecular mechanisms of amyloidosis. N Engl J Med
2003; 349:583–596.
32. Said SM, Sethi S, Valeri AM, et al. Renal amyloidosis: origin and clinico-
pathologic correlations of 474 recent cases. Clin J Am Soc Nephrol 2013;
8:1515–1523.
33. Gillmore JD, Lachmann HJ, Rowczenio D, et al. Diagnosis, pathogenesis,
treatment, and prognosis of hereditary fibrinogen A{alpha}-chain amyloidosis.
J Am Soc Nephrol 2009; 20:444–451.
34. Lachmann HJ, Booth DR, Booth SE, et al. Misdiagnosis of hereditary amy-
loidosis as AL (primary) amyloidosis. N Engl J Med 2002; 346:1786–1791.
35. Sethi S, Vrana JA, Theis JD, et al. Laser microdissection and mass spectro-
metry-based proteomics aids the diagnosis and typing of renal amyloidosis.
Kidney Int 2012; 82:226–234.
36. Leung N, Nasr SH, Sethi S. How I treat amyloidosis: the importance of
accurate diagnosis and amyloid typing. Blood 2012; 120:3206–3213.
37. Sethi S, Theis JD, Leung N, et al. Mass spectrometry based proteomic
diagnosis of renal immunoglobulin heavy chain amyloidosis. Clin J Am Soc
Nephrol 2010; 5:2180–2187.
38. Gertz MA. Immunoglobulin light chain amyloidosis: 2014 update on diag-
nosis, prognosis, and treatment. Am J Hematol 2014; 89:1132–1140.
39. Kambham N, Markowitz GS, Appel GB, et al. Heavy chain deposition disease:
the disease spectrum. Am J Kid Dis 1999; 33:954–962.
40. Moulin B, Deret S, Mariette X, et al. Nodular glomerulosclerosis with deposi-
tion of monoclonal immunoglobulin heavy chains lacking CH1. J Am Soc
Nephrol 1999; 10:519–528.
41. Nasr SH, Valeri AM, Cornell LD, et al. Renal monoclonal immunoglobulin
deposition disease: a report of 64 patients from a single institution. Clin J Am
Soc Nephrol 2012; 7:231–239.
42. Lin J, Markowitz GS, Valeri AM, et al. Renal monoclonal immunoglobulin
deposition disease: the disease spectrum. J Am Soc Nephrol 2001;
12:1482–1492.
43. Alexander MP, Nasr SH, Watson DC, et al. Renal crescentic alpha heavy
chain deposition disease: a report of 3 cases and review of the literature. Am J
Kidney Dis 2011; 58:621–625.
44. Herrera GA. Renal lesions associated with plasma cell dyscrasias: practical
approach to diagnosis, new concepts, and challenges. Arch Pathol Lab Med
2009; 133:249–267.
45. Royal V, Quint P, Leblanc M, et al. IgD heavy-chain deposition disease:
detection by laser microdissection and mass spectrometry. J Am Soc Nephrol
2015; 26:784–790.
46. Servais A, Fremeaux-Bacchi V, Lequintrec M, et al. Primary glomerulonephritis
with isolated C3 deposits: a new entity which shares common genetic risk
factors with haemolytic uraemic syndrome. J Med Genet 2007; 44:193–199.
47. Sethi S, Fervenza FC, Zhang Y, et al. C3 glomerulonephritis: clinicopatho-
logical findings, complement abnormalities, glomerular proteomic profile,
treatment, and follow-up. Kidney Int 2012; 82:465–473.
48. Sethi S, Fervenza FC, Zhang Y, et al. Proliferative glomerulonephritis
secondary to dysfunction of the alternative pathway of complement. Clin J
Am Soc Nephrol 2011; 6:1009–1017.
49. Pickering MC, D’Agati VD, Nester CM, et al. C3 glomerulopathy: consensus
report. Kidney Int 2013; 84:1079–1089.
50. Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis: a new look
at an old entity. N Engl J Med 2012; 366:1119–1131.
51. Sethi S, Rajkumar SV. Monoclonal gammopathy: associated proliferative
glomerulonephritis. Mayo Clinic Proc 2013; 88:1284–1293.
52. Jokiranta T, Solomon A, Pangburn M, et al. Nephritogenic lambda light chain
dimer: a unique human miniautoantibody against complement factor H.
J Immunol 1999; 163:4590–4596.
53. Meri S, Koistinen V, Miettinen A, et al. Activation of the alternative pathway of
complement by monoclonal lambda light chains in membranoproliferative
glomerulonephritis. J Exp Med 1992; 175:939–950.
54. Cheungpasitporn W, Leung N, Sethi S, et al. Refractory atypical hemolytic
uremic syndrome with monoclonal gammopathy responsive to bortezomib-
based therapy. Clin Nephrol 2015; 83:363–369.
55. Sethi S, Sukov WR, Zhang Y, et al. Dense deposit disease associated with
monoclonal gammopathy of undetermined significance. Am J Kidney Dis
2010; 56:977–982.
56. Bridoux F, Desport E, Frémeaux-Bacchi V, et al. Glomerulonephritis with
isolated C3 deposits and monoclonal gammopathy: a fortuitous association?
Clin J Am Soc Nephrol 2011; 6:2165–2174.
57. Zand L, Kattah A, Fervenza FC, et al. C3 glomerulonephritis associated with
monoclonal gammopathy: a case series. Am J Kid Dis 2013; 62:506–514.
www.co-nephrolhypertens.com 137