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Monoclonal gammopathy of renal significance (MGRS) Kidney International (2015) 87, 698–711; doi:10.1038/ki.2014.408;
regroups all renal disorders caused by a monoclonal published online 21 January 2015
immunoglobulin (MIg) secreted by a nonmalignant B-cell
clone. By definition, patients with MGRS do not meet the
criteria for overt multiple myeloma/B-cell proliferation, and Kidney disease is a frequent complication of monoclonal
the hematologic disorder is generally consistent with gammopathies that manifests with a wide range of renal
monoclonal gammopathy of undetermined significance lesions. These patterns are mostly determined by the physico-
(MGUS). However, MGRS is associated with high morbidity chemical characteristics of the pathogenic monoclonal
due to the severity of renal and sometimes systemic lesions immunoglobulin (MIg).1 The renal disease may complicate
induced by the MIg. Early recognition is crucial, as a previously diagnosed clonal B-cell disorder or be the initial
suppression of MIg secretion by chemotherapy often manifestation of the hematological disease. Two main
improves outcomes. The spectrum of renal diseases in MGRS categories of renal disorders associated with monoclonal
is wide, including old entities such as AL amyloidosis and gammopathies should be distinguished, depending on the
newly described lesions, particularly proliferative burden of the underlying plasma cell or B-cell clone. The first
glomerulonephritis with monoclonal Ig deposits and C3 group of renal disorders requires the secretion of large
glomerulopathy with monoclonal gammopathy. Kidney amounts of all or part of the MIg and is only observed in the
biopsy is indicated in most cases to determine the exact setting of a high tumor mass B-cell proliferation. This is
lesion associated with MGRS and evaluate its severity. typically illustrated by the massive precipitation of light chain
Diagnosis requires integration of morphologic alterations by (LC) in the lumen of distal tubules, which characterizes light-
light microscopy, immunofluorescence (IF), electron chain cast nephropathy, the most common cause of acute
microscopy, and in some cases by IF staining for Ig isotypes, kidney injury in multiple myeloma (MM). Light-chain cast
immunoelectron microscopy, and proteomic analysis. nephropathy is considered as a MM defining event because it
Complete hematologic workup with serum and urine protein always forms as the result of high monoclonal LC production,
electrophoresis, immunofixation, and serum-free light-chain indicating a high tumor burden, a situation that requires
assay is required. This review addresses the pathologic and urgent introduction of chemotherapy.2,3 Although rare,
clinical features of MGRS lesions, indications of renal biopsy, another example is glomerular intracapillary deposition of
and a proposed algorithm for the hematologic workup. MIgM to form thrombi in high tumor mass Waldenström’s
macroglobulinemia.4
The other group is renal diseases associated with low-
Correspondence: Nelson Leung, Division of Nephrology and Hypertension,
grade lymphoproliferative disorders. Although they may
Mayo Clinic, 200 First Street, Rochester, Minnesota 55905, USA. occur during symptomatic B-cell proliferations, these other
E-mail: leung.nelson@mayo.edu MIg-related renal lesions are mainly encountered in patients
Received 28 February 2014; revised 17 July 2014; accepted 24 July 2014; with a small B-cell clone and low malignant potential.5 Only
published online 21 January 2015 8% of patients with immunoglobulin light-chain (AL)
amyloidosis6 and 20% of patients with Randall-type ditions can be formulated without conflict with the current
monoclonal Ig deposition disease (MIDD)7 have evidence MM treatment guidelines. It should be noted that cytotoxic
of a symptomatic MM at diagnosis. This clone can be therapy including stem cell transplantation has been used in
expressed as any indolent B-cell lymphoid disorder, including AL amyloidosis in which the majority of patients do not meet
the so-called ‘smoldering’ asymptomatic MM and low-grade the criteria for symptomatic MM.11 Hence, this is one of the
lymphoplasmacytic lymphoma with Waldenström’s macro- first examples of successful treatment of a MGRS-related
globulinemia, or a monoclonal gammopathy of undeter- kidney disease. The treatment strategy of MGRS is based on
mined significance (MGUS). In this setting, structural chemotherapy that should be adapted to the nature of the
peculiarities of the MIg, particularly the variable domain, underlying clone, either lymphocytic or plasmacytic, to
and not the rate of production, are the main determinants of renal function and to the presence or not of extrarenal
renal lesions. The nonmalignant nature of these clones has involvement.12 Rapid suppression of the secretion of
been a source of confusion for clinicians when it comes to nephrotoxic MIg has been shown to favorably impact renal
treatment. Because many of these clones are best classified as and patient survival in most diseases associated with
MGUS, defined as a plasma cell proliferative disorder that MGRS, including AL amyloidosis, light-chain deposition
manifests o3 g/dl of monoclonal protein and o10% bone disease (LCDD), immunotactoid glomerulopathy, and proli-
marrow plasma cells, or smoldering MM, defined by 43 g/dl ferative glomerulonephritis with monoclonal Ig deposits
of monoclonal protein and/or 410% bone marrow plasma (PGNMID).13–16 In AL amyloidosis, renal response is closely
cells but without any end organ damage, chemotherapy is associated with the magnitude of hematological response, as
not indicated in patients with MGUS, smoldering MM, or renal response rate is significantly higher in patients who
low-grade lymphomas.8 According to the current treatment have achieved a serum-free light-chain (FLC) response of
guidelines, these patients require only clinical and biological more than 90%.17 Finally, in the absence of an efficient
surveillance as they may remain asymptomatic over a suppression of the nephrotoxic MIg, MGRS-related renal
prolonged period of time, and early therapy has not been lesions recur in the allograft in most patients, usually within
shown to be beneficial in the majority of patients. the first year after renal transplantation.18–22
Chemotherapy is only introduced when symptoms related to In addition to AL amyloidosis, the spectrum of MGRS
the underlying lymphocytic or plasmacytic proliferative process includes various other renal lesions. Most are due to
develop or are impending. Symptomatic MM is defined by deposition of a MIg fragment with distinct localization and
evidence of end organ damage, characterized by CRAB pattern of ultrastructural organization, usually resulting in
(hyperCalcemia, Renal impairment, Anemia, Bone disease). glomerular disorders but more rarely in tubular disorders
On the basis of the current guidelines, cytotoxic therapy is such as the Fanconi syndrome (FS). Glomerulopathies are
often withheld in patients with renal diseases associated with featured either by organized deposits, fibrillar (AL and Ig
MIg who do not meet the criteria for MM or symptomatic heavy chains (AH) amyloidosis) or microtubular (type I
lymphoma.9 Such an approach is not appropriate for these cryoglobulinemic glomerulonephritis, immunotactoid glo-
patients, as despite the absence of high tumor burden, they merulopathy), or by non-organized deposits (MIDD and
display high morbidity and even increased mortality. In an PGNMID). Importantly, our understanding of the spectrum
effort to address this need, the International Kidney and of MGRS is evolving, and, in addition to kidney deposition of
Monoclonal Gammopathy Research Group (IKMG) had their a MIg, other mechanisms may be implicated, involving the
inaugural meeting in Bath, UK, in 2009. Members of the secretion of various biological factors and/or autoantibody
IKMG come from the disciplines of nephrology, hematology, activity of the MIg. Examples include secretion of vascular
and nephropathology and from countries around the globe endothelial growth factor in the POEMS syndrome (poly-
including Austria, Australia, Canada, France, Italy, New neuropathy, organomegaly, endocrinopathy, monoclonal
Zealand, Spain, United Kingdom, and United States. Through gammopathy, and skin changes) that may trigger development
a series of subsequent meetings, the term monoclonal of renal endothelial cell injury and thrombotic microangio-
gammopathy of renal significance (MGRS) was refined and pathy-like lesions,23 membranoproliferative glomerulonephritis
introduced in 2012 to distinguish these monoclonal induced by dimeric monoclonal lambda LC acting as a ‘mini-
gammopathies from MGUS.10 The main goal was to clearly autoantibody’ against complement factor H,24,25 or mem-
delineate the benign hematological disorder MGUS, which branous nephropathy caused by a monoclonal IgG3 kappa
cannot be associated with any end organ damage, from MGRS targeting the phospholipase A2 receptor.26 Early recognition and
that is associated with severe consequences related to MIg prompt characterization of the type of MGRS is crucial, as it
deposition in the kidneys (and sometimes in other organs) determines the therapeutic strategy and strongly impacts renal
that considerably increase morbidity and may even impair prognosis.12 The purpose of this article is to provide keys for the
patient survival. It is important to recognize that like MGUS, diagnostic approach to recognize MGRS.
the diagnosis of MGRS does not exclude the possibility of
future hematologic disease progression. INDICATIONS AND TIMING OF KIDNEY BIOPSY
With its clear distinction from the ‘benign’ term of In a patient in whom MGRS is suspected, usually based on
MGUS, treatment strategies for MGRS-related kidney con- the coexistence of monoclonal gammopathy and renal
symptoms, it is essential to quickly and accurately assess the patients with glomerular involvement who display predomi-
characteristics of the monoclonal gammopathy, the under- nant albuminuria (usually accompanied with secretion of the
lying B-cell clone, the type of nephropathy, and its impact on MIg or a fragment of it) from those with tubulointerstitial
renal function. Baseline glomerular filtration rate is a major lesions.37 For instance, in patients with FS, proteinuria typically
determinant of renal outcome in most types of MGRS, as contains a small amount of albumin but predominantly mono-
shown in AL amyloidosis,17 MIDD,7 and PGNMID.27 In clonal LC and low-molecular weight proteins. These findings
addition, it is mandatory to carefully search for extrarenal should prompt search for symptoms of proximal tubule
manifestations, which may influence prognosis and influence dysfunction, including normoglycemic glycosuria, uricosuria,
therapeutic decisions. Rapid diagnostic assessment is phosphaturia, and proximal renal tubular acidosis.38,39 In those
particularly critical in patients with AL amyloidosis, in patients without urine abnormalities but impaired glomerular
whom concomitant heart, liver, or peripheral nerve filtration rate and evidence of monoclonal gammopathy, a
involvement is frequent, results in decreased survival, and kidney biopsy should be performed in the absence of an
affects therapeutic strategy. Median survival is approximately obvious cause of renal disease. Indeed, small cohorts of AL
6 months in AL patients with significant heart involvement.28 amyloidosis and LCDD patients with predominant vascular/
Efficient chemotherapy based on novel agents such as the tubulointerstitial deposits and 24 h urine protein excretion of
cyclophosphamide– less than 0.5 g/day have been reported.40,41
bortezomib–dexamethasone regimen is currently recom-
mended in the presence of amyloid cardiomyopathy to HEMATOLOGIC EVALUATION
achieve rapid and deep hematological response, a key factor The finding of monoclonal Ig deposits in the kidney indicates
for patient survival.29,30 Severe extrarenal manifestations are the presence of an underlying B-cell clone. Efforts should
also not uncommon in MIDD and type I cryoglobulinemia, be made to characterize this clone, which is a key point for
and osteomalacia frequently reveals FS. In patients with guiding the therapeutic strategy.12 Accordingly, in all cases,
symptoms suggestive of systemic AL amyloidosis, minimally a detailed hematologic evaluation should be performed
invasive biopsies of abdominal fat and minor salivary glands (Figure 1). In patients with IgG, IgA, or LC only MGRS,
may be performed initially.31,32 bone marrow aspirate, and biopsy are usually sufficient to
However, in most situations, a kidney biopsy with detailed identify the clone. Flow cytometry and/or immunohistolo-
immunofluorescence (IF) and electron microscopic (EM) gical studies of bone marrow cells are often useful to detect
studies to identify deposit composition and pattern of this clone as it may present without any morphologic
organization is needed. Because of the frequency of abnormalities. Skeletal radiographs are mandatory to detect
monoclonal gammopathies in patients aged over 50 years, bone lesions and can be supplemented by a vertebral (and
it is important that the correct correlation of the renal lesions pelvic) magnetic resonance imaging.
with monoclonal gammopathy is performed, as the presence Particularly, in patients with IgM MGRS, additional
of a monoclonal protein by itself is not equal to the causative imaging studies may be required, as the possibility of a
agent. This is illustrated by the fact that up to 10% of patients non-plasmacytic B-cell clone increases. A computer tomo-
with hereditary amyloidosis were initially misdiagnosed as graphy scan of the chest, abdomen, and pelvis may help
AL amyloidosis because of the presence of a serum MIg33 and identify lymph nodes that should undergo a biopsy.
that 10% of patients with amyloidosis derived from leukocyte The utility of positron emission tomography scan combined
cell-derived chemotaxin 2, which mainly affects the kidneys, with a computer tomography scan remains to be assessed.
have a serum MIg.34 Moreover, misdiagnosis of the amyloid Phenotypic characterization of peripheral blood lympho-
subtype may occur, because of nonspecific trapping of the cytes, including rearrangement of Ig genes, may be indicated.
MIg in the amyloid deposits.35 In addition, renal biopsy is In patients with MGRS, the likelihood of identifying the
indicated to assess the MGRS type and evaluate severity of B-cell clone significantly increases when a serum and/or urine
renal disease. This remains important even in patients with monoclonal protein can be detected.
advanced chronic kidney disease in whom kidney trans-
plantation is planned, as the disease generally recurs rapidly Screening for MIg
in the allograft in the absence of control of the underlying MGRS can present across a number of clinical scenarios,
clone.18–22 Kidney biopsy is a safe procedure in patients with from isolated proteinuria to end-stage kidney disease. It is
MGRS, as shown in a recent study of 148 patients with therefore imperative that the clinician considers the possibil-
monoclonal gammopathies in whom the rate of hemorrhagic ity of underlying monoclonal gammopathy in patients with
complications was 4.1%, similar to the control population.36 various renal manifestations and performs appropriate tests.
The spectrum of renal manifestations in MGRS is wide and In many cases, the MIg can be identified in the serum or
varies according to disease type and molecular characteristics of urine by a conventional EP. However, in some cases, the MIg
the pathogenic MIg (Tables 1–3). Renal failure and proteinuria, levels are very small and may not be detected by EP, likely
with or without hematuria, are the most common presenting reflecting the small size of the underlying B-cell clone and/or
symptoms. Electrophoresis (EP) and immunofixation of a 24-h the affinity of the MIg for tissues and organs. In fact, in
urine specimen should be performed in all cases to distinguish several MGRS renal lesions, the MIg may seemingly be
Abbreviations: CKD, chronic kidney disease; IF, immunofluorescence; LC, immunoglobulin light chains; LN, lymph nodes; LPL, lymphoplasmacytic lymphoma; MGRS, monoclonal gammopathy of renal significance; MM, multiple
demonstrated only in a kidney biopsy by IF or immuno-
Hematological disease
Symptomatic MM and
histochemistry.
Serum and urine immunofixation should be performed in
WM uncommon
all cases to identify the MIg isotype, even if the serum protein
EP is not informative, because it is more sensitive for
MGRS
MGRS
MM
MM
LPL
sensitive than the FLC assay among patients with small clones
that produce mostly intact immunoglobulins.42,43 Analysis of
Most common symptoms: hypouricemia, hypophosphatemia, normoglycemic glycosuria, generalized aminoaciduria, low-molecular weight proteinuria, and proximal (type 2) renal tubular acidosis.
the serum and urine by western blotting further increases the
Bone marrow,
involvement
Crystals (needle-shaped)
Ultrastructural findings
PTC LC inclusions
Vk3 (rare)
or Vk3
Proximal tubule
CKD
Crystal-storing histio-
are exposed when the LCs are free but hidden when the LCs
are bound (Freelite, Binding Site, Birmingham, UK).47 These
syndrome
cytosis
glomerular capillary walls; EP, electrophoresis; FLC, serum-free light chain assay; GN, glomerulonephritis; GOMMID, glomerulonephritis with organized microtubular immunoglobulin deposits; HC, immunoglobulin heavy chains;
Hypocomp., hypocomplementemia; IF, immunofluorescence; Ig, immunoglobulin; ITGN, immunotactoid glomerulonephritis; LC, immunoglobulin light chains; MM, multiple myeloma; MPGN, membranoproliferative
Abbreviations: AH, immunoglobulin heavy chain; AHL, immunoglobulin heavy and light chain; AL, immunoglobulin light chain; AKI, acute kidney injury; CKD, chronic kidney disease; CLL, chronic lymphocytic leukemia; CW,
Symptomatic MM uncommon
Hematological and immuno-
the serum. In the last few years, new FLC assays based on
monoclonal antibodies have become commercially available.
logical characteristics
Hypocomp. common
one epitope on a FLC.48–51 In an attempt to overcome this
B-cell lymphoma
B-cell lymphoma
MM uncommon
CLL (common)
limitation, manufacturers frequently use multiple mono-
Hypocomp.
clonal antibodies within one assay batch. Significant work
B30%
now needs to be undertaken to determine the comparability
MGRS
MGRS
MGRS
WMa
WMa
MM
of these monoclonal assays to the original polyclonal FLC
assays. Preliminary studies suggest that they may be
67% in AL, 80% in AH/
Serum EP/immunofixa-
Serum EP/immunofixa-
Serum EP/immunofixa-
tion: 35–67% Urine EP/
88% in AH/AHL -Urine
Urine EP/immunofixa-
complementary, although all international guidelines are
AHL -FLC: 76-88% in
Identification of an
tion: 76%
Frequent:
Frequent:
intracellular crys-
tals (crystal-cryo-
branched fibrils
globulinemia)
Randomly ar-
microtubules
hollow core
7–14 nm in
diameter
findings
Extra þ
glomerulonephritis; NS, nephrotic syndrome; Pred., predominantly; UN, unknown; WM, Waldenström’s macroglobulinemia.
(IgG14IgG24IgG3) (k4l)
in mesangium and CW
domain (CH1) deletion
(pred. subepithelial)
Glomerular thrombi
RENAL PATHOLOGY
(k4l)
MPGN
light)
Possible nephritic
Microhematuria
Microhematuria
Proteinuria, NS
Proteinuria, NS
Proteinuria, NS
Hypertension
Hypertension
CKD
CKD
uria
localization.56,57
GN
Hypertension vascular walls LCDD: mostly kappa (Vk4) arterial walls LHCDD, 67–100% in Hypocomp. common in g1
HCDD: truncated HC (g1, or HCDD and g3 HCDD
g3, or g4, or a), with CH1 Urine EP/immuno-
deletion. fixation: 42–90% in
703
review F Bridoux et al.: MGRS
Kidney biopsy a c
+ – C3 predominant –
No further
deposits hematologic
workup
Serum and urine +
monoclonal studies (protein
electrophoresis and Monoclonal –
immunofixation, FLC) gammopathy b d
+
Bone marrow C3nef
aspirate and biopsy and anti-H
autoantibodies
a b a b
c d c d
200 nm
within vascular lumens that may display a typical ‘grid-like’ eosin and electron dense with occasional ‘mottled
appearance.55 appearance’ on EM.77 LC proximal tubulopathy without
crystals can be of kappa or lambda types and is not usually
MGRS lesions with deposition of crystals associated with FS.77 A not uncommon diagnostic dilemma is
Light-chain proximal tubulopathy. (Figure 6): LC proximal distinguishing LC proximal tubulopathy without crystals
tubulopathy, previously referred to as the ‘LC Fanconi from the physiologic intracellular proximal tubular
syndrome’ is characterized by the presence of rod- or trafficking of LC (without pathologic significance). We
rhomboid-shaped hypereosinophilic and PAS-negative crys- recommend that a diagnosis of ‘LC proximal tubulopathy
tals within proximal tubular cells. Ultrastructurally, the without crystals’ should be reserved to cases associated with
crystals may appear granular or show lattice-like substruc- very large dysmorphic lysosomes, histologic evidence of acute
ture.72 Because of their intracellular localization and and/or chronic proximal tubular injury, marked swelling of
extensive crystallization, standard IF on frozen tissue may proximal tubular cells due to lysosomal indigestion, renal
fail to confirm their LC composition. IF on pronase-digested, insufficiency (not explained by other pathology), tubular
paraffin-embedded tissue, which has an antigen retrieval step, proteinuria (as opposed to pure overflow proteinuria), and/
and immunoEM are much more sensitive techniques, but the or clinical features of partial or complete FS.
latter is not widely used in renal pathology practice.73,74 Crystal-storing histiocytosis. (Figure 7): This is a rare
Patients with LC proximal tubulopathy with crystals may or complication of MM or MGRS, which typically involves the
may not have a complete or partial FS.38,39,75,76 The bone marrow but can also affect several extramedullary sites,
pathologic LC in this lesion is almost always kappa and including the kidney, peri-renal fat, lungs, and cornea.
restricted to the Vk1 subgroup. A more recently described Kidney biopsy reveals intracytoplasmic eosinophilic LC
pathologic variant of light-chain proximal tubulopathy called crystalline inclusions within interstitial histiocytes and
‘LC proximal tubulopathy without crystals’ manifests LC- occasionally within proximal tubular cells and podocytes.79
containing phagolysosomes within proximal tubular cells As in LC proximal tubulopathy with crystals, standard IF on
without crystal formation.72,77,78 The non-crystalline frozen tissue sometimes fails to demonstrate their LC
inclusions appear hypereosinophilic on hematoxylin and composition, which requires IF on pronase-digested
2 µm
Figure 9 | Pathology of proliferative glomerulonephritis with monoclonal IgG deposits. (a) Glomeruli exhibit marked global mesangial and
segmental endocapillary hypercellularity (H&E, X200). (b) On electron microscopy, there are large mesangial, intramembranous, and
subepithelial deposits, together with segmental duplication of the glomerular basement membrane. The electron dense deposits appear
granular (without substructure; X6000). (c–e) Glomeruli in this case of PGNMID show bright global mesangial and glomerular capillary wall
staining for IgG3 (c) and kappa (d). Glomeruli are negative for lambda (e), IgA, IgM, IgG1, IgG2, and IgG4 (not shown). Note the lack of tubular
basement membrane deposits, which is quite different from monoclonal immunoglobulin deposition disease of the Randall type (X100 for c–e).
H&E, hematoxylin and eosin; Ig, immunoglobulin; PGNMID, proliferative glomerulonephritis with monoclonal immunoglobulin G deposits.
Figure 10 | Pathology of C3 glomerulopathy. a–c are from a 69-year-old patient with IgG lambda MGRS and C3 glomerulonephritis.
Complement pathway workup showed CFH risk polymorphism (Y402H). On light microscopy, the glomerulus shows marked global mesangial
and segmental endocapillary hypercellularity with intracapillary infiltrating lymphocytes, monocytes, and some neutrophils (a; PAS, X200). On
immunofluorescence, there is global granular mesangial and glomerular capillary loop staining for C3 (b, X200). Glomeruli were negative for
IgG, IgA, IgM, kappa, and lambda in this case (not shown). Ultrastructurally, there are large electron dense mesangial deposits and scattered
subepithelial deposits (arrows; c, X7830). d–f are from a 59-year-old male with IgG kappa MGRS and dense deposit disease. Complement
pathway workup was positive for FH autoantibody. The glomerulus depicted shows global mesangial hypercellularity and segmental occlusion
of peripheral capillaries by endocapillary hypercellularity and influx of inflammatory cells (arrows). The glomerular basement membranes
appear segmentally thickened (d; H&E, X200). Immunofluorescence highlights global granular to semilinear glomerular capillary wall and
mesangial C3 deposits, with linear staining of Bowman’s capsule (e; X200). The defining feature of dense deposit disease is ‘sausage-like’
thickening of the glomerular basement membranes by highly electron dense intramembranous deposits. Large rounded mesangial electron
dense deposits are also seen (f; X6000). CFH, complement factor H; H&E, hematoxylin and eosin; MGRS, monoclonal gammopathy of renal
significance; PAS, periodic acid–Schiff.
supported by autologous blood stem cell transplantation. Am J Kidney Dis 49. Campbell JP, Cobbold M, Wang Y et al. Development of a highly-sensitive
2006; 47: 672–679. multi-plex assay using monoclonal antibodies for the simultaneous
24. Meri S, Koistinen V, Miettinen A et al. Activation of the alternative measurement of kappa and lambda immunoglobulin free light chains in
pathway of complement by monoclonal lambda light chains in serum and urine. J Immunol Methods 2013; 391: 1–13.
membranoproliferative glomerulonephritis. J Exp Med 1992; 175: 50. Nakano T, Nagata A. ELISAs for free human immunoglobulin light chains
939–950. in serum: improvement of assay specificity by using two specific
25. Jokiranta TS, Solomon A, Pangburn MK et al. Nephritogenic lambda light antibodies in a sandwich detection method. J Immunol Methods 2004;
chain dimer: a unique human miniautoantibody against complement 293: 183–189.
factor H. J Immunol 1999; 163: 4590–4596. 51. te Velthuis H, Knop I, Stam P et al. N Latex FLC-new monoclonal high-
26. Debiec H, Hanoy M, Francois A et al. Recurrent membranous performance assays for the determination of free light chain kappa and
nephropathy in an allograft caused by IgG3kappa targeting the PLA2 lambda. Clin Chem Lab Med 2011; 49: 1323–1332.
receptor. J Am Soc Nephrol 2012; 23: 1949–1954. 52. Hutchison CA, Harding S, Hewins P et al. Quantitative assessment of
27. Nasr SH, Satoskar A, Markowitz GS et al. Proliferative glomerulonephritis serum and urinary polyclonal free light chains in patients with chronic
with monoclonal IgG deposits. J Am Soc Nephrol 2009; 20: 2055–2064. kidney disease. Clin J Am Soc Nephrol 2008; 3: 1684–1690.
28. Kyle RA, Gertz MA, Greipp PR et al. A trial of three regimens for primary 53. Hutchison CA, Plant T, Drayson M et al. Serum free light chain
amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, measurement aids the diagnosis of myeloma in patients with severe renal
prednisone, and colchicine. N Engl J Med 1997; 336: 1202–1207. failure. BMC Nephrol 2008; 9: 11.
29. Palladini G, Dispenzieri A, Gertz MA et al. New criteria for response to 54. Palladini G, Dispenzieri A, Gertz MA et al. New criteria for response to
treatment in immunoglobulin light chain amyloidosis based on free light treatment in immunoglobulin light chain amyloidosis based on free light
chain measurement and cardiac biomarkers: impact on survival chain measurement and cardiac biomarkers: impact on survival
outcomes. J Clin Oncol 2012; 30: 4541–4549. outcomes. J Clin Oncol 2012; 30: 4541–4549.
30. Venner CP, Lane T, Foard D et al. Cyclophosphamide, bortezomib, and 55. Touchard G. Ultrastructural pattern and classification of renal monoclonal
dexamethasone therapy in AL amyloidosis is associated with high clonal immunoglobulin deposits. In: Touchard G, Aucouturier P, Hermine O,
response rates and prolonged progression-free survival. Blood 2012; 119: Ronco P (eds) Monoclonal gammopathies and the kidney. Kluwer
4387–4390. Academic Publishers: Dordrecht ; Boston, 2003 pp 95–120.
31. Picken MM. Amyloidosis-where are we now and where are we heading? 56. Gu X, Herrera GA. Light-chain-mediated acute tubular interstitial
Arch Pathol Lab Med 2010; 134: 545–551. nephritis: a poorly recognized pattern of renal disease in patients with
32. Merlini G, Wechalekar AD, Palladini G. Systemic light chain amyloidosis: plasma cell dyscrasia. Arch Pathol Lab Med 2006; 130: 165–169.
an update for treating physicians. Blood 2013; 121: 5124–5130. 57. Jain D, Green JA, Bastacky S et al. Membranoproliferative
33. Lachmann HJ, Booth DR, Booth SE et al. Misdiagnosis of hereditary glomerulonephritis: the role for laser microdissection and mass
amyloidosis as AL (primary) amyloidosis. N Engl J Med 2002; 346: spectrometry. Am J Kidney Dis 2014; 63: 324–328.
1786–1791. 58. Nasr SH, Said SM, Valeri AM et al. The diagnosis and characteristics of
34. Said SM, Sethi S, Valeri AM et al. Characterization and outcomes of renal renal heavy-chain and heavy/light-chain amyloidosis and their
leukocyte chemotactic factor 2-associated amyloidosis. Kidney Int 2014; comparison with renal light-chain amyloidosis. Kidney Int 2013; 83:
86: 370–377. 463–470.
35. Said SM, Sethi S, Valeri AM et al. Renal amyloidosis: origin and 59. Picken MM. Modern approaches to the treatment of amyloidosis: the
clinicopathologic correlations of 474 recent cases. Clin J Am Soc Nephrol critical importance of early detection in surgical pathology. Adv Anat
2013; 8: 1515–1523. Pathol 2013; 20: 424–439.
36. Fish R, Pinney J, Jain P et al. The incidence of major hemorrhagic 60. Howie AJ, Brewer DB. Optical properties of amyloid stained by Congo
complications after renal biopsies in patients with monoclonal red: history and mechanisms. Micron 2009; 40: 285–301.
gammopathies. Clin J Am Soc Nephrol 2010; 5: 1977–1980. 61. Shiiki H, Shimokama T, Yoshikawa Y et al. Renal amyloidosis. Correlations
37. Leung N, Gertz M, Kyle RA et al. Urinary albumin excretion patterns of between morphology, chemical types of amyloid protein and clinical
patients with cast nephropathy and other monoclonal gammopathy- features. Virchows Arch A Pathol Anat Histopathol 1988; 412:
related kidney diseases. Clin J Am Soc Nephrol 2012; 7: 1964–1968. 197–204.
38. Bridoux F, Sirac C, Hugue V et al. Fanconi’s syndrome induced by a 62. Picken MM. Immunoglobulin light and heavy chain amyloidosis AL/AH:
monoclonal Vkappa3 light chain in Waldenstrom’s macroglobulinemia. renal pathology and differential diagnosis. Contrib Nephrol 2007; 153:
Am J Kidney Dis 2005; 45: 749–757. 135–155.
39. Messiaen T, Deret S, Mougenot B et al. Adult Fanconi syndrome 63. Sethi S, Vrana JA, Theis JD et al. Laser microdissection and mass
secondary to light chain gammopathy. Clinicopathologic heterogeneity spectrometry-based proteomics aids the diagnosis and typing of renal
and unusual features in 11 patients. Medicine 2000; 79: 135–154. amyloidosis. Kidney Int 2012; 82: 226–234.
40. Eirin A, Irazabal MV, Gertz MA et al. Clinical features of patients with 64. Sethi S, Theis JD, Vrana JA et al. Laser microdissection and proteomic
immunoglobulin light chain amyloidosis (AL) with vascular-limited analysis of amyloidosis, cryoglobulinemic GN, fibrillary GN, and
deposition in the kidney. Nephrol Dia Transplant 2012; 27: 1097–1101. immunotactoid glomerulopathy. Clin J Am Soc Nephrol 2013; 8: 915–921.
41. Sicard A, Karras A, Goujon JM et al. Light chain deposition disease 65. Herrera GA, Turbat-Herrera EA. Ultrastructural immunolabeling in the
without glomerular proteinuria: a diagnostic challenge for the diagnosis of monoclonal light-and heavy-chain-related renal diseases.
nephrologist. Nephrol Dial Transplant 2014; 29: 1894–1902. Ultrastruct Pathol 2010; 34: 161–173.
42. Katzmann JA, Kyle RA, Benson J et al. Screening panels for detection of 66. Nasr SH, Valeri AM, Cornell LD et al. Fibrillary glomerulonephritis: a report
monoclonal gammopathies. Clin Chem 2009; 55: 1517–1522. of 66 cases from a single institution. Clin J Am Soc Nephrol 2011; 6:
43. Palladini G, Russo P, Bosoni T et al. Identification of amyloidogenic light 775–784.
chains requires the combination of serum-free light chain assay with 67. Rosenstock JL, Markowitz GS, Valeri AM et al. Fibrillary and
immunofixation of serum and urine. Clin Chem 2009; 55: 499–504. immunotactoid glomerulonephritis: distinct entities with different clinical
44. Anderson KC, Alsina M, Bensinger W et al. NCCN clinical practice and pathologic features. Kidney Int 2003; 63: 1450–1461.
guidelines in oncology: multiple myeloma. J Natl Compr Canc Netw 2009; 68. Nasr SH, Fidler ME, Cornell LD et al. Immunotactoid glomerulopathy:
7: 908–942. clinicopathologic and proteomic study. Nephrol Dial Transplant 2012; 27:
45. Dispenzieri A, Kyle R, Merlini G et al. International Myeloma Working 4137–4146.
Group guidelines for serum-free light chain analysis in multiple myeloma 69. Terrier B, Karras A, Kahn JE et al. The spectrum of type I cryoglobulinemia
and related disorders. Leukemia 2009; 23: 215–224. vasculitis: new insights based on 64 cases. Medicine (Baltimore) 2013; 92:
46. Sethi S, Zand L, Leung N et al. Membranoproliferative glomerulonephritis 61–68.
secondary to monoclonal gammopathy. Clin J Am Soc Nephrol 2010; 5: 70. Nasr SH, Markowitz GS, Reddy BS et al. Dysproteinemia, proteinuria, and
770–782. glomerulonephritis. Kidney Int 2006; 69: 772–775.
47. Bradwell AR, Carr-Smith HD, Mead GP et al. Highly sensitive, automated 71. Karras A, Noel LH, Droz D et al. Renal involvement in monoclonal (type I)
immunoassay for immunoglobulin free light chains in serum and urine. cryoglobulinemia: two cases associated with IgG3 kappa cryoglobulin.
Clin Chem 2001; 47: 673–680. Am J Kidney Dis 2002; 40: 1091–1096.
48. Davern S, Tang LX, Williams TK et al. Immunodiagnostic capabilities of 72. Kapur U, Barton K, Fresco R et al. Expanding the pathologic spectrum of
anti-free immunoglobulin light chain monoclonal antibodies. Am J Clin immunoglobulin light chain proximal tubulopathy. Arch Pathol Lab Med
Pathol 2008; 130: 702–711. 2007; 131: 1368–1372.
73. Nasr SH, Galgano SJ, Markowitz GS et al. Immunofluorescence on 83. Nasr SH, Markowitz GS, Stokes MB et al. Proliferative glomerulonephritis
pronase-digested paraffin sections: a valuable salvage technique for renal with monoclonal IgG deposits: a distinct entity mimicking immune-
biopsies. Kidney Int 2006; 70: 2148–2151. complex glomerulonephritis. Kidney Int 2004; 65: 85–96.
74. Gu X, Barrios R, Cartwright J et al. Light chain crystal deposition as a 84. Yahata M, Nakaya I, Takahashi S et al. Proliferative glomerulonephritis
manifestation of plasma cell dyscrasias: the role of immunoelectron with monoclonal IgM deposits without Waldenstrom’s
microscopy. Hum Pathol 2003; 34: 270–277. macroglobulinemia: case report and review of the literature. Clin Nephrol
75. Elliott MR, Cortese C, Moreno-Aspitia A et al. Plasma cell dyscrasia causing 2012; 77: 254–260.
light chain tubulopathy without Fanconi syndrome. Am J Kidney Dis 2010; 85. Soares SM, Lager DJ, Leung N et al. A proliferative glomerulo-
55: 1136–1141. nephritis secondary to a monoclonal IgA. Am J Kidney Dis 2006; 47:
76. Said SM, Assaad AM, Cerda J et al. Light chain tubulopathy without 342–349.
Fanconi syndrome. Nephrol Dial Transplant 2006; 21: 3589–3590. 86. Alpers CE, Tu WH, Hopper J Jr. et al. Single light chain subclass (kappa
77. Larsen CP, Bell JM, Harris AA et al. The morphologic spectrum and clinical chain) immunoglobulin deposition in glomerulonephritis. Hum Pathol
significance of light chain proximal tubulopathy with and without crystal 1985; 16: 294–304.
formation. Mod Pathol 2011; 24: 1462–1469. 87. Pickering MC, D’Agati VD, Nester CM et al. C3 glomerulopathy: consensus
78. Herrera GA. Renal lesions associated with plasma cell dyscrasias: practical report. Kidney Int 2013; 84: 1079–1089.
approach to diagnosis, new concepts, and challenges. Arch Pathol Lab 88. Sethi S, Sukov WR, Zhang Y et al. Dense deposit disease associated with
Med 2009; 133: 249–267. monoclonal gammopathy of undetermined significance. Am J Kidney Dis
79. El Hamel C, Thierry A, Trouillas P et al. Crystal-storing histiocytosis with 2010; 56: 977–982.
renal Fanconi syndrome: pathological and molecular characteristics 89. Zand L, Kattah A, Fervenza FC et al. C3 glomerulonephritis associated
compared with classical myeloma-associated Fanconi syndrome. Nephrol with monoclonal gammopathy: a case series. Am J Kidney Dis 2013; 62:
Dial Transplant 2010; 25: 2982–2990. 506–514.
80. Stokes MB, Aronoff B, Siegel D et al. Dysproteinemia-related nephropathy 90. Bridoux F, Desport E, Fremeaux-Bacchi V et al. Glomerulonephritis with
associated with crystal-storing histiocytosis. Kidney Int 2006; 70: 597–602. isolated C3 deposits and monoclonal gammopathy: a fortuitous
81. Lin J, Markowitz GS, Valeri AM et al. Renal monoclonal immunoglobulin association? Clin Am Soc Nephrol 2011; 6: 2165–2174.
deposition disease: the disease spectrum. J Am Soc Nephrol 2001; 12: 91. Sethi S, Rajkumar SV. Monoclonal gammopathy-associated proliferative
1482–1492. glomerulonephritis. Mayo Clin Proc 2013; 88: 1284–1293.
82. Alexander MP, Nasr SH, Watson DC et al. Renal crescentic alpha heavy 92. Kyle RA, Therneau TM, Rajkumar SV et al. Prevalence of monoclonal
chain deposition disease: a report of 3 cases and review of the literature. gammopathy of undetermined significance. N Engl J Med 2006; 354:
Am J Kidney Dis 2011; 58: 621–625. 1362–1369.