Monoclonal Gammopathy of Renal Significance: Review Article

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Review Article

Julie R. Ingelfinger, M.D., Editor

Monoclonal Gammopathy of Renal


Significance
Nelson Leung, M.D., Frank Bridoux, M.D., Ph.D., and Samih H. Nasr, M.D.​​

K
idney disease is a common cause of illness and death, affecting From the Divisions of Nephrology and
an estimated 37 million people in the United States alone. Hypertension Hypertension and of Hematology (N.L.)
and the Department of Laboratory Medi-
and diabetes are the most common causes of chronic kidney disease cine and Pathology (S.H.N.), Mayo Clin-
(CKD). Monoclonal gammopathy has emerged as an important cause of kidney ic, Rochester, MN; and Department of
injury and is responsible for a variety of glomerular, tubulointerstitial, and vascu- Nephrology and Centre d’Investigation
Clinique INSERM 1402, Centre de Ré-
lar lesions within the kidney.1 This review focuses on monoclonal gammopathy of férence Amylose AL et Autres Maladies
renal significance (MGRS), a term that describes any B-cell or plasma-cell clonal par Dépôt d’Immunoglobulines Mono-
disorder that does not fulfill the criteria for cancer yet produces a nephrotoxic clonales, Centre Hospitalier Universita-
ire, Université de Poitiers, Poitiers, and
monoclonal immunoglobulin that leads to kidney injury or disease. Centre National de la Recherche Scienti-
fique UMR7276, Université de Limoges,
Limoges — all in France (F.B.). Address
Cl a ssific at ion of C ondi t ions In volv ing Mono cl ona l reprint requests to Dr. Leung at 200 First
G a m mopath y St. SW, Rochester, MN 55905, or at l­ eung​
.­nelson@​­mayo​.­edu.
Monoclonal gammopathy is defined by the presence of a monoclonal immuno- N Engl J Med 2021;384:1931-41.
globulin in plasma, urine, or both that is produced most often by clonal plasma DOI: 10.1056/NEJMra1810907
cells and less commonly by B lymphocytes. The current hematologic criteria for Copyright © 2021 Massachusetts Medical Society.

classifying monoclonal gammopathy are based on the presence of a clonal mass


and end-organ damage. Once the minimal tumor burden is met, treatment is in-
dicated when organ function becomes affected. For example, the diagnosis of
multiple myeloma requires more than 10% bone marrow plasma cells or a mono-
clonal spike of more than 3 g per deciliter, as well as end-organ damage as defined
by the CRAB criteria (hypercalcemia, renal insufficiency, anemia, and bone le-
sions).2 The International Myeloma Working Group added three criteria in 2014
that strongly predict the progression to symptomatic myeloma (>60% bone mar-
row plasma cells, serum free light-chain ratio >100 with the level of the involved
free light chain >10 mg per deciliter, and >1 bone lesion on magnetic resonance
imaging).2
The criteria for treatment of chronic lymphocytic leukemia (CLL) are lympho-
cytosis (>5000 leukemic cells per cubic millimeter) and the presence of either
anemia or thrombocytopenia or the presence of symptomatic lymphadenopathy,
splenomegaly, or both.3 For lymphoplasmacytic lymphoma (formerly called
Waldenström’s macroglobulinemia), treatment is indicated when bone marrow
involvement is 10% or more and at least one of the following is present: anemia,
thrombocytopenia, cryoglobulinemia, or hyperviscosity syndrome.4
Patients who meet the tumor burden criterion but do not have evidence of end-
organ damage are given the diagnosis of smoldering multiple myeloma, low-grade
CLL, or smoldering lymphoplasmacytic lymphoma. Patients who neither meet the
clonal burden criterion nor have end-organ damage receive a diagnosis of mono-
clonal gammopathy of undetermined significance (MGUS), IgM MGUS (most com-
monly represented by the presence of lymphoplasmacytic lymphoma clones), or

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monoclonal B-cell lymphocytosis (most common- decades, it has become clear that kidney disor-
ly represented by the presence of CLL clones). By ders can be induced by nephrotoxic monoclonal
definition, patients who are considered to have immunoglobulins, regardless of the tumor bur-
MGUS and those who have smoldering myeloma den. From a hematologic point of view, these
do not have any end-organ damage. Treatment disorders would be diagnosed as MGUS or
is recommended only for patients meeting the smoldering myeloma or lymphoma, but the di-
criteria for cancer; all others should be observed agnosis of MGUS and smoldering myeloma ex-
or enrolled in a clinical trial. cludes the presence of any end-organ damage
Although the diagnostic classification and and is not an indication for hematologic treat-
treatment recommendations are valid for most ment. For years, the lack of recognition of the
patients, there are instances that are not covered peculiar pathophysiology of renal disorders in-
by the above-mentioned criteria. There may be a duced by monoclonal immunoglobulins prevent-
discrepancy between the tumor burden and or- ed patients from receiving effective therapeutic
gan (kidney) damage. In multiple myeloma, the strategies targeting the production of nephro-
kidney impairment criterion in CRAB is limited toxic immunoglobulins.
to kidney injury resulting from cast nephropa- MGRS fills the diagnostic gap without chang-
thy. Light-chain cast nephropathy is now consid- ing the definition of a malignant process. MGRS
ered a myeloma-defining event because nearly represents any B-cell or plasma-cell clonal disor-
all such cases meet the tumor burden criterion.2 der that does not meet current criteria for im-
However, kidney lesions other than cast nephrop- mediate treatment (in the case of cancer) but
athy do not satisfy the renal impairment crite- produces a nephrotoxic monoclonal immuno-
rion for symptomatic myeloma; thus, multiple globulin that directly or indirectly results in kid-
myeloma cannot be diagnosed in a patient pre- ney disease or injury.9 This diagnostic category
senting with monoclonal immunoglobulin de- includes MGUS and smoldering hematologic
position disease (MIDD) unless other CRAB cri- diseases. MGRS-associated kidney diseases are
teria are present. characterized by three features: first, these dis-
The criteria for classification become even eases do not respond well to immunosuppres-
more confusing when the tumor burden is not sive regimens used in the treatment of autoim-
met (bone marrow plasma-cell infiltration, <10%). mune nephropathies10-12; second, affected patients
This has led to the inaccurate use of the term have a very high rate of recurrence after kidney
“idiopathic,” which has been misinterpreted as transplantation (approximately 90%) if the mono-
benign disease.5-7 Moreover, kidney disease is not clonal gammopathy is not eliminated before or
part of the diagnostic criteria for symptomatic immediately after transplantation13,14; and third,
B-cell lymphoma.3,4 Thus, when patients with CLL affected patients are at risk for progression to
or lymphoplasmacytic lymphoma present with the corresponding hematologic cancer.8,15,16
kidney disease, treatment cannot be recommend-
ed unless one of the other criteria is met. Patients Mech a nisms of R ena l
who have monoclonal gammopathy–related kid- T ox ici t y from Mono cl ona l
ney disease without the requisite tumor burden Im muno gl obul ins
should not be considered to have a cancer, since
the hematologic disorder acts more like MGUS. Monoclonal immunoglobulins can cause kidney
However, such patients still have a clonal disor- damage through various mechanisms that can
der that requires effective treatment.8 The gap be separated by the presence of a high or low
in the diagnostic criteria has impeded treatment tumor burden. Kidney injury from a high tumor
recommendations for such patients. burden is represented by light-chain cast ne-
phropathy, which is characterized by monoclonal
light chains that bind to Tamm–Horsfall pro-
Fil l ing the Di agnos t ic G a p
tein (also known as uromodulin) through their
Until relatively recently, the pathogenic role of variable domain to form obstructive casts.17 This
monoclonal immunoglobulins in kidney disease process requires high levels of serum free light
was attributed mainly to overtly malignant con- chains (usually >150 mg per deciliter), which
ditions, such as multiple myeloma, lymphoplas- typically occur only in patients with multiple
macytic lymphoma, or CLL. Over the past two myeloma, lymphoplasmacytic lymphoma, or high-

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Monoclonal Gammopathy of Renal Significance

grade CLL; this explains why light-chain cast direct activation of the alternative pathway.28 Over-
nephropathy is not considered an MGRS-related activation of the alternative pathway, either sys-
kidney lesion.2,18-20 MGRS is most commonly as- temically or locally, results in glomerular deposi-
sociated with low levels of monoclonal gam- tion of C3, without deposition of the pathogenic
mopathy, and the most common mechanism is monoclonal immunoglobulins in the kidney. A
misfolding of a fragment of monoclonal immu- similar mechanism may be involved in monoclo-
noglobulin light chain, resulting in the forma- nal gammopathy–associated thrombotic micro-
tion of toxic amyloid multimers and amyloid fi- angiopathy. Finally, monoclonal immunoglobu-
brils (Fig. 1).21 Immunoglobulin light chains can lins can target antigens involved in kidney
also bear mutations in the variable domain, diseases related to polyclonal immunoglobulins,
rendering them resistant to the proteolytic pro- such as the phospholipase A2 receptor and the
cess that recycles free light chains in the endoly- α1(IV) and α2(IV) chains of collagen IV.29,30
sosomal compartment of proximal tubular cells
and leading to the formation of intracytoplasmic K idne y L e sions A sso ci ated
crystals. Such light-chain crystals or inclusions w i th MGR S
disrupt lysosomal function, inducing cellular
injury, impairing reabsorptive function, and re- The majority of kidney diseases associated with
sulting in light-chain proximal tubulopathy.22 MGRS are glomerular disorders, with light-chain
Monoclonal immunoglobulins in MIDD dis- proximal tubulopathy and crystal-storing histio-
play peculiar physicochemical characteristics of cytosis as the exceptions.9 MGRS-related kidney
the variable domain, including hydrophobic resi- lesions are classified according to the character-
dues, abnormal glycosylation, and positive charge. istics of the monoclonal immunoglobulin de-
These features promote their aggregation and posits on electron microscopy: organized, non-
deposition in the mesangium and along the organized, or absent deposits (Fig. 2). Organized
negatively charged glomerular and tubular base- deposits are further differentiated into fibrils
ment membranes.23,24 These monoclonal immuno- (e.g., in immunoglobulin light-chain–associated
globulins also activate cellular proliferation and amyloidosis [AL amyloidosis]), microtubules (e.g.,
extracellular matrix remodeling pathways, leading in immunotactoid glomerulonephritis or cryo-
to a phenotypic change in the mesangial cells. globulinemic glomerulonephritis), and crystals
Monoclonal free heavy chains are produced or inclusions (e.g., in light-chain proximal tubu-
in MIDD when a deletion of the first constant lopathy, crystal-storing histiocytosis, or crystal-
domain of the heavy chain makes the heavy globulin-induced nephropathy). Nonorganized
chain unable to bind the light chain in order to deposits are observed in MIDD and proliferative
form a whole immunoglobulin and allows secre- glomerulonephritis with monoclonal immuno-
tion of free heavy chains by the plasma cells.23 globulin deposits (PGNMID). Immunoglobulin
When monoclonal cryoglobulins are exposed to deposits are absent in C3 glomerulopathy with
temperatures below body temperature, they can monoclonal gammopathy and in thrombotic mi-
precipitate to form organized substructures (mi- croangiopathy associated with monoclonal gam-
crotubules or crystals), leading to occlusion and mopathy. The renal and extrarenal manifesta-
inflammation of small arterioles and capillaries tions and the pathological and hematologic
within glomeruli and altering the integrity of characteristics of the most common MGRS le-
the filtration barrier.25,26 Noncryoglobulin micro- sions are provided in Table 1.
tubular deposits are characteristic of immuno-
tactoid glomerulonephritis.27 Deposits of entire Di agnosis of MGR S-R el ated
immunoglobulins may also activate the classical Dise a se s
pathway of complement, leading to glomerular
inflammation and endocapillary proliferation. The incidence and prevalence of MGRS-associated
Recently, it has been shown that monoclonal diseases are unknown. In Olmsted County, Min-
immunoglobulins, and sometimes monoclonal nesota, the estimated incidence of MGUS is 7 to
light chains alone, have the capacity to deregu- 59 times as high as the incidence of glomerular
late the complement alternative pathway through diseases.31,32 Also in Olmsted County, the rate of
autoantibody activity against factor H or other MGUS is higher among males than among fe-
regulators of the alternative pathway or through males and increases after the age of 50 years.33

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The n e w e ng l a n d j o u r na l of m e dic i n e

A AL amyloidosis LCPT
Thrombotic microangiopathy
Crystallization
Endothelial-cell injury
(e.g., TMA or POEMs)
Resistance to
PT proteolysis
Fibrin
thrombi
Deposition
Misfolded LCs LCs with
and Cytokine production
Fibrillosis peculiar VL and complement
LC fragments mutations activation

Low-grade B-cell or
LCDD (MIDD) plasma-cell clonal C3 glomerulopathy
disorder

CAP activation

Positively Deposition of C3 and


Increased affinity for charged or complement terminal
basement membranes glycosylated LCs pathway proteins
Intact immunoglobulin

PGNMID Crystalglobulinemia
Entrapment in glomeruli

Crystallization
Complement activation Endothelial-cell
Fc-Fc injury and
Deposition of interactions thrombosis
immunoglobulin plus
complement proteins

B
Thrombotic microangiopathy

AL amyloidosis

LCDD

Crystalglobulin-induced
nephropathy
Immunotactoid GN

PGNMID

LCPT
C3GN

Cryoglobulinemic GN

1934 n engl j med 384;20 nejm.org May 20, 2021

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Monoclonal Gammopathy of Renal Significance

Figure 1 (facing page). Mechanisms of Monoclonal laboratory findings or a rapid loss in kidney
­Immunoglobulin Nephrotoxicity. function.
Mechanisms of renal toxicity from monoclonal immuno- Once the diagnosis of MGRS-related disease
globulins are shown in Panel A. Immunoglobulin light- is made, a hematologic evaluation should be
chain–associated amyloidosis (AL amyloidosis) is char- performed to identify the clone that is secreting
acterized by the deposition of misfolded monoclonal
the pathogenic monoclonal immunoglobulin. Se-
immunoglobulin light chains (LCs). Light-chain proxi-
mal tubulopathy (LCPT) is characterized by peculiar mu- rum and urine protein electrophoresis, immuno-
tations (hydrophobic residues) in the variable domain fixation, and a serum free light-chain assay
(VL) of monoclonal immunoglobulin LCs, rendering should be performed if the monoclonal protein
them resistant to the proteolytic process that recycles has not already been identified.36 A bone mar-
free LCs in the endolysosomal compartment of proxi-
row biopsy is often needed for clonal identifica-
mal tubular (PT) cells and resulting in the formation of
intracytoplasmic crystals. In thrombotic microangiopa- tion. The pathologic clone may also be detected
thy, immunoglobulins can activate complement through in a lymph-node biopsy specimen or by means of
the classical or alternative pathway or act as autoanti- peripheral-blood flow cytometry, especially in
bodies against factor H or other regulators of the alter- patients with lymphoma and CLL. Computed
native pathway, leading to endothelial-cell damage. In
tomography, with or without positron-emission
C3 glomerulopathy, monoclonal immunoglobulin acti-
vates complement through the alternative pathway tomography, can help to locate focal lesions
(CAP), resulting in the deposition of C3 and leading to outside the bone marrow, such as lymph-node or
glomerular inflammation and endocapillary proliferation. plasma-cell lesions. Plasma-cell clones are most
In crystalglobulin-induced nephropathy, monoclonal im- common in patients with AL amyloidosis, MIDD,
munoglobulin crystallizes or precipitates in small arte-
or light-chain proximal tubulopathy,24,37-39 where-
rioles, capillaries, and glomeruli. In proliferative glomer-
ulonephritis with monoclonal immunoglobulin deposits as at least 50% of the clones identified in patients
(PGNMID), monoclonal immunoglobulins are deposited with immunotactoid glomerulonephritis corre-
in the glomeruli, causing complement activation and spond to a CLL lineage.25,27 The odds of finding
leading to glomerular inflammation and proliferation. the pathologic clone are lower among patients
In monoclonal immunoglobulin deposition disease
who have immunotactoid glomerulonephritis or
(MIDD), monoclonal immunoglobulin LCs display un-
usual characteristics of the variable domain such as hy- type I cryoglobulinemic glomerulonephritis. Clon-
drophobic residues, positive charge, or abnormal glyco- al identification is most difficult in patients who
sylation. The LCs are deposited in vascular, glomerular, have PGNMID, more than 80% of whom have
and tubular basement membranes, causing activation a negative hematologic evaluation, especially
of transforming growth factor β (TGF-β), which induc-
those with monotypic glomerular IgG3 depos-
es matrix accumulation and a phenotypic change in the
mesangial cells. In the heavy-chain variant of MIDD, the its.40 Among detected clones in patients with
first constant domain of the heavy chain is deleted, which PGNMID, 50% are derived from plasma cells
makes the heavy chain unable to bind the LC and form and 50% correspond to B lymphocytes that ex-
a whole immunoglobulin and allows the heavy chain to press CD20.12,40 In addition to clonal identifica-
be secreted as a free heavy chain. Panel B shows local-
tion, testing of genetic markers such as B-cell
ization of MGRS lesions. C3GN denotes C3 glomerulo-
nephritis, GN glomerulonephritis, and LCDD light-chain lymphoma 2 (BCL2) and t(11;14) in bone marrow
deposition disease. biopsy specimens may provide additional thera-
peutic options for selected patients.41-43

Since the frequency of glomerular diseases also M a nagemen t of MGR S-R el ated
increases with age, it would not be uncommon Dise a se s
for patients with kidney disease to have MGUS.
Two independent studies have shown that The distinctive pathophysiological features of
MGRS-related diseases are present in 40 to 45% MGRS call for a management strategy that dif-
of patients with monoclonal gammopathy who fers from the strategies used for autoimmune-
undergo a kidney biopsy.34,35 A high urinary pro- mediated kidney diseases and hematologic can-
tein level (>1.5 g per day), an abnormal serum cers. An understanding of these differences
free light-chain ratio, and microscopic hematu- ensures adequate outcomes for affected patients.
ria are associated with MGRS lesions.35 Thus, a Whereas treatment of autoimmune-mediated kid-
kidney biopsy should be considered for patients ney diseases is guided by the renal histopatho-
who have monoclonal gammopathy with these logical findings, treatment of MGRS should be

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A B C

D E F

Figure 2. Pathological Features of MGRS-Associated Kidney Lesions.


AL amyloidosis (Panel A) is characterized by congophilic deposits composed of randomly oriented fibrils, which are positive for one im-
munoglobulin LC on immunofluorescence staining. In this example, immunofluorescence shows smudgy staining of the glomerular me-
sangium and vascular pole for kappa LC; the glomeruli were negative for lambda LC (not shown). In heavy-chain deposition disease (MIDD)
(Panel B), punctate, powdery, electron-dense deposits in the mesangium and along glomerular and tubular basement membranes are
composed of a portion of monoclonal heavy chain (most commonly, gamma). In this example of gamma heavy-chain deposition disease,
immunofluorescence reveals diffuse linear glomerular and tubular basement membrane, smudgy mesangial staining for IgG, and no
staining for IgA, IgM, kappa, or lambda. In the example of PGNMID (Panel C), immunofluorescence shows granular mesangial and glo-
merular capillary-wall staining for IgG3; glomeruli were also positive for IgG and kappa and negative for lambda, IgA, IgG1, IgG2, and
IgG4 (not shown). In contrast to amyloidosis and MIDD, there is no extraglomerular involvement. The high-power electron microscopy
image of immunotactoid glomerulopathy (Panel D) shows mesangial deposits composed of large microtubules organized in parallel
arrays. The longitudinal and cross sections of the microtubules show hollow centers. C3GN associated with monoclonal gammopathy
(Panel E) is characterized by large, granular mesangial (arrows) and small subendothelial (arrowhead) electron-dense deposits on elec-
tron microscopy. The glomerular deposits were positive for C3 and were negative for IgG, IgA, IgM, kappa, and lambda on immunofluo-
rescence staining (not shown). In a case of chronic thrombotic microangiopathy associated with monoclonal gammopathy (Panel F),
subendothelial “fluff” is evident on electron microscopy (arrows).

determined by the nature of the clone (B-cell or tially resulting in myelodysplastic syndrome and
plasma-cell) that produces the nephrotoxic mono- acute leukemia.51,52 Fortunately, these risks have
clonal immunoglobulin. For MGRS-related dis- been mitigated by the availability of newer anti-
eases, clone-directed therapy has been found to myeloma and antilymphoma therapies with bet-
be superior to the immunosuppressive therapy ter side-effect profiles, which has transformed
used in many autoimmune-mediated kidney dis- the prognosis for patients with MGRS.11
eases, such as glucocorticoids, calcineurin in- The goals of treatment also require adjust-
hibitors, mycophenolate mofetil, cyclophospha- ment for MGRS because most affected patients
mide, and low-dose rituximab.11,12,44-46 Favorable do not have a life-threatening condition, unless
outcomes in patients with MGRS, including extrarenal organs (Table 1) are involved (e.g., in
preservation of renal function, require clone- most cases of AL amyloidosis).9,26,47,53 The pri-
directed therapy, based on agents that were previ- mary objective in the management of MGRS is
ously restricted to patients with overt hemato- therefore preservation of kidney function rather
logic cancers.11,12,24,47-50 The past reluctance to use than immediate preservation of life,47 and this
such agents for the treatment of MGRS was objective should be considered in balancing the
based on the concern that prolonged use of alkyl- toxic effects of therapy and the potential bene-
ating agents would confer myelotoxicity, poten- fits. In patients who already have advanced CKD,

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Monoclonal Gammopathy of Renal Significance

the role of clone-directed therapy should be Maintenance therapy is generally not necessary,
shifted to reducing the risk of recurrent MGRS since long-term remission is usually achieved
after kidney transplantation, since preservation with a limited duration of chemotherapy.49,54,59
of kidney function is unlikely. In patients who Kidney transplantation is generally the best
are not candidates for transplantation, treatment option if end-stage kidney disease develops.
should be introduced only if extrarenal involve- However, high rates of recurrent nephropathy
ment is present or the diagnostic criteria for a have been reported among patients with MGRS
malignant process are met. in whom monoclonal gammopathy was not fully
The end points of therapy also differ between eradicated before kidney transplantation. In par-
MGRS and hematologic cancer. Since nephro- ticular, patients with PGNMID have had a recur-
toxicity derives from the monoclonal protein, rence rate approaching 90% after kidney trans-
complete elimination would be ideal, but at a plantation, with a median time to recurrence of
minimum, the monoclonal immunoglobulin level only 6 months.14 Graft loss has followed quickly
should be substantially reduced. A very good after the detection of recurrence in patients who
partial hematologic response (defined as a dif- were not rapidly treated. Untreated or insuffi-
ference between involved and uninvolved free ciently treated patients with MIDD have had a
light chain of <4 mg per deciliter or >90% reduc- similar risk of recurrence, but with a longer time
tion of the involved free light chain) has been to recurrence.13,60 We therefore recommend that
shown to be the minimum hematologic response patients who are candidates for kidney trans-
required for preservation of kidney function.11,50,54-56 plantation be treated until at least a very good
Some studies suggest that the kidney response partial response is achieved, if a hematologic
can be further improved by achieving extremely response can be measured. The only exception is
strong hematologic responses, such as no mini- patients with AL amyloidosis, since studies have
mal residual disease or a reduction of the in- shown that kidney allograft outcomes in such
volved free light chain to less than 2 mg per patients are similar whether they received clone-
deciliter.53,57 With plasma-cell clones, this is directed therapy before or after kidney trans-
currently best achieved with bortezomib-based plantation, as long as at least a very good partial
therapy.48,58,59 In patients with MIDD, a more response can be achieved.63-65 This finding is due
complete hematologic response may be achieved mainly to the lower risk and slower rate of recur-
with the use of high-dose melphalan followed by rence among such patients.
autologous stem-cell transplantation, but not all There are situations in which a pathologic
patients are eligible for the procedure.48,60 Dara- clone or even monoclonal protein could not be
tumumab, a monoclonal antibody against CD38, detected to help guide treatment selection, espe-
has shown high efficacy in patients with AL cially in patients with PGNMID. In these cir-
amyloidosis and is currently being tested for the cumstances, we have recommended the use of
treatment of MIDD and PGNMID.61,62 This agent anti–plasma-cell agents in patients with only
would be an outstanding addition to current IgG, IgA, or light-chain monoclonal gammopa-
treatment regimens for plasma-cell clones in thy and anti-CD20 monoclonal antibody therapy
patients with MGRS-related diseases if its bene- in those with an IgM monoclonal gammopathy.
fits, including high response rates and relatively Treatment has been guided by renal measures
low rates of adverse effects, could be confirmed. such as urinary protein levels and kidney func-
Patients with B-cell clones that express CD20 tion instead of the hematologic response. If
should be treated with rituximab-based thera- there is no favorable change in urinary protein
py.11,12,25 The particular combination with ritux- or serum creatinine levels after two or three cy-
imab depends on whether the involved clone is cles, therapy should be changed to target a dif-
of the CLL, lymphoplasmacytic, or other non- ferent clone.
Hodgkin’s lymphoma lineage. Frequent reassess-
ment of the hematologic measures (serum free C onclusions
light-chain level and the presence or absence of
a monoclonal spike) and kidney measures (se- MGRS is a relatively new diagnostic term and
rum creatinine and urinary protein levels) is im- concept, aimed at improving the classification of
portant in treating MGRS in order to evaluate the patients with kidney disease due to monoclonal
response to therapy and minimize toxic effects. proteins whose clinical course does not meet the

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1938
Table 1. Characteristics of the Most Common Lesions in Monoclonal Gammopathy of Renal Significance (MGRS).*

MGRS Disorder Renal Symptoms† Pathological Findings Extrarenal Manifestations Hematologic Disease Identification of M Protein
Lesions with organized
deposits
Immunoglobulin-related Heavy proteinuria (median protein, Light microscopy: Congo red–positive Common: heart failure, MGRS (80%), MM SPEP-SIF: 66–88%
amyloidosis (AL, 5–6 g/day), nephrotic syndrome deposits, mostly in glomeruli and postural hypotension, (16%), other (LPL UPEP-UIF: 67–80%
94%; AH and AHL, (66%), mild CKD (median creati- vessels peripheral neuropathy, or other lympho- Abnormal SFLC: 78–88%
6%) nine, 1.2 mg/dl); hematuria and Immunofluorescence: smudgy depos- GI symptoms, carpal mas [4%])
hypertension uncommon its positive for 1 LC in AL (mostly tunnel syndrome, liver
λ), 1 HC (mostly γ1 or γ4) with involvement
The

CH1 domain deletion in AH, 1 HC


and 1 LC in AHL
Electron microscopy: randomly ori-
ented fibrils (7–14 nm)
Monoclonal immunotac- Heavy proteinuria (median protein, Light microscopy: atypical membra- Exceedingly rare (mono- CLL (37–45%), MGRS SPEP-SIF: 50%
toid GN 6 g/day), nephrotic syndrome nous, membranoproliferative, neuritis multiplex, (52%), other small- UPEP-UIF: 42%
(59–70%), CKD (median creati- mesangial, or endocapillary dermal capillaritis) cell lymphomas Abnormal SFLC: 19–28%
nine, 1.5 mg/dl), hematuria (74– proliferative GN (8–11%), MM (4%)
89%), hypertension (56–84%), Immunofluorescence: monotypic IgG
hypocomplementemia (33%) (mostly IgG1κ) granular deposits
in mesangium and GBM
Electron microscopy: glomerular
microtubular deposits (14–60 nm)
n e w e ng l a n d j o u r na l

with frequent parallel arrangement

The New England Journal of Medicine


of

Type 1 cryoglobulinemic Proteinuria, nephrotic syndrome Light microscopy: membranoprolifera- Common: purpuric rash, MGRS (50%), B-cell SPEP-SIF: 76%
GN (38%), CKD (mean creatinine, tive or endocapillary proliferative skin ulcers, peripheral lymphoma or LPL UPEP-UIF: unknown
3 mg/dl), hematuria (71%), GN with monocyte infiltration and neuropathy, arthralgias (24–56%), MM Abnormal SFLC: unknown

n engl j med 384;20  nejm.org  May 20, 2021


hypertension, hypocomplement- often immune thrombi (7%)
emia (mostly low C4) (58%) Immunofluorescence: monotypic Ig

Copyright © 2021 Massachusetts Medical Society. All rights reserved.


(mostly IgGκ or IgMκ) granular
m e dic i n e

deposits in glomeruli and vessels


Electron microscopy: microtubular ex-
tracellular electron-dense deposits
and occasional intracellular crystals

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Light-chain proximal Proteinuria (median protein, 1.5– Light microscopy: proximal tubular Stress fracture (40%) MGRS (61–80%), MM SPEP-SIF: 71–100%
tubulopathy 2.5 g/day), mild CKD (median swelling (12–33%), other UPEP-UIF: 94–100%
creatinine, 1.9–2.0 mg/dl), proxi- Immunofluorescence: proximal tubular (3–8%) Abnormal SFLC: 91–100%
mal tubulopathy with or without staining κ (of crystalline variant) or
complete Fanconi’s syndrome λ (mostly of noncrystalline variant)
Electron microscopy: proximal tubular
LC crystals or lysosomal inclusions
MGRS Disorder Renal Symptoms† Pathological Findings Extrarenal Manifestations Hematologic Disease Identification of M Protein
Lesions with nonorga-
nized deposits
MIDD (LCDD, 83%; Proteinuria (median protein, 1.8– Light microscopy: nodular glomerulo- Mostly hepatic and cardiac MGRS (64–78%), MM SPEP-SIF: 64%
LHCDD, 8%; HCDD, 2.4 g/day), nephrotic syndrome sclerosis (67% of cases), thickened manifestations (35%) (18–34%), other UPEP-UIF: 68%
9%) (22%), CKD (median creatinine, TBM (LPL, lymphoma) Abnormal SFLC: 99–100%
3 mg/dl), hematuria (58–62%), Immunofluorescence: linear deposits (2%)
hypertension (55–83%) along GBM, TBM, and vessels of
1 LC (in LCDD), 1 LC and 1 HC (in
LHCDD), or 1 HC with CH1 dele-
tion (in HCDD)
Electron microscopy: punctate elec-
tron-dense deposits along GBM,
TBM, and vessels
PGNMID Heavy proteinuria (mean protein, Light microscopy: membranoprolifera- None MGRS (96%), MM SPEP-SIF: 20–30%
6 g/day), nephrotic syndrome tive, endocapillary proliferative, or (3–4%), lymphoma UPEP-UIF: 11%
(49%), CKD (mean creatinine, membranous GN (1%) Abnormal SFLC: 21%
2.8 mg/dl), hematuria (77%), Immunofluorescence: monotypic Ig
hypertension (38%) (mostly IgG3κ) granular deposits
in mesangium and GBM
Electron microscopy: electron-dense
deposits in glomeruli
C3 glomerulopathy with Proteinuria (median protein, Light microscopy: membranoprolifera- None MGRS (82–90%), MM SPEP-SIF: 99–100%
monoclonal gam- 3.2 g/day), nephrotic syndrome tive, mesangioproliferative, or (4–14%), lym­ UPEP-UIF: 100%
mopathy (43%), CKD (median creatinine, endocapillary proliferative GN phoma (6%) Abnormal SFLC: 53–75%
1.8 mg/dl), hematuria (84–89%), Immunofluorescence: C3 granular
low C3 (34–43%) deposits in mesangium and GBM
(with paucity of Ig deposits)
Electron microscopy: ill-defined elec-
tron-dense deposits in C3GN and

n engl j med 384;20  nejm.org  May 20, 2021

The New England Journal of Medicine


intramembranous and mesangial
highly electron-dense deposits in
dense-deposit disease
Monoclonal Gammopathy of Renal Significance

Lesions without immune


deposits

Copyright © 2021 Massachusetts Medical Society. All rights reserved.


Thrombotic microangi- Proteinuria (median protein, Light and electron microscopy: GBM Occasional MAHA, MGRS (90%), MM SPEP-SIF: 95%
opathy with monoclo- 3.2 g/day), nephrotic syndrome duplication, mesangiolysis, suben- POEMS syndrome (5%), lymphoma UPEP-UIF: 33%
nal gammopathy (43%), CKD (median creatinine dothelial “fluff,” thrombosis (10%) (5%) Abnormal SFLC: 28%
1.8 mg/dl), hematuria (84–89%), Immunofluorescence: no Ig deposits
hypocomplementemia (50%)

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* Percents are percentages of patients. AH denotes heavy-chain amyloidosis; AHL heavy- and light-chain amyloidosis; AL light-chain amyloidosis; CKD chronic kidney disease; C3GN C3
glomerulonephritis; GBM glomerular basement membrane; GI gastrointestinal; GN glomerulonephritis; HC heavy chain; HCDD heavy-chain deposition disease; Ig immunogobulin; LC
light chain; LCDD light-chain deposition disease; LHCDD light- and heavy-chain deposition disease; LPL lymphoplasmacytic lymphoma; MAHA microangiopathic hemolytic anemia;
MIDD monoclonal Ig deposition disease; MM multiple myeloma; PGNMID proliferative glomerulonephritis with monoclonal Ig deposits; POEMS polyneuropathy, organomegaly, endo-
crinopathy, M component, and skin changes; SFLC serum free light-chain; SPEP-SIF serum protein electrophoresis with immunofixation; TBM tubular basement membrane; and UPEP-
UIF urine protein electrophoresis with immunofixation.
† To convert the values for creatinine to micromoles per liter, multiply by 88.4.

1939
The n e w e ng l a n d j o u r na l of m e dic i n e

criteria for a hematologic cancer. The establish- clone-directed therapy has been shown to pre-
ment of this diagnosis has been instrumental in serve kidney function and prevent and treat re-
tailoring specific and efficient therapy for such current disease after kidney transplantation in
patients. Whereas the new term was created to instances in which immunosuppression has been
highlight the premalignant nature of the mono- ineffective. The recognition that premalignant
clonal gammopathies, it also differentiates pa- conditions can be responsible for end-organ
tients who have a monoclonal immunoglobulin– damage has spawned the concept of monoclonal
related kidney disease from those with MGUS. gammopathy of clinical significance (MGCS).66
Clone-directed therapy is justified in the treat- The concepts of both MGRS and MGCS are im-
ment of MGRS and does not violate the current proving our understanding of the pathogenic
diagnostic criteria and treatment recommenda- manifestations of monoclonal proteins and, one
tions for MGUS. With the addition of MGRS as hopes, may lead to better treatments with even
a category of kidney diseases, treatment is no fewer adverse effects.
longer directed by the histopathological find- Disclosure forms provided by the authors are available with
ings alone or by the tumor burden. Indeed, the full text of this article at NEJM.org.

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