CASE REPORT

Successful Renal Outcome in

Membranoproliferative Glomerulonephritis
Following Treatment of the Underlying
Subtle Clone: A Case Report
Ritika Rana, MBBS, MRCP; Paul Cockwell, MB BCh, FRCP, PhD;
Bindu Vydianath, MBBS, FRCPath; Mark Cook, MB ChB, PhD;
Guy Pratt, FRCP, FRCPath, MD; Mark Trehane Drayson, FRCPath, PhD;
and Jennifer Helen Pinney, BM BS, MD

Abstract

Membranoproliferative glomerulonephritis (MPGN) secondary to a monoclonal gammopathy is a rare

glomerular disease and is defined as a monoclonal gammopathy of renal significance. The disease is
characterized by glomerular monotypic immunoglobulin deposits and specific changes on light micro-
scopy and electron microscopy. Immunochemistry is required to establish monoclonality, and electron
microscopy helps to characterize the deposits ultrastructurally. Investigation for the underlying mono-
clonal protein should be done. We report a case of MPGN secondary to monoclonal gammopathy of renal
significance that responded to treatment of the underlying clone with chemotherapy, resulting in
improvement in renal function. Patients with MPGN and immunoglobulin deposition should be evaluated
for a monoclonal protein to guide the management strategy.
ª 2018 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/) n Mayo Clin Proc Inn Qual Out 2018;2(3):297-302

From the Department of

M
onoclonal gammopathy of renal sig- deposits are due to distal effects of the clonal
Renal Medicine (R.R., P.C.,
nificance (MGRS) refers to low- immunoglobulin.4-10 J.H.P.), Department of
grade plasma cell disorders that There are 2 major types of membranoproli- Histopathology (B.V.),
result in renal damage due to a nephrotoxic ferative glomerulonephritis (MPGN), immune Department of Haema-
tology (M.C., G.P.), and
monoclonal paraprotein and in which the complexemediated MPGN and complement- Institute of Immunology
underlying clonal disorder does not meet the mediated MPGN. Immune complexemediated and Immunotherapy
hematological criteria for specific treatment. MPGN has been classified into 3 groups: (M.T.D.), University of
Birmingham, Birmingham,
Unlike monoclonal gammopathy of undeter- chronic infections, autoimmune diseases, and UK.
mined significance (MGUS), which is not asso- MGRS. Although MGRS-related MPGN does
ciated with end-organ damage, MGRS causes not classify as a true “immune complex” disease,
renal damage that can have major clinical im- it is being recognized as a separate entity, im-
plications, including progression to end-stage mune complexemediated, and a cause in
renal failure (ESRF) and increased mortality some cases of complement-mediated MPGN.8
risk.1-3 In MGRS-related MPGN, there is an excess
A range of renal lesions have been described of a single type monoclonal immunoglobulin
with MGRS. The type of renal lesion depends on (MIg) or its components produced by an
the physicochemical property of the involved abnormal clone of a cell of B-cell lineage. The
monoclonal protein. The classification system clonal immunoglobulin has a structural config-
can be based on the ultrastructural features of uration that causes the histological changes of
the deposits. In most patients, the deposits MPGN, through either MIg deposition or
include or are a local product of clonal immuno- isolated complement deposition (C3 glomeru-
globulin. However, in C3 glomerulopathy, the lopathy).4-10 The finding of this pattern of

Mayo Clin Proc Inn Qual Out n September 2018;2(3):297-302 n https://doi.org/10.1016/j.mayocpiqo.2018.04.003 297
www.mcpiqojournal.org n ª 2018 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. This is an open access article under
the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 MAYO CLINIC PROCEEDINGS: INNOVATIONS, QUALITY & OUTCOMES

FIGURE 1. Pathology of membranoproliferative glomerulonephritis with monoclonal IgG deposits. A-C,

First biopsy. A, Glomeruli exhibit diffuse accentuation of the nodular pattern, with mesangial matrix
expansion (hematoxylin-eosin,
200). B, Silver stain, showing thickening of the membranes with double
contours and endocapillary proliferation. C, Immunohistochemistry highlights faint IgG in the peripheral
capillary loops. D-G, Second biopsy. D, Hypercellular glomerulus with nodular mesangial expansion,
endocapillary proliferation, thickening of glomerular basement membranes and double contours
(hematoxylin-eosin,
200). E, On silver staining, double contours of the GBMs and mesangial deposits are
seen. F, Electron microscopy showing marked expansion of the mesangium with granular subendothelial
deposits and moderate effacement of podocyte foot processes. G, Electron microscopy showing
mesangial areas with a fibril deposition. GBM ¼ glomerular basement membrane.

changes in a kidney biopsy necessitates evalua- clone is reported, and previously this would
tion for an underlying B-cell clone. Because have been described as MGUS.13,14 Other known
the clonal immunoglobulin is usually low grade, associated conditions are low-grade B-cell lym-
careful serum and urine studies are needed to phoma, lymphoplasmacytic lymphoma, chronic
establish the presence of MGRS; occasionally, lymphocytic leukemia, and multiple myeloma.14
despite clear evidence of an MGRS-related In some patients, there is no evidence of clonal
MPGN on kidney biopsy, a serum and/or urine plasma cell/B-cell lineage proliferation in the
clonal immunoglobulin is not detected.11,12 bone marrow, and the clone is being produced
Bone marrow biopsies performed in patients at an extramedullary site.
with MGRS-associated MPGN have revealed Although the pathogenesis of MGRS-
various conditions. Most commonly, a low-level related MPGN is now better understood,
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A CASE OF MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS

evidence regarding renal outcome after the 5.40 g/L. Serum immunoglobulin levels were
treatment of patients who have the underlying normal (IgG, 9.96 g/L; IgA, 1.49 g/L; IgM,
renal lesion is lacking. As renal outcomes are 1.31g/L); serum free light chain results showed
improved in other renal diseases that are asso- no evidence of free light chain clonality, with k
ciated with a clonal protein (eg, AL amyloid light chain of 26.30 mg/L, l light chain of
and MIg deposition disease), due to targeting 23.55 mg/L, and a k:l ratio of 1.1. Urine k
of the underlying cell clone,15-17 there is light chain level was 0.02 g/L, and urine l light
strong justification for this approach in chain level was 0.01 g/L. Urine was negative
patients with MGRS-related MPGN. It is now for free light chains on immunofixation.
accepted that when there is evidence of Immunology profile revealed a negative
MGRS, treatment with plasma cellebased antineutrophil cytoplasmic antibodies level,
therapy is indicated. and antinuclear antibodies titer was 1:10 (ho-
Here, we report a case of MGRS-related mogeneous pattern) with a negative double-
MPGN that illustrates the challenges associ- stranded DNA. Complement levels (C3 and
ated with the clinical management of this con- C4) were normal. Serology was negative for
dition. Kidney function monitoring, serial hepatitis B and C.
kidney biopsies, and bone marrow biopsies She underwent a renal biopsy that showed
showed disease progression; subsequent type 1 membranoproliferative glomerulone-
chemotherapy led to improvement in the phritis (Figure 1, A-C). There was diffuse
burden of the clonal immunoglobulin and accentuation of the nodular pattern, associated
marked improvement in kidney function and with mesangial matrix expansion. Double con-
proteinuria. tours were evident on silver staining, and there
was focal endocapillary proliferation. On im-
REPORT OF CASE munostaining, there was faint IgG and strong
A 66-year-old woman was referred to the diffuse C3d along the peripheral capillary
nephrology clinic with hypertension and an loops. Electron microscopy showed marked
active urinary sediment. She had previously expansion in the mesangial matrix, which
been investigated for microscopic hematuria demonstrated a filamentous appearance. There
with normal findings on prior renal tract ultra- were no mesangial and no subepithelial de-
sonography and cystoscopy. She had a history posits but several capillary loops contained
of myalgia, lower back pain, and occasional scattered subendothelial deposits. Marked
cramps. There was no history of weight loss, effacement of the foot processes was noted.
edema, arthritis, or rash. Her medical history There were no casts and Congo red stain
included hypothyroidism, Bell palsy, and a was negative.
neuro sarcoid that was not paraprotein related. Further investigations showed a small rise
She had no family history of kidney diseases. in IgG lambda paraprotein quantitation at 7.2
She was a nonsmoker and did not drink g/L. Skeletal survey was negative and bone
alcohol. She had 2 children with no history of marrow biopsy showed a clonal population
preeclampsia. of plasma cells with a skewed k:l ratio
Her blood pressure was 160/84 mm Hg, her of 1:5; these cells were CD117, cyclin D1,
weight was 82.1 kg, and her clinical examination CD20-negative, and CD56-positive,
results were normal. Urinalysis showed 3þ accounting for 2% to 3% of the total nucle-
protein and 3þ blood. Albumin-creatinine ated cell count. She had a full-body
ratio (ACR) was 268 mg/mmol; Modification of computed tomography scan that demon-
Diet in Renal Disease estimated glomerular filtra- strated small-volume adenopathy both above
tion rate (eGFR) was 64 mL/min per 1.73 m2, and below the diaphragm; this was felt to be
albumin concentration was 36 g/L, calcium and long-standing and related to her history of
alkaline phosphatase levels were normal, and he- sarcoid. She was diagnosed with MGUS, and
moglobin value was 10.9 g/dL (to convert to g/L, given the uncertainty as to whether there
multiply by 10.0) with normal hematinics. was a direct connection with her renal disease,
Serum protein electrophoresis showed an a period of monitoring was felt to be appro-
IgG lambda paraprotein on immunofixation, priate to determine whether there was a
and clonal immunoglobulin quantitation was need for treatment.
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 MAYO CLINIC PROCEEDINGS: INNOVATIONS, QUALITY & OUTCOMES

eGFR Paraprotein ACR

70 1400

60 1200
VCD
50 CTD 1000

ACR
40 800
GFR

30 600

20 400

10 5.4 6.7 7 200

4.3
0.6
0 0
13

13

14

14

14

15

15

15

16

16

16
01

01

01
20

20

20

20

20

20

20

20

20

20

20
/2

/2

/2
1/

1/

1/

1/

1/

1/

1/

1/

1/

1/

1/
/1

/1

/1
5/

8/

2/

5/

8/

2/

5/

8/

2/

5/

8/
11

11

11
FIGURE 2. Change in eGFR (mL/min/1.73 m2), ACR (mg/mmol), and paraprotein (g/L) with time. Arrow indicate initiation of
treatment with VCD and later with CTD. ACR ¼ albumin to creatinine ratio; CTD ¼ cyclophosphamide, thalidomide, and dexa-
methasone; eGFR ¼ estimated glomerular filtration rate; VCD ¼ velcade, cyclophospahamide, and dexamethasone.

Over the next 2 years, her proteinuria wors- more chronic damage, and an increase in extrav-
ened (ACR, 268 mg/mmol to 741 mg/mmol) asation of Tamm-Horsfall protein. This was pro-
and she developed nephrotic syndrome (albu- posed as a substantial contributing factor to the
min, 30 g/L). Discussion between her treating degree of chronic damage, and a proposed
nephrologist and hematologist resulted in mechanism for the increase in proteinuria. On
repeated staging of her plasma cell dyscrasia. A immunostaining, there was peripheral capillary
further bone marrow biopsy showed an increase loop staining with IgG and with C3d and C1q.
in clonal plasma cells to 10% with l light chain On electron microscopy, there was marked
restriction, consistent with plasma cell mesangial expansion with granular subendothe-
myeloma. Her M-protein level over this period lial deposition and moderate effacement of
increased from 5.4 g/L to 7.1 g/L, and there podocyte foot processes. The renal biopsy taken
was a 20% decline in her eGFR (64 mL/min to 2 years previously was reviewed again with light
51 mL/min) (Figure 2). chain immunostaining. There appeared to be
She received 4.5 cycles of attenuated borte- preferential l staining of the membranous de-
zomib, cyclophosphamide, and dexamethasone posits with negative k staining.
chemotherapy. Her treatment was complicated Because the renal biopsy was consistent
by fluid retention and macroscopic hematuria with ongoing active MIg deposition, it was
from cyclophosphamide, requiring mesna. A decided to target the clone further with a
repeated flexible cystoscopy did not reveal any thalidomide-based regimen, to aim for a
abnormality. The patient initially had a partial deeper clonal response.
response to chemotherapy; the paraprotein level She received 6 cycles of attenuated cyclo-
fell from 7.1 g/L to 3.5 g/L and subsequently pla- phosphamide, thalidomide, and dexamethasone
teaued (Figure 2). and her paraprotein fell to 0.6 g/dL (Figure 2).
Despite a partial hematological response, her After second-line treatment, the renal parame-
renal function and proteinuria continued to ters improved (ACR, 1115.8 mg/mmol to 154
deteriorate (eGFR, 64 mL/min to 42 mL/min; mg/mmol; eGFR, 19 mL/min to 47 mL/min),
ACR, 268 mg/mmol to 769 mg/mmol; resulting in a favorable renal outcome (Figure 2).
Figure 2). A repeated renal biopsy was per- She has completed 2 years of joint renal and
formed to assess for evidence of renal disease hematology follow-up since completing
progression; this again showed a membranopro- chemotherapy, and her current eGFR is
liferative pattern (Figure 1, D-G) but there was 54 mL/min per 1.73 m2 and ACR 25 mg/mmol.
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A CASE OF MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS

DISCUSSION treatment, to preserve and potentially restore

The MGRS-related MPGN is rare.18 This disease kidney function.
is characterized by glomerular nonorganized, A study at the UK National Amyloid Centre,
granular, monotypic immunoglobulin deposits in patients with light chain deposition disease,
(commonly IgG3k), without any deposits along reported that patients who achieved a complete
the tubular basement membrane.11 or very good partial hematological response with
The disease pathogenesis is not well un- chemotherapy had a mean improvement of
derstood. One theory is that the MIg rapidly 6.1 mL/min per year in glomerular filtration
deposits in glomeruli through entrapment rate compared with a mean glomerular filtration
and/or interaction with the negatively charged rate loss of 6.5 mL/min per year in patients with
glomerular constituents, to form definable partial or no response.24 Factors predictive of a
electron-dense deposits.11 Other theories sug- renal response in MIDD are pretreatment
gest the secretion of various biological factors eGFR more than 30 mL/min per 1.73 m2 and
or autoantibody activity of MIg.19 posttreatment difference in the involved and
Diagnosis requires a renal biopsy, screening noninvolved free light chain level less than
for a monoclonal protein, and a complete he- 40 mg/L.16 Although MIDD and light chain
matological work-up. Monoclonality in the deposition disease confer a different disease
renal biopsy can be determined by immunoflu- phenotype, these studies add weight to the
orescence, thereby providing clues to the un- conclusion that the goal of therapy in other
derlying pathophysiology. It is very important forms of MGRS, such as MGRS-related MPGN,
to correlate the specific MIg found on biopsy should be to target a deep clonal response.
with that found during the hematologic work- Because of the rare nature of this disease,
up to ensure a direct link is established there is no standard treatment strategy for pa-
between the MIg and type of nephropathy.20 tients with MGRS-related MPGN. Various
The diagnosis of this condition is often treatment regimens including immunosup-
challenging, because it has been reported pressive regimens have been reported in the
that many patients do not have an identifiable literature with variable outcomes.14,20,21
peripheral clone.20 Serum and urine MIg has Clone-directed treatment is recommended as
been reported to be found in only one-third first-line treatment in MGRS, and specific ther-
of patients, and a monoclonal proliferation of apy targeting B-cell and plasma-cell clones can
plasma cells in the bone marrow is found in be added on the basis of severity of kidney dis-
less than 10% of patients.15,18,21,22 ease and clinical judgment.12 The requirement
The term MGRS defines a group of condi- for treatment with chemotherapy needs to be
tions with a wide variety of histological findings carefully balanced against the potential risks
on renal biopsy. The clinical features and dis- associated with chemotherapy. Because
ease phenotype are broad and dependent on MGRS is a rare entity, collaborative efforts of
the underlying condition. The term MGRS both nephrologists and hematologists are
enables clinicians to distinguish monoclonal required to guide management.
gammopathies that result in development of Here, we report a case of MGRS with a
kidney disease from those that do not, and subtle underlying clone that progressed to
are not associated with conventional indica- multiple myeloma over time. Achievement of
tions for chemotherapy.15 Because MGRS- a near-complete clonal response was required
related MPGN is so rare, the literature sur- before any renal response occurred. Our pa-
rounding renal outcome is very limited. There tient showed improvement in both renal func-
are, however, studies of other conditions within tion and proteinuria after successful
the MGRS group that have looked at renal out- suppression of the underlying clone. The de-
comes. A study of 56 patients with monoclonal gree of improvement in both renal function
immunoglobulin deposition disease (MIDD) re- and proteinuria would suggest that the in-
ported that most patients (63%) who did not crease in chronic damage was not the main
receive treatment progressed to ESRF. In 32 pa- driver for the increase in proteinuria over
tients treated with chemotherapy, 11 (34%) time and highlights that there is scope for
progressed to ESRF.23 These results highlight improvement despite significant chronic
the importance of an early diagnosis to enable changes. Further studies are required to define
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 MAYO CLINIC PROCEEDINGS: INNOVATIONS, QUALITY & OUTCOMES

whether treatment has an impact on survival 9. Zand L, Kattah A, Fervenza FC, et al. C3 glomerulonephritis
associated with monoclonal gammopathy: a case series. Am J
in this rare disease. Kidney Dis. 2013;62(3):506-514.
10. Sethi S, Sukov WR, Zhang Y, et al. Dense deposit disease asso-
Abbreviations and Acronyms: ACR = albumin to creati- ciated with monoclonal gammopathy of undetermined signifi-
cance. Am J Kidney Dis. 2010;56(5):977-982.
nine ratio; eGFR = estimated glomerular filtration rate;
11. Bridoux F, Leung N, Hutchison CA, et al; International Kidney
ESRF = end-stage renal failure; MGRS = monoclonal and Monoclonal Gammopathy Research Group. Diagnosis of
gammopathy of renal significance; MGUS = monoclonal monoclonal gammopathy of renal significance. Kidney Int.
gammopathy of undetermined significance; MIDD = 2015;87(4):698-711.
monoclonal immunoglobulin deposition disease; MIg = 12. Bhutani G, Nasr SH, Said SM, et al. Hematologic characteristics
monoclonal immunoglobulin; MPGN = membranoprolifer- of proliferative glomerulonephritides with nonorganized mono-
ative glomerulonephritis clonal immunoglobulin deposits. Mayo Clin Proc. 2015;90(5):
587-596.
Potential Competing Interests: Dr Drayson is a medical 13. Leung N, Bridoux F, Hutchison CA, et al; International Kidney
advisor to and shareholder in Abingdon Health, which is and Monoclonal Gammopathy Research Group. Monoclonal
an immunodiagnostics company. The rest of the authors gammopathy of renal significance: when MGUS is no longer
undetermined or insignificant. Blood. 2012;120(22):4292-4295.
report no competing financial interests.
14. Sethi S, Zand L, Leung N, et al. Membranoproliferative glomer-
ulonephritis secondary to monoclonal gammopathy. Clin J Am
Publication dates: Received for publication March 8, 2018;
Soc Nephrol. 2010;5(5):770-782.
revisions received April 23, 2018; accepted for publication 15. Fermand JP, Bridoux F, Kyle RA, et al; International Kidney and
April 24, 2018. Monoclonal Gammopathy Research Group. How I treat
monoclonal gammopathy of renal significance (MGRS). Blood.
Correspondence: Address to Ritika Rana, MBBS, MRCP, Renal 2013;122(22):3583-3590.
Research Registrar, Queen Elizabeth Hospital, Mindelsohn 16. Cohen C, Royer B, Javaugue V, et al. Bortezomib produces high
Way, Birmingham, B15 2TH, UK (Ritika.Rana@uhb.nhs.uk). hematological response rates with prolonged renal survival in
monoclonal immunoglobulin deposition disease. Kidney Int.
2015;88(5):1135-1143.
17. Pinney JH, Lachmann HJ, Bansi L, et al. Outcome in renal Al
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