C3 glomerulonephritis in multiple myeloma: A case report and literature review

Abstract

Background:
C3 glomerulonephritis (C3 GN) is a recently defined entity characterized by predominant C3 deposition in glomeruli due to abnormal activation of the alternative pathway of complement system. C3 GN has been reported to be associated with several systemic diseases. However, the association between C3 GN and multiple myeloma (MM) has not been well established.

Methods:
We herein describe a case presenting with C3 GN on top of MM.

Results:
A 64-year-old Chinese female presented with gross hematuria, renal dysfunction, anemia, and weight loss. Results of serum immunofixation assay and bone marrow biopsy confirmed the diagnosis of IgG-λ-type MM. In addition, renal biopsy demonstrated histological findings characteristic of C3 GN, including mesangial and endocapillary proliferation under light microscope, electron-dense deposits under electron microscope, and diffuse granular deposition of C3 with no immunoglobulin under immunofluorescence microscope. These histological findings, combined with low serum C3 level, suggested the occurrence of C3 GN in the context of MM.

Conclusion:
This case study provides additional evidence to the literature in terms of the association between C3 GN and MM. We hypothesize that C3 GN may present as a new variant of nephropathy in MM and the mechanism behind this association merits further study.

Full text

C3 glomerulonephritis in multiple myeloma
A case report and literature review
Guang Yin, MD
∗
, Zhen Cheng, MD, Cai-Hong Zeng, MD, Zhi-Hong Liu, MD
Abstract
Background: C3 glomerulonephritis (C3 GN) is a recently defined entity characterized by predominant C3 deposition in glomeruli
due to abnormal activation of the alternative pathway of complement system. C3 GN has been reported to be associated with several
systemic diseases. However, the association between C3 GN and multiple myeloma (MM) has not been well established.
Methods: We herein describe a case presenting with C3 GN on top of MM.
Results: A 64-year-old Chinese female presented with gross hematuria, renal dysfunction, anemia, and weight loss. Results of
serum immunofixation assay and bone marrow biopsy confirmed the diagnosis of IgG-l-type MM. In addition, renal biopsy
demonstrated histological findings characteristic of C3 GN, including mesangial and endocapillary proliferation under light
microscope, electron-dense deposits under electron microscope, and diffuse granular deposition of C3 with no immunoglobulin
under immunofluorescence microscope. These histological findings, combined with low serum C3 level, suggested the occurrence
of C3 GN in the context of MM.
Conclusion: This case study provides additional evidence to the literature in terms of the association between C3 GN and MM. We
hypothesize that C3 GN may present as a new variant of nephropathy in MM and the mechanism behind this association merits
further study.
Abbreviations: C1q =complement 1q, C3 =complement 3, C3 GN =complement 3 glomerulonephritis, C3NeF =C3 nephritic
factor, CFH =complement factor H, CFHR =complement factor H related protein, CFI =complement factor I, IgA =immunoglobulin
A, IgG =immunoglobulin G, IgM =immunoglobulin M, MM =multiple myeloma.
Keywords: C3 glomerulonephritis, C3 glomerulopathy, case report, complement 3, multiple myeloma
1. Introduction
C3 glomerulonephritis (C3 GN) is a recently defined glomerulo-
nephritis characterized by glomerular deposition composed of C3
with minimal or no immunoglobulin.
[1,2]
The disease is caused by
abnormal activation of the alternative complement pathway and
may be associated with several conditions that result in
dysregulation of the pathway such as infection
[3]
and monoclonal
gammopathy.
[4]
As a relatively newly recognized entity, data
regarding the clinical and pathological features of C3 GN remain
limited, and its association with other systemic/renal diseases is
not well understood.
Multiple myeloma (MM) is a plasma cell neoplasm with a
common feature of renal involvement. A variety of renal diseases
have been observed in MM, of which myeloma cast nephropathy
and monoclonal immunoglobulin deposition disease are the most
frequent ones, followed by fibrillary glomerulonephritis, immu-
notactoid glomerulopathy, and crystalline histiocytosis as less
frequent variants.
[5]
To our knowledge, C3 GN has been
described in a number of cases of MM in the literature,
[6–8]
but
the association between C3 GN and MM has not been well
established. We herein describe a case presenting with typical
features of C3 GN and MM to evidence the association of the 2
entities. In addition, we propose the hypothesis that C3 GN may
be a new variant of nephropathy in MM.
2. Case report
A 64-year-old female presented to our hospital with a 3-month
history of gross hematuria, proteinuria, renal dysfunction,
anemia, and weight loss. Three months before presentation,
she had an attack of gross hematuria with urinary urgency and
dysuria, for which she started looking for medical attention at the
local hospital. She was found to have gross hematuria (red blood
cell count 80 10
6
/mL, pleomorphic type), elevated serum
creatinine (2.9 mg/dL), anemia (hemoglobin 63 g/L), and hyper-
globulinemia (41.0 g/L), and was treated with traditional Chinese
medicine. However, she was not responsive to the treatment, and
there was a rapid weight loss (10 kg) in the following 3 months.
Editor: Ikechi Okpechi.
Authors’contributions: GY initiated the idea of this study, collected data, and
drafted the manuscript. ZC participated in data collection. C-HZ carried out
histological examination of the kidney biopsy specimens. Z-HL participate d in
manuscript drafting and approved the final manuscript.
Written informed consent was obtained from the patient for publication of the
manuscript and any accompanying images. A copy of the written consent is
available for review.
The authors have no conflicts of interest to disclose.
National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing
University School of Medicine, Nanjing, China.
∗
Correspondence: Guang Yin, National Clinical Research Center of Kidney
Diseases, Jinling Hospital, Nanjing University School of Medicine, 305 East
Zhongshan Road, Nanjing 210002, China (e-mail: yinguang@medmail.com.cn).
Copyright ©2016 the Author(s). Published by Wolters Kluwer Health, Inc. All
rights reserved.
This is an open access article distributed under the Creative Commons
Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Medicine (2016) 95:37(e4843)
Received: 25 June 2016 / Received in final form: 15 August 2016 / Accepted:
19 August 2016
http://dx.doi.org/10.1097/MD.0000000000004843
Clinical Case Report Medicine®
OPEN
1

She was subsequently referred to our hospital for further
management. The patient’s medical and family history were
otherwise unremarkable.
On admission, physical examination revealed blood pressure
of 154/90 mm Hg, body mass index (BMI) of 22.0 kg/m
2
, and
anemic palpebral conjunctiva. Urinalysis showed gross hematu-
ria (red blood cell count 300 10
6
/mL, pleomorphic type),
proteinuria (1.67 g/24 h), and elevated levels of N-acetyl-b-D-
glucosaminidase (106.0 U/gCr, normal range 16.5 U/gCr) and
retinol binding protein (18.0 mg/L, normal range 0.5 mg/L).
Urinary output and osmolality was 1270 mL/24 h and 412
mOsm/kg·H
2
O, respectively.
Complete blood count showed severe anemia (hemoglobin 60
g/L) with normal counts of white blood cells and platelets. Kidney
function was greatly reduced (serum creatinine 2.43 mg/dL,
blood urea nitrogen 24.0 mg/dL, eGFR 20.5 mL/min/1.73 m
2
),
and total serum protein was significantly increased (77.0 g/L) in
the context of hypoalbuminemia (30.0 g/L) and hyperglobuline-
mia (47.0 g/L). Liver enzymes, serum electrolytes, and blood
glucose were within normal range. Serum level of C3 was
decreased (0.62 g/L, normal range 0.8–1.8 g/L), but levels of C4
and complement factor H (CFH) were normal. C3 nephritic
factor (C3NeF) and antifactor H antibody were negative.
Antinuclear antibody, antineutrophil cytoplasmic antibody,
and antiglomerular basement membrane antibody were negative.
Serology for hepatitis B was negative.
Given the presence of hyperglobulinemia, a quantitative study
of immunoglobulin subclasses was performed, revealing a
remarkable increase in immunoglobulin G (IgG, 41 g/L, normal
range 7–16 g/L) and decrease in immunoglobulin A (IgA, <0.26
g/L, normal range 0.7–4.0 g/L) and immunoglobulin M (IgM,
0.18 g/L, normal range 0.4–2.3g/L). Serum-free llight chain level
was greatly elevated (163.00 mg/L, normal range 6–20 mg/L),
whereas free klight chain level was normal. IgG-l-type
monoclonal immunoglobulin band was identified by immuno-
fixation electrophoresis. Furthermore, a bone marrow biopsy
showed hypercellularity with an increase in plasma cells (45.5%).
Given these findings, a diagnosis of MM was made in spite of the
absence of skull and pelvic bone lesions.
The patient subsequently underwent a renal biopsy to evaluate
renal damage. Histological findings were characteristic of C3
GN. Specifically, global mesangial matrix expansion and
mesangial hypercellularity were noted under light microscope,
with segmental thickening of Bowman’s capsule, proliferation of
endocapillary cells, and infiltration of mononuclear cells and
neutrophils in some glomeruli. Eosinophilic complexes were
observed in the subendothelial, intramembranous, and mesangial
areas (Fig. 1). There were moderate tubulointerstitial lesions with
a few mixed casts. Interstitial fibrosis was mild with moderate
infiltration of monocytes, plasma cells, and neutrophils (Fig. 2).
Congo red staining was negative. Additionally, electron
microscopy identified dense deposits primarily in the subendo-
thelial area, as well as in the mesangial, intramembranous, and
subepithelial areas (Fig. 3). Segmental fusion of foot process was
also noted. Immunofluorescence microscopy reveled positive
staining for C3 in the mesangium and along the capillary wall
(Fig. 4). Meanwhile, IgG, IgA, IgM, complement 1q (C1q), klight
chain, and llight chain staining were negative.
Figure 1. Light microscopy showing eosinophilic complexes in the mesangial
and subendothelial areas. Masson trichrome stain, 400magnification.
Figure 2. Light microscopy showing infiltration of mononuclear cells, plasma
cells, and neutrophils in the interstitium. Periodic acid-Schiff stain, 400
magnification.
Figure 3. Electron microscopy showing electron-dense deposits in the
subendothelial, intramembranous, and mesangial areas. Scale bar: 1 mm.
Yin et al. Medicine (2016) 95:37 Medicine
2

Taken together, the patient was diagnosed with C3 GN and
MM. She was treated with a chemotherapy regimen consisting of
thalidomide and dexamethasone. Despite of a decrease in serum-
free llight chain level, there was no significant improvement in
serum creatinine (3.16 mg/dL), hematuria (red blood cell count
2000 10
6
/mL), and anemia (hemoglobin 67 g/L) after 1 month.
The patient is now in follow-up.
3. Discussion
In this study, we describe a rare case presenting with C3 GN on
top of IgG-l-type MM, further strengthening the recently
recognized association between the 2 entities.
C3 GN has been reported to be associated with several
systemic disorders, but its association with MM has not been well
established. Development of C3 GN in the context of MM has
been described in only 5 patients in the literature.
[6–8]
The first
case, characterized by MM and proliferative glomerulonephritis
with granular glomerular deposition of C3, low serum C3, and
positive C3NeF activity, was reported even before the term of C3
GN was introduced.
[6]
The second case, who had smoldering
MM and glomerulonephritis featured by isolated C3 deposits,
was reported when the term of C3 GN had not been widely
accepted.
[7]
Recently, Cooper et al
[8]
reported 5 cases with C3
GN and plasma cell dyscrasia, including 2 presenting with
symptomatic myeloma and 1 with monoclonal gammopathy of
renal significance that progressed to symptomatic myeloma,
suggesting a potential relationship between C3 GN and MM. In
the present study, we presented a case with typical clinicopatho-
logic features of C3 GN and MM, providing additional evidence
for the association between C3 GN and MM.
Based on the present study and previous reports, we
hypothesize that C3 GN may be a new variant of renal
manifestation in MM. However, this causal relationship needs
further investigation. C3 GN is believed to be caused by
dysregulation of the alternative pathway of complement system.
This may be result from genetic mutations of proteins involved in
the pathway such as CFH, complement factor I (CFI), and
complement factor H related proteins (CFHRs).
[9]
However, it is
thought that genetic defect alone may not be sufficient to initiate
the disease in many patients.
[2,4]
A trigger factor that targets one
of the components of the pathway is often required for the
development of C3 GN, such as C3NeF, an autoimmune
antibody against C3 convertase,
[10]
and antifactor H antibody,
which targets CFH. In this study, the negative results of C3NeF
and antifactor H antibody excluded their roles in the pathogene-
sis of C3 GN in our patient. Instead, it is possible that the
abnormal monoclonal immunoglobulin produced by MM acts as
such a trigger factor that leads to abnormal activation of the
alternative complement pathway and contributes to the develop-
ment of C3 GN. The hypothesis that abnormal monoclonal
immunoglobulin may cause kidney diseases by dysregulating the
complement system has been proposed by Zand et al
[4]
based on
their observation in a case series of C3 GN associated with
monoclonal gammopathy. Further studies are needed to verify
this hypothesis and elucidate the effects of these abnormal
immunoglobulins on the complement system.
The association between C3 GN and MM has a number of
indications in clinical practice. First, as C3 GN is becoming better
recognized among physicians, it warrants a search for underlying
hematologic malignancy such as MM in patients with C3 GN.
Second, it suggests the importance of treating underlying
malignancy as part of the treatment of C3 GN. However,
chemotherapy may not contribute to an improvement in renal
function, depending on the stage of renal involvement.
In summary, this case study provides additional evidence for
the association between C3 GN and MM. Further studies are
needed to confirm this finding and clarify the mechanism behind
the association.
References
[1] Fakhouri F, Fremeaux-Bacchi V, Noel LH, et al. C3 glomerulopathy: a
new classification. Nat Rev Nephrol 2010;6:494–9.
[2] Pickering MC, D’Agati VD, Nester CM, et al. C3 glomerulopathy:
consensus report. Kidney Int 2013;84:1079–89.
[3] Sethi S, Fervenza FC, Zhang Y, et al. Atypical postinfectious
glomerulonephritis is associated with abnormalities in the alternative
pathway of complement. Kidney Int 2013;83:293–9.
[4] Zand L, Kattah A, Fervenza FC, et al. C3 glomerulonephritis associated
with monoclonal gammopathy: a case series. Am J Kidney Dis
2013;62:506–14.
[5] Kowalewska J, Nicosia RF, Smith KD, et al. Patterns of glomerular injury
in kidneys infiltrated by lymphoplasmacytic neoplasms. Hum Pathol
2011;42:896–903.
[6] Bourke E, Campbell WGJr, Piper M, et al. Hypocomplementemic
proliferative glomerulonephritis with C3 nephritic-factor-like activity in
multiple myeloma. Nephron 1989;52:231–7.
[7] Bridoux F, Desport E, Fremeaux-Bacchi V, et al. Glomerulonephritis
with isolated C3 deposits and monoclonal gammopathy: a fortuitous
association? Clin J Am Soc Nephrol 2011;6:2165–74.
[8] Cooper DL, Munday WR, Moeckel GW. C3 glomerulonephritis and
plasma cell dyscrasia: expanding the etiologic spectrum. Biol Med
2015;7:252.
[9] Servais A, Noel LH, Roumenina LT, et al. Acquired and genetic
complement abnormalities play a critical role in dense deposit disease
and other C3 glomerulopathies. Kidney Int 2012;82:454–64.
[10] Zhang Y, Meyer NC, Wang K, et al. Causes of alternative pathway
dysregulation in dense deposit disease. Clin J Am Soc Nephrol
2012;7:265–74.
Figure 4. Immunofluorescence microscopy showing positive staining for C3 in
the mesangium and along the capillary wall. 400magnification.
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