Emergence of proteinase 3-antineutrophil cytoplasmic antibody-associated glomerulonephritis with mesangial immune deposition during the clinical course of IgG λ monoclonal gammopathy of uncertain significance

Abstract

Patients with monoclonal gammopathy of uncertain significance (MGUS) is sometimes associated with renal diseases, usually due to the deposition of secreted monoclonal immunoglobulin or a fragment thereof, a condition which is defined as monoclonal gammopathy of renal significance. Patients with MGUS appear to be at increased risk for various autoimmune conditions. We report the case of a 68-year-old man developed nephritic syndrome and mild renal insufficiency during the course of IgG λ MGUS. Laboratory findings showed hypocomplementemia, cryoglobulinemia, proteinase 3-antineutrophil cytoplasmic antibody (PR3-ANCA) positivity and monoclonal proteins (λ light chain and λ-Bence-Jones protein) in the urine. A kidney biopsy revealed crescentic glomerulonephritis with mesangial immune deposits without paraproteins. Treatment with prednisolone for ANCA-associated glomerulonephritis, normalized urinalysis and decreased PR3-ANCA but MGUS persisted. This is a rare case of PR3-ANCA-associated glomerulonephritis with comorbid IgG λ MGUS with various pathological paraproteins. We highlight it as a clinical example with diagnostic and therapeutic implications.

Introduction

Monoclonal gammopathy of undetermined significance (MGUS), precursor of multiple myeloma (MM), is the most common type of plasma cell dyscrasia [1]. Patients with MGUS sometimes have renal diseases, usually due to the deposition of secreted monoclonal immunoglobulin (MIg) or a fragment thereof, a condition which is defined as monoclonal gammopathy of renal significance (MGRS) [2]. The spectrum of MGRS-associated disorders is wide, including MIg deposition disease, proliferative glomerulonephritis with MIg deposits and amyloidosis, cryoglobulinemic glomerulonephritis, light chain proximal tubulopathy, C3 glomerulopathy with monoclonal glomerulopathy, and so on [3].

Patients with MGUS/MM appear to be at increased risk for various autoimmune conditions [4]. The association between malignant hemopathy, including MM, and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) has been reported [5, 6]. One study reported that MIg present in the sera of patients with MGUS/MM exhibit specificities against both exogenous and self-antigens, including neutrophil cytoplasmic antigens [7].

In this report, we describe a rare case that presented with low-grade nephritic syndrome and mild renal insufficiency probably due to slowly progressive ANCA-associated glomerulonephritis in association with hypocomplementemia, cryoglobulinemia, proteinase 3 (PR3)-ANCA positivity and monoclonal proteins (λ light chains and λ-Bence-Jones protein) in the urine during the course of IgG λ MGUS.

Case report

A 68-year-old man with MGUS was admitted to our hospital for evaluation of his renal manifestations. He had a history of hypertension, hyperlipidemia and hyperuricemia. He presented with lumbago and slight body weight loss over the one year prior. In S-hospital, MIg-λ light chains in the serum were found, but plasma cells accounted for 4.1% of bone marrow cells. He was diagnosed as having MGUS. Since he had previously complained of slight appetite loss and fatigue associated with slight anemia over the past few months, he had been referred to the Division of Hematology in K-hospital one month before. Again, bone marrow examination did not support the development of MM or hematologic malignancies. However, an increase in serum creatinine (Cr) (from 0.81 to 1.15 mg/dL) over the past year was noted, and urine examination showed slight proteinuria (0.38 g/g Cr) and hematuria associated with red blood cell (RBC) casts. Other laboratory examinations revealed hemoglobin of 10.0 g/dL, C-reactive protein (CRP) of 3.14 mg/dL, hypocomplementemia, and a biological false-positive for syphilis but tests for antinuclear antibodies were negative. A year prior, there had been occult blood in the urine and the CRP test was positive. He was referred to our hospital and was admitted for kidney biopsy.

On admission, the patient had a height of 168.0 cm, a body weight of 57.0 kg, a temperature of 36.3 °C, and a blood pressure of 154/62 mmHg. His other physical examinations were unremarkable. He did not experience arthralgia or purpura. The initial laboratory findings are presented in Table 1. Laboratory tests detected nephritic syndrome and mild renal insufficiency, hypocomplementemia of C4, and elevated serum κ and λ free light chains (FLCs) and he was positive for CRP, PR3-ANCA, cryoglobulinemia (not quantitated), and C1q-binding immune complex. Examination of autoantibodies did not detect specific collagen diseases. Urinary immunoelectrophoresis showed monoclonal proteins (IgG λ light chains and λ-Bence-Jones protein). Computed tomography of the chest and paranasal sinus did not find granulomatosis with polyangiitis, though it revealed mild pulmonary emphysema. Abdominal echography showed normal-shaped kidneys.

Table 1.

Laboratory data on admission

Urine
Protein	2+
Occult blood	3+
Red blood cell	30–49/high power field
White blood cell	10–19/high power field
Red blood cell cast	Positive
Protein	0.6 g/g creatinine
NAG	45.2 U/L (0.7–11.2)
α1-microglobulin	32.4 mg/L (1.0–5.0)
Urine immunoelectrophoresis
IgG λ light chain	Positive
Bence-Jones protein-λ	Positive
Complete blood count
WBC	10,200 /µL
Hb	9.4 g/dL
Platelet	26.2 × 104 /µL
Blood chemistry
Total protein	6.8 g/dL
Albumin	2.8 g/dL
Urea nitrogen	19.5 mg/dL
Creatinine	1.21 mg/dL
Aspartate aminotransferase	13 U/L
Alanine aminotransferase	9 U/L
Alkaline phosphatase	207 U/L
γ glutamyltransferase	26 U/L
Lactate dehydrogenase	207 U/L
Na	138 mEq/L
K	4.0 mEq/L
Cl	108 mEq/L
Ca	8.7 mg/dL
P	2.9 mg/dL
LDL cholesterol	79 mg/dL
Estimated GFR	46.9 mL/min/1.73m2
Immunologic test
IgG	2477 mg/dL
IgA	276 mg/dL
IgM	230 mg/dL
κ free light chain	41.3 mg/L (3.3–19.4)
λ free light chain	89.2 mg/L (5.7–26.3)
κ/λ free light chain ratio	0.46
CH50	39 U/mL (32–58)
C3	96 mg/dL (65–135)
C4	11 mg/dL (13–35)
C-reactive protein	3.77 mg/dL
Rheumatoid factor	7.7 U/mL (0–14.9)
Antinuclear antibody	×40
Anti-dsDNA antibody	1.4 IU/mL (<9.0)
MPO-ANCA	1.0 U/mL (<3.4)
PR3-ANCA	20.9 U/mL (<3.4)
Anti-GBM antibody	2.0 U/mL (<2.9)
Cryoglobulin	Positive
Immune complex (C1q)	13.5 μg/mL (0–3)
HBs antigen	Negative
HCV antibody	Negative

NAG N-acetyl-β-d-glucosaminidase; GFR glomerular filtration rate; MPO-ANCA myeloperoxidase-anti-neutrophil cytoplasmic antibody; PR3-ANCA proteinase 3-anti-neutrophil cytoplasmic antibody; GBM glomerular basement membrane; HBs hepatitis B surface antigen; HCV hepatitis C virus

The values in the parentheses show the normal range

A kidney biopsy showed 2 globally sclerotic glomeruli out of 24 glomeruli. In non-sclerotic glomeruli, 3 showed cellular crescents with exudation of fibrin-like material and inflammatory cell infiltration in the intra- and extra-glomerular capillary area (Fig. 1A). Approximately half of the glomeruli showed a mild increase in mesangial cells and matrix (Fig. 1A). Mononuclear cell infiltration, tubular atrophy and fibrosis were found in approximately 15% of tubulointerstitial areas, mainly around the globally sclerotic or cellular crescentic glomeruli (Fig. 1A). RBC casts were found in the tubular lumen. The interlobular arteries and arterioles showed no vasculitis, but there was a mild to moderate degree of atherosclerosis and hyalinosis in the small arteries (Fig. 1A, B). Immunofluorescence staining was weakly positive for IgA, IgG, IgM, C3, κ and λ light chains in mesangial areas but negative for C1q. No immune reactants were found in the tubulointerstitial areas. The glomerular IgG subclasses mainly consisted of IgG2 with very weak positivity of IgG1 and IgG4, but IgG3 was negative (Fig. 1C–F). Paraffin immunofluorescence after antigen retrieval with proteinase K-aided digestion [8] showed enhanced positivity of immune reactants, which was found via immunofluorescence staining of frozen tissues, but did not reveal pathological paraprotein deposition (Fig. 1G–L). The direct fast scarlet stain was negative for amyloid. Electron microscopy revealed electron dense deposits lacking substructure in the mesangial areas, partial foot process effacement, and irregular thickening of the glomerular basement membrane (Fig. 2A). Marked platelet accumulation was found in the capillary lumen, and some platelets appeared to be in contact with endothelial cells (Fig. 2B). Infiltration of mononuclear cells and polymorphonuclear cells and fibrin deposition within the glomerular capillary lumina were also observed (Fig. 2C). There were no intracellular crystalline inclusions in renal tubules.

Fig. 1.

Kidney biopsy findings. A A light micrograph shows glomeruli with mild mesangial proliferation and focal segmental cellular crescent formation (arrow). There is mononuclear cell infiltration around the injured glomeruli. Original magnification ×200. Periodic acid-Schiff. B A small artery shows a mild sclerotic change, but no findings of vasculitis. Original magnification ×400. Elastica-Masson staining. C–F: Immunofluorescence staining shows mild granular positivity for IgG2 (D), trace positivity for IgG1 (C) and IgG4 (F) mainly in the mesangial areas, but negative for IgG3 (E). Original magnification ×200. G–L: Paraffin immunofluorescence after antigen retrieval with proteinase K-aided digestion shows trace positivity for IgA (G), and mild granular positivity for IgG (H), IgM (I), C3 (J), κ light chain (K) and λ light chain (L) mainly in the mesangial areas. Original magnification ×200

Fig. 2.

Electron micrograph of a glomerulus. A Electron dense deposits lacking substructure are found in the mesangial areas (arrows). Partial foot process effacement and irregular thickening of glomerular basement membrane are seen. Bar = 10.0 μm. B Marked platelet accumulation in the capillary lumen is found, and some platelets appear to be in contact with endothelial cell. Bar = 5.0 μm. C Infiltration of mononuclear cells and polymorphonuclear cells, and fibrin deposition within the glomerular capillary lumina are seen. Bar = 10.0 μm

Histologic characteristics of cryoglobulinemic glomerulonephritis are various, however, membranoproliferative glomerulonephritis is the predominant histologic pattern, seen in more than 90% of cases [9]. Crescent formation must be caused by the inflammation of glomerular capillary wall due to the subendothelial cryoglobulin deposition. The kidney biopsy in our patient showed the crescent formation, however, immunofluorescent pattern of immune reactants was not involved in the glomerular capillary walls, and electron microscopy did not show the subendothelial deposits even at the site of glomerular capillary wall injury. Therefore, our patient was diagnosed with ANCA-associated focal segmental crescentic glomerulonephritis and mild mesangial cell proliferation with a mesangial immune complex.

He was treated for AAV with 40 mg/day prednisolone, and his symptoms were soon alleviated. The urinalysis was almost normalized, renal function was stabilized, and anemia, hypocomplementemia, and cryoglobulinemia and CRP, PR3-ANCA and immune complex levels were normalized after prednisolone treatment (Fig. 3). In contrast, both κ and λ LFC levels decreased after the treatment, then only λ FLC levels gradually increased (Fig. 3) and the κ/λ FLC ratio dropped to 0.2. Urine monoclonal proteins (IgG λ and λ-Bence-Jones protein) were detected both at an early stage and at a follow-up 2 years after corticosteroid therapy (Fig. 3), indicating that IgG λ MGUS persisted.

Fig. 3.

The clinical course after the initial admission to our hospital. PSL prednisolone, U-prot urine protein/creatinine ratio, Cr serum creatinine, CRP C-reactive protein, PR3-ANCA proteinase 3-anti-neutrophil cytoplasmic antibody, Cryo cryoglobulin, IC immune complex, M-protein urinary monoclonal proteins (IgG λ light chains and λ-Bence-Jones protein), FLC free light chain

Discussion

MGRS was suspected in our patient before the kidney biopsy because he presented with nephritic syndrome with various MGUS-associated laboratory findings. He also was positive for PR3-ANCA; however, he did not show rapidly progressive glomerulonephritis but rather slowly progressive glomerulonephritis (the estimated glomerular filtration rate reduced by <50% over a 6-month period preceding diagnosis) [10].

The kidney biopsy revealed focal crescentic glomerulonephritis and mild mesangial proliferation with mesangial immune deposition. Proteinase K-aided digestion did not reveal pathological paraprotein deposits, further ruling out MGRS. As was the case for our patient, a recent study reported that substantial deposition of immunoglobulin or its complement was found in the mesangium and/or along the glomerular capillary wall in 53 ANCA-associated glomerulonephritis patients. In this study, deposition of C3 on the capillary wall was the most frequent finding, followed by deposition of C3+IgG and IgG alone. IgM and IgA were found in only two patients, along with C3 [11]. In a Japanese study on ANCA-associated glomerulonephritis with immunoglobulin deposition, IgG1 deposition was observed in all cases, but the incidence of IgG2, IgG3, and IgG4 deposition varied [12]. Immune complexes are thought to be deposited very early in the course of ANCA-associated glomerulonephritis and may play a role in the initiation of the disease process, although these deposits are usually removed by the severe inflammatory lesion before a biopsy is performed [13, 14]. The clinical course does not seem to be vary between groups with or without immunoglobulin deposition [15, 16]. After corticosteroid treatment, our patient’s symptoms, urinary abnormalities and inflammation were alleviated, and PR3-ANCA was normalized. Unlike our patient, previous studies have reported that patients with ANCA-associated glomerulonephritis with immune complex deposition have greater proteinuria than patients with classic pauci-immune glomerulonephritis [11, 15, 16]. On the other hand, similar to our patient, patients with immune complex deposition in ANCA-associated glomerulonephritis showed a higher prevalence of hypocomplementemia and greater glomerular cellularity [16]. In our patient, not only PR3-ANCA level but also hypocomplementemia and cryoglobulinemia were normalized with the disappearance of general inflammatory symptoms after corticosteroid treatment. Therefore, the clinical involvement of cryoglobulinemia could not be excluded.

While rare, there are reported cases of patients with both MGUS/MM and AAV. ANCA might be caused by MIg [7]. On the other hand, inflammation in the context of autoimmune disease may serve as a trigger for malignant hemopathies, including MGUS/MM [5]. It is also possible that a common genetic susceptibility underlies the development of both an autoimmune disease and MGUS/MM [4]. Upon clinically testing for ANCA, 7 cases were found to present with renal manifestations comorbid with MGUS/MM and rapidly progressive glomerulonephritis/acute kidney injury and were reported in detail [17–23]. Not all AAV patients were positive for ANCA [24]; in some ANCA-negative patients in consistent with AAV, the detection of ANCA with myeloperoxidase (MPO) in standard assays is masked by a natural inhibitor of MPO [25]. The detailed reports on the 10 patients that were ANCA-positive (n = 7) [17–23] or ANCA-negative (n = 3) [26–28] with MGUS (n = 3)/MM (n = 7) and rapidly progressive glomerulonephritis/acute kidney injury are listed in Table 2. Two cases were λ light chain MM, and 8 cases were κ light chain MGUS or MM. All 7 ANCA-positive patients had MPO-ANCA, and one had both MPO- and PR3-ANCA [21]. Eight cases showed renal AAV, and 2 cases with MM did not show renal vasculitis but showed cast nephropathy. Peak serum Cr levels ranged from 1.6 to 12 mg/dL, and 6 patients required hemodialysis. Five patients underwent maintenance hemodialysis, and 1 patient died even though the standard treatment for AAV or MM was provided upon diagnosis. One patient with MGUS was treated with standard MM therapy (bortezomib and dexamethasone) upon renal vasculitis relapse, and kidney function was improved and stabilized [26]. Our patient was a case of IgG γ MGUS and comorbid PR3-ANCA-associated glomerulonephritis and was well managed by corticosteroid monotherapy. However, though renal limited PR3-ANCA-positive vasculitis is extremely rare in Japan, it could not be excluded that the association of MGUS and AAV is fortuitous in our patient.

Table 2.

MGUS/MM patients with ANCA-positive or -negative rapidly progressive glomerulonephritis/acute kidney injury

Reported year [ref]	Age /Sex	Plasma cell dyscrasia	Serology	Symptoms	Renal manifestation	Renal histology	Treatment	Outcome
2005 [17]	72/M	IgG λ MM	MPO	Fever, malaise, anorexia, weight loss, myalgia, arthralgia	RPGN, Cr 8.0 mg/dL, prot 2 g/day	PICGN (crescentic), small vessel vasculitis	HD, PE, mPSL, CYC, PSL	Death due to hemorrhage
2013 [26]	60/M	IgG κ MGUS	Negative	Hypertension	RPGN, Cr 1.6 mg/dL, prot 1.9 g/gCr, hematuria	PICGN (focal)	Initial: IVCYC, steroids, AZP Relapse: Rx, CyA, BTZ, DEX	Improved renal function
2015 [27]	57/M	IgG κ MM	Negative	Nausea, emesis, weakness	RPGN, Cr 9.4 mg/dL, no prot, no hematuria	PICGN (sclerotic)	HD, BTZ, DEX	HD dependent
2016 [18]	64/F	IgG κ MM	MPO	Fatigue, poor appetite	RPGN, Cr 10.31 mg/dL, prot 3.5 g/day, hematuria	PICGN (mixed)	HD, supportive treatment	HD dependent
2017 [28]	58/F	IgG κ MM	Negative	Symptoms of polyarthropathy due to rheumatoid arthritis, rash, edema	RPGN, Cr 2.7 mg/dL (peak 3.1 mg/dL), prot 1.5 g/day, hematuria	PICGN (focal), arteriolar vasculitis	For rheumatoid arthritis; PSL, ETN, MTX, CYC For MM: BTZ, DEZ, For vasculitis: CYC	Improved renal function (Cr 1.2 mg/dL), death due to pulmonary hemorrhage
2019 [19]	46/M	IgG κ MGUS	MPO GBM	Fatigue, nausea, vomiting	RPGN, Cr 5.68 mg/dL, prot, hematuria	Crescentic GN with linear IgG,C3 staining	HD, PE, mPSL, CYC	HD dependent
2019 [20]	60/F	IgG κ MM	MPO GBM	Bone pain, loss of weight, anorexia, deep asthenia, edema	Anuric AKI, Cr12.44 mg/dL	Crescentic GN with linear IgG staining, κ LC cast nephropathy	HD For vasculitis: mPSL, PSL, IVCYC, PE For MM: THAL, CYC, DEZ	HD dependent
2019 [21]	85/M	IgG κ MM	MPO PR3	Weight loss, fatigue	CKD, Cr 1.6 mg/dL, RPGN, Cr 10.1 mg/dL, prot 2.416 g/day, hematuira	κ LC cast nephropathy	HD, BTZ, PE	HD dependent
2020 [22]	60/M	IgG λ MM	MPO	Cramping pain, psoriatic rash, onycholysis, mild edema	AKI, Cr 7.35 mg/dL, urinalysis not available	λ LC cast nephropathy	BTZ, DEX, THAL	Improved renal function (Cr 1.4 mg/dL)
2021 [23]	72/M	IgG κ MGUS	MPO	Generalized weakness, loss of appetite, edema, otitis media	AKI, Cr 2.08 mg/dL, mild prot, hematuria	Tubulointerstitial nephritis, κ LC restriction in the infiltrating plasma cells	PSL	Mild improved renal function
Our Case	68/M	IgG λ MGUS	PR3	Body weight loss, appetite loss, fatigue	Slowly progressive GN, mild prot, hematuria	PICGN (focal)	PSL	Stabilized renal function

M male, F female, MGUS monoclonal gammopathy of undetermined significance, MM multiple myeloma, MPO myeloperoxidase antineutrophil cytoplasmic antibody, PR3 proteinase 3-antineutrophil cytoplasmic antibody, RPGN rapidly progressive glomerulonephritis, GN glomerulonephritis, CKD chronic kidney disease, AKI acute kidney injury, Cr creatinine, prot proteinuria, PICGN pauci-immune crescentic glomerulonephritis, (focal) ≥50% normal glomeruli, (crescentic)  ≥50% cellular crescentic glomeruli, (sclerotic) ≥50% globally sclerotic glomeruli, (mixed) <50% normal, cellular crescentic, and globally sclerotic glomeruli, LC light chain, HD hemodialysis, PE plasma exchange, mPSL methylprednisolone pulse, PSL prednisolone, CYC cyclophosphamide, IVCYC intravenous cyclophosphamide, AZP azathioprine, Rx rituximab, CyA cyclosporin A, BTZ bortezomib, DEX dexamethasone, ETN etanercept, MTX methotrexate, THAL thalidomide

Rajkumar et al. reported that an abnormal κ/λ FLC ratio is an important risk factor for disease progression to malignancy and is independent of the size and type of serum M protein, two other known prognostic factors [29]. In our patient, the κ/λ FLC ratio changed from normal to 0.20 after corticosteroid therapy, indicating that IgG λ MGUS persisted after remission of AAV. If a pathological paraprotein systematically triggers neutrophil activation, resulting in AAV, a reduction in paraprotein production may be necessary to prevent the development of both malignant hemopathies and AAV. However, there is a lack of consensus as to when chemotherapies are justified in patients with MGUS with emerging comorbid autoimmune diseases.

In summary, this is a rare case of PR3-ANCA-associated glomerulonephritis with comorbid IgG λ MGUS that demonstrated various pathological paraproteins. We highlight it as a clinical example with diagnostic and therapeutic implications.

Funding

None.

Declarations

Conflict of interest

The authors have declared that no conflict of interest exists.

Compliance with Ethical Standards

This article does not contain any studies with human participants performed by any of the authors.

Informed consent

Written informed consent was obtained from the patient.