C3 glomerulonephritis associated with monoclonal gammopathy: a retrospective case series study from a single institute in China

Figures & data

Table 1. Demographic and clinical evaluation of patients with C3GN and monoclonal gammopathy.

Patient No.	Age(yrs)/Gender	Initial symptom	Disease courrse (m)	Anemia	HTN	Baseline SCr (μmol/L)	Baseline eGFR (ml/min/1.73m ^2)	UTP (g/24hr)	Urine microscopy	Alb (g/L)	Autoantibody	Cryoglobulin
1	46/M	Fatigue	5	No	No	95	82.37	2.08	Negative	42.7	Negative	Negative
2	62/M	Proteinuria	72	No	Yes	167	37.22	3.65	RBCs	28.3	Negative	NA
3	63/M	Gross hematuria	5	Yes	Yes	215.9	27.65	2.05	RBCs and WBCs	38.2	Negative	Negative
4	70/M	Edema	48	Yes	No	69.8	91	4.28	RBCs and WBCs	20	ANA 1：80	Negative
5	47/M	Edema	9	Yes	Yes	181.5	37.39	13.22	RBCs and WBCs	21.3	Negative	Negative
6	60/M	Proteinuria	6	Yes	Yes	102.1	84.68	0.72	Negative	29.6	Negative	NA
7	70/M	Edema	7	Yes	No	88.6	70.54	6.39	RBCs and WBCs	26.2	Negative	Negative
8	26/M	Edema	3	Yes	Yes	158	51.25	6.31	RBCs and WBCs	27.8	Negative	0
9	57/M	Edema	4	No	Yes	484.9	10.63	6.93	RBCs and WBCs	24.6	ANA 1：80	0
10	44/M	Microscopic hematuria	48	No	No	255.6	25.25	6.36	RBCs	20.7	Negative	NA
11	53/M	Edema	12	Yes	Yes	282	21.04	7.67	Negative	31.1	Negative	NA
12	47/M	Edema	30	Yes	No	101.2	75.77	7.28	RBCs and WBCs	24.5	Negative	Negative
13	76/M	Proteinuria	24	Yes	Yes	168.8	33.3	3.65	RBCs and WBCs	20.6	Negative	Negative
14	71/F	Edema	36	Yes	Yes	108.3	44.46	5.28	RBCs and WBCs	23.2	Negative	Negative
15	40/F	Edema	8	Yes	Yes	162.9	33.74	4.48	RBCs and WBCs	33	Negative	NA
16	41/F	Edema	48	Yes	Yes	195.1	26.93	19.03	RBCs and WBCs	20.2	Negative	polyclonal IgGκ
17	47/M	Elevated Scr	48	Yes	Yes	647.8	8.03	12.82	Negative	34.8	Negative	polyclonal IgG and monoclonal κ
18	47/M	Edema	3	No	No	60.69	113.28	0.24	Negative	36.2	Negative	NA
19	58/F	Proteinuria	3	No	No	83.1	67.08	1.15	RBCs	36.5	Negative	Negative

Abbreviations: WBCs: white blood cells; RBCs: red blood cells; N/A: not available; HTN: hypertension; UTP: proteinuria.

Table 2. Complement and hematological evaluation and kidney biopsy findings of patients with C3GN and monoclonal gammopathy.

Patient No.	C3 (g/L)	C4 (g/L)	CFH (ug/ml)	Anti-CFH antibody	C3-Nef	Serum/urine IFE	Plasma cell% on bone marrow	Pattern of renal injury	Immunofluorescopic findings	% GS glomeruli	% Crescents	% interstitial fibrosis	Electron dense deposits
1	0.89	0.27	NA	NA	NA	Negative / IgGκ	None	MsPGN	C3+	16	0	10	MES
2	0.88	0.21	NA	NA	NA	IgG λ/ IgGλ	1.5	FPGN	C3+++	46	0	45	MES,SU,SE
3	0.56↓	0.25	150.4↓	Negative	Negative	IgGκ / IgGκ	1.0	FPGN + TIN	C3+++	5	18	35	MES,SU,IM
4	0.51↓	0.06↓	187.3↓	Negative	Negative	IgGκ / IgGκ	6.0	EPGN	C3++, IgG±	6	0	10	MES,SE
5	0.81	0.25	608.7	Negative	Negative	IgGλ / IgGλ	None	FPGN + DN	C3+++, IgA+, IgG+, λ+	35	9	15	MES,IM,SE
6	0.59↓	N/A	NA	NA	NA	IgAκ / IgAκ	6.5	MsPGN	C3+++	0	0	0	MES,SU
7	0.59↓	0.246	452.6	Negative	Negative	IgGκ / IgGκ	3.0	MPGN	C3+++, IgA+	0	10	0	MES,SE
8	0.74	0.26	314.4	Negative	Negative	IgGκ / Negative	NA	MPGN	C3+++ ,IgA+, IgG+	32	27	30	MES,SU
9	0.39↓	0.12	252.4	Negative	Negative	IgGλ / IgGλ	2.5	FPGN + TIN	C3+++, IgA+	8	56	40	MES,SU
10	0.58↓	0.19	222.7↓	Negative	Negative	IgGλ / IgGλ	3	FPGN + TIN	C3+++	0	28	15	MES,SU,SE
11	0.57↓	0.374	547.5	Negative	Negative	IgGλ / IgGλ + λ	2.5	MPGN	C3+++, IgG±, IgM±, λ±	22	0	40	MES,SU
12	0.66	0.12	438.1	Negative	Negative	IgGκ / IgGκ + κ	1	MPGN	C3+++, C1q±	74	0	60	MES,SU,IM,SE
13	0.37↓	0.2	392.9	Positive	Positive	IgGλ / IgGλ	1.5-5.5	MPGN	C3+++, C1q±	0	17	10	MES,SU,SE,IM
14	0.50↓	0.26	432.2	Negative	Negative	IgGκ / IgGκ	2.0	MPGN	C3+++, IgM+	44	6	50	MES,SE,IM
15	0.55↓	0.18	NA	NA	NA	IgGκ / IgGκ	1.0	MPGN	C3+++, IgG±	2	36	20	MES,SU,IM
16	0.649	0.102↓	NA	NA	NA	IgGκ / IgGκ	2.0	MPGN with TMA	C3++, IgG±	4	12	40	MES, SU
17	0.575↓	0.109↓	575.7	Negative	Negative	IgGλ / IgGλ	1.0	MsPGN with TMA	C3+++, IgA+, IgM+	60	0	70	MES, IM
18	0.924	0.21	NA	NA	NA	IgAλ / λ	42.5	MsPGN with LCPT	C3+++, IgA+	0	0	0	MES, SU
19	<0.058↓	0.236	NA	NA	NA	IgGκ / IgGκ	1.5	FPGN + CLL interstitial infiltration	C3++,IgG±	0	25	10	SE

The normal range of C3 was 0.6–1.5g/L, C4 was 0.12–0.36 g/L, CFH was 247–1010.8 ug/ml in our institute.

CLL: chronic lymphocyte leukemia; DN: diabetic nephropathy; EPGN: Endocapillary proliferative glomerulonephritis; FPGN: focal proliferative glomerulonephritis; GS: globally sclerosed; IF: immunofluorescence; IG: immunoglobulin; IM: intramembranous; LCPT: light-chain proximal tubulopathy; MsPGN: mesangial proliferative glomerulonephritis; MES: mesangial; MPGN: membranoproliferative glomerulonephritis; SE: subepithelial; SU: subendothelial; TMA: thrombotic microangiopathy; TIN: tubulointerstitial nephritis.

Figure 1. Light, immunofluorescence, and electron microscopy findings in a C3GN patient with monoclonal gammopathy (patient #15). (A) Light microscopy showed a membranoproliferative pattern of injury with a small fibrocellular crescent formation (Periodic acid-silver methenamine + Masson trichrome staining, ×400). (B) Immunofluorescence staining showed bright C3 in the mesangial and along segmental capillary walls (×400). (C) Electron microscopy showed electron-dense deposits in subendothelial, intramembranous and mesangial regions (×8000).

Figure 2. Light, immunofluorescence, and electron microscopy findings in a C3GN patient with TMA-like lesions (patient #17). (A) Light microscopy showed a mesangial proliferative pattern of injury with endocapillary hypercellularity and segmental sclerosis (Periodic acid-silver methenamine + Masson trichrome staining, B × 400). (B) Immunofluorescence studies showed bright C3 in the mesangial and along segmental capillary walls (×400). (C): Electron microscopy showed electron-dense deposits in mesangial and intramembranous regions and subendothelial edema with narrowing of the capillary lumen (×8000).

Table 3. Treatment and kidney measures at follow up of patients with C3GN and monoclonal gammopathy.

Patient No.	Therapy	RASi	Follow-up time (months)	Death	Death Causes	Renal outcomes	Last time eGFR (ml/min/1.7m^2)	Last time UTP (g/d)
1	Supportive	No	Lost follow-up	NA	/	N/A	NA	NA
2	Supportive	Yes	43	No	/	ESRD after 12 months	NA	NA
3	Supportive	Yes	57	No	/	ESRD after 24 months	NA	NA
4	Supportive	Yes	45	No	/	Not dialysis-dependent	NA	NA
5	Supportive, PE*6	Yes	8	No	/	ESRD after 5 months	NA	NA
6	Supportive	Yes	Lost follow-up	NA	/	N/A	NA	NA
7	Supportive, PE*4	Yes	1	Yes	Sepsis	Not dialysis-dependent	NA	NA
8	Steroid alone for about 6 months	No	12	No	/	ESRD after 12 months	NA	NA
9	Steroid + CYC for about 4 months	No	15	Yes	Sepsis	Persistent ESRD	NA	NA
10	Steroid + CYC/MMF for about 12 months	Yes	45	No	/	Improved renal funcion	47.20	0.56
11	Steroid + CYC for about 6 montsh, and PE*4	Yes	13	No	/	ESRD after 6 months	NA	NA
12	Steroid + CYC/CsA/MMF for about 20 months and PE*9	Yes	27	No	/	eGFR decline > 50%	14.99.	11.72
13	Steroid + CYC/MMF for about 12 months and PE*6	No	20	No	/	Improved renal function	52.51	0.24
14	PE*5 and sequential RTX 500 mg once	Yes	10	Yes	GIB	ESRD after 10 months	NA	NA
15	Steroid, CYC and Following BD*6 cycles	Yes	44	No	/	Improved renal function	68.59	0.04
16	BCD*6 cycles	Yes	9	No	/	Stable renal function	21.75	12.9
17	BCD*4 cycles	Yes	8	No	/	Persistent ESRD	10.21	2.38
18	BCD*4 cycles + ASCT	Yes	21	No	/	eGFR decline > 50%	55.61	0.50
19	COP	Yes	34	No	/	eGFR decline > 25%	42.98	NA

ASCT: autologous stem cells transplantation; BCD: bortezomib + cyclophosphamide + dexamethasome; BD: bortezomib + dexamethasome; COP: cyclophosphamide + Oncovin + prednisone; CYC: cyclophosphamide; CsA: cyclosporine A; GIB: gastrointestinal bleeding; MMF: mycophenolate mofetil; PE: plasma exchange; RTX: rituximab.

Table 4. Previous reports of patients with C3G and monoclonal gammapathy.

Authors	Year	Patients, n	Age	M/F, n/n	Serum MIg, n	Haematological diagnosis, n	Treatment	Renal outcomes, n
Sethi et al. [11]	2010	10	60 (49–77)	2/8	IgGκ: 6 IgGλ: 3 IgA & IgGλ: 1	MGRS	No specific therapy	ESRD: 4; Worsen: 2; Stable: 4
Bridoux et al. [5]	2011	6	67.5 (40–74)	3/3	IgGκ: 4 IgGλ: 2	MGRS: 5 Smoldering MM: 1	No treatment: 2; Steroid: 1; Mel + Steroid: 1; Steroids + CYC: 1; BD: 1	ESRD: 5 Worsen: 1
Zand et al. [6]	2013	10	61.5 (22–69)	7/3	IgGκ: 6 IgGλ: 2 IgAλ: 1 IgMλ: 1	MGRS:9	Conservative: 4;	ESRD: 3; Stable 6; Improved: 1
Lloyd et al. [7]	2016	10	63.5 (52–90)	9/3	IgGκ: 8 IgGλ: 1 IgAκ: 1	MGRS: 5 MM: 4 Polyclonal plasmacytosis: 1	Conservative: 4; RTX + COP: 1; BD:1; Immunosuppressants: 4	ESRD: 5 Stable: 3; Improved: 2
Chauvet et al. [12]	2017	50	65 (38–82)	33/17	IgGκ: 36 IgGλ: 11 IgAκ: 1 I IgAλ: 1 λ LC only: 1	MGRS: 30 Smoldering MM: 15 Symptomatic MM: 2 CLL: 3	Conservative: 13; immunosuppressive therapy: 8; clone-directed chemotherapy: 29 (including bortezomib in 22 patients)	ESRD: 25 (9 in the chemotherapy group)
Ravindran et al. [9]	2018	36	60 (20–85)	25/11	IgG: 31 IgM: 3 IgA: 1 κ: 26 λ: 10	MGRS: 26 Smoldering MM: 2 Symptomatic MM: 5 CLL: 1 Cryoglobulinemia (type 1): 1 Cryoglobulinemia (type 2): 1	Conservative: 3; non-targeted therapy: 17; MIg-targeted therapy: 16	Improved or Stable : 44% of patient with MIg-targeted therapy and 41% of patients with non-targeted therapy.

BD: bortezomib + dexamethasome; COP: cyclophosphamide + Oncovin + prednisone; CYC: cyclophosphamide; ESRD: end-stage renal disease; MGRS: monoclonal gammopathy of renal significance; MM: multiple myeloma; MPGN: membranoproliferative glomerulonephritis; Mel: Melphalan; RTX: rituximab.

Sethi S, Sukov WR, Zhang Y, et al. Dense deposit disease associated with monoclonal gammopathy of undetermined significance. Am J Kidney Dis. 2010;56(5):977–982.

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Bridoux F, Desport E, Frémeaux-Bacchi V, et al. Glomerulonephritis with isolated C3 deposits and monoclonal gammopathy: a fortuitous association? Clin J Am Soc Nephrol. 2011;6(9):2165–2174.

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Zand L, Kattah A, Fervenza FC, et al. C3 glomerulonephritis associated with monoclonal gammopathy: a case series. Am J Kidney Dis. 2013;62(3):506–514.

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Lloyd IE, Gallan A, Huston HK, et al. C3 glomerulopathy in adults: a distinct patient subset showing frequent association with monoclonal gammopathy and poor renal outcome. Clin Kidney J. 2016;9(6):794–799.

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Chauvet S, Frémeaux-Bacchi V, Petitprez F, et al. Treatment of B-cell disorder improves renal outcome of patients with monoclonal gammopathy-associated C3 glomerulopathy. Blood. 2017;129(11):1437–1447.

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Ravindran A, Fervenza FC, Smith RJH, et al. C3 glomerulopathy associated with monoclonal Ig is a distinct subtype. Kidney Int. 2018;94(1):178–186.

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Data availability statement

All data generated or analyzed during this study are included in this published article.