A case of systemic sarcoidosis with mesangial proliferative glomerulonephritis showing predominant deposition of IgG in the mesangial region

Abstract

A 37-year-old African–British man was referred to our hospital for detailed examination because of persistent fever, swelling and pain in both ankle joints, and blurred vision for two months. Inguinal lymph node biopsy showed a large number of epithelioid granulomas without necrosis. Granulomatous anterior uveitis, nephropathy, high serum angiotensin-converting enzyme activity, and high serum-soluble interleukin-2 receptor were observed, and the diagnosis of systemic sarcoidosis was made. His serum creatinine was 1.4 mg/dL and hematuria, leukocyturia, and urine protein were also seen. The renal biopsy finding was mesangial proliferative glomerulonephritis, with no findings of granuloma formation or tubular interstitial nephritis. Immunofluorescence staining showed deposition of IgG, C3, and C1q in the mesangial region. IgG3 was dominant in subclass staining. There was no monoclonality on kappa and lambda staining. Electron microscopy showed predominant deposition in the mesangial region with some subepithelial and endothelial deposition. His hematuria and leukocyturia disappeared with steroid therapy, suggesting sarcoidosis-related nephropathy. A case of systemic sarcoidosis with mesangial proliferative glomerulonephritis showing predominant deposition of IgG in the mesangial region is presented. No cases of such histological findings have been reported so far, and it is necessary to analyze further cases to clarify the pathogenic significance of the renal biopsy findings observed in this case.

Introduction

Sarcoidosis is an unexplained inflammatory disease that forms epithelioid cell granulomas without necrosis. Renal lesions in sarcoidosis cases include lesions associated with abnormal calcium metabolism, glomerular lesions due to the background of systemic inflammatory diseases, and granulomatous interstitial nephritis. As to the glomerular lesions, a variety of different lesions have been described, including membranous nephropathy, IgA nephropathy, minimal-change disease, a proliferative or crescentic glomerulonephritis, and focal segmental glomerulosclerosis [1–3]. A case of systemic sarcoidosis with mesangial proliferative glomerulonephritis showing predominant deposition of IgG in the mesangial region is presented.

Case report

A 37-year-old African–British man had swelling and bilateral ankle pain, blurred vision, intermittent fever, and weight loss of 10 kg in 6 months. He visited a local doctor and was found to have renal dysfunction and a high CRP level, and he was referred to our hospital for detailed examination. At the time of admission, the patient was 164 cm tall and weighed 75.0 kg. Vital signs were as follows: temperature, 37.3 °C; pulse rate, 68 beats/min; blood pressure, 112/68 mmHg; respiratory rate, 16 breaths/min; and oxygen saturation, 98% (room air). Physical examination showed severe swelling and tenderness of bilateral ankles and swelling of the inguinal lymph nodes. The patient had a history of asthma, and eczema. He had no family history of renal disease.

Laboratory data at the time of admission are presented in Table 1. In addition to decreased renal function, laboratory examination showed elevated C-reactive protein (CRP), angiotensin-converting enzyme (ACE), and soluble interleukin-2 receptor (sIL2R) levels. Negative results were obtained for antinuclear antibodies, antineutrophil cytoplasmic antibodies, and rheumatoid factor. Urinalysis showed proteinuria of 0.7 g per gram creatinine, hematuria of 20–29 red blood cells per high-power field (HPF), and white blood cells of 5–9/HPF. No dysmorphic red blood cells or casts were observed. Urinary excretion of β2-microglobulin was in the normal range. Axillary and inguinal lymphadenopathy and a large number of patchy ground-glass shadows were observed on computed tomography (CT), mainly in the lower lobes of both lungs. No mediastinal hilar lymphadenopathy was observed. On close examination by an ophthalmologist demonstrated anterior ocular uveitis with lard-like posterior corneal deposits and Busacca nodules. Inguinal lymph node biopsy showed a large number of epithelioid granulomas without necrosis. Given all of these findings, he was diagnosed with systemic sarcoidosis.

Table 1.

Laboratory data at the time of admission

WBCs	6200/μL	CRP	8.7 mg/dL
Neutrophils	72%	IgG	1780 mg/dL
Eosinophils	4%	IgA	262 mg/dL
Basophils	1%	IgM	34 mg/dL
Monocytes	11%	C3	162 mg/dL
Lymphocytes	14%	C4	51 mg/dL
RBCs	506 × 104/μL	CH50	56 U/mL
Hb	12.2 g/dL	ANA	< 1:40
Hct	36.7%	P-ANCA	< 0.5 IU/mL
Plt	32.5 × 104/μL	C-ANCA	0.7 IU/mL
TP	7.7 g/dL	ACE	30.7 IU/L
Alb	3.5 g/dL	sIL2R	2320 U/mL
AST	68 IU/L	HBS-Ag	Negative
ALT	73 IU/L	HCV-Ab	Negative
LDH	237 IU/L	HIV-AgAb	Negative
BUN	15.7 mg/dL
Cre	1.35 mg/dL	Urinary P/C ratio	0.7 g/gCr
Ca	10.1 mg/dL	Urinary RBC	20–29/HPF
T-Chol	191 mg/dL	Urinary WBC	5–9/HPF
LDL-Chol	125 mg/dL	Urinary NAG	15.1 U/L
Glu	86 mg/dL	Urinary β2MG	227 μg/L
HbA1c	4.1%

ANA antinuclear antibody, P-ANCA perinuclear-antineutrophil cytoplasmic antibody, C-ANCA cytoplasmic-antineutrophil cytoplasmic antibody, ACE angiotensin-converting enzyme, sIL2R soluble interleukin-2 receptor, HBS hepatitis B surface, Ag antigen, HCV hepatitis C virus, Ab antibody, HIV human immunodeficiency virus, P/C protein/creatinine, RBC red blood cell, WBC white blood cell, NAG N-acetyl-glucosaminidase, β2MG beta 2 microglobulin

A renal biopsy was performed to investigate the pathology of this renal disease. Light microscopy examination of ten glomeruli showed one with global sclerosing changes, and mesangial proliferative change was noted in seven glomeruli, with no findings of granuloma formation or tubular interstitial nephritis (Fig. 1, a–c). Immunofluorescence staining showed deposition of IgG, C3, and C1q in the mesangial region (Fig. 1, d–h). There was no monoclonality on kappa and lambda staining (Fig. 1 i, j). Electron microscopy showed predominant deposition in the mesangial region with some subepithelial and endothelial deposition (Fig. 1, k–m). IgG3 was dominant in subclass staining (Fig. 2). From the above observations, the pathologic diagnosis was mesangial proliferative glomerulonephritis with predominant deposition of IgG in the mesangial region.

Fig. 1.

Renal biopsy specimens. a, b Periodic acid–Schiff staining. c Periodic acid–methenamine silver staining. d Immunofluorescent IgG staining. e Immunofluorescent IgA staining. f Immunofluorescent IgM staining. g Immunofluorescent C1q staining. h Immunofluorescent C3 staining. i Immunofluorescent kappa staining. j Immunofluorescent lambda staining. k, l, m Electron microscopy

Fig. 2.

Immunohistochemistry of paraffin tissue for IgG1 to 4. Immunofluorescence staining shows IgG3-dominant deposition in the mesangial region. a IgG1, b IgG2, c IgG3, d IgG4

Treatment was started with prednisolone 60 mg per day (0.8 mg/kg/day), and the patient’s general condition improved, CRP became negative, and ocular findings, lung lesion and bilateral ankle arthritis also improved. As to the nephropathy, hematuria and leukocyturia disappeared, and urinary protein decreased from 0.7 to 0.4 g. The creatinine level remained stable at about 1.3 to 1.5 mg/dL.

Discussion

It has been reported that clinically important renal lesions are found in about 35–50% of systemic sarcoidosis cases [4–7]. Renal lesions in sarcoidosis cases include lesions associated with abnormal calcium metabolism, glomerular lesions due to the background of systemic inflammatory diseases, and granulomatous interstitial nephritis [7]. As to the glomerular lesions, a variety of different lesions have been described, including membranous nephropathy, IgA nephropathy, minimal-change disease, a proliferative or crescentic glomerulonephritis, and focal segmental glomerulosclerosis [1–3]. A cohort study by Loffler et al. reported that 26% of patients had sarcoidosis with IgA nephropathy, and in all cases, treatment with prednisolone improved renal function and decreased urinary protein [2]. Auinger et al. also reported a case of sarcoidosis with ANCA-positive crescentic glomerulonephritis, suggesting some association between glomerulitis and sarcoidosis, although the details are unknown [8]. Table 2 shows a summary of case reports and observational studies of sarcoidosis with glomerular lesions published since 2000. According to this, membranous nephropathy was the most common in 20 cases, followed by IgA nephropathy in 16 cases. In addition, multiple cases of focal segmental glomerulosclerosis, necrotizing crescentic glomerulonephritis, and minimal-change nephrotic syndrome have also been reported. Based on the data in Table2, we illustrated the literature review of glomerulonephritis with sarcoidosis (after 2000) (Fig. 3). From this figure, it can be understood that most of the mesangial proliferative glomerulonephritis associated with sarcoidosis was IgA nephropathy, which was 16 out of 21 cases (76%). The other five cases were lupus nephritis with a full-house pattern, one case with C3, C4d, and C5b-9 deposits in the mesangial region, one case with IgM-immune complex in the mesangial region, and our case. From this, it can be said that the mesangial proliferative glomerulonephritis showing predominant deposition of IgG in the mesangial region seen in this case is rare.

Table 2.

Literature review of glomerulonephritis with sarcoidosis (after 2000)

Year	Author	Type of glomerulonephritis	Reference
2002	Altiparmak et al	FSGS	[10]
2002	Evangelista et al	Necrotizing crescentic GN	[11]
2003	Hamada et al	IgAN	[12]
2004	Soylu et al	Membranous nephropathy	[13]
2005	Hagiwara et al	Mesangial proliferative GN (C3, C4d, and C5b-9 deposits)	[14]
2005	Kahn et al	IgAN	[15]
2005	Kornev et al	IgAN	[16]
2006	Kanamori et al	IgM-immune complex GN	[17]
2007	Polaina et al	FSGS	[18]
2011	Knehtl et al	Membranous nephropathy (PLA2R-related)	[19]
2013	Martin-Navarro et al	FSGS	[20]
2013	Larsen et al	Membranous nephropathy (4 cases)	[21]
2013	Kabara et al	Necrotizing crescentic GN	[22]
2013	Stehle et al	Membranous nephropathy (11 cases), IgAN (6 cases), FSGS (4 cases), MCNS (3 cases), proliferative lupus nephritis (2 cases)	[1]
2013	Svobodova et al	Membranous nephropathy (PLA2R-related)	[23]
2014	Zilberman et al	Membranous nephropathy	[24]
2015	Löffler et al	IgAN (7 cases)	[2]
2015	Stehle et al	Membranous nephropathy (PLA2R-related)	[25]
2018	Al-Hwiesh et al	Necrotizing crescentic GN	[26]
2019	Akbari et al	IgAN	[27]
2019	Tsuchiya et al	Necrotizing crescentic GN (MPO-ANCA-positive)	[28]
2020	Sugai et al	Necrotizing crescentic GN	[29]
2021	Yoshida et al	Membranous nephropathy	[30]
Present case	Watanabe et al	Mesangial proliferative GN with IgG deposition	–

FSGS focal segmental glomerulosclerosis, GN glomerulonephritis, IgAN immunoglobulin A nephropathy, MCNS minimal-change nephrotic syndrome

Fig. 3.

Literature review of glomerulonephritis with sarcoidosis (after 2000). MN membranous nephropathy, IgAN IgA nephropathy, FSGS focal segmental glomerulosclerosis, NCGN necrotizing crescentic glomerulonephritis, Mes PGN mesangial proliferative glomerulonephritis, MCNS minimal-change nephrotic syndrome

In this report, a case of systemic sarcoidosis with mesangial proliferative glomerulonephritis showing predominant deposition of IgG in the mesangial region was presented. The glomerulus showed an increase in substrate and cell proliferation in the mesangial region, and the basement membrane showed no changes, such as spike formation or double contour. In addition, no findings suggestive of interstitial inflammation were found in the interstitial region. The characteristic finding of mesangial proliferative nephritis in this case was that IgG and complement were deposited on immunostaining, and IgG3 was predominant on subclass staining. An IgG3-dominant staining pattern is found in autoimmune diseases such as SLE and rheumatoid arthritis [9]. The IgG3-dominant deposition pattern in the present case may have been associated with sarcoidosis in some way, but the details are unknown. Since some kind of deposition disease such as light chain deposition disease (LCDD) was also in the differential diagnosis, κ and λ staining was also performed, but there was no monoclonality. No cases of such histological findings have been reported so far, and it is necessary to analyze further cases to clarify the pathogenic significance of the renal biopsy findings observed in this case.

Declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Human and animal rights

This article does not describe any studies with human participants or animals performed by any of the authors.

Consent for publication

Informed consent was obtained from the patient for publication of the case details.