Two cases of idiopathic multicentric Castleman disease with nephrotic syndrome treated with tocilizumab

Abstract

We report two cases of idiopathic multicentric Castleman disease (iMCD) with nephrotic syndrome (NS) treated with tocilizumab. Case 1 was a 58-year-old man diagnosed with iMCD prior to the onset of NS. Renal biopsy revealed membranous nephropathy, which was considered to be secondary membranous nephropathy associated with iMCD. Case 2 was a 49-year-old woman diagnosed with iMCD prior to NS. Renal biopsy revealed renal amyloidosis positive for Congo red staining and amyloid A protein immunostaining. In both the cases, the proteinuria improved after the initiation of glucocorticoid and tocilizumab therapy. Tocilizumab may be a good therapeutic choice for iMCD with NS.

Introduction

Castleman disease (CD) is a polyclonal non-neoplastic lymphoproliferative disease that was first reported by Dr. Benjamin Castleman in 1956 [1]. CD is classified in accordance with the pathological and clinical manifestations. CD is pathologically classified as the hyaline vascular type or the plasma cell type [2]. CD is clinically classified as unicentric CD in which the lesion is localized in only one region, and multicentric CD (MCD) in which the lesions are present in multiple regions and the patient has prominent clinical symptoms. MCD is divided into three forms: Kaposi's sarcoma-associated herpesvirus (KSH)/human herpesvirus 8 (HHV-8)-positive MCD, idiopathic MCD (iMCD), and MCD with polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome [3]. The pathogenesis of CD remains unclear, but interleukin (IL)-6 plays an important role in the pathological mechanism, and the symptoms and pathology can be explained by overproduction of IL-6 [4]. In Western countries, HHV-8 is frequently associated with the pathogenesis of MCD, especially in human immunodeficiency virus (HIV)-positive individuals. In contrast, Japanese MCD cases are very rare with HHV-8 [5].

The clinical symptoms of MCD include lymphadenopathy, anemia, splenomegaly, renal dysfunction, fever, etc. [5]. The pathological types of renal complications are heterogeneous. The renal complications of MCD are reportedly associated with a poor prognosis [6].

The treatment algorithm of iMCD was reported by the Castleman Disease Collaborative Network. Tocilizumab and glucocorticoid are recommended for the treatment of iMCD, irrespective of severity [7]. Tocilizumab is a humanized anti-human IL-6 receptor monoclonal antibody that blocks the activity of IL-6, thus treating the symptoms and biochemical abnormalities in patients with CD [8]. To our knowledge, there are only two case reports of a patient with CD with nephrotic syndrome who was treated with tocilizumab [9,10].

Herein, we report two cases in which tocilizumab treatment was effective for the treatment of iMCD with nephrotic syndrome.

Case reports

Case 1

A 58-year-old Japanese man was admitted to our hospital for treatment of nephrotic syndrome. Hematuria had been detected at the age of 42 years, and hematuria and proteinuria (2 +) had been detected at the age of 48 years. At the age of 51 years, the patient had been diagnosed with MCD based on his systemic manifestations, systemic lymphadenopathy, hypergammaglobulinemia, and the pathological findings of a lymph node biopsy. He was diagnosed with plasma cell type iMCD on the basis of systemic manifestations and biopsy findings (Fig. 1a).

Fig. 1.

a Histological view of the neck lymph node biopsy in case 1 (HE stain). There is widening of the interfollicular region and atrophy of the germinal center (× 40 magnification). A prominent increase and infiltration of plasma cells is seen in the interfollicular region (inset × 200 magnification). b, c Histological examination of a renal biopsy in case 1. b Diffuse capillary wall thickening with endocapillary hypercellularity and cellular crescent are seen. PAS stain, × 400 magnification. c There are vacuolated appearance and focal spike formation in the glomerular basement membrane. PAM stain, × 1000 magnification. d There is a moderate chronic tubulointerstitial damage with focal interstitial cellular infiltration. PAS stain, × 400 magnification

The patient had been monitored without therapy because he was clinically asymptomatic. His serum creatinine (s-Cr) increased from 0.74 mg/dl at the age of 51 years to 1.0 mg/dL at the age of 58 years. His blood pressure was 141/75 mmHg. He had bilateral axial and inguinal superficial lymphadenopathy with no tenderness and good mobility. Chest radiography showed bilateral hilar adenopathy. His electrocardiogram was normal. Computed tomography (CT) of the region from the neck to the pelvis showed systemic lymphadenopathy, multiple pulmonary infiltrative shadows, splenomegaly, and hepatomegaly. Laboratory findings are shown in Table 1. Renal biopsy revealed that seven of 21 glomeruli showed global sclerosis. The remaining glomeruli revealed diffuse capillary wall thickening with focal segmental endocapillary hypercellularity and four active crescents (cellular and fibrocellular) (Fig. 1b). Periodic acid methenamine silver stain (PAM stain) revealed diffuse vacuolated appearance and focal spike formation of glomerular basement membrane (Fig. 1c). Chronic tubulointerstitial damage with interstitial cellular infiltration was noticed (Fig. 1d). Immunofluorescence microscopy showed diffuse peripheral granular deposits of IgG (Fig. 2a). IgG subclass analysis revealed predominant deposition of IgG1 and IgG2 (Fig. 2b, c), while IgG3 and IgG4 were not detected (Fig. 2d, e). PLA2R was focally weakly positive too (Fig. 2f). Electron microscopy included only glomeruli with global sclerosis. Other causes of secondary membranous nephropathy such as infection, malignancy, autoimmune disease, and potential drugs were ruled out.

Table 1.

Laboratory findings at start of treatment

Urinalysis		Blood Chemistry		Serological test
Gravity	1.020	Total protein	8.7 g/dl	Immunoglobulin G	4156 mg/dL
pH	6.0	Albumin	2.1 g/dl	Immunoglobulin A	512 mg/dL
Protein	3 +	Asparatate aminotransferase	11 IU/L	Immunoglobulin M	227 mg/dL
	4.4 g/gCr	Alanine aminotransferase	7 IU/L	Complement activity	69 U/mL
Occult blood		1 + Lactate dehydrogenase	99 IU/L	C3 component	104 mg/dL
Glucose	-	Total cholesterol	115 mg/dL	C4 component	23 mg/dL
Ketone	-	LDL-Cholesterol	72 mg/dL	Antinuclear antibody	160
		Triglycerides	70 mg/dL	anti ds-DNA	6 IU/mL
Blood count		Uric acid	5.9 mg/dL	anti ss-DNA	10 AU/mL
White blood cell	10,540/μl	Urea nitrogen	19 mg/dL	Rheumatoid factor	12 U/mL
Red blood cell count	377/μL	Creatinine	1.2 mg/dL	MPO-ANCA	0.1 U/mL
Hemoglobin	9.6 g/l	eGFR	48 ml/min/1.73m2	PR3-ANCA	10 U/mL
Hematocrit	31%	Sodium	139 mEq/L	Hepatitis B virus, surface antigen	(-)
Platelets	52 × 104 μl	Potassium	4.7 mEq/L	Hepatitis C virus antibody	(-)
		Chroride	109 mEq/L	HHV8	(-)
		C-reactive protein	8.6 mg/dL	IL-6	36 Pg/mL

Fig. 2.

Immunofluorescence findings in case 1. There is marked peripheral granular deposits of IgG (a). IgG subclasses (b–e) and PLA2R (f) are shown. Predominant granular deposits of IgG2 (g) are present along the glomerular capillary. Weak peripheral granular deposits of PLA2R (f) is seen. IgG3 (d), IgG4 (e) are not seen. × 400 magnification

Based on these findings, the patient was diagnosed with secondary membranous nephropathy (MN) associated with iMCD. Methylprednisolone (500 mg/day) was administered as pulse therapy for three consecutive days, after which the patient was started on oral prednisolone (0.8 mg/day) daily and tocilizumab (8 mg/kg) every 2 weeks. After starting treatment, CRP and proteinuria improved immediately. Since then, CRP and urine protein have been sustained at low levels using low amounts of glucocorticoid and tocilizumab (Fig. 3). Imaging performed about 5 weeks after treatment initiation showed improvements in systemic lymphadenopathy, pulmonary infiltrative shadows, and hepatosplenomegaly.

Fig. 3.

Clinical course in case 1. Serial changes in plasma CRP and proteinuria (UP/UCr). Both CRP and proteinuria improved immediately after the initiation of treatment. CRP elevated when we could not administer tocilizumab every 2 weeks because of operation of bone fracture

Case 2

A 49-year-old Japanese woman was admitted to our hospital for further examination of nephrotic syndrome. Axillary lymphadenopathy had been detected when she was 38 years old. At the age of 38 years, she had general malaise, low-grade fever, and weight loss of 10 kg. CT showed bilateral pulmonary ground-glass opacity nodules, splenomegaly, hepatomegaly, and right renal enlargement. Bone marrow was normal. Thus, CD was suspected. Biopsies were taken from the lung and mediastinal and inguinal superficial lymph nodes at the age of 40 years. She was diagnosed with plasma cell type iMCD on the basis of systemic manifestations and biopsy findings (Fig. 4a). Renal biopsy revealed mild interstitial nephritis. No therapy was administered because of her asymptomatic condition. Laboratory results from when she was 48 years old stated that her urine protein was ± (this expression was not understood) and s-Cr was 0.67 mg/dl.

Fig. 4.

a Histological view of the inguinal lymph node in case 2 (HE stain). Low-powered magnification (× 40 magnification) shows dilatation of the interfollicular region and a lymphoid follicle with an atrophic germinal center. High-powered magnification (inset × 200 magnification) shows massive infiltration of plasma cells. These histological findings are almost identical to those of case 1. b–d Histological examination of a renal biopsy in case 2 shows amyloid deposition in the mesangial area of a glomerulus. b H&E staining reveals homogeneous H&E positive material in the mesangial area. × 400 magnification. c Congo red positivity is noticed in mesangial area. × 400 magnification. d Amyloid A protein deposits are present in the mesangial area (immunohistochemical stain for amyloid A). × 400 magnification

On admission to our hospital, laboratory findings were shown in Table 2. Chest radiology and electrocardiography were normal. CT of the region from the chest to the pelvis showed systemic lymphadenopathy, multiple pulmonary infiltrative shadows, splenomegaly, hepatomegaly, and mild bilateral renal enlargement. Renal biopsy revealed that five of 13 glomeruli showed global sclerosis. Eosinophilic amorphous materials were deposited in the mesangial area, and polar vessels were positive for hematoxylin and eosin (H&E) staining, Congo red staining, and amyloid A immunostaining (Fig. 4b, c, d). Immunofluorescence microscopy revealed non-specific weak deposition of IgM and C3 in the same region as the amyloid deposition. Staining for κ and λ was negative. Electron microscopy included no glomeruli. Renal biopsy specimens obtained when the patient was 40 years old were negative for both Congo red staining and amyloid A immunostaining. A colon biopsy was performed during this hospital admission (when the patient was 49 years old), and Dylon staining revealed eosinophilic amorphous materials in the ileum and large intestine. The patient was diagnosed with secondary renal and intestinal amyloidosis due to iMCD. She was started on oral prednisolone (0.6 mg/kg) daily, and tocilizumab (8 mg/kg) every 2 weeks. CRP elevation improved immediately, while the urine protein improved gradually (Fig. 5). Imaging performed about 6 months after treatment initiation showed improvements in the systemic lymphadenopathy, pulmonary infiltrative shadows, hepatosplenomegaly, and renal enlargement.

Table 2.

Laboratory findings at kidney biopsy

Urinalysis		Blood Chemistry		Serological test
Gravity	1.010	Total protein	9.2 g/d	l Immunoglobulin G	4522 mg/dL
pH	6.5	Albumin	1.9 g/d	l Immunoglobulin A	853 mg/dL
Protein	2 +	Asparatate aminotransferase	10 IU/L	Immunoglobulin M	334 mg/dL
	5.2 g/gCr	Alanine aminotransferase	6 IU/L	Complement activity	56 U/mL
Occult blood	±	Lactate dehydrogenase	109 IU/L	C3 component	120 mg/dL
Glucose	-	Total cholesterol	154 mg/dL	C4 component	14 mg/dL
Ketone	-	LDL-Cholesterol	78 mg/dL	Antinuclear antibody	40
		Triglycerides	49 mg/Dl	anti ds-DNA	4 IU/mL
	Blood count	Uric acid	4.4 mg/dL	anti ss-DNA	11 AU/mL
White blood cell	6650/μl	Urea nitrogen	9 mg/dL	Rheumatoid factor	< 5 U/mL
Red blood cell count	365/μL	Creatinine	0.9 mg/dL	MPO-ANCA	0.1 U/mL
Hemoglobin	10.2 g/l	eGFR	55 ml/min/1.73m2	PR3-ANCA	0.1 U/mL
Hematocrit	31%	Sodium	137 mEq/	L Hepatitis B virus, surface antigen	(-)
Platelet	s 42 × 104 μI	Potassium	3.7 mEq/L	Hepatitis C virus Antibody	(-)
		Chrorides	105 mEq/L	HHV8	(-)
		C-reactive protein	5.4 mg/dL	IL-6	26 Pg/mL
				SAA	666 μg/mL

Fig. 5.

Clinical course of case 2. Serial changes in plasma CRP and proteinuria (UP/UCr). CRP improved immediately after the initiation of treatment, while the proteinuria improved gradually. CRP was elevated when we could not administer tocilizumab every 2 weeks because of upper respiratory tract infection

Discussion

IL-6 is a pleiotropic cytokine that plays a pivotal role in the pathogenesis and clinical symptomatology in many patients with iMCD [11]. Tocilizumab is antihuman IL-6 receptor antibody and recognizes both IL-6R on the cell membrane and SIL-6R, and blocks signaling [12]. Tocilizumab improves the symptoms and biochemical abnormalities associated with MCD [8]. CRP is a good pharmacodynamic surrogate marker for IL-6 bioactivity [13].

A previous study showed that 19 of 76 patients with CD (25%) exhibited renal involvement. In particular, MCD is often associated with renal complications. A literature review of 64 cases revealed that amyloidosis was the main pathological characteristic seen on renal biopsy (39%), then small vessel lesions (thrombotic microangiopathy 8% and membranoproliferative glomerulonephritis 11%), while membranous nephropathy was seen in 3 of 64 cases (5%) [6]. Clinical and experimental studies suggest that IL-6 contributes to renal injury in glomerulonephritis and other forms of renal disease [14].

Regarding MN, PLA2R has been identified as a target antigen in primary MN. When histological findings are considered, the prevalence of anti-PLA2R antibody in Japanese patients with primary membranous nephropathy increases to 70% [15]. On the other hand, the main IgG subclass of IgG deposition in primary membranous nephropathy is IgG4, and PLA2R and IgG4 are co-expressed in primary MN patients, while IgG1 and IgG2 are dominant in secondary membranous nephropathy due to systemic lupus erythematosus [16]. In our case, IgG1 and IgG2 were dominant and IgG4 was negative. Moreover, PLA2R was only segmentally positive. PLA2R is expressed in normal kidney. In a previous report, two cases of five secondary MN were recognized with PLA2R expression in the kidney biopsy [17], suggesting that PLA2R is sometimes expressed in some other diseases apart from idiopathic MN. Based on this we diagnosed with secondary MN associated with iMCD in Case 1. Overproduction of IL-6 may induce glomerulonephritis such as MN, via the induction of polyclonal hypergammopathy and a variety of autoantibodies. About complication of crescents, of 19 CD cases with renal involvement, in 11 cases renal biopsy was performed. 3 of 11 cases were diagnosed with crescentic glomerulonephritis, and one case was complicated with MN [6]. Whether three cases had ANCA was not described, four of 12 patients with acute kidney injury were found to have ANCA or antiglomelular basement membrane. ANCA-associated vasculitis was reported in the Japanese CD patient [18]. In our case, PR3-ANCA was positive and turned negative after treatment.

Regarding renal amyloidosis, a major cause of amyloid A amyloidosis is sustained IL-6-induced production of serum amyloid A [19], which suggests that anti-IL-6 receptor antibody may be used as a potential treatment for secondary amyloid A amyloidosis. A previous case report showed that tocilizumab histologically improved non-nephrotic amyloid A renal amyloidosis in a patient with MCD [20], a second renal biopsy performed 1 year after the initiation of tocilizumab treatment showed the clearance of amyloid deposits.

Many patients with iMCD exhibit VEGF overproduction [21]. VEGF overproduction appears to initiate a feedback-mediated decrease in VEGF production by podocytes. A combination of increased serum levels, but decreased local production of VEGF may explain the development of thrombotic microangiopathy glomerular injury [22]. Although we have not measured serum as well as kidney VEGF expression, VEGF may also play a role in the pathogenesis of renal lesion of iMCD.

As described above, the renal histological lesions associated with CD are heterogenous. This heterogeneity may be due to the pleiotropic action of IL-6.

There are international, evidence-based consensus treatment guidelines for idiopathic MCD [7]. Tocilizumab and glucocorticoids are recommended for the treatment of iMCD regardless of severity. Siltuximab is recommended as front-line therapy, and tocilizumab can be used if siltuximab is not available; however, siltuximab is not authorized in Japan. If satisfactory results are not obtained from first-line therapy, second-line therapy (immunomodulatory agents) is recommended. According to this guideline, we treated using tocilizumab and glucocorticoids.

In our two cases, therapy with tocilizumab and glucocorticoids was effective in the treatment of iMCD with nephrotic syndrome. The urine protein was improved immediately in case 1, while this improvement was gradual in case 2. We assume that the amyloid pattern in case 2 may have required more time to improve the proteinuria compared with the glomerulonephritis pattern in case 1. These two cases suggest that tocilizumab may be a good therapeutic choice for iMCD with nephrotic syndrome.

Patients with iMCD may show only mild symptoms. However, this disease can cause renal complications and eventually lead to nephrotic syndrome. Care must be taken to avoid renal complications during the treatment of iMCD.

Compliance with ethical standards

Conflict of interest

All the authors have declared no competing interest.

Human and animal rights

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

Informed consent

Informed consent was obtained from all individual participants included in the study.