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Case Reports
. 2024 Dec 20:12:73-82.
doi: 10.5414/CNCS111337. eCollection 2024.

Significant response to tocilizumab in a case of immune deposits-related membranoproliferative glomerulonephritis and tubulointerstitial nephritis complicated by multicentric Castleman's disease

Hisashi Sugimoto  1 , Naoki Sawa  1 , Daisuke Ikuma  1 , Yuki Oba  1 , Hiroki Mizuno  1 , Akinari Sekine  1 , Masayuki Yamanouchi  1 , Eiko Hasegawa  1 , Tatsuya Suwabe  1 , Takehiko Wada  1 , Kei Kono  2 , Keiichi Kinowaki  2 , Kenichi Ohashi  2   3 , Kazuho Honda  4 , Yukiko Kanetsuna  5 , Kensuke Joh  6 , Yutaka Yamaguchi  7 , Yoshifumi Ubara  1
Affiliations
Case Reports

Significant response to tocilizumab in a case of immune deposits-related membranoproliferative glomerulonephritis and tubulointerstitial nephritis complicated by multicentric Castleman's disease

Hisashi Sugimoto et al. Clin Nephrol Case Stud. .

Abstract

A 47-year-old woman with a 12-year history of anemia and high C-reactive protein (CRP) levels was admitted to our hospital with worsening fatigue and night sweats. She had high levels of immunoglobulin G (IgG; 4182 mg/dL), IgA (630.6 mg/dL), and CRP (7.44 mg/dL); a low hemoglobin level (8.9 g/dL); urinary protein (11.83 g/day); and urinary sediment (20 - 29 red blood cells per high power field). On the basis of the clinical findings and biopsied lymph nodes, we diagnosed multicentric Castleman's disease (MCD). Light microscopy of kidney biopsy samples revealed various nephropathies, including membranoproliferative glomerulonephritis with crescentic formation and focal segmental sclerosis and tubulointerstitial nephritis. Immunofluorescence and electron microscopy revealed IgG-positive deposits in the subepithelial areas, mesangial areas, and tubular basement membrane. The patient's clinical findings including kidney disease improved after treatment with tocilizumab. MCD is considered to be caused by abnormally high levels of interleukin (IL)-6. Tocilizumab, an IL-6 receptor antagonist, was effective in this patient, indicating that the immune complex-related kidney findings were also related to MCD.

Keywords: membranoproliferative glomerulonephritis; multicentric Castleman’s disease; tubulointerstitial nephritis.

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Conflict of interest statement

The authors declare no competing financial interests and no conflicts of interest. Figure 1Axillary lymph node biopsy. Hematoxylin and eosin stain showed an increased number of follicles with large hyperplastic germinal centers showing a minor hyaline vascular pattern; however, only partial plasma cell infiltration was seen in the interfollicular region. Original magnification × 200; bar = 30 μm.Figure 2a – d1st kidney biopsy. a: Endocapillary proliferative changes characterized by endothelial cell swelling and hyperplasia (arrow) with mesangiolysis were noted, together with neutrophil and monocyte infiltration. Periodic acid methenamine silver (PAM) staining; original magnification × 400; bar = 50 μm. b: In the four glomeruli with more severe endothelial cell damage, cellular crescent formation (*) was seen, characterized by epithelial cell swelling and hyperplasia with massive hyaline drop degeneration (arrow). Periodic acid-Schiff stain (PAS) staining; original magnification × 400; bar = 50 μm. c: In addition to cellular crescent formation (*), fibrocellular crescent formation (arrow) was also observed. PAM staining; original magnification × 400; bar = 50 μm. d: Focal segmental sclerosis (arrow) was noted. Masson trichrome staining; original magnification × 400; bar = 50 μm.Figure 2e – h1st kidney biopsy. e: Endothelial cell swelling of arterioles (arrow) with lymphocytic infiltration was seen. PAM staining; original magnification × 200; bar = 30 μm. f: Focal inflammatory cell infiltrates in the tubular interstitium and tubulitis were noted. Hematoxylin and eosin staining; original magnification × 200; bar = 30 μm. g: Moderate atherosclerosis was present in the interlobular arteries (large level). Masson trichrome staining; original magnification × 100; bar = 100 μm. h: Hyalinosis of the arterioles was mild. PAS staining; original magnification × 200; bar = 20 μm.Figure 2i1st kidney biopsy. i: Lymph follicle formation was also observed in part of the tubulointerstitium. Original magnification × 200, bar = 50 μm.Figure 2j1st kidney biopsy. j: Immunofluorescence microscopy revealed granular deposits of immunoglobulin G (IgG), IgG1, IgG2, and C3 along the glomerular basement membrane, Bowman’s capsule, and tubular basement membrane. The GBM was partially positive for C1q and positive for IgG4. Original magnification × 100; bar = 20 μm. Figure 2k - n1st kidney biopsy. k: Electron microscopy revealed electron-dense deposits in subepithelial regions (arrow) of the glomerular basement membrane. l: Electron-dense deposits(arrow) in the mesangial area. m: Electron-dense deposits (arrow) on the tubular basement membrane. n: Electron-dense deposits(arrow) on the basement membrane of Bowman’s capsule. Table 1.Renal pathology. Renal biopsy findings1st2ndGlobal sclerosis0/2725/102Segmental sclerosis+–Mesangial matrix expansion±±Mesangial cell proliferation±±AcuteEndocapillary proliferative changes+–Crescent formation+–Interstitial inflammation+++ChronicDuplication of the basement membrane++Spike formation––Tubular atrophy+++Interstitial fibrosis+++Amyloid deposition––IFIgA deposition––IgG deposition (mesangial region)+±IgG deposition (capillary wall)++C3 deposition+–C1q deposition+–The findings from the first and second renal biopsies were recorded. The crescent formation and endothelial cell damage, which were considered acute lesions, showed improvement. Additionally, the deposits of C3 and IgG had also improved. IF = immunofluorescence. Figure 3Clinical course.Figure 42nd kidney biopsy. a+b: The endocapillary proliferative changes seen in the first biopsy were greatly improved. a: PAS staining; original magnification × 400, bar = 20 μm. b: PAM staining; original magnification × 400, bar = 20 μm. c: IgG deposition in IF was reduced in glomeruli; original magnification × 400, bar = 20 μm, d: C3 deposition in IF was reduced in glomeruli; original magnification × 400, bar = 20 μm. e: Subepithelial EDDs (arrow) were greatly reduced in EM, bar = 2.0 μm. f: Inflammatory cell infiltration and fibrosis of the tubulointerstitium improved to 15 – 20% of the cortical area. Masson trichrome staining; original magnification × 100, bar = 500 μm. Table 2.Renal pathology of Castleman’s disease reported to be associated with IL-6. ReferenceDiagnosis by renal pathology or clinical diagnosisTreatment[4]Mesangial matrix proliferation, mesangial cell proliferation, interstitial inflammation, fibroelastosisTocilizumab[5]AA amyloidTocilizumab[6]IgAVMMF + Tac + tocilizumab[7]Mesangial hypercellularity, matrix expansion, GBMs showed segmental double contouringTocilizumab[8]IgAVTocilizumab[10]Tubulointerstitial lymphoplasmatic infiltrates mimicking IgG4-related diseasePSL + tocilizumabThe renal pathology in Castleman’s disease, which has been associated with IL-6, is described. The renal lesions exhibit a variety of characteristics. GBMS = glomerular basement membranes; MMF = mycophenolate mofetil; Tac = tacrolimus; PSL = prednisolone.

Figures

Figure 1
Figure 1. Axillary lymph node biopsy. Hematoxylin and eosin stain showed an increased number of follicles with large hyperplastic germinal centers showing a minor hyaline vascular pattern; however, only partial plasma cell infiltration was seen in the interfollicular region. Original magnification × 200; bar = 30 μm.
Figure 2a – d
Figure 2a – d. 1st kidney biopsy. a: Endocapillary proliferative changes characterized by endothelial cell swelling and hyperplasia (arrow) with mesangiolysis were noted, together with neutrophil and monocyte infiltration. Periodic acid methenamine silver (PAM) staining; original magnification × 400; bar = 50 μm. b: In the four glomeruli with more severe endothelial cell damage, cellular crescent formation (*) was seen, characterized by epithelial cell swelling and hyperplasia with massive hyaline drop degeneration (arrow). Periodic acid-Schiff stain (PAS) staining; original magnification × 400; bar = 50 μm. c: In addition to cellular crescent formation (*), fibrocellular crescent formation (arrow) was also observed. PAM staining; original magnification × 400; bar = 50 μm. d: Focal segmental sclerosis (arrow) was noted. Masson trichrome staining; original magnification × 400; bar = 50 μm.
Figure 2e – h
Figure 2e – h. 1st kidney biopsy. e: Endothelial cell swelling of arterioles (arrow) with lymphocytic infiltration was seen. PAM staining; original magnification × 200; bar = 30 μm. f: Focal inflammatory cell infiltrates in the tubular interstitium and tubulitis were noted. Hematoxylin and eosin staining; original magnification × 200; bar = 30 μm. g: Moderate atherosclerosis was present in the interlobular arteries (large level). Masson trichrome staining; original magnification × 100; bar = 100 μm. h: Hyalinosis of the arterioles was mild. PAS staining; original magnification × 200; bar = 20 μm.
Figure 2i
Figure 2i. 1st kidney biopsy. i: Lymph follicle formation was also observed in part of the tubulointerstitium. Original magnification × 200, bar = 50 μm.
Figure 2j
Figure 2j. 1st kidney biopsy. j: Immunofluorescence microscopy revealed granular deposits of immunoglobulin G (IgG), IgG1, IgG2, and C3 along the glomerular basement membrane, Bowman’s capsule, and tubular basement membrane. The GBM was partially positive for C1q and positive for IgG4. Original magnification × 100; bar = 20 μm.
Figure 2k - n
Figure 2k - n. 1st kidney biopsy. k: Electron microscopy revealed electron-dense deposits in subepithelial regions (arrow) of the glomerular basement membrane. l: Electron-dense deposits(arrow) in the mesangial area. m: Electron-dense deposits (arrow) on the tubular basement membrane. n: Electron-dense deposits(arrow) on the basement membrane of Bowman’s capsule.
Figure 3
Figure 3. Clinical course.
Figure 4
Figure 4. 2nd kidney biopsy. a+b: The endocapillary proliferative changes seen in the first biopsy were greatly improved. a: PAS staining; original magnification × 400, bar = 20 μm. b: PAM staining; original magnification × 400, bar = 20 μm. c: IgG deposition in IF was reduced in glomeruli; original magnification × 400, bar = 20 μm, d: C3 deposition in IF was reduced in glomeruli; original magnification × 400, bar = 20 μm. e: Subepithelial EDDs (arrow) were greatly reduced in EM, bar = 2.0 μm. f: Inflammatory cell infiltration and fibrosis of the tubulointerstitium improved to 15 – 20% of the cortical area. Masson trichrome staining; original magnification × 100, bar = 500 μm.
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