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Membranoproliferative glomerulonephritis in the setting of multicentric angiofollicular lymph node hyperplasia (Castleman's disease) complicated by Evan's syndrome
  1. Hariklia Gakiopoulou1,
  2. Penelope Korkolopoulou1,
  3. Helen Paraskevakou1,
  4. Smaragdi Marinaki2,
  5. Michael Voulgarelis3,
  6. Anastasios Stofas1,
  7. Maria Lelouda1,
  8. Andreas C Lazaris1,
  9. John Boletis2,
  10. Efstratios Patsouris1
  1. 1Department of Pathology, School of Medicine, The National & Kapodistrian, University of Athens, Athens, Greece
  2. 2Department of Nephrology, Laikon Hospital, Athens, Greece
  3. 3Department of Pathophysiology, School of Medicine, The National & Kapodistrian, University of Athens, Athens, Greece
  1. Correspondence to Dr Hariklia Gakiopoulou, Department of Pathology, School of Medicine, The National & Kapodistrian University of Athens, 5 Iras str, Athens 15452, Greece; chgakiop{at}med.uoa.gr

Abstract

Systemic Castleman's disease is a lymphoproliferative disorder with various clinical presentations and incompletely understood aetiology. The authors report on a rare case of the plasma cell variant of Castleman's disease associated with autoimmune haemolytic anaemia and autoimmune thrombocytopenia (Evan's syndrome) and complicated by mixed nephrotic–nephritic syndrome and acute renal failure due to an underlying glomerulopathy with microscopic and immunofluorescence findings suggestive of membranoproliferative glomerulonephritis (MPGN) type I. Immunocomplexed glomerulonephritis is rare in Castleman's disease, while, to the best of our knowledge, constellation of all these autoimmune phenomena is reported for the first time suggesting that apart from the putative role of VEGF and IL-6 in the pathogenesis of the disease, a more generalised immunological disturbance occurs, probably through autoantibodies induced by active polyclonal B cells raised from Castleman's disease tumour.

  • Castleman disease
  • membranoproliferative glomerulonephritis type I
  • Evan syndrome
  • cytokines
  • autoantibodies
  • autoimmunity
  • histopathology
  • immunofluorescence
  • lymphoid lesions

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Introduction

Castleman's disease of the plasma cell or multicentric type is a systemic lymphoproliferative disorder with various clinical presentations and incompletely understood aetiology.1 Multicentric Castleman's disease is infrequently associated with renal manifestations, while the presence of overt nephrotic syndrome and/or acute renal failure due to an underlying glomerulopathy is a rare occurrence.2–9 However, it appears to be aetiologically related to the presence of Castleman's disease, since resolution of glomerulopathy follows disease remission.3 We report on a rare case of the plasma cell variant of Castleman's disease complicated by autoimmune haemolytic anaemia, autoimmune thrombocytopenia (Evan's syndrome) and associated with a mixed nephrotic–nephritic syndrome and acute renal failure due to an underlying glomerulopathy with light microscopic and immunofluorescence findings compatible with membranoproliferative glomerulonephritis type I. To the best of our knowledge, constellation of all these autoimmune disorders is reported for the first time.

Case report

A 17-year-old male with a known 2-year history of biopsy proven Castleman's disease of the plasma cell type complicated by autoimmune haemolytic anaemia and autoimmune thrombocytopenia (Evan's syndrome), presented with disease relapse associated with marked peripheral oedema followed by rapid deterioration of renal function. Urine protein excretion was at the nephrotic range, and urinanalysis showed active urinary nephritic sediment. Serum complement was decreased. Direct Coombs test was positive. Serum lactate dehydrogenase, C-reactive protein, interleukin-6 and vascular endothelial cell-derived growth factor were elevated. His autoantibody profile including antinuclear, anti-dsDNA, antineutrophilic, antiphospholipid and anti-GBM antibodies yielded negative/normal results. Hepatitis B, hepatitis C, human immunodeficiency virus and HHV-8 screening was negative. Our patient had not received anti-VEGF factors such as bezacizumab sometimes associated with proteinuria, nephrotic syndrome and hypertension.

A percutaneous renal biopsy was performed. The renal biopsy specimen showed diffuse global mesangial hyperplasia of both matrix and cells with focal endocapillary proliferation and subsequent glomerular lobular accentuation (figure 1). Basement membranes of the glomerular capillaries were thickened, and double contours were detected by periodic acid–Schiff and Silver stains (figure 1). The interstitium was not fibrotic and was not infiltrated by plasma or other inflammatory cells. Tubules contained occasional proteinaceous, granular or erythrocytic casts. Arterioles and arteries were unremarkable. Congo Red stain for the detection of amyloid was negative.

Figure 1

Mesangial and endocapillary proliferation with glomerular lobulation and thickened basement membranes with multiple double contours (periodic acid–Schiff ×400).

Immunofluorescence revealed immunodeposits for IgG (+++), IgM (++), C3 (+++), C1q (++), kappa light chain (++) and lambda light chain (+) with a predominantly peripheral, band-like subendothelial localisation (figure 2). Immunohistochemistry for VEGF, flk1, Flt-1, Flt-4 and IL-6 was negative. Immunohistochemistry for HHV8 was also negative in renal tissue.

Figure 2

Intense deposits for C3 (+++) with a predominantly peripheral, band-like subendothelial localisation (×400)

Taking into account the membranoproliferative pattern seen in light microscopy together with the immunofluorescence findings suggestive of activation of the classic complement pathway, a diagnosis of membranoproliferative glomerulolonephritis type I was supported. The patient was treated for the relapse of his primary disease with cyclophosphamide, vincristine, doxorubicin and prednisone aiming to also manage renal manifestations.

Discussion

We report for the first time the constellation of several autoimmune disorders in association with Castleman's disease of the multicentric type: autoimmune anaemia, autoimmune thrombocytopenia (Evan's syndrome) and membranoproliferative glomerulonephritis type I.

Glomerulopathies in the setting of Castleman's disease are rare, being observed almost solely in association with the plasma cell type of the disease. Sporadic case reports have included mesangial proliferative glomerulonephritis, thrombotic microangiopathy with a membranoproliferative pattern, fibrillar glomerulonephritis, crescentic glomerulonephritis and recently anti-GBM glomerulonephritis.2–10 Although a membranoproliferative-like pattern has been described in six previous cases,2–7 glomerular immunocomplex deposition has been encountered in only two of these cases: Said and Tarawneh reported for the first time a membranoproliferative glomerulonephritis type 1 in a 14-year-old boy with multicentric Castleman's disease, and Chan et al 2 years later.2 3

The role of cytokines (IL6 and VEGF) is well established in the pathogenesis of Castleman's disease.1 Taking into account the role of VEGF and IL6 in the control of proliferation, it has been suggested that these cytokines might contribute through paracrine or autocrine mechanisms—via primed mesangial or plasma cells—to the proliferation of mesangial and endothelial cells, while their deregulation could be injurious to the glomerular endothelium resulting in its detachment from the underlying basement membrane.5 7 The action of these cytokines might be responsible at least in part for the morphological changes mimicking a membranoproliferative pattern probably being, in fact, cases of thrombotic microangiopathy. In support of this pathogenetic mechanism, Seida et al observed increased expression of VEGF at a glomerular level in addition to its elevation in the circulation.5

However, in our study, immunostaining for IL-6, VEGF and its receptors (Flk-1, Flt-1 and Flt-4) was negative in renal tissue, plasma cell infiltrations were not observed, while, in contrast to the case of Seida et al, immunocomplexes indicative of activation of the classic complement pathway were detected by immunofluorescence. The additional presence in our case of autoimmune haemolytic anaemia and autoimmune thrombocytopenia suggests a more generalised immunological disturbance in multicentric Castleman's disease, which is supported by the following observations: (1) the detection of various types of autoantibodies in previously reported cases of Castleman's disease—associated or not with renal manifestations—like antiplatelet or anticardiolipin autoantibodies;8 11 (2) the recently described case of an anti-GBM glomerulonephritis in a Castleman's disease patient10 and the detection of anti-MPO antibodies in a previously reported case of crescentic glomerulonephritis seen in another Castleman's disease patient;9 and (3) the identification of a secreted autoantibody in cultured Castleman's tumour cells which reacts against epidermal proteins, in paraneoplastic pemphigus, a serious autoimmune skin disorder, seen in Castleman's disease.12

Finally, as far as the pathogenesis of membranoproliferative glomerulonephritis in Castleman's disease is concerned, one might implicate the production of immune complexes by the cells of a microlymphoma as it is hypothesised in the case of membranoproliferative glomerulonephritis associated with chronic lymphocytic leukaemia.13 In our case, however, this explanation does not hold true, since no evidence of microlymphoma was seen after reviewing the original material with multicentric Castleman's disease.

In conclusion, we report for the first time the constellation of several autoimmune phenomena (Evan's syndrome and membranoproliferative glomerulonephritis type I) in Castleman's disease. It is attractive to speculate that apart from the putative role of VEGF and IL-6 in the pathogenesis of renal lesions, autoantibodies might be induced by active polyclonal B cells raised from Castleman's disease tumour.

Take-home messages

  • The plasma cell variant of Castleman's disease is infrequently associated with renal manifestations.

  • Membranoprolipherative Glomerulonephritis type I in the setting of Castleman's disease coexistent with Evan's syndrome is reported for the first time.

  • Constellation of these autoimmune disorders suggests a more generalized immunologic disturbance in the plasma cell variant of Castleman's disease probably due to autoantibodies induced by active polyclonal B cells raised from Castleman's disease tumor.

References

Footnotes

  • HG & PK have equally contributed to this paper.

  • Competing interests None.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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