A Case of Castleman's Disease during the Long-Term Course of Membranous Nephropathy

Concomitant with nephrotic syndrome and multicentric castleman's disease (MCD) has only been described in a limited number of small studies and case reports. Among those, none confirmed the renal pathology prior to the onset of MCD, and none of the cases had a history of nephrotic syndrome. A 76 year-old Japanese man visited a nephrologist because of incident nephrotic syndrome. He had previously experienced three episodes of nephrotic syndrome, the last one 13 years ago, and had been diagnosed with membranous nephropathy by renal biopsy. Apart from these previous episodes, he also suffered from systemic lymphadenopathy, anemia, elevated C-reactive protein, polyclonal hypergammopathy, and elevated interleukin (IL)-6. An inguinal lymph node biopsy revealed CD138-positive plasma cells in the interfollicular region. Based on these findings, MCD was diagnosed. Renal biopsy indicated primary membranous nephropathy with spike lesions and bubbling in the basement membranes and deposition of immunoglobulin (Ig) G, IgA, IgM, and phospholipase A2 receptor along the glomerular basement membrane. Corticosteroid monotherapy successfully reduced the edema, proteinuria, and IL-6, but hypoalbuminemia was not sufficiently improved due to castleman's disease and remission of the nephrotic syndrome was not achieved. Later, tocilizumab was administered for remission induction in another facility. To the best of our knowledge, this represents the first report of Castleman's disease with previously diagnosed membranous nephropathy. This case does not provide a causal mechanism for the pathophysiology, but it may be worth suggesting possible involvement of MCD as a trigger for recurrence of membranous nephropathy.

Renal involvement in MCD has only been described in a limited number of small studies and case reports. A literature review of 64 cases published between 1975 and 2010 revealed amyloidosis as the main pathological characteristic seen on renal biopsy in 39% of cases, followed by membranoproliferative glomerulonephritis in 11%, thrombotic microangiopathy in 8%, and membranous nephropathy (MN) in only 3 cases (5%) [3]. Studies of biopsyconfrmed renal diseases in CD patients from France and China have also shown low frequencies of MN (0/19 cases and 1/11 cases, respectively) [3,4]. Collectively, nephrotic syndrome concomitant with CD, particularly MN, appears to be an extremely rare condition that may respond to corticosteroid therapy as a monotherapy or in combination with anti-IL-6 antibody treatment and other immunosuppressants to control disease activity [3,5].
In addition to such rare cases, we recently encountered a patient with CD during the long-term course of previously diagnosed MN.

Case Presentation
A 76-year-old Japanese man visited a nephrologist with complaints of edema and dyspnea. He had frst been diagnosed with nephrotic syndrome at 38 years old. Nephrotic syndrome had recurred at 57 and 63 years old. With the previous recurrence at 63 years old, he underwent renal biopsy and was diagnosed with MN (Ehrenreich-Churg stage II) with granular deposition of IgG, IgA, and IgM along the capillary wall. After the biopsy, he was treated with oral prednisolone (PSL) at 25 mg/day. Ten days later, the PSL dose was increased to 40 mg/day because urinary protein levels remained elevated. Urinary protein gradually decreased, and the patient achieved remission 3 months later. PSL was tapered and discontinued after 2 years of maintenance treatment. Although immunoglobulin (Ig) levels were not available, the ratio of albumin to globulin was 1.29 (total protein, 7.1 g/dL; albumin, 4.0 g/dL), suggesting that no hyperglobulinemia was present after remission at 65 years old.
During follow-up, edema of the lower extremity and pericardial efusion gradually developed, and he was referred to a cardiologist. Laboratory workup then revealed a recurrence of nephrotic syndrome, and he again consulted a nephrologist. Initially, body temperature was normal with no obvious abnormalities in other vital signs. On physical examination, the patient showed pitting edema of the lower extremities and lymphadenopathy bilaterally in the axillary and inguinal regions. Laboratory data showed massive proteinuria (4.4 g/day) and hypoalbuminemia (1.4 g/day) ( Table 1), suggesting nephrotic syndrome without hematuria. Notable fndings were newly developed polyclonal gammopathies (IgG, 3,468 mg/dL; IgA, 534 mg/dL; and IgM, 284 mg/dL). Anemia and systemic infammation were indicated from: hemoglobin, 9.8 g/dL; C-reactive protein, 0.63 mg/dL; and IL-6, 22.1 pg/mL (Reference; <7 pg/mL). Computed tomography (CT) showed multiple lymphadenopathies in the mediastinum, inguinal, and axillary regions. Blood culture, tuberculosis tests, tumor markers, and protein electrophoresis of sera and urine, and autoantibodies all yielded negative results. Figure 1 indicates the clinical course of this case. Before administration of PSL to treat nephrotic syndrome, an  inguinal lymph node biopsy was performed for a defnitive diagnosis. Light microscopy revealed difuse interfollicular infltration of plasma cells. Immunohistochemistry revealed CD20-positive lymphocytes in the follicular region and signifcant CD138-positive plasma cells in the interfollicular region ( Figure 2). As hyaline vascular proliferation was not evident, this case presents the plasma cell type of MCD rather than the hyaline-vascular type. Furthermore, additional staining to diagnose malignant lymphoma yielded negative results, and the lack of monoclonality indicated no evidence of deviation in the light chain limitation. Based on polyclonal gammopathy, the pathology of lymphadenopathy, and elevated IL-6, we diagnosed MCD with renal involvement. Nephrotic syndrome promptly responded to PSL, and proteinuria improved and reached 0.2 g/day by day 14, along with decreases in disease markers of MCD such as IgG, IgA, C-reactive protein, serum IL-6, and plasma vascular endothelial growth factor (VEGF). At the same time, leg edema, and pericardial efusion gradually improved. During the tapering of PSL, proteinuria was transiently elevated, and we performed a renal biopsy to evaluate the activity of renal involvement and the diferential diagnosis of primary or secondary MN. Te renal specimen contained 12 glomeruli, with global sclerosis in three. No infltration of infammatory cells or mesangial cellular proliferation, crescents, or adhesions were noted (Figure 3(a)). Glomerular capillaries were difusely and globally thickened and periodic acid methenamine silver staining showed spikes and bubbling in basement membranes (Figure 3(b)). Electron microscopy revealed subepithelial and intramembrane deposits of homogenous size estimated as Ehrenreich-Churg stage II late to III, partially with stage IV, and mild subendothelial enlargement ( Figure 3(c)). Immunofuorescent investigations showed marked granular deposition of IgG, IgA, and IgM along the glomerular basement membrane, but no staining for complement (Figure 3(d)). We further assessed IgG subclass and revealed positive staining for IgG4, while faintly stained in IgG1 and negatively stained in IgG2 and IgG3 (Figure 3(e)). Regarding antigen-specifc antibody staining, deposition of phospholipase A2 receptor (PLA2R) was positive in this case, while any other representative antigenspecifc antibodies were not stained (thrombospondin type-1domain-containing 7A, neural epidermal growth factorlike 1 and exostosin-1) (Figure 3(f )). Finally, he was diagnosed with recurrence of primary MN of Ehrenreich-Churg stage II to III coincident with MCD.
At discharge after 6 weeks of hospitalization, we performed a CT to confrm the efect of the lymph node reduction in size throughout the body. Te periaortic and lung hilar lymph nodes were reduced in size (Figure 4), as were the lymph nodes in the bilateral axillary and inguinal regions. Tis case of proteinuria was successfully controlled for 6 months with corticosteroid monotherapy, and proteinuria   Te serum level of immunoglobulins was high in addition to massive urinary protein, and polyclonal gammopathy was identifed. Before administration of prednisolone for the treatment of nephrotic syndrome, inguinal lymph node biopsy was performed. Nephrotic syndrome promptly responded to prednisolone and proteinuria improved along with decreased disease markers of Castleman's disease, such as IgG, IgA, C-reactive protein, serum IL-6, and plasma VEGF. During tapering of prednisolone, proteinuria transiently elevated. We performed renal biopsy to evaluate activity of renal involvement for decision making regarding long-term treatment. LN, lymph node; Ig, immunoglobulin; IL-6, interleukin-6; and VEGF, vascular endothelial growth factor.
was kept below 0.5 g/day. However, during the process of tapering PSL to 15 mg/day, the serum IgG titer (bottom; 1,275 mg/dL) began to increase, and at a PSL dose of 7.5 mg/ day, urinary protein increased from 0.5 g to 1.9 g, CRP changed from negative to positive (0.33 mg/dL), and polyclonal gammopathy (IgG 2,161 mg/dL, IgA 471 mg/dL, and IgM 445 mg/dL) appeared. Te patient was referred to another hospital for induction of anti-IL-6 therapy ( Figure 5). Combination therapy with PSL and tocilizumab has successfully decreased concentration of IgG, C-reactive protein, and proteinuria, again.

Discussion
Tis case displayed newly developed CD with nephrotic syndrome after remission of previously diagnosed MN. Te frst nephrotic episode occurred 38 years earlier, with the frst recurrence after 19 years, the second recurrence after another 6 years, and renal biopsy only performed at that time. Although IL-6 levels were not measured previously, the level of CRP was negative (<0.1 mg/dL), and there was no evidence of hypergammopathy in the previous episodes. We therefore speculated that diferences existed between the third recurrence of nephrotic syndrome (case presentation at 76 years old) and the course of the previous MN episodes (up to 63 years old). Since corticosteroids are expected to suppress lymph node proliferation and immunoglobulin production itself, the remission induction phase in this case was intended to confrm whether corticosteroid monotherapy improved nephrotic syndrome along with decreasing levels of IL-6 and CRP. Unfortunately, hypoalbuminemia was not sufciently improved, and remission of the nephrotic syndrome was not achieved, but a prompt decrease in urinary protein was achieved. We reviewed the 11 reported cases of MN with CD published between 1979 and 2021 [3,[5][6][7][8][9][10][11][12][13][14]. In some cases, the immunoglobulin deposition patterns in the glomerular capillary wall have not been fully described [3,5,9], but the remaining cases demonstrated IgG deposition. In the cases with IgA and IgM staining in renal specimens, they are deposited faintly [6,7,14] or not deposited [11,13]. Terefore, it seems to be rare for IgG, IgA, and IgM to all be deposited as in the present case. Subclasses pattern of IgG in the previous cases are mostly characterized as IgG1 (+), IgG2 (+), IgG3 (−), and IgG4 (−) [8,10,11,13]. In the present case, only IgG4 is stained, suggesting at least the past nephrotic syndrome was primary MN and the current episode can be considered a recurrence of primary MN. In previous cases, the deposition pattern of PLA2R in MN as a result of renal involvement of CD was controversial, but negative [13] or weakly positive [10,14]. Terefore, examinations for specifc antigens of MN in our case revealed predominant PLA2R deposition in the glomeruli, which supports the diagnosis of primary MN.   Tocilizumab (550 mg/body) Figure 5: Subsequent clinical course of the patient. In the case, proteinuria was successfully controlled for 6 months with corticosteroid monotherapy after discharge from our hospital. During the process of tapering prednisolone, serum IgG titer began to increase, and polyclonal gammopathy appeared. Te patient was referred to another hospital for induction of anti-IL-6 therapy, tocilizumab. Te disease markers of MCD such as serum IL-6 and plasma vascular endothelial growth factor were not examined.
Among the 11 reported cases of MN, no renal pathology was confrmed prior to the onset of CD. Similarly, none of the cases had any prior history of nephrotic syndrome. Most of the reports indicated that nephrotic syndrome developed at the same time as MCD, but in some cases MN was diagnosed several years after the onset of clinical signs suggestive of MCD [11,14]. Two cases underwent multiple renal biopsies. In one, fndings of MN had resolved after 2 years of treatment for MCD [7]. Granular deposition of IgG and C3, and to a lesser extent, IgM, was demonstrated in the frst renal biopsy specimen of the case; however, immunostaining was not performed in the second biopsy specimen [7]. Te other was evaluated for disease activity after 3 years of refractory MN to strengthen the treatment strategy [14]. In the case, positive IgG, IgA, and C3 granular deposition in the frst renal biopsy and the same staining pattern in the second biopsy was shown [14]. In our report, the patient underwent pathological evaluations of disease activity at an interval of 13 years. Granular deposits of IgG, IgA, and IgM in glomerular capillaries remained between the previous and the latest renal specimens, and the stage of MN had progressed. Immuno-histological fndings in these cases implied that the reversible pathological changes that result in the removal of long deposited subepithelial and intermembranous immunoglobulins are difcult to detect in MN.
Generally, the etiology of idiopathic CD is unknown, but the recognized central factors include lymph node hyperplasia with polyclonal B lymphocyte expansion and cytokine storm (IL-6 and VEGF) [15]. Te heterogeneity of the clinical course and renal involvement may be due to the pleiotropic actions of IL-6. A possible explanation is that overproduction of IL-6 may induce glomerulonephritis such as MN via polyclonal hypergammopathy and a variety of autoantibodies [10]. Although we could not directly confrm changes in the titer of blood PLA2R antibodies in this case, it was suggested that the serial increase in total IgG concentration contributed to the increased production of PLA2R antibodies and resulted in the recurrence of MN. Some CD cases respond well to corticosteroid monotherapy, and tocilizumab to counter excessive IL-6 production and other immunosuppressive agents can also efectively control disease activity when the efects of corticosteroid are incomplete. Renal involvement in CD cases often improves with treatment for CD [4]. Te MCD consensus guidelines recommend anti-IL-6 monoclonal antibody as the frst-line therapy for patients with severe CD, regardless of renal involvement [16]. However, the treatment strategy for MN in CD with a mild phenotype has not been established. An overview of past case reports showed that in one case with unicentric CD, MN improved only with resection of the afected lymph node [7]. Another case improved with corticosteroid monotherapy [4]. In most cases, improvement was achieved by tocilizumab [8,[10][11][12][13][14] or other immunosuppressive agents such as cyclophosphamide [4,7,9,13], mizoribine [14], and cyclosporine [9,14] in combination with corticosteroids. In our case, induction remission therapy with corticosteroids alone for 6 months proved efective, but it was insufcient for remission of both MN and CD, and the decision was made to add anti-IL-6 therapy in another facility.
Of special note in this case was the rarity of coincident MN and MCD, as the literature review of 11 cases also revealed, and no previous reports described results from renal biopsies taken prior to the development of MCD. As a limitation of this case report, we do not have any evidence to explain the causal links between previously diagnosed MN and newly developed CD, other than speculation that the long-term (38 years) PLA2R related primary MN was recurred by superimposition of plasma cell-driven infammation and overproduction of antibodies. Another limitation of this study was the absence of examination for human herpesviurs-8 as a diferential diagnosis for MCD.
To the best of our knowledge, this represents the frst report of CD coincident with previously diagnosed MN. Tis case does not provide insights into the causal mechanisms of the pathophysiology, but may be worth considering possible involvement of CD pathology as a trigger for primary MN recurrence.

Data Availability
Te data generated during the current case are available from the corresponding author upon reasonable request.

Conflicts of Interest
Te authors declare that there are no conficts of interest.