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A case report of an M protein-negative patient with POEMS syndrome associated with renal involvement

Abstract

Background

POEMS syndrome with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes is an uncommon plasma cell paraneoplastic syndrome involving multiple system. It is relatively rare in clinical practice, and renal involvement is a usual yet easily overlooked symptom.

Case presentation

We successfully treated a patient with M protein-negative POEMS syndrome with membranoproliferative glomerulonephritis (MPGN) findings and thrombotic microangiopathic changes by comparing the level of Vascular endothelial growth factor (VEGF) in the serum and the changes in polyserositis before and after the patient’s treatment.

Conclusion

POEMS syndrome clinically involves multiple systems and has complex symptoms. Because of the diversity of the disease manifestations, identification of atypical POEMS syndrome and timely intervention are important for patient survival and prognosis.

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Introduction

Characterized by polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes POEMS syndrome is a very rare plasma cell dyscrasia. According to the criteria updated in 2022, the necessary diagnostic criteria for POEMS syndrome are peripheral neuropathy; monoclonal plasma cell proliferation (M protein positive or plasmacytoma). The major diagnostic criteria meet one of the following: Castleman disease; osteosclerotic lesions; increased VEGF levels. And at least one of the minor conditions: organomegaly; extravascular volume overload; endocrine lesions; skin changes; papilledema; thrombocytosis/ polycythemia; papilledema [1,2,3]. The pathogenesis of POEMS syndrome is not well defined and may be related to abnormal proliferation of monoclonal gammopathy, VEGF overproduction may also have an effect on the disease [4,5,6,7,8]. It has also been reported that imbalance of cytokines (such as TNF-α, IL-6) may be one of the etiologic factors that predispose to POEMS syndrome and lead to disease progression [7, 9,10,11]. Although renal lesions are not a diagnostic criterion for POEMS syndrome, studies have shown that nearly 50% of patients have renal involvement, and conventional renal pathologic changes are membranoproliferative glomerulonephritis (MPGN), microangiopathies, and mesangiolytic lesions [1, 10, 12]. A retrospective study in China showed that renal function is an independent prognostic factor for patients with POEMS syndrome [12]. In this article, we provide a more comprehensive and in-depth study of this disease by reporting the case of a patient with M-protein negative POEMS syndrome with renal impairment.

Case report

A 52-year-old middle-aged male was admitted to our department with the findings of proteinuria for six months and lower extremity edema for three months. He had a history of hypertension for ten years. On admission, we found that the patient had multiple enlarged superficial lymph nodes. We conducted a preliminary evaluation of the patient, laboratory studies showed that his hemoglobin was slightly decreased, platelets were normal, c-reactive protein was slightly higher at 24.07 mg/mL, complement C3, C4 were not decreased, immunoglobulin G was low, and serum protein electrophoresis showed proper distribution. Proteinuria was 2.13 g/24 hour. In order to further understand the condition, the first renal biopsy was performed in 2022. The renal pathology showed that the glomeruli were enlarged and lobulated; endothelial cells showed vacuolar degeneration with diffuse swelling and proliferation, the glomerular mesangial cells and matrix were diffusely and moderately hyperplastic, and “double-track” structures could be seen (Fig. 1A, B). Renal immunofluorescence revealed C4d (1–2+/ vascular loops/granules) (Fig. 2A), whereas IgA, IgG, IgM, C3, Kappa(κ), Lambda(λ), PLA2R were negative. Electron microscopy revealed a marked widening of the subendothelial space, which contained flocculent material, erythrocytes, leukocytes, and cellular debris (Fig. 3A, B). In conclusion, based on the pathologic changes it was diagnosed as MPGN, but microangiopathic lesions was not exclude. We also performed a lymph node biopsy of the right neck of the patient to differentiate Castleman disease and other disorders, and we found the reactive hyperplasia of the lymph nodes with marked localized plasma cell hyperplasia, without restriction expressions in immunohistochemistry. Bone marrow biopsy showed normal myeloproliferative with a slight increase in localized plasma cells and no light chain restricted expression. Therefore, we formulated a treatment regimen of glucocorticoid (prednisone 60 mg/day) combined with Rituximab (375mg/m2) for the patient. With the treatment, the prednisone dose was gradually reduced to 15 mg/d, and the cumulative amount of Rituximab was 2.4 g. The patient’s urinary protein excretion substantially declined, and he was followed up regularly in the outpatient clinic. Approximately one and a half years ago (2023), the patient was readmitted for treatment due to worsening edema accompanied by numbness of limbs. His nerve conduction velocity and electromyography findings were consistent with polyneuropathy, showing impaired sensory and motor conduction function and myelin damage in multiple peripheral nerves of the limbs. In addition, his hematology test revealed endocrine hormone disruption with TSH of 15.009 mIU/L (normal range is 0.56–5.91 mIU/L) and FT3 of 1.62 pg/mL (normal range is 2.3–4.8 pg/mL), and testosterone reduced to 1.23 ng/mL. The patient’s serum creatinine and proteinuria levels rapidly increased (elevated creatinine to 190 µmol/L and increased 24-hour proteinuria to 1.23 g). Serum M protein remained negative, serum immunofixation electrophoresis was also normal; but serum free light chain quantification showed elevated free light chains (κ and λ) (60.91 mg/L and 48.47 mg/L respectively) and normal κ / λ (1.2567 Ratio), and no Bence-Jones proteins was found in urine (Fig. 4A). Cryoglobulin test was also negative, but we found patient’s serum VEGF was abnormally elevated at 937 pg/mL (normal range is 0-142 pg/mL). The second renal biopsies showed increased glomerular volume, diffuse swelling of endothelial cells with segmental hyperplasia, and hyperplasia of mesangial cells and stroma (Fig. 1C, D). Congo red staining (-). Moreover, the immunofluorescence of the four glomeruli obtained C3 (2–3+/ mesangial area/granules), C4d(2+/segmental vascular loop/granules) (Fig. 2B), but no evidence of positivity for IgA, IgG, IgM, κ, and λ was found. These results were consistent with pathologic changes in MPGN. Importantly, we found that the glomerular capillary endothelium showed obvious vacuolar degeneration, widening of the subendothelial space and cell debris were still visible. There was extensive fusion of the foot processes of the glomerular epithelial cells. However, no deposition of electron-dense material was found under electron microscopy (Fig. 3C, D). In summary, glomeruli changes were consistent with thrombotic microangiopathy (TMA)-like under electron microscopy. Beyond these information, cardiac ultrasound showed a moderate to large pericardial effusion; chest and abdominal CT manifested pleural and peritoneal effusion. It also showed splenomegaly, perinephric exudation and pelvic effusion (Fig. 4B, C). PET-CT showed uneven bone density and multiple nodular dense shadows in the ribs, thoracolumbar spine, pelvis, and femur, indicating bone sclerosis. Another, we found “glomeruloid hemangiomas” in the patient’s skin and papilledema in the left eye (Fig. 5). After multidisciplinary consultation, we finally defined the disease as M protein-negative variant POEMS syndrome. We administrated an anti-plasma cell BD therapy (the initial regimen was Bortezomib 1.3 mg/m2 on days 1, 8, 15, 22; Dexamethasone 40 mg on days 1, 8, 15, 22; and then in February of this year, BD treatment was adjusted to once every 15 days) to him. After that, we followed up the male for 14 months. At the beginning of the third cycle of treatment, the patient’s clinical symptoms were significantly relieved, as evidenced by the absence of chest tightness and fatigue, the serum creatinine was declined to 110umol/L, and the 24-hour proteinuria was about 0.93 g. The patient has completed 12 cycles of the BD regimen to date with a cumulative dose of 10.16 g of bortezomib. The patient’s lower extremity edema had completely disappeared, VEGF gradually decreased (currently 230.6 pg/mL), other serological indicators improved, polyserositis (thoracic cavity, abdominal cavity, pericardium) was gradually absorbed, and renal function continues to improve (the latest proteinuria was 0.5 g/24 hours and creatinine returned to normal), his peripheral neuropathy also significantly disappeared (Table 1; Figure 6).

Fig. 1
figure 1

Pathological changes in renal tissue before treatment (A-D). A1, B1, C2, D1: swelling and proliferation of endothelial cells; A2, B3, C1: “double contour sign”; A3, B2, D2: vacuolar degeneration of endothelial cells (Periodic Acid-Schiff stain are seen by light microscopy; original magnification x400)

Fig. 2
figure 2

Immune complex deposits in immunofluorescence (A, B)

Fig. 3
figure 3

TMA-like lesions in kidney tissue under electron microscope (A-D). A1, C2: swelling and proliferation of endothelial cells; A2, C1, B and D: widening of the lax layer within the glomerular basement membrane

Fig. 4
figure 4

Clinical characteristics of patients with POEMS syndrome (A indicated serum M protein and Bence-Jones proteins negative, respectively; B showed medium-large pericardial effusion; C revealed splenomegaly, ascites, and pleural effusion)

Fig. 5
figure 5

Patient present with characteristic skin changes (A) and papilledema (B)

Table 1 Serologic data of patient
Fig. 6
figure 6

The patient’s VEGF levels, 24-hour proteinuria and serum creatinine decreased

Discussion

POEMS syndrome is a rare clonal plasma cell paraneoplastic syndrome involving multiple systems [13]. Patients mainly present with symptoms of limb numbness and extravascular overload, so it is easily misdiagnosed as neurological and renal diseases. Therefore, we must pay attention to the patient’s multi-system symptoms and signs, which can provide important meaning for an accurate diagnosis. This patient tested negative for M protein on multiple occasions, but developed demyelinating polyneuropathy. On the other hand, patients developed sclerotic bone lesions, elevated VEGF levels, extravascular volume overload, and even endocrine system dysfunction. Therefore, this confirmed the diagnosis of POEMS syndrome in this male. View from this, the disease is sufficiently clinically challenging that, in addition to a common polyneuropathy, 95% of patients present with features of monoclonal plasma cell proliferation [14]. For the question of M protein negativity in our study, we also reviewed the literature, studies have shown that POEMS syndrome is a chronic inflammatory reaction of small clones of plasma cells with low levels of monoclonal protein, but at least 2/3 of patients have abnormal serum free light chains, but 80% of patients have a normal light chain ratio, which is consistent with the results of our patients [15,16,17]; and other studies have shown that may be that trace amounts of M protein in serum are not also recognized due to measurement limitation [8]. Interestingly, there are also a few data on cases of POEMS syndrome with polyclonal gammopathy, even with the same renal involvement [5]. However, we report for the first time a case of M protein-negative patients with concomitant MPGN findings and thrombotic microangiopathic changes, and thus may provide fascinating information to enrich the diversity of POEMS syndromes. We cannot ignore the fact that Castleman disease as one of the main diagnostic criteria for POEMS, which is pathologically characterized by atrophic or hyperplastic germinal centers, prominent follicular dendritic cells and angiogenesis, and polyclonal lymphocytosis [2]. Here the patient’s lymph node biopsy did not indicate the typical angiofollicular lymph node hyperplasia changes, renal pathology displayed negative Congo red staining with multiple organ damage, which further excluded plasma cell diseases such as Castleman disease, amyloidosis, and monoclonal gammopathy of undetermined significance (MGUS).

POEMS syndrome is rare clinically, and reports of renal involvement are relatively limited. Renal pathologic changes in POEMS syndrome were mostly focused on lesions of glomerular endothelial cells and mesangium in collection [1, 18, 19]. VEGF, as a critical indicator for disease activity, deserves to be explored for its relationship with renal lesions. VEGF acts as a multifunctional cytokine that can be expressed by tumor cells, macrophages, plasma cells, and other cells, and usually acts on the vascular endothelium and endothelial cells [1, 20]. It promotes cell proliferation, migration, and increased vascular permeability through high-affinity binding to two types of phosphotyrosine kinase receptors: VEGF receptor 1 (VEGFR1) and VEGF receptor 2 (VEGFR2) [21, 22]. In addition, Notch/DLL4 signaling can also regulate tip cell and stalk cell proliferation and induce vascular plexuses proliferation [23]. It has also been proposed that VEGF is required for glomerular endothelial cells fenestrae formation [24]. Moreover, VEGF is stimulated by hypoxia-inducible factor (HIF-1) under hypoxic conditions, which can locally upregulate VEGF expression [21]. VEGF overproduction promotes abnormal angiogenesis, induces endothelial cell dysfunction, affecting glomerular endothelial cells [25]. Besides, it may cause enlargement of the spleen and lymph nodes, and can also increase the permeability of the blood-nerve barrier, causing neurotoxic components to damage the nervous stystem [4, 7, 8, 26, 27]. VEGF also promotes tumor cell growth and metastasis and can alter the interaction of tumor cells with immune cells [28]; Wang et al. [29] found that VEGF overexpression in POEMS syndrome originated from bone marrow plasma cells, the mRNA levels of bone marrow plasma cells from the patients significantly expressed VEGF and were linearly correlated with serum VEGF. It is not difficult to find that with anti-plasma cell treatment, the serum level of VEGF decreases and the symptoms of patients are further improved. We also found that POEMS syndrome is a hypercoagulable state with a 30% incidence of arterial and venous thrombosis in patients [30]. This may be likely related to fibrinogen, thrombin-antithrombin complexes, as well as to the application of immunosuppressive agents, and reduced activity due to the patient’s neuropathy [2]. Therefore, low molecular heparin or antiplatelet agents should be used for prevention [2, 3]. POEMS syndrome can be treated with radiotherapy, autologous stem cell transplantation (ASCT), proteasome inhibitor (Bortezomib), immunomodulators (Lenalidomide), monoclonal antibodies (Daratumumab), bispecific antibodies (Teclistamab) [1,2,3]. Overall, the key to treatment is to target the removal of clonal plasma cells. Interestingly, studies showed that a bortezomib-based regimen significantly improved neurological symptoms, and another study even showed that patients who received this treatment had better kidney function [3, 31, 32]. In the initial treatment of the patient, we only used glucocorticoids combined with anti-CD20 monoclonal antibodies to treat MPGN. The patient’s edema gradually worsened, accompanied by renal function deterioration, and even more concerning was the patient’s symptoms of numbness and tingling in the extremities. When we identified POEMS syndrome and treated the patient with the BD regimen, the patient’s limb numbness symptoms basically disappeared, proteinuria gradually decreased, abdominal effusion and pleural effusion were absorbed, as well as a gradual decrease in VEGF level.

Conclusion

POEMS syndrome has diverse manifestations, with recurring symptoms and complex mechanisms. With this case we recognized undetectable monoclonal POEMS syndrome with renal damage. POEMS syndrome should be considered when patients present with multisystem pathologies such as unexplained peripheral neuropathy, refractory edema, or characteristic changes. In addition, we need to improve our understanding of the renal invasion associated with POEMS syndrome to prolong the survival time and improve the patients’ prognosis in future clinical practice.

Data availability

No datasets were generated or analysed during the current study.

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LWL: Wrote the manuscript and served as a contributing author; YZ, YLL and YZX: Experimental guidance; SH: Contributed to design of the study. All authors contributed to manuscript revision, read, and approved the submitted version.

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Correspondence to Shuang Hou.

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Liu, W., Zhou, Y., Li, L. et al. A case report of an M protein-negative patient with POEMS syndrome associated with renal involvement. BMC Nephrol 25, 472 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12882-024-03898-z

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