A relapse of POEMS syndrome presenting as acute kidney injury

Abstract

Peripheral neuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes (POEMS) syndrome is a rare disease, and only in a minority of cases, causes an impairment of kidney function. Here, we describe a case of a 55-year-old man with a history of POEMS syndrome who presented with acute kidney injury following a routine blood test. On further investigation, a relapse in POEMS syndrome was diagnosed, uniquely isolated to renal involvement.

Background

Peripheral neuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes (POEMS) syndrome is a rare multisystem disease secondary to plasma cell dyscrasia.¹ POEMS syndrome commonly presents in the fifth to sixth decade, its exact incidence unknown due to the complexity of the clinical presentation.² The diagnosis is made from clinical and laboratory features defined by the Mayo Clinic criteria.³

The standard treatment for POEMS syndrome has not been established¹; however, high-dose chemotherapy with autologous stem cell transplant (ASCT) has shown to be a promising regimen, with a recent retrospective analysis by Kourelis et al achieving a 10-year survival of 62%.⁴ Disease relapse remains a major factor, and due to the complex nature of the disease detecting relapse can be a diagnostic challenge.⁵ We describe the case of a 55-year-old man with known POEMS syndrome presenting with isolated renal impairment and proteinuria as a result of a relapse in the disease.

Case presentation

A 55-year-old Caucasian man presented to the renal clinic with deteriorating renal function. The patient was under haematology follow-up having been diagnosed with POEMS syndrome 11 years previously, which had been treated with high-dose Melphalan and ASCT leading to complete remission. Except for Amlodipine, the patient was prescribed no other regular medication.

On routine follow-up, it was noted that the patient had developed renal impairment and proteinuria, with a creatinine of 166 μmol/L, urea 14.3 mmol/L and urine protein:creatinine ratio of 124 mg/mmol. At this time, the patient was found to be well, he described no other symptoms and no abnormalities were found on clinical examination. His chest X-ray was normal. His full blood count showed a haemoglobin of 115 g/L, white cell count 5×10⁹/L, neutrophils 2.8×10⁹/L and platelets of 237×10⁹/L. Antineutrophil cytoplasmic antibody was negative, anti-nuclear antibody (ANA) was negative and complement factors C3 and C4 were in the normal range. A relapse of POEMS syndrome was not initially suspected, due to the absence of other organ involvement, and as such the patient was admitted for a kidney biopsy. On light microscopy, 20% of the glomeruli were found to be globally sclerosed. All remaining glomeruli appeared enlarged having a membranoproliferative glomerulonephritis (MPGN) like appearance with lobular architecture and endocapillary mesangial proliferation (figure 1). In one artery, moderate elastic reduplication was seen. Immunocytochemistry showed no definite granular deposits of IgA, IgM, IgG and C3, and electron microscopy revealed marked subendothelial oedema but no definite immune complex deposition (figure 2). The appearances on biopsy were in keeping with published literature on POEMS syndrome and were similar in appearance to the renal biopsy performed on the patient 11 years previously. The minimal amount of sclerosis seen on biopsy supports an acute relapse of POEMS syndrome rather than chronic activation of the disease.

Figure 1.

Kidney biopsy showing endocapillary oedema (arrowheads) and mesangial proliferation (arrows). (A) Periodic acid Schiff staining, 200× magnification. (B) Methenamine silver staining, 200× magnification.

Figure 2.

Electron microscopy image of glomerulus showing endocapillary swelling (arrows), 3000×magnification.

Outcome and follow-up

Further investigation revealed a mildly elevated prolactin level but otherwise normal endocrine function, no paraprotein or light chain disturbance, no significant abnormalities on nuclear medicine (NM) whole body fluorodeoxyglucose (FDG) positron emission tomography CT and a normal bone marrow biopsy (table 1). On initial presentation of POEMS syndrome, the patient was reported to have a low-level IgA paraprotein. Vascular endothelial growth factor (VEGF) was measured and found to be significantly elevated at 3670 pg/mL (normal,<771 pg/mL).

Table 1.

Summary of blood results

Testosterone	17.1 nmol/L (normal, 9.7–38.2 nmol/L)
Cortisol	162 nmol/L
Prolactin	295 mU/L (normal, 53–160 mU/L)
TSH	4.23 mU/L (normal, 0.3–4.4 mU/L)
fT4	10.4 pmol/L (normal, 9–19.1 pmol/L)
IgG	8.34 g/L (normal, 6–16 g/L)
IgA	3.43 g/L (normal, 0.8–4 g/L)
IgM	1.17 g/L (normal, 0.5–2 g/L)
Protein electrophoresis	No abnormal bands detected
kappa:lambda ratio	1.117 (normal, 0.37–3.1)

The changes on renal biopsy and elevated VEGF confirmed a relapse in POEMS syndrome. The patient’s rapidly deteriorating kidney function was of particular concern due to the significant reduction in life expectancy seen in the patient on haemodialysis. As such, the patient commenced treatment with Lenalidomide (10 mg daily for 21 days of a 28-day cycle) and pulsed Dexamethasone (40 mg). The patient has responded well to this treatment, and has initially received six cycles, with falling VEGF levels and improving renal function (figure 3). One year after relapse, the patient remains well with a creatinine of 107 μmol/L.

Figure 3.

Serum creatinine and VEGF level over time. Month 1 corresponds to initiation of chemotherapy treatment following diagnosis of POEMS relapse. POEMS, peripheral neuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes; VEGF, vascular endothelial growth factor.

Discussion

We have described a relapse of POEMS syndrome detected by abnormal renal function, with renal biopsy confirming MPGN-like lesions in keeping with the disease. The patient’s remaining systems were reviewed in accordance to the Mayo Clinic criteria. Of the major criteria, he had elevated VEGF factor, but no neurological deficit clinically; however, we did not perform nerve conduction studies, no monoclonal plasma cell proliferation and no bone pain or evidence of sclerotic bone lesions on X-rays performed. Of the minor criteria, he had no organomegaly, no evidence of extravascular volume overload, except for a mildly elevated prolactin level his endocrine axis was normal, he had no skin changes, no papilloedema and no polycythaemia. The relapse described appears limited clinically to renal involvement, and on review of the published literature, would appear to be a unique case.¹

The precise mechanism of MPGN in POEMS syndrome is unknown. Glomerular hypercellularity with endocapillary and mesangial proliferation is similar to the characteristic features of primary MPGN.^{6 7} Unlike primary MPGN, immunofluorescence is frequently negative, as in our case, helping to differentiate the cause of the renal lesions. Although the pathogenesis of POEMS syndrome is not fully understood, serum VEGF levels are used as a biomarker to determine response of the disease to treatment.⁸ VEGF is one of the most potent vascular permeability factors, with administration of VEGF found to cause tissue oedema.⁹ As such, the presence of oedema in the glomeruli is the pathognomonic renal lesion in POEMS syndrome, and in our case, is best demonstrated on electron microscopy (figure 2).¹⁰

As in this case, the benefit of early detection and treatment is supported by a retrospective study of 67 patients with POEMS syndrome and impaired renal function at diagnosis. Ye et al observed inferior survival in those with severe renal impairment (glomerular filtration rate (GFR) <30 mL/min/1.73 m²) but not in those with moderate impairment (estimated GFR 30–59 mL/min/1.73 m²) compared with patients without renal impairment.¹¹ This is reflected in a case report by Higashi et al where a patient with POEMS syndrome underwent serial renal biopsies.¹² The first biopsy showed no glomerulosclerosis, but after 14 months and no treatment yet initiated, a repeat biopsy showed >50% glomerulosclerosis.

The acute changes seen on biopsy in our patient with limited chronic damage demonstrate the effectiveness of the initial treatment of Melphalan and ASCT 11 years previously, and are in agreement with resolution of renal lesions following this treatment as described in a case report by Sanada et al.¹⁰ Furthermore, the marked improvement in renal function seen on treatment of the relapse in the disease with Lenalidomide and Dexamethasone is in agreement with Ye et al who have shown equivalent renal response in both ASCT-based treatment and novel-agent-based regimes.¹¹

Renal dysfunction is not one of the major diagnostic criteria for POEMS syndrome.¹ This case report highlights the importance of regular monitoring of renal function and proteinuria during outpatient clinic follow-up to detect a possible relapse of disease, and in cases where there is renal dysfunction for nephrology to be involved in a multidisciplinary approach to the patient’s care.

Learning points.

• Renal biopsy can be useful in establishing a diagnosis of peripheral neuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes (POEMS) syndrome, but its risks and benefits must be carefully weighed up.

• Routine measurement of renal function on follow-up of patients with POEMS syndrome may detect a relapse in the disease.

• It is important to consider rarer, multisystem diseases in the analysis of renal pathology.