A spectrum of clinicopathological features of nephropathy associated with POEMS syndrome

Yasushi Nakamoto1, Hirokazu Imai2, Tadashi Yasuda2, Hideki Wakui2 and Akira B. Miura2

1 Kichijoji Asahi Hospital, Tokyo, Japan, and 2 Third Department of Internal Medicine, Akita University School of Medicine, Akita, Japan

Correspondence and offprint requests to: Dr Yasushi Nakamoto, Kichijoji Asahi Hospital, 1–30–12 Kichijoji-Honcho, Musashino, Tokyo 180–0004, Japan.



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. In POEMS syndrome, substantial involvement of the kidney can occur and is reflected by proteinuria, haematuria, renal dysfunction, and renal failure requiring dialysis therapy. The mechanism by which renal dysfunction is induced and progresses to end-stage renal disease remains obscure. A pathogenic role of cytokines and growth factors has recently been implicated.

Methods. We reviewed cases of 52 Japanese patients with confirmed renal pathology who were reported in the literature, and personally analysed renal tissues from 22 subjects including nine patients of our own. Interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) were measured in our cases.

Results. Despite relatively mild renal symptomatology, about half of the cases had azotaemia with creatinine levels above 1.5 mg/dl and the BUN/creatinine ratio markedly raised by volume contraction or wasting. One-tenth of patients were placed on haemodialysis because of advanced or end-stage renal disease. Bilateral and unilateral contracted kidneys were found in four and two cases respectively. Pathological analyses disclosed two major changes: glomerular alterations and endarteritis-like lesions of renal small arteries. The former included glomerular enlargement, cellular proliferation, mesangiolysis and marked swelling of endothelial–mesangial cells. This structural disorganization led to a reduction in renal function to some degree by impairing the glomerular circulation. Vasculopathy of the small artery probably resulted in progressive renal damage and ultimately to kidney contraction. Serum IL-6 was elevated in about 40% of cases. IL-6 levels were found to be high in the ascites of three patients who were examined. In different studies, an increased level of VEGF was found in the peripheral blood (75–100%; overall 92.3%), but no apparent correlation with glomerular alterations was observed.

Conclusion. POEMS nephropathy can be one cause of end-stage renal disease with variable intrarenal pathological changes of a microangiopathic nature which have differential influences on renal function. A pathogenic role for VEGF in POEMS syndrome appears to be likely, but its causal relation to the nephropathy awaits further investigation.

Keywords: elevated BUN/creatinine ratio; endarteritis-like lesion of small artery; endothelial-mesangial cell swelling; glomerular enlargement; mesangiolysis; VEGF



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
POEMS syndrome [1] (Crow—Fukase syndrome [2], or Takatsuki's disease [3]) is a rare multisystem disorder characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal proteins and skin changes. Although not included in the acronym, substantial kidney involvement has been demonstrated in this disease [47]. In addition to the frequent incidence of proteinuria, haematuria, and renal dysfunction, renal failure requiring dialysis therapy can develop on occasions [812]. Glomerular alterations have been variously described as membranoproliferative glomerulonephritis (MPGN)-like changes [5], microangiopathic [13] or mesangiolytic [6] lesions. Subsequently the development of unilateral or bilateral kidney contraction [12] and systemic non-inflammatory arteriopathy with fibrous endarteritis [14] has also been observed, indicating that there is a wider range of pathological aspects than previously thought.

However, these findings are derived from sporadic single-case reports, and a more general picture of the nephropathy associated with POEMS syndrome needs to be based on a broader experience. In addition, the mechanism or pathway by which renal dysfunction is induced or progresses to end-stage renal disease remains obscure. Furthermore, a pathogenic role for cytokines such as interleukin-1ß (IL-1ß) [15] and interleukin-6 (IL-6) [10,1517] and vascular endothelial growth factor (VEGF) [18] in POEMS syndrome has recently been implicated. This should also be evaluated in relation to the nephropathy.

We performed a review of 52 cases of Japanese patients reported in the literature, and analysed the renal pathology from 22 subjects among them to delineate a spectrum of clinicopathological features. Here, we discuss the pathogenesis of POEMS syndrome with respect to our studies and recent data concerning cytokines and growth factor.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
A review of the literature revealed 52 cases of Japanese patients in whom renal pathology was confirmed as of the end of 1996. The cases included 27 patients reported in articles and the remaining 25 were cited in abstracts. In the latter cases, many authors kindly supplied complementary clinical data through a questionnaire. All patients manifested four or all of the five signs of POEMS. Polyneuropathy was present in all but one patient. Although a monoclonal protein was absent in 10 patients, four other signs of POEMS supported the diagnosis. In addition to POEMS, additional signs included papilloedema, serositis with massive fluid retention, leg oedema, clubbed fingers, and cutaneous angiomas. Isolated plasmacytoma was present in four patients involving the vertebra (one case), ischium (one), and ilium (two). Bone lesions in the remaining subjects, if they were present, were of the osteosclerotic type. Castleman-like lymphoma was observed in nine patients.

We personally examined the renal histopathology in 22 out of the 52 cases. In 1989 we reported renal biopsy findings in five patients with POEMS syndrome [6], and subsequently our file was extended to contain nine cases. Light microscopic renal tissue specimens from the remaining 13 cases were kindly provided by other institutions. Renal tissues from the nine cases in our hospital were processed as described previously [6].

Pathological changes were evaluated by three (YN, HI, TY) of the present authors without access to the clinical information. The degree of glomerular enlargement, cell proliferation, and cell swelling was graded as marked, moderate, mild, and minimal (or unremarkable). The presence or absence of mesangial loosening, mesangiolysis, microaneurysm, and nodular-like lesions were recorded (these have been illustrated elsewhere [6]). The type and distribution of tubulointerstitial injuries were also described. Intrarenal small arteries and arterioles were estimated and graded in a way similar to the glomerular lesions. All renal biopsy specimens contained more than 10 glomeruli.

In our patients, serum IL-6 was measured by ELISA (Fuji Bio Chemical, Tokyo, Japan) and serum vascular endothelial growth factor (VEGF) by ELISA calorimeter (American Research Products, USA). Blood samples were taken within 1 or 2 weeks before renal biopsy and kept at -70°C.



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Clinical features
The median age of the 52 patients (29 males and 23 females) was 49 years (range 28–75) (Table 1Go). There was no difference in age between genders. A majority of cases had monoclonal protein in blood (either IgA-{lambda} or IgG-{lambda}) and a minor group had polyclonal hypergammaglobulinaemia. There were no subjects with multiple myeloma or findings consistent with it. Three-quarters of patients exhibited trace to 1.0 g/day proteinuria, and a few had 1.0–2.0 g/day, but no patient was at the nephrotic level. In contrast, microhaematuria was seen in less than one-third and no one had gross haematuria. Blood pressure was generally normotensive or hypotensive even at the azotaemic stage, with hypertension defined as more than 140/90 mmHg present only in a small group.


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Table 1. Clinical features
 
Approximately one-half of the cases were azotaemic, with levels of creatinine greater than 1.5 mg/dl, and in one-third of cases, levels were above 2.0 mg/dl. The BUN/creatinine ratio (normal=approximately 10:1) was highly elevated (maximum=58.4) in all but one azotaemic patient. This abnormal ratio was often associated with extravascular fluid retention due to serositis, or marked cachexia (wasting). Overall, 11 patients (21.2%) were placed on haemodialysis because of intractable anasarca (four), anasarca and rapidly declining renal function (two) [19], and progressive renal failure due to contracted kidneys (four) or advanced glomerular sclerosis (one) [9].

Pathological features
In the majority of the cases, the glomerular alterations were described as MPGN-like lesions as exemplified by reports of Harada [20] and Takeshita [21] and their colleagues. This probably reflects the influence of the article by Sano et al. [5] who initially advocated the above term. There were four cases with bilaterally contracted kidneys, one with advanced glomerular sclerosis and two with unilateral kidney contraction. Intervals between the apparent onset and detection of renal contraction were 5–12 years (average 9).

Immunofluorescence staining for immunoglobulin heavy and light chains was reported in 44 cases. Positive results were found in 14 patients (31.8%) and samples from the remaining 30 patients (68.2%) were negative. No characteristic or specific pattern for heavy and light chains of immunoglobulins and mediators including complement components and fibrin were observed in the positive samples. However, one patient reported by Mizuiri et al. [7] had monoclonal IgA-{lambda} in the serum and glomerular deposition of selective {lambda} chains and IgA in a focal and segmental fashion.

Renal pathology was examined in 22 cases (renal biopsy and autopsy in 11 cases each). The most frequently observed alterations were glomerular enlargement and cell proliferation of varying degrees (Table 2aGo). The maximal glomerular enlargement reached a diameter of twice the normal reference size of approximately 200 µm (Figure 1Go). Glomerular enlargement and cell proliferation of more than moderate degree often gave rise to MPGN-like appearance. Additional glomerular lesions in decreasing frequency included mesangial loosening, mesangiolysis (Figure 2aGo), microaneurysm and nodular-like lesions. Mesangial loosening and mesangiolysis frequently coexisted, but the former was not a prerequisite of the latter at the light microscopic level. Mesangiolysis, microaneurysm, and nodular-like lesions appeared to occur as a progressive process. Nodular-like lesions often emerged when spaces created by mesangiolysis or microaneurysm were replaced with plasma components. Moreover, one-fifth of the cases manifested moderate to marked swelling or enlargement of endothelial-mesangial cells (Figure 2bGo). This was judged not to be a postmortem change because two biopsy specimens also showed a clear tendency of cellular swelling. This cell enlargement involved endothelial and mesangial cells. However, mutual correlation was not observed among glomerular enlargement, cell proliferation and cell swelling. Although these alterations distorted the glomerular structure, they did not accompany segmental or global sclerosis secondary to injury as often seen in IgA nephropathy, indicating that they did not link directly to the advanced, or end-stage renal damage.


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Table 2a. Clinicopathological features (22 personally reviewed cases)
 


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Fig. 1. Huge glomerular enlargement. This glomerulus is approximately 400 µm in diameter and exhibits a mild degree of lobulation. A loosely widened mesangial matrix and moderate cellular proliferation with minimal cell swelling are evident. Peripheral capillary walls appear to be thickened (Case no. 9, Table 2aGo). HE, x80.

 


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Fig. 2. Mesangiolysis and marked cell swelling. (A) At the top of the section, a mesangiolytic focus is seen with trapped red blood cells. The loosened mesangium and occasional double-contour of the capillary walls are evident in the remaining area of the section. PAM, x320. (B) Marked swelling of endothelial cells and mesangial cells can be seen. PAS, x400. (Both from case no. 15, Table 2aGo.).

 
In the tubulointerstitium, various changes were observed (Table 2bGo), including plasma cell nests (cases 8 and 9), angiofollicular cell nests (cases 14 and 19), and subcapsular cortical atrophy consisting of interstitial fibrosis and tubular atrophy (cases 2, 14, 15 and 18). On occasion, there was focally scattered loose infiltration of mononuclear cells. Two patients (cases 12 and 13) showed acute tubular necrosis or degeneration. They developed rapidly progressive renal failure superimposed on intractable anasarca and died of respiratory failure, despite intensive interventions including haemodialysis and plasmapheresis.


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Table 2b. Clinicopathological features (22 personally reviewed cases)
 
The present 22-case series included three patients (cases 20, 21 and 22) with bilaterally contracted kidneys and two patients (cases 2 and 7) with unilateral kidney contraction. The former three subjects had diffuse cortical atrophy and glomerular sclerosis, which was more prominent in the subcapsular region. Marked intimal proliferation the small arteries with severe luminal narrowing was also present (Figure 3Go). Two of them had no history of hypertension and the third was transiently hypertensive. Furthermore, other patients who had subcapsular atrophy often showed similar intimal changes of lesser degree. In these cases, the arterioles were usually unremarkable or had intimal hyalinosis of mild degree. In three patients with marked lesions of small arteries, the afferent arteriolar walls contained abundant renin granules. Thus it was obviously the vasculopathy of small arteries that led to cortical atrophy starting in the subcapsular region and progressing into the inner part, a common pattern of vascular nephropathy. Of note was that, in these three patients, glomeruli in the deep cortex still remained enlarged often along with other changes such as mesangiolysis and microaneurysms.



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Fig. 3. Small arterial lesions and atrophied cortex. (A) This small artery exhibits conspicuous intimal proliferation with severe luminal stenosis. The elastic lumina and medial muscle layer are relatively preserved. HE, x200. (B) Resultant cortical atrophy is seen with severely devastated tubulointerstitium. Glomeruli in the subcapsular area are globally sclerosed and those in the middle cortex are shrunken due to ischaemia. However, glomeruli in the deep cortex were still enlarged with MPGN-like lesions. PAM, x8. (Both from case no. 20, Table 2aGo.).

 
Unilaterally contracted kidneys from two cases were not morphologically evaluated, although the stenosis of renal artery and its main branches was ruled out. Kidney size in one case (no. 7) was confirmed to be bilaterally normal at the onset of this disease, and 11 years later, unilateral kidney contraction was found, but there was again no history of hypertension or other responsible episodes during the interval. In another case (no. 2), unilateral renal contraction was already present at diagnosis 5 years after the onset. However, the contralateral kidney showed subcortical atrophy with arteriosclerosis of moderate degree. Thus, it is probable that the above vasculopathy of intrarenal small arteries had occurred more prominently or selectively in one side. Those with unilateral or bilateral kidney contraction were longer survivors, suggesting that its development takes time.

Electron microscopic findings were available from 28 patients including eight of our subjects. A common change was a variable lucent widening of the subendothelial space (Figure 4Go). Electron-dense deposits were usually absent in the space, but were present in a few cases with positive immunofluorescence staining. Additional alterations included enlargement and proliferation of endothelial and mesangial cells and circumferential mesangial interposition. We postulate that the latter results from mesangiolysis [22]. The glomerular basement membrane was generally preserved with infrequent foot-process effacement. Although samples with marked cellular swelling as shown in Figure 2bGo were not examined by electron microscopy, that of moderate degree has been exhibited elsewhere [6]. On the other hand, it was found that fine mesangiolytic lesions discernible at the electron microscopic level coexisted with the subendothelial lucency in our eight patients regardless of the presence or absence of mesangial loosening at the light microscopic level.



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Fig. 4. Evidence of mesangiolysis is apparent in the centre of the section.Lucency of the subendothelial space is also diffusely present. Basement membranes are well preserved. the upper asterisk denotes fine mesangiolytic lesions and the lower asterisk shows a space created by fatty droplets trapped through mesangilytic splits. Arrowheads indicate glomerular basement membrane; M, mesangial cell; US, urinary space; x1500 (the same case as Fig. 1Go).

 
IL-6 and VEGF
Serum IL-6 was elevated in only two of our nine cases (Table 2bGo, cases 1 to 9). Subjects with elevated levels did not have any characteristic renal pathology compared with persons with normal values. Urinary IL-6 was not measured. VEGF was raised in all six patients examined. A higher level was observed in three patients (nos 7, 8 and 9) with isolated plasmacytoma or a plasma cell nest in the kidney. However, the individual level of VEGF did not correlate with various glomerular changes and tubulointerstitial or vascular lesions.

Outcome
The outcomes of the 52 patients reviewed in this study are summarized in Table 3Go. The interval from onset to final observation was on average 51.2 months (range 5–168). Twenty-seven subjects died and 25 are alive. The majority of patients received MP (melphalan and prednisolone) therapy as the base-line regimen, and occasionally additional cytotoxic drugs and steroid pulse therapy. The death rate in those who had serum creatinine greater than 2.0 mg/dl tended to be higher, but was not statistically different from patients with normal levels. Reports describing anecdotal experience have been published [9,10,23,24] and in effectively treated cases, renal function was normalized or stabilized, but frequent relapses occurred after various intervals ranging from several months to years. Furthermore, plasma exchange and haemodialysis did not definitely prolong life. No one could be maintained on regular haemodialysis beyond 24 months, since in many instances inherent or superimposed causes of death occurred (Table 4Go). Cachexia, which is characteristic of this disease, was the most frequent cause, followed by infection of various sorts, and other complications.


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Table 3. Outcome*
 

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Table 4. Causes of death
 


   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
POEMS syndrome appears to have a higher incidence in Japan and is therefore also called Japanese multisystem disease [25]. However, recent studies by Miralles et al. [26] in the USA and by Soubrier et al. [27] in France included a substantial number of cases, i.e. 38 and 25 respectively. A Chinese patient was also reported [28]. This disease is obviously universal even though there is a geographical or racial difference in prevalence. Since Sano et al. [5] described the development of MPGN-like glomerulopathy associated with POEMS syndrome, much attention has been paid in Japan to the renal involvement. Although the above studies on Caucasians [26,27] did not mention renal manifestations, Driedger and Pruzanski [4] in Canada first pointed out the appearance of proteinuria and elevated levels of BUN at a frequency of nearly 50% among subjects including Orientals. Subsequently, several case reports have been noted in Europe involving significant renal complications [25,29,30].

The present study focused on clinicopathological features of the renal involvement. Renal symptomatology was characterized by a higher frequency of proteinuria of trace to small amounts and a lesser incidence of microhaematuria and hypertension. A little more than half of the cases had azotaemia, with creatinine levels above 1.5 mg/dl, and overall one-fifth were placed on renal replacement therapy. This may reflect a biased case selection since all subjects underwent pathological examinations of the kidney tissue. We stress that in this disease, the BUN/creatinine ratio is often markedly elevated by volume contraction or wasting, and therefore the degree of renal function should be judged by creatinine, and not BUN.

Major injuries to the kidney included glomerular alterations and endarteritis-like lesions of the small artery. Because of the disorganized structure, the glomerular changes have a potential to reduce renal function through impaired glomerular circulation. Indeed, renal insufficiency was present in some cases. Moreover, when more severe volume contraction or other factors that further decrease renal circulation (e.g. endotoxaemia) are superimposed, accelerated renal failure may develop. Such a situation may lead to acute tubular necrosis.

On the other hand, the vasculopathy of the small artery, which is apparently unrelated to hypertension, appears to contribute to progressive renal damage, eventually resulting in bilateral or unilateral kidney contraction. Similar endarteritis-like lesions have been observed with light and electron microscopy at the level of the arteriole or capillary [25,30]. Gherardi et al. [14] described a systemic non-inflammatory arteriopathy with fibrous endarteritis in one patient with renal failure, although a figure was not presented. One case of this disease associated with pulmonary hypertension was also reported [31]. Furthermore, in four patients with POEMS syndrome, Lesprit et al. [32] recently observed acute arterial obliteration (AAO) secondary to thrombosis of atheromatous lesions that involved such large arteries as the carotid, subclavian, celiac, mesenteric, and iliac. Thus, these findings and ours indicate that POEMS syndrome could be associated with both micro- and macroangiopathic lesions, although the former is far more prevalent.

The pathogenesis of POEMS syndrome remains unsolved. Three candidates have thus far been pursued; IL-6, IL-1ß and VEGF. Serum IL-6 levels were elevated in only two of our nine cases. Among the 52 reviewed cases, serum IL-6 was positive in six of 15 patients measured (40%) including our series, whereas IL-6 levels in ascites were high in all three subjects examined (in two, serum IL-6 was normal). Comparable results in which high serum IL-6 levels were recorded in 38–54% of cases were reported by Hitoshi [17] and Gherardi [15] and their associates. Hitoshi et al. [17] further noted that there was no direct relationship between serum IL-6 levels and the presence or absence of Castleman-like lymphadenopathy. In the present series, lymphadenopathy was documented in only one case with elevated IL-6 in ascites. On the other hand, Soubrier et al. [27] postulated the presence of growth factor that does not cross-react with IL-6, after having compared the bioactivity and ELISA assay of IL-6, although they examined only two cases. Therefore the pathogenic role of IL-6 in POEMS syndrome is still unclear.

Gherardi et al. [15] observed elevated serum levels of IL-1ß in all of 13 samples taken over various intervals from five patients with POEMS syndrome, and suggested that lymph nodes may be sites of IL-1ß overproduction. IL-1ß is known to be one of the main mediators of endothelial cell activation, the other being tumour necrosis factor-{alpha} (TNF-{alpha}) [33]. Moreover, Lesprit et al. [32] found high serum levels of IL-1ß, IL-6, and TNF-{alpha} in all four patients with acute arterial obliteration, and they concluded that the arterial events might be related to the overproduction of these cytokines. These interesting results should be further confirmed.

Recently Watanabe et al. [18] demonstrated greatly raised levels of VEGF in six of eight patients with POEMS syndrome. Soubrier et al. [34] also observed elevated levels of VEGF in either serum or plasma samples from all of the 14 patients. In our study, similar results were obtained in all six cases examined. Thus, among 26 cases so far measured, VEGF from 24 patients was positive (92.3%). In our studies, higher values of VEGF in cases with plasmacytoma or tubulointerstitial plasma cell infiltration were observed. VEGF is a potent microvascular permeability-enhancing mediator and a selective mitogen for vascular endothelial cells. The former function may be related to serositis with massive fluid retention, and may reflect the hyperpermeability factor conceived by Takazoe et al. [19]. However, the level of VEGF was not correlated with glomerular alterations, since their behaviour was inconsistent, i.e. one case had huge, but another only mild, glomerular enlargement.

VEGF has been shown to be upregulated in the renal tubular cells of patients with chronically ischaemic kidneys due to the narrowing of preglomerular vessels [35]. This suggests that the VEGF elevation may be secondary to the renal pathology. The final answer will be gained when the causative agent(s) of POEMS syndrome are verified. Future studies should involve the culture of cells from plasmacytoma and identification of products secreted by the cells.



   Acknowledgments
 
Part of this work was presented at the XIIIth International Congress of Nephrology, Madrid, 1995.

We are deeply obliged to the following doctors for providing light microscopic kidney specimens: Prof. T. Kitajima, Jikei University; Dr Y. Amagasaki, Saiseikai Yokohama South Hospital; Dr H. Koizumi, Tachikawa Sougo Hospital; Prof. M. Nagase, Teikyo University; Prof. H. Shigematsu and Associate Prof. H. Oguchi, Shinshu University; Dr S. Aoki and Dr H. Iida, Toyama Prefecture Central Hospital; Prof. K. Kobayashi and Associate Prof. H. Yokoyama, Kanazawa University and Prof. K. Tomita and Dr S. Arima, Kumamoto University, and also to many doctors who responded to a questionnaire.



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 9. 9.98
Accepted in revised form: 4. 6.99