An association between the acute or chronic form of inflammatory demyelinating polyneuropathy (IDP) and nephrotic syndrome has occasionally been reported. However, the clinical pictures in IDP of these cases have attracted little attention to date. In the present report, we describe a 50-year-old man with IDP who developed quadriplegia with respiratory impairment followed by a remitting and relapsing course for several months with complete recovery, in which nephrotic syndrome appeared at the nadir and subsided in parallel with the neurological improvement. We also searched for the English-language literature from 1946 to 2012 April and found 32 cases of Guillain–Barré syndrome or chronic inflammatory demyelinating polyneuropathy with nephrotic syndrome. We analyzed the 33 cases including the present case, and found such features as: (i) male preponderance (84.8%); (ii) motor dominant impairments with favorable final outcomes; and (iii) proteinuria occurring simultaneously with neurological symptoms and ameliorating along with neurological improvement in the majority of the cases. Available data of nerve conduction studies consistently showed demyelinating neuropathy. These findings suggest that IDP with nephrotic syndrome might be a distinctive clinical entity possibly caused by immune reactions to antigen(s) shared by peripheral nerves and the glomerulus. As nephrotic syndrome is asymptomatic or transient in some cases, IDP with nephrotic syndrome might be more prevalent than we think.
An association between Guillain–Barré syndrome (GBS) and nephrotic syndrome has been occasionally reported in the past 40 years.[1, 2] From the 1980s, when chronic inflammatory demyelinating polyneuropathy (CIDP) was widely acknowledged, an association with nephrotic syndrome and CIDP has also been sporadically reported. Renal biopsies disclosed several types of glomerulonephritis, and the involvement of immunological processes against common antigens in the glomerulus and peripheral nervous system has been suggested. However, systematic analysis of the clinical pictures has been lacking, and it is unclear whether inflammatory demyelinating polyneuropathy (IDP) with nephrotic syndrome is a distinct clinical entity, and whether the pathological diagnoses of renal biopsies were related to the clinical course of IDP.
We report a case of IDP associated with nephrotic syndrome. We also reviewed the literature and analyzed the reported cases, especially in terms of the neurological view.
A 50-year-old man developed limb weakness a week after general fatigue resembling a cold. On admission, 5 weeks after the neurological onset, he could not walk and the muscle strength was 3 by manual muscle test (MMT) in both proximal and distal limb muscles. Generalized areflexia and glove and stocking type sensory disturbance, particularly in the vibratory sense, were noted. Cerebrospinal fluid examination showed 112 mg/dL protein and two cells per 1 μL. In the nerve conduction studies (NCS), the latencies of F waves were prolonged (Table 1). Magnetic resonance imaging showed gadolinium enhancement of the cauda equina. Antibodies against GM1, GM2, GM3, GD1a, GD1b, GD3, GT1b, GQ1b, asialo-GM1, galactocerebroside and GalNAc-GD1a were negative. Urinalysis showed mild proteinuria. The patient was diagnosed with GBS and intravenous immunoglobulin (IVIg; 400 mg/kg/day) was started. He became able to walk without assistance by week 7. However, in week 8, his muscle strength deteriorated again. Methylprednisolone (mPSL) 1 g for 3 days was ineffective. Bulbar palsy appeared and his vital capacity fell to 63% of estimated vital capacity. Then, edema was noticed in his limbs and hypoalbuminemia (2.1 g/dL) was disclosed. Urine protein was 2+ (at least 2.5 g of protein was lost into the urine per day). Microscopic analysis showed red blood cells (5–9/high power field), tubular epithelium and casts. Additional treatment with IVIg and oral prednisolone 40 mg ameliorated muscle weakness, sensory disturbance and proteinuria. In week 9, his vital capacity returned to normal. Hypoalbuminemia reached 1.5 g/dL and then became milder. Prednisolone was tapered to 10 mg. He was discharged at week 16. Renal biopsy was not carried out because of the rapid improvement of proteinuria. Prednisolone was tapered off by week 22 when he was free from both neurological and nephrological symptoms. On the next day, muscle weakness appeared again. On the second admission, hoarseness, muscle weakness, distal hypesthesia and generalized hyporeflexia were found. These symptoms were milder than those at the previous admission. Then we diagnosed the patient as having definite CIDP according to the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) CIDP diagnostic criteria. Urinalysis was normal. IVIg and oral prednisolone completely improved his neurological symptoms. Prednisolone 7 mg has been continued for several years to date and no relapse has occurred. The recent NCS was normal, including F wave latencies (Table 1).
We carried out a computer-based search (MEDLINE; National Library of Medicine, Bethesda, MD, USA) of English language articles published from 1946 to April 2012. We used the key words “proteinuria”, “nephrotic syndrome”, “membranous glomerulonephritis”, “focal segmental glomerulosclerosis” or “minimal change disease” on one side and “Guillain–Barré syndrome”, “acute inflammatory demyelinating polyneuropathy”, “chronic inflammatory demyelinating polyneuropathy” or “neuropathy” on the other. In addition, references cited by the articles produced by the literature search and the present case were included; a total of 33 cases were analyzed.[1-3, 5-30] We provisionally classified the 33 cases by the temporal course of disease as follows: GBS, duration to nadir was within 4 weeks and no relapse;[31, 32] and CIDP, duration to nadir was 8 weeks or more and/or relapses. Two patients defined as subacute inflammatory demyelinating polyneuropathy whose durations to nadir were between 4 and 8 weeks without relapses were included in CIDP in the present review. We could not adapt the current research criteria including electrodiagnostic tests[4, 32, 34] in the present retrospective study. We classified 12 cases as GBS and 21 cases as CIDP (Tables 2-4). Statistical analysis was carried out using JMP 8 (SAS Institute Inc., Cary, NC, USA).
Table 2. Clinical findings in 33 cases of inflammatory demyelinating polyneuropathy with nephrotic syndrome
The reports of 33 cases originated from various countries including the USA (13 cases), Australia (four cases), Taiwan (three cases), Germany (two cases), Japan (two cases), the UK (two cases), and one case each from Barbados, India, Italy, Korea, Switzerland, Tunisia and Turkey. The mean age of onset was mid 40s and nearly 85% of cases were male. Five cases were female, and were either schoolchildren or aged over 55 years. The main neurological symptoms were motor impairments, and the sensory disturbances were usually mild. We graded the severity of the motor impairments as follows: mild, able to walk or mean scores of MMT were more than 3; and moderate to severe, unable to walk or scores of MMT were 3 or less. Durations of illness were shorter in the cases with moderate to severe motor impairments in all IDP, but the difference did not reach statistical significance (P = 0.0552, Wilcoxon rank-sum test). Antiganglioside antibodies were investigated in four cases including the present case, and no specific findings were obtained.[15, 16, 23] NCS findings were described in eight of 12 GBS cases and 18 of 21 CIDP cases. They all indicated the presence of demyelinating neuropathy. As for symptoms of nephrotic syndrome, edema was noticed in 19 cases, whereas 12 cases (36.4%) were asymptomatic. Urinary protein excretion of each case was 1.9–25 g/day. Proteinuria appeared simultaneously with neuropathy in two-thirds of the cases. In most of the CIDP cases, proteinuria appeared or worsened at the nadir of the neurological symptoms, and reduced in parallel with the neurological improvement. Proteinuria improved in 13 cases and significant proteinuria persisted in the others. There was a tendency for follow-up periods to be shorter in the latter cases (P = 0.0853, Wilcoxon rank-sum test). Thus, the proteinuria might have improved much later in a fraction of the cases. Among the 10 cases with neurological relapses, significant proteinuria also recurred in three cases. As for therapy, two or more immunomodulating therapies were carried out in half of the GBS cases and most of the CIDP cases. Initial treatments were begun with corticosteroids, IVIg or plasma exchange in most of the cases, and were sometimes ineffective or only transiently effective. Relapses of neuropathy occurred in half of the CIDP cases; however, there was only one case with more than two relapses. The overall outcomes of neuropathy were favorable in both the GBS and CIDP cases, except a patient with GBS who died of respiratory failure complicating bronchopneumonia.
Renal biopsies were carried out in 28 patients (Fig. 1). There were no relationships between the histological diagnoses of renal biopsies, and forms of neuropathy, neurological severities, number of relapses or outcomes of neuropathy and proteinuria.
Diagnostic issues on reports of GBS/CIDP with nephrotic syndrome
We found 33 cases from many countries reported in English between the years 1946–2012. Because more than one-third of the patients lacked edema and that nephrotic syndrome was sometimes transient, there could have been more overlooked cases. These findings imply that this syndrome occurs around the world and might not be as rare as previously thought.
Since the early 1990s, GBS has been well known to include both demyelinating and axonal subtypes. In Europe and North America, 90% of GBS cases are the demyelinating subtype, whereas axonal subtype dominates in northern China and is estimated as 40% of GBS in Japan.[35, 36] Electrophysiological findings are crucial to diagnose each subtype. In the present study, we could obtain data of NCS in two-thirds of the cases, in all of which demyelination was indicated, whereas we could not precisely determine whether axonal type or demyelinating type in the rest of the GBS cases. Because two-thirds of GBS cases originated from Europe, North America and Australia, and any antiganglioside antibodies-related axonal subtypes were never described, we concluded that GBS in the present study was essentially the demyelinating subtype (acute inflammatory demyelinating polyneuropathy [AIDP]).
Current diagnostic criteria classify IDP in GBS/AIDP and CIDP by the temporal course of the diseases. The criteria are vague, because the durations of illness could be defined by the patients' reports. Atypical cases are not rare, so that diagnosing one as GBS/AIDP or CIDP is sometimes difficult, especially in the early stages of the diseases.[37, 38] The present retrospective study has a number of limitations, such as incompleteness of the clinical data, especially in neurological findings in some cases, and diversity in the follow-up periods. Furthermore, because the definition of CIDP was established around 1980, current diagnostic criteria had not been adapted in the reports written before the 1980s. Thus, we inevitably reclassified all the cases according to our provisional classification criteria based on the current diagnostic criteria, and consequently several cases were reclassified as different IDP forms from original ones. Then, in contrast to the general view,[24, 25, 30] we found that CIDP with nephrotic syndrome was more common than GBS/AIDP with nephrotic syndrome. Among CIDP cases, relapses occurred in half of the cases, but more than two relapses were reported in only one case. There are also no cases with intractable CIDP with progressive courses. Therefore, GBS/AIDP and CIDP in the present series might be combined as benign IDP with a wide range of disease courses.
Neurological and nephrological features of IDP with nephrotic syndrome
We found some characteristics in IDP with nephrotic syndrome. First, males were preferentially affected. Both GBS and CIDP have been reported to have only slight male predominance (ratio to men to women 1.78 (1.36–2.33), no sex difference, slightly more common in males), and it has been estimated that approximately 60% of cases are male in primary glomerulonephritis.[41-43] In contrast, in IDP with nephrotic syndrome, nearly 85% of cases were male and there were no female patients of childbearing age, thus the possible protective effects of estrogen or other factors related to sex could be speculated in this syndrome. Second, neurological symptoms were mainly motor impairments, and sensory disturbances were relatively mild in the majority of the cases. Although more than half of the cases received combined therapies because of inadequate efficacy of initial therapies, overall outcomes of neurological symptoms were quite favorable in most of the cases, suggesting that axonal damage was usually mild.
In the nephrological aspects, the major histological diagnoses of renal biopsies were membranous glomerulonephritis, focal segmental glomeruloscrelosis and minimal change disease and proportions of histological types did not deviate from those in the general population.[42-44] There were no relationships between the histological diagnoses of renal biopsies and clinical findings of neuropathy. Although the pathological diagnoses were divergent, nephrotic syndrome appeared simultaneously with the neuropathy, and worsened and improved in parallel with the neurological symptoms in the majority of the patients. This concordance in the disease course strongly suggests that the association of IDP with nephrotic syndrome is not merely a coincidence, but that common antigens of both the peripheral nervous system, especially myelin, and the glomerulus might be involved.
Protein 0 as a candidate for the target molecules
In GBS and CIDP, involvement of humoral immune mechanisms and cell-mediated immune mechanisms has been elucidated.[36, 40] Recent advances in the research established a close relationship between antiganglioside antibodies and clinical variants of GBS.[35, 36, 45] Because some gangliosides are also expressed in the kidney, these gangliosides could be a candidate for the target molecules in an immune reaction. In IDP with nephrotic syndrome, however, investigations of antiganglioside antibodies were carried out in four cases including the present case, and we could not find any possible antiganglioside antibodies involved in this syndrome.
In contrast, recent investigations in nephrotic syndrome have increasingly highlighted podocytes, which are highly specialized cells with a cardinal role in maintaining the glomerular filtration barrier, and producing growth factors for both mesangial cells and endothelial cells. With their foot process, they compose slit diaphragms with neighboring podocytes, and effacement of the foot processes is thought to be a key structure involved in nephrotic syndrome. Interestingly, many biological similarities between podocytes and central or peripheral nervous systems, including processes with branching morphology and intracellular traffic machinery, as well as common proteins, have been noted. Among them, myelin protein 0 (P0) is a common protein in podocytes and the peripheral nervous system. P0 is a major structural protein of peripheral myelin, and mutations of the P0 gene cause the demyelinating type of hereditary neuropathy (Charcot–Marie–Tooth disease [CMT]). In podocytes, P0 has shown to colocalize with nephrin, which is a component of the slit diaphragm. Although the function of P0 in podocytes is still elusive, P0−/− mice showed not only neuropathy, but also albuminuria, and an association of nephropathy with CMT of the P0 mutation has been reported. Thus, P0 could be a key molecule in the pathomechanism of IDP with nephrotic syndrome. There have been several studies of antibodies against P0 in IDP, which yielded various results using different methodologies.[51-53] However, whether these IDP patients with anti-P0 antibody had any feature of nephropathy or not was never described.
Awareness of the clinical entity of IDP with nephrotic syndrome could be helpful for clinicians managing patients with IDP. Patients with IDP with nephrotic syndrome showed several clinical characteristics, such as male predisposition, motor dominant neurological deficits and, even if the nadirs of symptoms were severe or the neurological symptoms progressed after the initial therapies, their outcomes were favorable. The symptoms of nephrotic syndrome, such as edema, were not evident in some cases, thus sequential urinalysis might be necessary in the management of IDP. Renal biopsies are useful to reveal histopathological backgrounds of nephrotic syndrome; however, histological diagnoses of nephropathy do not seem to affect the outcome of both neuropathy and proteinuria in this syndrome. Further accumulation of cases and the investigation of common antigens in both peripheral myelin and glomerulus are expected to show the pathomechanism of this unique syndrome, and provide us knowledge of the physiology of the peripheral nervous systems and the glomerulus.
We thank to Mr Brent Bell for reading the manuscript.