The short- and long-term outcomes of membranous nephropathy treated with intravenous immune globulin therapy

Hitoshi Yokoyama1,2, Satoshi Goshima1, Takashi Wada1, Masayoshi Takaeda1, Kengo Furuichi1, Ken-ichi Kobayashi1,2, Hiroshi Kida3 and the Kanazawa Study Group for Renal Diseases and Hypertension

1 First Department of Internal Medicine, 2 Division of Blood Purification, Kanazawa University School of Medicine, and 3 Department of Internal Medicine, Kanazawa National Hospital, Kanazawa, Japan

Correspondence and offprint requests to: Hitoshi Yokoyama MD DMSc, First Department of Internal Medicine and Division of Blood Purification, Kanazawa University School of Medicine, 13–1 Takara-machi, Kanazawa 920–8641, Japan.



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Appendix
 References
 
Background. A considerable diversity in prognosis is seen with membranous nephropathy (MN). A recent report showed beneficial effects of immune globulin (Glb) therapy in Heymann nephritis, a rat model of MN. However, the early and late clinical effects of Glb in human MN have remained unclear.

Methods. We studied retrospectively 86 patients with primary MN from 1965 to 1988 who were followed for at least 5 years, or until renal or actual death. Thirty patients were non-randomly treated with 1–3 courses of intravenous immune globulin, 5–10 g/day (100–150 mg/kg/day) for 6 consecutive days. Based on electron microscopic (EM) findings, the patients were divided into two subtypes, i.e. homogeneous type with synchronous electron-dense deposits, and heterogeneous type with various stages of dense deposits, due to their different clinical outcomes.

Results. There was no difference in the initial clinicopathological states between Glb (n=30) and non-Glb group (n=56) (70 vs 68% in nephrotic state; 37 vs 39% in female, 50 vs 52% in homogeneous type, 50 vs 48% in heterogeneous type respectively). For the homogeneous type, at 6 months post-treatment, Glb therapy had induced earlier remission as compared to non-Glb treatments with corticosteroid alone or together with cyclophosphamide (57 vs 10% respectively, P=0.006). However, there was no significant difference in the early therapeutic effect for the heterogeneous type (13% for Glb vs 5% for non-Glb in remission after 6 months), or in the final outcome for all groups (18% for Glb vs 10% for non-Glb in renal death after 15 years). No adverse effects were recorded during or after Glb therapy.

Conclusions. Our results suggest that short-term relatively low-dose intravenous Glb therapy has a beneficial effect in the earlier induction of remission in a subgroup of MN, the homogeneous type with EM findings of synchronous electron-dense deposits, but does not alter the long-term outcome of human MN.

Keywords: membranous nephropathy; immune globulin therapy; complement; electron-dense deposits



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Appendix
 References
 
Idiopathic membranous nephropathy (MN), caused by immune-complex deposition in glomerular capillaries, has a considerable heterogeneity in prognosis. Overall, about 25% of the patients with idiopathic membranous nephropathy will achieve spontaneous remission [13]. On the other hand, 15–20% of Japanese patients, and one-third to one-half of patients in other countries, develop end-stage renal failure or die from complications such as infection, cardiovascular episodes or malignancy [46]. Conflicting results have been seen for the therapeutic effects of various treatments because of an inability to demarcate the different prognostic groups [2,6].

Intravenous high-dose immune globulin therapy has beneficial effects in various antibody-mediated diseases in humans, including idiopathic thrombocytopenic purpura [78], Kawasaki disease [9], and some renal diseases such as lupus nephritis [10,11], IgA nephropathy [12], anti-neutrophilic cytoplasmic antibody positive vasculitis [13], and idiopathic membranous nephropathy [14]. Recently Nangaku et al. demonstrated beneficial effects of intravenous high-dose immune globulin even in Heymann nephritis, a rat model of membranous nephropathy in which similar mechanisms, such as activation of complements, may be operative as in humans [15]. However, the early and late clinical effects of intravenous immune globulin in human membranous nephropathy have remained unclear.

In this study, we analysed data from 30 Japanese patients with primary membranous nephropathy treated with intravenous immune globulin therapy and 56 historical controls. We also divided membranous nephropathy into two subtypes based on electron microscopic findings; i.e. homogeneous type with synchronous electron-dense deposits and heterogeneous type with various stages of dense deposits.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Appendix
 References
 
Patients and design of treatment
We enrolled 86 Japanese patients (53 men and 33 women, aged 17–80 years, mean 44 years), who were admitted to the First Department of Internal Medicine of Kanazawa University Hospital or its affiliated hospitals between 1965 and 1988. We followed these patients for at least 5 years, or until renal or actual death. Diagnosis was confirmed in all patients by percutaneous needle renal biopsies. Patients with secondary membranous nephropathy such as lupus nephritis, or membranous nephropathy related to hepatitis B virus or malignancy were excluded from this study according to the clinical and laboratory findings. Between 1983 and 1988, 30 patients were given 1–3 courses of intravenous immune globulin, 5–10 g/day (100–150 mg/kg/day) for 6 consecutive days, total dose 600–900 mg/kg (Fujisawa or Green Cross, Osaka, Japan) in a non-blind and non-randomized manner. There were no significant differences between the intravenous immune globulin treated group and non-immune globulin (historical control) group in clinical and laboratory backgrounds, as shown in Table 1Go. Renal biopsies and treatments were all conducted with the informed consent of the patients.


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Table 1. Characteristics of 86 patients with idiopathic membranous nephropathy classified according to immune globulin or non-globulin therapy
 
Study design and response to treatment
This study is a retrospective analysis for the historical control group from 1965 to 1997. The immune globulin therapy group was followed from 1983 to 1998. Responses to treatment with intravenous immune globulin, steroid alone or together with immunosuppressants, or no treatment, were judged in the same way. Clinical status was defined as follows: the nephrotic state, the presence of heavy proteinuria (greater than 3.5 g/day or 3+ (300 mg/dl) to 4+ (1000 mg/dl) by Multistics) and hypoalbuminaemia (levels less than 30 g/l); incomplete remission type II, i.e. normal serum albumin levels (more than 30 g/litre) with a mean daily proteinuria of 1.0–3.5 g for 7 consecutive days or 2+ (100 mg/dl) to 3+ (300 mg/dl) by Multistics; incomplete remission type I, i.e. normal serum albumin levels (more than 30 g/l) with a mean daily proteinuria of less than 1.0 g for 7 consecutive days or + (30 mg/dl) by Multistics; complete remission, i.e. daily proteinuria of less than 0.2 g with normal serum albumin levels. Renal dysfunction was defined as a serum creatinine level of greater than 132.6 µmol/litre (1.5 mg/dl) or glomerular filtration rate defined by endogenous creatinine clearance (CCr) of less than 60 ml/min. Renal death was defined as the necessity for haemodialysis, peritoneal dialysis, or renal transplantation.

Pathohistological studies
For light microscopic examination, kidney specimens were fixed in 10% phosphate-buffered formalin (pH 7.4), embedded in paraffin, and cut into 4 µm sections. These specimens were stained with haematoxylin and eosin (HE), periodic acid Schiff reagent (PAS), Mallory-azan, and periodic acid silver methenamine (PAM), and examined by light microscopy, with an emphasis on capillary lesions. We determined the presence or absence of capillary-wall lesions and evaluated the appearance of lesions (double contour, bubble like appearance, and spike formation). Renal tissue specimens were examined by two observers with no knowledge of the patients' clinical courses to establish the diagnosis by standard pathological methods. In addition, immunofluorescent examination was also performed on all fresh frozen specimens, which were embedded in OCT compound, snap frozen in n-hexane cooled with a mixture of dry ice and acetone, and cut into 6-µm sections using a cryostat (Tissue-Tek II systems; Miles, Naperville, IL, USA). Sections were treated with fluorescein isothiocyanate (FITC)-labelled anti-human IgG ({gamma}-chain), IgA ({alpha}-chain), and IgM (µ-chain) sheep IgG/F(ab')2 antibodies and FITC-labelled anti-human C3c and C1q rabbit IgG antibodies (Cappel, West Chester, PA, USA) for immunofluorescent studies. More than three glomeruli were examined in each specimen, and the intraglomerular immunofluorescence staining of immunoglobulins and complements were arbitrarily graded on a scale from 0 to 3: 0, none; 0.5, scattered; 1, weakly diffuse; 2, moderately diffuse; 3, strongly diffuse, and a mean score was calculated.

One hundred and seven specimens were fixed with glutaraldehyde and osmium tetroxide, embedded in Epon (Epok) 812 (Oken Shoji Co, Tokyo, Japan), cut into 0.1 µm sections, double-stained with uranyl acetate and lead citrate, and examined with a Hitachi H-600 electron microscope (Hitachi Co, Tokyo, Japan). For the electron microscopic study, we examined the specimens with an emphasis on the stage and synchronicity of subepithelial and intramembranous electron-dense deposits. We modified the classification of Rosen et al. [16], and arbitrarily classified specimens showing synchronous electron-dense deposits with a single stage as homogeneous type, and others having various stages of electron-dense deposits as heterogeneous type (Figure 1Go).



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Fig. 1 Subtypes of membranous nephropathy. (a) Homogeneous type (original magnification, x3000); (b) heterogeneous type (original magnification, x3000).

 
Second biopsies were obtained from 20 patients 4 to 12 weeks after intravenous immune globulin therapy. Intensity of immunofluorescence and the character of subepithelial electron-dense deposits were compared between pre- and post-intravenous immune globulin therapy.

Laboratory investigations
We measured urinary protein quantitatively using the Pyrogallol red method, and semi-quantitatively using Multistics (Miles, Tokyo): -, negative; +, 30 mg/dl; 2+, 100 mg/dl; 3+, 300 mg/dl; 4+, 1000 mg/dl of albumin. Serum total protein, albumin, creatinine and immunoglobulin G (IgG) levels were examined before and 1, 2, 4, 8, 16 and 24 weeks after intravenous immune globulin therapy. We also analysed circulating T lymphocyte subsets using flow cytometry (Ortho Spectrum III, Ortho Pharmaceutical Co., Raritan, New Jersey, USA) using monoclonal antibodies (CD4 (OKT4) and CD8 (OKT8), Ortho), and calculated the CD4/CD8 ratio.

Statistical analysis
Statistical analyses were performed using Wilcoxon's rank-sum test, Student's t- and Fisher's exact tests for paired and unpaired data, chi-square test, and the Kaplan and Meier life-table method. P values less than 0.05 were accepted as statistically significant. SAS software was used in these statistical calculations [17].



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Appendix
 References
 
Patients' backgrounds
There was no difference in age, gender, or initial clinicopathological state between the intravenous immune globulin (n=30) and non-immune globulin groups (n=56) (70 vs 68% in nephrotic state; 37 vs 39% in female, 50 vs 52% in homogeneous type, 50 vs 48% in heterogeneous type respectively. The follow-up period after treatment was significantly longer in the control (non-immune globulin) group, but there was no difference in the pre-treatment history of illness (Table 1Go). Of the controls, 17 patients were treated with corticosteroid alone and 22 patients with corticosteroid and immunosuppressants.

Response to intravenous immune globulin therapy
After intravenous globulin administration, serum IgG levels rose significantly from an initial 820±80 mg/dl to 1390±100 mg/dl at 2 weeks (mean±SEM, P<0.005) and 1120±110 mg/dl at 4 weeks (P<0.01). Serum total protein and albumin levels gradually increased to normal levels (more than 30g/l for albumin) at 4 weeks post-treatment. These parameters had entered the normal ranges 24 months later (Figure 2a,bGo). Proteinuria was unchanged at 4 weeks post-treatment (4.1±0.5 g/day before, 4.1±0.4 g/day at 2 weeks and 4.2±0.7 g/day at 4 weeks). The CD4/CD8 ratio of circulating T-lymphocyte subsets was initially elevated at 2.33±0.21 and quickly decreased to the normal range, 1.85±0.23 at 2 weeks and 1.73±0.18 at 4 weeks. The CD4/CD8 ratio continued to decrease until 6 months post-treatment in the complete remission group. However, these parameters returned to initial levels after 6 months in the non-complete remission group (Figure 2cGo).



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Fig. 2 Alteration of serum protein, albumin, IgG levels, and circulating T-lymphocyte subsets. (a) Serum total protein and albumin levels gradually increased and returned to the normal levels after treatment; (b) serum IgG levels rose significantly from 820±80 mg/dl to 1390±100 mg/dl at 2 weeks and 1120±110 mg/dl at 4 weeks later; (c) the CD4/CD8 ratio of circulating T-lymphocyte subsets was initially high at 2.33±0.21 and quickly decreased to the normal range after treatment. In non-complete remission patients ({blacklozenge}), the CD4/CD8 ratio rose after 6 months. Values are mean±SEM. *P<0.05; **P<0.01; ***P<0.005 by paired Student's t-test.

 
Good responses were seen in 13 patients to intravenous immune globulin therapy, defined as complete remission, and 17 patients had non-complete remission. Of the latter, 11 showed incomplete remission type II with normal serum creatinine levels (<1.5 mg/dl), three patients had continued nephrotic state with renal dysfunction, and three entered end-stage renal failure. No significant differences were seen in age, previous therapy, dosages of intravenous immune globulin, or clinical state between the complete and non-complete remission groups. Patients showing homogeneous type electron microscopic findings predominated in the intravenous immune globulin therapy complete remission group (Table 2Go).


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Table 2. Characteristics of 30 patients with idiopathic membranous nephropathy classified according to response to intravenous immune globulin therapy
 
Figure 3Go shows the clinical course and electron microscopic findings of a representative patient with steroid-resistant prolonged nephrotic state and large synchronous electron-dense deposits, who had good response to intravenous immune globulin.



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Fig. 3 A case of membranous nephropathy. (a) Clinical course in a 43-year-old male patient; (b) electron microscopic findings before intravenous immune globulin therapy showing large synchronous electron-dense deposits (original magnification, x3000); (c) electron microscopic findings after intravenous immune globulin therapy, showing new glomerular capillary basement membrane below the epithelial cells. Subepithelial deposits lost electron density. (Original magnification, x3000.).

 
No adverse effects were recorded during or after intravenous immune globulin therapy in any patients.

Changes in pathological findings following intravenous immune globulin therapy
Following intravenous immune globulin therapy, 20 patients underwent second renal biopsy 4 to 12 weeks post-treatment. No remarkable changes were seen in subepithelial IgG or electron-dense deposits. However, the intensity of glomerular C3c staining was significantly reduced post-treatment (z value=-2.497, n=20, P=0.0125 by Wilcoxon's rank-sum test). In one patient who underwent a third renal biopsy at 9 months after three courses of intravenous immune globulin therapy, the intensity of the glomerular subepithelial electron-dense deposits decreased as shown in Figure 3cGo.

Relationship between response to treatment and the subtypes of membranous nephropathy
For the homogeneous type, intravenous immune globulin more often induced remission at 6 months post-treatment as compared with the control group (57 vs 10% respectively, P=0.0061). However, there was no significant difference in early therapeutic effects for the heterogeneous type (13% for the intravenous immune globulin vs 5% for the control group in remission after 6 months), or the responses at 2 and 5 years in both subtypes. There was no difference in the final clinical and functional outcomes between the two groups (renal death rate of 18% for intravenous immune globulin (n=14) vs 10% for the control group (n=46) after 15 years by Kaplan-Meier life-table analysis, Figure 4Go, Table 4Go).



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Fig. 4. Renal survival rates for the intravenous immune globulin therapy group and non-immune globulin therapy group in membranous nephropathy. There was no difference in the final clinical outcome between the groups; renal death rates of 18% for the intravenous immune globulin group and 10% for the non-immune globulin therapy group at 15 years using the Kaplan-Meier life-table method.

 

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Table 4. Final renal function of 86 patients with idiopathic membranous nephropathy classified according to therapy and pathological subtypes
 


   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Appendix
 References
 
The mechanism(s) of therapeutic effects of intravenous immune globulin in immune-complex mediated diseases including lupus nephritis and membranous nephropathy has been speculated to involve the blocking of Fc receptors, anti-idiotype inhibition of pathogenic immunoglobulin, or the regulation of the complement cascade by preventing the binding of activated C3 to antibody-coated targets [11,18,19]. Nangaku et al. found that even intraperitoneal immune globulin injection (600 mg/kg) reduced proteinuria by over 50% in rat Heymann nephritis, accompanied by reduction in glomerular C5b-9 and C3c staining and urinary C5b-9 excretion [15]. In this study, levels of proteinuria, glomerular IgG deposition and subepithelial electron-dense deposits were unchanged 4 weeks after intravenous immune globulin therapy, but glomerular C3c staining was reduced, as demonstrated with the rat Heymann nephritis model. In part, the therapeutic effects of intravenous immune globulin in human membranous nephropathy may be due to a reduction in ongoing complement activation in the glomerulus.

In humans, the initial reduction of proteinuria during intravenous immune globulin therapy was unremarkable, but serum protein and albumin levels were increased 4 weeks after intravenous immune globulin therapy. Complete remission was achieved at 6 months in 13 patients. These findings suggest that intravenous immune globulin may ameliorate the glomerular injury in human membranous nephropathy not only by a reduction in complement activation in the initial phase, but also other mechanisms acting in the later phase. In this study, we found that circulating T lymphocyte subsets were altered before clinical improvements were seen in membranous nephropathy. The exact mechanism of this alteration in the CD4/CD8 ratio by intravenous immune globulin therapy is still unclear, but a normalization of T lymphocyte subsets may lead to accelerated antibody production by reducing discordant T lymphocyte function in human membranous nephropathy. In fact, intravenous immune globulin has been reported to decrease circulating specific antibodies in autoimmune diseases, such as anti-platelet antibodies in idiopathic thrombocytopenic purpura, or antineutrophilic antibodies in autoimmune neutropenia of infancy [20,21]. In addition, Durandy et al. [22] reported that intravenous immune globulin given in a daily dose of 80 mg/kg to non-immunodeficient children for 15 days suppressed Pokeweed mitogen-stimulated differentiation and maturation of B lymphocytes to plasma cells, with the effects lasting at least 5 months. In this study, the CD4/CD8 ratio of circulating T lymphocytes normalized at 4 weeks after intravenous immune globulin therapy, the effect lasting at least 6 months, with the exception of non-complete remission and relapsed patients. These long-term effects on the immune system may lead to a reduction in immune-complex formation and induce clinical remission in most cases of the homogeneous type and some of the heterogeneous type of human membranous nephropathy.

In this study, we arbitrarily divided human membranous nephropathy into two subtypes; homogeneous type and heterogeneous type based on their different patterns of subepithelial deposits and clinical courses. The heterogeneity of membranous nephropathy has been previously reported, and Rosen et al. [16] delineated the morphological and clinical patterns; short with one generation of deposits, short/repeated, long/rapid, and long/slow. We simplified their classification with one generation of deposits, short/repeated, and long/rapid as the homogeneous type and long/slow as the heterogeneous type because of their synchronicity and clinical courses. The results of this study, with most of the homogeneous type showing good clinical and renal functional outcomes, tend to confirm the above arbitrary classification. In the long-term, intravenous immune globulin suppressed abnormal antibody production within 6 months, and induced clinical remission in the homogeneous type but not in the heterogeneous type, perhaps because disease activity in the latter continues beyond the long-term effects of intravenous immune globulin.

Intravenous immune globulin has potential complications such as anaphylactic reactions, the risk of contamination with unknown infective agents, and acute renal failure [23,24]. In this study, such complications were not recorded and at these dosages intravenous immune globulin therapy is considered safe. The cost of intravenous immune globulin therapy ($7600 for 1 course) may be higher than the cost of other therapies [11]. However, infection is an important cause of morbidity and mortality in patients with severe membranous nephropathy, especially patients treated with corticosteroid or immunosuppression therapy as previously reported [5]. Not only the cost but also the benefits of intravenous immune globulin therapy, i.e. reduced risk of infection and shorter admission periods due to earlier remission, should be taken in account when considering the indications for intravenous immune globulin therapy in idiopathic membranous nephropathy. In the therapeutic strategy for human membranous nephropathy, short term treatment with intravenous immune globulin therapy may be the first choice when patients have the homogeneous type of disease and corticosteroids or immunosuppressants are contra-indicated due to the risks of infection or for other reasons. For the heterogeneous type, short-term treatment with intravenous immune globulin therapy was not effective. Combination with other therapies or repeated treatments with intravenous immune globulin therapy may be considered in the future.

In summary, our results suggest that short-term intravenous immune globulin therapy has the beneficial effect of giving earlier remission in a subtype of membranous nephropathy, patients with the homogeneous type showing synchronous electron-dense deposits, but does not change the long-term outcome in human membranous nephropathy.



   Appendix
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Appendix
 References
 
Co-operating members of the Kanazawa Study Group for Renal Diseases and Hypertension: Shinichi Takeda (Kurobe Municipal Hospital), Takero Naito (Toyama Prefectural Hospital), Satoshi Ohta (Toyama Municipal Hospital), Kenzo Ikeda (Koseiren Takaoka Hospital), Shigehiko Sato (Tonami Municipal Hospital), Yuji Yamada (Hakui Public Hospital), Hiromichi Ohta (Kahoku Central Hospital), Toshio Abe (Kanazawa City Hospital), Norihiko Sakai, Chikako Takaeda-Segawa, Miho Shimizu (Kanazawa University Hospital), Mitsuhiro Yoshimura, Kazuya Takasawa, Ichiro Matsuda (Kanazawa National Hospital), Yukimasa Hisada (Kanazawa Red-Cross Hospital), Yoshitaka Koshino (Koshino Hospital), Denzi Uno (Matsuto-Ishikawa Central Hospital), Teruo Asamoto (Neagari General Hospital), and Saburo Nakamura (Tsuruga Municipal Hospital).


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Table 3. Response to intravenous immune globulin therapy vs corticosteroid or corticosteroid with immunosuppressants in subtypes of membranous nephropathy
 


   Acknowledgments
 
HY was supported by a Grant-in-Aid (No. 09671157) from the Ministry of Education, Science, Sports and Culture of Japan. We would like to thank Dr Naohisa Tomosugi (Kanazawa Medical University, Japan) for his kind advice, and Ms Minako Kaida for her excellent electron microscopic technique.



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Appendix
 References
 

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Received for publication: 13. 5.98
Accepted in revised form: 4. 6.99





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