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NDT Advance Access published online on July 2, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn363
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Monoclonal immunoglobulin deposition disease associated with membranous features

Atsushi Komatsuda1, Rie Masai1, Hiroshi Ohtani2, Masaru Togashi1, Nobuki Maki1, Ken-ichi Sawada1 and Hideki Wakui1

1 Third Department of Internal Medicine, Akita University School of Medicine 2 Department of Nephrology and Dialysis, Akita Kumiai General Hospital, Akita, Japan

Correspondence and offprint requests to: Atsushi Komatsuda, Third Department of Internal Medicine, Akita University School of Medicine, 1-1-1 Hondo, Akita City, Akita 010-8543, Japan; Tel: +81 18 884 6116; Fax: +81 18 836 2613. E-mail: komatsud{at}med.akita-u.ac.jp



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Very few cases of non-organized and non-Randall-type monoclonal immunoglobulin deposition disease (MIDD) associated with membranous features have been reported. Information on clinicopathological features and prognosis in this entity is limited.

Methods. We reviewed 5443 renal biopsies processed at our department, and identified three patients with MIDD associated with membranous features. We evaluated clinicopathological features and outcomes in these patients.

Results. All patients had proteinuria, and one patient developed nephrotic syndrome. Renal insufficiency was not observed. Cryoglobulin or monoclonal protein in serum and urine was not detected. A renal biopsy showed thickening of the glomerular capillary walls and spike formation. Tubulointerstitial and vascular alterations were mild or absent. Immunofluorescence studies revealed granular IgG3-{kappa} deposits in two patients and IgG1-{kappa} deposits in one patient, along the glomerular capillary walls. Immunofluorescence studies using antibodies specific for {gamma}-heavy chain Fab containing CH1 domain, CH2 domain and CH3 domain did not show any apparent deletion. On confocal microscopy, glomerular colocalization of light and heavy chains was observed. Electron microscopy showed predominant subepithelial granular deposits without distinct ultrastructural organization. All patients were treated with steroids, and good effects were observed. A follow-up renal biopsy performed in one patient showed histological improvements. No patient developed myeloma or other haematological malignancy during the course of follow-up (mean 44 months).

Conclusions. MIDD associated with membranous features is an extremely rare but distinctive entity. Our study suggests glomerular deposition of a nondeleted whole immunoglobulin molecule. Patients with this entity appear to respond well to steroid therapy.

Keywords: clinicopathological features; membranous nephropathy; monoclonal immunoglobulin deposition disease; prognosis; proliferative glomerulonephritis with monoclonal IgG deposits



   Introduction
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 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults. The main pathological feature on electron microscopy is the presence of subepithelial electron-dense deposits. The characteristic immunofluorescence finding is granular staining for polyclonal immunoglobulins and complements along the glomerular basement membranes [1].

Very few cases of non-organized and non-Randall-type monoclonal immunoglobulin deposition disease (MIDD) associated with membranous features or similar cases have been reported in the literature [2–5]. Ultrastructural glomerular lesion in Randall-type MIDD is characterized by continuous linear deposits of finely granular electron-dense material along the inner aspect of the glomerular basement membranes [6]. Four cases of glomerulopathy with IgG-{kappa} or IgG-{lambda} deposits were reported by Bridoux et al. in 2001. In their series of patients, granular parietal deposits without distinct ultrastructural organization were predominantly membranous [2]. One of these patients was described in detail by Touchard in 2003 [3]. They proposed the term non-organized and non-Randall-type MIDD to individualize this rare entity. A similar case was also described by Evans et al. [4] in 2003. Nasr et al. [5] reported 10 cases of proliferative glomerulonephritis (GN) with monoclonal IgG deposits in 2004. In their series of patients, one patient had membranous features on light microscopy. The single case with membranous features in Nasr's series [5] had IgG1-{kappa} deposits. In this case, the postbiopsy follow-up time was limited to 2 months. Information on clinicopathological features and prognosis in non-organized and non-Randall-type MIDD associated with membranous features or proliferative GN associated with membranous features is presently limited.

In the present study, we reviewed 5443 renal biopsies processed at our department, and identified three patients with MIDD associated with membranous features. Two patients had IgG3-{kappa} deposits and one patient had IgG1-{kappa} deposits. These deposits were not organized and not of Randall type on electron microscopy. We evaluated clinicopathological features and outcomes in these patients. We also characterized these paraprotein deposits by immunofluorescence studies.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
Patients
This study was based on the renal histological records (1979–2007) of 5443 patients studied at Akita University Hospital and its affiliated hospitals. Glomerular stainings for light and heavy chains were evaluated in 4864 patients by immunofluorescence studies. MIDD associated with membranous features was defined by the modified criteria for proliferative GN with monoclonal IgG deposits [5]: (1) the presence of glomerular monoclonal IgG deposits restricted to a single IgG subclass and a single light chain isotype, associated with membranous features without proliferative patterns; (2) the presence of granular (‘immune complex type’) deposits by electron microscopy and (3) the absence of clinical and laboratory evidence of cryoglobulinaemia. There were three patients with MIDD associated with membranous features. There were four patients with proliferative GN with monoclonal IgG deposits associated with membranoproliferative features.

Clinical and laboratory information was obtained on each patient at the time of renal biopsy. Follow-up information was obtained in all patients. Hypertension was defined as systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg, or the use of antihypertensive medications at the time of biopsy. Nephrotic syndrome was defined as urinary protein ≥3.5 g/day, hypoalbuminaemia (serum albumin ≤3.0 g/dl) and oedema. Renal insufficiency was defined as serum creatinine ≥1.2 mg/dl. Positive serum protein and urine protein immunoelectrophoresis were defined by the presence of monoclonal bow.

A follow-up renal biopsy was performed in one patient (patient 1) after 4-year treatment.

Pathological studies
The renal biopsy specimens were processed using standard techniques for light, immunofluorescence and electron microscopy. Determination of the IgG subclass was performed on cryostat sections. Sections were stained with mouse monoclonal antibodies to human IgG1 (clone 8c/6-39), IgG2 (clone HP6014), IgG3 (clone HP6050) and IgG4 (clone HP6025) (The Binding Site, Birmingham, UK), followed by fluorescein isothiocyanate (FITC)-conjugated anti-mouse IgG (Cappel, Aurora, OH, USA). Renal biopsy specimens from all patients were further examined with monoclonal antibodies specific for human {gamma}-heavy chain Fab containing CH1 domain, CH2 domain and CH3 domain. Cryostat sections from patients were stained with mouse monoclonal antibodies to human IgG (Fab) (clone TM15) (American Research Products, Belmont, MA, USA), IgG (Fc)-CH2 domain (clone 8A4) (AbD Serotec, Oxford, UK) and IgG (Fc)-CH3 domain (clone A57H) (AbD Serotec), followed by FITC-conjugated anti-mouse IgG or anti-mouse IgM (Cappel).

Confocal microscopy was also performed using cryostat sections from all patients. For double labelling of specimens for IgG1 or IgG3 and {kappa}-light chain, mouse monoclonal antibody to human IgG1 and IgG3 (The Binging Site) and rabbit polyclonal antibody to human {kappa}-light chain (Gene Tex, San Antonio, TX, USA) were used as the first antibodies. Alexa Fluor 488 anti-mouse IgG (Molecular Probes, Eugene, OR, USA) and Alexa Fluor 546 anti-rabbit IgG (Molecular Probes) were used as the second antibodies.



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
Clinical features
Clinical features in our three patients with MIDD associated with membranous features are summarized in Table 1. All patients were males. The median age was 37 years (range 24–44). At presentation, no patient had hypertension and one patient had oedema. There were no symptoms or signs of multiple myeloma or cryoglobulinaemia in all patients. All patients had proteinuria, and one patient developed nephrotic syndrome. Microscopic haematuria was present in one patient. Renal insufficiency (serum creatinine ≥1.2 mg/dl) was not present in any patient. Leukocytosis was found in two patients, but anaemia or thrombocytopenia was not observed in any patient. Serum levels of calcium, IgA and IgM were normal in all patients, but serum IgG levels decreased in two patients. Hypocomplementaemia was found in one patient. Serological workup showed no anti-nuclear antibody or cryoglobulin in any patient. By serum and urine protein immunoelectrophoresis, monoclonal protein in blood or Bence–Jones protein was not detected in any patient. Other studies for the detection of monoclonal proteins, such as immunoblotting, and bone marrow examinations were not performed in any patient.


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  		Table 1 Clinical data at presentation and outcomes in three patients with MIDD associated with membranous features

 
All patients were treated with steroids alone, and none of them received angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists. Patient 1 was treated with methylprednisolone pulse therapy (500 mg/ day) for 3 days followed by oral prednisolone therapy (30 mg/day) for 4 weeks. Thereafter, prednisolone was tapered gradually. Patients 2 and 3 were treated with oral prednisolone therapy (40 mg/day for 4 weeks and 30 mg/day for 8 weeks, respectively). Thereafter, prednisolone was tapered gradually. Good effects on proteinuria were observed in all patients. Renal function was reserved in all patients. No patient developed myeloma or other haematological malignancy, during the course of follow-up (mean 44 months).

Pathological features
Pathological features in our three patients with MIDD associated with membranous features are summarized in Table 2. Renal histological findings in a representative case (patient 3) are shown in Figures 1 and 2. Light microscopy showed thickening of the glomerular capillary walls and spike formation without proliferative patterns such as endocapillary and mesangial proliferation. Homogenous giant deposits were observed in two patients. Tubulointerstitial and vascular alterations were mild or absent in all patients. Congo red staining for amyloid was negative in all patients. Immunofluorescence studies revealed glomerular IgG-{kappa} deposits in all patients. Staining for {lambda}-light chain was negative in all cases. The deposits stained only for a single IgG subclass: IgG3 (with negative IgG1, IgG2 or IgG4) in two patients and IgG1 (with negative IgG2-4) in one patient. There was no granular peripheral capillary wall staining for IgA or IgM in all patients. Glomerular C3 and C1q deposits were also found in three and two patients, respectively. Significant deposition along the tubular basement membranes was not observed in any patient. By electron microscopy, non-organized and non-Randall-type granular electron-dense deposits were identified in the subepithelial space of the glomerular basement membranes in one patient. Predominant subepithelial deposits with subendothelial and mesangial deposits were observed in two patients (Figure 2).


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  		Table 2 Renal biopsy findings in three patients with MIDD associated with membranous features

 

Figure 1
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  		Fig. 1 A representative case of MIDD associated with membranous features (patient 3). (A) Light microscopy of a glomerulus shows thickening of the glomerular capillary walls and giant deposits without proliferative patterns. Periodic acid-Schiff staining (original magnification x400). (B) Periodic acid-methenamine-silver staining shows spike formation (original magnification x400). Immunofluorescence microscopy for IgG-heavy chain (C), {gamma}3-heavy chain (D), {kappa}-light chain (E) and {lambda}-light chain (F) displays strong staining for IgG-heavy chain, {gamma}3-heavy chain and {kappa}-light chain along the glomerular capillary walls with a granular texture, but no significant staining for {lambda}-light chain (original magnification x400).

 

Figure 2
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  		Fig. 2 A representative case of MIDD associated with membranous features (patient 3). Electron microscopy reveals finely granular electron dense deposits in predominant glomerular subepithelial locations (short arrows), subendothelial deposits (long arrow), mesangial deposits (arrowheads) and paramesangial giant deposits (asterisk). (The bar represents 2 µm.)

 
Biopsy specimens from all patients were also stained with antibodies specific for {gamma}-heavy chain Fab containing CH1 domain, CH2 domain and CH3 domain. The results did not show any apparent deletion. Dual immunostaining of biopsy specimens from all patients disclosed colocalization of {gamma}1- or {gamma}3-heavy chain and {kappa}-light chain along the glomerular capillary walls (Figure 3).


Figure 3
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  		Fig. 3 Dual immunostaining of kidney from a patient (patient 3) with IgG3-{kappa} deposits by antibodies to {gamma}3-heavy chain and {kappa}-light chain. A renal biopsy specimen from patient 3 was stained with mouse monoclonal antibody to {gamma}3-heavy chain and rabbit polyclonal antibody to {kappa}-light chain, followed by Alexa Fluor 488 anti-mouse IgG and Alexa Fluor 546 anti-rabbit IgG. (A) Glomerular deposits of {gamma}3-heavy chain are shown in green. (B) Glomerular deposits of {kappa}-light chain are shown in red. (C) The merge image, where colocalization of {gamma}3-heavy chain and {kappa}-light chain is shown in yellow along the glomerular capillary walls.

 
A follow-up renal biopsy performed in one patient after 4-year treatment showed remarkable histological improvements of thickening of the glomerular capillary walls and spike formation (Figure 4).


Figure 4
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  		Fig. 4 Renal histological improvements in one patient (patient 1). (A) and (B) Initial biopsy specimens. (C) and (D) Follow-up biopsy specimens after 4-year treatment. (A) and (C) Periodic acid-Schiff staining (original magnification x400). (B) and (D) Periodic acid-methenamine-silver staining (original magnification x400). There are remarkable improvements of thickening of the glomerular capillary walls and spike formation after treatment.

 


   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
In the present study, we reviewed 5443 renal biopsies, and identified three patients with MIDD associated with membranous features. Glomerular deposits were not organized and not of Randall type in these patients. This novel form of glomerulopathy is an extremely rare entity (biopsy incidence 0.055%).

Very few cases of non-organized and non-Randall-type MIDD associated with membranous features or similar cases have been reported in the literature [2–5]. Bridoux et al. [2] reported four cases of glomerulopathy with IgG-{kappa} or IgG-{lambda} deposits (2 IgG3-{kappa}, 1 IgG2-{kappa}, and 1 IgG3-{lambda}). In their patients, granular parietal deposits were predominantly membranous. Touchard [3] described one of these patients in detail, a 48-year-old man. This patient developed hypertension and nephrotic syndrome with renal insufficiency. A renal biopsy showed thickened glomerular capillary walls with IgG3-{lambda} and complement deposits. Serum immunoelectrophoresis detected no monoclonal component. However, immunoblotting revealed the presence of monoclonal IgG3-{lambda}. After six courses of melphalan and prednisolone, remission of the nephrotic syndrome was obtained. Renal insufficiency also improved. Evans et al. [4] reported an 81-year-old woman with follicular B-cell lymphoma who developed nephrotic syndrome. Bence-Jones protein ({kappa}-chain) was detected. This patient died from pulmonary thromboembolism 7 weeks after the start of chemotherapy. Postmortem histological examination of the kidneys and elution studies revealed subepithelial granular IgG1-{kappa} deposits. There was no evidence of cryoprecipitability of the monoclonal protein. A 63-year-old woman in Nasr's series [5] had proliferative GN with IgG1-{kappa} deposits associated with membranous features. The total urinary protein for 24 h was 2g, serum albumin was 2.7 g/dl and serum creatinine was 0.9 mg/dl. IgG-{kappa} paraprotein was detected in serum and urine. This patient was treated with an angiotensin-converting inhibitor, but the postbiopsy follow-up time was limited to 2 months.

All our three patients with MIDD associated with membranous features had proteinuria, and one patient developed nephrotic syndrome. Renal insufficiency was not observed. In our patients, monoclonal protein was not detected in serum and urine. The inability to identify a corresponding monoclonal protein may relate to its presence at very low titers, below the level of detection by standard immunoelectrophoresis, or to rapid rates of tissue deposition [5]. All our patients responded well to steroid therapy. A follow-up renal biopsy performed in one patient after 4-year treatment showed remarkable histological improvements. No patient developed myeloma or other haematological malignancy during the course of follow-up (mean 44 months). Longer follow-up is needed to determine implications for the possible development of haematological malignancy.

Hypocomplementaemia was present in one of our three patients with MIDD associated with membranous features. This patient had IgG1 deposits. Glomerular C3 and C1q deposits were also observed. This may result from the high complement fixation ability of {gamma}1-heavy chain [7]. The mechanism of hypocomplementaemia in our patient presumably involves complement consumption through activation on {gamma}1-heavy chain deposits.

Previously reported cases of non-organized and non-Randall-type MIDD associated with membranous features [2] and our cases had IgG1-{kappa}, IgG2-{kappa}, IgG3-{kappa} or IgG3-{lambda} deposits. This suggests that patterns of IgG subclass deposits in MIDD associated with membranous features are different from those in idiopathic MN characterized by a predominant IgG4 deposition [8]. Our immunofluorescence studies showed colocalization of {gamma}1- or {gamma}3-heavy chain and {kappa}-light chain along the glomerular capillary walls and no apparent deletion in {gamma}-heavy chain CH1 domain, CH2 domain and CH3 domains in all patients. This suggests paraprotein of deposits of a nondeleted whole immunoglobulin molecule. The single case of proliferative GN with monoclonal IgG deposits associated with membranous features in Nasr's series [5] also stained for {gamma}-heavy chain CH1 domain, CH2 domain and CH3 domains. In contrast, a deletion of CH1 domain was found in most patients with heavy chain deposition disease (HCDD), another form of glomerulopathy associated with monoclonal IgG deposits [9]. Light microscopic, immunofluorescence, and electron microscopic features in MIDD associated with membranous features are also different from those in HCDD, which is characterized by nodular sclerosing glomerulopathy and detectable paraprotein deposits within basement membranes throughout the kidney [10].

In conclusion, MIDD associated with membranous features is an extremely rare but distinctive entity. Our immunofluorescence studies suggest paraprotein deposits of a nondeleted whole immunoglobulin molecule. Patients with this entity appear to respond well to steroid therapy. The accumulation of cases is needed for further determination of its clinicopathological features and outcome.



   Acknowledgments
 
This work was supported in part by the Global COE Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

  1. Falk RJ, Jennette JC, Nachman PH. Primary glomerular disease. In: Brenner & Rector's the Kidney—Brenner BM, ed. (2004) Philadelphia: Saunders. 1293–1380.
  2. Bridoux F, Binaut R, Zanetta G, et al. Glomerulopathy with non-organized and non-Randall type monoclonal immunoglobulin deposits: a rare entity. J Am Soc Nephrol (2001) 12:94A. abstract.
  3. Touchard G. Ultrastructural pattern and classification of renal monoclonal immunoglobulin deposits. In: Monoclonal Gammopathies and the Kidney—Touchard G, Aucouturier P, Hermine O, Ronco P, eds. (2003) Dordrecht, The Netherlands: Kluwer. 95–117.
  4. Evans DJ, Macanovic M, Dunn MJ, et al. Membranous glomerulonephritis associated with follicular B-cell lymphoma and subepithelial deposition of IgG1-{kappa} paraprotein. Nephron Clin Pract (2003) 93:c112–c118.[CrossRef][Web of Science][Medline]
  5. Nasr SH, Markowitz GS, Stokes MB, et al. Proliferative glomerulonephritis with monoclonal IgG deposits: a distinct entity mimicking immune-complex glomerulonephritis. Kidney Int (2004) 65:85–96.[CrossRef][Web of Science][Medline]
  6. Preud’homme J-L, Aucouturier P, Touchard G, et al. Monoclonal immunoglobulin deposition disease (Randall type). Relationship with structural abnormalities of immunoglobulin chains. Kidney Int (1994) 46:965–972.[Web of Science][Medline]
  7. Miletic VD, Frank MM. Complement-immunoglobulin interactions. Curr Opin Immunol (1995) 7:41–47.[CrossRef][Web of Science][Medline]
  8. Imai H, Hamai K, Komatsuda A, et al. IgG subclasses in patients with membranoproliferative glomerulonephritis, membranous nephropathy, and lupus nephritis. Kidney Int (1997) 51:270–276.[Web of Science][Medline]
  9. Ronco P, Plaisier E, Mougenot B, et al. Immunoglobulin light (heavy)-chain deposition disease: from molecular medicine to pathophysiology-driven therapy. Clin J Am Soc Nephrol (2006) 1:1342–1350.[Abstract/Free Full Text]
  10. Kambham N, Markowitz GS, Appel GB, et al. Heavy chain deposition disease: the disease spectrum. Am J Kidney Dis (1999) 33:954–962.[Web of Science][Medline]
Received for publication: 14. 3.08
Accepted in revised form: 5. 6.08


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