|Year : 2021 | Volume
| Issue : 2 | Page : 282-287
|A tale of monoclonal immunoglobulin: Clinicopathological analysis of proliferative glomerulonephritis with monoclonal immunoglobulin deposit
Priyanka Maity1, Saugat Dasgupta2, Keya Basu1, Moumita Sengupta1, Arpita Roy Chowdhury2, Manimoy Bandopadhyay3
1 Department of Pathology, IPGMER and SSKM Hospital, Kolkata, West Bengal, India
2 Department of Nephrology, IPGMER and SSKM Hospital, Kolkata, West Bengal, India
3 Department of Anatomy, IPGMER and SSKM Hospital, Kolkata, West Bengal, India
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|Date of Submission||15-Jan-2020|
|Date of Decision||27-Feb-2020|
|Date of Acceptance||16-Apr-2020|
|Date of Web Publication||9-Apr-2021|
| Abstract|| |
Background: Proliferative glomerulonephritis with monoclonal immunoglobulin deposit (PGNMID) is an entity with a variable clinical and histological spectrum, which mimics immune-complex mediated glomerulonephritis on light microscopy. In this article, we aim to describe the clinical and pathological features of six cases of PGNMID that we encountered during our routine practice. Materials and Methods: The study was of the prospective type carried out from February 2018 to August 2019. The renal biopsies that we received in our department, were processed for light microscopy, immunofluorescence microscopy, and electron microscopy. Light microscopic findings were carefully re-evaluated by two experienced renal pathologists. Key diagnostic features were 1) Monoclonal staining of glomeruli for one immunoglobulin (Ig) subclass and single light chain, 2) Membranoproliferative glomerulonephritis (MPGN) pattern (rarely membranous or crescentic), 3) Subendothelial and mesangial (rarely subepithelial) deposits. Results: We diagnosed five cases of IgG PGNMID and one case of IgA PGNMID with a mean age 53 ± 10.33 years. The most common histological pattern, seen in three cases was MPGN. IgG3 deposits were identified in five cases out of which k light chain restriction was present in four cases and λ light chain restriction was present in one case. IgA deposits were identified in one case that had λ light chain restriction. One patient suffered from multiple myeloma. Conclusions: The renal biopsy especially immunofluorescence analysis is the key modality for diagnosis of PGNMID where it shows staining of the glomerulus for a single heavy-chain subclass and a single light-chain isotype. Electron microscopic evaluation is necessary to differentiate PGNMID from other renal diseases with monoclonal immunoglobulin deposits.
Keywords: Immunofluorescence analysis, light microscopy, proliferative glomerulonephritis with monoclonal immunoglobulin deposit, renal biopsy
|How to cite this article:|
Maity P, Dasgupta S, Basu K, Sengupta M, Chowdhury AR, Bandopadhyay M. A tale of monoclonal immunoglobulin: Clinicopathological analysis of proliferative glomerulonephritis with monoclonal immunoglobulin deposit. Indian J Pathol Microbiol 2021;64:282-7
|How to cite this URL:|
Maity P, Dasgupta S, Basu K, Sengupta M, Chowdhury AR, Bandopadhyay M. A tale of monoclonal immunoglobulin: Clinicopathological analysis of proliferative glomerulonephritis with monoclonal immunoglobulin deposit. Indian J Pathol Microbiol [serial online] 2021 [cited 2021 May 16];64:282-7. Available from: https://www.ijpmonline.org/text.asp?2021/64/2/282/313271
| Introduction|| |
Proliferative glomerulonephritis resulting from immune complexes have polyclonal staining of glomerular deposits. Monoclonal immunoglobulin deposits in glomeruli occur in heavy chain deposition disease, light and heavy chain deposition disease, type1 cryoglobulinemia and immunotactoid glomerulonephritis. In 2004 Nasr SH et al. reported 10 patients with a novel form of glomerular injury related to monoclonal immunoglobulin (Ig) deposition that could not be attributed to any of the aforementioned conditions. They termed it proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID).
Lack of association with systemic infection or any autoimmune disease makes this entity ambiguous regarding pathogenesis and thus etiology based management becomes difficult. It is postulated as a renal manifestation of monoclonal gammopathy of renal significance (MGRS), however overt hematological malignancy is rarely encountered.
In this article, we describe clinical and pathological features of six cases of PGNMIDD that we encountered during our routine practice. Five cases had monoclonal IgG3 deposition while one had monoclonal IgA deposition.
| Materials and Methods|| |
We conducted a single center, prospective study of patients diagnosed with PGNMIDD on biopsy at a tertiary care center from February 2018 to August 2019. This study was approved by the ethics committee.
For inclusion into the study, the subjects were required to meet the following criteria: 1) Monoclonal staining of glomeruli for one immunoglobulin subclass and single light chain immunofluorescence microscopy, 2) Membranoproliferative pattern or membranous pattern or mesangioproliferative pattern or crescents on light microscopy. We have excluded the patients with cryoglobulinemia, transplanted kidney, primary neoplastic conditions, and inconclusive results from the study.
We have collected the following laboratory data for each of the subjects of this study: complete blood count, blood glucose, urine analyses, serum urea, serum creatinine, blood urea nitrogen (BUN), serum albumin, serum cholesterol, serum hepatitis B surface antigen (HBs Ag), anti-hepatitis C virus antibody (anti-HCV Ab), anti-streptolysin O (ASO) titer, serum anti-nuclear antibody (ANA), serum myeloperoxidase (MPO) antineutrophil cytoplasmic antibodies (ANCAs), serum PR3 ANCA, serum double stranded deoxyribonucleic acid (dsDNA), serum C3 and C4 levels. Clinical parameters (age, sex, blood pressure, skin lesions, arthralgia, edema, obesity) were also documented for each of the subject.
Depending on the clinical presentation and laboratory parameters the patients were categorized into four clinical syndromes. 1) Occult nephritis: hematuria/or mild proteinuria (0.5 g/d < quantitative urinary protein <1 g/d), or proteinuria (1 g/d ≤ quantitative urinary protein ≤3.5 g/d) without hematuria and estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2. 2) Nephritic syndrome: Mild to moderate proteinuria (1 g/d ≤ urinary protein excretion ≤3.5 g/d) with hematuria, may be accompanied by edema and hypertension and eGFR ≥60 mL/min/1.73 m2. 3) Nephrotic syndrome: High proteinuria (urinary protein >3.5 g/d), low serum albumin (<30 g/L), hyperlipidaemia, high degree of edema and eGFR ≥60 mL/min/1.73 m2 and 4) End-stage renal disease: Decrease in glomerular filtration rate (eGFR <60 mL/min/1.73 m2), may be accompanied by anaemia, hypertension or oedema.
Renal biopsies were done by tru-cut semi-automatic renal biopsy gun. Hematoxylin and Eosin (H and E), Periodic acid-Schiff (PAS), silver methenamine, and Masson's Trichrome (MT) stained sections were prepared for light microscopy and all slides were examined by two nephropathologists. Specimen for immunofluorescence microscopy were received in normal saline and were stained using fluorescein isothiocyanate (FITC) conjugated polyclonal rabbit anti-sera against human IgG, IgM, IgA, C3, C1q, kappa, lambda (DAKO, Germany). Immunofluorescence findings were categorized from '+' to '++++' according to intensity. The location and pattern of staining were also documented. Control slides were also examined simultaneously. Cryostat sections were stained with monoclonal antihuman FITC coated antibody against IgG 1-4 (Sigma-Aldrich) and were used for the determination of IgG subclass. For electron microscopic examination, samples were collected in 2.5% glutaraldehyde and after processing, evaluation was done by scanning transmission electron microscope. Measurement of the resulting images was performed using Zeiss KS400 (Carl Zeiss Imaging Systems, Germany). The system was calibrated using the marker bar on the electron micrographs. The magnifcation data were verified by a grating replica with parallel lines (2160 lines/mm; EMS, Washington, USA).
Bone marrow examination was done in all patients to rule out hematological malignancy. Serum and urine protein electrophoresis along with serum-free light chain assay was carried out to detect paraproteinemia.
| Results|| |
We diagnosed six cases of PGNMID. The clinical findings are summarized in [Table 1]. Out of six patients, five were males and one was female. All were adults. The mean age of presentation was 53 years (range 42 to 63). Four patients had anasarca while two had haematuria. One of the patients had both hypertension and diabetes mellitus. Proteinuria was present in all of them. The mean 24 hours urinary protein was 4.8 gm (range 1.80 to 11.2 gm). Nephrotic range proteinuria was present in two patients. All the patients had renal insufficiency (serum creatinine >1.2 mg/dl), and the mean serum creatinine was 2.6 mg/dl (range 1.4 to 3.9 mg/dl). The mean C3 value was 84.6 gm/dl (range 61.2 to 108.0 gm/dl). On serum protein electrophoresis and urine protein electrophoresis, one patient had serum paraproteinemia. None had concurrent serum and urinary paraproteinemia. All cases underwent serum free light chain assay. One patient with a kappa-lambda ratio of 2.272 (kappa free light chain 56.80 mg/dl and lambda light chain 25.00 mg/dl) was subsequently diagnosed as a case of multiple myeloma by both bone marrow aspiration and radiological analysis. The bone marrow examination, in this case, showed 40% of plasma cells. The other five cases showed 2%-3% of plasma cells in the bone marrow. Serum β2 microglobulin was 4148 ng/ml in the diagnosed case of multiple myeloma.
Serum cryoglobulin titers were negative. None of the patients had any systemic manifestations of cryoglobulinemia. ANA, anti-dsDNA, anti-GBM, ANCA were negative in all the cases. There was no history of infection, rheumatoid arthritis, and systemic lupus erythematosus in any patient.
The renal biopsy findings are detailed in [Table 2]. A number of glomeruli sampled for light microscopy ranged from 5 to 21 (mean 11.17). The mean glomeruli involved by global glomerulosclerosis was 2.83 (range 1 to 6). One case showed the presence of extra capillary proliferation in 4% glomeruli. The crescent formation was lacking in the other five cases. The most common histological pattern, seen in three cases was membranoproliferative glomerulonephritis (MPGN) characterized by irregular glomerular capillary wall thickening and mesangial hypercellularity. The other patterns observed were one case of membranous glomerulonephritis characterized by uniform glomerular capillary wall thickening, one case of mesangial proliferative glomerulonephritis with crescent and one case of diffuse global glomerulosclerosis.
|Table 2: Summary of light microscopic, immunofluorescence, and electron microscopic findings|
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Five cases showed interstitial inflammation that was focal in four cases and diffuse in one case. The degree of interstitial fibrosis and tubular atrophy (IFTA) was mild in four cases and moderate in two cases while none had a severe degree of IFTA. Arterial and arteriolar sclerosis was present in two cases out of which one had concurrent vascular amyloid deposition.
On immunofluorescence microscopy, monoclonal immunoglobulin deposits were seen in all the six cases. IgG3 deposits were identified in five cases out of which k light chain restriction was present in four cases and λ light chain restriction was present in one case. IgA deposits were identified in one case that had λ light chain restriction which was subsequently diagnosed as a case of multiple myeloma.
On electron microscopy, three cases had subendothelial deposits; one had mesangial deposits while the remaining two showed subepithelial deposits. The deposits were of nonorganized type and did not have substructure as observed in immunotactoid and cryoglobulinemic glomerulonephritis. After correlating the findings on light microscopy, immunofluorescence microscopy and electron microscopy with the clinical features, the diagnosis of PGNMID was made. Five cases were of IgG3-PGNMID and one case was of IgA-PGNMID.
The finding of monoclonality in immunofluorescence always directs the nephrologist to look for MGRS in absence of features for overt multiple myeloma. MGRS now have well-defined treatment protocol different from nonspecific management of proteinuria and renal dysfunction. Before biopsy was available, because of high proteinuria and rapidly progressive renal dysfunction 2 of these patients were initiated on steroids, 2 were having subnephrotic proteinuria with relatively stable renal function so they were put on RAS blockers. The patient with high proteinuria, egfr <15 ml/min was put on hemodialysis and light microscopy also showed PGNMID associated with >40% IFTA. As per our institutional protocol, MGRS cases are treated as per clone detected and with hematologist consultation. For plasma cell clone usual regimen is rituximab based regimen either (R-CHOP) or bortezomib and rituximab. The patient with IgA lambda in immunofluorescence had high plasma cell percentage in the bone marrow and was put on bortezomib based therapy. Before chemotherapy initiation patient and his family members were explained about the possible drug side effects based on age and other comorbidities. The eGFR slope was static in the patient who was started with chemotherapy and tolerated the drug well. All patients were followed up for a mean of 9.5 months (range 2-18 months) during which one patient developed end-stage renal disease and was on hemodialysis.
| Discussion|| |
PGNMID is a rare disease. There is sparse literature describing this entity.,,,, This renal limited disorder shows monoclonal staining for one IgG subclass and a single light chain. The deposits have a coarse granular pattern. Monoclonal immunoglobulin G3 (IgG3) with k light chain restriction is most common followed by IgG1 k subclass. On light microscopy, the most common pattern is a membranoproliferative pattern. Occasionally mesangial proliferation or membranous patterns can be observed. On electron microscopy, the deposits are predominantly mesangial and subendothelial. Rarely subepithelial deposits can be seen.
Proliferative glomerulonephritis with monoclonal IgG deposits has been documented in adults with a mean age of 55 years. Torrealba J et al. reported a case of the same disease in a 17 years old female. In our study, the mean age was 53 years. The presenting features of PGNMID include nephrotic-range proteinuria in about half, haematuria in three-fourths, and reduced glomerular filtration rate in two-thirds. One-third of patients have detectable circulating monoclonal antibodies and multiple myeloma is rare. All our six patients had proteinuria and renal insufficiency. Hematuria was present in two patients. One patient had serum paraproteinemia and one patient suffered from multiple myeloma.
The immune complex-mediated glomerulonephritis has deposits of polyclonal antibodies complexed to endogenous or exogenous antigens in glomeruli. Unlike MPGN resulting from immune complexes, all six of our cases had monoclonal staining of glomerular deposits. Monoclonal IgG deposition occurs in heavy chain deposition disease, light and heavy chain deposition disease, type1 cryoglobulinemia and immunotactoid glomerulonephritis. Heavy chain deposition disease shows only heavy chain deposits while in our cases there was the presence of both heavy and light chain deposits. All our six cases showed glomerular deposits ruling out light and heavy chain deposition disease where there is most often tubular deposit. Type 1 cryoglobulinemia shows intracapillary infiltrating monocytes and glassy intraluminal deposits. Immunotactoid glomerulonephritis shows monoclonal staining for IgG1. These features were absent in our cases. Moreover, on EM the deposits in our cases were of nonorganized type and did not have substructure. A new variant of monoclonal immunoglobulin deposition disease has been described by Komatsuda A et al. where there is a linear deposition of monoclonal immunoglobulin γ1 CH 2 heavy chain along glomerular and tubular basement membranes and granular deposition of κ light chain within the mesangial area.
In our study, five cases had IgG3 deposition in glomeruli that showed monoclonal staining for a single light chain isotype. In a study, Nasr SH et al. showed monoclonal glomerular deposits in kidneys from 37 patients with proliferative glomerulonephritis. Most of the cases had deposits of IgG3 followed by IgG1 and IgG2. IgG4 deposition was absent. Wen J et al. described five patients who presented with renal insufficiency after kidney transplantation. All of them had developed PGNMID. Three had monoclonal IgG3k deposits and two had monoclonal IgG3λ deposits in glomeruli. Merhi B et al. presented two cases of PGNMID in kidney allografts out of which one showed IgG1k deposits while the other showed IgG3k deposits. IgA deposits were identified in one case that had λ light chain restriction. The subclass of IgA could not be identified. Crescents were present in this case. Soares SM et al. described a case of a 35 years old woman who presented with edema, proteinuria, hematuria, and hypertension. Renal biopsy showed diffuse endocapillary proliferation and increased mesangial cellularity. Immunofluorescence examination showed monoclonal IgA deposits with λ light chain restriction in the glomeruli. Horino T et al. reported a case of IgA- PGNMID in a 54-year-old Japanese woman. Singh G et al. described a case of proliferative glomerulonephritis with monotypic IgA-kappa deposits in a 10-year-old child. In [Table 3] we have compared our study with the previous studies.
The exact pathogenesis of PGNMID is unknown. PGNMID is a type of monoclonal gammopathy of renal significance (MGRS). In our study, multiple myeloma was diagnosed in one case that had IgA deposits with λ light chain restriction. The rest of the cases were considered as MGRS. Glomerular deposits in MGRS can be monoclonal or polyclonal with variable ultrastructural morphology ranging from organized like microtubules to nonorganized like powdery appearance. The most common glomerular deposit in PGNMID is IgG3 [Figure 1],[Figure 2],[Figure 3]. Out of the four subclasses of IgG, the nephritogenic one is IgG3, which can be attributed to its intrinsic properties. It is the most positively charged subclass with a molecular weight higher than other subclasses. It has the highest aggregability and can fix complement. In our study, the patient with multiple myeloma had IgAλ serum M spike. He developed lytic bony lesions. In a study, Jagtap SV et al. observed that anemia (75%), lymphocytosis (33.3%), elevated erythrocyte sedimentation rate (ESR) (66.7%), increased serum creatinine (83.3%), increased serum calcium (91.7%), and Bence Jones proteinuria (50%) were seen in various cases of multiple myeloma.
|Figure 1: Kidney biopsy findings. (a) Immunofluorescence microscopy shows strong (3+), granular glomerular capillary wall and mesangial staining by IgG3. (400x). (b) a glomerulus with global mesangial and segmental endocapillary hypercellularity and basement membrane double contours (arrow). (Periodic acid-Schiff stain; 100x). (c) Immunofluorescence microscopy shows strong (3+), granular glomerular capillary wall and mesangial staining by kappa. (400x). (d) Immunofluorescence microscopy shows negative lambda staining. (400x)|
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|Figure 2: Kidney biopsy finding. (a) Glomerulus with uniform diffuse and global basement membrane thickening. (Periodic acid-Schiff stain; 100x), (b) Basement membrane spikes (arrow) (silver methenamine stain; original magnification 400x). (c) Immunofluorescence microscopy shows strong (3+), granular glomerular capillary wall by IgG3. (400x) (d) Immunofluorescence microscopy shows strong (2+), granular glomerular capillary wall staining by kappa. (400x) (e) Immunofluorescence microscopy shows negative lambda staining. (400x)|
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|Figure 3: Kidney biopsy finding. (a) Glomerulus with mesangial hypercellularity. (Periodic acid-Schiff stain; 100x), (b) Circumferential fibro cellular crescent (silver methenamine stain; original magnification 100x). (c) Immunofluorescence microscopy shows perivascular lambda positivity. (d) Immunofluorescence microscopy shows strong (4+), granular mesangial positive expression by IgA. (400x). (e) Immunofluorescence microscopy shows negative kappa staining. (400x). (f) Immunofluorescence microscopy shows strong (3+), granular mesangial staining by lambda. (400x)|
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Around one-third of patients with PGNMID improved, one third developed chronic kidney disease, and around 20% progressed to end-stage kidney disease. Elevated serum creatinine and a higher degree of glomerulosclerosis and interstitial fibrosis are associated with poor prognosis. PGNMID may recur in the transplanted kidney. In our study, on follow- up, one case developed end-stage renal disease. To determine the optimal therapeutic regimen for PGNMID, the study of a larger cohort of patients is required. Until such a study, treatment recommendations include renin-angiotensin system blockers, prednisolone, and bortezomib-based regimen.
| Conclusions|| |
PGNMID is a novel form of glomerulonephritis. We have described five cases of IgG PGNMID and one case of IgA PGNMID. On LM and EM, PGNMID mimics immune-complex type glomerulonephritis. Staining of the glomerulus for a single light-chain isotype and a single heavy-chain subclass is essential for the diagnosis. Electron microscopic evaluation is necessary to differentiate PGNMID from other renal diseases with monoclonal immunoglobulin deposits. Larger studies of PGNMID are required to define the exact nature of the disease, the association with hematological malignancy and to formulate an optimal therapeutic approach. Longer follow-up of the patients is required to study the course of the disease.
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Conflicts of interest
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Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]
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