Hemato-Renal Profile of Proliferative Glomerulonephritis with Monoclonal Immunoglobulin Deposits

Introduction

Proliferative glomerulonephritis with monoclonal immune deposits (PGNMID) is an immune complex glomerulonephritis with monoclonal immunoglobulin deposits within glomeruli.¹ These deposits are characterized by electron microscopy (EM) as nonorganized and electron-dense located in subendothelial, mesangial, or subepithelial regions.² A quarter to one-third of patients progress to kidney failure despite immunosuppression.³ A circulating monoclonal immunoglobulin detected by immunofixation electrophoresis (IFE) or serum free light chain (FLC) assay or a nephropathic clone detected by flowcytometry is seen in only 25–30% of cases.^3,4 This study reports the hemato-renal profile of PGNMID patients at a tertiary care center and aims to determine the clinical implications of circulating monoclonal immunoglobulin (MIg), histopathological pattern and type of monoclonal light chain restriction in kidney biopsy, and type of therapy on renal outcomes.

Materials and Methods

This was an observational retrospective biopsy registry cohort [Glomerular Research and Clinical Experiments—Proliferative Glomerulonephritis with Monoclonal Immunoglobulin Deposits (GRACE-PGNMID)] done among out- and inpatient services of the Department of Nephrology at Christian Medical College, Vellore. Consent was waived as it was retrospective data collection from electronic medical records. In total, 11,459 native adult kidney biopsies were performed between January 2013 and December 2020, of which 16 cases met the following diagnostic criteria of PGNMID (biopsy incidence of 0.1%) [Supplemental Figure 1]:

• 1.

  Light microscopy (LM) showing a proliferative pattern like membranoproliferative or endocapillary proliferative or mesangioproliferative glomerulonephritis.

• 2.

  Immunofluorescence (IF) staining for a single light chain (kappa or lambda) and heavy chain (gamma, alpha or mu) isotype indicating monoclonality.

• 3.

  Granular electron-dense deposits with no substructure in mesangial, subendothelial, and/or subepithelial locations by EM.

• 4.

  Absence of clinical and laboratory evidence of cryoglobulinemia.

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Figure 1:

Histopathology of proliferative glomerulonephritis with monoclonal immunoglobulin deposits. (a) Glomerulus with marked mesangial expansion, mesangial hypercellularity, segmental endocapillary hypercellularity and segments of irregular capillary wall thickening with reduplication (bold black arrow) (Periodic acid schiff stain; original magnification X 400). (b) Three glomeruli with circumferential cellular crescents with underlying glomerular capillary tuft showing global endocapillary hypercellularity with lobular accentuation. Adjacent interstitium shows edema with severe acute tubular injury. (Hematoxylin and eosin stain; original magnification X 100). (c-e) Immunofluorescence microscopy displaying global, granular capillary wall, along with mesangial staining for IgG (4+ intensity) (c) and kappa light chain (4+ intensity) (d). There is no staining for lambda light chain (e). (original magnification X 400). (f) Ultrastructural examination displaying abundant large subendothelial electron dense immune complex type deposits along with concomitant mesangial deposits. Podocytes show global effacement. A diagnostic substructure is not evident. (Transmission electron microscopy, original magnification X 6000).

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Results

Discussion

PGNMID is a rare entity classified under the umbrella of monoclonal gammopathy of renal significance (MGRS) (biopsy incidence of 0.1%). To our knowledge, this is the largest case series of PGNMID from Indian subcontinent. The mean age of our cohort was much lower than previous studies^3-13 with an equal incidence in males and females [Supplemental Table 2]. This is in contrast to the study by Nasr et al. who first described this entity primarily in elderly white female population.⁴ We observed that kappa-PGNMID patients were younger with a male preponderance. In a series of 17 cases of “light chain only” variant PGNMID described by Nasr et al., majority (71%) had kappa restricted deposits. The median age at presentation however was 62 (range, 44–84) years, with majority (76%) being males.¹³

The most common presentation was nephritic-nephrotic syndrome (69%). The median eGFR at presentation was 36 (IQR, 24–75) mL/min/1.73 m², which was comparable to previous studies.^3,4 We observed that patients with MPGN patterns and those with detectable circulating MIg had more proteinuria at presentation. None of our patients had extra-renal involvement as reported in previous studies.⁶

A circulating MIg by IFE was detected in only 25% cases, which was similar to previous studies (20–37%) [Supplemental Table 2].^4,8 An abnormal serum kappa: lambda FLC ratio was observed in 38% of our cases. None of the seven lambda-PGNMID patients had circulating monoclonal lambda light chain, whereas, half of the kappa-PGNMID patients had detectable circulating monoclonal kappa light chain. This may be explained by the low rate of monoclonal protein production in PGNMID which may be below the diagnostic threshold of currently available tools.⁶ PGNMID patients who undergo kidney transplantation experience high rates of early recurrence after renal transplantation with almost half of the patients losing their graft over a median period of three years.^9-11 And again only 20% of these patients with recurrent PGNMID have a detectable circulating MIg (10). The other possible hypothesis is a “glomerular sieving phenomenon” due to the ability of IgG3 (the predominant heavy chain in PGNMID) to bind to negatively charged glomerular basement membrane and self-aggregate leading to high intraglomerular concentration.^7,12 This explains why patients with “light chain only” variant of PGNMID have higher rates of detectable serum paraprotein (73% by serum electrophoresis and 83% by serum FLC assays).¹³

Only 8% (1/13) of our patients had bone marrow plasmacytosis >10% as reported in previous studies (0–17%).³ Patients with circulating MIg had a higher median percentage of plasma cells on bone marrow biopsy. None of our patients showed monoclonal restriction of marrow plasma cells by IHC. In contrast, half of the patients of “light chain only” variant of PGNMID had bone marrow plasmacytosis >10% with monoclonal light chain restriction.¹³ Bhutani et al. detected a nephropathic clone in 25% of PGNMID patients by bone marrow flow cytometry and in 11% by peripheral blood flow cytometry. The nephropathic clones detected were plasma cell (60%), B cell (30%), and lymphoplasmacytic cell (10%).³ In a study by Gumber et al., a nephropathic clone was detected in 32% of patients by bone marrow flow cytometry. The detected clones were plasma cell (50%), B cell (33%), and lymphoplasmacytic cell (17%).⁸

MPGN was the most common light microscopy pattern seen in our study, similar to previous studies [Supplemental Table 2].^4,8 Nasr et al. classified PGNMID into four stages based on the timing of kidney biopsy from the onset of disease. Stage 1 is a latent phase associated with monoclonal deposits in kidney with no mesangial proliferation and is clinically silent. Stage 2 is characterized by mesangial proliferation and mild proteinuria. Stages 3 and 4 PGNMID patients have endocapillary proliferative and membranoproliferative glomerulonephritis, respectively.⁹ None of our patients had membranous nephropathy, which is a rare pattern of PGNMID.^14,15 In a series of 26 patients with allograft PGNMID, MPGN pattern was one of the predictors of allograft loss.¹⁰ We observed that patients with MPGN pattern had better renal outcomes despite higher degree of proteinuria at presentation.

In our study, IgG was the predominant monoclonal immunoglobulin detected in kidney, as reported in previous studies.^3,4 There was almost an equal distribution of kappa and lambda PGNMID cases in our series unlike kappa predisposition seen in adults^3-7,16 and lambda predisposition seen in pediatric series.^17,18 Biclonality (mismatch in monoclonal light chain detected in circulation and kidney biopsy) was seen in 8% of patients, similar to previous studies (7–14%).^3,8,13 Subepithelial granular electron-dense deposits were more commonly seen in kappa-PGNMID patients.

One-third of patients in our cohort progressed to kidney failure (18–67% in previous studies) despite majority (81%) receiving some form of immunosuppression.^3,8,13,16 Clone-directed therapy in PGNMID is gaining a lot of interest in recent years.^8,19-21 In a case series of the eight ‘light chain only’ variant PGNMID cases treated with plasma cell targeted chemotherapy, six attained complete hematological and renal remission, one attained partial hematological remission with worsening kidney function and one had neither hematological nor renal remission.¹³ In a cohort of 64 PGNMID patients from China, Zou et al. reported CR rates of 23%, 53%, and 50% with steroid, immunomodulatory drugs (thalidomide or lenalidomide) along with dexamethasone, and bortezomib-based plasma cell chemotherapy, respectively.²² Complete or partial renal remission was attained in 73%, 54%, and 29% of PGNMID patients (65 patients from 3 case series) treated with clone-directed, immunosuppressive, and conservative therapy, respectively.²³ In a series of 10 PGNMID patients treated with daratumumab (monoclonal anti-CD38 antibody), four attained CR, and remaining six attained PR. There was a significant decline in proteinuria from 4.3 g/day at baseline to 1.2 g/day at the end of 12 months.²⁴ In a series of five cases of bortezomib-resistant PGNMID treated with daratumumab for a median duration of 11.2 (range 5–19.1) months, one attained complete renal and hematological remission, two attained PR and two had no remission (of which one patient had histological improvement of immune deposits).²⁵ The other mjor cohorts are compared with this study in Supplementary Table 3. The major limitations of clone-directed therapy are low detection rate of nephropathic clones (25–32%), therapy-related toxicity, and absence of detectable clone to assess response to therapy.^6,24-27 Supplemental Table 4 summarizes the recommended workup in PGNMID and the currently available treatment options. Supplementary Figure 2 summarizes the current treatment recommendations of PGNMID.

Our study is not without limitations. The small size of our cohort and short duration of follow-up is a major limitation of our study. IgG subtyping is not routinely done at our center due to resource limitations. All our patients showed a clear light chain restriction by IF microscopy and each antibody testing was repeated at least twice by different technicians and interpreted by two renal pathologists to confirm concordance in reporting. All patients had typical granular electron-dense deposits without substructure in mesangial, subendothelial, and/or subepithelial locations on EM. Almost 70% of our patients received immunosuppression tailored to regimens used in glomerulonephritis (27–81% in previously reported cohorts). This depicts the real-world scenario wherein nephrologists and hematologists shy away from using toxic chemotherapeutic regimens in absence of detectable clones. Zou et al. reported lower rates of M protein detection in PGNMID patients treated with steroid (3%) as compared to those treated with bortezomib-based plasma cell chemotherapy (40%).²² Bone marrow flow cytometry was not done in any of our patients, which could have increased the likelihood of detecting small pathogenic clones.

Conclusion

PGNMID is a rare renal disease with a biopsy incidence of 0.1% in our registry data spanning over 8 years. Only a quarter of patients with PGNMID had circulating MIg. The presence of circulating MIg, type of monoclonal light chain restriction in kidney biopsy, and type of therapy did not predict renal outcomes. Patients with MPGN pattern had favorable renal outcomes despite a higher degree of proteinuria at presentation. One-third of patients progressed to kidney failure despite immunosuppressive therapy necessitating the need for aggressive clone-directed chemotherapy. The future directions would be to develop sophisticated diagnostic techniques sensitive to pick up small nephropathic clones, unravel the patho-mechanisms of renal injury, and need for a combined hemato-renal clinic for early diagnosis and initiation of clone-directed chemotherapy.