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American Journal of Kidney Diseases

Light Chain–Only Immunotactoid Glomerulopathy: A Case Report

Open AccessPublished:October 31, 2022DOI:https://doi.org/10.1053/j.ajkd.2022.08.025

      Abstract

      The monotypic variant of immunotactoid glomerulopathy (ITG), strongly associated with low grade lymphoproliferate disorders, is characterized histologically by glomerulonephritis and microtubular deposits of monoclonal IgG. We report a patient with high risk κ light chain multiple myeloma who presented with acute kidney injury, hematuria, proteinuria, and hypocomplementemia. Kidney biopsy revealed ITG concomitant with κ myeloma cast nephropathy. The glomerular microtubular deposits stained for κ and C3 only. Proteomic analysis of glomeruli and atypical casts detected Ig κ constant domain and a single VL variability subgroup (IGKV3) in both glomeruli and casts (without Ig γ, α, μ, or λ). C3, C5, C6, C7, and C9 were detected in glomeruli. No autoantibodies against alternative pathway of complement proteins were detected. Despite clone-directed chemotherapy, the patient remained dialysis dependent. We describe a light chain-only variant of ITG. Pathogenesis potentially involves activation of the alternative pathway of complement by a nephrotoxic κ light chain.

      Introduction

      Immunotactoid glomerulopathy (ITG) is a rare glomerular disease characterized by glomerular immunoglobulin (Ig) deposits of microtubules, with a distinct hollow center, that are arranged at least focally in parallel arrays, in the absence of a clinicopathologic diagnosis of cryoglobulinemic glomerulonephritis or lupus nephritis.
      • Rosenmann E.
      • Eliakim M.
      Nephrotic syndrome associated with amyloid-like glomerular deposits.
      • Fogo A.
      • Qureshi N.
      • Horn R.G.
      Morphologic and clinical features of fibrillary glomerulonephritis versus immunotactoid glomerulopathy.
      • Nasr S.H.
      • Kudose S.S.
      • Said S.M.
      • et al.
      Immunotactoid glomerulopathy is a rare entity with monoclonal and polyclonal variants.
      • Javaugue V.
      • Dufour-Nourigat L.
      • Desport E.
      • et al.
      Results of a nation-wide cohort study suggest favorable long-term outcomes of clone-targeted chemotherapy in immunotactoid glomerulopathy.
      Two thirds ITG are characterized by monoclonal Ig (MIg) deposits on immunofluorescence (IF), and strongly associated with hematologic disease, usually low-grade lymphoma or monoclonal gammopathy of renal significance (MGRS), whereas an association with symptomatic multiple myeloma (MM) is very rare.
      • Nasr S.H.
      • Kudose S.S.
      • Said S.M.
      • et al.
      Immunotactoid glomerulopathy is a rare entity with monoclonal and polyclonal variants.
      ,
      • Javaugue V.
      • Dufour-Nourigat L.
      • Desport E.
      • et al.
      Results of a nation-wide cohort study suggest favorable long-term outcomes of clone-targeted chemotherapy in immunotactoid glomerulopathy.
      The remaining cases show polyclonal Ig deposits and are less commonly associated with hematologic conditions.
      • Nasr S.H.
      • Kudose S.S.
      • Said S.M.
      • et al.
      Immunotactoid glomerulopathy is a rare entity with monoclonal and polyclonal variants.
      Here we describe a unique case of ITG composed of Ig light chain (LC)-only (ITG-LC). Proteomic, IF, and complement system studies suggest activation of the alternative pathway of complement (APC) by a nephrotoxic κ-LC.

      Case Report

      A 76-year-old woman with no significant past medical history presented with generalized malaise, weakness and epistaxis. She was found to have a systolic blood pressure in the 220s mmHg, acute kidney injury with serum creatinine 7.7 mg/dL (normal two months prior), potassium 6.3 mmol/L, and hemoglobin 7.7 g/dL, without edema, skin rash and peripheral lymphadenopathy. Urinalysis showed 3+ protein, 3+ blood, trace leukocytes, 4+ bacteria, 123 WBC/HPF, >182 RBC/HPF and urine protein to creatinine ratio 1024 mg/g. Other laboratory results included serum albumin 3.1 g/dL, calcium 8.6 mg/dL, normal liver function tests and negative antibodies to myeloperoxidase, proteinase 3, glomerular basement membrane (GBM), phospholipase A2 receptor, hepatitis C virus, hepatitis B virus surface antigen, and antinuclear antibody. C3 was 76 (80-165 mg/dL) and C4 was 35.9 (14-44 mg/dL). Serum cryoglobulin was not tested. Prednisone was initiated. Urine protein electrophoresis with immunofixation (IFE) revealed 525 mg/dL protein (27% albumin) with an M spike 239.3 mg/dL (45%, free κ-LC on IFE). Serum protein electrophoresis with IFE showed two M spikes at beta-gamma region 0.2 g/dL and 0.1 g/dL (both free κ-LC). Serum κ and λ FLCs were 30,045 mg/L (3.3-19.4 mg/L) and 12.7 mg/L (5.7-26.3 mg/L) respectively, with κ/λ FLC at 2365.8 (0.26-1.65).
      Kidney biopsy (Figure 1) revealed endocapillary proliferative and exudative glomerulonephritis. The tubulointerstitium exhibited acute cast nephropathy, acute tubular injury, mild interstitial inflammation, and moderate tubular atrophy and interstitial fibrosis. By IF, there was diffuse global granular mesangial and GBM staining for C3 (3+) and κ (2+) in a similar distribution, and the casts stained positive for κ with negative staining for λ in the glomeruli and tubular casts. Glomeruli were negative for IgG, IgG subclasses, IgM, IgA, C1q, and C4d. IF on paraffin tissue sections after pronase digestion confirmed negative staining for IgG and λ, and positive staining for κ in the glomeruli and the casts. Heavy/light chain IF (HLC-IF) revealed weak (1+) glomerular and tubular cast staining for IgG-κ with negative staining for IgG-λ. Ultrastructurally, there were massive mesangial, segmental subepithelial and subendothelial deposits composed entirely of straight, large microtubules with the mean external diameter of 53 nm (range 30 to 87 nm) with focal parallel alignment. The pathologic diagnosis was LC-only ITG concomitant with myeloma cast nephropathy (MCN).
      Figure thumbnail gr1
      Figure 1Kidney biopsy findings of kappa light chain only immunotactoid glomerulopathy and myeloma cast nephropathy. Light microscopy shows abundant atypical periodic acid-Schiff (PAS) negative tubular casts with acute tubular injury and interstitial inflammation at low power (A). A glomerulus exhibits global endocapillary hypercellularity and influx of lymphocytes and neutrophils, and thickened glomerular basement membrane(B, PAS). Atypical PAS negative tubular casts (white arrow) are associated with mononuclear cell and giant cell reaction (black arrow); the glomerulus depicted exhibits thickened glomerular basement membranes and mild mesangial hypercellularity (C, PAS). No crescents, necrosis, segmental sclerosis, glomerular basement membrane spikes or double contours, pseudothrombi or vascular lesions are noted. Congo red stain is negative. By immunofluorescence, there is diffuse global granular mesangial and capillary wall staining for C3 (D) and kappa (E), with negative staining for lambda (F). Tubular casts (white arrows) stain positive for kappa (E) with negative staining for lambda (F). Glomeruli are negative for IgG, IgG subclasses, IgM, IgA, C1q, and C4d (not shown). By immunofluorescence performed on paraffin tissue sections after pronase digestion, the staining for IgG is again negative in glomeruli and tubular casts (G), and the staining for kappa and lambda is similar to the routine immunofluorescence with diffuse global granular mesangial and capillary wall and tubular casts staining for kappa (H) and negative staining for lambda (I). Ultrastructurally, there are massive mesangial, segmental subepithelial and subendothelial deposits (J) which are composed of microtubules (K). No hump-shaped subepithelial deposits without substructure or intracytoplasmic crystals are identified anywhere in the kidney. Atypical tubular casts also focally exhibit microtubular substructure in which the microtubules are smaller in diameter than the glomerular microtubular deposits (L). Original magnification, x100 for A, x400 for B and C, x200 for D-I, x2900 for J, x49,000 for K, x23,000 for L.

      Additional Investigations

      To characterize the proteomic content, we performed laser microdissections of the glomeruli and atypical casts, followed by LC MS/MS (Figure 2; Item S1 and Figure S1). Ig κ constant domain and variable domain derived from a single VL variability subgroup (IGKV3) were detected in both glomeruli and casts, without Ig γ, α, μ, or λ. Additionally, C3 and complement terminal complex proteins (C5, C6, C7, and C9) were detected in glomeruli (but not in tubular casts), without proteins of the classical complement pathway (C1, C2, and C4). Expectedly, uromodulin was detected only in the casts.
      Figure thumbnail gr2
      Figure 2Proteomic findings of kappa light chain only immunotactoid glomerulopathy and myeloma cast nephropathy. A scaffold display of Ig components, complement proteins and structural proteins detected in the patient’s glomeruli and myeloma casts per analysis by liquid chromatography tandem mass spectrometry. Numbers in green boxes are the number of tandem mass spectrometry spectra associated with the protein in the respective sample, which is a surrogate measure of abundance. Proteins with MS/MS counts of 5 or higher are considered for clinical interpretation. High spectra for Ig κ constant domain and a single VL variability subgroup (IGKV3) were detected in both glomeruli and casts, without spectra for Ig γ, α, μ, or λ. The sequence templates we used did not allow distinctions to be made between two closely related genes (IGKV3-15 and IGKV3-20). Abundant spectra for C3 and spectra for complement terminal complex proteins (C5, C6, C7, and C9) were detected in glomeruli (but not in tubular casts), without spectra for the classical complement pathway (C1, C2, and C4). Uromodulin was detected only in the atypical casts.
      In addition, patient serum sample was screened for autoantibodies of Ig γ, κ, or λ specificity targeting 6 proteins of APC (factor H, factor I, complement receptor 1, C3b, factor B, and properdin) by ELISA (Item S1) and no autoantibodies were identified.
      Bone marrow biopsy with flow cytometry immunophenotyping showed a large kappa restricted plasma cell population involving 90% of total marrow cellularity. The neoplastic cells stained negative for IgG and lambda, and positive for kappa (Figure S2). Cytogenetics were normal but FISH analysis was consistent with high-risk MM (MAFB/IGH fusion, 17p-, 1q-, trisomy (3,7,11), t (14;20)). PET scan revealed diffuse marrow stimulation. The patient was diagnosed with high risk κ-LC MM. Hemodialysis was initiated and she was treated with daratumumab, cyclophosphamide, bortezomib, and dexamethasone (CyBorD DARA). Five months post-biopsy (3 months after initiation of chemotherapy), she had a serum M-spike of 0.2 g/dl, with a partial decline of κ FLC to 6915 mg/dL and κ/λ FLC to 532. She remained dialysis dependent.

      Discussion

      Because of their low molecular weight, Ig LCs are filtered through the glomerulus and may produce tubular injury (e.g., MCN, LC proximal tubulopathy). Deposition of monoclonal nephrotoxic LCs often involves all renal compartments, including glomeruli, vessels, and tubules (e.g., AL amyloidosis, LC deposition disease). In these LC nephropathies, glomerular inflammation is generally absent or mild, and C3 deposition is rare. In contrast, entire MIg molecules are less likely to filter through the glomerulus and therefore can deposit in glomeruli, leading to complement activation, leukocyte infiltration, and glomerular cell proliferation, culminating in glomerulonephritis (e.g., proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID), cryoglobulinemic glomerulonephritis type I and II, monotypic variant of ITG).
      • Leung N.
      • Bridoux F.
      • Nasr S.H.
      Monoclonal Gammopathy of Renal Significance.
      However, intriguingly, a LC-only variant of PGNMID (PGNMID-LC), a proliferative glomerulonephritis associated with κ-LC fibrils, a case of LC-only ITG, and a case of LC-only immunotactoid gastropathy have recently been described.
      • Nasr S.H.
      • Larsen C.P.
      • Sirac C.
      • et al.
      Light chain only variant of proliferative glomerulonephritis with monoclonal immunoglobulin deposits is associated with a high detection rate of the pathogenic plasma cell clone.
      • Steinberg A.G.
      • Fox L.C.
      • Bender S.
      • et al.
      Proliferative Glomerulonephritis With Fibrils, Monoclonal kappa Light Chain, and C3 Deposits.
      • Jen K.Y.
      • Fix O.K.
      • Foster E.N.
      • Laszik Z.G.
      • Ferrell L.D.
      Monoclonal light chain deposits within the stomach manifesting as immunotactoid gastropathy.
      • Sugita E.
      • Sonoda H.
      • Ryuzaki M.
      • et al.
      Diagnosis of monoclonal immunotactoid glomerulopathy with positive λ chain by immunoelectron microscopy.
      Here we describe a unique case of ITG composed of LC-only (ITG-LC). The patient presented with acute kidney injury, hematuria, proteinuria and hypocomplementemia and was diagnosed with LC MM, an uncommon variant of MM (15-20%) characterized by only a LC in the serum or urine (without heavy chain) and associated with a higher incidence of kidney failure.
      • Kyle R.A.
      • Gertz M.A.
      • Witzig T.E.
      • et al.
      Review of 1027 patients with newly diagnosed multiple myeloma.
      Kidney biopsy revealed κ ITG-LC concurrent with MCN. Our case is different from classic ITG in 3 aspects: 1) The glomerular deposits are composed of Ig-LC only; 2) It is associated with high tumor burden MM contrary to classic ITG, which is generally associated with low grade lymphoma and/or MGRS; and 3) It is likely mediated by APC activation, similar to PGNMID-LC.
      • Nasr S.H.
      • Larsen C.P.
      • Sirac C.
      • et al.
      Light chain only variant of proliferative glomerulonephritis with monoclonal immunoglobulin deposits is associated with a high detection rate of the pathogenic plasma cell clone.
      In contrast, the IF and proteomic findings in classic ITG favor activation of the classical pathway of complement by IgG.
      • Nasr S.H.
      • Kudose S.S.
      • Said S.M.
      • et al.
      Immunotactoid glomerulopathy is a rare entity with monoclonal and polyclonal variants.
      ,
      • Nasr S.H.
      • Fidler M.E.
      • Cornell L.D.
      • et al.
      Immunotactoid glomerulopathy: clinicopathologic and proteomic study.
      Findings that favor APC activation by nephrotoxic κ-LC in our patient include the glomerular co-deposition of C3 (without C1q or C4d), the detection of C3 and C5-9 (but not C1, C2, and C4) by proteomic analysis of glomeruli, and the low serum C3 (but not C4). APC activation (initiated in the fluid phase or locally on the glomerular surface) likely initiates downstream inflammatory mediators, leading to proliferative glomerulonephritis. About half of patients with C3 glomerulopathy associated with a monoclonal gammopathy (MIg-C3G) have anti-complement autoantibodies (particularly anti-CR1 and anti-FH).
      • Chauvet S.
      • Roumenina L.T.
      • Aucouturier P.
      • et al.
      Both Monoclonal and Polyclonal Immunoglobulin Contingents Mediate Complement Activation in Monoclonal Gammopathy Associated-C3 Glomerulopathy.
      ,
      • Ravindran A.
      • Fervenza F.C.
      • Smith R.J.H.
      • Sethi S.
      C3 glomerulopathy associated with monoclonal Ig is a distinct subtype.
      Direct activation of APC by MIg has been confirmed in 2 patients with MIg-C3G.
      • Jokiranta T.S.
      • Solomon A.
      • Pangburn M.K.
      • Zipfel P.F.
      • Meri S.
      Nephritogenic lambda light chain dimer: a unique human miniautoantibody against complement factor H.
      ,
      • Johnson C.K.
      • Zuniga S.C.
      • Dhawale T.
      • Zhang Y.
      • Smith R.J.H.
      • Blosser C.D.
      Monoclonal Gammopathy of Renal Significance Causes C3 Glomerulonephritis Via Monoclonal IgG Kappa Inhibition of Complement Factor H.
      In both patients, the MIg (λ in 1 and IgGκ in 1) inhibited FH
      • Jokiranta T.S.
      • Solomon A.
      • Pangburn M.K.
      • Zipfel P.F.
      • Meri S.
      Nephritogenic lambda light chain dimer: a unique human miniautoantibody against complement factor H.
      ,
      • Johnson C.K.
      • Zuniga S.C.
      • Dhawale T.
      • Zhang Y.
      • Smith R.J.H.
      • Blosser C.D.
      Monoclonal Gammopathy of Renal Significance Causes C3 Glomerulonephritis Via Monoclonal IgG Kappa Inhibition of Complement Factor H.
      . We did not detect autoantibodies of Ig γ, κ, or λ specificity against 5 proteins of APC (factor H, factor I, complement receptor 1, factor B, or properdin) in our patient. Interestingly, it was recently shown that in patients with MIg-C3G, the MIg could directly activate APC by serving as a complement-activating surface.
      • Chauvet S.
      • Roumenina L.T.
      • Aucouturier P.
      • et al.
      Both Monoclonal and Polyclonal Immunoglobulin Contingents Mediate Complement Activation in Monoclonal Gammopathy Associated-C3 Glomerulopathy.
      The mechanisms by which k-LC activated APC in our patient are unknown. The nephrotoxic κ-LC in our patient is derived from the IGKV3 variability subgroup, which has also been reported in PGNMID-LC
      • Nasr S.H.
      • Larsen C.P.
      • Sirac C.
      • et al.
      Light chain only variant of proliferative glomerulonephritis with monoclonal immunoglobulin deposits is associated with a high detection rate of the pathogenic plasma cell clone.
      , another LC glomerulopathy associated with APC activation, but is infrequent in renal AL amyloidosis (most commonly IGLV6)
      • Comenzo R.L.
      • Zhang Y.
      • Martinez C.
      • Osman K.
      • Herrera G.A.
      The tropism of organ involvement in primary systemic amyloidosis: contributions of Ig V(L) germ line gene use and clonal plasma cell burden.
      , LC deposition disease (most commonly IGKV4),
      • Joly F.
      • Cohen C.
      • Javaugue V.
      • et al.
      Randall-type monoclonal immunoglobulin deposition disease: novel insights from a nationwide cohort study.
      and LC proximal tubulopathy (most commonly IGKV1).
      • Sirac C.
      • Herrera G.A.
      • Sanders P.W.
      • et al.
      Animal models of monoclonal immunoglobulin-related renal diseases.
      The weak glomerular staining for IgG-k by HLC-IF likely represents cross-reactivity of IgG-κ antibody with free κ deposits for multiple reasons: a) the neoplastic plasma cells were negative for IgG, and no monoclonal IgG molecule was detected in the serum or urine; b) the weak glomerular IgG-k staining was accompanied by similar staining of atypical casts; c) the glomeruli and casts were negative for IgG by pronase IF, which contrary to HLC-IF, has an antigen retrieval step; d) no IgG was detected in glomeruli or casts by mass spectrometry; and e) we have observed cross-reactivity of IgG-k and IgM-k with κ LC deposits in few cases of other LC nephropathies, including AL-k amyloidosis (eg, case # 23 in the validation study
      • Nasr S.H.
      • Fidler M.E.
      • Said S.M.
      • Koepplin J.W.
      • Altamirano-Alonso J.M.
      • Leung N.
      Immunofluorescence staining for immunoglobulin heavy chain/light chain on kidney biopsies is a valuable ancillary technique for the diagnosis of monoclonal gammopathy-associated kidney diseases.
      ) and a recent case of PGNMID-LC (unpublished data).

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