Advertisement

Pathophysiology and management of monoclonal gammopathy of renal significance

Ankur Jain, Richard Haynes, Jaimal Kothari, Akhil Khera, Maria Soares and Karthik Ramasamy

Data supplements

Article Figures & Data

Figures

  • Figure 1.

    Classification of MGRS based on the ultrastructural findings of the monoclonal deposits. *Includes non-MGRS kidney diseases, such as anti-glomerular basement membrane (glomerular basement membrane (GBM) disease, membranous nephropathy, and Henoch-Schonlein purpura (HSP). These are presumed to be due to a monoclonal protein acting as an autoantibody (against antigen on glomerular basement membrane in anti-GBM disease and PLA2R in membranous nephropathy). Notably, a single subclass restriction (IgG1κ), absence of PLA2R staining, and associated proliferative changes on renal biopsy are indicative of MGRS in occasional cases of membranous nephropathy with monoclonal immunoglobulin.37 Rare cases of HSP with IgA nephropathy have been associated with monoclonal IgA or MM. These patients experience frequent relapses and a high recurrence rate postrenal transplantation.9 FG, fibrillary glomerulopathy; Ig, immunoglobulin; ITG, immunotactoid glomerulonephritis.

  • Figure 2.

    Mechanisms of MGRS pathogenicity. VEGF, vascular endothelial growth factor.

  • Figure 3.

    Proposed step-wise algorithm for the diagnosis of MGRS. *Renal biopsy advised if ≥1 of acute kidney injury (AKI) stage 3, estimated glomerular filtration rate (eGFR) < 60 mL/min per 1.73 m2 and >2 mL/min per 1.73 m2 per year decline, proteinuria and hematuria, albumin/creatinine ratio > 30 mg/mmol, and FS (hypouricemia).9 *Renal biopsy considered if ≥1 of AKI stage 1 or 2, eGFR < 60 mL/min per 1.73 m2 and <2 mL/min per 1.73 m2 per year decline, albumin/creatinine ratio 3 to 30 mg/mmol and eGFR > 60 mL/min per 1.73 m2, hematuria and eGFR < 60 mL/min per 1.73 m2, and evidence of light chain proteinuria.9 *Defer renal biopsy if stable eGFR, bland urinalysis, and no evidence of light chain proteinuria.9 In ∼40% of cases, monoclonal protein is not demonstrated in serum/urine. In such cases, renal biopsy should be considered in the diagnostic algorithm depending on the clinical suspicion.3 In cases of MGRS-compatible renal lesion with monoclonal immunoglobulin deposition, a diagnosis of MGRS should be considered and therapy instituted, because a monoclonal protein might not be demonstrated in some of these cases, despite a thorough evaluation (eg, PGNMID, FG). The latter situation could arise due to the extremely small amount of monoclonal protein that escapes detection by conventional methods or a result of pitfalls in the current diagnostic assays. IEM, immunoelectron microscopy; IF, immunofluorescence; LMD, laser microdissection; TM, tandem mass spectrometry. Adapted from Leung et al9 with permission.

  • Figure 4.

    Features of LCPT. IHC stained strongly positive for κ light chain in proximal tubules; λ (data not shown) was negative (original magnification ×400; DAB + Harris’s hematoxylin stain; left panel). TE microscopy image shows rhomboid crystal inclusions (*) in keeping with light chain proximal tubulopathy (original magnification ×4000; right panel).

  • Figure 5.

    Features of an LCDD. Glomerulus with nodular mesangial expansion (arrowheads; original magnification ×400; PAS; upper left panel). IF showed strong positivity for κ light chain (upper right panel); compare with negative λ (lower left panel) in glomerular and tubular basement membranes and mesangial nodules, in keeping with a κ LCDD (original magnification ×200; fluorescein isothiocyanate). TE microscopy image shows powdery electron-dense deposits along basement membranes (arrowheads) in keeping with LCDD (original magnification ×6000, fluorescein isothiocyanate; lower right panel).

  • Figure 6.

    Features of a C3GN in the setting of MGRS. Glomerulus with segmental endocapillary hypercellularity (original magnification ×400; hematoxylin & eosin stain; upper left panel). Glomerulus with segmental capillary tuft fibrinoid necrosis (original magnification ×400; hematoxylin & eosin stain; right panel). IF showed C3-dominant deposits in the mesangium and capillary loops, in keeping with a C3-dominant GN (original magnification ×400; fluorescein isothiocyanate; lower left panel).

  • Figure 7.

    Diagnostic work-up for clonal identification in MGRS. *Imaging could help identify lymphadenopathy in low-grade, low-stage lymphoma.9 **Imaging could be performed to identify plasmacytoma, bone lesions in a suspected case of MM, and when bone marrow aspiration (BMA) and biopsy fails to detect the plasma cell clone.9 Note: despite a similar work-up, a distinction between B-cell and LPL clone is helpful, both for a precise diagnosis, and for wider therapeutic options available for LPL (both rituximab- and bortezomib-based therapies). MYD88 mutation is positive in about 90% cases of LPL/WM.9 A positive result would therefore be supportive, but an absence would not rule out the diagnosis. Considering a low proliferative rate of low-grade B-cell lymphoproliferative disorders, and LPL, positron emission tomography–computed tomography (PET-CT) may have a lower degree of sensitivity compared to high-grade NHL. However, PET-CT could be useful in such cases given the avoidance of iodinated contrast, and a potential for directed biopsy from an area of increased metabolic uptake to enhance the diagnostic yield.3 FCM, flow cytometry; FDG-avid LN, fluorodeoxyglucose avid lymph nodes; FISH, fluorescent in situ hybridization; LDH, lactate dehydrogenase; WBCT, whole-body computed tomography.

Tables

  • Table 1.

    Classification of MGRS entities based on presence and site of deposition of monoclonal proteins in renal structures

    MGRS with monoclonal protein deposition in renal structures
    Glomerular depositionTubulointerstitial depositionIntrarenal vascular deposition
    Amyloidosis (AL/AH/AHL)LCPT with and without crystalsAmyloidosis
    Monoclonal fibrillary glomerulopathyCSHCrystalglobulinemia
    Immunotactoid glomerulopathyAmyloidosisMIDD
    Cryoglobulinemic GN (types I and II)MIDDCryoglobulinemic GN (types I and II)
    MIDD (LCDD/HCDD/HLDD)
    PGNMID
    MPGN associated with monoclonal immunoglobulin
    MN secondary to monoclonal immunoglobulin
    MGRS without monoclonal protein deposition in renal structures
    Glomerular involvementTubulointerstitial involvementIntrarenal vascular involvement
    C3GNTMA
    TMAPOEMS syndrome
    POEMS syndrome
    • AH, heavy chain amyloidosis; AHL, heavy and light chain amyloidosis; AL, light chain amyloidosis; C3GN, C3 glomerulonephritis; CSH, crystal-storing histiocytosis; HCDD, heavy chain deposition disease; HLDD, heavy and light chain deposition disease; LCDD, light chain deposition disease; LCPT, light chain proximal tubulopathy; MN, membranous nephropathy; POEMS, polyneuropathy organomegaly endocrinopathy monoclonal gammopathy, and skin changes.

    • Adapted from Ciocchini et al5 with permission.

  • Table 2.

    Incidence of detectable monoclonal protein, most commonly found MGs, and the reported hematological disorders associated with MGRS

    Type of monoclonal immunoglobulin depositionAssociated renal pathologiesIncidence of detectable MGMost common type of paraprotein/MGAssociated hematological disorders
    Intact immunoglobulin molecule/immunoglobulin molecule with truncated heavy chain*ALH amyloidosis4,10,28,29*97%-100%IgGλMM, CLL
    LHCDD10,28,29,46,47*SPEP/IFE: 80%-100%IgGκMM (50%)
    UPEP/IFE: 80%-100%
    sFLC assay: 100%
    Cryoglobulinemic GN28,29,48,49Type 1: 76%-82.5%Type I IgG/IgM with κType 1: MM, WM, CLL, B-NHL, MGRS, HCL
    Type 2: 40%-49%Type II IgMκType 2: B-CLPD, LPL, MALToma, WM
    PGNMID10,29,31,5020%-30%IgG3Rare (4.4%): MM, CLL, NHL
    ITG9,28,29,5163%-71%IgG1CLL (19%), LPL (13%), MM (13%)
    FG28,52-5415%-17%IgGMM, CLL
    Light chains onlyAL amyloidosis4,10,28,2997%-100%VIMM, LPL, CLL
    LCDD10,28,29,46,47SPEP/IFE: 25%-76%IVMM (39%-59%), MGRS (39%), LPL
    UPEP/IFE: 42%-90%
    sFLC assay: 100%
    LCPT9,28,29,41,5593.4%-97%IMGRS (27%-46%), MM (14%-33%), SMM (15%-51%), NHL (4%), CLL (2%), WM (8%)
    CSH9,28,29,5681.8%-90%κMM, LPL, MGRS (rare)
    Heavy chains onlyAH amyloidosis4,10,28,29*97%-100%IgGMM
    HCDD10,28,29,46,47*SPEP/IFE: 67%-100%IgG1MM (29%)
    UPEP/IFE: 50%-100%
    sFLC assay: 100%
    No monoclonal protein xdemonstrable in kidneysC3G (C3GN and DDD)28,29,45,57-6033%-83% IgGκMGRS (60%-77.8%), MM (4%-13.9%), SMM (5.6%-30%), CLL/lymphoma (5.6%-6%), type 1 cryoglobulinemia (2.8%)
    TMA29,5713.7% (>50 y, 21%; >60 y, 24%)IgGκMGRS (75%), MM (5%), SMM (5%), POEMS (10%), T-cell lymphocytic leukemia (5%)
    AtypicalMN secondary to monoclonal immunoglobulin19,370%-21.4%IgG1κCLL/SLL (17.8%-28.5%), MM (7.1%), SMZL (3%)
    • B-CLPD, B-cell chronic lymphoproliferative disorder; B-NHL, B-cell NHL; DDD, dense deposition disease; HCL, hairy cell leukemia; IFE, immunofixation electrophoresis; LHCDD, light and heavy chain deposition disease; LPL, lymphoplasmacytic lymphoma; MALToma, mucosa-associated lymphoid tissue lymphoma; SLL, small lymphocytic lymphoma; SMZL, splenic marginal zone lymphoma; SPEP, serum protein electrophoresis; UPEP, urine protein electrophoresis.

    • * Shows entities with truncated heavy chains.

    • Provisional MGRS entities.

  • Table 3.

    Syndromic approach to the clinical presentation of MGRS

    Clinical syndrome/presentationAssociated MGRS entities
    NSAmyloidosis (glomerular), MIDD
    Nephritic-nephrotic syndrome (proteinuria, hematuria, hypertension, low complement levels, and renal insufficiency)PGNMID, ITG, FG, C3G with monoclonal immunoglobulin, cryoglobulinemic GN
    Acute renal failureTMA, MIDD, and crystalglobulinemia
    Proteinuria/progressive renal insufficiencyLCPT (with/without FS), MIDD, amyloidosis (tubulointerstitial and vascular), CSH, TMA
    • Adapted from Sethi et al29 with permission.

  • Table 4.

    Summary of the reported end-organ manifestations in MGRS entities

    MGRS subtypeOrgans affected/manifestationsReferences
    AmyloidosisHeart, liver, autonomic nerves, skin, gastrointestinal tract, pulmonary62
    MIDDLiver, heart, peripheral nerves, lung, skin (seen in 35% of cases)28,63-65
    Cryoglobulinemic GNVasculitis, Raynaud’s phenomenon, purpura, livedo reticularis, arthralgia, peripheral neuropathy29,48,49
    C3GSkin necrosis11
    LCPT with FSOsteomalacia28
    CrystalglobulinemiaSkin rash, polyarthralgia, neuropathy29,66
    CSHFS, spleen, lymph nodes, macrophage activation, cornea, lungs, thyroid, parotid gland, synovium, liver, brain, skin, subcutaneous fat9,55
    POEMS syndromeSensory motor polyneuropathy, organomegaly, endocrinopathy, skin61
  • Table 5.

    Summary of the main pathological findings in MGRS

    Glomerular diseasesLMIF/IHCEM
     AmyloidosisCongo red+ mesangial expansion/nodulesAL: LC restriction (mostly λ)Unbranched randomly distributed fibrils (8-12 nm diameter)
    Hairbrush projections from glomerular basement membranesAH: HC deposits (g1 or g4, or a)
    Congo red+ deposits in interstitium and vessel walls (occasional)AHL: LC and HC deposits
     FG*Congo red, silver mesangial expansionMesangial and capillary loop IgG, C3, κ and λ depositsUnbranched, randomly distributed 15-20 nm diameter fibrils
    Positivity for DNAJB9 on IHC
     ITGMembranous-like or MPGN-like changesCoarse mesangial IgG (monoclonal in 60% of cases), C3 and occasional IgM depositsMicrotubules (20-60 nm diameter)
    Congo red, silver mesangial expansion
     Type I cryoglobulinemic GNMPGN patternMonoclonal immunoglobulin (most frequently κ) of the same type as found in circulation, C3, C4 depositsPaired microtubules (25-40 nm diameter)
    Endocapillary proliferative pattern/exudation
    PAS+ capillary pseudothrombi common
     MIDDMesangial proliferation and Congo red, silver+ mesangial matrix expansion/nodulesLCDD: mesangial and/or glomerular basement membrane monoclonal LC depositsPowdery electron-dense deposits along inner aspect of glomerular basement membranes, mesangium, and outer aspect of tubular basement membranes
    HCDD: κ and λ negative, staining for 1 of the immunoglobulins (most commonly IgG or IgM)
     PGNMIDEndocapillary proliferative GN/MPGNMonoclonal immunoglobulin or, more rarely, monoclonal LC depositsNonorganized mesangial, subendothelial, and subepithelial electron-dense deposits
     Membranous GN with monoclonal immunoglobulinMembranous changes (spikes, lucencies)Monoclonal immunoglobulin depositsNonorganized subepithelial electron-dense deposits
     C3G associated with monoclonal gammopathyEndocapillary proliferative GN/MPGNGranular, C3-dominant depositsNonorganized mesangial, subendothelial, and subepithelial electron-dense deposits
    Dense osmiophilic transformation of basement membranes if DDD
     TMAGlomerular and/or arterial TMAPauci-immune pattern; occasional C3 trappingAcute: subendothelial flocculent material
    Chronic: new subendothelial basement membrane and/or subendothelial widening
    Tubulointerstitial diseases
     LCPTProximal tubular vacuolation/fragmentationLC inclusions within tubular epitheliumIntralysosomal or free rhomboid-shaped crystals in proximal tubules
    Intracytoplasmic inclusions, often crystalloid
     Miscellaneous
     CSHAccumulated crystals within macrophages/histiocytes within glomerular or peritubular capillaries and in the mesangiumLC crystalloid inclusions within macrophages/histiocytesRhomboid and needle-shaped crystalloid inclusions and vacuoles within macrophages/histiocytes.
    • HC, heavy chain; LC, light chain.

    • * Occasional cases of FG could show congophilia (congophilic FG). These cases could be reliably distinguished from amyloid deposits by DNAJB9 immunostain or mass spectroscopy.72

  • Table 6.

    Consensus opinions for the treatment of selected MGRS conditions

    MGRS entityCurrent consensus/recommendation
    MIDDCKD stage I-III: bortezomib-based therapy, followed by ASCT (in the absence of extrarenal manifestations and good performance status)
    CKD stage IV-V: eligible for renal transplant, bortezomib-based therapy followed by ASCT; not eligible for renal transplant, bortezomib-based therapy only (to protect extrarenal organs, heart)
    PGNMIDCKD stage I-II with proteinuria < 1 g/d and nonprogressive disease: symptomatic treatment
    CKD stage I-II with proteinuria > 1 g/d or progressive disease and CKD stage III-IV: chemotherapy* with or without ASCT
    CKD stage V: eligible for renal transplant, chemotherapy followed by ASCT; not eligible for renal transplant, symptomatic management; no identifiable MG: no consensus, may benefit from chemotherapy prior to renal transplant
    ITGCLL-type regimens incorporating bendamustine/corticosteroids/cyclophosphamide with rituximab
    For cases not associated with CLL, bortezomib-based regimens
    Type 1 cryoglobulinemic GNTreatment indication: symptomatic/progressive systemic disease (renal), depends on underlying clone
     Plasma cell: antimyeloma drugs (ASCT may be considered)
     LPL clone: treat along lines of WM (rituximab backbone)
     B-cell clone: rituximab-based therapy
    Type 2 cryoglobulinemic GNHCV+
     Minimally symptomatic: antiviral therapy
     Symptomatic vasculitis: rituximab/high-dose dexamethasone (+ antiviral therapy)
     Rapidly progressive renal disease: TPE + definitive therapy as for symptomatic vasculitis (above)
    HCV
     Minimally symptomatic: observation
     Symptomatic vasculitis: rituximab
    WM/B-cell NHL: rituximab-based regimens (according to the underlying condition)
    LCPT with FSCKD stage I-III: chemotherapy based on bortezomib/cyclophosphamide/thalidomide/bendamustine, ASCT may be considered for nonresponding patients
    CKD stage IV-V: eligible for renal transplant, bortezomib-based therapy followed by ASCT; not eligible for renal transplant, symptomatic management
    • HCV, hepatitis C virus; TPE, therapeutic plasma exchange.

    • Adapted from Fermand et al.90

    • * For PGNMID cases, choice of chemotherapy should be clone directed. For plasma cell clone, bortezomib-based regimens, like cyclophosphamide/bortezomib/dexamethasone; for B-cell clone, rituximab-based regimens may be used. Because clone is detected in only ∼30% of cases of PGNMID, an empirical therapy directed at the hypothesized clone may be used.92