The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group

Abstract

The term monoclonal gammopathy of renal significance (MGRS) was introduced by the International Kidney and Monoclonal Gammopathy Research Group (IKMG) in 2012. The IKMG met in April 2017 to refine the definition of MGRS and to update the diagnostic criteria for MGRS-related diseases. Accordingly, in this Expert Consensus Document, the IKMG redefines MGRS as a clonal proliferative disorder that produces a nephrotoxic monoclonal immunoglobulin and does not meet previously defined haematological criteria for treatment of a specific malignancy. The diagnosis of MGRS-related disease is established by kidney biopsy and immunofluorescence studies to identify the monotypic immunoglobulin deposits (although these deposits are minimal in patients with either C3 glomerulopathy or thrombotic microangiopathy). Accordingly, the IKMG recommends a kidney biopsy in patients suspected of having MGRS to maximize the chance of correct diagnosis. Serum and urine protein electrophoresis and immunofixation, as well as analyses of serum free light chains, should also be performed to identify the monoclonal immunoglobulin, which helps to establish the diagnosis of MGRS and might also be useful for assessing responses to treatment. Finally, bone marrow aspiration and biopsy should be conducted to identify the lymphoproliferative clone. Flow cytometry can be helpful in identifying small clones. Additional genetic tests and fluorescent in situ hybridization studies are helpful for clonal identification and for generating treatment recommendations. Treatment of MGRS was not addressed at the 2017 IKMG meeting; consequently, this Expert Consensus Document does not include any recommendations for the treatment of patients with MGRS.

Fig. 1. Localization of MGRS-associated renal lesions.

Monoclonal gammopathy of renal significance (MGRS)-associated lesions can involve one or more renal compartments. In immunotactoid glomerulonephritis, C3 glomerulopathy and proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID), MGRS-associated lesions involve only the glomeruli, whereas in light-chain proximal tubulopathy (LCPT), MGRS-associated lesions involve only the proximal tubules. MGRS-associated lesions in cryoglobulinaemic glomerulonephritis mainly involve the glomeruli but can occasionally affect blood vessels in the form of intravascular cryoglobulin thrombi or endovasculitis. Immunoglobulin-related amyloidosis and monoclonal immunoglobulin deposition disease (MIDD) usually affect all renal compartments, including glomeruli, vessels and the tubulointerstitium. GBM, glomerular basement membrane.

Fig. 2. Categorization of MGRS-associated renal lesions.

Monoclonal gammopathy of renal significance (MGRS)-associated renal lesions (blue boxes) are initially separated by the presence or absence of monoclonal immunoglobulin deposits in kidney biopsy samples. They are further subcategorized by the ultrastructural characteristics of the deposits into organized and non-organized. Organized deposits are further subdivided into fibrillar, microtubular and inclusions or crystalline categories. Images of typical histological sections stained with haematoxylin and eosin (H&E), periodic acid–Schiff or Masson trichrome stain and Congo red (top) are paired with immunofluorescence studies of frozen tissue sections (bottom) to reveal the specific immunoglobulin species. Pink box: the miscellaneous category represents polyclonal glomerulopathies that sometimes present with monoclonal immunoglobulin deposits, such as monotypic membranous nephropathy and monotypic anti-glomerular basement membrane disease. Purple box: thrombotic microangiopathy currently has a provisional status as an MGRS-associated lesion pending further evidence. Because this lesion has no immunoglobulin deposits and is best identified by electron microscopy, the immunofluorescence and H&E stained sections were replaced by an electron micrograph. LCPT, light-chain proximal tubulopathy; MIDD, monoclonal immunoglobulin deposition disease; PGNMID, proliferative glomerulonephritis and monoclonal immunoglobulin deposits.

Fig. 3. Ultrastructural appearance of MGRS-associated lesions.

Top row: electron microscopy images showing fibrillar or microtubular deposits. a | Small randomly oriented fibrils of mean thickness 10 nm in a patient with immunoglobulin light-chain-κ amyloidosis (original magnification ×49,000). b | Randomly oriented fibrils with mean thickness of 15 nm in a patient with fibrillary glomerulonephritis (original magnification ×52,000). c | Deposits composed of microtubules with hollow centres organized in parallel arrays and with a mean thickness of 26 nm in a patient with immunotactoid glomerulopathy (original magnification ×49,500). d | Focal deposits composed of short microtubules with hollow centres with a mean thickness of 29 nm in a patient with cryoglobulinaemic glomerulonephritis (original magnification ×40,000). Centre row: electron microscopy images showing crystals or inclusions. e | Proximal tubular cells filled with moderately electron-dense, light-chain crystals that have rod and rhomboid shapes in a patient with crystalline light-chain proximal tubulopathy. The crystals are predominantly free within the cytoplasm, not membrane bound (original magnification ×2,700). f | Numerous light-chain crystals with rod, rectangle or rhomboid shapes within the cytoplasm of interstitial infiltrating histiocytes in a patient with crystal-storing histiocytosis (original magnification ×4,200). g | Needle-shaped, electron-dense crystals in the mesangium and within phagolysosomes of infiltrating inflammatory cells in a patient with cryocrystalglobulinaemia (original magnification ×9,300). The crystals showed monotypic staining for IgG and κ light chains on pronase immunofluorescence. Bottom row: electron microscopy images showing non-organized deposits. h | Finely granular, highly electron-dense deposits along a tubular basement membrane in a patient with light-chain deposition disease (original magnification ×15,000). i | Large, discrete (mesangial, subendothelial and subepithelial) granular, electron-dense deposits in a patient with proliferative glomerulonephritis with monoclonal immunoglobulin deposits (original magnification ×6,000). j | Mesangial deposits and a hump-shaped subepithelial deposit located overlying the glomerular basement membrane reflection over the mesangium in a patient with C3 glomerulonephritis associated with monoclonal gammopathy (original magnification ×9,300). k | ‘Sausage-like’ thickening of the glomerular basement membrane associated with highly electron-dense intramembranous deposits in a patient with dense deposit disease associated with monoclonal gammopathy (original magnification ×4,800). MGRS, monoclonal gammopathy of renal significance.

Fig. 4. Algorithm for renal biopsy evaluation in patients suspected to have MGRS.

Kidney biopsy analysis in patients suspected to have monoclonal gammopathy of renal significance (MGRS) should include light microscopy (including staining the paraffin sections with haematoxylin and eosin, periodic acid−Schiff, Masson trichrome, Jones methenamine silver and Congo red). Immunofluorescence studies conducted on frozen tissue should include staining for IgG, IgM, IgA, C1q, C3 and κ and λ light chains. Finally, transmission election microscopy should be conducted. This standard renal biopsy approach enables diagnosis of MGRS in the majority of affected patients. In some individuals, ancillary techniques are needed to establish the diagnosis, including mass spectrometry, immunogold electron microscopy, immunofluorescence staining for IgG subtypes and paraffin immunofluorescence. The indications for these ancillary techniques are detailed in Table 2. AKI, acute kidney injury; eGFR, estimated glomerular filtration rate; MGUS, monoclonal gammopathy of undetermined significance; MIDD, monoclonal immunoglobulin deposition disease; TMA, thrombotic microangiopathy.