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Review
. 2018 Jul;29(7):1810-1823.
doi: 10.1681/ASN.2017121319. Epub 2018 Apr 27.

The Complexity and Heterogeneity of Monoclonal Immunoglobulin-Associated Renal Diseases

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Free PMC article
Review

The Complexity and Heterogeneity of Monoclonal Immunoglobulin-Associated Renal Diseases

Sanjeev Sethi et al. J Am Soc Nephrol. .
Free PMC article

Abstract

Monoclonal gammopathies are characterized by the overproduction of monoclonal Ig (MIg) detectable in the serum or urine resulting from a clonal proliferation of plasma cells or B lymphocytes. The underlying hematologic conditions range from malignant neoplasms of plasma cells or B lymphocytes, including multiple myeloma and B-cell lymphoproliferative disorders, to nonmalignant small clonal proliferations. The term MGUS implies presence of an MIg in the setting of a "benign" hematologic condition without renal or other end organ damage. The term MGRS was recently introduced to indicate monoclonal gammopathy with MIg-associated renal disease in the absence of hematologic malignancy. Most MIg-associated renal diseases result from the direct deposition of nephrotoxic MIg or its light- or heavy-chain fragments in various renal tissue compartments. Immunofluorescence microscopy is essential to identify the offending MIg and define its tissue distribution. Mass spectrometry is helpful in difficult cases. Conditions caused by direct tissue deposition of MIg include common disorders, such as cast nephropathy, amyloidosis, and MIg deposition diseases, as well as uncommon disorders, such as immunotactoid glomerulopathy, proliferative GN with MIg deposits, light-chain proximal tubulopathy, and the rare entities of crystal-storing histiocytosis and crystalglobulinemia. Indirect mechanisms of MIg-induced renal disease can cause C3 glomerulopathy or thrombotic microangiopathy without tissue MIg deposits. Treatment of MIg-associated renal disease is aimed at eliminating the clonal plasma cell or B-cell population as appropriate. Both the renal and the underlying hematologic disorders influence the management and prognosis of MIg-associated renal diseases.

Keywords: Renal pathology; kidney disease; multiple myeloma.

Figures

Figure 1.
Figure 1.
Hematologic conditions causing monoclonal Ig–associated renal disease. The hematologic conditions are divided into plasma cell derived and B-cell derived, which are further subdivided into malignant and nonmalignant/premalignant conditions. MGRS, monoclonal gammopathy of renal significance.
Figure 2.
Figure 2.
Clinical presentation of monoclonal Ig–associated renal disease. MIDD, monoclonal Ig deposition disease; PGNMID, proliferative GN with monoclonal Ig deposits; RPGN, rapidly progressive GN.
Figure 3.
Figure 3.
Pathology of monoclonal Ig–associated renal disease. IF, immunofluorescence; LCPT, light-chain proximal tubulopathy; MIDD, monoclonal Ig deposition disease; PGNMID, proliferative GN with monoclonal Ig deposits. *Interstitium, tubules, and vessels may be involved in addition of glomeruli. **Usually polyclonal.
Figure 4.
Figure 4.
MIDD due to κ–LCDD. A 95-year-old man presents with AKI, nephrotic syndrome, and serum creatinine 2.7 mg/dl (increased from baseline 1.4 mg/dl 4 months prior) with lower extremity edema, urine protein 7 g/d, and serum protein electrophoresis with immunofixation showing elevated monoclonal κ-light chains. Renal biopsy shows the following. (A) Nodular sclerosing glomerulopathy with nodular mesangial expansion by partially silver-negative material associated with foci of circumferential mesangial interposition (Jones methenamine silver). Original magnification, ×400. (B) Thick ribbon-like periodic acid–Schiff (PAS)-positive deposits involving the tubular basement membranes (PAS). Original magnification, ×400. (C) Electron microscopic demonstration of finely granular punctate powdery deposits along the lamina rara interna of the glomerular capillary walls. Original magnification, ×8000. (D) Immunofluorescence staining for κ-light chain only distributed in the mesangial nodules, with weak linear staining of glomerular basement membranes and stronger linear staining of Bowman’s capsule and the tubular basement membranes. Original magnification, ×200. (E) Intense diffuse linear immunofluorescence staining for κ-light chain in the distribution of the tubular basement membranes associated with sparse interstitial positivity. Original magnification, ×400. (F) Punctate peppery deposits involving the tubular basement membrane and to a lesser extent, the adjacent interstitial capillary basement membrane (electron micrograph). Original magnification, ×10,000.
Figure 5.
Figure 5.
PGNMID with monoclonal IgG3-κ deposits. A 56-year-old woman presents with edema and mixed acute nephritic and nephrotic syndrome, serum creatinine 2.75 mg/dl, urine protein 4.2 g/d, serum albumin 2.1 g/dl, urinalysis with 4+ protein and microhematuria with serum protein electrophoresis and urine protein electrophoresis with immunofixation negative for monoclonal protein, reduced serum C3, normal serum C4, and negative cryoglobulin titer. Renal biopsy shows the following. (A) Diffuse and global proliferative GN with membranoproliferative features and infiltrating mononuclear leukocytes (hematoxylin and eosin). Original magnification, ×400. (B) Well developed membranoproliferative pattern with mesangial interposition and duplication of glomerular basement membranes, causing luminal narrowing (Jones methenamine silver). Original magnification, ×400. (C) Electron micrograph showing subendothelial and mesangial electron dense deposits with capillary narrowing by infiltrating mononuclear leukocytes. The deposits have an ordinary granular texture, with no evidence of organized substructure. Original magnification, ×6000. (D) Immunofluorescence showing positive staining for IgG subtype 3 involving the mesangium and semilinear glomerular capillary walls, similar to the staining seen for IgG. There was no staining for IgG subtypes 1, 2, or 4 and no staining for IgM or IgA. Stains for complement components were positive with 3+ C3 and 2+ C1q in the same distribution as IgG (not shown). Original magnification, ×600. (E) The same glomerulus shows intense staining for κ-light chain in a mesangial and peripheral capillary wall distribution. There was no staining for IgG or κ-light chain involving the tubular basement membranes, Bowman’s capsule, or vessel walls. Original magnification, ×600. (F) The same glomerulus has negative staining for λ-light chain. Original magnification, ×600.
Figure 6.
Figure 6.
κ–LCPT, crystalline type. Several different examples of light-chain proximal tubulopathy are illustrated. (A) A case with abundant trichrome clear or weakly red intracellular crystals that distort the cytoplasm of proximal tubular epithelial cells throughout the biopsy (Masson trichrome). Original magnification, ×400. (B) Although the initial immunofluorescence stain for κ-light chain performed on frozen sections was negative (not shown), repeat immunofluorescence on pronase-digested paraffin sections is brightly positive for κ-light chain only in the distribution of the intracellular needle-shaped crystals. There was negativity for λ-light chain (not shown). Original magnification, ×400. (C) By electron microscopy, the proximal tubular cells are engorged with rhomboidal crystals throughout the full thickness of their cytoplasm. The proximal epithelial cells show acute injury with loss of brush border and shedding of cytoplasmic fragments and degenerating cellular debris into the lumen. Original magnification, ×5000. (D) An example with hexagonal trichrome red crystals irregularly distributed within the proximal tubular cell cytoplasm. The tubular epithelial cells exhibit acute injury but no intraluminal casts (Masson trichrome). Original magnification, ×400. (E) A case with large crystalline inclusions staining by immunofluorescence for κ-light chain only within the cytoplasm of proximal tubular cells was revealed following antigen retrieval by application of pronase digestion to paraffin sections. Original magnification, ×400. (F) High-power view of a representative proximal tubular cell from the same patient as in C above shows rhomboidal and other geometric-shaped crystals with lateral striations, indicating periodicity. The crystals are located within membrane-bound phagolyosomes or free within the cytosol of proximal tubular cells (electron micrograph). Original magnification, ×30,000.
Figure 7.
Figure 7.
Crystal-storing histiocytosis (CSH) and crystalglobulinemia. (A) A case of CSH resembles acute interstitial nephritis with a mixture of interstitial lymphocytes and larger histiocytes containing eosinophilic needle-shaped inclusions (hematoxylin and eosin). Original magnification, ×600. (B) CSH: trichrome stain highlights the trichrome-red needle-shaped crystals within the interstitial histiocytes. There is tubular atrophy and interstitial fibrosis (Masson trichrome). By immunofluorescence, the crystals stained exclusively for κ-light chain (not shown). Original magnification, ×600. (C) CSH: immunostain for CD68 reveals the histiocytic phenotype of the interstitial cells, with cytoplasm that is distorted by crystalline inclusions. Original magnification, ×600. (D) CSH: electron micrograph showing interstitial histiocytes stuffed with electron dense intracytoplasmic crystals that invaginate the nucleus (electron micrograph). Original magnification, ×6000. (E) Crystalglobulinemia: a 47-year-old man presents with leukocytoclastic vasculitis of the skin, weakness, AKI, and creatinine 6.5 mg/dl. The glomerular capillaries are filled with pseudothrombi staining by immunofluorescence for κ and IgG (not shown), with negative staining for λ (not shown). Original magnification, ×400. (F) Crystalglobulinemia: a glomerular capillary lumen is occluded by a large plug of intraluminal electron dense crystals forming a type of crystalline “thrombus.” There are no deposits involving the glomerular basement membranes or the mesangial matrix (electron micrograph). After the kidney biopsy, a bone marrow biopsy was performed and showed 30% κ-restricted plasma cells, leading to a diagnosis of MM. Original magnification, ×4000.
Figure 8.
Figure 8.
AH (IgG) amyloidosis diagnosed by mass spectrometry. A 62-year-old woman presented with progressive rise in serum creatinine and proteinuria over 1 year, leading to kidney biopsy. (A and B) Light microscopy showing (A) weakly periodic acid–Schiff-positive and (B) silver-negative mesangial nodules. (C and D) Immunofluorescence microscopy showed bright 3+ mesangial and capillary wall staining for (C) IgG and (D) C3, with negative staining for κ- and λ-light chains. (E and F) Electron microscopy showed fibrillary deposits in the mesangium and capillary walls, raising the possibility of AH (IgG) amyloidosis or fibrillary GN. However, both (G) Congo red and (H) DNAJB9 staining were negative. (I) Laser microdissection/mass spectrometry studies confirmed the AH (IgG) amyloidosis by detecting large signature amyloid spectra of IgG1, apo E, and A-IV. Subsequent serum electrophoresis studies revealed M spike consisting of monoclonal IgG heavy chains only. (Amyloid mass spectrometry data were courtesy Dr. Paul Kurtin.)

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