REVIEW ARTICLE

Renal Involvement in Monoclonal Gammopathy
Turki Al-Hussain, MD,* Maged H. Hussein, MD,w Hadeel Al Mana, MD,*
and Mohammed Akhtar, MD, FCAP, FRCPA, FRCPath*

NORMAL STRUCTURE OF IMMUNOGLOBULINS
Abstract: Monoclonal gammopathy is produced by neoplastic or Immunoglobulins are antibodies consisting of glyco-
non-neoplastic expansion of a clone of plasma cells or B lympho-
cytes. Monoclonal gammopathy of unknown significance is char-
proteins arranged as Z1 units. Each of these units contains
acterized by low levels of the monoclonal protein and a relatively 4 polypeptide chains: 2 identical heavy chains and 2 iden-
small population of clonal lymphocytes or plasma cells in the bone tical light chains (Fig. 1). The amino terminal ends of these
marrow. In these cases, the patient is asymptomatic with no evi- polypeptide chains show considerable variation in amino
dence of overt myeloma or lymphoma. The abnormal serum pro- acid composition and are referred to as the variable regions,
tein may be present as a complete immunoglobulin molecule or which determine the antigen specificity of the antibodies.
may consist of Z1 of its components such as light chains or heavy Each light chain is made up of around 220 amino acids and
chains. These proteins may cause a variety of diseases in various has a molecular weight of 25 kD. The genes coding for k
tissues and organs, of which the kidney appears to be the most and l light chains are situated on chromosomes 2 and 22,
vulnerable. Renal involvement in monoclonal gammopathy may
occur as part of a generalized disease such as amyloidosis, immu-
respectively. There is very little variation within the con-
noglobulin deposition disease, and cryoglobulinemia. In addition, stant (CL) region of k light chain and l light chain; k CL is
there may be evidence of kidney damage by processes which are coded for by a single gene and l CL by one of several gene
renal specific. These include light chain proximal tubulopathy, light segments. In contrast, the variable (VL) region of a light
chain cast nephropathy, and a variety of glomerulopathies chain comprises 4 framework regions which form a
encompassing a wide spectrum of disease patterns. hydrophobic core, and within which are scattered 3 seg-
ments of hypervariable amino acid sequences called com-
Key Words: monoclonal, gammopathy, unknown significance,
plementarity determining regions. The remaining parts of
immunoglobulin deposition, casts, light chains, amyloid, cry-
the light and heavy chains are composed of Z1 constant
oglobulin, tubulopathy, glomerulonephritis
regions. The amino acid sequences in the constant regions
(Adv Anat Pathol 2015;22:121–134) do not manifest any variation. Each light chain consists of 1
variable domain VL and 1 constant domain CL. The heavy
chains consist of a variable domain, VH, and 3 constant
domains CH1, CH2, and CH3. Each heavy chain has about
M onoclonal gammopathies reflect a wide spectrum of
related diseases in which increased amounts of
immunoglobulins are produced by a clone of plasma cells
twice the number of amino acids and molecular weight
(B50,000 kD) compared with light chains (B25,000 kD).
Heavy and light chains are bound by covalent disulfide
or B lymphocytes. The monoclonal immunoglobulin is
bonds, forming a bilaterally symmetric structure. Each Ig
recognized as an abnormal band of restricted migration on
monomer is bivalent as it contains 2 antigen-binding sites.
serum or urine electrophoresis and is termed as M com-
The hinge region is the area of the H chains between the
ponent or paraprotein. The abnormal protein may be in the
first and second C region domains and is held together by
form of intact immunoglobulin or immunoglobulin frag-
disulfide bonds (Fig. 1). This flexible hinge is found in IgG,
ments, such as free light and/or heavy chains. This may be
IgA, and IgD, but not in IgM or IgE. Each immunoglo-
accompanied by the presence of monoclonal B cells or
bulin monomer has an approximate molecular weight of
plasma cells in the bone marrow.1,2 These proteins may be
150,000 kD.11
responsible for tissue damage in a range of body organs.
The 5 primary classes of immunoglobulins are IgG,
Among these organs, the kidney seems to be especially
IgM, IgA, IgD, and IgE. These are distinguished by the
vulnerable and is indeed the most frequently involved organ
type of heavy chain found in the molecule. IgG molecules
in patients with monoclonal gammopathy.3–7
have heavy chains known as g-chains; IgMs have m-chains;
The purpose of this review is to describe the
IgAs have a-chains; IgEs have E-chains; and IgDs have d-
pathophysiology of immunoglobulins and discuss the
chains. The heavy chains differ from each other in the
pathology and pathogenesis of a wide spectrum of renal
amino acid sequences.8–12
diseases associated with monoclonal gammopathies.
Antibody classes differ in valency as a result of dif-
ferent numbers of units (monomers) that join to form the
From the *Department of Pathology and Laboratory Medicine; and complete protein. IgG usually exists as a monomer, IgA as
wDepartment of Medicine, King Faisal Specialist Hospital and
Research Center, Riyadh, Kingdom of Saudi Arabia.
a dimer in secretions but as a monomer in serum, and IgM
The authors have no funding or conflicts of interest to disclose. as a pentamer, thus functioning IgM antibodies have 5 Y-
Reprints: Mohammed Akhtar, MD, FCAP, FRCPA, FRCPath, shaped units containing a total of 10 light chains, 10 heavy
Department of Pathology and Laboratory Medicine (MBC 10), chains, and 10 antigen-binding sites.8–12
King Faisal Specialist Hospital and Research Centre, P.O. Box
3354, Riyadh 11211, Kingdom of Saudi Arabia (e-mails:
makhtar69@kfshrc.edu.sa; dr.mohammed.akhtar@gmail.com). PRODUCTION OF IMMUNOGLOBULINS
All figures can be viewed online in color at http://www.anatomic
pathology.com. Immunoglobulins are normally produced in response
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. to exposure to foreign substances (antigens), such as

Adv Anat Pathol  Volume 22, Number 2, March 2015 www.anatomicpathology.com | 121

where the antigen-specific B cells undergo infections may also be associated with monoclonal gamm- proliferation and later differentiate into plasma cells. Each B cell is capable of producing a single consist of an intact immunoglobulin. The heavy chain in mono- binding site. Effector B cells usually start secreting antibody production of a single abnormal clone of a plasma cell or B while they are still small lymphocytes.8:1. or rarely the heavy chain only. The variable regions of heavy In contrast to the great diversity of normal immuno- and light chains determine the antigen specificity of the anti.anatomicpathology. each representing approx- imately 10% of the cases. Plasma cells seem to have completely and irreversibly committed most of their pro- tein-synthesizing machinery to making antibody and are incapable of further growth and division.Al-Hussain et al Adv Anat Pathol  Volume 22. In some cases.com Copyright r 2015 Wolters Kluwer Health. derived either from a malignant clone or from a proliferative population of cells. characterized by a unique antigen. Similarly. At the end stage of lymphocyte. Clonal expansion of these cells is the underlying abnormality among the monoclonal gammopathies. viruses. Many of the plasma cells die after several days. which have not yet developed into plasma cells. gammopathies contains an immunologically homogenous immunoglobulin commonly referred to as a paraprotein or bacteria. the immunoglobulin in patients with monoclonal body. Normally. The circulating M-protein may molecules. rheumatoid FIGURE 2. Autoimmune diseases such as systemic lupus erythematosis. but the majority of light chains in the serum is bound to heavy chains in the form of immunoglobulin. or other chronic germinal centers. 122 | www. D. Sjogren disease. may occasionally be accompanied by monoclonal gamm- kines that stimulate cell proliferation. The process of antibody production starts with a arthritis. whereas the light chain is lowing which the cell proliferates (with the aid of a helper T either k or l in type. the production of an M-protein component does not seem to be a response by the immune system to an offending antigen. M. Around two thirds of light chain production is k and this is reflected in a serum ratio of k isotype to l isotype of 1. FIGURE 1. and mixed connective tissue disease are usually naive B lymphocyte with a surface receptor coming in contact associated with polyclonal increase in gammaglobulins. or lym- phocytes resulting in an abnormal k to l ratio. 2).8–12 Within the effector B cells and plasma cells. fungi. viral hepatitis. This process is also aided by T-helper cells which produce cyto. or soft tissue.2 cell). Other less common conditions associated with monoclonal gammopathy are Waldenstro¨m macroglobulinemia (WM) and B-cell lymphoma/leukemia. If a disease is caused by a monoclonal line of plasma cells. the condition is called plasma cell dyscrasia.2 The monoclonal gammopathies may be encountered in a number of diseases. Inc. This gives rise to active opathy. light and heavy chains are separately produced within the endoplasmic reticulum and are then assembled to produce the complete antibody before secretion. with the same unique antigen-binding site as the cell-surface antibody that served earlier as the surface antigen receptor on the naive or memory B cell. but not both. globulins. or E. Usually. The presence of M-protein is usually detected by dedicated to produce an antigen-specific antibody.1. Each of the chains has 1 variable (yellow) and several constant regions (red). All rights reserved. species of antibody. globulin classes G. . Diagram depicting the structure of an antibody composed of 2 light chains and 2 heavy chains joined by several MONOCLONAL GAMMOPATHY disulfide bonds (S-S). although some survive longer in the bone marrow and continue to secrete anti- bodies into the blood for months and even years. fol. excess of k-expressing or l-expressing plasma cells. Demonstration of clonality depends on light chain restriction.1. but with the corresponding antigen triggering the cell to proliferate. the most common of which is mul- tiple myeloma representing approximately 60% of cases. For further details please see the text. peripheral circu- lation. Free light chains normally exist in the serum at low levels. 3A). and differentiates into an antibody-secreting effector Monoclonal gammopathies result from an over- cell (Fig. there is a 40% overproduction of light chains compared with heavy chains. the light chain only. A. March 2015 their maturation pathway they differentiate into plasma cells which secrete large amounts of soluble antibody. Number 2. which are opathy. HIV. A naive or memory B cell is activated by clonal gammopathy may be from any 1 of the 5 immuno- exposure to an antigen matching its surface receptor. monoclonal gammopathies may occur as a result of abnor- mal B cells. These cells may be found in the bone marrow. serum and/or urine protein electrophoresis (Fig. and a variety of other protein monoclonal M-protein.

Patients with MG can develop a large variety of patients with MGUS have no symptoms or other apparent related renal lesions. measurement of The natural history of MGUS is variable with some free light chains in the serum has become a common patients having a normal lifespan without ever progressing method to screen and follow patients with plasma cell to overt multiple myeloma or other related lymphoproli- dyscrasias.20.anatomicpathology. a similar but much smaller peak is describe cases that would otherwise meet the criteria for present.12–18 MONOCLONAL GAMMOPATHY OF RENAL SIGNIFICANCE The term “monoclonal gammopathy of renal sig- FIGURE 3. non-IgM. or glomeruli. as compared with multiple myeloma and related PATTERNS OF RENAL INVOLVEMENT BY diseases. It must be pointed out.Adv Anat Pathol  Volume 22. In cases of MGUS. Inc. hypercalcemia. at a concen. and a bone marrow with <10% proteins or their components. and is typically detected as divided into 2 groups. In a patient with monoclonal nificance” (MGRS) has been proposed by the International gammopathy. Smoldering multiple myeloma is inflammatory cells by monoclonal protein and stimulation defined by a serum M-protein >3 g/dL or >10% bone of cytokines and/or chemokines resulting in damage of marrow involvement by clonal plasma cells in the absence parenchymal cells. 3B). The third group may never manifest a malignant process but instead develops tissue damage because of Monoclonal gammopathy of undetermined sig- deposition of monoclonal protein (MGRS) (Fig. In recent years. or serum hyperviscosity related to the or obstruction along with abnormal recruitment of proliferative process. light monoclonal plasma cells. Furthermore. a prominent monoclonal peak (M) is present in Kidney and Monoclonal Gammopathy Research Group to the g region. anemia. and B-cell lymphoma/ leukemia may develop at the rate of about 1% to 2% a year. Thus. Some ultimately manifest as a malignant lymphoplasmacytic cell proliferation accompanied by evi- MONOCLONAL GAMMOPATHY OF dence of tissue damage due to deposition of abnormal UNDETERMINED SIGNIFICANCE proteins.13–18 some patients with MG. The dis- tinction between MGUS and MGRS is important because Immunofixation is used to identify the type of protein in the the monoclonal protein seems to be the direct cause of M-component and to distinguish it from a polyclonal kidney disease in such cases and treatment that targets the gammopathy.19 by protein electrophoresis. www. MGUS indicates monoclonal gammopathy of unknown MGUS. and light chain type. The incidence of MGUS seems to be 2 to 3 times higher in blacks than that in whites and is more frequent in men as compared with women.21 There may be tubular toxicity renal insufficiency. a patient with MGUS requires lifetime follow-up surveilance.com | 123 . the levels of antibody and the number of mono. IgM MGUS has the potential to progress to WM. that in of end-organ damage. As this rate does not decrease with time. nificance (MGUS) is a condition in which an M-protein is found in the blood during standard laboratory tests. or complete immunoglobulin in blood vessels.7 gammopathy which occurs in over 3% of the general white Patients with renal involvement due to MG may be population over the age of 50. Follow-up studies have revealed that MGUS pop- ulation in a given community acts as a substrate from which cases of multiple myeloma. Immunofixation may also be useful for responsible clone is associated with restoration and pres- detecting low levels of M-component that is not detectable ervation of kidney function. The renal abnormalities in a serum monoclonal protein (M-protein). Immunoelectropheresis patterns in monoclonal gammopathy (A) and MGUS (B). This group includes Copyright r 2015 Wolters Kluwer Health. Non-IgM MGUS is the most common subtype and has the potential to progress to multiple myeloma with all of its complication.1. March 2015 Renal Involvement in Monoclonal Gammopathy clinical symptoms and disorders unrelated to myeloma. MG may result from direct deposition of varying abnormal tration <3 g/dL (Fig. tubules. The first group includes cases where an incidental finding when patients undergo a protein kidney involvement is part of a systemic disease affecting electrophoresis as part of an evaluation for a wide variety of several other organs and tissues. There is no evidence of end-organ chain. however. the renal lesion may be the result MGUS is the commonest form of monoclonal of an unrelated disease process.3–7. WM. clonal immunoglobulin deposits in the kidney. The diversity of renal lesions in these clinical problems related to multiple myeloma or other cases may reflect the spectrum of the immunoglobulin lymphoproliferatve diseases. 4). It is defined by the presence of abnormalities in these disorders. However. LC-MGUS may progress to light chain multiple myeloma.2 ferative disorder. such as heavy chain. but demonstrate renal insufficiency and mono- significance. MGUS may be IgM. MONOCLONAL GAMMOPATHY clonal cells in the bone marrow is lower. All rights reserved. damage such as lytic bone lesions.18 MGUS may be divided into 3 distinct subtypes based on the composition of the abnormal protein produced by the monoclonal cell population. Light chain MGUS (LC-MGUS) is a unique subtype of MGUS in which the secreted protein lacks heavy chain component. Number 2.

AL amyloidosis is usually associated includes conditions such as light chain proximal tubulop. In cases with predom- Other glomerulopathies inantly tubular deposition there may be signs of tubular GN indicates glomerulonephritis. The light chains are taken up by the clinical manifestations of a neoplastic process. Congo red staining is the most common method used to identify amyloid. deposition of abnormal serum proteins may increased amounts of light chains.22 the presence of light chains. amyloidosis. All rights reserved. In rare cases glomerular involvement may be Membranous GN minimal or completely absent. Inc. liver. Patients with MGUS may have a variable outcome. Rarely heavy chains Glomerulonephritis with or without participation by light chains may also give With organized deposits Immunotactoid GN rise to amyloid deposits. 5). light chain cast nephropathy (LCCN). For example. In some patients the gammopathy remains stable. The most commonly affected loid. The mesangial cells.anatomicpathology. and patients manifests a renal-specific disease pattern. Renal Involvement in Monoclonal Gammopathy electron microscope is more sensitive and may be helpful in Part of systemic disease suspected cases when light microscopy is nondiagnostic. dysfunction occasionally leading to acquired Fanconi syn- drome. with plasma cell dyscrasias including multiple myeloma. 6A–C). monoclonal immunoglobulin deposition dis- ease (MIDD).com Copyright r 2015 Wolters Kluwer Health. l light chains appear to have a greater Light chain cast nephropathy affinity to form amyloid than k chains. Following exposure to In a third group. and the Membranoproliferative GN interstitium. a patient may formed when the circulating light chains are taken up and have systemic light chain deposition disease (LCDD) along internalized by tissue macrophages.Al-Hussain et al Adv Anat Pathol  Volume 22. mesangial cells assume a result in tissue damage (usually kidney involvement) without any macrophage phenotype. others progress FIGURE 5.27. and Approximately 5% of patients with WM may also develop various types of glomerulopathies (Table 1).23–26 the 2 groups. The light chains are partially metabolized AL AMYLOIDOSIS within lysosomes and are then secreted into the surrounding AL amyloidosis is a condition in which an abnormal matrix. these patients may not C3 nephritis manifest significant proteinuria. Under the polarizing microscope. down within the lysosomes to produce amyloid fibrils. The lesions in amyloidosis. Amyloid fibrils when examined by Renal-specific disease x-ray diffraction reveal an antiparallel conformation with a b- Light chain proximal tubulopathy pleated sheet structure. amyloid is characterized by the Monoclonal immunoglobulin deposition disease presence of randomly disposed nonbranching fibrils. athy (LCPT). AL amyloid is derived from free light chains and is ferent combinations may exist. in with a renal-specific lesion such as LCCN. however. are not mutually exclusive and dif.30 Fibrillary GN In renal amyloidosis there is a predominant involve- With nonorganized deposits ment of the glomeruli along with variable amyloid deposits Proliferative GN with monoclonal IgG in blood vessels. 7). heart. which gastrointestinal tract. seem to acquire a macrophage phenotype and thus participate actively in the genesis of amyloid (Fig. eration of amyloid by mesangial cells.29. although the TABLE 1. tubular basement membranes. which are then deposited in the interstitial spaces. Rarely amyloid deposits may be limited to blood 124 | www. and cryoglobulinema. Number 2. 8 to Cryoglobulinemia 12 nm in diameter (Fig. March 2015 FIGURE 4. MGUS indicates mesangial cells through endocytosis and are then partially broken monoclonal gammopathy of unknown significance. At AL amyloidosis the ultrastructural level. . amyloid appears as a Congo red–staining material that exhibits apple-green bire- fringence (Figs. The second group of organs in amyloidosis are the kidney.28 The resulting misfolded light chain fragments proteinaceous material derived from immunoglobulin light form the characteristic eosinophilic tissue deposits of amy- chains is deposited in tissues. Diagram depicting the cellular mechanism for gen- to overt lymphoproliferative disorder (usually multiple myeloma).

All rights reserved. Number 2. All the MIDDs later stages. March 2015 Renal Involvement in Monoclonal Gammopathy FIGURE 6. The glomerulus stains with Congo red and with polarized microscopy it shows birefringence (apple-green). Within the glomeruli. 84. A. Inc. 9. The manner of renal involvement by LCDD is somewhat different from that seen in other organs where deposition of light chain is the only pathology. 9A). Approximately 50% to 60% of patients with LCDD have associated lymphoproliferative disorder. 8A.Adv Anat Pathol  Volume 22.39–45 Extrarenal involvement by LCDD is primarily noted at autopsy and is usually confined to the perivascular regions of the affected organs. 7 had HCDD. there are multiple nodular lesions within the mesangial areas. liver.45 51 In a study focusing on the predominant site of amyloid had LCDD. Amyloidosis. vessels. These nodules FIGURE 7. www. In addition. involvement of several other organs.33–44 In a nosis in such patients appears to be more favorable. proteinuria. randomly arranged amyloid fibrils (8 to 12 nm in light chain deposition and may be indistinguishable from diameter) in the glomerular basement membrane. heavy chain deposition disease chronic kidney disease with little or no proteinuria. LCDD was first recognized by The term Monoclonal Immunoglobulin Deposition Randall et al46 as an infiltration of light chains involving Disease is used to encompass a multitude of deposition multiple organs. heart. Prog. In the kidney. Patients with these disorders typically present with the a focal segmental manner that becomes diffuse and global in nephrotic syndrome and renal insufficiency. Electron micrograph demonstrates are composed of mesangial matrix with variable amounts of nonbranching. The remaining cases develop LCDD in the setting of progression of MGUS or with no evidence of neoplastic plasma cell proliferation. light chains are deposited along the basement membranes of the glomerular capillaries and along the tubular basement membranes and on electron microscopy appear as flocculent to granular electron dense material (Figs. The mesangial matrix is expanded with eosinophilic amorphous material (H&E stain). including kidney. Amyloidosis. deposition in cases of renal amyloidosis. and 6 had LCDD and HCDD.4% vascular. On electron Copyright r 2015 Wolters Kluwer Health. and 6% tubulointerstitial distribution not have a fibrillar organization and lack affinity for Congo pattern.anatomicpathology. and GI tract. B and C.6% showed glo. most commonly multiple myeloma. whereas the degree prominent renal dysfunction and usually asymptomatic of proteinuria reflects the glomerular amyloid load. B).31 These patients present with slowly progressive diseases including LCDD. LCDD is by far the most common type among the immunoglobulin deposition diseases and may serve as a MONOCLONAL IMMUNOGLOBULIN prototype for the description of the clinicopathologic fea- DEPOSITION DISEASE tures of the entire group.32 Serum creatinine correlates well with the extent have essentially similar clinical and pathologic features with of interstitial fibrosis and tubular atrophy. These diseases differ from amyloidosis in that the deposits do merular. Renal involvement is a constant feature which may present as renal insufficiency.com | 125 . Please see this image in color online. those seen in diabetic nephropathy (Fig. series of 64 patients with MIDD reported by Nasr et al. (HCDD). as well as mixed LCDD and HCDD. amyloid is initially deposited in red. and nephrotic syndrome.

Electron micrograph demonstrating a mesangial nodule with scattered deposits of granular electron-dense material (light chains) within the mesangial matrix nodule. Immunofluorescence microscopy demonstrates mesangial staining with an antiserum for k light chain.anatomicpathology. which transform into a myofibroblastic predominantly of mesangial matrix with variable deposits phenotype with marked increase in profiles of rough of light chains (Fig. A renal biopsy study by Pirani FIGURE 9. Inc. there is linear staining of the tubular basement membranes. 126 | www. and may be characterized by massive subendothelilal and The mechanism of the development of nodular mesangial deposits resembling that in lupus nephritis. A. these nodules are composed mesangial cells. Electron micrographs demonstrate granular electron-dense material in the inner aspect of the glomerular basement membranes (A) and outer aspect of the tubular basement membranes (B). B. All rights reserved. Please see this image in color online.47 mesangial lesions has been attributed to interaction The frequency of LCDD is unknown.Al-Hussain et al Adv Anat Pathol  Volume 22. 5 had LCDD. 10). 9B). C. In a renal biopsy between light chains and receptors on the surface of study by Mallick et al48 of 260 patients with idiopathic mesangial cells (Fig. Light chain deposition disease. Prominent mesangial nodules resembling diabetic glomerulosclerosis (H&E stain). March 2015 FIGURE 8. A and B. which produces excess amount of usually reveals deposition of k light chain within the mesangial matrix giving rise to the nodular lesions. In addition. 9C).26–27 In mesangium. microscopic examination. along the capillary walls and along tubular rare cases the glomerular lesion may lack nodular changes basement membranes (Fig. . Light chain deposition disease. Immunofluorescent microscopy endoplasmic reticulum.com Copyright r 2015 Wolters Kluwer Health. This leads to activation of the proteinuria. Number 2.

March 2015 Renal Involvement in Monoclonal Gammopathy FIGURE 12.Adv Anat Pathol  Volume 22. Copyright r 2015 Wolters Kluwer Health. www. whereby the mesangial cells assume a myofibroblastic A monoclonal protein of the same light-chain isotype is phenotype with abundant profiles of rough endoplasmic retic- usually demonstrated in serum or urine. Diagram depicting the cellular processes that give nification (inset). The receptor activation triggers a cell response. Please see this image in color online. Please see this image in color online. CRYOGLOBULINEMIA Cryoglobulins are immunoglobulins that precipitate et al49 reported 47 patients with plasma cell dyscrasia. Cryoglobulinemias are Light chains in patients with LCDD appear to have classified into 3 types according to the immunoglobulin affinity for a variety of tissues thus explaining the dis. composition.50–52 thus is not included among monoclonal gammopathies. Electron micrograph of cryoglobulinemic glomer- ulonephritis demonstrates subendothelial deposits. which seem to determine the physicochemical factor activity) and polyclonal IgG. This results in production of increased amounts of matrix proteins. Type I cryoglobulin consists typically of mon- tribution of these deposits in specific locations in several oclonal IgM. B. composed of approximately 30 nm paired microtubules. Inc. osition disease. Approximately 85% of cases oglobulins contain only polyclonal immunoglobulins and of LCDD are associated with k light-chain deposition. these deposits exhibit an organized substructure rise to the nodular lesions in the mesangium in light chain dep.anatomicpathology. and organs. in when cooled below body temperature and redissolve on whom 24 had cast nephropathy and 10 had LCDD. does not activate complement in vitro. ulum. Cryoglobulins may be composed of only immu- disease is found in approximately 5% of patients with noglobulins or may contain a mixture of immunoglobulins multiple myeloma at autopsy. All rights reserved. The glomerulus shows numerous intracapillary protein thrombi (PAS stain). A. On high mag- FIGURE 10.53–57 FIGURE 11. The light chains interact with receptors on the surface of mesangial cells. This affinity for tissues is dependent on the leads to symptoms of hyperviscosity. Cryoglobulinemic glomerulonephritis. type II cryoglobulins sequence of amino acids in the variable region of the light contain a monoclonal IgM (presenting with rheumatoid chains.7 and complement components. The glomerulus shows proliferative changes with MPGN type-1 pattern (H&E stain). and type III cry- properties of the light chains. The heating. which are deposited in the mesangium with resulting mesangial nodular lesions. Number 2.com | 127 .

Cryoglobulins are generated by the III are seen mostly in combination with autoimmune and clonal expansion of B cells. Light chain proximal tubulopathy. Cryoglobulins type II and with type II or type III. Inc. amorphous or granular dense deposits presence of massive intracapillary and subendothelial may be found within the capillary lumina (hyaline thrombi) immunoglobulin aggregates. 11A. All rights reserved. such as hepatitis C. Ultrastructure may also the glomerular lumina. or indolent (as in MGUS). 128 | www. and less commonly with other frequently associated with type I cryoglobulinemia than lymphoproliferative disorders. expansion is polyclonal in type III cryoglobulinemia. By contrast.13 Other patterns include focal show deposits with organized substructure with paired.Al-Hussain et al Adv Anat Pathol  Volume 22.com Copyright r 2015 Wolters Kluwer Health. mesangial proliferative. Renal lesions are less multiple myeloma and WM. whereas negative for l light chain in (C). including and membranous glomerulonephritis. neuropathies. Immunofluorescence microscopy demonstrates staining of these crystals with an antiserum for k light chain. . smoldering (WM. in the context of either lym- infectious diseases.anatomicpathology. with or as a result of plasma cell dyscrasias. The proximal tubules reveal numerous intracytoplasmic crystals (Masson trichrome stain). Number 2.53–57 (multiple myeloma). which may almost obliterate and in subendothelial location. March 2015 Type I cryoglobulins are seen mostly in combination segmental or diffuse proliferative. Cryoglobulins type phoproliferative disorders or persistent immune stimulation II may occasionally be seen in patients with plasma cell triggered by chronic infections or autoimmune diseases. A. FIGURE 13. skin lesions such as vasculitis and clonal expansion of a clone that can be overtly malignant thrombosis. B). ulonephritis (Figs. The typical histopathologic When renal biopsy specimens are examined with feature of renal involvement of cryoglobulinemia is the electron microscopy. B. and glomerulonephritis. B-cell appearance reminiscent of membranoproliferative glomer. plasmacytoid lym- The most frequent pattern of glomerular lesion is an phoma). dyscrasia. Clinical manifestations in cryoglobulinemia Types I and II cryoglobulinemias result from the mono- include arthritis.

occlusion is more frequent in type I cryoglobulinemia. Crystal formation may be a prominent feature of LCPT. Precipitation of partially degraded proteins results in accumulation of crystalline structures within the lysosomes of the tubular cells.com | 129 . absorptive capacity of the tubules resulting in light chain ticularly type II.anatomicpathology. In patients with overt multiple myeloma. microtubular. Occasionally the crystals may have fibrillar architecture. usually rhomboid. All rights reserved. Intratubular casts in light chain cast nephropathy are formed by interaction of uromodulin with light chain filtered light chains may also influence the physicochemical prop- through the glomerulus. excretion of light chains in and can be associated with hyperviscosity syndrome and the urine. is not a requirement for the light chains resulting in formation of insoluble casts. the cold-induced acral necrosis. Processing of pathologi- patients with MG. Excess generates large immune complexes with IgG and complement amounts of light chains may on occasion be produced in fractions. 12). catabolized by lysosomal degradation and their amino acids oglobulin precipitation in the microcirculation. In some cases the immune glomerulus. The tubular epithelial cell contains numerous rhomboid crystals. square. and immune are reabsorbed and recycled. LCCN. if any. Number 2. As a result there is little. association with other related malignant processes such as Three types of renal-specific lesions may be seen in malignant lymphoma and WM. particularly an efficient system for reabsorption of proteins by endo- lupus nephritis in the absence of cryoglobulinemia. which which is well within the absorptive capacity of the tubules. which is normally pro. and/or annular forms measuring 20 weight 22 to 25 kD) and are freely filtered through the to 30 nm in diameter (Fig.58. diagnosis of LCPT. Inc. however. Vascular chains in the glomerular filtrate is relatively small (< 0. March 2015 Renal Involvement in Monoclonal Gammopathy FIGURE 16.59 cytosis mediated by cubulin and megalin endocytic recep- Two major mechanisms may be at play to varying tors. C). and cally large quantities of light chains leads to accumulation several types of glomerulonephritis.61–68 Furthermore. Resistance to complete intralysosomal breakdown is a feature almost exclusively seen in cases with k light chains. or rectangular in configuration. opathy.60 Within the proximal tubules. is usually accompanied by high cryoglobulin concentrations. which may interfere with absorption of other substances in the glomerular fil- trate. the light chains are degrees across the different types of cryoglobulinemia: cry. LIGHT CHAIN PROXIMAL TUBULOPATHY Light chains are relatively small proteins (molecular curved. Normally the amount of light complex–mediated inflammation of blood vessels. although amino acid sequences at the variable region of the FIGURE 15. which has normally reabsorbed by the proximal tubules. 13A). 14). The presence of the abnormal proteins is recognizable at light microscopic examination and light chain may be demonstrated by immunofluorescent microscopy. Rarely. par. 13B. The presence of crystals within the duced in the ascending loop of Henle. Immune complex–mediated amount of light chains may reach >20 g/d exceeding the vasculitis is more frequent in mixed cryoglobulinemias. online. Uromodulin. of large numbers of phagolysosomes within the cytoplasm of proximal tubular cells. Please see this image in color FIGURE 14. and found in the lysosomes of the tubular cells by EM (Fig. some of the light chains may be resistant to proteolysis resulting in their accumulation within the tubular cells (Fig. Light chains in the glomerular filtrate are deposits may have a “fingerprint”-like pattern.5 g). crystals can be seen in glomerular cells including podocytes as well as in interstitial cells and histiocytes. The crystals are electron dense.Adv Anat Pathol  Volume 22. forms a strong bond with proximal tubular cells.3–7 These include LCPT. www. Electron micrograph of light chain proximal tubul. which demonstrates pre- dominant presence of one of the light chains (Figs. which have also been noted in other types of renal diseases. as several cases of LCPT without Copyright r 2015 Wolters Kluwer Health. particularly C1q. erties of the light chains. in which the monoclonal IgM component excretion in the urine as Bence Jones proteins. Light chain cast nephropathy featuring intratubular light chain casts with alteration of the tubular epithelium and scattered giant cells (H&E stain).

In patients with overt myeloma.74 Volume depletion is a significant risk factor in that it slows the flow of urine within the tubules and increases the light chain concentration. The first description of LCPT in the proximal be distinguished from ordinary proteinaceous casts. which may be organized or nonorganized. These deposits have a fibrillar or a tubular substructure but unlike amyloid fibrils. A specific binding site for immu- noglobulin light chains has been identified on uromodulin. Electron micrograph of fibrillary glomerulonephritis glomerulopathy are uncommon causes of glomerular dis- with subepithelial deposits composed of randomly arranged ease in patients with MG. 16). kidney biopsy is usually immunofluorescent microscopy and by recognition of required for confirmation of clinical impression. These cases may be diagnosed by patients with multiple myeloma who present with acute or demonstration of monoclonality of intratubular protein on chronic renal failure. The glomerulonephritis with organized deposits is charac- terized by immunoglobulin deposition in the mesangium or along the glomerular capillaries. <100 with focal foreign body giant cell formation (Fig. these deposits are Congo red negative. Subsequently. Glomerulopathies with non- organized glomerular deposits is a heterogenous group of glomerular lesions. Fibrillary glomerulonephritis with mesangial matrix expansion and thickening of the peripheral capillary walls (PAS diuretics and nonsteroidal anti-inflammatory agents are stain). The cases of LCPT have been described in the English language obstructing casts may cause tubular rupture. Immunoelectron microscopy may tubules. The casts dle-shaped crystals were noted in the proximal tubular cells may be surrounded by proliferation of tubular epithelial cells on electron microscopic examination. The casts are generally described as “brittle” due to also be helpful in determining the clonality of the intracellular the frequent finding of cracks in the casts. increased urinary concen- tration of calcium due to hypercalcemia and use of radio- contrast material may also precipitate renal failure due to crystals have now been reported.com Copyright r 2015 Wolters Kluwer Health.anatomicpathology. thereby promoting the formation of casts. The biopsy excessive numbers of large granules of reabsorbed proteins reveals presence of variable numbers of hard eosinophilic casts within the lysosomes by light microscopy and electron within the ascending part of loop of Henle as well as collecting microscopic examination.3–6 GLOMERULONEPHRITIS A large variety of glomerular lesions may be encoun- tered in patients with MG. 15). known to enhance the tendency for cast formation.75–79 are due to l light chains which are more amenable to Diagnosis of LCCN may be suspected clinically in lysosomal degradation.64 Most of these cases increased cast formation.63. are nonspecific and variable. . These casts should light chains.73. All rights reserved. The casts are formed due to a strong affinity between light chains in the glomerular filtrate with uromodulin (Tam Horsfall protein) produced normally in the thick ascending loop of Henle (Fig. with extrava- literature as case reports and small case series. The most common forms of Congo red–negative fibrillar glomerular deposi- tion diseases are fibrillary glomerulonephritis and immu- notactoid glomerulopathy. March 2015 LIGHT CHAIN CAST NEPHROPATHY LCCN refers to a condition in which there is protei- naceous cast formation within the thick ascending loop of Henle.70–72 It is usually caused by large amounts of mono- clonal free light chains produced in multiple myeloma. which binds to the complementarity determining region within the variable region of immunoglobulin light chains. GLOMERULONEPHRITIS WITH ORGANIZED DEPOSITS Fibrillary glomerulonephritis and immunotactoid FIGURE 18.69 sation of monoclonal light chain into the interstitium causing inflammation and fibrosis. This site consists of a linear sequence of 9 amino acids. however. Number 2. Inc. strongly positive for periodic acid Schiff (PAS) stain.Al-Hussain et al Adv Anat Pathol  Volume 22. LCPT may also enhance cast for- mation by increasing the amounts of unabsorbed light chains in the urine. usually resulting in acute or chronic renal fail- ure. which are tubular epithelial cell cytoplasm was reported in 1957. Nee.80–97 These may be categorized into 2 distinct subtypes depending on the nature of glo- merular deposits. The light microscopic findings nonbranching fibrils (15 to 25 nm in diameter). Several therapeutic agents such as loop FIGURE 17. Please see this image in color online. showing histologic patterns 130 | www.

Similar cases FIGURE 20. www. mem- capillary walls.com | 131 . 17).anatomicpathology. focal or diffuse proliferative or immunoglobulin-negative C3-positive glomerulonephritis membranoproliferative glomerulonephritis. with or without (C3 nephritis). In addition to being smaller. 18). with a diameter ranging from 15 to 25 nm versus the 8 regardless of the predominant morphologic pattern may be to 12 nm amyloid fibrils (Fig. Glomerulonephritis in a given case may antibody disease. a membranous pattern. These cases dosis. however. there are random subclass (IgG1. are of immunoglobulin origin. IgM.80–82 GLOMERULONEPHRITIS WITH NONORGANIZED DEPOSITS Glomerular lesions with nonorganized immunoglobu- lin deposits may be caused by 2 immunologic mechanisms involving activation of classic and alternate pathways. The glomerulus shows proliferative changes with endocapillary proliferation and cellular crescent (PAS stain). Both types of deposits.84–98 also be seen.83 crescent formation. membranoproliferative changes. and k and or l light chains. and mem- with variable staining patterns. and C1q may manifest variable combinations of these changes. 19). Proliferative glomerulonephritis with monoclonal IgG. Immunofluorescence microscopy is with nonorganized deposits are quite variable and may positive for IgG. which are electron microscopy.80–82 Glomerulopathies associated with immunoglobulin The pathognomonic pathologic findings are seen on deposition usually contain deposits of IgG. IgG2. and IgG3) restricted and may show a fibrillar deposits in the mesangium and along the glomerular predominance of endocapillary proliferation. Deposition of IgA. or membranous patterns. C3. B). the fibrils in fibrillary glomerulonephritis are more randomly disposed than microtubular deposits observed in immunotactoid glomerulopathy which tend to be ordered in parallel bundles. Glomerular deposition of the monoclonal immunoglobu- lins with activation of the classic pathway of complement FIGURE 19. in contrast to fibrillary glomerulonephritis. Number 2. A.Adv Anat Pathol  Volume 22. branoproliferative. Inc. Please see this image in color online. All rights reserved. Electron micrograph demonstrates subendothelial electron-dense deposits without substructure. Electron micrograph of immunotactoid glomerul- results in an immunoglobulin-positive C3-positive glomer- opathy depicting subendothelial deposits composed of numer- ous microtubules (30 to 50 nm in diameter). B. The include mesangial proliferation. 20A. In fibrillary GN. and mesangial Histologic patterns of glomerulopathies associated expansion (Fig. The immunoglobulins acterized by the formation of microtubules that are much may manifest k and/or l light chain isotype. Copyright r 2015 Wolters Kluwer Health. Immunotactoid glomerul. is char. Glomerular lesions involving activation of alternate pathway are characterized by deposition of com- plement factors of the alternative pathway through inhib- that may be seen with other glomerulonephritides including ition of alternative pathway–regulating proteins resulting in mesangial proliferative. The fibrils are larger than those in amyloi. March 2015 Renal Involvement in Monoclonal Gammopathy larger than the fibrils in fibrillary glomerulonephritis and measure 30 to 50 nm in diameter (Fig. oclonal IgG deposition (PGNMID). ulonephritis. occasionally exhibiting a branous glomerulopathy with or without crescentic changes linear IgG staining pattern similar to that seen in anti-GBM (Figs. variable endocapillary fibrillary deposits may be extensive and may be associated proliferation. categorized as proliferative glomerulonephritis with mon- opathy.

monoclonal immunoglobu. Arch Pathol Lab Med. Neumann HPH. J Am Soc Nephrol. risk stratification.24:1121–1127. Therneau TM. C3 immunostaining (without immunoglobulins) and 13. these cases are associated with WM. 2003. monoclonal gammopathies. Am J Kidney Dis. as well as focal gammopathy of undetermined significance (MGUS) and and segmental glomerulosclerosis. Dispenzieri A.84–99 with plasma cell dyscrasias. bulin monoclonal gammopathy of undetermined significance membranous.13:184–186. Renal lesions associated with plasma cell may be an underlying lymphoma/leukemia. and challenges. Immunoglobulins—structure and function.17:2533–2545. Nasr SH.Al-Hussain et al Adv Anat Pathol  Volume 22. Blood.14:1924–1933. rare cases of a variety of other glomerular diseases for recategorizing disease entities in the presence of evolving occurring in association with MG have been described. seen in PGNMID. Lascombe MB. Wadhera RK. Dispenzieri A. Korbet SM. patients had myeloma. 824–830. Lorenz EC. Monoclonal centic glomerulonephritis (ANCA negative). 2011. relapsed. 2007. et al. Number 2. February 9. Rajkumar SV.92–94 between the structure (antigenicity of antibody molecules) Histologically. 2006.133:249–267. pauci immune cres. Therneau TM. 2013. Bridoux F. Adv association with deposition of monoclonal IgM k. sus perspectives risk factors for progression and guidelines for monitoring and management. Renal failure due to combined cast nephropathy. and glomeruli. Sethi S. clonal IgA k associated with IgA myeloma have also been 6. Practical approach to diagnosis. Myeloma-related kidney disease. blood vessels.85:933–942. J Clin Oncol. Am J Kidney Dis. 19. Multiple myeloma.375:1721–1728. Phildelphia.med. similar to that Annu Rev Immunol. . clonal gammopathy of undetermined significance: implications tides.125:S41–S52. Burton DR. elucidated in the past decade. classification.354:1362–1369. whereas in others there 4.sc. A common etiology involving dysregula.50:155–165. Katzmann JA. et al. The largest series by Dingli and col. These include dense deposit disease. leagues reported on 13 patients with FSGS. Lichtman AH. and mesangial locations. Paueksakon P. 132 | www. A variety of disorders. 2. intra. Primary systemic amyloidosis: clinical 1. et al. 2006. et al. involvement. lins may inactivate alternate pathway–regulating proteins. Mayer G.anatomicpathology. 2010. Nephrol Dial Transplant. Schroeder HW. Three-dimensional resulting in uncontrolled C3 activation and immunoglobulin. Durie BG. Arch Pathol Lab Med. 2010. which relapsed when the myeloma review. Available at: http:// autoantibodies playing an important role in a proportion of pathmicro.21:36–47.98–102 Focal segmental smoldering (asymptomatic) multiple myeloma: IMWG consen- glomerulosclerosis may be caused by a variety of con. Kyle RA. Nasr SH. 2003:43–64. Kyle RA. Leung N.123: amyloidosis in plasma cell disorders. et al. Semin Hematol. of any lymphoproliferative disorder. Lancet. Liu F. Heher EC. 1988. Rare cases of pro. Kyle RA. Prevalence and remains unclear. Attaelmannan M. Levinson SS. Inc. 11. but it has been reported rarely in association with a 16. Neuberger MS. of these 4 N Engl J Med. Goes NB. MG may be associated with a wide correlations in multiple myeloma: a case series of 190 patients spectrum of disease processes in the kidney involving all with kidney biopsies. Rajkumar SV.59:786–794.50:155–165. Leung N. 23. nephropathy following treatment of myeloma. 2010. 2007. 5th ed. Prevalence of monoclonal Patients treated for myeloma experienced improvement in gammopathy of undetermined significance: a systematic their renal lesion. Structure and function of antibodies. REFERENCES 24. Cavacini L. structure of antibodies. Rajkumar SV. Gertz MA. Differential diagnosis of 25.102 20. share the key features of dominant complement C3 deposits PA: Saunders. 5. and management of mono- In addition to the above-mentioned glomerulonephri. Mayo Clin Proc. Monoclonal gammopathy: significance and possible causality in renal C3 NEPHRITIS disease. or no evidence dyscrasias. Gertz MA. in the glomerulus. 2012. A single case of collapsing variant of risk of progression of light-chain monoclonal gammopathy of FSGS has also been reported in a patient with myeloma. et al.25:1340–1343. Accessed patients. Kidney disease associated reported.100 The pathogenesis of FSGS in patients with MG 18. pathophysiological processes are involved in the patho. Clin Chem. 2010. and the remaining 9 had MGUS. 15.htm.edu/mayer/igstruct2000. Amsterdam: Elsevier. Schwartz MM. Molecular Genetics of Immunoglobu- lins. Kyle RA. In the context of MG. of monoclonal gammopathy of undetermined significance. Another gammopathy of renal significance: when MGUS is no longer case report demonstrated partial remission of collapsing undetermined or insignificant. OTHER GLOMERULOPATHIES 14. However. Kyle RA. whereas others are confined to the kidney. 2010. Sethi S. et al. Leukemia. scientific evidence. 2014.85:945–948. Abbas AK. Alzari PM. Advances in the diagnosis. All rights reserved. Chap- ter 4 in microbiology and immunology.6:555–580. Monica P. Mu¨ller AMS. Leung N. et al. 2006. Structure and function of tion of the alternate pathway of complement has been immunoglobulins. Renal manifestations of plasma cell interstitium. 21. Am J Kidney Dis. 17. Kyle RA. Some of Chronic Kidney Dis. 1999. Merlini G. Nelson B. 2009. Rajkumar SV. Donna Weber D. Prevalence plasma cell disorder.101 undetermined significance: a retrospective population-based The disease presented before pamidronate therapy and cohort study. Poshusta TL. Harry W. 1987:1–50. 2010.120:4292–4295. In: Calabi membranoproliferative pattern with bright capillary wall F. the C3 glomerulonephritis associated and function (antigen recognition by antibody molecules). Melvin M. J Allergy Clin Immunol. new concepts. with MG may have a variable morphology.32:45–59. Poljak RJ.com Copyright r 2015 Wolters Kluwer Health. Immunoglo- immune complex–like deposits in subepithelial.92–94 and smoldering Waldenstro¨m macroglobulinemia. A summary of the relationship negative C3-positive glomerulonephritis. 1995. C3 nephritis is a recent disease classification comprising 8.11: 108–113.46:1230–1238. Chapter 3 Antibodies and Antigens several rare types of glomerulonephritis. March 2015 of proliferative glomerulonephritis may also be seen in 3. Hutchison CA. liferative glomerulonephritis due to deposition of mono. Seldin DC. Alexanian R. Revelo PM. 7. Primary (AL) monoclonal gammopathies. components of the renal parenchyma including tubules. Monoclonal showed partial improvement following treatment. Mayo Clin Proc. Clin Lym- phoma Myeloma Leuk. eds. amyloidosis and light-chain genesis of these diseases. with genetic defects and/or 10. et al. Am J Kidney Dis. some of which are part a systemic deposition disease. Valeri AM. Rajkumar SV. Clinicopathologic In summary. These disorders in Cellular and Molecular Immunology. Herrera GA. Oncologist. ditions.42:87–95. et al. 9. 22. Buadi FK. Understanding and identifying and laboratory features in 474 cases. 2012. Amyloidosis: pathogenesis and new therapeutic options. 2000. 2014. Geibel A. in a majority of cases there is a 12.

Nephrol Dial Transplant. J Am a rare variant with clinical follow-up of 7 years. Pirani CL. chronic lymphocytic leukemia. Am J Med. 2006.90:37–42. Dosa S. Type I cryoglobu- globulin deposition disease.79:1289–1301. Wiech T. 56. Piedagnel R. et al. Int. ellular rhomboid shaped crystalline inclusions in a case of IgG 47. et al. itis. Q J Med. literature. Cryoglobu- features and prognosis in immunoglobulin light and heavy linaemia and rapidly deteriorating renal function in chronic chain deposition disease. Kyle RA. tations of systemic light chain deposition.2012:573650. Nephrol Dial Transplant. Amyloidosis-associated kidney disease. Batuman V. Renal monoclonal 57. Am J Kidney Dis. Hill P. The cryoglobu- 2012. Intracellular and extrac- 1976. Joseph L. Togashi M. Hematol Oncol and biological characteristics of seven cases and review of the Clin North Am. Kidney Int. et al. 1991. Case Rep Nephrol. Markowitz GS. Herrera GA. Clin J Am Soc Nephrol.26: 34. Markowitz GS. Nephrol Dial Transplant. 41. Clin J Am Soc Nephrol.10:208–221. et al. Clin J Am Soc Nephrol. Strom EH. 52. (heavy)-chain deposition disease: from molecular medicine to 55. The biology 49. Solomon A.55:391–394. proteinuria. et al. myeloma. Kapur U. Ultrastructural ‘fingerprint’ risk of progression of light-chain monoclonal gammopathy of in cryoprecipitates and glomerular deposits: a clinicopatho- undetermined significance (LCMGUS): a newly defined logic analysis of fingerprint deposits. et al. Lancet. 231–239. Am J Kidney Dis. et al. 1998. 35. Myeloma light Virchows Arch.7: cases associated with IgG3 cryoglobulin. chains are ligands for cubilin (gp280). L12a gene in V-kappa(1) light chain deposition disease: 30. 60.3:258–268. et al.48:72–79. et al.Adv Anat Pathol  Volume 22. Michael J. tubulopathy. Soc Nephrol. Ramos-Casals M. Valeri AM. Arch Pathol Lab Med. Hopfer H. 2002. Clin Nephrol. 2004. Fogazzi GB. heavy-chain. Buxbaum J.131:1368–1372. Fresco R. Hutchison CA. Droz D. et al.87:2186–2190. 2011.and heavy-chain deposition diseases. 61. 1999. Mod Pathol. 44. Light-chain. spectrum and clinical significance of light chain proximal J Am Soc Nephrol. Livartowski J. 1978.26:3057–3059. 145–175. Membranopro- pathophysiology-driven therapy. The morphologic immunoglobulin deposition disease: the disease spectrum. Lin J.379:348–360. Clin J Am Soc Nephrol. 62.425:271–280.26:2877–2884. Masai R. 2010. Protease from a single institution. 2009. Structure of a 31. Chen HH. et al. AL-amyloidosis and light-chain 48. 29. Payet J. Number 2. Harris AA.275: 40. Stringer SJ. Favre G. Plaisier E. Navar GL. 2007. Lancet. www. Cornell LD. Larsen CP. Sharma SG. Mullinax F. et al. 42. 33. et al. Plaisier E. 2002. Matoso A. et al.21:263–269. and cryoglobulinemia.128:875–879. Nasr SH. Bonsib SM. et al. Renal monoclonal 58. 2004. 45. 32. Randall RE. Am J Hematol. 2012. Bell JM. Valeri AM. Karjalainen L. et al. Gon˜i F. 37. March 2015 Renal Involvement in Monoclonal Gammopathy 26.42: pathologic spectrum of immunoglobulin light chain proximal 1154–1163. Renal amyloidosis 53. Kavian N. Am J Kidney Dis. 51. Immunoglobulin light 63. Development of renal monoclonal kappa chain of the V kappa IV subgroup in the failure without proteinuria in a patient with monoclonal kidney and plasma cells in light chain deposition disease. 1999. 2004. Steven M. Gu X.1:1342–1350. D’Agati V. et al. et al. Stone JH.18:998–1004. Pathol. significance deposition disease light chains induce divergent phenotypic and treatment of paraprotein in patients presenting with transformations of human mesangial cells.57:775–788. IgG1 lambda light and 50. Nephron. 1994. 11 cases. Stevens F.12:1482–1492. Weiss DT. Preud’homme JL. Sandhu A. Fibrillary inclusions monoclonal light chain deposits: morphological aspects in in light chain proximal tubulopathy associated with myeloma. Danon F. Primary amyloidosis potential effects on aberrant protein conformation and associated with a novel heavy-chain fragment (AH amyloi. 1984. Light chain F246–F254. Fogazzi GB. Toly-Ndour C. Acheson EJ. Markowitz GS. Mougenot B. resistance and binding of Ig light chains in myeloma- 46. Banfi G. Mol Cell Biol. All rights reserved. Renal monoclonal 2011. tubulopathy with and without crystal formation. Teng J. Immunoglobulin light 1101–1103. 2012. 2011. Leboulleux M. 68. Brouet JC. 2010. Kidney Int. 38.155:2009–2017.47: 84:1322–1338. immunoglobulin deposition disease: a report of 64 patients 67.24:1462–1469.13:1235–1248. Kidney cell dyscrasias: ultrastructural observations. Somatic mutations of the heavy chain renal amyloidosis. Silva F. 1995. Inc. ‘idiopathic’ proteinuria without myeloma. Renal pathologic 65. Mallick NP. Biologic and clinical revisited: amyloid distribution. 2006. 43. Clinicopathological 54. Lelongt B. Williamson WC. entity. Acute renal failure spectrum in an autopsy series of patients with plasma cell with lambda light chain-derived crystals in a patient with IgD dyscrasia. Renal monoclonal 66. et al.40:1091–1096. Valeri AM. 1974. Richardson CA. and pleur- J Am Soc Nephrol. Callard P. Lab Invest. An 80-year-old man with renal immunoglobulin deposition disease: the disease spectrum.5:75–76. et al. Purhonen AK. Murphy CSO. Lesavre P.5:6. et al.6. Cogne´ M. 2001. Chang A.1:1342–1350. Basnayake K. 2005. Cid MC. disease of the kidney. et al. Expanding the istics and prognostic factors. dosis). et al. Mikkola M. hematuria. Su CF. Dember LM.anatomicpathology. Birn H. Copyright r 2015 Wolters Kluwer Health. Am J Med. et al. Alyanakian MA. Am J Kidney Dis. presentation of AL kappa amyloidosis.17:3458–3471. Prevalence and 59. 2003. dynamics and biochemical type. 27. Sun Y. et al. Mougenot B. Valeri AM. 2012. Katzmann JA. 2002.44:1121–1125. Clin Nephrol. Gabaldon D. JGrun¨feld JP. A report of 86 cases. Nasr SH. hemiparesis. Renal granular 64. Leuk Lymphoma. Christensen EL. Somerville C.7:231. et al. Dispenzieri A.375:1721–1728. 1994. et al. et al. Peltier J3. significance of cryoglobulins. Courtellemont C. et al. Ganeval D. Ronco P. ISRN 2006. Renal lesions in plasma of immunoglobulin free light chains and kidney injury. D’Amico M.54:767–777. deposition. Rizack T. associated tubulopathies. 1987. Lin J. linaemias. lambda restricted plasma cell myeloma: a case report and ing the pathologic spectrum of light chain deposition disease: review of the literature. Barton K. Herrera GA. a rare entity: analysis of clinical light. Megalin and cubilin: multifunctional 39. Yeh JC. Renal immunoglobulin deposition disease: a report of 64 patients involvement in monoclonal (type I) cryoglobulinemia two from a single institution. et al. Clin Kidney J. gammopathy of undetermined significance: an unusual J Clin Invest. Gallo G. et al. Am J Physiol. Treaba DO. Detection. Bauwens M. Arch Pathol Lab Med. 2012. 2011. 36. 2013. 2010. Peutz-Kootstra CJ. Manifes. 2006.60:293–299. Ronco P.71:9–20. et al. Mougenot B. Keeling J. Light chain (heavy)-chain deposition disease: from molecular medicine to proximal tubulopathy: expanding the pathologic spectrum pathophysiology-driven therapy. 2001. Am J Kidney Dis. Diagn Pathol. et al. Verroust PJ. Vidal R. Corbett RW. 28. et al. Colvin R. Duncan N. Cook HT. deposition disease with renal involvement: clinical character. Mod Pathol. Morphological aspects in 24 patients.12:1482–1492.45:171–176. Wakui H. Cornell LD. Clauvel JP. and linemia in multiple myeloma. Expand. liferative glomerulonephritis. Pozzi C. Noel LH.com | 133 . insufficiency. Light chain deposition endocytic receptors.70:7. Nonamyloidotic monoclonal immuno. Am J Pathol. 2012. lymphocytic leukaemia. et al. 2011. Nasr SH. with and without deposition of crystalline inclusions.

et al. Korean syndrome. Coldefy O. 86. et al. 2011. 70. contrast media. Am the literature. Sethi S. Clin Kidney J. Bourke E. Cornell LD. Kidney Int. Monoclonal gammopathy-associated 73. Clin J Am Soc Nephrol.366:1119–1131. Rosin L.6:294–304. Hypercalcemia can Kidney Dis. Jha V. Kidney Dis.6:1609–1616. 2011.24:302–305. Cornell LD.6:122–132.com Copyright r 2015 Wolters Kluwer Health. 134 | www. Go¨bel H. 1989. Bridoux F. Kid. Nephrol Dial Transplant. Fervenza FC. et al. Zanetta G.22: glomerulonephritis associated with follicular B-cell lym- 465–477. 83.55:1136–1141. Clin J Am Soc Nephrol. Stokes MB. 1992.27:450–453. Hypocomple- Clin Med. Am J Kidney Dis. Multiple myeloma 89. Pathogenesis and treatment of myeloma kidney. 2011. Nasr SH. J Kidney Dis. Fenves AZ. Sanders PW.27:4137–4146. 2013. Desport E. 2001. 2004. J Pathol. Barnes JL. and immunotactoid glomerulonephritis: distinct entities with 98. et al. potentiate the nephrotoxicity of Bence Jones proteins.183:519–521. Elliott MW. 79. Rajkumar SV. Mapping the binding domain of proliferative glomerulonephritis. et al. Immunotactoid rituximab. protein. Rosenstock JL. Dense deposit disease in association with different clinical and pathologic features. Watson DC. Dial Transplant. 2012. Monoclonal gammopathy-associated pauci-immune extraca- 2012. Markowitz GS. Lee JG. Rota S. Am J ney Int.11:2309–2312. Thomas B.43:e10–e12. Tantoco MR. focal segmental glomerulosclerosis following chemotherapy merulonephritis. Dingli D. Single light chain 102. . Ohtani H. Trillo A. Lymphoplasma. Nasr SH. Nasr SH. Morene-Aspitia A. Am J Kidney Dis. 92. Am J Kidney Dis. Moon KC.62:1764–1775. Mayo Clin Proc. Kreisberg R. Monoclonal presenting as acute renal failure. et al. cryoglobulinemic glomerulonephritis with monoclonal Ig Kidney Int. ulonephritis and immunotactoid (microtubular) glomerulop. Huang ZQ. 85. Perez NS. 2003.8:2007–2017. cytic lymphoma causing light chain cast nephropathy. Sakhuja V. Inc. Patterns of non athy are associated with distinct immunologic features. et al. Kattah A. Valeri AM. Ying WZ. Nasr SH. Abstract. Smolens P. allograft. 2013. Am 1284–1293. Kidney disease and 3888–3894. Focal and segmental Waldenstro¨m’s macroglobulinemia: case report and review of glomerulosclerosis and plasma cell proliferative disorders. C3 glomerulonephritis Nephrol Dial Transplant. 2008. Hugue V. 1985. 2003. 52:231–237.55:B66. 2010.77:254–260. J Clin Invest.93:c112–c118. Alexander MP. alpha heavy chain deposition disease: a report of 3 cases and 82. Guiard E. Number 2. Fidler ME. et al. Ren Fail. Renal involvement in 95. Garcia-Herrera A. Bridoux F. Nephron Clin Pract. A case of proliferative dyscrasia causing light chain tubulopathy without Fanconi glomerulonephritis with monoclonal IgG deposits. 2004. 1996.158:1859–1866. Nakaya I. Plasma cell 87. Komatsuda A. Glomerulopathy with 74.anatomicpathology. Multiple myeloma 88. Am J 77. Heher EC. et al. immunoglobulin deposition disease associated with 2011. Fibrillary glomer. Jain N. 2001.62:506–514. Membranous multiple myeloma: a 10-year study. Alpers CE. Proliferative glomer- and severe renal failure: a clinicopathologic study of outcome ulonephritis with monoclonal IgG deposits recurs in the and prognosis in 34 patients. et al. Nephrol 63:1450–1461. 93.58:621–625. Franziska Grundmann F. phoma and subepithelial deposition of IgG1-kappa para- 80. et al. et al. 2004. Fibrillary review of the literature. Radiology. 2002. Yahata M. glycoprotein.65:85–96. 96. Hum Pathol. J Nephrol. 1987. Lee JE. 91. Baudouin B. mentemic proliferative glomerulonephritis with C3 nephritic- 78. et al.10:460. Cortese C. Glomer- 75. Becker JA. 2000. Fre´meaux-Bacchi V. 71. J Am Soc Nephrol. for myeloma. Laubach JP. Tu WH. 1987. N Engl J Med.23: 72.46:278–282.2:94a. glomerulopathy: clinicopathologic and proteomic study. Nephrol. Sepandj F. March 2015 69. Macanovic M. et al. Karras A.6:327–329. Plaisier E. Fervenza FC. et al. Clin J Am Soc Nephrol. et al. et al. Remission of collapsing subclass (kappa chain) immunoglobulin deposition in glo. multiple myeloma.99:732. Proc (Bayl Univ Med Cent). et al. pillary proliferative glomerulonephritis successfully treated 84. 2003. McCarthy CS.124:484–488. Nephron. et al. Binaut R. monoclonal gammopathy of unknown significance. Witthus M. et al. Medicine. 99. gammopathy: a fortuitous association? Clin J Am Soc 76. Zand L. et al. Campbell WG Jr. Proliferative 101. Kuo VC. Proliferative with bortezomib. J Lab 94. Mougenot B. Plevak MF. Rennke HG. Sanders PW.6:2165–2174. nephritis—a new look at an old entity. 2011. 2010. Varma S. Membranoproliferative glomerulo. et al. 2012. associated with monoclonal gammopathy: a case series.23:987–991. Localization of a single binding site non-organized and non-Randall type monoclonal immuno- for immunoglobulin light chains on human Tamm-Horsfall globulin deposits a rare entity.88: immunoglobulin light chains for Tamm-Horsfall protein. Piper M. Monoclonal glomerulonephritis with monoclonal IgG deposits: a distinct gammopathy of uncertain significance (MGUS) and focal entity mimicking immune-complex glomerulonephritis.66:126–137. Mehta AN. Hopper J Jr. et al. 2013.Al-Hussain et al Adv Anat Pathol  Volume 22. 97. glomerulonephritis with monoclonal IgM deposits without 100. Markowitz GS. 1997. 2012. ulonephritis with isolated C3 deposits and monoclonal J Lab Clin Med. Clin Nephrol. 2013. Takahashi S. Cavenagh J. Larson DR. Sethi S. Sethi S. et al. Sheaf M. 1994. Shah S. Sanders PW. deposits: correlation with IgG subclass and response to 81. Bridoux F. Renal crescentic Nephrol Dial Transplant. Dunn MJ. Masai R. 90. et al. All rights reserved. membranous features. Evans DJ. segmental glomerulosclerosis (FSGS)—a case report. Multiple myeloma and factor-like activity in multiple myeloma.