Abstract
Paraproteinemia-associated kidney diseases are complex disorders that can affect every segment of the nephron. These diseases result from deposition of monoclonal immunoglobulins or monoclonal immunoglobulin fragments that include free heavy chains and free light chains. Kidney damage from deposition of monoclonal free light chains occurs most commonly and is therefore the major focus of this review. Production, renal handling, and clinical detection of immunoglobulin light chains are described, followed by descriptions of the major associated glomerular and tubular diseases. A discussion of Waldenström macroglobulinemia is also included in this chapter.
Keywords
multiple myeloma, cast nephropathy, amyloidosis, monoclonal immunoglobulin deposition disease, acute kidney injury, paraprotein, immunoglobulin, light chain, proximal tubulopathy, Fanconi syndrome, fibrillary glomerulonephritis, immunotactoid glomerulopathy, Waldenström macroglobulinemia
Paraproteinemic kidney diseases are typically the result of deposition of immunoglobulin fragments (heavy chains and light chains; Fig. 28.1 ) in specific parts of the nephron, and they can be divided generally into those diseases that manifest primarily as glomerular or as tubulointerstitial injury ( Box 28.1 ). Glomerular diseases include AL-type amyloidosis (amyloid composed of light chains), AH-type amyloidosis (amyloid composed of heavy chains), monoclonal immunoglobulin deposition disease (MIDD, which includes light-chain deposition disease [LCDD], heavy-chain deposition disease, and light- and heavy-chain deposition disease), proliferative glomerulonephritis with monoclonal immunoglobulin deposition (PGMID), paraprotein-associated C3 glomerulopathy, immunotactoid glomerulopathy, and glomerulonephritis associated with type I cryoglobulinemia. In this review, AL-type amyloidosis, monoclonal LCDD, fibrillary glomerulonephritis, and immunotactoid glomerulopathy will be discussed. Patterns of tubular injury include Fanconi syndrome, proximal tubulopathy, and cast nephropathy (also known as “myeloma kidney”). In addition to these paraproteinemic kidney lesions, this chapter includes a discussion of Waldenström macroglobulinemia.
Glomerulopathies
AL-type and AH-type amyloidoses
Monoclonal immunoglobulin deposition disease
Proliferative glomerulonephritis with monoclonal immunoglobulin deposition
Paraprotein-associated C3 glomerulopathy
Paraprotein-associated fibrillary glomerulonephritis
Immunotactoid glomerulopathy
Cryoglobulinemia, type I
Tubulointerstitial Lesions
Cast nephropathy (“myeloma kidney”)
Fanconi syndrome
Proximal tubulopathy
Tubulointerstitial nephritis (rare)
Vascular Lesions
Asymptomatic Bence Jones proteinuria
Hyperviscosity syndrome
Neoplastic cell infiltration (rare)
Aside from notable exceptions, such as AH-type amyloidosis and heavy-chain deposition disease, immunoglobulin light-chain deposition is directly responsible for most of the kidney pathologic alterations that occur with paraproteinemia. In one large study of multiple myeloma, kidney dysfunction was present in approximately 2% of patients who did not exhibit significant urinary free light-chain levels, while increasing urine free light-chain levels were strongly associated with kidney failure, with 48% of myeloma patients who had high urinary monoclonal free light chains having kidney failure and associated poor survival. The type of kidney lesion induced by light chains depends on the physicochemical properties of these proteins.
Immunoglobulin Light-Chain Metabolism and Clinical Detection
The original description of immunoglobulin light chains is attributed to Dr. Henry Bence Jones in 1847. He reported these unique proteins, which now bear his name, and correlated this early urinary biomarker with the disease known as multiple myeloma. More than a century later, Edelman and Gally demonstrated that Bence Jones proteins were immunoglobulin light chains.
Plasma cells synthesize light chains that become part of the immunoglobulin molecule (see Fig. 28.1 ). In normal states, a slight excess production of light, compared to heavy, chains appears to be required for efficient immunoglobulin synthesis, but this excess results in the release of polyclonal free light chains into the circulation. After entering the bloodstream, light chains are handled similarly to other low-molecular-weight proteins, which are usually removed from the circulation by glomerular filtration. Unlike albumin, these monomers (molecular weight ~22 kDa) and dimers (~44 kDa) are readily filtered through the glomerulus and are reabsorbed by the proximal tubule. Endocytosis of light chains into the proximal tubule occurs through a single class of heterodimeric, multiligand receptor that is composed of megalin and cubilin. After endocytosis, lysosomal enzymes hydrolyze the proteins, and the amino-acid components are returned to the circulation. The uptake and catabolism of these proteins are very efficient, with the kidney readily handling the approximately 500 mg of free light chains produced daily by the normal lymphoid system. However, in the setting of a monoclonal gammopathy, light chain production increases, and binding of light chains to the megalin-cubilin complex can become saturated, allowing light chains to be delivered to the distal nephron and to appear in the urine as Bence Jones proteins.
Light chains are modular proteins that possess two independent globular regions, termed constant (C L ) and variable (V L ) domains (see Fig. 28.1 ). Light chains can be isotyped as kappa (κ) or lambda (λ), based on sequence variations in the constant region of the protein. Within the globular V L domain are four framework regions that consist of β sheets that develop a hydrophobic core. The framework regions separate three hypervariable segments that are known as complementarity determining regions (CDR1, CDR2, and CDR3; see Fig. 28.1 ). The CDR domains, which represent those regions of sequence variability among light chains, form loop structures that constitute part of the antigen-binding site of the immunoglobulin. Diversity among the CDR regions occurs because the V L domain is synthesized through rearrangement of multiple gene segments. Thus, although possessing similar structures and biochemical properties, no two light chains are identical; however, there are enough sequence similarities among light chains to permit categorizing them into subgroups. There are four κ and ten λ subgroups, although, of the λ subgroups, most patients (94%) with multiple myeloma express λI, λII, λIII, or λV subgroups. Free light chains, particularly the λ isotype, often homodimerize before secretion into the circulation.
The multiple kidney lesions from monoclonal light chain deposition affect virtually every compartment of the kidney (see Box 28.1 ) and may be explained by sequence variations, particularly in the V L domain of the offending monoclonal light chain. The light chains that are responsible for monoclonal LCDD are frequently members of the κIV subfamily and appear to possess unusual hydrophobic amino-acid residues in CDR1. In AL-type amyloidosis, sequence variations in the V L domain of the precursor light chain confer the propensity to polymerize to form amyloid. A classic kidney presentation of multiple myeloma is Fanconi syndrome, which is produced almost exclusively by members of the κI subfamily. Unusual nonpolar residues in the CDR1 region and absence of accessible side chains in the CDR3 loop of the variable domain of κI light chains result in homotypic crystallization of the light chain in this syndrome. In cast nephropathy, the secondary structure of CDR3 is a critical determinant of cast formation. In summary, sequence variations in the V L domain appear to determine the type of kidney lesion that occurs with monoclonal light chain deposition.
Free light chains were originally detected with turbidimetric and heat tests. Because these tests lack sensitivity, they are no longer in use. The qualitative urine dipstick test for protein also has a low sensitivity for detection of light chains. Although some Bence Jones proteins react with the chemical impregnated onto the strip, other light chains cannot be detected; the net charge of the protein may be an important determinant of this interaction. Because of the relative insensitivity of routine serum protein electrophoresis (SPEP) and urinary protein electrophoresis (UPEP) for free light chains, these tests are no longer recommended as screening tools in the diagnostic evaluation of the underlying etiology of kidney disease. SPEP is positive in 87.6% of multiple myelomas but only 73.8% of immunoglobulin light-chain (AL) amyloidosis and 55.6% of LCDD. The sensitivity of the UPEP is also low: among a population of 2799 plasma cell dyscrasia patients, only 37.7% had a positive UPEP.
Highly sensitive and reliable immunoassays now are available to detect the presence of monoclonal light chains in the urine and serum and are adequate tests for screening when both urine and serum are examined. When a clone of plasma cells exists, significant amounts of monoclonal light chains appear in the circulation and the urine. In healthy adults, the urinary concentration of polyclonal light chain proteins is about 2.5 mg/L. Causes of monoclonal light-chain proteinuria, a hallmark of plasma cell dyscrasias, are listed ( Box 28.2 ). Urinary light chain concentration is generally between 0.02 and 0.5 g/L in patients with monoclonal gammopathy of undetermined significance (MGUS) and is often much higher (range 0.02 to 11.8 g/L) in patients with multiple myeloma or Waldenström macroglobulinemia. Immunofixation electrophoresis is sensitive and detects monoclonal light chains and immunoglobulins, even in very low concentrations, but it is a qualitative assay that may be limited by interobserver variation. A nephelometric assay that quantifies serum-free κ and λ light chains is also useful to nephrologists, because most of the kidney lesions in paraproteinemias are caused by light chain overproduction and much less commonly by heavy chains or intact immunoglobulins. Because an excess of light chains, compared with heavy chains, is synthesized and released into the circulation, this sensitive assay detects small amounts of serum polyclonal free light chains in healthy individuals. This assay can also distinguish polyclonal from monoclonal light chains and further quantifies the free light chain level in the serum. Quantifying serum light chain levels may be of use clinically, to monitor chemotherapy as well as to serve as a risk factor for development of kidney failure, because myeloma patients with baseline serum-free monoclonal light chain levels greater than 750 mg/L correlated with depressed kidney function (serum creatinine concentration ≥2 mg/dL) and more aggressive myeloma. In the evaluation of kidney disease, particularly if amyloidosis is suspected, perhaps the ideal screening tests for an associated plasma cell dyscrasia include immunofixation electrophoresis of serum and urine and quantification of serum free κ and λ light chains, which have been added as a diagnostic criterion for myeloma. The addition of serum free light chain assay to immunofixation increases detection of multiple myeloma, Waldenström macroglobulinemia, and smoldering multiple myeloma.
Multiple myeloma
AL-type amyloidosis
Monoclonal light-chain deposition disease
Waldenström macroglobulinemia
MGUS
POEMS syndrome (rare)
Heavy-chain (µ) disease (rare)
Lymphoproliferative disease (rare)
MGUS , Monoclonal gammopathy of undetermined significance; POEMS , syndrome consisting of polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes.
Glomerular Lesions of Plasma Cell Dyscrasias
AL-Type Amyloidosis
More than 23 different amyloid proteins have been identified. They are named according to the precursor protein that polymerizes to produce amyloid. Amyloid proteins are characterized by a misfolding event that renders them insoluble and therefore deposit in organs as fibrils, leading to dysfunction. AL-type amyloidosis, which is also known as “primary amyloidosis,” represents a plasma cell dyscrasia that is characterized by organ dysfunction related to deposition of amyloid and usually only a mild increase in monoclonal plasma cells in the bone marrow. However, about 20% of patients with AL-type amyloidosis exhibit overt multiple myeloma or other lymphoproliferative disorder. In AL-type amyloidosis, the amyloid deposits are composed of immunoglobulin light chains versus AA-type amyloidosis, where the precursor protein (serum amyloid A protein) is an acute phase reactant. The identification of the type of amyloid protein is an essential first step in the management of these patients.
AL-type amyloidosis is a systemic disease that typically involves multiple organs ( Table 28.1 ). Cardiac infiltration frequently produces congestive heart failure and is a common presenting manifestation of primary amyloidosis. Infiltration of the lungs and gastrointestinal tract is also common but is generally asymptomatic. Dysesthesias, orthostatic hypotension, diarrhea, and bladder dysfunction from peripheral and autonomic neuropathies can occur. Amyloid deposition can also produce an arthropathy that resembles rheumatoid arthritis, a bleeding diathesis, and a variety of skin manifestations that include purpura. Kidney involvement is common in primary amyloidosis. In a retrospective review of 84 patients with biopsy-proven AL amyloid, 42% needed dialysis with median survival of less than one year following initiation of kidney replacement therapy.
| Isotype | ORGAN INVOLVEMENT | ||||||
|---|---|---|---|---|---|---|---|
| Kidney | Heart | Liver | Neurologic | GI | Lung | ||
| AL-amyloid | λ > κ | +++ | +++ | + | + | +++ | ++++ |
| LCDD | κ > λ | ++++ | +++ | +++ | + | Rare | Rare |
Pathology
Glomerular lesions are the dominant kidney features of AL-type amyloidosis and are characterized by the presence of mesangial nodules and progressive effacement of glomerular capillaries ( Fig. 28.2 ). In the early stage, amyloid deposits are usually found in the mesangium and are not associated with an increase in mesangial cellularity. Deposits may also be seen along the subepithelial space of capillary loops, and may penetrate the glomerular basement membrane in more advanced stages. Immunohistochemistry demonstrates that the deposits consist of light chains, although the sensitivity of this test is not high. Amyloid has characteristic tinctorial properties and stains with Congo red, which produces an apple-green birefringence when the tissue section is examined under polarized light and with thioflavins T and S. On electron microscopy, the deposits are characteristic, randomly oriented, nonbranching fibrils 7 to 10 nm in diameter. In some cases of early amyloidosis, glomeruli may appear normal on light microscopy; however, careful examination can identify scattered monotypic light chains on immunofluorescence microscopy. Ultrastructural examination with immunoelectron microscopy to show the fibrils of AL-type amyloid may be required to establish the diagnosis early in the course of kidney involvement. Ultrastructural and immunohistochemical examination of biopsies of an affected organ establish the diagnosis, although tissue diagnosis of AL-type amyloidosis can also be difficult, because commercially available antibodies may not detect the presence of the light chain in the tissue. In uncertain cases, the amyloid can be extracted from tissue and examined with tandem mass spectrometry to determine the chemical composition of the amyloid. As the disease advances, mesangial deposits progressively enlarge to form nodules of amyloid protein that compress the filtering surfaces of the glomeruli and cause kidney failure. Epithelial proliferation and crescent formation are rare in AL-type amyloidosis.
