Nephrol Dial Transplant (2014) 29: 1799–1801 doi: 10.1093/ndt/gfu206 Advance Access publication 3 June 2014
More light shed on light chains Paisit Paueksakon and Agnes B. Fogo Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
Correspondence and offprint requests to: Agnes B. Fogo; E-mail: [email protected]
1799
IN FOCUS
© The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
disease unrelated to monoclonal protein [12]. The classic spectrum of renal disease caused by monoclonal immunoglobulin molecules includes AL amyloidosis, LCDD, light and heavy chain deposition disease (LHCDD), and heavy chain deposition disease (HCDD), all of which classically present with proteinuria; light chain cast nephropathy (LCN), which typically has less proteinuria but acute kidney injury, and cryoglobulinemic glomerulonephritis, which presents often as nephritic syndrome or as vasculitis. More recently, the disease spectrum was expanded to include light chain proximal tubulopathy, also called light chain Fanconi syndrome. These patients have tubular dysfunction and Fanconi syndrome, typically with less proteinuria and acute kidney injury. In addition, most cases of immunotactoid glomerulopathy have a clonal component [13]. In 2004, Nasr et al. [14] described a novel form of glomerular injury related to monoclonal immunoglobulin (IgG) deposition, the so-called proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID). This disease shows glomerular granular electron-dense deposits, mimicking usual immune complex deposits, but stains only for a single light chain and lambda heavy chain subclass, without tubular basement membrane deposits. Most patients with PGNMID present with nephrotic-range proteinuria and only ∼30% of patients with PGNMID have a detectable M-spike in serum. The current observations by Sicard et al. [15] further expand the range of light chain-related kidney disease. About 85% of all light chains with plasma cell dyscrasia are nephrotoxic. The morphologic manifestations depend on the renal compartments targeted by the nephrotoxic light and/or heavy chain. The majority of nephrotoxic light chains (∼70%) affect the tubulointerstitial compartment and are referred to as tubulopathic. The remaining 30% of nephrotoxic light chains preferentially involve the glomerular compartment (glomerulopathic light chains). Combinations of different patterns of renal damage can be seen in the same patient. The most common combinations are AL amyloid with LCCN, or LCDD with LCCN. Clearly, it is challenging for the light chain to form a β-pleated sheet and thus form amyloid, while at the same time undergo conformational changes leading to LCDD (see below). The physicochemical properties of the involved
Downloaded from http://ndt.oxfordjournals.org/ at UQ Library on October 14, 2014
An astute observation 169 years ago brought attention to an association between plasma cell dyscrasia and renal disease. Dr MacIntire observed peculiar abnormalities in his patient’s urine, which was noted to be opaque, acid and with high density with a specific gravity of 1.035. On 30 October 1845, Dr Thomas Watson, a leading clinician in London, and Dr Bence-Jones (BJ), a well-recognized chemical pathologist, performed a number of tests and concluded that the unknown component was of a proteinaceous nature and referred to it as an ‘oxide of albumin, the dehydrated deeutoxide’. Today, we know this material as monoclonal light chain, also referred to as BJ protein [1]. The term ‘multiple myeloma’ was introduced by von Rustizky in 1893 [2]. The disease was rarely recognized until 1889, when Kahler [3] recognized that one of his patients had a similar urine finding as described by Dr McIntire. Light chain cast nephropathy was described by Decastello [4] in 1909. The two types of light chains, kappa and lambda, were not recognized until 1956, followed by demonstration that serum light chains and BJ proteins of myeloma patients were the same [5, 6]. The spectrum of light chain-related kidney disease was next expanded by Randall et al. [7] in 1976, with two autopsies from patients with plasma cell dyscrasia with widespread findings of a disease that he referred to as ‘systemic light chain deposition disease (LCDD)’. This LCDD showed ultrastructural findings of osmiophilic subendothelial and tubular basement membrane densities with deposition of kappa light chains. Heavy chain deposition disease was first described in 1993 by Aucouturier et al. [8]. In 1931, Magnus-Levy [9] raised the question of BJ protein as the ‘mother substance’ of amyloidosis, and light chain (AL) amyloidosis was recognized by Apitz [10] in 1940. In 1985, Jacquot et al. [11] were the first to describe three patients with LCDD associated with AL. Thus, renal involvement in plasma cell dyscrasia is heterogeneous, but not all patients with a monoclonal protein develop related kidney disease. Testing for monoclonal proteins in urine and serum is a routine part of the evaluation of proteinuric adult middle-aged or older patients. In our kidney biopsy practice, about half of patients undergoing renal biopsy with some evidence of a monoclonal protein had kidney
1800
IN FOCUS
manifestation of LCDD, occurring in 59% of previous series of patients. However, in some cases of LCDD, the pathologic light chain clearly may be particularly tubulopathic, as shown in the current study. Ischemic tubulointerstitial lesions were prominent, including tubular microcyst formation in one case. In addition, massive arteriolar light-chain deposits were observed in 71% of patients and may have led to ischemic tubulointerstitial injury. The underlying physiochemical characteristics that determined glomerular versus tubular basement membrane localization remain to be determined. Sicard et al. show tantalizing data in two of their patients, hypothesizing potential impact of glycosylation of the light chain. Whether prospective analysis of such properties of monoclonal proteins could predict disease pattern remains unknown. The dyssynchronous tubular basement membrane deposits versus glomerular basement membrane deposits in some of these cases are of particular interest in this context. The glomerular endothelial cells are fenestrated, allowing for filtration, and are covered by the glycocalyx, which may also modulate the filtration barrier. The podocyte is a highly specialized cell with foot processes and slit diaphragms extending over the outer aspect of the glomerular basement membranes. The glomerular basement membrane is porous, which allows passage of water and small molecules. In addition, both the glomerular basement membranes and the cell surfaces contain anionic sites, which electrostatically restrict molecules with negative charge. Therefore, larger molecules such as albumin or light-chain proteins are restrained from passing through to the urinary space by charge as well as size. In contrast to glomerular endothelial cells and glomerular basement membranes, tubular basement membranes lack this selective permeability function. Molecular studies in four of the patients in Sicard’s study [15] fail to demonstrate common molecular characteristic of the kappa light-chain V domains except for high pI values, a usual characteristic of LCDD light chains that could explain the granular deposits by charge interaction between cationic light chains and anionic heparin sulfate proteoglycan of basement membranes. Thus, it is possible that light-chain deposits localized to tubular basement membranes without glomerular basement membrane deposits could result in only mild tubular proteinuria from altered tubular resorption but without glomerular proteinuria. However, the precise characteristics underlying the heterogeneous localization and response to monoclonal light chains remain largely unknown. Importantly, the current study shows that tubulointerstitial LCDD without significant glomerular proteinuria is a severe and probably underdiagnosed renal complication of monoclonal gammopathies. Further research will be necessary to answer key questions regarding monoclonal proteins and their effects on the kidney. What are the potential mechanisms leading to different patterns of renal damage? Why do some monoclonal proteins not cause kidney disease? Why do some light chains just cause light chain proximal tubulopathy without tubular or glomerular deposits? Why does AL amyloidosis rarely involve the medulla, in contrast to certain hereditary apolipoprotein amyloids? Despite these open questions, an exciting story of light chains and renal damage that began with the astute observation from Dr MacIntire has been further advanced by the current study.
P. Paueksakon and A.B. Fogo
Downloaded from http://ndt.oxfordjournals.org/ at UQ Library on October 14, 2014
immunoglobulin molecules appear to be the primary pathologic determinant of the pattern of tissue injury. Elegant studies by Dr Alan Solomon investigated the nephrotoxic potential of BJ protein by injecting BJ protein from patients with multiple myeloma or AL amyloidosis into mice [16]. In most cases, the pattern of light-chain deposition induced in the mouse kidney was similar to that found in the patients. This study showed conclusive evidence that the abnormal lightchain protein is primarily responsible for the occurrence and type of light-chain-associated disease. In clinical and pathologic terms, LCDD, LHCDD and HCDD are described under the general term of monoclonal immunoglobulin deposition disease (MIDD). These deposits do not have fibrillar organization, lack affinity for Congo red stain and commonly involve tubular and glomerular compartments. Amyloid forms due to one-dimensional elongation of fibrillary structure resulting in a β-pleated sheet structure. In contrast, MIDD seems to involve a one-step precipitation of Ig chain [17]. The same light chain can form granular aggregates or amyloid fibrils, depending on the environment, and varying partially folded associated proteins, such as serum amyloid P component, may be responsible for the amorphous or fibrillary aggregation pathway. In LCDD, kappa chain isotype restriction is observed in ∼80% of cases, whereas AL amyloidosis is more commonly caused by lambda light chain. The VκIV subgroup may be overrepresented in LCDD. This subgroup has a longer complementarity-determining region 1 loop, which is part of an antigen-binding site that contains several unusual hydrophobic residues [17]. These hydrophobic residues are glycosylated and increase the light-chain propensity to precipitate in tissue and displace the equilibrium from soluble toward deposited amorphous forms. The light chain in LCDD can also stimulate mesangial cells to increase synthesis of extracellular matrix proteins, which may contribute to the nodular sclerosis commonly observed [18]. Previously, the clinical dogma has held that patients with LCDD present with proteinuria, usually nephrotic range. Only 16% of patients with LCDD were previously reported to have
More light shed on light chains Paisit Paueksakon and Agnes B. Fogo Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
Correspondence and offprint requests to: Agnes B. Fogo; E-mail: [email protected]
1799
IN FOCUS
© The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
disease unrelated to monoclonal protein [12]. The classic spectrum of renal disease caused by monoclonal immunoglobulin molecules includes AL amyloidosis, LCDD, light and heavy chain deposition disease (LHCDD), and heavy chain deposition disease (HCDD), all of which classically present with proteinuria; light chain cast nephropathy (LCN), which typically has less proteinuria but acute kidney injury, and cryoglobulinemic glomerulonephritis, which presents often as nephritic syndrome or as vasculitis. More recently, the disease spectrum was expanded to include light chain proximal tubulopathy, also called light chain Fanconi syndrome. These patients have tubular dysfunction and Fanconi syndrome, typically with less proteinuria and acute kidney injury. In addition, most cases of immunotactoid glomerulopathy have a clonal component [13]. In 2004, Nasr et al. [14] described a novel form of glomerular injury related to monoclonal immunoglobulin (IgG) deposition, the so-called proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID). This disease shows glomerular granular electron-dense deposits, mimicking usual immune complex deposits, but stains only for a single light chain and lambda heavy chain subclass, without tubular basement membrane deposits. Most patients with PGNMID present with nephrotic-range proteinuria and only ∼30% of patients with PGNMID have a detectable M-spike in serum. The current observations by Sicard et al. [15] further expand the range of light chain-related kidney disease. About 85% of all light chains with plasma cell dyscrasia are nephrotoxic. The morphologic manifestations depend on the renal compartments targeted by the nephrotoxic light and/or heavy chain. The majority of nephrotoxic light chains (∼70%) affect the tubulointerstitial compartment and are referred to as tubulopathic. The remaining 30% of nephrotoxic light chains preferentially involve the glomerular compartment (glomerulopathic light chains). Combinations of different patterns of renal damage can be seen in the same patient. The most common combinations are AL amyloid with LCCN, or LCDD with LCCN. Clearly, it is challenging for the light chain to form a β-pleated sheet and thus form amyloid, while at the same time undergo conformational changes leading to LCDD (see below). The physicochemical properties of the involved
Downloaded from http://ndt.oxfordjournals.org/ at UQ Library on October 14, 2014
An astute observation 169 years ago brought attention to an association between plasma cell dyscrasia and renal disease. Dr MacIntire observed peculiar abnormalities in his patient’s urine, which was noted to be opaque, acid and with high density with a specific gravity of 1.035. On 30 October 1845, Dr Thomas Watson, a leading clinician in London, and Dr Bence-Jones (BJ), a well-recognized chemical pathologist, performed a number of tests and concluded that the unknown component was of a proteinaceous nature and referred to it as an ‘oxide of albumin, the dehydrated deeutoxide’. Today, we know this material as monoclonal light chain, also referred to as BJ protein [1]. The term ‘multiple myeloma’ was introduced by von Rustizky in 1893 [2]. The disease was rarely recognized until 1889, when Kahler [3] recognized that one of his patients had a similar urine finding as described by Dr McIntire. Light chain cast nephropathy was described by Decastello [4] in 1909. The two types of light chains, kappa and lambda, were not recognized until 1956, followed by demonstration that serum light chains and BJ proteins of myeloma patients were the same [5, 6]. The spectrum of light chain-related kidney disease was next expanded by Randall et al. [7] in 1976, with two autopsies from patients with plasma cell dyscrasia with widespread findings of a disease that he referred to as ‘systemic light chain deposition disease (LCDD)’. This LCDD showed ultrastructural findings of osmiophilic subendothelial and tubular basement membrane densities with deposition of kappa light chains. Heavy chain deposition disease was first described in 1993 by Aucouturier et al. [8]. In 1931, Magnus-Levy [9] raised the question of BJ protein as the ‘mother substance’ of amyloidosis, and light chain (AL) amyloidosis was recognized by Apitz [10] in 1940. In 1985, Jacquot et al. [11] were the first to describe three patients with LCDD associated with AL. Thus, renal involvement in plasma cell dyscrasia is heterogeneous, but not all patients with a monoclonal protein develop related kidney disease. Testing for monoclonal proteins in urine and serum is a routine part of the evaluation of proteinuric adult middle-aged or older patients. In our kidney biopsy practice, about half of patients undergoing renal biopsy with some evidence of a monoclonal protein had kidney
1800
IN FOCUS
manifestation of LCDD, occurring in 59% of previous series of patients. However, in some cases of LCDD, the pathologic light chain clearly may be particularly tubulopathic, as shown in the current study. Ischemic tubulointerstitial lesions were prominent, including tubular microcyst formation in one case. In addition, massive arteriolar light-chain deposits were observed in 71% of patients and may have led to ischemic tubulointerstitial injury. The underlying physiochemical characteristics that determined glomerular versus tubular basement membrane localization remain to be determined. Sicard et al. show tantalizing data in two of their patients, hypothesizing potential impact of glycosylation of the light chain. Whether prospective analysis of such properties of monoclonal proteins could predict disease pattern remains unknown. The dyssynchronous tubular basement membrane deposits versus glomerular basement membrane deposits in some of these cases are of particular interest in this context. The glomerular endothelial cells are fenestrated, allowing for filtration, and are covered by the glycocalyx, which may also modulate the filtration barrier. The podocyte is a highly specialized cell with foot processes and slit diaphragms extending over the outer aspect of the glomerular basement membranes. The glomerular basement membrane is porous, which allows passage of water and small molecules. In addition, both the glomerular basement membranes and the cell surfaces contain anionic sites, which electrostatically restrict molecules with negative charge. Therefore, larger molecules such as albumin or light-chain proteins are restrained from passing through to the urinary space by charge as well as size. In contrast to glomerular endothelial cells and glomerular basement membranes, tubular basement membranes lack this selective permeability function. Molecular studies in four of the patients in Sicard’s study [15] fail to demonstrate common molecular characteristic of the kappa light-chain V domains except for high pI values, a usual characteristic of LCDD light chains that could explain the granular deposits by charge interaction between cationic light chains and anionic heparin sulfate proteoglycan of basement membranes. Thus, it is possible that light-chain deposits localized to tubular basement membranes without glomerular basement membrane deposits could result in only mild tubular proteinuria from altered tubular resorption but without glomerular proteinuria. However, the precise characteristics underlying the heterogeneous localization and response to monoclonal light chains remain largely unknown. Importantly, the current study shows that tubulointerstitial LCDD without significant glomerular proteinuria is a severe and probably underdiagnosed renal complication of monoclonal gammopathies. Further research will be necessary to answer key questions regarding monoclonal proteins and their effects on the kidney. What are the potential mechanisms leading to different patterns of renal damage? Why do some monoclonal proteins not cause kidney disease? Why do some light chains just cause light chain proximal tubulopathy without tubular or glomerular deposits? Why does AL amyloidosis rarely involve the medulla, in contrast to certain hereditary apolipoprotein amyloids? Despite these open questions, an exciting story of light chains and renal damage that began with the astute observation from Dr MacIntire has been further advanced by the current study.
P. Paueksakon and A.B. Fogo
Downloaded from http://ndt.oxfordjournals.org/ at UQ Library on October 14, 2014
immunoglobulin molecules appear to be the primary pathologic determinant of the pattern of tissue injury. Elegant studies by Dr Alan Solomon investigated the nephrotoxic potential of BJ protein by injecting BJ protein from patients with multiple myeloma or AL amyloidosis into mice [16]. In most cases, the pattern of light-chain deposition induced in the mouse kidney was similar to that found in the patients. This study showed conclusive evidence that the abnormal lightchain protein is primarily responsible for the occurrence and type of light-chain-associated disease. In clinical and pathologic terms, LCDD, LHCDD and HCDD are described under the general term of monoclonal immunoglobulin deposition disease (MIDD). These deposits do not have fibrillar organization, lack affinity for Congo red stain and commonly involve tubular and glomerular compartments. Amyloid forms due to one-dimensional elongation of fibrillary structure resulting in a β-pleated sheet structure. In contrast, MIDD seems to involve a one-step precipitation of Ig chain [17]. The same light chain can form granular aggregates or amyloid fibrils, depending on the environment, and varying partially folded associated proteins, such as serum amyloid P component, may be responsible for the amorphous or fibrillary aggregation pathway. In LCDD, kappa chain isotype restriction is observed in ∼80% of cases, whereas AL amyloidosis is more commonly caused by lambda light chain. The VκIV subgroup may be overrepresented in LCDD. This subgroup has a longer complementarity-determining region 1 loop, which is part of an antigen-binding site that contains several unusual hydrophobic residues [17]. These hydrophobic residues are glycosylated and increase the light-chain propensity to precipitate in tissue and displace the equilibrium from soluble toward deposited amorphous forms. The light chain in LCDD can also stimulate mesangial cells to increase synthesis of extracellular matrix proteins, which may contribute to the nodular sclerosis commonly observed [18]. Previously, the clinical dogma has held that patients with LCDD present with proteinuria, usually nephrotic range. Only 16% of patients with LCDD were previously reported to have
