The Proximal Tubule Toxicity of Immunoglobulin Light Chains

Abstract

Plasma and B cells dyscrasias that overproduce monoclonal immunoglobulin free light chains (FLCs) affect the kidney frequently in various ways. The hematologic dyscrasia responsible for the production of FLCs may or may not meet the criteria for cancer, such as multiple myeloma (MM) or lymphoma, or may remain subclinical. If there is overt malignancy, the accompanying kidney disorder is called myeloma- or lymphoma-associated. If the dyscrasia is subclinical, the associated kidney disorders are grouped as monoclonal gammopathy of renal significance. Glomeruli and tubules may both be involved. The proximal tubule disorders comprise a spectrum of interesting syndromes, which range in severity. This review focuses on the recent insights gained into the patterns and the mechanisms of proximal tubule toxicity of FLCs, including subtle transport disorders, such as proximal tubule acidosis, partial or complete Fanconi syndrome, or severe acute or chronic renal failure. Histologically, there may be crystal deposition in the proximal tubule cells, acute tubule injury, interstitial inflammation, fibrosis, and tubule atrophy. Specific structural alterations in the V domain of FLCs caused by somatic hypermutations are responsible for crystal formation as well as partial or complete Fanconi syndrome. Besides crystal formation, tubulointerstitial inflammation and proximal tubulopathy can be mediated by direct activation of inflammatory pathways through cytokines and Toll-like receptors due to cell stress responses induced by excessive FLC endocytosis into the proximal tubule cells. Therapy directed against the clonal source of the toxic light chain can prevent progression to more severe lesions and may help preserve kidney function. Plasma and B cells dyscrasias that overproduce monoclonal immunoglobulin free light chains (FLCs) affect the kidney frequently in various ways. The hematologic dyscrasia responsible for the production of FLCs may or may not meet the criteria for cancer, such as multiple myeloma (MM) or lymphoma, or may remain subclinical. If there is overt malignancy, the accompanying kidney disorder is called myeloma- or lymphoma-associated. If the dyscrasia is subclinical, the associated kidney disorders are grouped as monoclonal gammopathy of renal significance. Glomeruli and tubules may both be involved. The proximal tubule disorders comprise a spectrum of interesting syndromes, which range in severity. This review focuses on the recent insights gained into the patterns and the mechanisms of proximal tubule toxicity of FLCs, including subtle transport disorders, such as proximal tubule acidosis, partial or complete Fanconi syndrome, or severe acute or chronic renal failure. Histologically, there may be crystal deposition in the proximal tubule cells, acute tubule injury, interstitial inflammation, fibrosis, and tubule atrophy. Specific structural alterations in the V domain of FLCs caused by somatic hypermutations are responsible for crystal formation as well as partial or complete Fanconi syndrome. Besides crystal formation, tubulointerstitial inflammation and proximal tubulopathy can be mediated by direct activation of inflammatory pathways through cytokines and Toll-like receptors due to cell stress responses induced by excessive FLC endocytosis into the proximal tubule cells. Therapy directed against the clonal source of the toxic light chain can prevent progression to more severe lesions and may help preserve kidney function. An abnormal monoclonal plasma cell proliferation is frequently observed in the elderly population.1Kyle R.A. Larson D.R. Therneau T.M. et al.Long-term follow-up of monoclonal gammopathy of undetermined significance.N Engl J Med. 2018; 378: 241-249Crossref PubMed Scopus (190) Google Scholar In most cases, this proliferation is asymptomatic, is only detected by the presence of a monoclonal immunoglobulin spike in serum protein electrophoresis, and is called monoclonal gammopathy of undetermined significance. However, monoclonal gammopathy of undetermined significance evolves at slow rate (1% per year) to MM,1Kyle R.A. Larson D.R. Therneau T.M. et al.Long-term follow-up of monoclonal gammopathy of undetermined significance.N Engl J Med. 2018; 378: 241-249Crossref PubMed Scopus (190) Google Scholar which is the malignant form of plasma cell proliferation with an incidence rate of approximately 1.1% among all cancers and constitutes 12% to 13% of hematologic malignancies in the United States.2Greenlee R.T. Murray T. Bolden S. Wingo P.A. Cancer statistics, 2000.CA Cancer J Clin. 2000; 50: 7-33Crossref PubMed Scopus (3916) Google Scholar Despite the relatively low incidence rate among cancers, MM is considered the most common malignancy that leads to end-stage renal disease (ESRD). According to the US Renal Data System, approximately 1.2% of patients with ESRD have associated MM.3Reule S. Sexton D.J. Solid C.A. et al.ESRD due to multiple myeloma in the United States, 2001-2010.J Am Soc Nephrol. 2016; 27: 1487-1494Crossref PubMed Scopus (22) Google Scholar Renal dysfunction, defined as serum creatinine elevation ≥1.3 mg/dl, occurs in 48% of patients with newly diagnosed MM.4Kyle R.A. Gertz M.A. Witzig T.E. et al.Review of 1027 patients with newly diagnosed multiple myeloma.Mayo Clin Proc. 2003; 78: 21-33Abstract Full Text Full Text PDF PubMed Scopus (1523) Google Scholar Approximately 19% of patient have an estimated glomerular filtration rate of <30 ml/min/1.73 m2 at the time of diagnosis,5Dimopoulos M.A. Delimpasi S. Katodritou E. et al.Significant improvement in the survival of patients with multiple myeloma presenting with severe renal impairment after the introduction of novel agents.Ann Oncol. 2014; 25: 195-200Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar and 8% require renal replacement therapy.6Blade J. Fernandez-Llama P. Bosch F. et al.Renal failure in multiple myeloma: presenting features and predictors of outcome in 94 patients from a single institution.Arch Intern Med. 1998; 158: 1889-1893Crossref PubMed Scopus (323) Google Scholar Importantly, one large study concluded that reversibility of renal dysfunction was a more important prognostic factor than the response to chemotherapy.7Knudsen L.M. Hjorth M. Hippe E. Renal failure in multiple myeloma: reversibility and impact on the prognosis. Nordic Myeloma Study Group.Eur J Haematol. 2000; 65: 175-181Crossref PubMed Scopus (310) Google Scholar Besides MM, small indolent B and plasma cell clones that do not meet the criteria of cancer can also associate with a large variety of monoclonal paraprotein-related kidney diseases, so this syndrome was recently regrouped under the term of monoclonal gammopathy of renal significance.8Leung N. Bridoux F. Batuman V. et al.The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group.Nat Rev Nephrol. 2019; 15: 45-59Crossref PubMed Scopus (142) Google Scholar, 9Leung N. Bridoux F. Hutchison C.A. et al.Monoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificant.Blood. 2012; 120: 4292-4295Crossref PubMed Scopus (345) Google Scholar, 10Sirac C. Herrera G.A. Sanders P.W. et al.Animal models of monoclonal immunoglobulin-related renal diseases.Nat Rev Nephrol. 2018; 14: 246-264Crossref PubMed Scopus (22) Google Scholar Therefore, MM and other monoclonal lymphoproliferative disorders became diseases of rising interest to nephrologists and onconephrologists. This close association of plasma cell dyscrasias with kidney disease relates especially to the production of monoclonal immunoglobulin FLCs. Kidney lesions related to FLCs include a variety of glomerular diseases such as monoclonal light chain deposition disease and amyloid light-chain– type amyloidosis,8Leung N. Bridoux F. Batuman V. et al.The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group.Nat Rev Nephrol. 2019; 15: 45-59Crossref PubMed Scopus (142) Google Scholar,11Doshi M. Lahoti A. Danesh F.R. et al.Paraprotein-related kidney disease: kidney injury from paraproteins-what determines the site of injury?.Clin J Am Soc Nephrol. 2016; 11: 2288-2294Crossref PubMed Scopus (47) Google Scholar myeloma cast nephropathy,12Sanders P.W. Mechanisms of light chain injury along the tubular nephron.J Am Soc Nephrol. 2012; 23: 1777-1781Crossref PubMed Scopus (55) Google Scholar,13Batuman V. The pathogenesis of acute kidney impairment in patients with multiple myeloma.Adv Chronic Kidney Dis. 2012; 19: 282-286Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar and, particularly, proximal tubule injury, which is the subject of this review. Unlike intact immunoglobulins, FLCs are low-molecular-weight proteins that are removed from the circulation through glomerular filtration.14Wochner R.D. Strober W. Waldmann T.A. The role of the kidney in the catabolism of Bence Jones proteins and immunoglobulin fragments.J Exp Med. 1967; 126: 207-220Crossref PubMed Scopus (195) Google Scholar Filtered FLCs are reabsorbed into the proximal tubule by binding to a luminally expressed multiligand receptor composed of megalin and cubilin.15Batuman V. Verroust P.J. Navar G.L. et al.Myeloma light chains are ligands for cubilin (gp280).Am J Physiol. 1998; 275: F246-F254PubMed Google Scholar,16Klassen R.B. Allen P.L. Batuman V. et al.Light chains are a ligand for megalin.J Appl Physiol. 2005; 98: 257-263Crossref PubMed Scopus (76) Google Scholar After endocytosis, FLCs usually undergo degradation, permitting return of the amino acid components to the circulation.17Maack T. Johnson V. Kau S.T. et al.Renal filtration, transport, and metabolism of low-molecular-weight proteins: a review.Kidney Int. 1979; 16: 251-270Abstract Full Text PDF PubMed Scopus (629) Google Scholar, 18Christensen E.I. Devuyst O. Dom G. et al.Loss of chloride channel ClC-5 impairs endocytosis by defective trafficking of megalin and cubilin in kidney proximal tubules.Proc Natl Acad Sci U S A. 2003; 100: 8472-8477Crossref PubMed Scopus (257) Google Scholar, 19Kozyraki R. Fyfe J. Verroust P.J. et al.Megalin-dependent cubilin-mediated endocytosis is a major pathway for the apical uptake of transferrin in polarized epithelia.Proc Natl Acad Sci U S A. 2001; 98: 12491-12496Crossref PubMed Scopus (214) Google Scholar This system is highly efficient, with only approximately 1 to 10 mg of polyclonal FLCs escaping reabsorption by the proximal tubule and subsequently appearing in the urine each day.20Berggård I. Peterson P.A. Polymeric forms of free normal k and λ chains of human immunoglobulin.J Biol Chem. 1969; 244: 4299-4307Abstract Full Text PDF PubMed Google Scholar However, monoclonal B or plasma cell proliferation can lead to a significant increase of circulating FLCs, which can exceed 100,000 mg/l.21Mead G.P. Carr-Smith H.D. Drayson M.T. et al.Serum free light chains for monitoring multiple myeloma.Br J Haematol. 2004; 126: 348-354Crossref PubMed Scopus (173) Google Scholar As a result, monoclonal FLCs accumulate within the proximal tubular epithelium. Saturation of the megalin/cubilin receptor permits FLCs to escape absorption, appearing in the tubular fluid of distal nephron segments and finally in the urine as Bence Jones proteins. An amazing feature of MM is that during the renal of FLCs, a spectrum of kidney disorders can P.W. Herrera G.A. et of glomerular and tubulointerstitial renal lesions associated with immunoglobulin light chain Google Scholar and the circulating is for renal C.A. P. S. et of light chains with renal in myeloma Am Soc Nephrol. PubMed Scopus Google Scholar This focuses on the pathogenesis of major of proximal tubule injury related to production and metabolism of interesting proteins: proximal tubulopathy and proximal tubule Myeloma cast which is the other major tubulointerstitial renal associated with P.W. Mechanisms of light chain injury along the tubular nephron.J Am Soc Nephrol. 2012; 23: 1777-1781Crossref PubMed Scopus (55) Google Scholar tubule cells are the most cell type in the and are to FLCs in in patients with is not that proximal tubulopathy is common among renal is a large of that FLCs a variety of toxicity on there is in the of FLC to in the of the FLC of as a of toxicity in most C. Herrera G.A. Sanders P.W. et al.Animal models of monoclonal immunoglobulin-related renal diseases.Nat Rev Nephrol. 2018; 14: 246-264Crossref PubMed Scopus (22) Google Scholar,11Doshi M. Lahoti A. Danesh F.R. et al.Paraprotein-related kidney disease: kidney injury from paraproteins-what determines the site of injury?.Clin J Am Soc Nephrol. 2016; 11: 2288-2294Crossref PubMed Scopus (47) Google Scholar,13Batuman V. The pathogenesis of acute kidney impairment in patients with multiple myeloma.Adv Chronic Kidney Dis. 2012; 19: 282-286Abstract Full Text Full Text PDF PubMed Scopus (20) Google P.W. Nephrol. PubMed Scopus Google C.A. Batuman V. J. et al.The pathogenesis and of acute kidney injury in multiple Rev Nephrol. PubMed Scopus Google Scholar tubulopathy associated with FLCs a spectrum of one may be subtle tubule disorders, such as partial or complete Fanconi syndrome which is in the severe of the spectrum is structural in the proximal tubules with of associated renal M. Lahoti A. Danesh F.R. et al.Paraprotein-related kidney disease: kidney injury from paraproteins-what determines the site of injury?.Clin J Am Soc Nephrol. 2016; 11: 2288-2294Crossref PubMed Scopus (47) Google et al.Light chain proximal and in the Am Soc Nephrol. 2016; 27: PubMed Scopus Google Scholar a significant of proximal from or in is that there are a variety of inflammatory as by inflammatory cell and more interstitial and tubule G.A. associated with monoclonal light the spectrum of and Med. 2014; PubMed Scopus Google Scholar tubule also frequently cast which is a distal tubule disorder associated with Myeloma may inflammatory responses in the kidney the proximal disorders from or inflammatory of FLCs, or a of in direct which of and and direct with transport as well as activation of inflammatory pathways in kidney V. The pathogenesis of acute kidney impairment in patients with multiple myeloma.Adv Chronic Kidney Dis. 2012; 19: 282-286Abstract Full Text Full Text PDF PubMed Scopus (20) Google R. et light chains proximal tubule cells through the PubMed Google S. et light chains and kidney Clin 2019; PubMed Scopus (22) Google Scholar with and in of the proximal tubule direct with amino acid and and transport, through of with V. S. R. of myeloma light chains on and transport in renal proximal tubule Google Scholar, V. M. S. chain on and uptake by renal Int. Full Text PDF PubMed Scopus Google Scholar, P.W. Herrera G.A. Bence Jones protein toxicity in proximal tubule in Int. Full Text PDF PubMed Scopus Google Scholar with cell in and in that FLCs factor and protein to and into the of inflammatory including and protein and V. The pathogenesis of acute kidney impairment in patients with multiple myeloma.Adv Chronic Kidney Dis. 2012; 19: 282-286Abstract Full Text Full Text PDF PubMed Scopus (20) Google S. et light chains and kidney Clin 2019; PubMed Scopus (22) Google V. tubular injury in Nephrol. PubMed Scopus Google Scholar, S. C. Batuman V. of pathways in light production in human proximal tubule J Renal Physiol. 2003; PubMed Scopus Google Scholar, S. C. et of light chains cytokines through activation of in human proximal tubule Int. Full Text Full Text PDF PubMed Scopus Google Scholar, et light chains in renal cells through a PubMed Scopus Google Scholar of Toll-like receptors through the and of 1 to stress and and kidney C. Herrera G.A. Sanders P.W. et al.Animal models of monoclonal immunoglobulin-related renal diseases.Nat Rev Nephrol. 2018; 14: 246-264Crossref PubMed Scopus (22) Google Scholar,11Doshi M. Lahoti A. Danesh F.R. et al.Paraprotein-related kidney disease: kidney injury from paraproteins-what determines the site of injury?.Clin J Am Soc Nephrol. 2016; 11: 2288-2294Crossref PubMed Scopus (47) Google S. et light chains and kidney Clin 2019; PubMed Scopus (22) Google et light chains in renal cells through a PubMed Scopus Google Scholar In with kidney and in both FLCs can and of proximal tubule C. Herrera G.A. Sanders P.W. et al.Animal models of monoclonal immunoglobulin-related renal diseases.Nat Rev Nephrol. 2018; 14: 246-264Crossref PubMed Scopus (22) Google R. et light chains proximal tubule cells through the PubMed Google S. et light chains and kidney Clin 2019; PubMed Scopus (22) Google Scholar of FLCs to responses at FLC that may in the glomerular of a patient with MM, there was among is that the are associated with stress in the et light chains in renal cells through a PubMed Scopus Google Sanders P.W. role of 1 in monoclonal free light J 2012; Full Text Full Text PDF PubMed Scopus Google Scholar that the protein as 1 a significant role in the pathway in Sanders P.W. role of 1 in monoclonal free light J 2012; Full Text Full Text PDF PubMed Scopus Google Scholar inflammatory require FLC endocytosis, that endocytosis of light such as and can the inflammatory V. 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C. et of kidney in myeloma cast a study of 2016; PubMed Scopus Google Scholar and G.A. associated with monoclonal light the spectrum of and Med. 2014; PubMed Scopus Google Scholar significant proximal lesions in MM fibrosis, tubule and inflammatory cell are in the kidney of patients with with and In the of patients with myeloma cast in to the of the presence of tubule was associated with A. C. et of kidney in myeloma cast a study of 2016; PubMed Scopus Google Scholar In G.A. associated with monoclonal light the spectrum of and Med. 2014; PubMed Scopus Google Scholar review of kidney lesions in of the related to proximal G.A. associated with monoclonal light the spectrum of and Med. 2014; PubMed Scopus Google Scholar proximal tubule lesions in MM not be related to the and that endocytosis of monoclonal FLCs into the proximal tubule can in a spectrum of inflammatory and that the for the of proximal tubulopathy in patients with tubule a during plasma cell dyscrasias a proximal tubulopathy associated with The of during both in plasma cells and in the V. myeloma with in the cells and in the PubMed Scopus Google Scholar, G.L. and in the myeloma Google Scholar, S. M. et of the in the myeloma cells and kidney of Jones protein type Google Scholar and associated with renal by et R.A. et syndrome in of a form of J Med. Full Text PDF PubMed Scopus Google Scholar The features of monoclonal comprise or in of and a with in the of most proximal tubule have to be associated with disorders and meet the criteria for monoclonal gammopathy of renal et al.Light chain proximal and in the Am Soc Nephrol. 2016; 27: PubMed Scopus Google T. S. et Fanconi syndrome to light chain and features in 2000; PubMed Scopus (173) Google M. V. et in renal of monoclonal light Fanconi a of PubMed Scopus Google Scholar are also usually observed in monoclonal plasma cells, and was that to the slow progression of the hematologic C. Bridoux F. M. et renal Fanconi by through Nephrol. PubMed Scopus Google Scholar the association of proximal tubule with partial or et al.Light chain proximal and in the Am Soc Nephrol. 2016; 27: PubMed Scopus Google G.A. associated with monoclonal light the spectrum of and Med. 2014; PubMed Scopus Google Scholar of also T. S. et Fanconi syndrome to light chain and features in 2000; PubMed Scopus (173) Google S. M. et light of monoclonal immunoglobulin light chains from patients with and PubMed Scopus (55) Google F. C. V. et syndrome induced by a monoclonal light chain in J Kidney Dis. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar is by a dysfunction of the reabsorption including all and endocytosis of low-molecular-weight proteins. include proximal tubule acidosis, and low-molecular-weight and chronic kidney disease are the most and usually the of the hematologic inflammatory and interstitial are common not M. V. et in renal of monoclonal light Fanconi a of PubMed Scopus Google Scholar In to cast the and features of monoclonal FLC in a that to a of the of the T. S. et Fanconi syndrome to light chain and features in 2000; PubMed Scopus (173) Google S. M. et light of monoclonal immunoglobulin light chains from patients with and PubMed Scopus (55) Google Scholar, F. C. V. et syndrome induced by a monoclonal light chain in J Kidney Dis. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, T. F. T. deposition of Bence Jones protein in the renal tubular cells in a patient with the Fanconi syndrome with 1998; PubMed Scopus Google Scholar the monoclonal FLC is to the with FLCs from the and T. S. et Fanconi syndrome to light chain and features in 2000; PubMed Scopus (173) Google S. M. et light of monoclonal immunoglobulin light chains from patients with and PubMed Scopus (55) Google A. G. et of V light chains in syndrome. chain V and in Google Scholar This of V structural and to to feature of toxic FLCs is to of the FLCs with various including or the to proteins and a that to the V S. M. et light of monoclonal immunoglobulin light chains from patients with and PubMed Scopus (55) Google M. et and binding of light chains in Int. 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S. et monoclonal light renal Fanconi Am Soc Nephrol. 2016; 27: PubMed Scopus Google Scholar a single that the to be associated with the toxicity of the the of FLCs in MM can the cell trafficking to stress and inflammatory FLCs to be highly toxic to at low This low to toxicity is with the of in indolent proliferation with low FLC et al.Light chain proximal and in the Am Soc Nephrol. 2016; 27: PubMed Scopus Google T. S. et Fanconi syndrome to light chain and features in 2000; PubMed Scopus (173) Google M. V. et in renal of monoclonal light Fanconi a of PubMed Scopus Google Scholar in the V domain caused by somatic hypermutations in the of FLC toxicity of crystal In of FLCs significant and in no in the cells. In of FLCs from patients with cast or amyloid or FLC in no toxic in a of proximal tubule only a of circulating monoclonal FLC in lesions and dysfunction that the C. Bridoux F. 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S. et monoclonal light renal Fanconi Am Soc Nephrol. 2016; 27: PubMed Scopus Google Scholar, C. Bridoux F. C. et of the monoclonal chain V domain and reversibility of renal in a of Fanconi PubMed Scopus (47) Google Scholar tubulopathy and proximal tubule are related to the amino acid and of the domain of the S. et light chains and kidney Clin 2019; PubMed Scopus (22) Google A. G. et of V light chains in syndrome. chain V and in Google Scholar, M. et and binding of light chains in Int. Full Text PDF PubMed Scopus Google Scholar, C. A. Bridoux F. et in models for syndrome or cast myeloma PubMed Google Scholar, A. C. S. et monoclonal light renal Fanconi Am Soc Nephrol. 2016; 27: PubMed Scopus Google Scholar, C. Bridoux F. C. et of the monoclonal chain V domain and reversibility of renal in a of Fanconi PubMed Scopus (47) Google Scholar tubulopathy may be relatively FLCs can this is a in MM and significant of FLC to of the FLC leads to stress and of as well as inflammation and interstitial tubule is a highly toxicity associated with a FLCs. lesions may with low of the FLC and may be observed more frequently in monoclonal gammopathy of renal significance than in tubule occurs with in the and associated The is is by a to include interstitial inflammation and

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