The biology of immunoglobulin free light chains and kidney injury

Basnayake, Kolitha; Stringer, Stephanie; Hutchison, Colin A.; Cockwell, Paul

doi:10.1038/ki.2011.94

Cited by 93 publications

(61 citation statements)

References 188 publications

(214 reference statements)

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“…Thus casts may form as a result of the binding and subsequent aggregation of monoclonal FLC to Tamm-Horsfall protein (THP), also referred to as uromodulin (12). Furthermore, certain amino acid sequence variations, such as those seen in the CDR3 region of the immunoglobulin FLC, are associated with a high affinity to THP (3,13), and these alterations might have played a role for the myeloma cast nephropathy also observed in our case. It has been assumed that the filtered FLCs form fibrils inside the tubules (3).…”

Section: Discussionmentioning

confidence: 88%

“…Amyloidosis is reported to be present in approximately 30% of monoclonal gammopathies with multiple myeloma and renal involvement (2). Amyloidosis is a systemic disease and is likely to damage all compartments of the kidney, but is rare in the tubuli (3). Therefore, in patients with multiple myeloma, several types of casts can be observed, including light chain casts, Tamm-Horsfall protein casts, hyaline casts, and light chain crystal casts, however, there have been only a few reports of light chain amyloid casts (4).…”

Section: Introductionmentioning

confidence: 99%

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Rapid Deterioration of the Renal Function Caused by the Coexistence of Intratubular Amyloidosis and Myeloma Cast Nephropathy

et al. 2015

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Multiple myeloma presents with various kidney injuries, including cast nephropathy, light chain deposition disease, and amyloidosis. Cast nephropathy is the most common form and mostly consists of monoclonal immunoglobulin light chains with Tamm-Horsfall protein. Immunoglobulin light chain (AL) amyloidosis may affect all compartments of the kidney, but it is rare in the tubuli. We herein present a rare case with rapid progression of renal failure caused by the co-occurrence of intratubular amyloidosis and cast nephropathy due to multiple myeloma. Our case suggests unique amyloidogenic light chain cast, which can form amyloid fibrils under specific tubular fluid conditions, and illustrates the complicated light chain pathophysiology.

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Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Rapid Deterioration of the Renal Function Caused by the Coexistence of Intratubular Amyloidosis and Myeloma Cast Nephropathy

et al. 2015

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“…This is in contrast to the use of the assay in the diagnosis and monitoring of paraproteinemia, where the isotypes are used to screen for an LC paraprotein as defined by the presence of an abnormal LC ratio and elevation of the involved isotype (24)(25)(26). With an elevated FLC in the absence of a paraprotein, the ratio of the isotypes remains within the normal range, although this range shifts slightly in CKD because of the differential retention of kFLC (11,27).…”

Section: Discussionmentioning

confidence: 91%

Association of Serum Ig Free Light Chains with Mortality and ESRD among Patients with Nondialysis-Dependent CKD

Ritchie

Assi²,

Burmeister³

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives High levels of serum polyclonal combined Ig free light chains are associated with inflammation and decreased excretory kidney function, and they are an independent risk factor for mortality. Whether combined Ig free light chain predicted mortality and progression to ESRD in a stages 3-5 CKD cohort was assessed.Design, setting, participants, & measurements This was a prospective cohort study of 872 patients with stages 3-5 CKD (nondialysis) recruited into the Chronic Renal Insufficiency Standards Implementation Study. Patients were recruited to the Chronic Renal Insufficiency Standards Implementation Study in an unselected manner from secondary care nephrology clinics between 2004 and 2010. Combined Ig free light chain was measured at recruitment and analyzed by quartiles. The cohort was followed up for a median of 41.4 months (interquartile range =28.3-68.0 months). Cox regression analysis was undertaken to determine the variables associated with mortality and progression to ESRD.Results Combined Ig free light chain quartiles were ,49.4, 49.4-68.8, 68.9-100.7, and .100.7 mg/L. An independent association with death and progression to ESRD was associated with the third and fourth combined Ig free light chain quartiles (quartile 3: death: hazard ratio, 1.49; 95% confidence interval, 1.02 to 2.18; P=0.04; ESRD: hazard ratio, 1.72; 95% confidence interval, 1.0 to 2.97; P=0.05; quartile 4: death: hazard ratio, 1.99; 95% confidence interval, 1.34 to 2.93; P,0.001; ESRD: hazard ratio, 3.73; 95% confidence interval, 2.1 to 6.3; P,0.001). The other independent risk factors were (1) preexisting cardiovascular disease, age .65 years old, and eGFR=15-30 ml/ min per 1.73 m 2 for death and (2) age #65 years old, eGFR,30 ml/min per 1.73 m 2 , urinary protein-to-creatinine ratio .30 mg/mmol, and serum phosphate level .4.65 mg/dl for progression to ESRD.Conclusions An elevated serum combined Ig free light chain level is an independent risk factor for mortality and progression to ESRD in patients with stages 3-5 CKD managed in secondary care.

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“…Much progress has been made in elucidating the molecular events that lead to monoclonal Ig-mediated kidney injury, which have been the subject of a recent review (29). Light chains are filtered at the glomerulus and undergo clathrin-dependent endocytosis by the megalin/cubilin receptor system.…”

Section: Mechanisms Of Myeloma and Plasma Cell-associated Kidney Injurymentioning

confidence: 99%

Kidney Disease and Multiple Myeloma

Heher

Rennke

Laubach

et al. 2013

Clinical Journal of the American Society of Nephrology

145

122

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SummaryKidney injury is a common complication of multiple myeloma and other plasma cell dyscrasias, and it is associated with increased mortality. Multiple pathogenic mechanisms can contribute to kidney injury in the patient with myeloma, some of which are the result of nephrotoxic monoclonal Ig and some of which are independent of paraprotein deposition. The pathogenic mechanisms that underlie paraprotein-related kidney disease are increasingly well understood. A novel assay allowing the quantification of free light chains in the serum has aided the diagnosis of new onset disease and allowed for the earlier detection of relapse. Novel myeloma agents have shown considerable promise in reversing renal failure in some patients and improving outcomes. Stem cell transplantation remains a mainstay of management for younger patients with myeloma who are suitable candidates for intensive therapy, whereas the role of new drugs, plasma exchange, and kidney transplantation continues to evolve.

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The biology of immunoglobulin free light chains and kidney injury

Cited by 93 publications

References 188 publications

Rapid Deterioration of the Renal Function Caused by the Coexistence of Intratubular Amyloidosis and Myeloma Cast Nephropathy

Rapid Deterioration of the Renal Function Caused by the Coexistence of Intratubular Amyloidosis and Myeloma Cast Nephropathy

Association of Serum Ig Free Light Chains with Mortality and ESRD among Patients with Nondialysis-Dependent CKD

Kidney Disease and Multiple Myeloma

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