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Paul Cockwell - One of the best experts on this subject based on the ideXlab platform.
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Serum free light chain level at diagnosis in Myeloma Cast Nephropathy—a multicentre study
Blood Cancer Journal, 2020Co-Authors: Punit Yadav, Nelson Leung, Insara Jaffer Sathick, Elizabeth E. Brown, Mark Cook, Paul W. Sanders, Paul CockwellAbstract:Myeloma Cast Nephropathy (MCN) is a common cause of severe renal impairment in multiple Myeloma (MM). The level of free light chain (FLC) that causes MCN varies substantially and there is uncertainty about the threshold level that should be used to inform clinical practice. In a multicentre cohort study of 103 patients with a diagnosis of MM and biopsy-confirmed MCN made between 2002–2014, we report prospectively measured levels of serum FLC at diagnosis obtained using a single nephelometric assay (Freelite®) and we explore the relationship between serum FLC level at diagnosis with renal outcome and patient survival. Using a landmark approach, overall survival (OS) was compared between patients who achieved independence from dialysis compared to those who remained dialysis dependent at 3-month, 6-month, 9-month, and 12-month time points. The median serum FLC level at diagnosis was 7531 mg/L (range 107–114600). Serum creatinine was 535 μmol/L (range 168–2993) and eGFR 7 ml/min/1.73 m^2 (range 1–34). Six patients (5.8%) had an FLC level 500 mg/L should be considered the threshold level associated with the development of MCN.
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Serum free light chain level at diagnosis in Myeloma Cast Nephropathy-a multicentre study.
Blood cancer journal, 2020Co-Authors: Punit Yadav, Nelson Leung, Insara Jaffer Sathick, Elizabeth E. Brown, Mark Cook, Paul W. Sanders, Paul CockwellAbstract:Myeloma Cast Nephropathy (MCN) is a common cause of severe renal impairment in multiple Myeloma (MM). The level of free light chain (FLC) that causes MCN varies substantially and there is uncertainty about the threshold level that should be used to inform clinical practice. In a multicentre cohort study of 103 patients with a diagnosis of MM and biopsy-confirmed MCN made between 2002–2014, we report prospectively measured levels of serum FLC at diagnosis obtained using a single nephelometric assay (Freelite®) and we explore the relationship between serum FLC level at diagnosis with renal outcome and patient survival. Using a landmark approach, overall survival (OS) was compared between patients who achieved independence from dialysis compared to those who remained dialysis dependent at 3-month, 6-month, 9-month, and 12-month time points. The median serum FLC level at diagnosis was 7531 mg/L (range 107–114600). Serum creatinine was 535 μmol/L (range 168–2993) and eGFR 7 ml/min/1.73 m2 (range 1–34). Six patients (5.8%) had an FLC level 500 mg/L should be considered the threshold level associated with the development of MCN.
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High cutoff versus high-flux haemodialysis for Myeloma Cast Nephropathy in patients receiving bortezomib-based chemotherapy (EuLITE): a phase 2 randomised controlled trial
The Lancet. Haematology, 2019Co-Authors: Colin A. Hutchison, Paul Cockwell, Veronica Moroz, Arthur R. Bradwell, Lesley Fifer, Julian D. Gillmore, Mark D Jesky, Markus Storr, Julie Wessels, Christopher G. WinearlsAbstract:Summary Background In multiple Myeloma, severe acute kidney injury due to Myeloma Cast Nephropathy is caused by pathogenic free light chain immunoglobulin in serum. High cutoff haemodialysis (HCO-HD) can remove large quantities of free light chain immunoglobulin from serum, but its effect on clinical outcomes is uncertain. We therefore aimed to assess whether HCO-HD could increase the frequency of renal recovery in patients with de novo multiple Myeloma, severe acute kidney injury, and Myeloma Cast Nephropathy relative to treatment with standard high-flux haemodialysis (HF-HD). Methods In this open-label, phase 2, multicentre, randomised controlled trial (EuLITE), we recruited patients with newly diagnosed multiple Myeloma, biopsy-confirmed Cast Nephropathy, and acute kidney injury that required dialysis from renal services in 16 hospitals in the UK and Germany. Patients were randomly assigned (1:1) by random number generation to receive intensive HCO-HD (in sessions lasting 6–8 h) or standard HF-HD and they were stratified by age and centre. Patients and the medical staff treating them were not masked to treatment allocation. Patients received bortezomib, doxorubicin, and dexamethasone chemotherapy, and were then followed up for 2 years. The primary outcome was independence from dialysis at 90 days after random allocation to groups, which was assessed in an intention-to-treat population. The trial has completed follow-up, and is registered at the ISRCTN registry, number ISRCTN45967602. Findings Between June 7, 2008, and Sept 18, 2013, we recruited 90 patients, of whom 43 (48%) were randomly assigned to receive HCO-HD and 47 (52%) were randomly assigned to receive HF-HD. All 90 patients were included in the analysis of the primary outcome. One (2%) patient from the HF-HD group withdrew consent before receiving treatment. During treatment, nine (21%) patients from the HCO-HD group and two (4%) patients in the HF-HD group discontinued trial treatment. After 90 days, 24 (56%) patients in the HCO-HD group and 24 (51%) patients in the HF-HD group were independent from dialysis (relative risk 1·09, 95% CI 0·74–1·61; p=0·81). During the 2-year follow-up, 98 serious adverse events were reported in the HCO-HD group and 82 serious adverse events were reported in the HF-HD group. The most common serious adverse events were infections and adverse events related to the cardiovascular and thrombotic and musculoskeletal systems. During the first 90 days, 26 infections were reported in the HCO-HD group and 13 infections were reported in the HF-HD group, including 14 lung infections in the HCO-HD group and three lung infections in the HF-HD group. Interpretation In this phase 2 study, HCO-HD did not improve clinical outcomes for patients with de novo multiple Myeloma and Myeloma Cast Nephropathy who required haemodialysis for acute kidney injury and who received a bortezomib-based chemotherapy regimen relative to those receiving HF-HD. These results do not support proceeding to a phase 3 study for HCO-HD in these patients. Funding Gambro, Janssen, and Binding Site.
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Diagnostic accuracy of monoclonal antibody based serum immunoglobulin free light chain immunoassays in Myeloma Cast Nephropathy
BMC Clinical Pathology, 2012Co-Authors: Colin A. Hutchison, Paul Cockwell, Mark CookAbstract:Background The development of serum immunoassays for the measurement of immunoglobulin free light chains has led to a paradigm shift in the diagnosis, assessment and monitoring of patients with plasma cell dyscrasias. The impact of these immunoassays which employ polyclonal antibodies was most notable for those patients who were previously classified as non-secretory multiple Myeloma. Recently new monoclonal antibody based assays have become available. The purpose of this study was to compare the diagnostic sensitivity of these new assays with those already in clinical practice. Methods Sera from 30 patients who present with severe acute kidney injury and multiple Myeloma were identified for analysis. A head to head comparison of the two commercially available free light chains assays was then undertaken to determine if their diagnostic sensitivity and specificity were comparable. Results In this first assessment of the utility of these new assays, we found that one of 17 patients with a lambda monoclonal free light chain resulting in acute kidney injury were not identified and a further 12% of patients were wrongly classified as having levels below those associated with disease specific acute kidney injury. Conclusion These results suggest that caution should be applied to the use of new free light chain assays in the assessment of patients with a monoclonal gammopathy.
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Diagnostic accuracy of monoclonal antibody based serum immunoglobulin free light chain immunoassays in Myeloma Cast Nephropathy
BMC clinical pathology, 2012Co-Authors: Colin A. Hutchison, Paul Cockwell, Mark J. CookAbstract:The development of serum immunoassays for the measurement of immunoglobulin free light chains has led to a paradigm shift in the diagnosis, assessment and monitoring of patients with plasma cell dyscrasias. The impact of these immunoassays which employ polyclonal antibodies was most notable for those patients who were previously classified as non-secretory multiple Myeloma. Recently new monoclonal antibody based assays have become available. The purpose of this study was to compare the diagnostic sensitivity of these new assays with those already in clinical practice. Sera from 30 patients who present with severe acute kidney injury and multiple Myeloma were identified for analysis. A head to head comparison of the two commercially available free light chains assays was then undertaken to determine if their diagnostic sensitivity and specificity were comparable. In this first assessment of the utility of these new assays, we found that one of 17 patients with a lambda monoclonal free light chain resulting in acute kidney injury were not identified and a further 12% of patients were wrongly classified as having levels below those associated with disease specific acute kidney injury. These results suggest that caution should be applied to the use of new free light chain assays in the assessment of patients with a monoclonal gammopathy.
Colin A. Hutchison - One of the best experts on this subject based on the ideXlab platform.
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High cutoff versus high-flux haemodialysis for Myeloma Cast Nephropathy in patients receiving bortezomib-based chemotherapy (EuLITE): a phase 2 randomised controlled trial
The Lancet. Haematology, 2019Co-Authors: Colin A. Hutchison, Paul Cockwell, Veronica Moroz, Arthur R. Bradwell, Lesley Fifer, Julian D. Gillmore, Mark D Jesky, Markus Storr, Julie Wessels, Christopher G. WinearlsAbstract:Summary Background In multiple Myeloma, severe acute kidney injury due to Myeloma Cast Nephropathy is caused by pathogenic free light chain immunoglobulin in serum. High cutoff haemodialysis (HCO-HD) can remove large quantities of free light chain immunoglobulin from serum, but its effect on clinical outcomes is uncertain. We therefore aimed to assess whether HCO-HD could increase the frequency of renal recovery in patients with de novo multiple Myeloma, severe acute kidney injury, and Myeloma Cast Nephropathy relative to treatment with standard high-flux haemodialysis (HF-HD). Methods In this open-label, phase 2, multicentre, randomised controlled trial (EuLITE), we recruited patients with newly diagnosed multiple Myeloma, biopsy-confirmed Cast Nephropathy, and acute kidney injury that required dialysis from renal services in 16 hospitals in the UK and Germany. Patients were randomly assigned (1:1) by random number generation to receive intensive HCO-HD (in sessions lasting 6–8 h) or standard HF-HD and they were stratified by age and centre. Patients and the medical staff treating them were not masked to treatment allocation. Patients received bortezomib, doxorubicin, and dexamethasone chemotherapy, and were then followed up for 2 years. The primary outcome was independence from dialysis at 90 days after random allocation to groups, which was assessed in an intention-to-treat population. The trial has completed follow-up, and is registered at the ISRCTN registry, number ISRCTN45967602. Findings Between June 7, 2008, and Sept 18, 2013, we recruited 90 patients, of whom 43 (48%) were randomly assigned to receive HCO-HD and 47 (52%) were randomly assigned to receive HF-HD. All 90 patients were included in the analysis of the primary outcome. One (2%) patient from the HF-HD group withdrew consent before receiving treatment. During treatment, nine (21%) patients from the HCO-HD group and two (4%) patients in the HF-HD group discontinued trial treatment. After 90 days, 24 (56%) patients in the HCO-HD group and 24 (51%) patients in the HF-HD group were independent from dialysis (relative risk 1·09, 95% CI 0·74–1·61; p=0·81). During the 2-year follow-up, 98 serious adverse events were reported in the HCO-HD group and 82 serious adverse events were reported in the HF-HD group. The most common serious adverse events were infections and adverse events related to the cardiovascular and thrombotic and musculoskeletal systems. During the first 90 days, 26 infections were reported in the HCO-HD group and 13 infections were reported in the HF-HD group, including 14 lung infections in the HCO-HD group and three lung infections in the HF-HD group. Interpretation In this phase 2 study, HCO-HD did not improve clinical outcomes for patients with de novo multiple Myeloma and Myeloma Cast Nephropathy who required haemodialysis for acute kidney injury and who received a bortezomib-based chemotherapy regimen relative to those receiving HF-HD. These results do not support proceeding to a phase 3 study for HCO-HD in these patients. Funding Gambro, Janssen, and Binding Site.
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Patients with multiple Myeloma have excellent long‐term outcomes after recovery from dialysis‐dependent acute kidney injury
European journal of haematology, 2015Co-Authors: Punit Yadav, Colin A. Hutchison, Lesley Fifer, Kolitha Basnayake, Stephanie Stringer, Mark Jesky, Kym I.e. Snell, Jennifer Pinney, Mark T. Drayson, Mark CookAbstract:Objectives The aim of this study was to report the long-term outcomes in patients with multiple Myeloma (MM) who receive dialysis treatment for acute kidney injury (AKI) due to Myeloma Cast Nephropathy and subsequently recover renal function. Methods Patients presenting with dialysis-dependent AKI secondary to Myeloma Cast Nephropathy and subsequently recovering independent renal function between January 2005 and December 2012 were included in this study. Both renal and haematological parameters were collected at multiple time points as part of routine clinic practice. Factors associated with renal function and overall survival (OS) were determined. Results Twenty-four patients fulfilled the criteria for inclusion. Mean age was 62.1 years; 75% were male and 75% were of White ethnicity. The median OS was 64.1 months (95% confidence interval [CI] 34.8–93.3). Twenty-three (95.8%) patients remained dialysis-independent until death or end of follow-up; one patient required further haemodialysis treatment during the follow-up period. The independent determinant of worse OS was a known history of chronic kidney disease (CKD) at presentation. Shorter length of time on haemodialysis and higher percentage reduction in clonal serum FLC at day 21 from baseline predicted better excretory renal function (estimated glomerular filtration rate) at 6 months. Conclusion In this series, the large majority of patients with MM and dialysis-dependent AKI secondary to Myeloma Cast Nephropathy who recovered independent renal function had no requirement for further dialysis. Survival following recovery of renal function is good, and early variables are independently associated with survival and future renal function.
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Extended high cut-off haemodialysis for Myeloma Cast Nephropathy in Auckland, 2008-2012.
Nephrology (Carlton Vic.), 2014Co-Authors: Jasmine Tan, Michael Lam-po-tang, Colin A. Hutchison, Janak R De ZoysaAbstract:Myeloma Cast Nephropathy contributes to high morbidity and early mortality associated with the development of end-stage renal disease. Treatment with extended high cut-off haemodialysis coupled with novel anti-Myeloma therapies enables significant reduction of serum-free light chains and has been shown to improve renal outcomes. In this case series, medical records of 6 patients who received high cut-off haemodialysis for biopsy-proven Cast Nephropathy were retrospectively reviewed. Patients received a total of 344 hours of high cut-off haemodialysis and concurrent chemotherapy. Only 50% became dialysis independent following treatment. One patient who achieved sustained remission remained dialysis dependent. The added benefit of high cut-off haemodialysis in the light of novel anti-Myeloma therapies requires further evaluation.
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Diagnostic accuracy of monoclonal antibody based serum immunoglobulin free light chain immunoassays in Myeloma Cast Nephropathy
BMC Clinical Pathology, 2012Co-Authors: Colin A. Hutchison, Paul Cockwell, Mark CookAbstract:Background The development of serum immunoassays for the measurement of immunoglobulin free light chains has led to a paradigm shift in the diagnosis, assessment and monitoring of patients with plasma cell dyscrasias. The impact of these immunoassays which employ polyclonal antibodies was most notable for those patients who were previously classified as non-secretory multiple Myeloma. Recently new monoclonal antibody based assays have become available. The purpose of this study was to compare the diagnostic sensitivity of these new assays with those already in clinical practice. Methods Sera from 30 patients who present with severe acute kidney injury and multiple Myeloma were identified for analysis. A head to head comparison of the two commercially available free light chains assays was then undertaken to determine if their diagnostic sensitivity and specificity were comparable. Results In this first assessment of the utility of these new assays, we found that one of 17 patients with a lambda monoclonal free light chain resulting in acute kidney injury were not identified and a further 12% of patients were wrongly classified as having levels below those associated with disease specific acute kidney injury. Conclusion These results suggest that caution should be applied to the use of new free light chain assays in the assessment of patients with a monoclonal gammopathy.
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Diagnostic accuracy of monoclonal antibody based serum immunoglobulin free light chain immunoassays in Myeloma Cast Nephropathy
BMC clinical pathology, 2012Co-Authors: Colin A. Hutchison, Paul Cockwell, Mark J. CookAbstract:The development of serum immunoassays for the measurement of immunoglobulin free light chains has led to a paradigm shift in the diagnosis, assessment and monitoring of patients with plasma cell dyscrasias. The impact of these immunoassays which employ polyclonal antibodies was most notable for those patients who were previously classified as non-secretory multiple Myeloma. Recently new monoclonal antibody based assays have become available. The purpose of this study was to compare the diagnostic sensitivity of these new assays with those already in clinical practice. Sera from 30 patients who present with severe acute kidney injury and multiple Myeloma were identified for analysis. A head to head comparison of the two commercially available free light chains assays was then undertaken to determine if their diagnostic sensitivity and specificity were comparable. In this first assessment of the utility of these new assays, we found that one of 17 patients with a lambda monoclonal free light chain resulting in acute kidney injury were not identified and a further 12% of patients were wrongly classified as having levels below those associated with disease specific acute kidney injury. These results suggest that caution should be applied to the use of new free light chain assays in the assessment of patients with a monoclonal gammopathy.
Guillermo A Herrera - One of the best experts on this subject based on the ideXlab platform.
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Proximal tubulopathies associated with monoclonal light chains: the spectrum of clinicopathologic manifestations and molecular pathogenesis.
Archives of pathology & laboratory medicine, 2014Co-Authors: Guillermo A HerreraAbstract:Context.—Lesions associated with monoclonal light and heavy chains display a variety of glomerular, tubular interstitial, and vascular manifestations. While some of the entities are well recognized, including light and heavy chain deposition diseases, AL (light chain) and AH (heavy chain) amyloidosis, and light chain (“Myeloma”) Cast Nephropathy, other lesions centered on proximal tubules are much less accurately identified, properly diagnosed, and adequately understood in terms of pathogenesis and molecular mechanisms involved. These proximal tubule–centered lesions are typically associated with monoclonal light chains and have not been reported in patients with circulating monoclonal heavy chains. Objective.—To determine the incidence of proximal tubulopathies in a series of patients with monoclonal light chain–related renal lesions and characterize them with an emphasis on clinical correlations and elucidation of molecular mechanisms involved in their pathogenesis. Design.—A study of 5410 renal biopsie...
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Renal pathologic spectrum in an autopsy series of patients with plasma cell dyscrasia.
Archives of pathology & laboratory medicine, 2004Co-Authors: Guillermo A Herrera, Lija Joseph, Aubrey J. Hough, Bart BarlogieAbstract:Renal dysfunction in plasma cell dyscrasias is common. It is the second most common cause of death in patients with Myeloma. We evaluated 77 sequential autopsies performed on patients dying from complications of plasma cell dyscrasias during an 11-year period at the University of Arkansas for Medical Sciences. These consisted of 15% of all the autopsies performed during this time. The kidneys were evaluated by light microscopy using hematoxylin-eosin-stained sections as well as Congo red and thioflavin T stains when amyloidosis was in the differential diagnosis. Immunofluorescence was performed on selected cases. The most common lesion identified was Cast Nephropathy (30%). Other findings included acute tubulopathy, AL-amyloidosis, light chain deposition disease, tubulointerstitial nephritis associated with monotypic light chain deposits, thrombotic microangiopathy, renal infarction, fungal infection, and plasma cell tumor nodules. Autolysis, an expected finding in autopsy evaluations, was significant in 25 cases. Renal lesions are heterogeneous in these patients. In some cases, combined pathologic lesions were noted. Myeloma Cast Nephropathy predominated among all the renal lesions noted.
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Monoclonal Light Chain–Mesangial Cell Interactions: Early Signaling Events and Subsequent Pathologic Effects
Laboratory Investigation, 2001Co-Authors: William J Russell, James Cardelli, Edward Harris, R John Baier, Guillermo A HerreraAbstract:Glomerulopathic monoclonal light chains (G-LC) interact with mesangial cells (MC), resulting in alterations of mesangial homeostasis. Early signaling events control mitogenic activities and cytokine production, which in turn participate in the subsequent pathologic events. Mesangial homeostasis is affected in two very different ways, depending on whether the G-LC is from a patient with light chain deposition disease (LCDD) or light chain–related amyloidosis (AL-Am). In contrast, tubulopathic (T)-LC chains from patients with Myeloma Cast Nephropathy do not significantly interact with MC and result in no alterations in mesangial homeostasis. Therefore, understanding early events in the monoclonal LC–MC interactions is fundamental. MC in culture were exposed to LC obtained and purified from the urine of patients with plasma cell dyscrasias and biopsy-proven renal disease, including LCDD, AL-Am, and Myeloma Cast Nephropathy. Incubation of MC with G-LC, but not T-LC, resulted in cytoskeletal and cell shape changes, activation of platelet-derived growth factor-β (PDGF-β) and its corresponding receptor, cytoplasmic to nuclear migration of c-fos and NF-κβ signals, and production of monocyte chemoattractant protein-1 (MCP-1), as well as increased expression of Ki-67, a proliferation marker. Although NF-κβ activation was directly related to MCP-1 production, c-fos activation regulated proliferative signals and cytoskeletal changes in MC. Amyloidogenic LC were avidly internalized by the MC, whereas LCDD-LC effector targets were located at the MC surface. These cellular events are likely initiated as a result of interactions of the G-LC with yet-uncharacterized MC surface receptors. Dissecting the events taking place when G-LC interact with MC may define potential important targets for selective therapeutic manipulation to ameliorate or prevent the glomerular injury that ensues.
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Monoclonal light chain--mesangial cell interactions: early signaling events and subsequent pathologic effects.
Laboratory investigation; a journal of technical methods and pathology, 2001Co-Authors: William J Russell, Edward Harris, R John Baier, James A. Cardelli, Guillermo A HerreraAbstract:Glomerulopathic monoclonal light chains (G-LC) interact with mesangial cells (MC), resulting in alterations of mesangial homeostasis. Early signaling events control mitogenic activities and cytokine production, which in turn participate in the subsequent pathologic events. Mesangial homeostasis is affected in two very different ways, depending on whether the G-LC is from a patient with light chain deposition disease (LCDD) or light chain-related amyloidosis (AL-Am). In contrast, tubulopathic (T)-LC chains from patients with Myeloma Cast Nephropathy do not significantly interact with MC and result in no alterations in mesangial homeostasis. Therefore, understanding early events in the monoclonal LC-MC interactions is fundamental. MC in culture were exposed to LC obtained and purified from the urine of patients with plasma cell dyscrasias and biopsy-proven renal disease, including LCDD, AL-Am, and Myeloma Cast Nephropathy. Incubation of MC with G-LC, but not T-LC, resulted in cytoskeletal and cell shape changes, activation of platelet-derived growth factor-beta (PDGF-beta) and its corresponding receptor, cytoplasmic to nuclear migration of c-fos and NF-kappa beta signals, and production of monocyte chemoattractant protein-1 (MCP-1), as well as increased expression of Ki-67, a proliferation marker. Although NF-kappa beta activation was directly related to MCP-1 production, c-fos activation regulated proliferative signals and cytoskeletal changes in MC. Amyloidogenic LC were avidly internalized by the MC, whereas LCDD-LC effector targets were located at the MC surface. These cellular events are likely initiated as a result of interactions of the G-LC with yet-uncharacterized MC surface receptors. Dissecting the events taking place when G-LC interact with MC may define potential important targets for selective therapeutic manipulation to ameliorate or prevent the glomerular injury that ensues.
Mark Cook - One of the best experts on this subject based on the ideXlab platform.
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Serum free light chain level at diagnosis in Myeloma Cast Nephropathy—a multicentre study
Blood Cancer Journal, 2020Co-Authors: Punit Yadav, Nelson Leung, Insara Jaffer Sathick, Elizabeth E. Brown, Mark Cook, Paul W. Sanders, Paul CockwellAbstract:Myeloma Cast Nephropathy (MCN) is a common cause of severe renal impairment in multiple Myeloma (MM). The level of free light chain (FLC) that causes MCN varies substantially and there is uncertainty about the threshold level that should be used to inform clinical practice. In a multicentre cohort study of 103 patients with a diagnosis of MM and biopsy-confirmed MCN made between 2002–2014, we report prospectively measured levels of serum FLC at diagnosis obtained using a single nephelometric assay (Freelite®) and we explore the relationship between serum FLC level at diagnosis with renal outcome and patient survival. Using a landmark approach, overall survival (OS) was compared between patients who achieved independence from dialysis compared to those who remained dialysis dependent at 3-month, 6-month, 9-month, and 12-month time points. The median serum FLC level at diagnosis was 7531 mg/L (range 107–114600). Serum creatinine was 535 μmol/L (range 168–2993) and eGFR 7 ml/min/1.73 m^2 (range 1–34). Six patients (5.8%) had an FLC level 500 mg/L should be considered the threshold level associated with the development of MCN.
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Serum free light chain level at diagnosis in Myeloma Cast Nephropathy-a multicentre study.
Blood cancer journal, 2020Co-Authors: Punit Yadav, Nelson Leung, Insara Jaffer Sathick, Elizabeth E. Brown, Mark Cook, Paul W. Sanders, Paul CockwellAbstract:Myeloma Cast Nephropathy (MCN) is a common cause of severe renal impairment in multiple Myeloma (MM). The level of free light chain (FLC) that causes MCN varies substantially and there is uncertainty about the threshold level that should be used to inform clinical practice. In a multicentre cohort study of 103 patients with a diagnosis of MM and biopsy-confirmed MCN made between 2002–2014, we report prospectively measured levels of serum FLC at diagnosis obtained using a single nephelometric assay (Freelite®) and we explore the relationship between serum FLC level at diagnosis with renal outcome and patient survival. Using a landmark approach, overall survival (OS) was compared between patients who achieved independence from dialysis compared to those who remained dialysis dependent at 3-month, 6-month, 9-month, and 12-month time points. The median serum FLC level at diagnosis was 7531 mg/L (range 107–114600). Serum creatinine was 535 μmol/L (range 168–2993) and eGFR 7 ml/min/1.73 m2 (range 1–34). Six patients (5.8%) had an FLC level 500 mg/L should be considered the threshold level associated with the development of MCN.
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Patients with multiple Myeloma have excellent long‐term outcomes after recovery from dialysis‐dependent acute kidney injury
European journal of haematology, 2015Co-Authors: Punit Yadav, Colin A. Hutchison, Lesley Fifer, Kolitha Basnayake, Stephanie Stringer, Mark Jesky, Kym I.e. Snell, Jennifer Pinney, Mark T. Drayson, Mark CookAbstract:Objectives The aim of this study was to report the long-term outcomes in patients with multiple Myeloma (MM) who receive dialysis treatment for acute kidney injury (AKI) due to Myeloma Cast Nephropathy and subsequently recover renal function. Methods Patients presenting with dialysis-dependent AKI secondary to Myeloma Cast Nephropathy and subsequently recovering independent renal function between January 2005 and December 2012 were included in this study. Both renal and haematological parameters were collected at multiple time points as part of routine clinic practice. Factors associated with renal function and overall survival (OS) were determined. Results Twenty-four patients fulfilled the criteria for inclusion. Mean age was 62.1 years; 75% were male and 75% were of White ethnicity. The median OS was 64.1 months (95% confidence interval [CI] 34.8–93.3). Twenty-three (95.8%) patients remained dialysis-independent until death or end of follow-up; one patient required further haemodialysis treatment during the follow-up period. The independent determinant of worse OS was a known history of chronic kidney disease (CKD) at presentation. Shorter length of time on haemodialysis and higher percentage reduction in clonal serum FLC at day 21 from baseline predicted better excretory renal function (estimated glomerular filtration rate) at 6 months. Conclusion In this series, the large majority of patients with MM and dialysis-dependent AKI secondary to Myeloma Cast Nephropathy who recovered independent renal function had no requirement for further dialysis. Survival following recovery of renal function is good, and early variables are independently associated with survival and future renal function.
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Diagnostic accuracy of monoclonal antibody based serum immunoglobulin free light chain immunoassays in Myeloma Cast Nephropathy
BMC Clinical Pathology, 2012Co-Authors: Colin A. Hutchison, Paul Cockwell, Mark CookAbstract:Background The development of serum immunoassays for the measurement of immunoglobulin free light chains has led to a paradigm shift in the diagnosis, assessment and monitoring of patients with plasma cell dyscrasias. The impact of these immunoassays which employ polyclonal antibodies was most notable for those patients who were previously classified as non-secretory multiple Myeloma. Recently new monoclonal antibody based assays have become available. The purpose of this study was to compare the diagnostic sensitivity of these new assays with those already in clinical practice. Methods Sera from 30 patients who present with severe acute kidney injury and multiple Myeloma were identified for analysis. A head to head comparison of the two commercially available free light chains assays was then undertaken to determine if their diagnostic sensitivity and specificity were comparable. Results In this first assessment of the utility of these new assays, we found that one of 17 patients with a lambda monoclonal free light chain resulting in acute kidney injury were not identified and a further 12% of patients were wrongly classified as having levels below those associated with disease specific acute kidney injury. Conclusion These results suggest that caution should be applied to the use of new free light chain assays in the assessment of patients with a monoclonal gammopathy.
Simon Desmeules - One of the best experts on this subject based on the ideXlab platform.
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Effectiveness of Haemodiafiltration with Heat Sterilized High-Flux Polyphenylene HF Dialyzer in Reducing Free Light Chains in Patients with Myeloma Cast Nephropathy.
PloS one, 2015Co-Authors: Mathieu Rousseau-gagnon, Mohsen Agharazii, Sacha A. De Serres, Simon DesmeulesAbstract:In cases of Myeloma Cast Nephropathy in need of haemodialysis (HD), reduction of free light chains using HD with High-Cut-Off filters (HCO-HD), in combination with chemotherapy, may be associated with better renal recovery. The aim of the present study is to evaluate the effectiveness of haemodiafiltration (HDF) in reducing free light chain levels using a less expensive heat sterilized high-flux polyphenylene HF dialyzer (HF-HDF). In a single-centre prospective cohort study, 327 dialysis sessions were performed using a 2.2 m2 heat sterilized high-flux polyphenylene HF dialyzer (Phylther HF22SD), a small (1.1m2) or large (2.1 m2) high-cut-off (HCO) dialyzer (HCOS and HCOL) in a cohort of 16 patients presenting with dialysis-dependent acute Cast Nephropathy and elevated free light chains (10 kappa, 6 lambda). The outcomes of the study were the mean reduction ratio (RR) of kappa and lambda, the proportion of treatments with an RR of at least 0.65, albumin loss and the description of patient outcomes. Statistical analysis was performed using linear and logistic regression through generalized estimating equation analysis so as to take into account repeated observation within subjects and adjust for session duration. There were no significant differences in the estimated marginal mean of kappa RR, which were respectively 0.67, 0.69 and 0.70 with HCOL-HD, HCOS-HDF and HF-HDF (P = 0.950). The estimated marginal mean of the proportions of treatments with a kappa RR ≥0.65 were 68%, 63% and 71% with HCOL-HD, HCOS-HDF and HF-HDF, respectively (P = 0.913). The estimated marginal mean of lambda RR were higher with HCOL-HDF (0.78), compared to HCOL-HD and HF-HDF (0.62, and 0.61 respectively). The estimated marginal mean proportion of treatments with a lambda RR ≥0.65 were higher with HCOL-HDF (81%), compared to 57% in HF-HDF (P = 0.042). The median albumin loss were 7, 21 and 63 g/session with HF-HDF, HCOL-HD and HCOL-HDF respectively (P = 0.044). Among survivors, 9 out of 10 episodes of acute kidney injuries became dialysis-independent following a median time of renal replacement therapy of 40 days (range 7-181). Therefore, in patients with acute dialysis-dependent Myeloma Cast Nephropathy, in addition to chemotherapy, HDF with a heat sterilized high-flux polyphenylene HF dialyzer could offer an alternative to HCO dialysis for extracorporeal kappa reduction with lower albumin loss.
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effectiveness of haemodiafiltration with heat sterilized high flux polyphenylene hf dialyzer in reducing free light chains in patients with Myeloma Cast Nephropathy
PLOS ONE, 2015Co-Authors: Mathieu Rousseaugagnon, Mohsen Agharazii, Sacha A. De Serres, Simon DesmeulesAbstract:Introduction In cases of Myeloma Cast Nephropathy in need of haemodialysis (HD), reduction of free light chains using HD with High-Cut-Off filters (HCO-HD), in combination with chemotherapy, may be associated with better renal recovery. The aim of the present study is to evaluate the effectiveness of haemodiafiltration (HDF) in reducing free light chain levels using a less expensive heat sterilized high-flux polyphenylene HF dialyzer (HF-HDF). Methods In a single-centre prospective cohort study, 327 dialysis sessions were performed using a 2.2 m2 heat sterilized high-flux polyphenylene HF dialyzer (Phylther HF22SD), a small (1.1m2) or large (2.1 m2) high-cut-off (HCO) dialyzer (HCOS and HCOL) in a cohort of 16 patients presenting with dialysis-dependent acute Cast Nephropathy and elevated free light chains (10 kappa, 6 lambda). The outcomes of the study were the mean reduction ratio (RR) of kappa and lambda, the proportion of treatments with an RR of at least 0.65, albumin loss and the description of patient outcomes. Statistical analysis was performed using linear and logistic regression through generalized estimating equation analysis so as to take into account repeated observation within subjects and adjust for session duration. Results There were no significant differences in the estimated marginal mean of kappa RR, which were respectively 0.67, 0.69 and 0.70 with HCOL-HD, HCOS-HDF and HF-HDF (P = 0.950). The estimated marginal mean of the proportions of treatments with a kappa RR ≥0.65 were 68%, 63% and 71% with HCOL-HD, HCOS-HDF and HF-HDF, respectively (P = 0.913). The estimated marginal mean of lambda RR were higher with HCOL-HDF (0.78), compared to HCOL-HD and HF-HDF (0.62, and 0.61 respectively). The estimated marginal mean proportion of treatments with a lambda RR ≥0.65 were higher with HCOL-HDF (81%), compared to 57% in HF-HDF (P = 0.042). The median albumin loss were 7, 21 and 63 g/session with HF-HDF, HCOL-HD and HCOL-HDF respectively (P = 0.044). Among survivors, 9 out of 10 episodes of acute kidney injuries became dialysis-independent following a median time of renal replacement therapy of 40 days (range 7–181). Conclusion Therefore, in patients with acute dialysis-dependent Myeloma Cast Nephropathy, in addition to chemotherapy, HDF with a heat sterilized high-flux polyphenylene HF dialyzer could offer an alternative to HCO dialysis for extracorporeal kappa reduction with lower albumin loss.
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Clinical and biochemical characteristics.
2015Co-Authors: Mathieu Rousseau-gagnon, Mohsen Agharazii, Sacha A. De Serres, Simon DesmeulesAbstract:CN: Myeloma Cast Nephropathy;LCDD: Light Chain Deposition Disease; MM: Multiple Myeloma; AKI: acute kidney injury. Values are mean ±SD or median (range)* 1 subject had two distinct episodes of AKIOne patient received bortezomid- and Revlimid-based regimen. Another patient with two episodes of AKI received Bortezomib and Revlimid respectively for the first and second episode.Clinical and biochemical characteristics.
