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Vivette D Dagati - One of the best experts on this subject based on the ideXlab platform.
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renal monoclonal Immunoglobulin Deposition disease a report of 64 patients from a single institution
Clinical Journal of The American Society of Nephrology, 2012Co-Authors: Samih H. Nasr, Anthony M Valeri, Vivette D Dagati, Lynn D Cornell, Mary E Fidler, Sanjeev M Sethi, Nelson LeungAbstract:Summary Background and objectives To better define the clinical-pathologic spectrum and prognosis of monoclonal Immunoglobulin Deposition disease (MIDD), this study reports the largest series. Design, setting, participants, & measurements Characteristics of 64 MIDD patients who were seen at Mayo Clinic are provided. Results Of 64 patients with MIDD, 51 had light chain Deposition disease, 7 had heavy chain Deposition disease, and6hadlightandheavychainDepositiondisease.Themeanageatdiagnosiswas56years,and23patients(36%) were #50 years of age. Clinical evidence of dysproteinemia was present in 62 patients (97%), including multiple myeloma in 38 (59%). M-spike was detected on serum protein electrophoresis in 47 (73%). Serum free light chain ratio was abnormal in all 51 patients tested. Presentation included renal insufficiency, proteinuria, hematuria, and hypertension. Nodular mesangial sclerosis was seen in 39 patients (61%). During a median of 25 months of follow-up(range,1–140)in 56patients,32 (57%) hadstable/improvedrenal function,2(4%)had worsening renal function, and 22 (39%) progressed to ESRD. The mean renal and patient survivals were 64 and 90 months, respectively. The disease recurred in three of four patients who received a kidney transplant. Conclusions Patients with MIDD generally present at a younger age than those with light chain amyloidosis or light chain cast nephropathy. Serum free light chain ratio is abnormal in all MIDD patients, whereas only threequarters have abnormal serum protein electrophoresis. The prognosis for MIDD is improving compared with historical controls, likely reflecting earlier detection and improved therapies. Clin J Am Soc Nephrol 7: 231–239, 2012. doi: 10.2215/CJN.08640811
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high dose chemotherapy and autologous stem cell transplantation with melphalan in patients with monoclonal Immunoglobulin Deposition disease associated with multiple myeloma
Blood, 2007Co-Authors: Hani Hassoun, Vivette D Dagati, Brian T Rafferty, Carlos D Flombaum, Virginia M Klimek, Adam D Cohen, Adam Boruchov, Tarun Kewalramani, Lilian Reich, Heather LandauAbstract:Introduction: Monoclonal Immunoglobulin Deposition disease (MIDD) includes several disorders that are characterized by the Deposition of serum monoclonal gamma-globulins in various organs, most notably in the kidney resulting in renal dysfunction. There is no standard therapy for MIDD. We report our experience with high dose chemotherapy and autologous peripheral blood stem cell transplantation (HDC/ASCT) in patients with MIDD associated with underlying multiple myeloma (MM). Methods: We have done a retrospective analysis of patients seen at MSKCC with biopsy proven MIDD associated with MM and who underwent HDC/ASCT between 2002 and 2007. Results: Seven patients, all male with a median age of 46, had MM and MIDD. Five had Light Chain Deposition Disease (LCDD), 1 Light and Heavy Chain Deposition Disease (LHCDD), and 1 Light Chain Crystal Deposition Disease (LCCDD). All were stage IB by Durie-Salmon classification. Bone marrow plasmacytosis was a median of 21% (range 10 to 41%). Serum immunofixation showed an IgG kappa monoclonal band in only 2 patients while serum protein electrophoresis showed a monoclonal spike in only 1 of the 2. A monoclonal kappa light chain was detected by serum Free Light Chain Assay in all 7 patients. The diagnosis of MIDD was confirmed by immunofluorescence staining and electron-microscopy examination of kidney biopsy specimens in all patients. Three patients were dialysis dependent before HDC/ASCT. All patients received Melphalan 140 mg/m 2 followed by peripheral blood stem cell rescue. The treatment was well tolerated with no mortality and no unexpected morbidity. This treatment modality was effective in controlling the underlying plasma cell dyscrasia and light chain production as six patients achieved complete hematologic remission (CR, by EORTC criteria) post-transplantation and remain in CR after a median follow up of 18.6 months (2.9 to 64.8 months). One patient achieved partial remission (PR). The median progression free survival has not been reached but the patient with a PR had progression of his MM and is currently receiving second-line therapy. Among the 4 patients who were dialysis independent at the time of HDC/ASCT, the renal function has improved compared to pre-HDC/ASCT in 2, remained stable in 1 (who achieved hematologic PR), and worsened in 1 leading to hemodialysis despite hematologic CR. Among the three patients who were dependent on hemodialysis at the time of HDC/ASCT, 2 have undergone kidney transplantation 14.1 and 45.7 months after HDC/ASCT and have a normal creatinine clearance 30.9 and 64.8 months after HDC/ASCT, respectively. The third patient remains in hematologic CR but has resumed peritoneal dialysis after a two-month-period of dialysis independence post-HDC/ASCT. He is currently being evaluated for kidney transplantation. Conclusions: Our results corroborate previous encouraging but limited experience with HDC/ASCT in MIDD and compare favorably with historical reports of conventional therapy in this patient population. These results also argue in favor of kidney transplantation in patients who achieve a hematologic CR after HDC/ASCT for MM associated with MIDD.
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renal monoclonal Immunoglobulin Deposition disease midd the columbia experience
2003Co-Authors: Glen S Markowitz, Anthony M Valeri, Neeraja Kambham, William H Sherman, Gerald B Appel, Vivette D DagatiAbstract:Renal manifestations of plasma cell dyscrasia are diverse and include AL amyloidosis, myeloma cast nephropathy, monoclonal Immunoglobulin Deposition disease, light chain Fanconi syndrome, cryoglobulinemic glomerulonephritis, and renal infiltration by lymphoplasmacytic malignancies. The non-amyloidotic monoclonal Immunoglobulin Deposition diseases (MIDD) are a family of related disorders that share the clinical-pathologic features of nodular sclerosing glomerulopathy, nephrotic proteinuria, and renal insufficiency1. These entities are defined by the Deposition within renal basement membranes of monoclonal light and/or heavy chains, producing a characteristic linear immunofluorescence pattern in all renal compartments. The three subtypes of MIDD include light chain (LCDD)2–4, light and heavy chain (LHCDD)5–6, and heavy chain Deposition diseases (HCDD)7–10. LCDD comprises the vast majority of cases, with relatively few examples of LHCDD and HCDD11. The lower reported incidence of LHCDD and HCDD may depend to some extent on the pathologist’s familiarity with these entities and the diagnostic accuracy of the pathologic interpretation. Over 80% of LCDD manifest renal deposits of k light chain. Cases of HCDD have included examples of γ1, γ2, γ3, γ4 and α-heavy chain subtypes7–10,12. In all the cases of HCDD reported to date there is a common deletion of the CHI constant domain of the γ heavy chain13,14.
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renal monoclonal Immunoglobulin Deposition disease the disease spectrum
Journal of The American Society of Nephrology, 2001Co-Authors: Glen S Markowitz, Anthony M Valeri, Neeraja Kambham, William H Sherman, Gerald B Appel, Vivette D DagatiAbstract:This study reports the clinicopathologic findings and outcome in 34 patients with renal monoclonal Immunoglobulin Deposition disease (MIDD), which included 23 light-chain DD (LCDD), 5 light- and heavy-chain DD (LHCDD), and 6 heavy- chain DD (HCDD). A total of 23 patients had pure MIDD, whereas 11 patients had LCDD with coexistent myeloma cast nephropathy (LCDD & MCN). Renal biopsy diagnosis pre- ceded clinical evidence of dysproteinemia in 68% of all cases. By immunofluorescence, the composition of deposits included 11k/1l (LCDD), 3IgGk/2IgGl (LHCDD), 5g/1a (HCDD), and 10k/1l (LCDD & MCN). Patients with pure MIDD pre- sented with mean serum creatinine of 4.2 mg/dl, nephrotic proteinuria, and hypertension. Cases of HCDD were associated with a CH1 deletion and frequently had hypocomplementemia and a positive hepatitis C virus antibody but negative hepatitis C virus PCR. LCDD & MCN is a morphologically and clini- cally distinct entity from pure MIDD, presenting with higher creatinine (mean, 7.8 mg/dl; P 5 0.01), greater dialysis depen- dence (64 versus 26%; P 5 0.053), subnephrotic proteinuria, and less nodular glomerulopathy (18 versus 100%; P , 0.0001). Multiple myeloma was more frequently diagnosed in LCDD & MCN than in pure MIDD (91 versus 31%; P 5 0.025). Renal and patient survivals were significantly worse in patients with LCDD & MCN (mean, 4 and 22 mo, respective- ly), compared with patients with pure MIDD (mean, 22 and 54 mo). Chemotherapy stabilized or improved renal function in 10 of 15 patients (67%) with pure MIDD who presented with creatinine of ,5.0 mg/dl, emphasizing the importance of early detection. On multivariate analysis, initial creatinine was the only predictor of renal and patient survival in pure MIDD, underscoring the prognostic significance of the renal involvement.
Michel Cogne - One of the best experts on this subject based on the ideXlab platform.
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Animal models of monoclonal Immunoglobulin-related renal diseases
Nature Reviews Nephrology, 2018Co-Authors: Christophe Sirac, Vincent Javaugue, Sebastien Bender, Guillermo A. Herrera, Paul W. Sanders, Vecihi Batuman, Maria Victoria Ayala, Jiamin Teng, Elba A. Turbat-herrera, Michel CogneAbstract:Monoclonal Immunoglobulin Deposition produces complex diseases with heterogeneous phenotypes, making it difficult to identify the underlying mechanisms of Immunoglobulin aggregation and Deposition. In this Review, the authors discuss animal models of various human Immunoglobulin Deposition diseases, and each model's drawbacks and contributions to our understanding of these diseases. The renal Deposition of monoclonal Immunoglobulins can cause severe renal complications in patients with B cell and plasma cell lymphoproliferative disorders. The overproduction of a structurally unique Immunoglobulin can contribute to the abnormal propensity of monoclonal Immunoglobulins to aggregate and deposit in specific organs. A wide range of renal diseases can occur in multiple myeloma or monoclonal gammopathy of renal significance, including tubular and glomerular disorders with organized or unorganized Immunoglobulin deposits. The development of reliable experimental models is challenging owing to the inherent variability of Immunoglobulins and the heterogeneity of the pathologies they produce. However, although imperfect, animal models are invaluable tools to understand the molecular pathogenesis of these diseases, and advances in creating genetically modified animals might provide novel approaches to evaluate innovative therapeutic interventions. We discuss the strategies employed to reproduce human monoclonal Immunoglobulin-induced kidney lesions in animal models, and we highlight their advantages and shortcomings. We also discuss how these models have affected the management of these Deposition diseases and might do so in the future. Finally, we discuss hypotheses that explain some limitations of the various models, and how these models might improve our understanding of other nephropathies without Immunoglobulin involvement that have similar pathogenic mechanisms. Numerous renal diseases occur owing to the Deposition of a monoclonal Immunoglobulin, including multiple myeloma and monoclonal gammopathy of renal significance Understanding the molecular pathogenesis of human Immunoglobulin Deposition diseases and testing new therapeutic strategies requires relevant animal models, which is a challenge owing to the heterogeneity of these diseases Models based on the injection of purified human Immunoglobulins and on tumour grafts that produce the monoclonal Immunoglobulin have revealed several early pathogenic events in Immunoglobulin Deposition and demonstrated the efficacy of innovative therapeutic agents Advances in transgenic techniques have allowed the creation of mouse models that faithfully reproduce the human diseases and have aided in unravelling the pathogenic mechanisms of monoclonal Immunoglobulin Deposition Animal models are invaluable tools to study the process of Deposition and to explore the direct toxicity of monoclonal Immunoglobulins in tissues and Immunoglobulin-producing plasma cells
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Animal models of monoclonal Immunoglobulin-related renal diseases
Nature Reviews Nephrology, 2018Co-Authors: Christophe Sirac, Vincent Javaugue, Sebastien Bender, Guillermo A. Herrera, Paul W. Sanders, Vecihi Batuman, Maria Victoria Ayala, Jiamin Teng, Elba A. Turbat-herrera, Michel CogneAbstract:Monoclonal Immunoglobulin Deposition produces complex diseases with heterogeneous phenotypes, making it difficult to identify the underlying mechanisms of Immunoglobulin aggregation and Deposition. In this Review, the authors discuss animal models of various human Immunoglobulin Deposition diseases, and each model's drawbacks and contributions to our understanding of these diseases.
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monoclonal Immunoglobulin Deposition disease a review of Immunoglobulin chain alterations
International Journal of Immunopharmacology, 1994Co-Authors: J L Preudhomme, Pierre Aucouturier, G Touchard, Amhed Amine Khamlichi, Anna Rocca, Luc Denoroy, Michel CogneAbstract:Abstract Monoclonal Immunoglobulin Deposition disease, a complication of overtly malignant or apparently benign immunoproliferative disorders, is a severe disease featuring tissue Deposition of monoclonal light, light and heavy, or heavy chains. A number of converging arguments strongly suggest a direct pathogenetic role of structural abnormalities or peculiarities of variable regions of light and/or heavy chains (associated with deletions in the constant region for the heavy chains). Recent structural data on these abnormal Immunoglobulin chains are reviewed.
Vaishali Sanchorawala - One of the best experts on this subject based on the ideXlab platform.
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high dose melphalan and stem cell transplantation in patients on dialysis due to Immunoglobulin light chain amyloidosis and monoclonal Immunoglobulin Deposition disease
Biology of Blood and Marrow Transplantation, 2018Co-Authors: Felipe Batalini, Laura Econimo, Karen Quillen, Mark J Sloan, Shayna Sarosiek, Dina Brauneis, Andrea Havasi, Lauren Stern, Laura M Dember, Vaishali SanchorawalaAbstract:The kidney is the most common organ affected by Immunoglobulin light-chain (AL) amyloidosis and monoclonal Immunoglobulin Deposition disease (MIDD), often leading to end-stage renal disease (ESRD). High-dose melphalan and stem cell transplantation (HDM/SCT) is effective for selected patients with AL amyloidosis, with high rates of complete hematologic response and potential for improved organ dysfunction. Data on tolerability and response to HDM/SCT in patients with ESRD due to AL amyloidosis and MIDD are limited. We analyzed data on toxicity, efficacy, and hematologic and renal response of HDM/SCT in 32 patients with AL amyloidosis and 4 patients with MIDD who were dialysis-dependent for ESRD treated at Boston Medical Center between 1994 and 2016. The most common grade 3/4 nonhematologic toxicities were infections (75%), metabolic abnormalities (56%), mucositis (42%), constitutional symptoms (39%), pulmonary complications (39%), and diarrhea (28%). Treatment related mortality (defined as death within 100 days of SCT) occurred in 8% (3 of 36). A complete hematologic response was achieved in 70% of evaluable patients (19 of 27) at 1 year after HDM/SCT. In the entire cohort, median overall survival (OS) after HDM/SCT was 5.8 years; median OS was 1 year for those who did not achieve a complete hematologic response and 8 years for those who did achieve a complete hematologic response. Twelve patients (33%) underwent kidney transplantation after successful treatment with HDM/SCT at a median of 2.4 years after SCT. HDM/SCT is safe and effective in inducing hematologic complete responses and prolonging survival in patients with ESRD from AL amyloidosis and MIDD. Achievement of a durable hematologic response can make these patients possible candidates for renal transplantation.
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high dose melphalan and autologous stem cell transplantation in al amyloidosis and monoclonal Immunoglobulin Deposition disease associated end stage renal disease requiring dialysis
Blood, 2010Co-Authors: Vaishali Sanchorawala, Karen Quillen, Mark J Sloan, Laura M Dember, Kathleen T Finn, Nancy T Andrea, Adam Segal, Gheorghe Doros, Martha Skinner, David C SeldinAbstract:Abstract 3553 Treatment of AL amyloidosis (AL) and monoclonal Immunoglobulin Deposition disease (MIDD) with high dose melphalan and autologous stem cell transplant (HDM/SCT) offers a high rate of durable complete hematologic responses and leads to clinical responses and improvement in survival. The development of end-stage renal disease (ESRD) is common among patients with AL amyloidosis and MIDD-associated renal disease leading to requirement for renal replacement therapy. Because of toxicity associated with HDM/SCT, there has been concern about its safety in patients with ESRD Therefore the role of HDM/SCT for patients with renal insufficiency has been called into question. Here we report on standard operating procedure, toxicities, hematologic responses and survival of patients with ESRD treated with HDM/SCT for AL amyloidosis and MIDD. Between 7/1994 and 6/2010, 32 patients with AL amyloidosis and 4 patients with MIDD associated ESRD were treated with HDM/SCT. The median age was 53 (range, 28–68). There were 21 (58%) males and 18 (50%) with kappa clonal plasma cell dyscrasia. Organ involvement distribution was typical for this disease: 75% patients (n=27) had 2 or more organs involved; 25% (n=9) had only renal involvement and 28% (n=10) had symptomatic cardiac involvement. The median duration of dialysis-dependence prior to HDM/SCT was 3.4 months and the median time from diagnosis to HDM/SCT was 6.5 months. Peripheral blood stem cells were mobilized using G-CSF alone at 10–16 m/kg/day for 3–4 days. Melphalan was administered intravenously in divided doses on 2 consecutive days. Oral cryotherapy was administered during and 15 minutes before and after infusion of melphalan since 2/2002 to reduce the incidence and severity of mucositis. The total dose of melphalan ranged from 100–200 mg/m2, depending on age, severity of cardiac disease and performance status. Stem cells were infused 24–72 hours after completion of melphalan. Hemodialysis patients were dialyzed according to the patient9s usual schedule but with an interval of at least 2 hours between the administration of melphalan or infusion of stem cells and the initiation of hemodialysis. An extra session of hemodialysis was performed either on the second day of melphalan infusion and/or the day of stem cell infusion. Peritoneal dialysis exchanges were performed according to the patient9s usual schedule. Antimicrobial prophylaxis with an oral quinolone, acyclovir and fluconazole was started on D + 1. Five patients received peritoneal dialysis and the remainder received hemodialysis. Thirty-one % (n=11) received 200 mg/m2 HDM, 47% (n=17) 140 mg/m2 HDM and 22% (n=8) 100 mg/m2 HDM. Treatment-related mortality, defined as deaths within 100 days of SCT, occurred in 6% (n=2/36). There were no deaths during stem cell mobilization and collection or stem cell infusion. There were additional 7 deaths (19%) during the first year after HDM/SCT. Hematologic response was assessed at 1 year following HDM/SCT. Hematologic complete response (CR) was defined as absence of monoclonal gammopathy by serum and urine by IFE, absence of clonal plasma cells in the bone marrow, and normalization of serum free light chain concentration and ratio since 2003. CR occurred in 70% (n=19) of 27 surviving patients at 1 year following HDM/SCT. The median time to neutrophil and platelet engraftment was 10 and 14 days, respectively. The median number of red cell and platelet transfusion was 4 units and 6 packs, respectively. Thirteen (36%) patients developed grade 3 or 4 mucositis. Of note, 45% (n=10/22) developed grade 3 or 4 mucositis before institution of oral cryotherapy compared to 14% (n=2/14) after its initiation (p=0.07). The median survival for the entire group of 36 patients is 64 months (5.3 years) from the time of SCT. The median survival is 62 months from the time of initiation of dialysis. The median survival is 74 months (6.1 years) for the patients achieving a CR compared to 38 months (3.1 years) for those not achieving a CR (p=0.439). Nine patients with hematologic CR have either undergone or are awaiting renal transplantation. In conclusion, HDM/SCT is an effective treatment in selected patients with AL amyloidosis or MIDD associated ESRD with treatment-related morbidity and mortality and outcomes similar to those for non-dialysis patients. Disclosures: No relevant conflicts of interest to declare.
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long term results of high dose melphalan and autologous stem cell transplantation in non amyloid monoclonal Immunoglobulin Deposition disorders
Blood, 2009Co-Authors: Saulius Girnius, Karen Quillen, David C Seldin, Kathleen T Finn, Nancy T Andrea, John Mark Sloan, Vaishali SanchorawalaAbstract:Abstract 4356 Monoclonal Immunoglobulin Deposition Disorder (MIDD) is a plasma cell dyscrasia in which whole Immunoglobulins or heavy or light chain subunits form non-fibrillar deposits in various tissues, causing organ dysfunction. Several studies have previously reported that high dose melphalan and autologous stem cell transplantation (HDM/SCT) is safe and effective at achieving a complete hematologic response in this disease, but long term data is sparse. Hematological complete response is defined as normalization of serum free light chain ratio and concentration, bone marrow exam with less than 5% plasma cells, and absence of monoclonal gammopathy in serum and urine by immunofixation electrophoresis. Between 2003 and 2008, ten patients with MIDD were treated with HDM/SCT at a dose of 200mg/m 2 (n=6) or 100-140 mg/m 2 (n=4) depending upon age and clinical status and were assessed for hematologic responses and improvements in organ function at 3-6 and 12 months, and annually thereafter. The median age was 45 years (range, 34 to 70); all but one patient were male. Six patients had kappa clonal predominance and four patients had lambda clonal predominance. All ten patients had renal involvement, two were on dialysis and one had undergone a renal transplant. Two patients also had extrarenal manifestations with cardiac involvement. The median creatinine clearance was 26 mL/min (range 20 to 100) and the median 24 hour urine total protein excretion was 4,037 mg (range, 458 to 15,632). Peripheral blood stem cells were collected after GCSF mobilization and a median of 6.9 ×10 6 CD34cells/kg were collected. There was no treatment related mortality within 100 days of SCT. One patient developed end stage renal disease during the peri-transplant period. Of the seven patients who have had follow-up of at least a year, five (71%) achieved a complete hematological response (CR) and two (29%) had a partial hematological response. One patient died six months after HDM/SCT due to progressive disease. Clinical and organ responses were also evident after HDM/SCT in 5 out of 7 patients. The median creatinine clearance was 42 mL/min (range, 38-55) and the median 24 hour urine total protein excretion was 179 mg (range, 150 to 349) at 2 years after treatment. Of the five patients with hematologic CR, 3 (60%) have relapsed at a median of 3 years (range, 2-3). Two of the 5 patients continue to have hematologic CRs at four and six years after HDM/SCT. In summary, HDM/SCT in MIDD often results in hematological CRs, as well as an improvement in renal function. However, the 5-year relapse rate is high. This group of patients may benefit from maintenance anti-plasma cell therapy. Disclosures: No relevant conflicts of interest to declare.
Vincent Javaugue - One of the best experts on this subject based on the ideXlab platform.
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randall type monoclonal Immunoglobulin Deposition disease novel insights from a nationwide cohort study
Blood, 2019Co-Authors: Florent Joly, Camille Cohen, Vincent Javaugue, Sebastien Bender, Mohamed Belmouaz, Bertrand Arnulf, Bertrand Knebelmann, M Nouvier, Vincent Audard, Francois ProvotAbstract:Monoclonal Immunoglobulin Deposition disease (MIDD) is a rare complication of B-cell clonal disorders, defined by Congo red negative–deposits of monoclonal light chain (LCDD), heavy chain (HCDD), or both (LHCDD). MIDD is a systemic disorder with prominent renal involvement, but little attention has been paid to the description of extrarenal manifestations. Moreover, mechanisms of pathogenic Immunoglobulin Deposition and factors associated with renal and patient survival are ill defined. We retrospectively studied a nationwide cohort of 255 patients, with biopsy-proven LCDD (n = 212) (including pure LCDD [n = 154], LCDD with cast nephropathy (CN) [n = 58]), HCDD (n = 23), or LHCDD (n = 20). Hematological diagnosis was monoclonal gammopathy of renal significance in 64% and symptomatic myeloma in 34%. Renal presentation was acute kidney injury in patients with LCCD and CN, and chronic glomerular disease in the other types, 35% of whom had symptomatic extrarenal (mostly hepatic and cardiac) involvement. Sequencing of 18 pathogenic LC showed high isoelectric point values of variable domain complementarity determining regions, possibly accounting for tissue Deposition. Among 169 patients who received chemotherapy (bortezomib-based in 58%), 67% achieved serum free light chain (FLC) response, including very good partial response (VGPR) or above in 52%. Renal response occurred in 62 patients (36%), all of whom had achieved hematological response. FLC response ≥ VGPR and absence of severe interstitial fibrosis were independent predictors of renal response. This study highlights an unexpected frequency of extrarenal manifestations in MIDD. Rapid diagnosis and achievement of deep FLC response are key factors of prognosis.
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Animal models of monoclonal Immunoglobulin-related renal diseases
Nature Reviews Nephrology, 2018Co-Authors: Christophe Sirac, Vincent Javaugue, Sebastien Bender, Guillermo A. Herrera, Paul W. Sanders, Vecihi Batuman, Maria Victoria Ayala, Jiamin Teng, Elba A. Turbat-herrera, Michel CogneAbstract:Monoclonal Immunoglobulin Deposition produces complex diseases with heterogeneous phenotypes, making it difficult to identify the underlying mechanisms of Immunoglobulin aggregation and Deposition. In this Review, the authors discuss animal models of various human Immunoglobulin Deposition diseases, and each model's drawbacks and contributions to our understanding of these diseases. The renal Deposition of monoclonal Immunoglobulins can cause severe renal complications in patients with B cell and plasma cell lymphoproliferative disorders. The overproduction of a structurally unique Immunoglobulin can contribute to the abnormal propensity of monoclonal Immunoglobulins to aggregate and deposit in specific organs. A wide range of renal diseases can occur in multiple myeloma or monoclonal gammopathy of renal significance, including tubular and glomerular disorders with organized or unorganized Immunoglobulin deposits. The development of reliable experimental models is challenging owing to the inherent variability of Immunoglobulins and the heterogeneity of the pathologies they produce. However, although imperfect, animal models are invaluable tools to understand the molecular pathogenesis of these diseases, and advances in creating genetically modified animals might provide novel approaches to evaluate innovative therapeutic interventions. We discuss the strategies employed to reproduce human monoclonal Immunoglobulin-induced kidney lesions in animal models, and we highlight their advantages and shortcomings. We also discuss how these models have affected the management of these Deposition diseases and might do so in the future. Finally, we discuss hypotheses that explain some limitations of the various models, and how these models might improve our understanding of other nephropathies without Immunoglobulin involvement that have similar pathogenic mechanisms. Numerous renal diseases occur owing to the Deposition of a monoclonal Immunoglobulin, including multiple myeloma and monoclonal gammopathy of renal significance Understanding the molecular pathogenesis of human Immunoglobulin Deposition diseases and testing new therapeutic strategies requires relevant animal models, which is a challenge owing to the heterogeneity of these diseases Models based on the injection of purified human Immunoglobulins and on tumour grafts that produce the monoclonal Immunoglobulin have revealed several early pathogenic events in Immunoglobulin Deposition and demonstrated the efficacy of innovative therapeutic agents Advances in transgenic techniques have allowed the creation of mouse models that faithfully reproduce the human diseases and have aided in unravelling the pathogenic mechanisms of monoclonal Immunoglobulin Deposition Animal models are invaluable tools to study the process of Deposition and to explore the direct toxicity of monoclonal Immunoglobulins in tissues and Immunoglobulin-producing plasma cells
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Animal models of monoclonal Immunoglobulin-related renal diseases
Nature Reviews Nephrology, 2018Co-Authors: Christophe Sirac, Vincent Javaugue, Sebastien Bender, Guillermo A. Herrera, Paul W. Sanders, Vecihi Batuman, Maria Victoria Ayala, Jiamin Teng, Elba A. Turbat-herrera, Michel CogneAbstract:Monoclonal Immunoglobulin Deposition produces complex diseases with heterogeneous phenotypes, making it difficult to identify the underlying mechanisms of Immunoglobulin aggregation and Deposition. In this Review, the authors discuss animal models of various human Immunoglobulin Deposition diseases, and each model's drawbacks and contributions to our understanding of these diseases.
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bortezomib produces high hematological response rates with prolonged renal survival in monoclonal Immunoglobulin Deposition disease
Kidney International, 2015Co-Authors: Camille Cohen, Vincent Javaugue, Bertrand Knebelmann, Bruno Royer, Raphael Szalat, Khalil El Karoui, Alexis Caulier, Arnaud Jaccard, Sylvie Chevret, G TouchardAbstract:Monoclonal Immunoglobulin Deposition disease (MIDD) is a rare complication of plasma cell disorders, defined by linear Congo red-negative deposits of monoclonal light chain, heavy chain, or both along basement membranes. While renal involvement is prominent, treatment strategies, such as the impact of novel anti-myeloma agents, remain poorly defined. Here we retrospectively studied 49 patients with MIDD who received a median of 4.5 cycles of intravenous bortezomib plus dexamethasone. Of these, 25 received no additional treatment, 18 also received cyclophosphamide, while 6 also received thalidomide or lenalidomide. The hematological diagnoses identified 38 patients with monoclonal gammopathy of renal significance, 10 with symptomatic multiple myeloma, and 1 with Waldenstrom macroglobulinemia. The overall hematologic response rate, based on the difference between involved and uninvolved serum-free light chains (dFLCs), was 91%. After median follow-up of 54 months, 5 patients died and 10 had reached end-stage renal disease. Renal response was achieved in 26 patients, with a 35% increase in median eGFR and an 86% decrease in median 24-h proteinuria. Predictive factors were pre-treatment eGFR over 30ml/min per 1.73m 2 and posttreatment dFLC under 40mg/l; the latter was the sole predictive factor of renal response by multivariable analysis. Thus, bortezomib-based therapy is a promising treatment strategy in MIDD, mainly when used early in the disease course. dFLC response is a favorable prognostic factor for renal survival.
Joel N. Buxbaum - One of the best experts on this subject based on the ideXlab platform.
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nonamyloidotic monoclonal Immunoglobulin Deposition disease light chain heavy chain and light and heavy chain Deposition diseases
Hematology-oncology Clinics of North America, 1999Co-Authors: Joel N. Buxbaum, Gloria GalloAbstract:B-cell proliferative disorders may display their pathogenic effects by increased cell numbers, increased concentrations of the molecules produced by those cells, or both. Immunoglobulins, a major secretory product of terminally differentiated B cells, are the mediators of specific forms of tissue pathology seen in multiple myeloma, occult plasma cell dyscrasias, Waldenstrom's disease, and chronic lymphocytic leukemia. Intact monoclonal Immunoglobulins, by virtue of their properties as antibodies, can have autospecificity with either immune complex or direct tissue damage. They can also self-aggregate to produce syndromes associated with hyperviscosity. When only light chains are produced, or when the light chains produced are greater than the amount of heavy chain synthesized by the expanded clone, or, less commonly, when some forms of truncated heavy chain are secreted, three forms of tissue damage have been described. All have the kidney as a major target organ. 45 In myeloma kidney light chains become insoluble in the renal tubular lumen, forming dense casts (Bence Jones cast nephropathy [BJCN]). Its occurrence is a function of both plasma cell load and the physicochemical properties of the specific light chain, requiring both large amounts of the protein and a tendency to aggregate under the conditions of concentration and pH achievable in the human nephron. The property appears to be independent of light-chain class. In primary amyloidosis (AL) and heavy-chain amyloidosis (AH) light chains or their fragments (most commonly of the λ class) or truncated heavy chains form fibrillar, Congo red–binding deposits in many tissues which ultimately result in organ compromise. The more recently recognized form of light-chain Deposition, light-chain Deposition disease (LCDD), is characterized by Deposition of non-Congophilic material which appears amorphous with conventional histologic methods. It is detected by its reactivity with specific anti-Immunoglobulin light-chain (usually anti κ) antisera. 41 The original definition of Immunoglobulin light chains as the precursor of both amyloid and LCDD forms of tissue Deposition has been expanded with the recognition that some heavy chains with domain deletions can produce amyloidosis (designated as AH) and that the non-Congophilic tissue deposits may be comprised of Immunoglobulin heavy-chain fragments as a major component (light-and-heavy-chain Deposition disease [LHCDD]) or as a sole component (heavy-chain Deposition disease [HCDD]). To encompass all the identified forms of monoclonal Immunoglobulin-related tissue Deposition under a single rubric, the designation monoclonal Immunoglobulin Deposition disease (MIDD) has been suggested, 3 with AL, AH, LCDD, LHCDD and HCDD as subtypes, and with the deposits further defined on the basis of the class of Immunoglobulin polypeptide involved and its ultrastructure. It has been argued that, if the basic mechanisms governing tissue Deposition in amyloid and nonamyloid MIDD (NAMIDD) are different, grouping them together is inappropriate. 40 If, however, the two forms of deposits represent different aspects of the same pathogenetic process resulting from the production of the same protein during the course of a monoclonal B-cell expansion, such a classification is appropriate. At present, the issue is unsettled, although the authors believe that current data favor a unimodal process with variations. Primary amyloidosis and LCDD appear to be more dependent than myeloma kidney on the particular structure of the light chain, because AL and LCDD occur both in the presence and in the absence of clinical myeloma. 2 In autopsy and in clinical series of consecutive patients with multiple myeloma, 11% to 20% of patients display tissue amyloid Deposition. 25,31,35 Conversely, data from many centers indicate that only 20% of all AL patients have myeloma at the time of presentation. 31 Although there are fewer studies in which the incidence of LCDD in myeloma has been determined, the best estimates indicate that 5% to 10% of myeloma patients have LCDD. 25,35 Review of the first 150 reported cases of well-documented NAMIDD suggests that myeloma was present in 50% to 60% of the cases; however, in many of these cases, the criteria used to establish the diagnosis of myeloma were not clearly stated. 4 It is possible that more limited forms of plasma cell dyscrasia, not fulfilling all the requirements for myeloma, were included. For example, studies from French investigators revealed that 20 of 26 patients were diagnosed as having myeloma at the time of presentation or developed the requisite diagnostic features over the 2-year period following recognition of the tissue deposits. 6 The latter observation suggests that some of these patients could have been classified as having smoldering myeloma. 32 Among the LCDD patients identified by renal biopsy and treated by the authors, 6 of 24 (25%) had a confirmed diagnosis of myeloma with nodular infiltrates in bone marrow biopsies at the time of identifiable tissue Deposition. All 6 patients with confirmed myeloma had typical BJCN accompanying the monoclonal light-chain Deposition. Fourteen of the remaining 18 individuals had nodular glomerulopathy with less aggressive plasma cell proliferative disease (10% or fewer bone marrow plasma cells) and a clinical and pathologic picture similar to that of AL. A similar distribution is suggested by data from the Mayo Clinic. 21 The authors believe that larger numbers of patients with nonamyloid monoclonal Immunoglobulin Deposition who have undergone complete immunohistologic analysis and clinical evaluation should be studied systematically to determine definitively whether there is a relationship between the pattern of renal involvement and the degree of plasma cell proliferative disease. This may be a significant issue with respect to prognosis and treatment because the authors have found that patients with LCDD, cast nephropathy, and myeloma have a shorter survival time than those with nodular glomerulopathy.
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mechanisms of disease monoclonal Immunoglobulin Deposition amyloidosis light chain Deposition disease and light and heavy chain Deposition disease
Hematology-oncology Clinics of North America, 1992Co-Authors: Joel N. BuxbaumAbstract:In addition to being a marker of disease, the homogeneous Immunoglobulins found in monoclonal plasma cell disorders may produce signs and symptoms related to the presence of increased amounts of a single protein with certain structural and functional characteristics. Monoclonal Immunoglobulin Deposition disease of either the amyloid or nonamyloid types may occur in the course of clinical myeloma or be associated with a more limited monoclonal proliferative disorder similar to that previously characterized as monoclonal gammopathy of uncertain significance (MGUS). Their occurrence in the setting of a limited clonal expression converts the outcome of the process from benign to fatal due to the Deposition of the clonal products in vital organs. The tendency to deposit appears to be a property of the chemical structure of the Ig polypeptide involved and the way it is processed, either in the course of its synthesis and secretion or during its passage through blood vessels and tissue parenchyma.
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Monoclonal Immunoglobulin Deposition Disease: Light Chain and Light and Heavy Chain Deposition Diseases and Their Relation to Light Chain Amyloidosis: Clinical Features, Immunopathology, and Molecular Analysis
Annals of Internal Medicine, 1990Co-Authors: Joel N. Buxbaum, Alan Solomon, Joseph V. Chuba, Gerard C. Hellman, Gloria GalloAbstract:Monoclonal Immunoglobulin Deposition occurs in tissues as Congo Red binding fibrils in light chain amyloidosis, as less structured deposits in light chain Deposition disease, and as similar but distinct deposits in light and heavy chain Deposition disease. The nonamyloid forms were found in 13 patients who had evidence of plasmacytic dyscrasia by the immunohistochemical detection of Immunoglobulin light chains of kappa or lambda class (with or without staining for a single heavy chain isotype) and by the absence of amyloid P component in tissue sections that did not show the birefringence characteristic of amyloid after Congo Red staining. All but two of the patients presented with proteinuria with or without azotemia. Clinical syndromes involving other organ systems were less common but occasionally severe. Four patients had overt multiple myeloma. Three others had hypercalcemia and mild bone marrow plasmacytosis but no lytic lesions. Analyses of Immunoglobulin synthesis in bone marrow cells from seven patients showed excess light chains in all and incomplete light chains or heavy chain fragments in six, regardless of whether an intact monoclonal protein or related subunit was in the serum or urine. The fibrillar (amyloidotic) and nonfibrillar forms of monoclonal Immunoglobulin Deposition occur either in overt multiple myeloma or in the course of less neoplastically aggressive plasmacytic dyscrasias. Bone marrow cells from patients with either type produce Immunoglobulin fragments that are related to those deposited in the affected tissues.
