Monoclonal Immunoglobulin Light Chains Research Articles

A review of recent clinical trials to evaluate disease-modifying therapies in the treatment of cardiac amyloidosis.

Cardiac amyloidosis (CA) is a serious condition that results in infiltrative cardiomyopathy and heart failure with preserved ejection fraction (HFpEF) that is caused by the extracellular deposition of amyloid fibrils within heart tissue. While many important features of CA have been known for years, its prevalence in elderly patients with HF is increasingly being recognized. Plasma cells produce monoclonal immunoglobulin light chains which results in the formation and aggregation of amyloid fibrils that are responsible for AL amyloidosis. CA is classified as originating from either transthyretin (ATTR) or light chain (AL) amyloidosis. ATTR CA may result from a genetic mutation in the TTR gene, which is inherited (ATTRv), or from age-related deposition from wild-type ATTR (ATTRwt). Cardiac involvement in AL amyloidosis is attributed to either of two mechanisms: the extracellular deposition of amyloid fibril in the myocardium, or direct cardiotoxicity from the fibril aggregates. Typing of amyloid fibrils, a critical determinant of therapy, has also improved with wider availability of laser capture and mass spectrometry of histologic specimens. Specific and accurate evaluation of CA is now possible using cardiac magnetic resonance imaging and bone scintigraphy tracers. Survival in CA has improved markedly as novel chemotherapy agents have become available, but challenges remain in advanced disease. Broadening the amyloid-specific therapeutic landscape to include RNA inhibitors, fibril formation stabilizers and inhibitors, and immunotherapeutic targeting of amyloid deposits holds promise and may improve outcomes in systemic and cardiac amyloidoses. Treatment strategies for CA has recently undergone transformative changes, leading to some progress in outcomes for certain patients. Here, we discuss the basic features of CA as well as the emergence of novel, disease-modifying strategies that have been recently evaluated in clinical trials for the treatment of CA.

Cardiac transthyretin amyloidosis in patients with conduction system disease

Abstract Background/Introduction Cardiac amyloidosis (CA) is characterized by extracellular deposition of misfolded proteins in the heart. The data suggest that cardiac amyloidosis is underappreciated as a cause of common cardiac diseases or syndromes. More than 98% of currently diagnosed cardiac amyloidosis result from fibrils consisting of monoclonal immunoglobulin light chains (AL) or transthyretin (ATTR). The natural history of ATTR cardiomyopathy commonly includes both the conduction system disease and arrhythmias, which may occur years before the onset of heart failure. Conduction abnormalities are commonly encountered among patients with CA and constitute an important cause of morbidity and mortality. Most reports agree that pacemakers are most common in wild type ATTR-CA, followed by hereditary ATTR-CA and, finally, AL-CA. Purpose As unexplained LV wall thickness ≥ 12 mm is a screening sign of possible cardiac ATTR, systematicscreening for CA in patients requiring permanent pacemakers with unexplained LV wall thickness of ≥ 12 mm seems to be rational and could possibly lead to early diagnosis of cardiac ATTR. To the best of our knowledge, the usefulness of such screening has not been investigated before. This project, therefore, aims to determine the prevalence of cardiac ATTR and its subtypes in this preselected group, and to propose the most suitable battery of diagnostic procedures for this purpose. Methods Population to be tested: Consecutive patients ≥50 years referred for permanent pacemaker implantation with unexplained LV wall thickness ≥12 mm determined by echocardiography. The research protocol was that of an open-label prospective study. Biochemistry samples including serum troponin I and NT-proBNP were collected before pacemaker implantation. All patients were screened for ATTR-CA according to the recommendations of the Position statement of the ESC Working group on myocardial and pericardial diseases. Tc-DPD scintigraphy scan served as a gold standard for determining the diagnosis of cardiac ATTR. Results Out of 100 consecutive patients meeting inclusion criteria, 15 % suffered from amyloidosis (12 patients were diagnosed with ATTR and 3 with AL cardiac amyloidosis). Table 1 shows a variety of parameters, many of which differed between patient groups with and without amyloidosis, confirming the wide range of parameters significantly associated with cardiac amyloidosis; our ongoing research in this field could lead to the development of a scoring system for detection of cardiac amyloidosis. Conclusions The prevalence of cardiac amyloidosis in the investigated group was 15 %. Systematic screening for ATTR in patients with unexplained LV wall thickness ≥ 12 mm requiring permanent pacemaker implantation seems to be rational and could possibly lead to an earlier diagnosis of cardiac amyloidosis, especially ATTR.

Improving early mortality risk detection in light-chain cardiac amyloidosis patients with routine echocardiographic indicators and mayo staging

Abstract Background Light-chain cardiac amyloidosis (AL-CA) is a fatal cardiomyopathy caused by the deposition of monoclonal immunoglobulin light-chain in the cardiac fibers, conduction system, valves, and other parts of the heart. The Mayo 2004 staging system is widely used to assess the prognosis of AL-CA. Those in the highest-risk categories, Mayo 2004 stage IIIb, exhibit extremely poor responses to conventional treatment regimens, resulting in high early mortality rates. However, within the same stage, prognostic outcomes among patients can still vary significantly. Hence, a more detailed stratification of high-risk patients is crucial for pinpointing those at extreme risk. Objective To investigate whether conventional echocardiographic measurements can enhance the identification of high-risk patients with early mortality in AL-CA on the basis of existing risk stratification. Methods Continuous enrollment of patients diagnosed with AL-CA at our center from May 2020 to December 2022. Clinical data, echocardiography, and follow-up results of the patients were collected. Logistic regression analyses were used to identify risk factors for early mortality, with risk factor thresholds calculated using Receiver Operating Characteristic (ROC) curves. Kaplan-Meier survival analysis was employed to assess endpoint events. The diagnostic efficacy of the model was evaluated using the area under the ROC curve and the Integrated Discrimination Improvement (IDI). Results A total of 76 patients were included with an average age of 59±10 years. Among them, 51 were male (67.1%). The median follow-up duration was 10 months (ranging from 5 to 20 months). Early mortality, defined as death within 6 months, occurred in 20 patients (26.3%). Twenty-three patients were categorized under the Mayo 2004 stage IIIb (30.3%). The 6-month mortality rate for patients in the Mayo 2004 stage IIIb was 56.5%. The sensitivity of early diastolic transmitral flow velocity to early diastolic mitral annular tissue velocity ratio divided left ventricular ejection fraction [(E/e’) /LVEF] in predicting early mortality in patients with AL-CA is 63%, and the specificity is 92%.When compared to the Mayo 2004 stage IIIb alone, (E/e')/LVEF≥0.5 combined with the Mayo 2004 stage IIIb had an area under the curve of 0.731 and 0.824, respectively, in the ROC curve. The IDI was 0.113 (95% CI: 0.013-0.213, P=0.026), representing an 11.3% enhancement in the predictive value of early mortality in AL-CA patients. Conclusion Routine echocardiography derived E/e' to LVEF ratio offered added prognostic value for early mortality beyond Mayo staging.Kaplan-Meier survival curve

Heart Failure with Preserved Ejection Fraction and Cardiac Amyloidosis in the Aging Heart.

Heart Failure with Preserved Ejection Fraction (HFpEF) is one of the most frequent causes of heart failure in the world's population (about 19-55%), and is commonly associated with a high rate of hospitalization (almost 70-80%) and with increased mortality (40-50% in a 5-year timeframe). The elderly are more often affected, with higher rates of hospitalizations than young people, and currently almost 70% of the population aged 65 years old has HFpEF. An increase in cardiomyocyte stiffness, thus resulting in diastolic dysfunction, increased filling pressures and heart failure with preserved ejection fraction are characteristics features of the disease. In addition, among the various causes of HFpEF, cardiac amyloidosis (CA) can provoke diastolic dysfunction and increased wall stiffness directly from intercellular deposition of insoluble proteic substances and their toxic activity. Totally, almost 30 different proteins are able to form deposits, but the most frequently involved are transthyretin and misfolded monoclonal immunoglobulin light chains, which bring to two clinical conditions called transthyretin amyloidosis (ATTR) and light-chain amyloidosis (AL). Although there has been increasing attention on ATTR-CA in recent years, the actual prevalence remains underestimated, especially in people of advanced age, as well as its real impact as a cause of HFpEF, and only data derived from autoptic exams are currently available. Moreover, CA itself often mimics HFpEF, and some conflicting data on the use of predictive scores are described in the literature. The close relationship between HFpEF and CA, especially in older population and the main pathophysiological mechanisms which bond these two conditions are described in this focused review. The need to screen red flags for ATTR-CA in elderly patients with HFpEF is urgently advised, because a prompt recognition of the disease can optimize the approach to the disease with an early therapeutic, life-saving choice.

Diagnostic Modalities in the Detection of Cardiac Amyloidosis.

Cardiac amyloidosis (CA) results mainly from the infiltration of the myocardium by either immunoglobulin light-chain fibrils (AL) or transthyretin fibrils (ATTR), causing restrictive cardiomyopathy and eventually death if untreated. AL derives from monoclonal immunoglobulin light chains produced by plasma cell clones in the bone marrow, while ATTR is the misfolded form of hepatically derived transthyretin (TTR) protein and can be hereditary (ATTRv) or wild-type (ATTRwt). Over the last decade, improvements in diagnostic imaging and better clinical awareness have unleashed a notable presence of CA in the community, especially ATTR in the elderly population. These multimodality imaging modalities include echocardiography, cardiac magnetic resonance, and radionuclide scintigraphy with bone-avid tracers. There has been remarkable progress in the therapeutic landscape as well, and there are disease-modifying therapies available now that can alter the course of the disease and improve survival if initiated at an early stage of the disease. There remains an unmet need for detecting this disease accurately and early so that these patients can benefit the most from newly emerging therapies.

Light-Chain Deposition Diseases of the CNS: Review of Pathogenesis, Imaging Features, and Radiographic Mimics.

Light-chain deposition disease (LCDD) is a rare CNS disorder characterized by the extracellular accumulation of monoclonal immunoglobulin light chains in various organs. LCDD typically arises secondary to an underlying plasma cell dyscrasia, such as monoclonal gammopathy of undetermined significance or multiple myeloma. However, rare cases can occur in the absence of a demonstrable plasma cell disorder. The kidneys, liver, lungs, and heart are the most affected organs. Intracerebral LCDD, particularly without an underlying plasma cell neoplasm, represents an exceedingly uncommon entity with limited documented cases in the literature. This review article explores the pathogenesis, histopathologic features, and characteristic neuroimaging findings of intracerebral LCDD. We emphasize the diverse imaging presentations of this disease, which can closely resemble other neurologic pathologies. Recognizing these potential mimics is crucial for avoiding misdiagnosis, especially in the absence of a known underlying plasma cell disorder. This article aims to provide a comprehensive overview from a neuroradiologic perspective, facilitating the recognition and differentiation of this challenging entity.

Outcomes of Modified Mayo Stage IIIa and IIIb Cardiac Light-Chain Amyloidosis: Real-World Experience in Clinical Characteristics and Treatment-67 Patients Multicenter Analysis.

Light-chain amyloidosis (AL) is a rare multisystem disorder characterized by the deposition of misfolded amyloid fibrils derived from monoclonal immunoglobulin light chains in various organs. One of the most common organs involved in AL is the heart, with 50-70% of patients clinically symptomatic at diagnosis. We conducted a multi-center, retrospective analysis of 67 patients diagnosed between July 2012 and August 2022 with the European 2012 modification of Mayo 2004 stage III cardiac AL. The most important factors identified in the univariate Cox analysis contributing to a longer OS included Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 1, New York Heart Association functional classification (NYHA FC) ≤ 2, the use of autologous stem cell transplantation (ASCT) after induction treatment, achieving a hematological response (≥very good partial response) and cardiac (≥partial response) response after first-line treatment. The most important prognostic factors with the most significant impact on OS improvement in patients with modified Mayo stage III cardiac AL identified by multivariate Cox analysis are ECOG PS ≤ 1, NYHA FC ≤ 2, and achieving hematological response ≥ VGPR and cardiac response ≥ PR after first-line treatment.

Cardiac Amyloidosis: A Contemporary Review of Medical and Surgical Therapy.

Amyloidosis is a systemic disease initiated by deposition of misfolded proteins in the extracellular space, due to which multiple organs may be affected concomitantly. Cardiac amyloidosis, however, remains a major cause of morbidity and mortality in this population due to infiltrative /restrictive cardiomyopathy. This review attempts to focus on contemporary medical and surgical therapies for the different types of cardiac amyloidosis. Amyloidosis affecting the heart are predominantly of the transthyretin type (acquired in the older or genetic in the younger patients), and the monoclonal immunoglobulin light chain (AL) type which is solely acquired. A rare form of secondary amyloidosis AA type can also affect the heart due to excessive production and accumulation of the acute-phase protein called Serum Amyloid A" (SAA) in the setting of chronic inflammation, cancers or autoinflammatory disease. More commonly AA amyloidosis is seen in the liver and kidney. Other rare types are Apo A1 and Isolated Atrial Amyloidosis (AANF). Medical therapies have made important strides in the clinical management of the two common types of cardiac amyloidosis. Surgical therapies such as mechanical circulatory support and cardiac transplantation should be considered in appropriate patients. Future research using AI driven algorithms for early diagnosis and treatment as well as development of newer genetic engineering technologies will drive improvements in diagnosis, treatment and patient outcomes.

Urine Immunofixation Electrophoresis for Diagnosis of Monoclonal Gammopathy: Evaluation of Methods for Urine Concentration.

Examination of urine by immunofixation electrophoresis (UIFE) is one of the tests recommended for screening and monitoring of monoclonal gammopathies, especially multiple myeloma. Unlike the serum free light chain measurement, a positive result on urine immunofixation is diagnostic for monoclonal immunoglobulin light chains. Urine is usually concentrated, generally by membrane filtration, prior to electrophoresis. Alternative methods to membrane filtration for urine concentration were examined. Residual urine specimens submitted for urine protein electrophoresis were concentrated by precipitation of the proteins by ammonium sulfate salt precipitation, precipitation with ethanol and acetonitrile, and by desiccation. The concentrated specimens were subjected to immunofixation electrophoresis using antisera to free light chains (FLC). The results were compared with those from conventional immunofixation electrophoresis using specimens concentrated by membrane filtration. Ammonium sulfate, ethanol, and acetonitrile precipitation results were less than satisfactory. Concentration by desiccation provided results comparable, if not better than, those by membrane filtration and conventional UIFE. The cost of desiccation is minimal compared to more than $5.00/specimen cost of concentration by membrane filtration. The differences in the results with conventional UIFE and the method described here are likely due to (a) variability in the reactivity of different antisera to free monoclonal light chains, and (b) obscuration of monoclonal free light chains by co-migration with intact immunoglobulin monoclonal proteins. Concentrating urine by desiccation for immunofixation electrophoresis is technically simple, inexpensive, and provides results comparable to concentrating by membrane filtration. Using FLC provides a more sensitive assay than using conventional antisera.

Amyloid Protein in AL-Amyloidosis. Natural History and Potential for Regression

Amyloid light chain amyloidosis is the most commonly seen form of systemic amyloidosis and is characterized by the accumulation of circulating monoclonal immunoglobulin light chain precursors arising from an abnormal clone of plasma cells. These light chain precursors demonstrate a propensity for misfolding, aggregation and deposition as highly stable fibrillar cross-linked beta sheets in various tissues and organs in a manner characteristic of other forms of systemic amyloidosis. There have been great advances in the treatment of the underlying plasma cell dyscrasia with improved long-term survival but the persistence of extracellular amyloid deposits in the tissues of vital organs, particularly the heart and kidney remains a significant cause of morbidity and mortality even in those patients in whom a hematological complete response has been achieved. This review focuses on the importance of early diagnosis and treatment on limiting the extent of amyloid protein accumulation and organ dysfunction and the current state of knowledge on the potential for resorption and clearance of these amyloid deposits in patients with amyloid light chain amyloidosis. The status of current novel anti-fibrillar agents is reviewed and future strategies for effectively intervening to improve organ function and survival these individuals is discussed.

Comparison of Renal Function before and after Autologous Stem Cell Transplantation in Egyptian Patients with Multiple Myeloma and Renal Insufficiency: A Retrospective Study.

Renal failure is a common feature of multiple myeloma (MM) that occurs in 20%-40% of newly diagnosed patients with MM and is the result of monoclonal immunoglobulin light chains. Many studies have examined the effect of autologous stem cell transplantation (ASCT) in MM patients with renal impairment and the safety of performing the transplantation in patients with renal failure. This study aimed to compare renal function before and after ASCT in Egyptian MM patients with renal insufficiency to evaluate the effect of ASCT on renal recovery. Our study included 31 MM patients with renal impairment out of 400 patients who met the criteria of the International Myeloma Working Group for symptomatic MM. The estimated glomerular filtration rate (eGFR) calculated by the Modification of Diet in Renal Disease formula was compared before and after the transplant. Only four patients (12.9%) were dependent on dialysis. Six of those with a history of hemodialysis (HD) who were either dependent on dialysis or dialyzed according to need achieved independence from HD. There was no significant correlation between the degree of renal impairment and the disease's status at the time of transplantation (P = 0.86). The study showed significant improvements in serum creatinine levels compared with its value before the transplant (P = 0.016) and in eGFR (P = 0.004). In total, 45% of patients achieved renal improvement, shown by a 25% increase in GFR above the baseline. There was a significant improvement of renal function after ASCT in MM patients with renal impairment.

Clinical characterization and outcomes of a cohort of colombian patients with AL Amyloidosis.

Amyloid light chain (AL) amyloidosis is characterized by amyloid fibril deposition derived from monoclonal immunoglobulin light chains, resulting in multiorgan dysfunction. Limited data exist on the clinical features of AL amyloidosis. This study aims to describe the clinical characteristics, treatments, and outcomes in Colombian patients with AL amyloidosis. A retrospective descriptive study was conducted at three high-complexity centers in Medellín, Colombia. Adults with AL amyloidosis diagnosed between 2012 and 2022 were included. Clinical, laboratory, histological, treatment, and survival data were analyzed. The study included 63 patients. Renal involvement was most prevalent (66%), followed by cardiac involvement (61%). Multiorgan involvement occurred in 61% of patients. Amyloid deposition was most commonly detected in renal biopsy (40%). Bortezomib-based therapy was used in 68%, and 23.8% received high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HDCT-ASCT). Hematological response was observed in 95% of patients with available data. Cardiac and renal organ responses were 15% and 14%, respectively. Median overall survival was 45.1 months (95% CI: 22.2-63.8). In multivariate analysis, cardiac involvement was significantly associated with inferior overall survival (HR 3.27; 95% CI: 1.23-8.73; p=0.018), HDCT-ASCT had a non-significant trend towards improved overall survival (HR 0.25; 95% CI: 0.06-1.09; p=0.065). In this study of Colombian patients with AL amyloidosis, renal involvement was more frequent than cardiac involvement. Overall survival and multiorgan involvement were consistent with data from other regions of the world. Multivariate analysis identified cardiac involvement and HDCT-AHCT as possible prognostic factors.

Outcomes Associated with Clone-Directed Therapies for Monoclonal Gammopathy of Renal Significance

Background: Monoclonal Gammopathy of Renal Significance (MGRS) is a category of diseases not meeting criteria for cancer, in which a clonal population of B-lymphoid or plasma cells produces a nephrotoxic protein leading to kidney injury. Informal consensus has arisen that therapy targeting the causal clone is most likely to be efficacious, and the primary goal of therapy is to prolong renal survival. Light chain (AL) amyloidosis has been extensively studied, yet there is a paucity of data describing outcomes associated with clone-directed therapy for the various subtypes of non-AL MGRS. Methods: This was a retrospective analysis of patients treated at two National Cancer Institute (NCI)-designated cancer centers in the United States. Medical records of adult patients seen between January 2010 and March 2023 were screened for MGRS. Patients were eligible if they had renal biopsy-confirmed histopathologic findings compatible with MGRS. AL amyloidosis was excluded. The primary outcome was renal survival, defined as time from diagnosis of MGRS to requiring renal replacement therapy (RRT) or renal transplant, with patients censored at last follow up or death. Baseline characteristics were described, including 24-hour proteinuria, estimated glomerular filtration rate (eGFR), whether a clonal population of B cells or plasma cells could be identified on histopathologic examination of marrow or lymph node biopsy, concentration of monoclonal protein, and involved serum free light chain concentration. Initial therapy was reported, although differences in outcomes across therapeutic strategies were not compared. Baseline clinical characteristics between patients who required RRT and those who did not were compared. Baseline clinical variables and time to RRT were compared across the two most common MGRS subtypes in the cohort: proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) and light chain deposition disease (LCDD). Continuous variables were compared across subgroups using Wilcoxon rank-sum test. Time-to-event outcomes were analyzed according to the Kaplan-Meier method. All analyses were conducted using R version 3.6.1. Results: In total, 65 patients were included, 23 (35%) of whom ultimately required RRT or transplant. Four patients died, all after RRT. Median baseline proteinuria was 2802 mg/24h (IQR 972.5 - 4492.0) and median eGFR was 33.0 mL/min (IQR 23 - 53) for the entire cohort. In all cases proteinuria was mostly albumin. Median baseline involved light chain concentration was 8.3 mg/dL (IQR 3.1 - 26.4). A majority of patients (n=33, 51%) had no identifiable serum monoclonal protein. The two most common MGRS subtypes were PGNMID (n = 26) followed by LCDD (n = 21). Clonal populations thought to be causing MGRS were identified in 41/64 patients (64%), including 37 (58%) with plasma cell clones, 1 (2%) with a lymphoplasmacytic lymphoma clone, and 3 (4.7%) with other B-cell clones. Clones were not identified in 23 (36%). The most common chemotherapy agents included bortezomib (n=42, 64%) and rituximab (n=14, 22%). Compared to patients not requiring RRT, patients requiring RRT had higher baseline proteinuria (median 3531 vs. 1980 mg/24h, p<0.001) and lower eGFR (median 16 v. 44 mL/min, p<0.001); differences in serum free light chain concentrations were not significant ( Figure 1). A clonal population thought to be causing MGRS was identified on bone marrow biopsy in a majority of LCDD patients (n = 20, 95%), while clones were infrequently found in PGNMID (n = 6, 23%). The vast majority (n=20, 95%) of patients with LCDD received bortezomib-based therapy. Initial therapy in patients with PGNMID was more evenly divided: 9 (35%) received bortezomib-based therapy, 10 (38%) received rituximab-based therapy, and 6 (23%) received other regimens. Despite differences in therapeutic approach, patients with LCDD and in patients with PGNMID had similar risk of RRT (cumulative risk 35% v. 43%, p=0.54; HR 0.83 (95% CI 0.52-1.33); p =0.44) ( Figure 2). Conclusion: Patients with MGRS remain at high risk of requiring RRT even with clone-directed therapy. Despite differences in pathogenic clones and therapeutic strategies, outcomes of patients with PGNMID and LCDD are similar. Because the severity of baseline renal function across MGRS histologies predicts renal survival, early diagnosis and treatment is likely critical to improving renal outcomes.

Value of nuclide scintigraphy in the diagnosis and prognosis of cardiac amyloidosis.

Amyloidosis is a local or systemic disease caused by the deposition of misfolded proteins outside the cell, with rapid progression, and dire prognosis. Common types of cardiac amyloidosis are monoclonal immunoglobulin light chain amyloidosis (AL-CA) and transthyretin cardiac amyloidosis (ATTR-CA). Nuclear medicine examinations can be accurate, rapid, and non-invasive to help diagnose diseases and can effectively predict the prognosis of patients with CA. Technetium (99Tcm)-labeled bisphosphonate imaging has been included in the consensus of experts and has become the first-line imaging method for the diagnosis of ATTR-CA. 123I-metaiodoenzylguanidine (MIBG) as a norepinephrine analogue can effectively assess cardiac sympathetic innervation in patients with CA. Aβ- amyloid imaging agents such as 11C-pittsburgh compound B and 18F-flubetaben are expected to be new techniques for diagnosing AL-CA and incorporating them into cardiac staging systems for AL-CA patients in the future. New imaging agents such as 18F-NaF has been widely used in the diagnosis, treatment response monitoring, and prognosis assessment of CA. Summarizing the research value of nuclide imaging in CA may provide new ideas for clinical realization of early detection of CA and accurate assessment of disease prognosis.

Clinical and Cardiovascular Magnetic Resonance Imaging Features of Cardiac Amyloidosis.

Amyloidosis is a systemic disease characterized by the accumulation of insoluble aggregates in various organs, leading to parenchymal damage. When these amyloid fibrils are deposited in the extracellular matrix of the cardiac structures, the condition is referred to as cardiac amyloidosis (CA). The extent of organ involvement determines the degree of cardiac impairment, which can significantly impact prognosis. The two most implicated proteins in CA are transthyretin and misfolded monoclonal immunoglobulin light chains. These proteins give rise to two distinct clinical forms of CA: transthyretin amyloidosis (ATTR-CA) and light-chain amyloidosis (AL-CA). ATTR-CA is further classified into two subtypes: ATTRm-CA, which occurs at a younger age and is caused by hereditary misfolded mutated proteins, and ATTRwt-CA, which is an acquired wild-type form more commonly observed in older adults, referred to as senile amyloidosis. While AL-CA was considered the most prevalent form for many years, recent autopsy studies have revealed an increase in cases of ATTRwt-CA. This narrative review aims to describe the clinical and imaging features of CA, with a particular focus on cardiac complications and mortality associated with the AL form. Early identification and differentiation of CA from other disorders are crucial, given the higher risk and severity of cardiac involvement in AL-CA. Furthermore, emphasis is placed on the potential utility of cardiovascular magnetic resonance imaging in detecting early cases of CA.

New Onset Nephrotic - Range Proteinuria in a Patient with Chronic Kidney Disease - Not Always What it Seems

Light chain deposition disease (LCDD) is a rare condition that is characterized by the deposition of monoclonal immunoglobulin light chains in glomerular and tubular basement membranes. We report the case of a 72-year-old male with long-standing and stable chronic kidney disease (CKD) presumably due to hypertension.

Pathological characteristics of light chain crystalline podocytopathy

Monoclonal immunoglobulin light chain (LC) crystalline inclusions within podocytes are rare, poorly characterized entities. To provide more insight, we now present the first clinicopathologic series of LC crystalline podocytopathy (LCCP) encompassing 25 patients (68% male, median age 56 years). Most (80%) patients presented with proteinuria and chronic kidney disease, with nephrotic syndrome in 28%. Crystalline keratopathy and Fanconi syndrome were present in 22% and 10%, respectively. The hematologic condition was monoclonal gammopathy of renal significance (MGRS) in 55% and multiple myeloma in 45%. The serum monoclonal immunoglobulin was IgG κappa in 86%. Histologically, 60% exhibited focal segmental glomerulosclerosis (FSGS), often collapsing. Ultrastructurally, podocyte LC crystals were numerous with variable effacement of foot processes. Crystals were also present in proximal tubular cells as light chain proximal tubulopathy (LCPT) in 80% and in interstitial histiocytes in 36%. Significantly, frozen-section immunofluorescence failed to reveal the LC composition of crystals in 88%, requiring paraffin-immunofluorescence or immunohistochemistry, with identification of kappa LC in 87%. The LC variable region gene segment, determined by mass spectrometry of glomeruli or bone marrow plasma cell sequencing, was IGKV1-33 in four and IGKV3-20 in one. Among 21 patients who received anti-plasma cell-directed chemotherapy, 50% achieved a kidney response, which depended on a deep hematologic response. After a median follow-up of 36 months, 26% progressed to kidney failure and 17% died. The mean kidney failure-free survival was 57.6 months and was worse in those with FSGS. In sum, LCCP is rare, mostly associates with IgG κappa MGRS, and frequently has concurrent LCPT, although Fanconi syndrome is uncommon. Paraffin-immunofluorescence and electron microscopy are essential to prevent misdiagnosis as primary FSGS since kidney survival depends on early diagnosis and subsequent clone-directed therapy.

Understanding AL amyloidosis with a little help from in vivo models.

Monoclonal immunoglobulin (Ig) light chain amyloidosis (AL) is a rare but severe disease that may occur when a B or plasma cell clone secretes an excess of free Ig light chains (LCs). Some of these LCs tend to aggregate into organized fibrils with a β-sheet structure, the so-called amyloid fibrils, and deposit into the extracellular compartment of organs, such as the heart or kidneys, causing their dysfunction. Recent findings have confirmed that the core of the amyloid fibrils is constituted by the variable (V) domain of the LCs, but the mechanisms underlying the unfolding and aggregation of this fragment and its deposition are still unclear. Moreover, in addition to the mechanical constraints exerted by the massive accumulation of amyloid fibrils in organs, the direct toxicity of these variable domain LCs, full-length light chains, or primary amyloid precursors (oligomers) seems to play a role in the pathogenesis of the disease. Many in vitro studies have focused on these topics, but the variability of this disease, in which each LC presents unique properties, and the extent and complexity of affected organs make its study in vivo very difficult. Accordingly, several groups have focused on the development of animal models for years, with some encouraging but mostly disappointing results. In this review, we discuss the experimental models that have been used to better understand the unknowns of this pathology with an emphasis on in vivo approaches. We also focus on why reliable AL amyloidosis animal models remain so difficult to obtain and what this tells us about the pathophysiology of the disease.

Machine learning algorithms to automate differentiating cardiac amyloidosis from hypertrophic cardiomyopathy.

Cardiac amyloidosis has a poor prognosis, and high mortality and is often misdiagnosed as hypertrophic cardiomyopathy, leading to delayed diagnosis. Machine learning combined with speckle tracking echocardiography was proposed to automate differentiating two conditions. A total of 74 patients with pathologically confirmed monoclonal immunoglobulin light chain cardiac amyloidosis and 64 patients with hypertrophic cardiomyopathy were enrolled from June 2015 to November 2018. Machine learning models utilizing traditional and advanced algorithms were established and determined the most significant predictors. The performance was evaluated by the receiver operating characteristic curve (ROC) and the area under the curve (AUC). With clinical and echocardiography data, all models showed great discriminative performance (AUC > 0.9). Compared with logistic regression (AUC 0.91), machine learning such as support vector machine (AUC 0.95, p = 0.477), random forest (AUC 0.97, p = 0.301) and gradient boosting machine (AUC 0.98, p = 0.230) demonstrated similar capability to distinguish cardiac amyloidosis and hypertrophic cardiomyopathy. With speckle tracking echocardiography, the predictive performance of the voting model was similar to that of LightGBM (AUC was 0.86 for both), while the AUC of XGBoost was slightly lower (AUC 0.84). In fivefold cross-validation, the voting model was more robust globally and superior to the single model in some test sets. Data-driven machine learning had shown admirable performance in differentiating two conditions and could automatically integrate abundant variables to identify the most discriminating predictors without making preassumptions. In the era of big data, automated machine learning will help to identify patients with cardiac amyloidosis and timely and effectively intervene, thus improving the outcome.

The dark side of current analytic methods for Bence Jones Proteinuria.

Bence Jones proteinuria (BJP) refers to monoclonal free immunoglobulin light chains detected in urine, deriving from the clonal expansion of plasma cells in the bone marrow in patients with plasma cell dyscrasias, associated with monoclonal gammopathies of uncertain origin. This review summarizes routinely diagnostic procedures to assess BJP highlighting critical steps of pre-analytical, analytical, and post-analytical phases. The best option for BJP detection is the first morning void urine sample and immunofixation electrophoresis detection technique (IFE) the recommended method, with the employment of specific polyvalent antisera. Other qualitative tests for a quick evaluation of BJP are currently available. Densitometric analysis performed on the 24-hour urine is the recommended method to quantify BJP. To overcome the 24-hour collection, it is possible to use morning urine sample and correlate the assessed value of BJP to creatininuria. In addition to the traditional ones, we here reviewed screening methods currently used to avoid false negatives and reduce the time around test (TAT), together with immunochemical quantification methods for increased sensitivity, after checking BJP by IFE. Mass spectrometry emerges as a new challenge in the determination of BJP. The employment of different based-assays methods may be useful for diagnostic purposes to improve the accuracy of BJP monitoring in monoclonal gammopathies.