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Light chain amyloidosis is one of the most common forms of systemic amyloidosis. The disease is caused by the misfolding and aggregation of immunoglobulin light chains to insoluble fibrils. These fibrils can deposit in different tissues and organs such as heart and kidney and cause organ impairments that define the clinical presentation. In this study, we present an overview of IGLV-IGLJ and IGLC germline utilization in 85 patients classified in three clinically important subgroups with dominant cardiac, renal as well as cardiac and renal involvement. We found that IGLV3 was the most frequently detected IGLV-family in patients with dominant cardiac involvement, whereas in renal patients IGLV1 were most frequently identified. For patients with dominant heart and kidney involvement IGLV6 was the most frequently detected IGLV-family. In more detailed analysis IGLV3-21 was observed as the most dominant IGLV-subfamily for patients with dominant heart involvement and IGLV1-44 as the most frequent IGLV-subfamily in the group of patients with dominant kidney involvement. For patients with dominant heart and kidney involvement IGLV6-57 was the most frequently detected IGLV-subfamily. Additionally, we were able to show an exclusive linkage between IGLJ1 and IGLC1 as well as between IGLJ2 and IGLC2 in the fully assembled IGL mRNA., Competing Interests: The authors have declared that no competing interests exist.

Amyloidosis is a rare group of diseases characterized by abnormal folding of proteins and extracellular deposition of insoluble fibrils. It can be localized to one organ system or can have systemic involvement. The kidney is the most common organ to be involved in systemic amyloidosis often leading to renal failure and the nephrotic syndrome. The two most common types of renal amyloidosis are immunoglobulin light chain-derived amyloidosis (AL) and reactive amyloidosis (AA). A novel form of amyloidosis (ALECT2) derived from leukocyte chemotactic factor 2 (LECT-2) and primarily involving the kidneys was first described by Benson et al in 2008. The liver was subsequently identified as the second most common organ involved in ALECT2 amyloidosis. LECT-2 is a unique protein that can form amyloid deposits even in its unmutated form. Patients with ALECT2 present with minimal proteinuria in contrast to other forms of amyloidosis especially AL and AA. They may present with slightly elevated serum creatinine. Nephrotic syndrome and hematuria are rare. ALECT2 can be found in association with other types of amyloidosis as well as malignancies or autoimmune diseases. ALECT2 may be confused with amyloidosis associated with light and heavy chain monoclonal gammopathy if the immunofluorescence is positive with anti-light chain and anti-AA sera. The other organs involved are the duodenum, adrenal gland, spleen, prostate, gall bladder, pancreas, small bowel, parathyroid gland, heart, and pulmonary alveolar septa, but consistently uninvolved organs included brain and fibroadipose tissue. A renal biopsy along with characteristic features found on immunohistochemistry and mass spectrometry is diagnostic of ALECT2. ALECT2 should be suspected when all markers for AL and AA are negative. Proper diagnosis of ALECT2 can determine need for supportive care versus more aggressive interventions., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Cast nephropathy (CN) is associated with a unfavourable outcome in monoclonal light chain (mLC) disease, but also more possible LC-related renal diseases as well as non-LC-related disease can occur. Thus, it is crucial to understand the underlying renal disease. On the other hand, LC can interfere with coagulation preventing kidney biopsy as the gold standard. We sought to develop a non-invasive algorithm to diagnose CN with a good sensitivity and specificity., Method: We analysed data from patients with mLC disease who underwent kidney biopsy. The patients were classified in 4 groups according the renal histology: CN, AL amyloidosis, light chain deposition disease, and other renal disease. Afterwards, different algorithms were calculated for their sensitivity and specificity., Results: CN showed a significant higher concentration of serum-free LC and urine LC (LCu), but there was a wide and overlapping range with the other groups. The best accuracy was achieved for a LCu/GFR ratio >2 in patients with lambda LC and either a LCu/GFR > 1 and proteinuria <8 g/24 h or a LCu/GFR > 5 in patients with proteinuria >8 g/24 h in patients with kappa LC. In lambda LC, the sensitivity and specificity for CN was 94% and 90%, respectively; in kappa LC 87% and 81%, respectively., Discussion: In patients with coagulation disturbances due to LC, a non-invasive algorithm can separate patients with CN from other renal disease in mLC disease., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Kidney involvement in immunoglobulin-related amyloidosis (AIg) is common. Although patients with renal-limited AIg tend not to have the high mortality that patients with cardiac amyloidosis have, they do experience significant morbidity and impact on quality of life. The complexity of the pathogenesis remains incompletely understood. Models have been established to prognosticate and assess for the response to therapy. Patients with advanced renal impairment from immunoglobulin light chain amyloidosis still have poor renal prognosis, and better therapy is needed in order to preserve kidney function. Patients who develop end-stage renal disease can undergo renal replacement therapy with kidney transplantation., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aims: To test the hypothesis that the fibril morphology and the fibril protein primary structure are conserved across different patients suffering from the common variant of systemic Amyloid A ( AA) amyloidosis. Methods: Amyloid fibrils were extracted from the renal tissue of four patients. The fibril morphology was analysed in negatively stained samples with transmission electron microscopy (TEM). The fibril protein identity and fragment length were determined by using mass spectrometry. Results: The fibrils show a consistent morphology in all four patients and exhibit an average width of ∼9.6 nm and an average pitch of ∼112 nm. All fibrils are composed of polypeptide chains that can be assigned to human serum amyloid A (SAA) 1.1 protein. All fragments lack the N-terminal arginine residue and are C-terminally truncated. Differences exist concerning the exact C-terminal cleavage site. The most prominent cleavage site occurs at residues 64-67. Conclusions: Our data demonstrate that AA amyloid fibrils are consistent at the level of the protein primary structure and fibril morphology in the four analysed patients.

Background and Objectives: Light chain (AL) amyloidosis frequently involves the kidney, causing significant morbidity and mortality. A pathologic scoring system with prognostic utility has not been developed. We hypothesized that the extent of amyloid deposition and degree of scarring injury on kidney biopsy, could provide prognostic value, and aimed to develop pathologic scoring tools based on these features., Methods: This is a case-control study of 39 patients treated for AL amyloidosis with biopsy-proven kidney involvement at a large academic medical center. Our novel scoring tools, composite scarring injury score (CSIS) and amyloid score (AS) were applied to each kidney biopsy. The primary outcome was progression to dialysis-dependent end-stage kidney disease (ESKD) using a 12-month landmark analysis., Results: At 12 months, nine patients had progressed to ESKD. Patients with an AS ≥7.5 had a significantly higher cumulative incidence of ESKD than those with AS <7.5 (p = .04, 95% CI 0.13-0.64)., Conclusions: Using a 12-month landmark analysis, AS correlated with progression to ESKD. These data suggest that a kidney biopsy, in addition to providing diagnostic information, can be the basis for a pathologic scoring system with prognostic significance.