Amyloidosis is a group of heterogeneous diseases characterized by the deposition of amyloid fibrils in various organs and tissues. Membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome in adults. We report three cases of early-stage MN occurring concurrently with distinct types of renal amyloidosis: apolipoprotein A-I (AApoA-I) amyloidosis, leukocyte chemotactic factor 2 (ALECT2) amyloidosis, and monoclonal immunoglobulin light-chain (AL) amyloidosis. Each case represents a different pathogenic mechanism, therapeutic approach, and clinical prognosis. These cases underscore the pivotal role of renal pathology in the accurate diagnosis of patients with coexisting amyloidosis and MN. Correct classification of renal amyloidosis is essential for guiding therapy and predicting outcomes. When amyloidosis coexists with MN or other potentially treatable renal diseases, therapeutic decisions should prioritize the condition with the greater potential for organ damage or the one most responsive to available treatment.

Amyloid deposition is an increasingly recognized contributor to chronic kidney disease and end-stage renal disease. It can result from various underlying conditions, including monoclonal gammopathies and chronic inflammatory states. Diagnosis is typically established by kidney biopsy demonstrating characteristic amyloid deposits. ALECT2 (leukocyte chemotactic factor 2) amyloidosis can present as nephrotic-range proteinuria. ALECT2 amyloidosis is an uncommon and under-recognized.

The aim of this study is to explore the quantity profiles of amyloid signature proteins (serum amyloid P component, SAP; apolipoprotein E, ApoE; apolipoprotein A-IV) in common types of renal amyloidosis by mass spectrometry and immunostaining methods. Twenty-one patients with renal amyloidosis of different types evaluated at the Renal Pathological Center of Peking University First Hospital from 2000 to 2021 were enrolled. Immunohistochemistry (IHC) and laser microdissection combining with mass spectrometry (LMD-MS) were applied to investigate the localization and quantity profiles of signature proteins in renal amyloidosis. The co-localization relationships among signature proteins and amyloid fibrils, as well as the ultrastructural localization of SAP were examined by laser scanning confocal microscopy (LSCM) and immuno-electron microscopy (IEM), respectively. By MS-based proteomic analysis, large spectra numbers of ApoE and its higher abundance were noted in four types of amyloidosis when compared with SAP, and ApoA-IV was absent in ALECT2 amyloidosis. LSCM showed ApoE and SAP co-localized with amyloid fibrils in renal AL-κ, AL-λ and ALECT2 amyloidosis. ApoA-IV co-localized with amyloid fibrils in AL-κ and AL-λ amyloidosis, but was not found in ALECT2 amyloidosis. By semi-quantitative analysis based on LSCM and IEM, the quantity levels of signature proteins in AL-κ appeared to be lower than that in AL-λ (P < 0.05) or ALECT2 (P < 0.05), while there was no significant difference between AL-λ and ALECT2 amyloidosis. Both of SAP and ApoE were the ubiquitous signature components of renal amyloidosis (AL, AA, ALECT2), as well as ApoA-IV in AL and AA, but not in ALECT2. ApoE was the key signature protein in renal amyloidosis. The quantity levels of signature proteins investigated through LCSM/IEM demonstrated variability among different types, with AL-κ amyloidosis appeared to have a lower level. Not applicable.

ALECT2 amyloidosis is a rare systemic disease characterized by the pathological deposition of leukocyte cell-derived chemotaxin-2 (LECT2) as amyloid fibrils, primarily affecting the kidneys and liver. The molecular mechanisms underlying LECT2 aggregation remain poorly defined, hindering diagnostic and therapeutic development. Here, we present cryo-electron microscopy structures of ex-vivo ALECT2 fibrils extracted from a patient's kidney. We identified three fibril polymorphs: a predominant single-protofilament morphology and two minor double-protofilament morphologies. The dominant single-protofilament morphology comprises the full-length 133-residue LECT2 protein and retains all three native disulfide bonds. Low-resolution reconstructions of double-protofilament morphologies suggest they adopt a similar fold to the single protofilament morphology, but form paired assemblies with different inter-filament interfaces. Mass spectrometry also reveals acetylation within the fibrils. These findings offer critical insights into the structural basis of ALECT2 amyloid formation and identify molecular features that could inform future diagnostic and therapeutic approaches.

The diagnosis of amyloidosis requires high clinical suspicion and is often made only after significant clinical symptoms arise. Here, we present a case of amyloidosis diagnosed in a patient with an enlarging incidental adrenal cyst. Imaging and biochemical evaluation suggested that the cyst was benign and non-functional. Adrenalectomy was performed to treat symptoms of mass effect, and surgical pathology led to the diagnosis of leukocyte cell-derived chemotaxin 2 (ALECT2) associated adrenal amyloidosis. Patients with ALECT2 amyloidosis may have subclinical involvement of the adrenal glands, subcutaneous fat, and other tissues before developing the more common manifestation of renal amyloidosis. Early identification of patients with ALECT2 amyloidosis can assist in prevention of renal morbidity. Prevention of chronic kidney disease (CKD) should be among the main goals of managing patients with ALECT2 amyloidosis.