👤 Alessia Buglioni

Most newly discovered membranous nephropathy (MN) antigens have been mutually exclusive, but there are rare cases of dual antigen MN based on immunohistochemistry (IHC)/immunofluorescence (IF) or serologic testing. Here, we searched for cases of dual antigen MN at Mayo Clinic and Arkana Laboratories with the diagnosis established by light/electron microscopy and IF. At Mayo Clinic, we performed laser capture microdissection of glomeruli followed by liquid chromatography tandem mass spectrometry (LC MS/MS) on paraffin-embedded kidney biopsy tissue to detect 12 MN antigens. Nine cases of dual antigen MN (four at Mayo Clinic, five at Arkana Laboratories) were confirmed by both LC MS/MS and IHC/IF. The detected antigens were NELL1 + CNTN1 (two cases), NCAM1 + EXT1/2 (two cases), and one case each NDNF + NELL1, NELL1 + PLA2R1, THSD7A + PLA2R1, PCDH7 + PLA2R1, and CNTN1 + PCDH7. Median age at diagnosis was 68 years (range 23-84). Eight patients presented with nephrotic syndrome and microscopic hematuria. Median serum creatinine at diagnosis was 1 mg/dL. The underlying conditions, when present, and serological characteristics, correlated with the involved antigens. The frequency at Mayo Clinic was 2.6% of PLA2R1-negative MN cases. Given that IHC/IF and LC MS/MS for MN antigen detection are typically not pursued in PLA2R1-associated MN, dual-antigen MN is likely underdiagnosed. Dual-antigen MN can involve a variety of MN antigens, including those that are podocyte-expressed, transmembrane, or secreted. Most patients with MN present with nephrotic syndrome and microscopic hematuria. Further studies are needed to understand the pathophysiology of dual-antigen MN and determine their role both in the therapeutic approach and clinical outcomes. Our findings suggest that LC MS/MS is a valuable methodology for detection of dual antigen MN. Show less

Amyloidosis derived from apolipoprotein C-II (AApoCII) is a recently discovered, rare form of amyloidosis. Data on clinical presentations and natural history are very limited. This study defines the clinicopathologic, proteomic, and outcome characteristics of renal AApoCII. Case series. Twenty-five renal AApoCII cases were identified from the Mayo Clinic Tissue Proteomics Laboratory archives from January 2008 through January 2024. All patients were White, 19 were≥65 years old at diagnosis, and 18 were female. Seven had a family history of chronic kidney disease (CKD). Patients presented with proteinuria (median 3.3g/day) and reduced kidney function (n=16; median creatinine, 1.6mg/dL). No patients had clinical evidence of other organ involvement by amyloidosis or features of monogenic hypertriglyceridemia. Histologically, amyloid deposits were often weakly positive for Congo red and involved glomeruli in all cases (with a nodular pattern in 22), whereas extraglomerular involvement was less common and generally mild. Proteomic analysis revealed abundant spectra for Apo C-II and for all 3 amyloid signature proteins (apolipoprotein E, apolipoprotein A-IV, and serum amyloid P) in all cases and detected an Apo C-II variant in 14 (K19T [p.Lys41Thr] in 12 and E47V [p.Glu69Val] in 2). Among 22 patients with follow-up information available, there were 12 end-stage kidney disease (ESKD) events and 2 deaths without ESKD during an average follow-up period of 75.5±12.5 (SE) months. Retrospective design, small sample size, APOC2 gene sequencing performed in a smaller subset. AApoCII mostly affects the kidney and manifests in the elderly with proteinuria and CKD. A minority of these patients had a family history of kidney disease. Kidney failure occurred in about half, whereas overall survival was more favorable. Amyloidosis derived from apolipoprotein C-II (AApoCII) is very rare, and data on clinicopathologic and outcome characteristics are scant. This study of 25 patients with AApoCII diagnosed by mass spectrometry at the Mayo Clinic Tissue Proteomics Laboratory revealed that most patients were elderly White females who presented with proteinuria and reduced kidney function, without involvement of other organs. A family history of kidney disease was often lacking. Pathologically, most cases exhibited nodular glomerular involvement. Proteomic analysis revealed abundant protein spectra for Apo C-II and amyloid signature proteins, and identified an Apo C-II variant in over half of cases (most commonly the p.Lys41Thr variant). The cumulative incidence of kidney failure was over 50% at 5 years follow-up. Only 4 deaths occurred over an average follow-up period of 76 months. Show less

The PICALM::MLLT10 fusion is a rare but recurrent cytogenetic abnormality in acute leukemia, with limited clinicopathologic and outcome data available. Herein, we analyzed 156 acute leukemia patients with PICALM::MLLT10 fusion, including 12 patients from our institutions and 144 patients from the literature. The PICALM::MLLT10 fusion preferentially manifested in pediatric and young adult patients, with a median age of 24 years. T-lymphoblastic leukemia/lymphoma (T-ALL) constituted 65% of cases, acute myeloid leukemia (AML) 27%, and acute leukemia of ambiguous lineage (ALAL) 8%. About half of T-ALL were classified as an early T-precursor (ETP)-ALL. In our institutions' cohort, mediastinum was the most common extramedullary site of involvement. Eight of 12 patients were diagnosed with T-ALL exhibiting a pro-/pre-T stage phenotype (CD4/CD8-double negative, CD7-positive), and frequent CD79a expression. NGS revealed pathogenic mutations in 5 of 6 tested cases, including NOTCH1, and genes in RAS and JAK-STAT pathways and epigenetic modifiers. Of 138 cases with follow-up, pediatric patients (<18 years) had 5-year overall survival (OS) of 71%, significantly better than adults at 33%. The 5-year OS for AML patients was 25%, notably shorter than T-ALL patients at 54%; this distinction was observed in both pediatric and adult populations. Furthermore, adult but not pediatric ETP-ALL patients demonstrated inferior survival compared to non-ETP-ALL patients. Neither karyotype complexity nor transplant status had a discernible impact on OS. In conclusion, PICALM::MLLT10 fusion is most commonly seen in T-ALL patients, particularly those with an ETP phenotype. AML and adult ETP-ALL patients had adverse prognosis. PICALM::MLTT10 fusion testing should be considered in T-ALL, AML, and ALAL patients. Show less