RATIONALE & OBJECTIVE: 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. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: Twenty-five renal AApoCII cases were identified from the Mayo Clinic Tissue Proteomics Laboratory archives from January 2008 through January 2024. FINDINGS: 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. LIMITATIONS: Retrospective design, small sample size, APOC2 gene sequencing performed in a smaller subset. CONCLUSIONS: 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. PLAIN-LANGUAGE SUMMARY: 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.