Focal segmental glomerulosclerosis (FSGS) involves glomerular scarring and podocyte injury. FSGS treatment typically involves the use of corticosteroids and immunosuppressants. In patients with steroid-resistant FSGS, however, no ideal treatment exists. Extracorporeal therapies such as plasma exchange and low-density lipoprotein apheresis (LDL-A) may be promising options for managing lipid-mediated nephrotoxicity found in patients with steroid-resistant FSGS. Unfortunately, these extracorporeal techniques are inaccessible in many low- and middle-income countries (LMICs) due to high costs and infrastructure challenges. The use of extracorporeal therapies for FSGS management was evaluated at a single center. Additionally, a literature search was conducted across multiple databases to identify studies that explored FSGS treatment modalities in LMICs. Eligibility was assessed based on discussion of viability, efficacy, and application of therapies. At a single center, we found that double filtration plasmapheresis (DFPP) with the Evaflux filter was the most frequently used and most effective method of extracorporeal therapy for FSGS in terms of remission. The development of improvements in extracorporeal therapy, such as modified double filtration plasmapheresis (DFPP), may offer cost improvements due to reduced fluid replacement, which may lead to increased use in LMICs. Twinning programs and governmental intervention may be used to address the gaps in FSGS care in LMICs. Future efforts involve expanding access to plasmapheresis in the management of FSGS, especially in resource-limited settings.

Oxidized phospholipids (OxPL) are generated at sites of oxidative stress and tissue injury, where they function as prototypic danger-associated molecular patterns that trigger inflammation, cell death, and tissue remodeling. The natural IgM antibody E06, and derivative formats such as E06-scFv, recognize the phosphocholine epitope on OxPL but not on native phospholipids, providing powerful tools to probe the biology of OxPL across cardiovascular and noncardiovascular disease. In this review, we summarize experimental and translational evidence implicating OxPL as mediators of atherogenesis, myocardial ischemia-reperfusion injury, nonalcoholic steatohepatitis and hepatocellular carcinoma, bone loss, lung fibrosis and acute lung injury, sepsis, neuroinflammation, and pain. In multiple murine models, genetic or passive approaches that express or deliver E06-based constructs neutralize OxPL, attenuate inflammation, improve tissue function, and reduce lesion burden, establishing OxPL as an actionable driver rather than a passive byproduct of oxidative stress. We further highlight how E06 has been leveraged to develop sensitive immunoassays for OxPL on apoB-containing lipoproteins and on Lp(a) (lipoprotein[a]; OxPL-apo[a]). These biomarkers consistently associate with incident and recurrent cardiovascular events and link OxPL biology to human lipoprotein metabolism, particularly the preferential enrichment of OxPL on Lp(a). We review emerging data on how established and novel therapies, including statins, PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors, lipoprotein apheresis, and Lp(a)-targeted antisense and RNA-based agents, modulate OxPL, and discuss how these interventions may help test the OxPL hypothesis in outcomes trials. Finally, we outline key challenges and opportunities for translating OxPL-directed strategies to the clinic, including issues of specificity, immunogenicity, timing, and patient selection. Collectively, these insights position OxPL and its selective neutralization by E06-like antibodies as a unifying mechanism and promising therapeutic target across diverse inflammatory and cardiometabolic diseases.

Lipoprotein apheresis: From familial hypercholesterolemia and elevated lipoprotein(a) to emerging roles in peripheral arterial and renal disease.

LDL cholesterol (LDL-C) is the central causal factor for atherosclerotic cardiovascular disease (ASCVD), and its reduction is a cornerstone of both primary and secondary prevention. Since the introduction of statins more than three decades ago, LDL-C-lowering therapy has expanded substantially, now encompassing ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9)-targeting agents, bempedoic acid, and other emerging modalities. This expanding therapeutic landscape has improved the feasibility of achieving guideline-recommended LDL-C targets, but it has also increased the complexity of clinical decision making. This review provides a contemporary and practical overview of the LDL-C-lowering strategies, beginning with the initial evaluation of patients with elevated LDL-C, including differentiation between primary and secondary causes and the identification of familial hypercholesterolemia (FH). We summarize the current treatment targets for primary and secondary prevention, highlight the optimal selection and use of statins, and discuss the assessment and management of statin intolerance, including the role of the nocebo effect. Non-statin therapies, including ezetimibe, bile acid sequestrants, PCSK9 inhibitors, inclisiran, and bempedoic acid, are reviewed with an emphasis on their mechanisms, efficacy, and clinical positioning. Advanced therapies for severe dyslipidemia, such as lipoprotein apheresis, lomitapide, and evinacumab, are also discussed in this review. Finally, we outline the future directions, including oral PCSK9 inhibitors, next-generation cholesteryl ester transfer protein (CETP) inhibitors, lipoprotein(a)-lowering agents, and genome-editing approaches. Collectively, these developments offer new opportunities to address unmet clinical needs, particularly in patients with FH, statin intolerance, and residual cardiovascular risk. A comprehensive understanding of these therapies is essential for further reducing the burden of ASCVD in the coming decades.

Homozygous familial hypercholesterolaemia (HoFH) is a rare condition characterised by markedly elevated low-density lipoprotein and early-onset atherosclerotic cardiovascular disease. Described here is a woman with HoFH and premature ischaemic heart disease who presented during her first pregnancy with poorly-controlled hyperlipidaemia. Despite ongoing treatment with lipid-lowering therapy and lipoprotein apheresis, she developed exertional angina at 17 weeks' gestation and was diagnosed with multi-vessel coronary artery disease. She underwent successful off-pump coronary artery bypass grafting at 19 weeks. She made a good recovery and the rest of her pregnancy progressed well, with delivery of a healthy infant at 37 weeks following emergency caesarean section. This case highlights the high cardiovascular risk associated with HoFH in pregnancy and the importance of multi-disciplinary management, including consideration of lipid-lowering therapy, lipoprotein apheresis and surgical intervention.

Lipoprotein apheresis in the era of new lipid-lowering therapies.

Lipoprotein(a) [Lp(a)] is a causal and independent cardiovascular risk factor for atherosclerotic cardiovascular disease and calcific aortic valve stenosis, with elevated levels observed in approximately 20% of the general population. Plasma Lp(a) concentrations are predominantly determined by genetic factors, particularly polymorphisms of the LPA gene, which modulate apolipoprotein(a) [apo(a)] size and influence its hepatic synthesis. Structurally, Lp(a) consists of an LDL-like particle containing apolipoprotein B100, covalently bound to apo(a), conferring markedly enhanced atherogenic, pro-inflammatory, and prothrombotic properties compared with an LDL particle. In the absence of therapies specifically approved for Lp(a) reduction, current clinical management relies on an intensive approach to global cardiovascular risk reduction. ESC/EAS guidelines recommend aggressive lowering of LDL cholesterol, particularly through high-intensity statin therapy and, in patients at high or very high risk, the addition of ezetimibe and PCSK9 inhibitors, in order to mitigate the residual risk associated with elevated Lp(a) levels. Lipoprotein apheresis represents the only intervention capable of producing a substantial and immediate reduction in Lp(a); however, its use is limited to selected patients due to its invasive nature and limited availability. In parallel, innovative therapies targeting LPA gene silencing-such as antisense oligonucleotides and small interfering RNA-as well as oral agents inhibiting Lp(a) assembly, are in advanced stages of development. These approaches have demonstrated Lp(a) reductions of up to 80-90%, offering concrete prospects for a causal therapeutic strategy, pending the results of cardiovascular outcome trials.

Lipoprotein apheresis as rescue therapy in lipoprotein glomerulopathy: The role of plasmatic extracellular vesicle removal.

Steroid-resistant nephrotic syndrome (SRNS) in children carries a poor prognosis, and recent discoveries implicate anti-nephrin autoantibodies (ANABs) as mediators of podocyte injury. Lipoprotein apheresis, originally developed for familial hypercholesterolemia, has been explored as rescue therapy in refractory SRNS, but its immunologic effects remain uncertain. This case demonstrates a decline in ANAB titers accompanied by clinical improvement following lipoprotein apheresis. We report a 7-year-old male of Afro-Caribbean descent with biopsy findings consistent with minimal change disease and punctate IgG staining who presented with steroid-resistant nephrotic syndrome. He was unresponsive to tacrolimus, rituximab, mycophenolate mofetil, and five therapeutic plasma exchange sessions, and developed severe anasarca requiring extracorporeal ultrafiltration. Compassionate-use lipoprotein apheresis was initiated. Twelve sessions were performed over about ten weeks. Serial plasma ANAB testing showed a marked decrease with lipoprotein apheresis. Clinically, urine output increased, edema resolved, and ultrafiltration was discontinued about seven weeks after the final session, although nephrotic-range proteinuria persisted. This case highlights the potential immunomodulatory role of lipoprotein apheresis in ANAB-mediated podocytopathy. Improvement despite lack of response to therapeutic plasma exchange suggests that lipoprotein apheresis may remove certain antibodies and immune complexes more efficiently compared to conventional therapeutic plasma exchange. Serial ANAB monitoring provided a biomarker correlating with treatment response. Controlled studies are needed to clarify the mechanisms and define the role of lipoprotein apheresis in ANAB-positive SRNS patients.

Lipoprotein apheresis for lowering Lp(a): the conceptual confusion between 'acute removal' and 'chronic control' may mislead clinical interpretation.

WCN26-3097 EFFICACY AND MECHANISMS OF LIPOPROTEIN APHERESIS ON PERIPHERAL ARTERIAL DISEASE WITHOUT CONCURRENT SEVERE HYPERCHOLESTEROLEMIA

Homozygous familial hypercholesterolaemia (HoFH) is characterized by markedly elevated low-density lipoprotein cholesterol (LDL-C). Most individuals with HoFH do not reach LDL-C targets with standard lipid-lowering therapies (LLTs). However, low density lipoprotein receptor (LDLR)-independent LLTs have demonstrated effectiveness in these individuals. This post hoc subanalysis examined concomitant use of two LDLR-independent treatments, lipoprotein apheresis (LA) and evinacumab (an angiopoietin-like 3 inhibitor), in participants with HoFH from three clinical studies of evinacumab. We included participants with HoFH who received 15 mg/kg evinacumab in any Regeneron-sponsored clinical study. Participants were stratified by concurrent LA treatment at study baseline. The primary outcome was mean change in LDL-C from baseline to Week 24. Other outcomes included change in LA frequency and safety. Outcomes were examined descriptively. A total of 138 participants were included, 59 (43%) undergoing LA at baseline and 79 (57%) not undergoing LA at baseline. From baseline to Week 24, mean (standard deviation) LDL-C was reduced in participants undergoing LA at baseline (-42.9% [23.8]) and those who were not (-50.8% [30.5]). Reductions in LDL-C in both subgroups were observed across all examined timepoints. Among those undergoing LA at baseline, LA frequency was reduced in 17 (29%) participants and increased in two (3%) participants. Evinacumab was well-tolerated in both subgroups. This study demonstrated considerable benefit of evinacumab for individuals with HoFH, with or without concurrent LA. Evinacumab appeared to lessen LA burden for some individuals. This analysis suggests that LA and evinacumab can be combined without compromising efficacy or safety.

Lipoprotein apheresis (LA) is the only approved treatment for patients with elevated lipoprotein(a) [Lp(a)]. The Lp(a)FRONTIERS APHERESIS trial investigated whether pelacarsen reduces the need for LA in patients from Germany with elevated Lp(a) and established cardiovascular disease (CVD). Adult patients with Lp(a) levels >60 mg/dl who had undergone ≥35 LA sessions in the prior year were randomized to receive pelacarsen 80 mg or placebo every 4 weeks for 52 weeks. Weekly LA sessions were performed if the Lp(a) measurement from the prior visit was >60 mg/dL. The primary endpoint was the rate of performed LA sessions normalized to the weekly LA schedule (the number of actual LA sessions divided by the number of planned LA sessions during the 52-week period). Secondary endpoints were time to LA avoidance (for ≥24 consecutive weeks) and total LA avoidance from week 12 to week 52. Fifty-one patients were randomized (mean age 61.7 years, mean Lp(a) at baseline 85.4 mg/dL, and mean 44.0 LA sessions in the past 12 months), with 25 of 26 (96.2%) in the pelacarsen arm and 23 of 25 (92.0%) in the placebo arm completing the study. Baseline characteristics were generally balanced between treatment arms. Pelacarsen reduced the mean rates of LA (0.16 vs 0.93 in placebo, odds ratio 0.006, 95% confidence interval [CI] 0.003, 0.013; P < .0001) and substantially increased the hazard of achieving LA avoidance (hazard ratio: 88.3; P = .0014; median time to achieve LA avoidance: 6.1 weeks) and total LA avoidance (odds ratio: 163.2; P = .0005). The placebo-adjusted Lp(a) change from baseline at week 52 was -72% (95% CI: -79%, -61%; P < .0001). Treatment emergent adverse events were similar between arms, except for mostly mild injection site erythema (pelacarsen 38.5%; placebo 0%). Pelacarsen is a highly effective and well-tolerated Lp(a)-targeted therapy that substantially reduces the need for LA in patients with elevated Lp(a) and established CVD. NCT05305664.

Lipoprotein(a)-lowering therapies: a promising future.

Recurrent focal segmental glomerulosclerosis (rFSGS) is a significant cause of graft failure in pediatric patients. Low-density lipoprotein apheresis (LDL-A) is an FDA-approved treatment for pediatric FSGS, but its efficacy is unclear. This systematic review and descriptive meta-analysis aimed to determine the efficacy of LDL-A in pediatric kidney transplant recipients with rFSGS. We performed a comprehensive search in Ovid MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Embase (Elsevier), CINAHL (EBSCO), and Scopus (Elsevier) on May 14th, 2024. Studies deemed eligible to be included were case reports, case series, randomized controlled trials, non-randomized controlled trials, and observational studies that reported patient-level data for subjects less than 18years old who were administered any protocol of LDL-A following FSGS recurrence post-kidney transplant, and that provided remission status and urine protein-creatinine ratio (UPCR) ranges or values from at least one follow-up after LDL-A initiation. From the 8 studies that met the inclusion criteria, there were 25 patients who received LDL-A following rFSGS diagnosis post-transplant who were included for meta-analysis. Each study was assessed for selection bias, attrition bias, reporting bias, publication bias, and funding conflicts. The remission status for each patient was determined by the UPCR measured at the latest follow-up reported. Complete remission was defined as UPCR 0.2g/g, partial remission as UPCR between 0.2 and 2.0g/g, and no remission as UPCR 2.0g/g. For our main outcome, the proportions of patients that achieved complete or partial remission were determined by study, then pooled estimates of effect size were calculated using a random-effects inverse-variance model. As a secondary outcome, the average effects of LDL-A on measures of kidney function were quantified by determining the median across individual changes in serum albumin, serum creatinine, estimated glomerular filtration rate (eGFR), and UPCR. Finally, subgroup analyses comparing remissions between LDL-A protocols were performed using Fisher's exact test. The pooled proportion of patients that achieved complete remission or partial remission was 0.36 (95% confidence interval (CI), 0.13-0.61) and 0.37 (95% CI, 0.14-0.62), respectively, at a median follow-up duration of 8months (IQR 6-24months) after LDL-A initiation. Median serum albumin and eGFR values were increased following LDL-A while UPCR decreased, consistent with clinical improvement. No significant differences in remissions were detected between LDL-A protocols, though the detection of real effects may be limited due to small sample sizes and heterogeneity. All the included studies have moderate/high risk of bias due to study type, report type, and sample size. There is substantial variability between LDL-A protocols and previous treatments received by patients, possibly contributing to heterogeneity in outcomes between studies. LDL-A achieved a complete remission rate of 36% (95% CI, 0.13-0.61) and a partial remission rate of 37% (95% CI, 0.14-0.62). Despite limited cases, LDL-A may be effective for pediatric rFSGS post-kidney transplant, warranting studies on its early use post-transplant. PROSPERO (ID CRD42024544869).

Lipoprotein apheresis (LA) may influence hemostasis, but reported effects are inconsistent. We quantitatively assessed changes in fibrinogen, plasminogen, activated partial thromboplastin time (aPTT) and thrombin time (TT). Following PRISMA, PubMed, Scopus, and Web of Science were searched to August 2025 for observational human studies reporting pre-/post-apheresis values. Weighted mean differences (WMD) with 95% confidence intervals (CIs) were pooled using random- or fixed-effects models according to heterogeneity. Prespecified subgroups compared modality (DALI, HELP) and treatment duration (≤ 1 year, > 1 year). Meta-regression, publication bias and leave-one-out sensitivity analyses were performed. From 678 records, 38 publications were eligible. LA reduced fibrinogen (60 studies; n = 1615; WMD = -107.46 mg/dL, 95% CI: -125.3 to -89.63; p < 0.001) and prolonged aPTT (14 studies; n = 406; WMD = +47.9 s, 95% CI: 34.29-61.51; p < 0.001). No significant change was observed for plasminogen (5 studies; n = 171; WMD = -1.89 mg/dL, 95% CI: -5.14 to 1.36; p = 0.29) or TT (4 studies; n = 54; WMD = +2.56 s, 95% CI: -0.25 to 5.37; p = 0.59). Fibrinogen fell with both modalities and durations, greater with HELP (-139.13 mg/dL) than DALI (-58.9 mg/dL). aPTT increased with both, numerically larger with DALI (+90.21 s) than with HELP (+26.95 s). Repeated LA lowers fibrinogen and prolongs aPTT, with no clear pooled effect on plasminogen or TT. These findings support routine periprocedural coagulation monitoring and standardized reporting across modalities.

Lipoprotein apheresis (LA) is an established therapy for severe, drug-refractory dyslipidemias. Nevertheless, clinicians often monitor hepatic and muscle enzymes during treatment because transient biochemical shifts can be misinterpreted as injury. In this study, we synthesize the evidence on how repeated apheresis sessions affect circulating enzymes. We systematically searched PubMed, Scopus and Web of Science from inception to August 2025 for observational human studies reporting pre- and post-apheresis values (mean and SD) for aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK). Effects were expressed as weighted mean differences (WMD, IU/L). Of 267 records screened, 9 articles (published 1998-2006) met eligibility for quantitative synthesis, yielding 9 ALT, 8 AST, 7 ALP, 6 GGT, 9 LDH and 6 CPK study estimates. Pooled analyses showed significant decreases in AST (WMD = -0.87; 95% CI: -1.51 to -0.23; p = 0.007), ALP (WMD = -6.28; CI: -11.75to -0.80; p = 0.02), LDH (WMD = -11.12; CI: -17.01 to -5.24; p = 0.001) and CPK (WMD = -6.91; CI: -13.06 to -0.75; p = 0.02). However, levels of ALT (WMD = -0.78; CI: -2.10 to 0.53; p = 0.29) and GGT (WMD = -2.64; CI: -8.71 to 3.44; p = 0.39) were unchanged. Across repeated-session studies, LA does not elevate hepatic or muscle injury markers and is associated with modest reductions in AST, ALP, LDH, and CPK. These findings support the biochemical safety profile of apheresis and suggest that routine enzyme monitoring should be interpreted in context.

Children and adolescents with homozygous familial hypercholesterolemia (HoFH) routinely require advanced lipid-lowering therapies (LLTs). We assess the long-term efficacy and safety of evinacumab, a novel LLT, in children and adolescents with HoFH. Study 17100 (NCT04233918) was a phase 3, single-arm, open-label study enrolling 20 children aged 5-11 years with HoFH. ELIPSE-OLE (NCT03409744) was a phase 3, single-arm study enrolling 14 adolescents aged 12-17 years with HoFH. Participants received intravenous evinacumab 15mg/kg every 4 weeks; all individuals received stable LLT and most received lipoprotein apheresis (60% of children aged 5-11 years; 64% of adolescents aged 12-17 years). Outcomes included change from baseline to weeks 48 and 72 in low-density lipoprotein cholesterol (LDL-C) and other lipid parameters. Safety was assessed as treatment-emergent adverse events (TEAEs). In children aged 5-11 years, mean (standard deviation [SD]) baseline LDL-C (301.9 [149.1] mg/dL) was lowered by 45% (131.1mg/dL) at week 48 and 41% (115.8mg/dL) at week 72. In adolescents aged 12-17 years, mean (SD) baseline LDL-C (300.4 [100.5] mg/dL) was lowered by 48% (156.4mg/dL) at week 48 and 51% (165.6mg/dL) at week 72. TEAEs occurred in 100% and 86% of participants aged 5-11 and 12-17 years, respectively. TEAEs were considered treatment related in four individuals aged 5-11 years (20%); no one aged 12-17 years had treatment-related TEAEs (0%). Evinacumab markedly reduced LDL-C in children and adolescents with HoFH, beyond optimized standard LLT and lipoprotein apheresis. LDL-C remains above goal in most pediatric patients with HoFH, and evinacumab should be routinely considered whenever further LDL-C lowering is needed.

BackgroundHomozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by extreme elevations in low-density lipoprotein cholesterol levels and premature cardiovascular disease.ObjectivesThe objective of this study was to assess the prevalence, clinical presentation, and current therapeutic approaches for aortic stenosis in Canadian patients with HoFH.MethodsDemographic data, lipid profiles, and genetic testing results for patients with HoFH were collected prospectively since 2008. Reports from echocardiography, cardiac catheterization, and surgical or transcatheter interventions involving the aortic valve and/or ascending aorta were retrieved from medical records.ResultsData were available for 63 patients with either a clinical diagnosis (n = 14, 22.2%) or genetic confirmation (n = 49, 77.8%) of HoFH. The median age at diagnosis was 14.0 years (Q1-Q3: 6.0 to 31.0), the median highest recorded low-density lipoprotein cholesterol level was 13.0 mmol/L (Q1-Q3: 10.6-16.3), and 17 patients (27.0%) developed moderate-to-severe aortic stenosis. Extensive calcification of the aortic valve and ascending aorta, combined with severe valvular and/or supravalvular stenosis and coronary ostial stenosis, necessitated complex and often consecutive surgical procedures. Six transcatheter aortic valve replacements were performed in 4 patients, 4 of which failed. Thirteen patients (20.6%) underwent at least 1 surgical aortic valve procedure. Patients developed aortic stenosis at a young age despite intensive treatment, including lipoprotein apheresis started at an early age.ConclusionsModerate-to-severe aortic stenosis was observed in 27.0% of patients in the Canadian HoFH Registry, with 20.6% requiring invasive intervention. The severe aortic phenotype associated with HoFH requires complex, multidisciplinary surgical management in specialized centers with appropriate expertise.

Beyond lipids: Systemic effects of lipoprotein apheresis.