LDL-apheresis Research Articles

The Efficacy of the Transdermal Isosorbide Dinitrate Patch in Patients With Chronic Limb-Threatening Ischemia.

Recently, the number of patients with peripheral artery disease (PAD), including those with chronic limb-threatening ischemia (CLTI), has increased because of the increasing number of diabetic or dialysis patients worldwide. Revascularization is an important therapy for patients with CLTI. However, we sometimes experience refractory cases with insufficient peripheral circulation or microcirculation after revascularization. In this situation, additional therapy can be administered, such as low-density lipoprotein apheresis, high-pressure oxygen therapy, and spinal cord stimulation. However, they are not effective in some cases. Some reports have also indicated that transdermal isosorbide dinitrate patch (ISDN-P) is a useful therapy for PAD. As the efficacy of ISDN-P for patients with CLTI is not well-known, we examined it in this study. We assessed the skin perfusion pressure (SPP) after affixing an ISDN-P on the foot, because SPP measurement has proved useful in the assessment of PAD and is a good indicator of wound healing potential. The SPP (dorsal and plantar aspects) after ISDN-P application on the foot of healthy volunteers increased (n = 8; mean ± SD, 12.6 ± 7.9 [P = .12], and 21.2 ± 7.7 mm Hg [P < .05], respectively), as did SPP of patients with CLTI (n = 10; mean ± SD, 19.8 ± 2.5 [P < .01], and 14.1 ± 5.9 mm Hg [P < .05], respectively). All the patients who received an ISDN-P on the foot had no major complication, and no significant change in blood pressure. In conclusion, the ISDN-P is one of the effective and safe therapies for patients with CLTI.

Concurrent minimal change nephrotic syndrome and type 1 diabetes mellitus in an adult Japanese woman: a case report

BackgroundConcurrent type 1 diabetes mellitus (T1DM) and idiopathic nephrotic syndrome is rare, and most previously reported cases were in children. We report the case of an adult woman who developed T1DM and minimal change nephrotic syndrome (MCNS) nearly simultaneously.Case presentationA 24-year-old woman had first presented to another hospital with nausea, vomiting, and fatigue. She was diagnosed with diabetic ketoacidosis and T1DM on the basis of her hyperglycemia, ketoacidosis, and positive anti-glutamic acid decarboxylase antibody test result. Rapid infusion of normal saline and insulin administration alleviated hyperglycemia and ketoacidosis. Two weeks after admission, however, she developed nephrotic syndrome (NS) with rapidly decreasing urine volume. She was referred to our hospital with a diagnosis of acute kidney injury. Although she temporarily required dialysis and high doses of insulin, within 1 month NS and acute kidney injury had been alleviated by oral prednisolone and low-density lipoprotein apheresis. Renal biopsy showed minor glomerular abnormalities without diabetic nephropathy, so we diagnosed her with MCNS. Seven weeks after the discharge, NS relapsed, and cyclosporine was added to prednisolone. However, NS relapsed twice within the next 4 months, so we started her on rituximab. At 6 months after initiating rituximab therapy, she remained in complete remission.Her mother also had T1DM but not MCNS. The patient had HLA-DRB1*09:01/09:01, DQB1*03:03/03:03, and her mother had HLA-DRB1*04:05/09:01, DQB1*03:03/04:01.ConclusionsConcurrent T1DM and MCNS is rare and their coexistence might be coincidental. Alternatively, they might have been caused by an underlying, unidentified genetic predisposition. Previous reports and our patient’s findings suggest that specific HLA alleles and haplotypes or a Th1/Th2 imbalance might be associated with T1DM and MCNS that occurred nearly simultaneously.

Review of LDL-C Lowering with Focus on New and Emerging Agents

Identify the benefits and limitations of statin therapy as a treatment option for lowering LDL-C. Intensify treatment in appropriate patients or refer for intensification. Describe the safety and efficacy of ezetimibe, bempedoic acid, PCSK9 inhibitors, LDL apheresis. Describe the safety and efficacy of medications in late-stage development or under review by the FDA for LDL-C reduction.

Effects of LDL apheresis on proteinuria in patients with diabetes mellitus, severe proteinuria, and dyslipidemia

Patients with diabetes mellitus and severe proteinuria present with poor renal prognoses, despite improvements in diabetes and kidney disease therapies. In this study, we designed a low-density lipoprotein (LDL)-cholesterol apheresis treatment for patients with diabetic nephropathy (DN)/diabetic kidney disease and severe proteinuria. This was a multicenter prospective LICENSE study to confirm the impact of LDL apheresis on proteinuria that exhibited hyporesponsiveness to treatment. In addition, we sought to determine the efficacy and safety of LDL apheresis by comparing the outcomes to those of historical controls in patients with diabetes, refractory hypercholesterolemia, and severe proteinuria. This was a prospective, multicenter study, including 40 patients with diabetes, severe proteinuria, and dyslipidemia. LDL apheresis was performed 6-12 times over a 12-week period. The primary endpoint was the proportion of patients with a decrease in proteinuria excretion of at least 30% in the 6months after starting therapy. The secondary endpoints included serum creatinine levels and laboratory variables, which were evaluated 4, 6, 12, 18, and 24months after therapy initiation. LDL apheresis was performed on 40 registered patients with diabetes. The proportion of cases in which proteinuria decreased by 30% or more after 6months of LDL apheresis was 25%, which was similar to that of historical controls. The overall survival and end-stage kidney disease-free survival rates were significantly higher in the LICENSE group compared to those in historical controls. Our results suggest that LDL apheresis may be effective and safe for patients with diabetes, proteinuria, and dyslipidemia. Trial registration number: jRCTs042180076.

Loss-of-function mutation of PCSK9 as a protective factor in the clinical expression of familial hypercholesterolemia

Rationale:Proprotein convertase subtilisin/kexin 9 or PCSK9 is a protein whose main function is to regulate the number of low-density lipoprotein receptors (LDLR) present on the cell surface. Loss-of-function mutations in PCSK9 have been related to low LDL-cholesterol levels and a decrease in the risk of cardiovascular events.Patient concerns:We present the case of a 27-year-old woman, offspring of a patient with familial homozygous hypercholesterolemia, who presented with mild-moderate hypercholesterolemia.Diagnosis:Genetic analysis was performed by next generation sequencing using a customized panel of 198 genes. Sanger sequencing was used to confirm the presence of the variants of interest. The genetic analysis showed a pathogenic heterozygous mutation in LDLR [exon 6:c.902A>G:p(Asp301Gly)], as well as a loss-of-function heterozygous variant in PCSK9 [exon1:c.137 G>T:p.(Arg46Leu)]. The genetic analysis of the index case's mother revealed compound heterozygosity for 2 different mutations in LDLR [c.902A>G:p.(Asp301Gly); c.1646G>T:p.(Gly549Val)] in exon 6 and in exon 11, respectively, and the same loss-of-function variant in PCSK9 that had been found in her daughter [(PCSK9:exon1:c.137G>T:p.(Arg46Leu)]. The maternal grandfather of the index case presented the same genetic variants as his granddaughter.Interventions:The index case did not receive any specific treatment for hypercholesterolemia. The loss-of-function variant in PCSK9 protected her from higher LDL-cholesterol levels, provided she kept partial activity of the LDLR. In her mother, instead, a PCSK9 inhibitor was tried but failed to achieve lipid control. The reason for this may be the complete absence in LDL receptor activity. LDL apheresis was started afterwards, resulting in adequate lipid level control.Outcomes:To the date, the index case has achieved to maintain adequate total and LDL-cholesterol levels without any other intervention. She has had no known cardiovascular complication.Lessons:Loss-of-function mutations in PCSK9 could protect from developing more severe forms of hypercholesterolemia. The finding of these mutations (LDLR-PCSK9) in three consecutive generations could imply an adaptive mechanism against the development of hypercholesterolemia.

Lomitapide for treatment of homozygous familial hypercholesterolemia: The Québec experience

Background and aimsHomozygous familial hypercholesterolemia (HoFH) is an orphan disease, most often caused by bi-allelic mutations of the LDLR gene. Patients with HoFH have elevated LDL-C levels >13 mmol/L, tendinous xanthomata and severe, premature atherosclerotic cardiovascular disease (ASCVD). Untreated, most HoFH patients die of ASCVD in youth. New therapeutic modalities include lomitapide, an inhibitor of microsomal triglyceride transfer protein that lowers hepatic LDL-C production. We have recently identified 79 Canadian patients with HoFH. Here, we describe our experience with lomitapide in the province of Quebec, a geographic area known to have a high prevalence of HoFH. MethodsThis is a retrospective case series of 12 HoFH patients followed at three lipidology centers in the province of Quebec. ResultsMean age of the patients was 44 ± 18 years; age at time of HoFH diagnosis ranged from 2 to 59 years. All patients were on a statin and ezetimibe 10 mg/day and five patients were treated with LDL apheresis. Treatment with lomitapide reduced LDL-C levels by 38% (intention-to-treat). Intolerable gastrointestinal side effects were observed in 3/12 patients and were the main reason for treatment discontinuation. Three patients tolerated lomitapide at doses ranging between 5 and 30 mg/day without major side effects. Downwards drug titration was necessary in the 6 remaining patients because of gastrointestinal side effects (n = 5) and elevated liver enzymes (n = 1), and 2 of them finally discontinued treatment. ConclusionsLomitapide may be used to further decrease LDL-C in HoFH patients; gastrointestinal side effects and hepatic toxicity may limit adherence.

Plaque Regression and Endothelial Progenitor Cell Mobilization With Intensive Lipid Elimination Regimen (PREMIER).

Low-density lipoproteins (LDLs) are removed by extracorporeal filtration during LDL apheresis. It is mainly used in familial hyperlipidemia. The PREMIER trial (Plaque Regression and Progenitor Cell Mobilization With Intensive Lipid Elimination Regimen) evaluated LDL apheresis in nonfamilial hyperlipidemia acute coronary syndrome patients treated with percutaneous coronary intervention. We randomized 160 acute coronary syndrome patients at 4 Veterans Affairs centers within 72 hours of percutaneous coronary intervention to intensive lipid-lowering therapy (ILLT) comprising single LDL apheresis and statins versus standard medical therapy (SMT) with no LDL apheresis and statin therapy alone. Trial objectives constituted primary safety and primary efficacy end points and endothelial progenitor cell colony-forming unit mobilization in peripheral blood. Mean LDL reduction at discharge was 53% in ILLT and 17% in SMT groups (P<0.0001) from baseline levels of 116.3±34.3 and 110.7±32 mg/dL (P=0.2979), respectively. The incidence of the primary safety end point of major peri-percutaneous coronary intervention adverse events was similar in both groups (ILLT, 3; SMT, 0). The primary efficacy end point, percentage change in total plaque volume at 90 days by intravascular ultrasound, on average decreased by 4.81% in the ILLT group and increased by 2.31% in the SMT group (difference of means, -7.13 [95% CI, -14.59 to 0.34]; P=0.0611). The raw change in total plaque volume on average decreased more in the ILLT group than in the SMT group (-6.01 versus -0.95 mm3; difference of means, -5.06 [95% CI, -11.61 to 1.48]; P=0.1286). Similar results were obtained after adjusting for participating sites, age, preexisting coronary artery disease, diabetes mellitus, baseline LDL levels, and baseline plaque burden. There was robust endothelial progenitor cell colony-forming unit mobilization from baseline to 90 days in the ILLT group (P=0.0015) but not in SMT (P=0.0844). PREMIER is the first randomized clinical trial to demonstrate safety and a trend for early coronary plaque regression with LDL apheresis in nonfamilial hyperlipidemia acute coronary syndrome patients treated with percutaneous coronary intervention. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01004406 and NCT02347098.

P0764STUDY OF 15 CASES OF CHOLESTEROL CRYSTAL EMBOLISM WITH LOW-DENSITY LIPOPROTEIN APHERESIS

Abstract Background and Aims Cholesterol crystal embolism (CCE) causes renal damage, and there is a high risk of end-stage renal disease. Corticosteroids, statins and low-density lipoprotein apheresis (LDL-A) have been used to treat CCE, but the prognosis remains poor and treatment not yet established. This study evaluated the efficacy of LDL-A in patients with CCE. Method We performed a retorospective study of 15 Japanese patients in clinical and histological diagnosis of CCE was made April 2015 to December 2017. 10(67%) patients were diagnosed pathologically on skin biopsy and others were diagnosed clinically. All patients had shown CKD with eGFR &amp;lt;60 mL/min/1.73m2 before being diagnosed with CCE. All patients received LDL-A; of these, 13 (87%) also received corticosteroids. The median estimated GFR diagnosis (at baseline) were 13.4 mL/min/1.73m2, and were analyzed stratified into High eGFR group(H) and Low eGFR group(L). Differences in eGFR, 1 month, 3 months and 1 year after LDL-A, were compared in these groups. Results High eGFR group was significantly higher than Low eGFR group over all observation periods (at 1 month; H:21.3 ± 8.9 vs L:15.9 ± 5.6, P=0.023, at 3 months; H:25.9 ± 10.3 vs L:15.4 ± 5.4, P=0.035, at 1 year; H:21.7 ± 8.9 vs L:13.2 ± 5.7, P=0.01). In high eGFR group, eGFR was no change during the observation period and no decrease significantly. In Low eGFR group, eGFR increased significantly at 1 month and 3 months compared to baseline (10.5 ± 2.1 at baseline, 15.9 ± 5.6 at 1month, P=0.007, 15.4 ± 5.4 at 3month, P=0.01), but was comparable to baseline at 1 year. Conclusion In this study, introduction of LDL-A may have the effect of maintaining renal function over the long term at 1year regardless of eGFR at diagnosed as CCE.

Mental status and physical activity in patients with homozygous familial hypercholesterolemia: A subgroup analysis of a nationwide survey (A-HIT1 registry)

Homozygous familial hypercholesterolemia (HoFH) is a rare, life-threatening disease due to high serum low-density lipoprotein (LDL) cholesterol levels. LDL cholesterol-lowering interventions are fundamental for patients with HoFH. It was aimed to investigate the association between the mental status of patients with HoFH and healthy lifestyle behaviors. This subgroup analysis of the A-HIT1 population included the data of patients aged ≥18years with a clinical diagnosis of HoFH undergoing therapeutic LDL apheresis. Besides the demographic and clinical characteristics of patients, healthy lifestyle behaviors were assessed, and psychiatric symptoms were screened by Symptom Check List (SCL-90-R). The highest percentage for pathology was observed in dimensions of obsessive-compulsive, somatization, interpersonal sensitivity, and depression in SCL-90-R. Patients with any cardiovascular condition have more psychiatric symptoms in different fields of SCL-90-R. The outcomes of the correlative analysis indicated that lower the age of the first coronary event better the psychiatric status, probably denoting a better adaptation to disease and its treatment. Among 68 patients, 36 patients were not exercising regularly. Patients with regular physical activity had significantly lower scores in most dimensions of SCL-90-R and there was no association between regular physical activity and other investigated variables. The strongest predictor of regular exercising was global severity index of SCL-90-R. In the HoFH population, there was a high prevalence of mental disturbances. Better psychiatric status was associated with regular exercising. Therefore, assessing the mental status of patients with HoFH and referring patients in need, to a psychiatrist, may improve the outcome of patients.

Heparin-induced lipoprotein precipitation apheresis in dyslipidemic patients: A multiparametric assessment.

Low-density lipoprotein (LDL) apheresis (LA) selectively eliminates lipoproteins containing apolipoprotein B 100 (ApoB100) on patients affected by severe dyslipidemia. In addition to lowering lipids, LA is thought to exert pleiotropic effects altering a number of other compounds associated with atherosclerosis, such as pro- and anti-inflammatory cytokines or pro-thrombotic factors. More knowledge needs to be gathered on the effects of LA, and particularly on its ability to modify blood components other than lipids. We performed a multiparametric assessment of the inflammatory, metabolic and proteomic profile changes after Heparin-induced lipoprotein precipitation (H.E.L.P.) apheresis on serum samples from nine dyslipidemic patients evaluating cholesterol and lipoproteins, plasma viscosity and density, metabolites, cytokines, PCSK9 levels and other proteins selectively removed after the treatment. Our results show that H.E.L.P. apheresis is effective in lowering lipoprotein and PCSK9 levels. Although not significantly, complement and inflammation-related proteins are also affected, indicating a possible transient epiphenomenon induced by the extracorporeal procedure.

Evaluation of lipid services in the Republic of Ireland.

Abnormal cholesterol profiles are a major risk factor for cardiovascular disease and severe triglyceride disorders cause life threatening pancreatitis. Identification and treatment of these disorders are essential. We evaluated the services available in Ireland to manage these problems. We contacted key personnel in 40 hospitals, 32 public and 8 private providing lipid measurements to assess investigation and treatment availability during 2017/2018. In public hospitals, 4 had designated lipid clinics (Dublin 3, Galway 1) (2.9 times < UK), 19 had general clinics and 9 had no service. In private hospitals, 2 had designated clinics, Limerick and Cork, and others had interested physicians. Clinics were run by cardiologists, chemical pathologists, endocrinologists or clinical pharmacologists. One clinic had a lipid nurse versus 75% in the UK. All but one provided full lipid profiles, 15 ordered Lp(a), 9 apoproteins B/A-1 and 9 genetic testing. Lp(a) and apoprotein measurements were provided locally in one hospital and one provided genetic testing. Lipid-lowering drugs were used in all hospitals and 45% had access to PCSK-9 inhibitors. No hospital provided LDL apheresis or plasma exchange. Limitations for service provision included lack of physician interest n= 9, nursing support n= 22, office space n= 13, clinic space n= 22, laboratory support n= 16, nutritional support n= 12 and pharmacy support n= 5. There are very limited resources available to manage lipid problems in the republic of Ireland relative to the under-resourced UK. Most services rely on interested physicians but ancillary resources are lacking. Where services are available, all drug treatments are utilised.

Lomitapide treatment in a female with homozygous familial hypercholesterolaemia: a case report.

BackgroundHomozygous familial hypercholesterolaemia (FH) is an autosomal-dominant inherited disease presenting with highly elevated low-density lipoprotein cholesterol (LDL-C) levels. Untreated, the patient can develop atherosclerosis and cardiovascular disease already in adolescence. Treatment with statins and ezetimibe is usually not sufficient and LDL apheresis is often required. Lomitapide, an inhibitor of the microsomal triglyceride transfer protein, reduces LDL-C and triglyceride levels and can be used alone or in combination with other therapies in homozygous FH. However, experience with this agent is still limited.Case summaryWe present a young female who was diagnosed with homozygous FH at 6 years of age. She shows a complete lack of normal LDL receptor activity and no cholesterol-lowering effect from statins. The patient was treated with LDL apheresis from 7 years of age. When LDL apheresis treatment extended to twice a week, she began to experience adverse effects, including catheter-related complications, infections, and hospital admissions. When lomitapide treatment was initiated, the frequency of apheresis reduced, the LDL-C levels improved and she has not had any further hospital admissions since. Initially, she suffered from gastrointestinal disturbances. However, after 3 years of treatment with lomitapide 20 mg/day, the patient has not experienced any adverse effects.DiscussionIn this female with homozygous FH adding lomitapide treatment to LDL apheresis has contributed to improved LDL-C levels, a reduction in LDL apheresis sessions and enhanced quality of life. No adverse effects have been reported. These findings suggest that lomitapide can be a drug of choice in patients with homozygous FH.

Autosomal recessive hypercholesterolemia: Case report

Autosomal recessive hypercholesterolemia (ARH; OMIM #603813) is a very rare monogenic disorder affecting less than 1 in 1000,000 people and is characterized by very high levels of low-density lipoprotein cholesterol (LDL-C), leading to aggressive and premature atherosclerotic cardiovascular disease if left untreated. Lowering of LDL-C is the main target of the treatment. We report on a 29-year-old male patient born in nonconsanguineous Lithuanian family homo(hemi-)zygous for LDLRAP1 gene variant causing ARH. This variant is not present in population databases and, to our knowledge, has not been reported in scientific literature before. The earliest clinical sign, noticed at the age of 5 years, was painful and enlarging nodules on Achilles tendons. At the age of 10 years, xanthomas of the metacarpal joint area on both hands emerged. The first lipid panel was performed at the age of 12 years. In accordance with Dutch Lipid Clinic Network diagnostic criteria for familial hypercholesterolemia (FH), definite FH (type IIA hyperlipoproteinemia) was diagnosed and the treatment with cholestyramine 4 grams per day was initiated. As the patient was 15 years old, direct adsorption of low-density lipoprotein apheresis was started and repeated monthly. At the age of 20 years, along with lipoprotein apheresis, 10 mg of rosuvastatin daily intake was prescribed. At the age of 28 years, the dose of rosuvastatin was increased to 40 mg per day, and 10 mg of ezetimibe daily intake was added. At the age of 28 years, homozygous LDLRAP1 gene variant NM_015627.2:c.488A>C, NP_056442.2:p.(Gln163Pro) causing autosomal recessive hypercholesterolemia was determined by genetic testing. This case report implies that ARH, being an extremely rare disorder, is a severe disease. As there is limited routine testing, including genetic testing, patients suffering from both this disease and FH may remain undiagnosed. Cascade screening and genetic counseling differ for ARH as compared with FH, as the carrier of a pathogenic variant in the LDLRAP1 gene does not have marked total cholesteroland LDL-C elevations. However, genetic testing of the proband and their relatives is essential to evaluate the risk of development of FH and to provide prognosis as well as adequate, timely treatment. To improve the quality of life of patients with FH and prolong their life expectancy, national registries of FH and wider laboratory and genetic testing are undoubtedly necessary. A national FH screening program was set up in Lithuania, which helps to identify, monitor, and treat subjects with FH.

Implementation and 2‐year outcomes of the first FDA‐approved implantable apheresis vascular access device

Patients requiring chronic apheresis treatments typically lack sufficient peripheral venous access to support long-term therapy. Historically, central venous tunneled catheters, septum-bearing subcutaneous ports, and fistulas were used to obtain required blood flow rates for apheresis procedures. In 2017, the US Food and Drug Administration approved the first intravascular device specifically designed for apheresis therapy, the PowerFlow Implantable Apheresis IV Port. Several preimplementation meetings with key hospital stakeholders were held to determine the most efficient and safest strategy for integrating the PowerFlow device into our practice. Interventional radiologists implanted the apheresis port in patients meeting specified criteria. Performance metrics and adverse events were evaluated over a 2-year period, July 2017 through June 2019. Eighteen patients underwent apheresis therapy using the PowerFlow port. The most common apheresis therapy provided was extracorporeal photopheresis, followed by therapeutic plasma exchange and low-density lipoprotein apheresis. Flow rates up to 90 mL/min were obtained; the rates were limited by patient tolerance for the apheresis procedure. Complications included infection, obstruction due to fibroblastic sleeve, and migration of the vascular device. The estimated risk of PowerFlow-associated bloodstream infection in the study population was 0.18 per 1000 intravascular device days. The PowerFlow Implantable Apheresis IV Port can achieve flow rates necessary for all apheresis therapies and is a promising alternative vascular access device for patients undergoing apheresis.

Suggested clinical approach for the diagnosis and management of ‘statin intolerance’ with an emphasis on muscle‐related side‐effects

Hyperlipidaemia is a major risk factor for cardiovascular morbidity and mortality. 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors ('statins') are first-line therapies for hyperlipidaemia. For each 1.0 mmoL/L reduction in low-density lipoprotein (LDL)-cholesterol, statins reduce the risk of major vascular events by 21% and all-cause mortality by 9%. Owing to their clinical effectiveness and excellent safety profile, many Australians are prescribed statins. There has been widespread reporting of possible side-effects, particularly muscle pains. Conversely, statin cessation relating to possible side-effects exposes patients to increased risk of vascular events and death. Although there is clinical consensus for diagnosing rare side-effects (e.g. myopathy or rhabdomyolysis), confirming that statins cause other less common side-effects (e.g. memory impairment) is difficult as strong randomised trial evidence related to statins and non-muscle-related side-effects is lacking. A stepwise approach to possible statin intolerance, consistent definitions and a simple flowchart may improve diagnosis and management. An increasing array of potential treatments is emerging, including intermittent statin dosing, new LDL-lowering drugs, LDL apheresis and supplements. Optimal statin use and management of statin intolerance should improve cardiovascular care and clinical outcomes.

PCSK9 Inhibition: New Treatment Options and Perspectives to Lower Atherogenic Lipoprotein Particles and Cardiovascular Risk.

To summarize latest clinical studies and to put them into perspectives for clinical relevant subgroups and new therapeutic options. Have investigated PCSK9 inhibitors in patients with very high cardiovascular risk and insufficient LDL cholesterol lowering under current maximal tolerated lipid-lowering therapy, patients with statin intolerance, or genetic forms of familiar hypercholesterolemia, and patients on LDL apheresis. Purpose of recent cardiovascular endpoint trials has proven cardiovascular benefit of this new approach. PCSK9 inhibition with fully humanized antibodies has proven to be effective, safe, and well-tolerated in reducing cardiovascular risk by LDL cholesterol lowering. Therefore, research interests are to elucidate additional roles and effects of PCSK9 modulation on inflammation and cellular processes of the atherosclerotic plaque and to develop alternative therapeutic strategies addressing PCSK9 as a proven and therefore promising drug target.

Dyslipidemia and cardiovascular health in childhood nephrotic syndrome.

Children with steroid-resistant nephrotic syndrome (SRNS) are exposed to multiple cardiovascular risk factors predisposing them to accelerated atherosclerosis. This risk is negligible in steroid-sensitive nephrotic syndrome, but a substantial proportion of children with SRNS progress to chronic kidney disease, exacerbating the already existing cardiovascular risk. While dyslipidemia is an established modifiable risk factor for cardiovascular disease in adults with NS, it is uncertain to what extent analogous risks exist for children. There is increasing evidence of accelerated atherosclerosis in children with persistently high lipid levels, especially in refractory NS. Abnormalities of lipid metabolism in NS include hypertriglyceridemia and hypercholesterolemia due to elevated apolipoprotein B-containing lipoproteins, decreased lipoprotein lipase and hepatic lipase activity, increased hepatic PCSK9 levels, and reduced hepatic uptake of high-density lipoprotein. Existing guidelines for the management of dyslipidemia in children may be adapted to target lower lipid levels in children with NS, but they will most likely require both lifestyle modifications and pharmacological therapy. While there is a lack of data from randomized controlled trials in children with NS demonstrating the benefit of lipid-lowering drugs, therapies including statins, bile acid sequestrants, fibrates, ezetimibe, and LDL apheresis have all been suggested and/or utilized. However, concerns with the use of lipid-lowering drugs in children include unclear side effect profiles and unknown long-term impacts on neurological development and puberty. The recent introduction of anti-PCSK9 monoclonal antibodies and other therapies targeted to the molecular mechanisms of lipid transport disrupted in NS holds promise for the future treatment of dyslipidemia in NS.

SUN-034 Liposorber® LA-15 system for LDL apheresis in drug resistant primary focal segmental glomerulosclerosis patients: Interim results from a prospective, multicenter, single-arm intervention study

Focal segmental glomerulosclerosis (FSGS) is the major cause of end stage renal disease (ESRD) in the United States and worldwide. Primary FSGS carries poor prognosis as spontaneous remission is rare and more rapidly progress to ESRD within 2-8 years in nephrotic range proteinuria patients. Management of FSGS patients refractory to standard treatments or resistant to steroids remains a major challenge. Low-density lipoprotein apheresis (LDL apheresis) is a novel therapy for drug resistant (corticosteroids and/or calcineurin inhibitors) primary FSGS and post-renal transplant primary FSGS recurrence.

Effect of Low-Density Lipoprotein Apheresis for Nephrotic Idiopathic Membranous Nephropathy as Initial Induction Therapy.

Low-density lipoprotein apheresis (LDL-A) has been used for nephrotic syndrome (NS) caused by focal segmental glomerulosclerosis in Japan. Idiopathic membranous nephropathy (iMN) can also cause treatment-resistant NS. Therefore, we investigated the effect of LDL-A during initial induction for it. This retrospective, observational, and single-center study enrolled consecutive iMN patients who received steroids from March 2000 to May 2015. We compared data between 11 patients treated with LDL-A (LDL-A group) and 27 patients without (non-LDL-A group) at baseline and 4 and 8 weeks later. Reduction rate of proteinuria and increase rate of serum albumin in LDL-A group were significantly higher than the other after 4 weeks (P = 0.036 and 0.030) and 8 weeks (P = 0.030 and <0.001), respectively. There was no adverse event caused by LDL-A and immunosuppressant dose was not significantly different. In conclusion, LDL-A may be an effective choice for initial induction of nephrotic iMN.

Helper-dependent adenovirus-mediated gene transfer of a secreted LDL receptor/transferrin chimeric protein reduces aortic atherosclerosis in LDL receptor-deficient mice.

Familial hypercholesterolemia (FH) is a genetic hyperlipidemia characterized by elevated concentrations of plasma LDL cholesterol. Statins are not always effective for the treatment of FH patients; unresponsive patients have poor prognosis and rely on LDL apheresis. In the past, we developed safe and effective gene therapy strategies for the expression of anti-atherogenic proteins using PEGylated helper-dependent adenoviral (HD-Ad) vectors. We recently developed a HD-Ad vector for the expression of the soluble form of the extracellular portion of the human LDL receptor (LDLR) fused with a rabbit transferrin dimer (LDLR-TF). We evaluated the efficacy of theLDLR-TF chimeric protein in CHOLDLA7, a cell line lacking LDLR expression, restoring the ability to uptake LDL. Subsequently, we administered intravenously1 × 10E13 vp/kg of this vector in LDLR-deficient mice and observed amelioration of lipid profile and reduction of aortic atherosclerosis. Finally, we studied LDL distribution after HD-Ad vector-mediated expression of LDLR-TF in LDLR-deficient mice and found LDL accumulation in liver, and in heart and intestine. These results support the possibility of lowering LDL-C levels and reducing aortic atherosclerosis using a secreted therapeutic transgene; the present strategy potentially can be modified and adapted to non-systemic gene transfer with expression of the secreted chimeric protein in muscle or other tissues. Intramuscular or local administration strategies could improve the safety profile of this strategy and facilitate applicability.