Clinical practice recommendations on lipoprotein apheresis for children with homozygous familial hypercholesterolaemia: An expert consensus statement from ERKNet and ESPN.

Homozygous familial hypercholesterolaemia is a life-threatening genetic condition, which causes extremely elevated LDL-C levels and atherosclerotic cardiovascular disease very early in life. It is vital to start effective lipid-lowering treatment from diagnosis onwards. Even with dietary and current multimodal pharmaceutical lipid-lowering therapies, LDL-C treatment goals cannot be achieved in many children. Lipoprotein apheresis is an extracorporeal lipid-lowering treatment, which is used for decades, lowering serum LDL-C levels by more than 70% directly after the treatment. Data on the use of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia mainly consists of case-reports and case-series, precluding strong evidence-based guidelines. We present a consensus statement on lipoprotein apheresis in children based on the current available evidence and opinions from experts in lipoprotein apheresis from over the world. It comprises practical statements regarding the indication, methods, treatment goals and follow-up of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia and on the role of lipoprotein(a) and liver transplantation.

An update on lipid apheresis for familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is an inherited metabolic defect leading to increased total cholesterol and low-density cholesterol (LDL) from birth onwards. Homozygous FH, presenting with clear clinical features, has a prevalence of ~ 1 per million. Prevalence of heterozygous FH is 1/500 European population. Atherosclerotic burden depends on the degree and duration of high LDL exposure. In severe cases, early detection is critical, and aggressive lipid-lowering therapies should begin in early childhood to reduce coronary heart disease risk. Pediatric therapeutic concepts correspond to adults and are orientated at LDL plasma concentration. Mean LDL plasma target value during treatment is < 135 mg/dL. Medication in childhood consists of ezetemibe, statins, resins, and PCSK-9 inhibitors, with consideration for age restrictions. Only a minority achieve the treatment target with drug therapy alone. Therapeutic apheresis for the treatment of hypercholesterolemia selectively removes lipoproteins from blood (lipid apheresis (LA)). LA has a long tradition in adult medicine and is also safely used in children by a variety of methods, if customized to special pediatric needs. LA reduces cholesterol levels independently of residual LDL-receptor function and not only achieves reduction or disappearance of xanthomas but also inhibits progression of or mitigates aortic valve stenosis and supravalvular aortic stenosis as well as coronary artery and other atherosclerotic lesions. Cardiovascular prognosis of patients with otherwise untreatable FH depends largely on timely use of LA. Taking into account LA as a lifelong treatment, starting early in childhood, it is important to accommodate therapy modalities, such as treatment frequency and point of time, into the life of the individual.

Phase 1, single-dose study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of etelcalcetide in pediatric patients with secondary hyperparathyroidism receiving hemodialysis.

BACKGROUND: Data on the safety, efficacy of etelcalcetide in children with secondary hyperparathyroidism (sHPT) are limited. METHODS: This phase 1 study (NCT02833857) evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) of single-dose etelcalcetide (0.035 mg/kg intravenously) in pediatric hemodialysis patients (two cohorts; 1: 12-< 18 years; 2: 2-< 12 years). Treatment-emergent adverse events (AEs), PK/PD were assessed post-dose on D1 at 10 min and 4 h, on multiple days until D10, and at end of study (D30). RESULTS: Etelcalcetide administered to 11 patients (mean [SD] age 10.3 [4.3] years; cohort 1, n = 6; cohort 2, n = 5) was well tolerated. AEs were consistent with established safety profiles in adults. Two patients (1 per cohort) reported treatment-related AEs (cohort 1: hypocalcemia; cohort 2: headache, paresthesia, vomiting). No serious AEs or deaths were reported. Mean serum corrected calcium (cCa) for all patients was maintained > 2.25 mmol/L. After etelcalcetide dosing, PK exposures declined, with mean Cmax, AUClast, and AUCinf exposures higher in cohort 1. Median percent change in serum intact parathyroid hormone (iPTH) from baseline (cohort 1: 51.2 pmol/L; cohort 2: 84.0 pmol/L) reached the nadir on D1 at 4 h (cohort 1: - 33.4%; cohort 2: - 64.2%). Mean total calcium and cCa reached nadirs on D3 at 2.39 mmol/L, and ionized Ca on D1 at 4 h. CONCLUSIONS: Single-dose etelcalcetide (0.035 mg/kg) was well tolerated with expected PK and safety profiles. Overall pattern of changes in serum iPTH and serum calcium was similar between cohorts and consistent with expected responses to etelcalcetide.

Cardiovascular Outcome of Pediatric Patients With Bi-Allelic (Homozygous) Familial Hypercholesterolemia Before and After Initiation of Multimodal Lipid Lowering Therapy Including Lipoprotein Apheresis.

Twenty-four patients with bi-allelic familial hypercholesterolemia commencing chronic lipoprotein apheresis (LA) at a mean age of 8.5 ± 3.1 years were analysed retrospectively and in part prospectively with a mean follow-up of 17.2 ± 5.6 years. Mean age at diagnosis was 6.3 ± 3.4 years. Untreated mean LDL-C concentrations were 752 mg/dl ± 193 mg/dl (19.5 mmol/l ± 5.0 mmol/l). Multimodal lipid lowering therapy including LA resulted in a mean LDL-C concentration of 184 mg/dl (4.8 mmol/l), which represents a 75.5% mean reduction. Proprotein convertase subtilisin/kexin type 9-antibodies contributed in 3 patients to LDL-C lowering with 5 patients remaining to be tested. After commencing chronic LA, 16 patients (67%) remained clinically stable with only subclinical findings of atherosclerotic cardiovascular disease (ASCVD), and neither cardiovascular events, nor need for vascular interventions or surgery. In 19 patients (79%), pathologic findings were detected at the aortic valve (AV), which in the majority were mild. AV replacement was required in 2 patients. Mean Lipoprotein(a) concentration was 42.4 mg/dl, 38% had >50 mg/dl. There was no overt correlation of AV pathologies with other ASCVD complications, or Lipoprotein(a) concentration. Physicochemical elimination of LDL particles by LA appears indispensable for patients with bi-allelic familial hypercholesterolemia and severe hypercholesterolemia to maximize the reduction of LDL-C. In conclusion, in this rare patient group regular assessment of both the AV, as well as all arteries accessible by ultrasound should be performed to adjust the intensity of multimodal lipid lowering therapy with the goal to prevent ASCVD events and aortic surgery.

Practice of lipoprotein apheresis and short-term efficacy in children with homozygous familial hypercholesterolemia: Data from an international registry.

BACKGROUND AND AIMS: Homozygous familial hypercholesterolemia (hoFH) may cause life-threatening atherosclerotic cardiovascular disease in childhood. Lipoprotein apheresis (LA) is considered a pivotal treatment option, but data on its efficacy, safety and optimal performance are limited. We therefore established an international registry on the execution and outcomes of LA in HoFH children. Here we report LA policies and short-term outcomes. METHODS: We approached centers worldwide, involved in LA in children with hoFH for participation. We collected information on clinical and treatment characteristics on patients aged 0-19 years between November 2016 and November 2018. RESULTS: We included 50 children, treated at 15 sites. Median (IQR) LDL-C levels at diagnosis, on medication and on LA were 19.2 (16.2-22.1), 14.4 (10.8-16.7) mmol/L and 4.6 mmol/L, respectively. Median (IQR) time between diagnosis and start of LA was 2.8 (1.0-4.7) years. Six (12%) patients developed cardiovascular disease during that period. Most children received LA either weekly (43%) or biweekly (37%). Seven (17%) patients reached mean LDL-C levels <3.5 mmol/L, all of them treated at least weekly. Xanthomas were present in 42 (84%) patients at diagnosis and disappeared completely in 19 (45%) on LA. Side effects of LA were minor. There were significant differences in LA conduction between sites in terms of frequency, responsible medical specialities and vascular access. CONCLUSIONS: LA is a safe treatment and may effectively lower LDL-C in children with HoFH. However, there is room for improvement with respect to time of onset and optimization of LA therapy in terms of frequency and execution.

Case Report: Exome Sequencing Reveals LRBA Deficiency in a Patient With End-Stage Renal Disease.

Background: Lipopolysaccharide-responsive and beige-like anchor protein (LRBA) deficiency is characterized by autoimmunity, chronic diarrhea, and immunodeficiency. Minor renal manifestations have been found in a few patients, but kidney disease has not been systematically studied and may remain underdiagnosed in this highly variable entity. Results: Our patient initially presented with pancytopenia, enteropathy, hypogammaglobulinemia, and failure to thrive at the age of 15 months. Chronic kidney disease was diagnosed at 6 years. A renal biopsy taken at 11 years of age showed interstitial nephritis. The patient progressed rapidly to end-stage renal disease (ESRD) and underwent kidney transplantation at the age of 12 years. Bronchiolitis obliterans, post-transplant lymphoproliferative disease (PTLD), and chronic rejection complicated the post-transplant management. Graft loss required reinstitution of hemodialysis within 3 years. After negative results of different targeted sequencing strategies, exome sequencing identified a homozygous nonsense mutation (p.Q1010*) in the LRBA gene more than 21 years after the patient's initial presentation. Conclusions: We report here the development of ESRD and long-term follow-up in a patient with LRBA deficiency. A molecular diagnosis in rare (kidney) disease like LRBA deficiency bears many advantages over a descriptive diagnosis. A precise diagnosis may result in improved (symptomatic) treatment and allows differentiating treatment- and procedure-related complications from manifestations of the primary disease.

Acute dialysis in children: results of a European survey.

The number of children with acute kidney injury (AKI) requiring dialysis is increasing. To date, systematic analysis has been largely limited to critically ill children treated with continuous renal replacement therapy (CRRT). We conducted a survey among 35 European Pediatric Nephrology Centers to investigate dialysis practices in European children with AKI. Altogether, the centers perform dialysis in more than 900 pediatric patients with AKI per year. PD and CRRT are the most frequently used dialysis modalities, accounting for 39.4% and 38.2% of treatments, followed by intermittent HD (22.4%). In units treating more than 25 cases per year and in those with cardiothoracic surgery programs, PD is the most commonly chosen dialysis modality. Also, nearly one quarter of centers, in countries with a gross domestic product below $35,000/year, do not utilize CRRT at all. Dialysis nurses are exclusively in charge of CRRT management in 45% of the cases and pediatric intensive care nurses in 25%, while shared management is practiced in 30%. In conclusion, this survey indicates that the choice of treatment modalities for dialysis in children with AKI in Europe is affected by the underlying ethiology of the disease, organization/set-up of centers and socioeconomic conditions. PD is utilized as often as CRRT, and also intermittent HD is a commonly applied treatment option. A prospective European AKI registry is planned to provide further insights on the epidemiology, management and outcomes of dialysis in pediatric AKI.

Neutral pH and low-glucose degradation product dialysis fluids induce major early alterations of the peritoneal membrane in children on peritoneal dialysis.

The effect of peritoneal dialysates with low-glucose degradation products on peritoneal membrane morphology is largely unknown, with functional relevancy predominantly derived from experimental studies. To investigate this, we performed automated quantitative histomorphometry and molecular analyses on 256 standardized peritoneal and 172 omental specimens from 56 children with normal renal function, 90 children with end-stage kidney disease at time of catheter insertion, and 82 children undergoing peritoneal dialysis using dialysates with low-glucose degradation products. Follow-up biopsies were obtained from 24 children after a median peritoneal dialysis of 13 months. Prior to dialysis, mild parietal peritoneal inflammation, epithelial-mesenchymal transition and vasculopathy were present. After up to six and 12 months of peritoneal dialysis, blood microvessel density was 110 and 93% higher, endothelial surface area per peritoneal volume 137 and 95% greater, and submesothelial thickness 23 and 58% greater, respectively. Subsequent peritoneal changes were less pronounced. Mesothelial cell coverage was lower and vasculopathy advanced, whereas lymphatic vessel density was unchanged. Morphological changes were accompanied by early fibroblast activation, leukocyte and macrophage infiltration, diffuse podoplanin presence, epithelial mesenchymal transdifferentiation, and by increased proangiogenic and profibrotic cytokine abundance. These transformative changes were confirmed by intraindividual comparisons. Peritoneal microvascular density correlated with peritoneal small-molecular transport function by uni- and multivariate analysis. Thus, in children on peritoneal dialysis neutral pH dialysates containing low-glucose degradation products induce early peritoneal inflammation, fibroblast activation, epithelial-mesenchymal transition and marked angiogenesis, which determines the PD membrane transport function.

Multimodal lipid-lowering treatment in pediatric patients with homozygous familial hypercholesterolemia-target attainment requires further increase of intensity.

BACKGROUND: Familial hypercholesterolemia (FH) causes premature cardiovascular disease (CVD). Lipoprotein apheresis (LA) is recommended as first-line lipid-lowering treatment (LLT) for homozygous (ho) FH. METHODS: Efficacy of multimodal LLT including lifestyle counseling, drug treatment, and LA was analyzed in 17 pediatric hoFH or compound heterozygous (c-het) FH patients, who commenced chronic LA in Germany before the age of 18. RESULTS: At time of diagnosis, mean low-density lipoprotein cholesterol (LDL-C) concentration was 19.6 mmol/l (756 mg/dl). Multimodal LLT resulted in 73% reduction of mean LDL-C concentration including a 62% contribution of LA. Only three children (18%) achieved mean LDL-C concentrations below the recommended pediatric target of 3.5 mmol/l (135 mg/dl). In 13 patients (76%) during chronic LA, neither cardiovascular events occurred nor was CVD progression detected clinically or by routine imaging techniques. In four patients (24%), cardiovascular events documented progression of CVD despite weekly LA, including one death due to coronary and cerebrovascular CVD which was not stabilized after commencing LA. Based on the mutational status, only 6 out of the 17 children were candidates for proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibition. Two already responded with further LDL-C decrease by 40%. CONCLUSIONS: Next to drug therapy, regular LA is an essential component of LLT for approaching LDL-C targets in children with hoFH or c-hetFH, which was successful only in a minority of children. Progression of CVD morbidity and resulting mortality remain unresolved issues. Early and intensified multimodal LLT guided by risk factors beyond LDL-C concentration is needed to improve outcome.

Disease control via intensified lipoprotein apheresis in three siblings with familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH), the prevalent monogenic form of hypercholesterolemia, carries the risk of premature coronary heart disease. Lipoprotein-apheresis is established in children with severe dyslipidemia. We present 3 siblings with a negative/negative residual low-density lipoprotein (LDL) receptor mutation (p.Trp577Arg), unresponsive to drug treatment. OBJECTIVE: Intensified lipoprotein-apheresis is well tolerated and results in permanently low lipid values without harming the health-related quality of life in children. METHODS: Three homozygous FH siblings, aged 7-13 years, had been treated with statins and ezetimibe for 12 months but still showed highly elevated low-density lipoprotein cholesterol (LDL-C) plasma concentrations. They were started on double-filtration plasmapheresis that was subsequently intensified according to plasma lipid levels. RESULTS: Each lipoprotein apheresis session reduced LDL-C concentration by 66% to 70%. Treated plasma volume was doubled after 6 months due to a sustained rebound of LDL-C between sessions. However, the rebound remained unchanged. Only an increase in frequency of sessions to every 3 to 4 days resulted in acceptable pre-treatment LDL-C concentrations (Cmax). Neither cessation of statins nor reduction of plasma exchange volume to 1.5 fold in follow-up influenced Cmax. Intensified therapy did not harm health-related quality of life as assessed by PedsQL and was well tolerated. CONCLUSIONS: In pediatric FH patients unresponsive to drug treatment, intensified lipoprotein apheresis can normalize plasma lipid levels. Apparently, treatment frequency rather than volume has greater influence on its efficacy. The potential burden of intensified therapy to daily life has to be regarded. Serum lipid levels in FH should be normalized to minimize cardiovascular risk.

Mycophenolate Mofetil Therapy in Children With Idiopathic Nephrotic Syndrome: Does Therapeutic Drug Monitoring Make a Difference?

BACKGROUND: Idiopathic nephrotic syndrome (INS) necessitates administration of corticosteroids or corticoid-sparing agents in 60% of the cases for prolonged periods resulting in serious adverse effects. METHODS: To avoid these complications, we investigated the efficacy and safety of mycophenolate mofetil (MMF) in our retrospective single-center study with 15 patients presenting with complicated courses of INS and aspired to estimate a cutoff level for mycophenolic acid-area under the curve (MPA-AUC) values, which can predict relapses with high sensitivity. RESULTS: Seven of 15 patients stayed in remission while receiving MMF. Average frequency of relapses was 1.39 (0.28-2.5) per year. In case of relapses, patients had lower predose and estimated AUC0-12 levels of MPA (P = 0.02 and 0.001, respectively). Based on the results of receiver operating characteristic analysis, we consider an estimated MPA-AUC0-12 lower than 44.6 mg·h·L(-1) as a risk factor for future relapses (91% sensitivity, 57% specificity, P = 0.06) because the prevalence of relapse is significantly lower (0.07 versus 0.5, P = 0.02), if the estimated MPA-AUC0-12 is >44.6 mg·h·L(-1). During MMF administration, we did not detect any adverse event requiring discontinuation of treatment. CONCLUSIONS: In conclusion, we demonstrate MMF as an alternative treatment for children with complicated INS to maintain remission without serious side effects. Furthermore, we propose a higher therapeutic target range of MPA-AUC0-12 (>45 mg·h·L(-1)) than used in transplanted children underlining the crucial role of therapeutic drug monitoring.

Transitional Care and Adherence of Adolescents and Young Adults After Kidney Transplantation in Germany and Austria: A Binational Observatory Census Within the TRANSNephro Trial.

Transition from child to adult-oriented care is widely regarded a challenging period for young people with kidney transplants and is associated with a high risk of graft failure. We analyzed the existing transition structures in Germany and Austria using a questionnaire and retrospective data of 119 patients transferred in 2011 to 2012. Most centers (73%) confirmed agreements on the transition procedure. Patients' age at transfer was subject to regulation in 73% (18 years). Median age at transition was 18.3 years (16.5-36.7). Median serum creatinine increased from 123 to 132 µmol/L over the 12 month observation period before transfer (P = 0.002). A total of 25/119 patients showed increased creatinine ≥ 20% just before transfer. Biopsy proven rejection was found in 10/119 patients. Three patients lost their graft due to chronic graft nephropathy.Mean coefficient of variation (CoV%) of immunosuppression levels was 0.20 ± 0.1. Increased creatinine levels ≥ 20% just before transfer were less frequently seen in patients with CoV < 0.20 (P = 0.007). The majority of pediatric nephrology centers have internal agreements on transitional care. More than half of the patients had CoV of immunosuppression trough levels consistent with good adherence. Although, 20% of the patients showed increase in serum creatinine close to transfer.

Ultrasound-guided percutaneous renal biopsy in 295 children and adolescents: role of ultrasound and analysis of complications.

INTRODUCTION: Percutaneous renal biopsy (PRB) is a decisive diagnostic procedure for children and adolescents with renal diseases. Aim of this study was to evaluate retrospectively the complication rates of percutaneous kidney biopsies and their therapeutic consequences to assess the role of ultrasound-guidance including Doppler ultrasound examinations in preparation, execution and follow-up care and to present a recommended protocol. PATIENTS AND METHODS: Institutional review board approved this retrospective study; informed consent was waived. Between 1997 and 2011 a total of 438 ultrasound-guided biopsies were performed in 295 patients, 169 of the biopsies were performed on kidney transplants. Average age of patients was 10.2+/-5.2 years (range of 15 days until age of 23). Before and post biopsy ultrasound examination including Doppler examination was carried out. Biopsy itself was ultrasound monitored. Complications were analysed with regard to age of patient, kidney transplants, year of occurrence, number of punctures, performing physician and time interval of occurrence to develop an optimized protocol for ultrasound-guidance. RESULTS: In 99% of cases successful PRB were performed, i.e. enough kidney parenchyma for histological analysis was obtained. No lethal or major complication that required surgical intervention occurred. Eighteen relevant complications were observed (complication rate: 4.1%). Except in one case in which additional MRI diagnostic was necessary, ultrasound examination after 4 hours post biopsy or even earlier when symptoms occurred, was able to detect complications and determine indications for intervention. CONCLUSION: Ultrasound-guided PRB is an established and effective method in children and adolescents, but shows a certain rate of complications and therefore should not be indicated without diligence. Ultrasound including Doppler ultrasound is a valuable tool in preparation, guidance of biopsy, detection of complications and in follow-up care. Ultrasound examinations (including Doppler) pre-, during and 4 hours post kidney biopsy and, depending from case, a few days until weeks after biopsy is recommended.